Diabetic cardiomyopathy | Revista Clínica Española

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Cepeda-Rodrigo, Ó. Lorenzo" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Lorenzo-Almorós" "email" => array:1 [ 0 => "atos2904@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.M." "apellidos" => "Cepeda-Rodrigo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Ó." 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There is a reduction in the expression of glucose transporters to the cell interior, especially GLUT-4, resulting in increased expression of the peroxisome proliferator-activated receptor-α (PPAR-α), which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance. In this process, free fatty acids are employed over glucose. PPAR-α activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3. Resulting in less efficient ATP production. The excess of fatty acids also saturates the β-oxidation, producing an excess of ceramides, diacylglycerol and reactive oxygen species (ROS), which are accumulated in the cytoplasm increasing lipotoxicity. Moreover, the excess glucose generates polyols and hexosamine, which activate pro-oxidant and proinflammatory pathways and generate advanced glycation end products (AGE), thereby increasing the glucotoxicity. The arrows indicate the metabolic changes. Abbreviations: ATP/O2, adenosine triphosphate/oxygen ratio; β-ox, beta-oxidation, ETC, electron transport chain; G6P, glucose 6 phosphate; TAG, triacylglycerides; TCA, tricarboxylic acid." ] ] ] "textoCompleto" => "BackgroundAlthough the relationship between diabetes and heart failure (HF) has been known for years, the first author to mention the notable association between HF and diabetes was Leyden in 1881.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In 1954, Lundbaek was the first to describe diabetic cardiomyopathy (DCM) specifically as a cardiomyopathy that affects two-thirds of elderly patients with diabetes.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> In 1972, Rubler showed the postmortem association between DCM and diabetes without the influence of other diseases in patients with diabetes but no coronary artery disease, HF with reduced ejection fraction (HFrEF) and in the presence of microvascular complications.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Since then, there have been various definitions for DCM,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> but there is still a lack of universally accepted criteria for the condition. Most definitions are based on clinical criteria and require the absence of other conditions for the diagnosis of DCM. Some definitions require the absence of coronary artery disease,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> while others also require the absence of arterial hypertension.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> Other definitions require the absence of other cardiovascular diseases (in addition to coronary artery disease and arterial hypertension) such as valvular heart disease<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> and congenital heart disease.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> In contrast, definitions proposed by other authors mention pathophysiological criteria such as ventricular dilation or hypertrophy, interstitial fibrosis and diastolic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>In 2018, the European Society of Cardiology<a class="elsevierStyleCrossRef" href="#bib0065">13</a> stated that there was no definition for DCM. Thus, the most widespread definition refers to myocardial dysfunction that occurs in the absence of other cardiovascular diseases.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> Nevertheless, this definition seems unrealistic, given that diabetes typically coexists with other cardiovascular diseases such as arterial hypertension and ischemic heart disease.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> For this reason, some authors have proposed defining DCM as cardiac disorders that are not explained by other cardiovascular or noncardiovascular diseases and that can be attributed to diabetes.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Epidemiology and prevalenceGiven the lack of consensus on the definition of DCM, we cannot accurately determine the prevalence or incidence of the disease.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Nevertheless, clinical trials with patients with type 2 diabetes (DM2) found a prevalence of HF of 10–30%.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> In the Reykjavik study, the prevalence of HF in patients with diabetes in the general population was estimated at approximately 12%.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In contrast, the number of patients with a diabetic etiology in clinical trials of HFrEF (according to the researchers’ assignment, which could be interpreted as DCM) has been estimated at <1%.<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a> However, the presence of possible DCM was reported in a US cohort of patients with dilated cardiomyopathy with the HFrEF phenotype.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Moreover, clinical trials with patients with HF have found an estimated prevalence of diabetes of approximately 30%.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> In the Kaiser Permanent study population, the patients with DM2 younger than 75 years had a 3–4-fold greater risk of HF than the patients without diabetes. For those older than 75 years, the risk was double.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> DM2 also worsens the prognosis of patients with HFrEF and is even more deleterious for those with HF with preserved ejection fraction (HFpEF), for whom the mortality and hospitalization risk is increased.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Thus, patients with DM2 are estimated to have a 75% greater cardiovascular mortality risk and risk of hospitalization for HF compared with patients without diabetes.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> For patients with diabetes and HF who are older than 65 years, the mortality risk increases 10 fold.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> In general, a 1% reduction in glycated hemoglobin is estimated to reduce the risk of HF by 16%.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>Pathophysiology and clinical presentation of the diseaseThere is an interrelationship between diabetes and HF, where each affects the other.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> HF entails the activation of 2 neurohormonal systems: the renin-angiotensin-aldosterone system and the sympathetic nervous system. The first increases sodium and water retention, while the second activates hepatic lipolysis, lipogenesis and gluconeogenesis, contributing to insulin resistance and consequently diabetes. Hyperglycemia in diabetes is in turn responsible for the microvascular and macrovascular complications. For macrovascular complications, the increase in blood glucose produces coronary disorders and loss of cardiomyocytes, which leads to ischemic heart disease and HFrEF, while sarcomere stiffness and fibrosis are responsible for left ventricular restriction and HFpEF. Inflammation has a marked influence on both mechanisms.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Therefore, HF in diabetes can be due to macroangiopathy, with impairment of the coronary arteries, causing myocardial ischemia, or through primary impairment of the cardiac muscle (cardiomyopathy).<a class="elsevierStyleCrossRef" href="#bib0135">27</a>Numerous mechanisms have been proposed to explain myocardial dysfunction in DCM. Cardiac mechanisms are therefore not the sole influence; vascular and systemic methods also play a role, considering that dysfunction in obtaining energy and contractility disorders play a critical role in DCM.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Energy substrate disorderUnder normal conditions, the myocardium consumes free fatty acids (70%) and glucose (30%) as fuel. However, the heart is a highly flexible metabolic organ and can change energy sources according to their availability. The heart can even use lactate, pyruvate, glycerol, and beta-hydroxybutyrate during fasting.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> This process is regulated by the Randle cycle, in which the key factor for employing a certain substrate in the heart is glucose availability: high blood glucose levels decrease the oxidation rate of free fatty acids and vice versa.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>In HF, abnormalities occur in the processing of energy at the mitochondrial level. Thus, despite the increasing levels of free fatty acids and glucose (as well as their uptake in cardiomyocytes), these cannot be metabolized as free fatty acids and pyruvate, respectively, due to the blocking of the pyruvate dehydrogenase complex, which leads to their accumulation in the cell’s cytosol. This causes a detour towards the generation of intermediate metabolites that induce altered signaling, lipotoxicity, and glucotoxicity.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> The change in energy substrate oxidation entails reduced activity of the Krebs cycle, which produces the electron donors NADH and FADH<a class="elsevierStyleCrossRef" href="#bib0010">2</a> in the electron transport chain, thereby reducing the phosphocreatine/adenosine triphosphate (ATP) flow.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> The myocardium could be said to function in HF as “an engine out of fuel”, especially in conditions of increased energy demand such as exercise (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0155">31</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>In diabetes, in contrast, there is a loss of energy flexibility, with reduced expression of glucose transporters (GLUT1 and especially GLUT4) to the cell interior, resulting in increased expression of the peroxisome proliferator-activated receptor-alpha α (PPAR-α), which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance. In this process, free fatty acids are employed over glucose.<a class="elsevierStyleCrossRefs" href="#bib0150">30,32</a> In the long term, this process favors mitochondrial uncoupling,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> which requires a greater quantity of oxygen for each ATP molecule generated. This energy inefficiency occurs due to 2 mechanisms: 1) fatty acid oxidation requires 8–11% more oxygen for each carbon than glucose oxidation<a class="elsevierStyleCrossRefs" href="#bib0130">26,34</a>, and 2) PPAR-α activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Both mechanisms promote mitochondrial uncoupling and the disappearance of the proton gradient, resulting in less efficient ATP production. The excess of fatty acids also saturates beta-oxidation, producing an excess of ceramide, diacylglycerol, and reactive oxygen species (ROS) that accumulate in the cytoplasm of the cardiomyocyte, contributing to cardiac steatosis and oxidative stress,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> which increase lipotoxicity. In turn, the excess circulating glucose that cannot be assimilated due to the lack of GLUT receptors generates polyols and hexosamine, which activate pro-oxidant and proinflammatory pathways<a class="elsevierStyleCrossRef" href="#bib0025">5</a> and create advanced glycation end products (AGEs), thereby increasing glucotoxicity (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>When there is a lack of useful fuel, ketone production (mainly of D-beta-hydroxybutyrate) is increased, thereby providing a potential alternative fuel for oxidative phosphorylation,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> which could improve the energy efficiency by approximately 24%.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Ketones are typically produced in fasting conditions when they are released by adipose tissue through incomplete oxidation of free fatty acids.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> Ketone bodies are therefore found in greater numbers in HF when the availability of other fuels (glucose and fatty acids) decreases. However, it is not known whether the presence of ketone bodies constitutes a cause, consequence, or compensatory mechanism in HF.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Ketones increase the uptake of free fatty acids in cardiomyocytes, thereby improving energy efficiency.Calcium and sodium homeostasis disorderin vitro overexpression of calcium/calmodulin-dependent protein kinase II has been reported in DM2 and HF,<a class="elsevierStyleCrossRef" href="#bib0195">39</a> which causes a reduction in the calcium (Ca²+) of the sarcoplasmic reticulum and a reduction in the cytosolic Ca²+ transient amplitude.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> This process contributes to contractile dysfunction and the generation of arrhythmias<a class="elsevierStyleCrossRef" href="#bib0195">39</a> through the reduced activity of actin-myosin-troponin complexes.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> As a result of the parallel increase in activity of the sodium–hydrogen antiporter 1 (NHE-1), which regulates pH and prevents cell damage by ischemia-reperfusion.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> there is an increase in intracellular sodium (Na+) in the cardiomyocyte.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> It has been reported that obesity and insulin produce NHE activation,<a class="elsevierStyleCrossRefs" href="#bib0215">43,44</a> while mineralocorticoid receptor antagonists block NHE activation.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> In HFrEF, disorders in the transport of cytoplasmic Na+–Ca²+ hinder its use by mitochondria, promoting oxidative stress and energy deficiency, thereby affecting cell contractility.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>In turn, the lack of useful fuel and the generation of lipotoxicity/glucotoxicity promotes calcium imbalance, mitochondrial and sarcoplasmic reticulum failure, apoptosis, and inflammation, leading to cardiomyocyte dysfunction.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>Insulin resistanceThe myocardium in HF presents insulin resistance due to the increase in adrenergic tone, the presence of inflammatory molecules, oxidative stress, and tissue hypoperfusion, among other factors.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> Insulin resistance is associated with increased hepatic lipolysis, lipogenesis, and gluconeogenesis, to provide the cardiomyocyte with fuel.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> However, excess fuel contributes to the generation of lipotoxicity/glucotoxicity, the reduced availability of nitric oxide, and the generation of ROS.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Insulin resistance also affects other signaling pathways, such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)<a class="elsevierStyleCrossRef" href="#bib0255">51</a> and titin pathways,<a class="elsevierStyleCrossRef" href="#bib0260">52</a> which promote cardiomyocyte hypertrophy and reduced distensibility (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In fact, insulin resistance is an independent risk factor for mortality in stable patients with chronic HF.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> It is not known, however, whether reducing insulin resistance improves the prognosis through the recovery of contractility.<a class="elsevierStyleCrossRef" href="#bib0140">28</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Potential role of epicardial fatObesity increases the risk of HF.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> The deleterious effect of obesity at the cardiovascular level has classically been thought to occur through hemodynamic mechanisms of ventricular overload.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> However, most patients with obesity have slightly larger ventricles, low natriuretic peptide levels, and renal function impairment.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Thus, the proposed pathophysiological mechanism would be the reduction in myocardial distensibility, while the main phenotype would be HFpEF.<a class="elsevierStyleCrossRefs" href="#bib0280">56,57</a>Obesity promotes chronic systemic inflammation,<a class="elsevierStyleCrossRef" href="#bib0290">58</a> which in turn is accompanied by an increase in epicardial fat and especially perivascular fat.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Due to its unique properties as a neuroendocrine organ and in intimate contact with the myocardium,<a class="elsevierStyleCrossRefs" href="#bib0300">60,61</a> epicardial fat assumes an active role in obesity, changing its biological characteristics towards adipogenesis<a class="elsevierStyleCrossRef" href="#bib0300">60</a> and promoting the secretion of fatty acids and proinflammatory cytokines (leptin, tumor necrosis factor-alpha, interleukin-1-beta and interleukin-6), as well as reducing the anti-inflammatory cytokine adiponectin.<a class="elsevierStyleCrossRefs" href="#bib0310">62,63</a> In addition, the secretion of the previously mentioned cytokines promotes the infiltration of macrophages and the generation of fibrosis.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> Epicardial fat has also been linked to the onset of atrial arrhythmias due to the generation of fibrosis,<a class="elsevierStyleCrossRefs" href="#bib0320">64,65</a> with diastolic abnormalities<a class="elsevierStyleCrossRef" href="#bib0330">66</a> and multiple organ dysfunction due to the systemic release of inflammatory mediators (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<a class="elsevierStyleCrossRef" href="#bib0275">55</a><elsevierMultimedia ident="fig0020"></elsevierMultimedia>Statins have been related to the reduction in epicardial fat,<a class="elsevierStyleCrossRef" href="#bib0335">67</a> and a pleiotropic effect at this level is speculated beyond their lipid-lowering role.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> In contrast, antidiabetic treatments that cause weight gain have shown an increased risk of HF in clinical trials,<a class="elsevierStyleCrossRef" href="#bib0345">69</a> with the potential role occurring through an increase in epicardial fat.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> In contrast, metformin and sodium–glucose co-transporter-2 inhibitors not only reduce epicardial fat but also decrease inflammation and improve the ventricular dynamic in animal studies.<a class="elsevierStyleCrossRefs" href="#bib0355">71,72</a>Endothelial dysfunctionDiabetes is associated with endothelial dysfunction through the reduction in nitric oxide, among other factors.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Several antidiabetic drugs act by activating PI3K, which controls the activity of endothelial nitric oxide synthase.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In fact, intensive glycemic control reduces the microvascular but not the macrovascular complications, indicating a probable protective effect at the endothelial level beyond the glycemic effect.<a class="elsevierStyleCrossRef" href="#bib0365">73</a>Therefore, DCM would be the result of not just cardiac disorders but complex systemic phenomena.Some authors (such as Maisch and Alter) initially supported the presence of 4 progressive stages in DCM, with the progressive addition of microscopic and macroscopic disorders. Thus, stage 1 of DCM would include asymptomatic patients with diastolic dysfunction; stages 2 and 3 would be defined by diastolic dysfunction; and stage 4 would be defined by symptomatic HF, fibrosis and left ventricular dilation.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> However, this theory has been criticized because the various stages often coexist in the same patient and that there are currently no diagnostic means for determining whether the abnormalities encountered are attributable exclusively to diabetes.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> In addition, the clinical evidence that HFpEF progresses to HFrEF is limited and has been reported subsequent to a myocardial ischemic event or in patients older than 80 years but not in diabetes.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> This classification was not developed in patient cohorts but rather experimentally.Although the disease was initially reported with the HFrEF phenotype, an increasing number of authors (such as Seferović<a class="elsevierStyleCrossRef" href="#bib0135">27</a>) support the presence of 2 independent phenotypes in DCM (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). Thus, HFpEF and HFrEF are the results of different mechanisms responsible for restrictive and dilated cardiac remodeling. Nevertheless, the factors that determine the development of a dominant phenotype are not known.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> At the structural level, the onset of DCM with the restrictive/HFpEF phenotype is completely different from the dilated/HFrEF phenotype,<a class="elsevierStyleCrossRefs" href="#bib0380">76,77</a> as are the pathophysiological mechanisms underlying each phenotype. Numerous potential mechanisms that could contribute to myocardial dysfunction in DCM have been described. However, hyperglycemia, lipotoxicity, and insulin resistance would be the mechanisms most related to the restrictive/HFpEF phenotype, while autoimmunity phenomena would be the most influential for the dilated/HFrEF phenotype. Both phenotypes would also experience coronary microvascular rarefaction, defined as the reduction in the capillary surface in proportion to the cardiomyocyte’s surface, as well as the deposit of AGEs. Hyperglycemia increases protein kinase-C activity in fibroblasts, promoting fibrosis in both phenotypes. The presence of diabetes would therefore have a key effect in increasing left ventricular stiffness, which would affect the generation of diastolic dysfunction, both in HFrEF and HFpEF.<a class="elsevierStyleCrossRef" href="#bib0380">76</a><elsevierMultimedia ident="fig0025"></elsevierMultimedia>In the restrictive/HFpEF phenotype, the left ventricle is not dilated but rather hypertrophied and rigid. Cardiomyocytes are also hypertrophied, with a normal sarcomeric structure but high resting tension and reactive fibrosis (increased collagen deposit among the cardiomyocytes). In this phenotype, endothelial dysfunction predominates in the coronary microvasculature, triggered by the subclinical inflammation related to the comorbidities and directly by the hyperglycemia, lipotoxicity, and microvascular rarefaction. This endothelial dysfunction affects the cardiac remodeling and reduces nitric oxide availability, which in turn decreases protein kinase-G activity. This decrease produces a reduction in distensibility and increases cardiomyocyte stiffness by the hyperphosphorylation of cytoskeletal proteins such as titin. In the dilated/HFrEF phenotype, in contrast, the loss of cardiomyocytes by ischemia or toxicity predominates,<a class="elsevierStyleCrossRef" href="#bib0390">78</a> a loss triggered by inflammation/autoimmunity, hyperglycemia, and lipotoxicity, which results in oxidative stress by tissue hypoxia. The left ventricle is increased in size, with sarcomeric damage and replacement fibrosis (deposit of collagen fibers not only between cardiomyocytes but also in extensive areas replacing the lost cardiomyocytes).Diagnosis of diabetic cardiomyopathyFor patients with diabetes, the suspected diagnosis in DCM is established with signs and symptoms consistent with HF, ruling out the presence of coronary artery disease, valve disease, congenital heart disease, hypertension, and infiltration disease, as well as with increased natriuretic peptide levels.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The definitive diagnosis would be reached through endomyocardial biopsy, which would histologically report the typical findings described above. Nevertheless, the invasive nature of the procedure and its associated risks require alternative techniques, with biopsy relegated to experimental studies<a class="elsevierStyleCrossRef" href="#bib0025">5</a> or, in the event of suspected infiltration disease, when not assessable by other diagnostic techniques. Imaging techniques are useful for describing the structural abnormalities of HF, although they do not describe the pathognomonic abnormalities of diabetes or of DCM.<a class="elsevierStyleCrossRefs" href="#bib0025">5,15</a> The most noteworthy of these techniques is echocardiography, specifically the speckle-tracking technique, which can measure myocardial deformation during the cardiac cycle in 3 axes: radial, longitudinal and circumferential.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Patients with diabetes have myocardial deformation abnormalities in all directions, and longitudinal deformation abnormalities have been reported in patients with prediabetes.<a class="elsevierStyleCrossRef" href="#bib0395">79</a> Furthermore, the reduction in longitudinal deformation has been associated with cardiovascular events at 10 years in patients with DM2.<a class="elsevierStyleCrossRef" href="#bib0400">80</a> Magnetic resonance imaging (MRI) can be useful for DCM, especially for detecting associated deposit disease, fibrosis, or underlying ischemia. In particular, tagged MRI is useful for measuring the deformation during the cardiac cycle and thereby diagnosing DCM in its initial stages.<a class="elsevierStyleCrossRef" href="#bib0405">81</a> According to the recommendations of international guidelines, physicians should search for the typical disorders of each HF phenotype (HFrEF and HFpEF) using these techniques, especially ultrasonography.<a class="elsevierStyleCrossRef" href="#bib0410">82</a>To diagnose DCM, other entities that can cause HF need to be ruled out, such as ischemic heart disease, valvular heart disease, and congenital heart disease.Numerous circulating biomarkers have been studied for diagnosing DCM, most of which are from experimental studies. The detection of DCM would be a reflection of the disease’s processes, such as steatosis, contractility disorder, and fibrosis.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The most noteworthy biomarkers in human studies are listed below (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Cardiotrophin 1, a member of the family of glycoprotein 130 cytokines that is released in response to oxidative stress to modulate hypertrophy, contractility, fibrosis and ischemia, as well as the cardiac remodeling in DCM.<a class="elsevierStyleCrossRef" href="#bib0415">83</a></li><li class="elsevierStyleListItem" id="lsti0010">•Activin A, a member of the transforming growth factor-beta (TGF-β) family, released by epicardial fat to promote the entry of glucose into the cell through Akt phosphorylation. High activin A levels have been related to left ventricular hypertrophy in patients with DM2.<a class="elsevierStyleCrossRef" href="#bib0420">84</a></li><li class="elsevierStyleListItem" id="lsti0015">•Heart-type fatty acid-binding protein (HFABP), a cardiac cytosolic protein that transports fatty acids to the mitochondria for degradation and generation of ATP. HFABP levels are undetectable in healthy patients, but it is released into the blood when there is cardiac damage and in DM2.<a class="elsevierStyleCrossRef" href="#bib0425">85</a></li><li class="elsevierStyleListItem" id="lsti0020">•TGF-β, a protein that activates Smad signaling, which increases extracellular matrix protein expression.<a class="elsevierStyleCrossRef" href="#bib0430">86</a> High TGF-β levels have been found in patients with DM2 with or without diastolic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0435">87</a></li><li class="elsevierStyleListItem" id="lsti0025">•Procollagen type I N-terminal propeptide (PINP) and matrix metalloproteinase-7 (MMP-7): proteins related to the accumulation and degradation of the extracellular matrix. An increase in the PINP/MMP-7 ratio favors the development of cardiac fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0440">88,89</a></li><li class="elsevierStyleListItem" id="lsti0030">•Insulin-like growth factor binding protein-7 (IGFBP-7), a modulator of insulin receptor activity. IGFBP-7 levels are high in patients with diabetes with systolic dysfunction and cardiac fibrosis.<a class="elsevierStyleCrossRef" href="#bib0450">90</a></li></ul><elsevierMultimedia ident="fig0030"></elsevierMultimedia>However, further studies are needed with patient cohorts specifically diagnosed with DCM to determine not only the diagnostic and prognostic utility of these and other biomarkers but also to determine their normal ranges and thereby establish early therapeutic strategies to prevent disease progression.Treatment of diabetic cardiomyopathyTo date, there are no specific treatments for DCM. Ideally, treatment for DCM should reverse the pathophysiological disorders reported in the disease. Therapies commonly employed for treating diabetes could therefore have a potential role in DCM. Once again, however, most results come from experimental studies. Studies in patients diagnosed with DCM are therefore needed to investigate the potential role of these and other new drugs in the disease. Once the findings indicate HF (both the HFrEF and HFpEF phenotypes), the treatments should follow the recommendations of international clinical guidelines.<a class="elsevierStyleCrossRef" href="#bib0410">82</a>The main therapies currently available for DM2 and their potential role in DCM are listed below.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0035">•Metformin. Acts by inhibiting the enzymes of the mitochondrial respiratory chain (complex I), reducing ATP production, and increasing AMP production.<a class="elsevierStyleCrossRef" href="#bib0455">91</a> The drug, therefore, has a potential role in obtaining mitochondrial energy. Moreover, AMP activates the AMP-activated protein kinase (AMPK), inhibiting the synthesis of cholesterol and lipids and reducing hepatic gluconeogenesis.<a class="elsevierStyleCrossRef" href="#bib0460">92</a> Through AMPK, metformin also increases the availability of nitric oxide, thereby improving endothelial function.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Although there are no clinical trials with metformin in patients with DM2 and HF, cohort and case-control studies, reviews and meta-analyses have shown that metformin reduces mortality and readmissions due to HF.<a class="elsevierStyleCrossRefs" href="#bib0465">93,94</a> Currently, the recommendation is to employ metformin as first-line therapy for patients with DM2 and HF.<a class="elsevierStyleCrossRef" href="#bib0410">82</a></li><li class="elsevierStyleListItem" id="lsti0040">•Glitazones and thiazolidinediones. These insulin-sensitizing agents activate the nuclear receptor PPAR-¿, which has beneficial effects on the storage of free fatty acids in adipose tissue for re-establishing glucose as a source of cell energy. These agents also improve nitric oxide-dependent vasodilation and have positive effects on inflammation and vascular remodeling.<a class="elsevierStyleCrossRefs" href="#bib0475">95,96</a> However, these agents cause sodium and water retention, and some studies have shown an increased risk of HF, in particular with rosiglitazone<a class="elsevierStyleCrossRef" href="#bib0485">97</a> and pioglitazone.<a class="elsevierStyleCrossRef" href="#bib0490">98</a> Glitazones are therefore currently contraindicated for HF.<a class="elsevierStyleCrossRef" href="#bib0410">82</a></li><li class="elsevierStyleListItem" id="lsti0045">•Glucagon-like peptide-1 receptor agonists. These agents decrease blood glucose by increasing insulin secretion, reducing glucagon, and decreasing body weight.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Numerous effects have been demonstrated in animals, including reduced damage in ischemia/reperfusion, improved remodeling, and improved endothelial function due to the increase in nitric oxide.<a class="elsevierStyleCrossRefs" href="#bib0495">99,100</a> In clinical trials, liraglutide<a class="elsevierStyleCrossRef" href="#bib0505">101</a> and semaglutide<a class="elsevierStyleCrossRef" href="#bib0510">102</a> decreased the combined event of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke in patients with high-risk DM2 and a history of cardiovascular events, acting in secondary prevention.</li><li class="elsevierStyleListItem" id="lsti0050">•Dipeptidyl peptidase 4 inhibitors. These agents exert their hypoglycemic effect by increasing insulin secretion and reducing glucagon secretion, as with glucagon-like peptide-1 agonists.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> These agents have demonstrated neutral cardiovascular effects,<a class="elsevierStyleCrossRef" href="#bib0515">103</a> except for saxagliptin, which in the SAVOR-TIMI trial showed a 27% increase in the risk of hospitalization for HF<a class="elsevierStyleCrossRef" href="#bib0520">104</a> and is, therefore, contraindicated in these patients.</li><li class="elsevierStyleListItem" id="lsti0055">•Sodium–glucose cotransporter 2 inhibitors. These hypoglycemic agents produce the inhibition of sodium/glucose cotransporter 2 of the proximal convoluted renal tubule, thereby promoting the renal elimination of glucose (glycosuria) and sodium independently of insulin secretion. These agents are also responsible for other beneficial hemodynamic effects such as increased diuresis (diuretic effect), reduced systolic blood pressure and reduced intravascular volume, as well as reduced cardiac preload and afterload, thereby improving the myocardial oxygen supply.<a class="elsevierStyleCrossRef" href="#bib0525">105</a> These agents also exert metabolic effects on cardiomyocytes, reported mostly in experimental studies,<a class="elsevierStyleCrossRef" href="#bib0530">106</a> such as the increase in ketone bodies, in fatty acids and in glucagon and reduced intracellular sodium through NHE inhibition, which could mediate an anti-inflammatory and antioxidant effect. These studies have related SGLT-2 inhibitors to improved obtention of mitochondrial energy,<a class="elsevierStyleCrossRef" href="#bib0140">28</a> reversal of the Na+/Ca²+ imbalance,<a class="elsevierStyleCrossRef" href="#bib0535">107</a> and reduction of epicardial fat.<a class="elsevierStyleCrossRefs" href="#bib0540">108,109</a> In the EMPA-REG OUTCOME study,<a class="elsevierStyleCrossRef" href="#bib0550">110</a> empagliflozin decreased the combined event of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke by 38% and reduced the risk of hospitalization for HF by 35%, although only 10% of the study patients had a previous history of HF. Recently, the EMPA-HEART study<a class="elsevierStyleCrossRef" href="#bib0555">111</a> employed cardiac MRI to investigate the potential role of empagliflozin in left ventricular remodeling (at baseline and at 6 months) in 97 patients with DM2 and stable coronary artery disease. Empagliflozin reduced the ventricular mass, especially in those patients with a higher grade of baseline hypertrophy. Studies with small numbers of patients have reported improvements in diastolic function at 3 months in patients with diabetes undergoing treatment with empagliflozin.<a class="elsevierStyleCrossRef" href="#bib0560">112</a> Recently, the DAPA-HF trial<a class="elsevierStyleCrossRef" href="#bib0565">113</a> studied the effect of dapagliflozin added to standard therapy for patients with HFrEF (with or without DM2) and showed a reduction in cardiovascular mortality and hospitalizations for HF, as well as improved quality of life for the active treatment group, both in the presence and absence of diabetes. Dapagliflozin was also well-tolerated, without a higher rate of treatment withdrawal. This study’s results opened the door to potential treatments for HF and DCM with this pharmacological group.</li><li class="elsevierStyleListItem" id="lsti0060">•Insulin. The intensive use of insulin has failed to demonstrate an improvement in diastolic function in DCM with the HFpEF phenotype.<a class="elsevierStyleCrossRef" href="#bib0570">114</a> Treatment with insulin, far from reversing the metabolic disorders of diabetes, is associated with weight gain and sodium and water retention.</li><li class="elsevierStyleListItem" id="lsti0065">•Other treatments, such as zinc supplements, copper chelators, AGE blockers, and beta-blockers, have been tested in animal studies, with apparently beneficial results.<a class="elsevierStyleCrossRef" href="#bib0075">15</a></li></ul>ConclusionsAlthough the consideration of DCM as a separate entity and attributed exclusively to diabetes has been questioned and is currently the subject of controversy, studies conducted with patients with diabetes suggest the presence of a characteristic cardiac impairment, with pathophysiology differentiated from that of other entities, systemic and complex. Studies conducted with diabetic treatments such as SGLT-2 inhibitors suggest a potential role in diabetic cardiomyopathy. Nevertheless, a consensus definition might be needed in order to design clinical trials with patients with DCM and thereby advance our understanding, diagnosis and treatment of this condition.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1657504" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1473221" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1657503" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1473220" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology and prevalence" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Pathophysiology and clinical presentation of the disease" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Energy substrate disorder" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Calcium and sodium homeostasis disorder" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Insulin resistance" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Potential role of epicardial fat" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Endothelial dysfunction" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Diagnosis of diabetic cardiomyopathy" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Treatment of diabetic cardiomyopathy" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-10-03" "fechaAceptado" => "2019-10-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1473221" "palabras" => array:3 [ 0 => "Diabetic cardiomyopathy" 1 => "Diabetes" 2 => "Heart failure" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1473220" "palabras" => array:3 [ 0 => "Miocardiopatía diabética" 1 => "Diabetes" 2 => "Insuficiencia cardiaca" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The relationship between diabetes and heart failure is complex and bidirectional. Nevertheless, the existence of a cardiomyopathy attributable exclusively to diabetes has been and is still the subject of controversy, due, among other reasons, to a lack of a consensus definition. There is also no unanimous agreement in terms of the physiopathogenic findings that need to be present in the definition of diabetic cardiomyopathy or on its classification, which, added to the lack of diagnostic methods and treatments specific for this disease, limits its general understanding. Studies conducted on diabetic cardiomyopathy, however, suggest a unique physiopathogenesis different from that of other diseases. Similarly, new treatments have been shown to play a potential role in this disease. The following review provides an update on diabetic cardiomyopathy." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La relación entre la diabetes y la insuficiencia card́iaca es compleja y bidireccional. No obstante, la existencia de una miocardiopatía como entidad propia y atribuible exclusivamente a la diabetes ha sido y es motivo de controversia hoy día. Esto es debido, entre otros motivos, a la ausencia de una definición de consenso. Tampoco existe unanimidad en cuanto a los hallazgos fisiopatogénicos presentes en la miocardiopatía diabética ni en su clasificación. Esto, añadido a la ausencia de métodos diagnósticos propios o de tratamientos específicos en la enfermedad, limita el conocimiento general de la patología. Sin embargo, los estudios realizados en miocardiopatía diabética sugieren una fisiopatogenia propia diferenciada de la de otras entidades. De la misma manera, nuevos tratamientos han demostrado tener un papel potencial en esta enfermedad. En la siguiente revisión realizamos una actualización de la miocardiopatía diabética." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Lorenzo-Almorós A, Cepeda-Rodrigo JM, Lorenzo Ó. Miocardiopatía diabética. Rev Clin Esp. 2022;222:100–111." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1259 "Ancho" => 2175 "Tamanyo" => 232399 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Metabolic disorders in heart failure. Despite increasing free fatty acid and glucose levels, as well as their uptake, these cannot be metabolized as free fatty acids and pyruvate, respectively, by blocking PDC, which leads to its accumulation in cytosol. This causes a detour towards the generation of intermediate metabolites that induce lipotoxicity and glucotoxicity. The change in energy substrate oxidation entails reduced activity of the Krebs cycle, thereby reducing the phosphocreatine/adenosine triphosphate flow. The arrows indicate the metabolic changes. Abbreviations: AGE; advanced glycosylation end products; ATP/O2, adenosine triphosphate/oxygen ratio; β-ox, beta-oxidation, ETC, electron transport chain; G6P, glucose 6 phosphate; PDC, pyruvate dehydrogenase complex; TAG, triacylglycerides; TCA, tricarboxylic acid." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1584 "Ancho" => 2175 "Tamanyo" => 296448 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Metabolic disorders in diabetes. There is a reduction in the expression of glucose transporters to the cell interior, especially GLUT-4, resulting in increased expression of the peroxisome proliferator-activated receptor-α (PPAR-α), which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance. In this process, free fatty acids are employed over glucose. PPAR-α activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3. Resulting in less efficient ATP production. The excess of fatty acids also saturates the β-oxidation, producing an excess of ceramides, diacylglycerol and reactive oxygen species (ROS), which are accumulated in the cytoplasm increasing lipotoxicity. Moreover, the excess glucose generates polyols and hexosamine, which activate pro-oxidant and proinflammatory pathways and generate advanced glycation end products (AGE), thereby increasing the glucotoxicity. The arrows indicate the metabolic changes. Abbreviations: ATP/O2, adenosine triphosphate/oxygen ratio; β-ox, beta-oxidation, ETC, electron transport chain; G6P, glucose 6 phosphate; TAG, triacylglycerides; TCA, tricarboxylic acid." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1034 "Ancho" => 2175 "Tamanyo" => 215332 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Influence of insulin resistance on dilated cardiomyopathy." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1412 "Ancho" => 2175 "Tamanyo" => 202926 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Physiological pathogenesis of epicardial fat in dilated cardiomyopathy." ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1716 "Ancho" => 2175 "Tamanyo" => 275330 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Predominant phenotypes in dilated cardiomyopathy." ] ] 5 => array:8 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1187 "Ancho" => 2175 "Tamanyo" => 179836 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Potential biomarkers and metabolic processes in dilated cardiomyopathy." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:114 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asthma and diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Zeitschr Klin Med" "fecha" => "1881" "volumen" => "3" "paginaInicial" => "358" "paginaFinal" => "364" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic angiopathy: a specific vascular disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0140-6736(54)90924-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1954" "volumen" => "266" "paginaInicial" => "377" "paginaFinal" => "379" "link" => array:1 [ …1] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is there a diabetic cardiopathy?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Pathogenetische Fakt des Myokardinfarkts" "fecha" => "1969" "paginaInicial" => "63" "paginaFinal" => "71" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New type of cardiomyopathy associated with diabetic glomerulosclerosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0002-9149(72)90595-4" "Revista" => array:5 [ "tituloSerie" => "Am J Cardiol" "fecha" => "1972" "volumen" => "30" "paginaInicial" => "595" "link" => array:1 [ …1] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic approaches for diabetic cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cardiovasc Diabetol" "fecha" => "2017" "volumen" => "16" "paginaInicial" => "28" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Diabetes Investig" "fecha" => "2014" "volumen" => "5" "paginaInicial" => "623" "paginaFinal" => "634" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy revisited" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2007" "volumen" => "115" "numero" => "25" "paginaInicial" => "32" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/eht108" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2013" "volumen" => "34" "paginaInicial" => "3035" "paginaFinal" => "3087" "link" => array:1 [ …1] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjmed.2008.03.046" "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "2008" "volumen" => "121" "paginaInicial" => "748" "paginaFinal" => "757" "link" => array:1 [ …1] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The diabetic cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00592-010-0180-x" "Revista" => array:5 [ "tituloSerie" => "Acta Diabetol" "fecha" => "2011" "volumen" => "48" "paginaInicial" => "173" "link" => array:1 [ …1] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Second in a series on diabetes and the heart: diabetic cardiomyopathy — mechanisms and mode of diagnosis. E-Journal-of-Cardiology-Practice/Volume-14/Second-in-a-series-on-diabetes-and-the-heart-diabetic-cardiomyopathy-mechanisms-and-mode-of-diagnosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "E J Clin Pract ESC" "fecha" => "2016" "volumen" => "14" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Vasc Health Risk Manag" "fecha" => "2010" "volumen" => "21" "paginaInicial" => "883" "paginaFinal" => "889" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ejhf.1170" "Revista" => array:5 [ "tituloSerie" => "Eur J Heart Fail" "fecha" => "2018" "volumen" => "20" "paginaInicial" => "853" "link" => array:1 [ …1] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocardial dysfunction and cardiovascular disease in type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/00365513.2016.1155230" "Revista" => array:5 [ "tituloSerie" => "Scand J Clin Lab Invest" "fecha" => "2016" "volumen" => "76" "paginaInicial" => "271" "link" => array:1 [ …1] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Heart heartjnl-2" "fecha" => "2018" "volumen" => "105" "paginaInicial" => "337" "paginaFinal" => "345" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The association between glucose abnormalities and heart failure in the population-based Reykjavik study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.28.3.612" "Revista" => array:5 [ "tituloSerie" => "Diabetes Care" "fecha" => "2005" "volumen" => "28" "paginaInicial" => "612" "link" => array:1 [ …1] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF)" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Eur J Heart Fail" "fecha" => "2014" "volumen" => "16" "paginaInicial" => "817" "paginaFinal" => "825" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of candesartan in patientswith chronic heart failure and reduced left-ventricular systolicfunction taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(03)14283-3" "Revista" => array:7 [ "tituloSerie" => "Lancet" "fecha" => "2003" "volumen" => "362" "paginaInicial" => "767" "paginaFinal" => "771" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes and idiopathic cardiomyopathy: a nationwide case-control study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.26.2.279" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2003" "volumen" => "26" "paginaInicial" => "279" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.24.9.1614" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2001" "volumen" => "24" "paginaInicial" => "1614" "paginaFinal" => "1619" "link" => array:1 [ …1] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Eur Heart J" "fecha" => "2013" "volumen" => "15" "paginaInicial" => "194" "paginaFinal" => "202" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-preserve trial (Irbesartan in Heart Failure with preserved ejection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.116.024593" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2017" "volumen" => "135" "paginaInicial" => "724" "paginaFinal" => "735" "link" => array:1 [ …1] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure prevalence, incidence, and mortality in the elderly with diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.27.3.699" "Revista" => array:5 [ "tituloSerie" => "Diabetes Care" "fecha" => "2004" "volumen" => "27" "paginaInicial" => "699" "link" => array:1 [ …1] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "BMJ" "fecha" => "2000" "volumen" => "321" "paginaInicial" => "405" "paginaFinal" => "412" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Concomitant diabetes mellitus and heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cpcardiol.2014.09.002" "Revista" => array:6 [ "tituloSerie" => "Curr Probl Cardiol" "fecha" => "2015" "volumen" => "40" "paginaInicial" => "7" "paginaFinal" => "43" "link" => array:1 [ …1] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Eur Heart J" "fecha" => "2018" "volumen" => "39" "paginaInicial" => "424" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Eur Heart J" "fecha" => "2015" "volumen" => "36" "paginaInicial" => "171" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CV protection in the EMPA-REG OUTCOME trial: a ‘Thrifty Substrate’ hypothesis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Diabetes Care" "fecha" => "2016" "volumen" => "39" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "1963" "volumen" => "1" "paginaInicial" => "78" "link" => array:1 [ …1] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metabolic remodelling in heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41569-018-0044-6" "Revista" => array:5 [ "tituloSerie" => "Nat Rev Cardiol" "fecha" => "2018" "volumen" => "15" "paginaInicial" => "457" "link" => array:1 [ …1] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The failing heart — an engine out of fuel" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa060096" "Revista" => array:5 [ "tituloSerie" => "N Engl J Med" "fecha" => "2007" "volumen" => "356" "paginaInicial" => "11" "link" => array:1 [ …1] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mechanisms of diabetic cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Diabetologia" "fecha" => "2014" "volumen" => "57" "paginaInicial" => "660" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mitochondrial uncoupling, ROS generation and cardioprotection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Biochim Biophys Acta Bioenerg" "fecha" => "2018" "volumen" => "1859" "paginaInicial" => "94" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocardial fatty acid metabolism in health and disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Physiol Rev" "fecha" => "2010" "volumen" => "90" "paginaInicial" => "207" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1096/fj.00-0351com" "Revista" => array:5 [ "tituloSerie" => "FASEB J" "fecha" => "2001" "volumen" => "15" "paginaInicial" => "833" "link" => array:1 [ …1] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nutritional ketosis alters fuel preference and thereby endurance performance in athletes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cmet.2016.07.010" "Revista" => array:5 [ "tituloSerie" => "Cell metab" "fecha" => "2016" "volumen" => "24" "paginaInicial" => "256" "link" => array:1 [ …1] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ketone bodies as a fuel for the brain during starvation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Biochem Mol Biol Educ" "fecha" => "2005" "volumen" => "33" "paginaInicial" => "246" ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Failing heart and starving brain: ketone bodies to the rescue" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.116.022141" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2016" "volumen" => "134" "paginaInicial" => "265" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ehf2.12336" "Revista" => array:6 [ "tituloSerie" => "ESC Heart Fail" "fecha" => "2018" "volumen" => "5" "paginaInicial" => "642" "paginaFinal" => "646" "link" => array:1 [ …1] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Calcium signaling in diabetic cardiomyocytes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cell Calcium" "fecha" => "2014" "volumen" => "56" "paginaInicial" => "372" ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCRESAHA.108.175141" "Revista" => array:5 [ "tituloSerie" => "Circ Res" "fecha" => "2008" "volumen" => "103" "paginaInicial" => "891" "link" => array:1 [ …1] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Am Heart Assoc" "fecha" => "2015" "volumen" => "4" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Translocation of the Na+/H+ exchanger 1 (NHE1) in cardiomyocyte responses to insulin and energy-status signalling" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1042/BJ20100717" "Revista" => array:5 [ "tituloSerie" => "Biochem J" "fecha" => "2010" "volumen" => "432" "paginaInicial" => "515" "link" => array:1 [ …1] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of leptin on Na(+)-H(+) antiport (NHE 1) activity of obese and normal subjects erythrocytes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Mol Cell Endocrinol" "fecha" => "2001" "volumen" => "183" "numero" => "1–2" "paginaInicial" => "1" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.HYP.0000102863.23854.0B" "Revista" => array:5 [ "tituloSerie" => "Hypertension" "fecha" => "2003" "volumen" => "42" "paginaInicial" => "1171" "link" => array:1 [ …1] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Calcium signaling and reactive oxygen species in mitochondria" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCRESAHA.117.312287" "Revista" => array:5 [ "tituloSerie" => "Circ Res" "fecha" => "2018" "volumen" => "122" "paginaInicial" => "14" "link" => array:1 [ …1] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocardial cell death in human diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.res.87.2.112" "Revista" => array:5 [ "tituloSerie" => "Circ Res" "fecha" => "2010" "volumen" => "87" "paginaInicial" => "112" "link" => array:1 [ …1] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metabolic impairment in heart failure: the myocardial and systemic perspective" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2014" "volumen" => "64" "paginaInicial" => "138" ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adaptation and maladaptation of the heart in diabetes: part I" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.cir.0000012466.50373.e8" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2002" "volumen" => "105" "paginaInicial" => "1727" "paginaFinal" => "1731" "link" => array:1 [ …1] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2013.02.092" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2013" "volumen" => "62" "paginaInicial" => "263" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PKB/Akt: a key mediator of cell prolife-ration, survival and insulin responses?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Cell Sci" "fecha" => "2001" "volumen" => "114" "numero" => "Pt 16" "paginaInicial" => "2903" "paginaFinal" => "2910" "link" => array:1 [ …1] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.yjmcc.2010.02.012" "Revista" => array:6 [ "tituloSerie" => "J Mol Cell Cardiol" "fecha" => "2010" "volumen" => "48" "paginaInicial" => "910" "paginaFinal" => "916" "link" => array:1 [ …1] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2005.02.093" "Revista" => array:5 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2005" "volumen" => "46" "paginaInicial" => "1019" "link" => array:1 [ …1] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Obesity and the risk of heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa020245" "Revista" => array:5 [ "tituloSerie" => "N Engl J Med" "fecha" => "2002" "volumen" => "347" "paginaInicial" => "305" "link" => array:1 [ …1] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Circulation" "fecha" => "2018" "volumen" => "137" "paginaInicial" => "16" ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence Supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2017" "volumen" => "136" "paginaInicial" => "1" "paginaFinal" => "6" ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The HFpEF obesity phenotype: the elephant in the Room." "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2016" "volumen" => "68" "paginaInicial" => "200" ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adipose tissue, inflammation, and cardiovascular disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/01.RES.0000163635.62927.34" "Revista" => array:6 [ "tituloSerie" => "Circ Res" "fecha" => "2005" "volumen" => "96" "paginaInicial" => "939" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Local adipose tissue depots as cardiovascular risk factors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cardiores.2007.03.008" "Revista" => array:6 [ "tituloSerie" => "Cardiovasc Res" "fecha" => "2007" "volumen" => "75" "paginaInicial" => "690" "paginaFinal" => "701" "link" => array:1 [ …1] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The double role of epicardial adipose tissue as pro- and anti-inflammatory organ" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2008-1062724" "Revista" => array:5 [ "tituloSerie" => "Horm Metab Res" "fecha" => "2008" "volumen" => "40" "paginaInicial" => "442" "link" => array:1 [ …1] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Local and systemic effects of the multifaceted epicardial adipose tissue depot" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrendo.2015.58" "Revista" => array:5 [ "tituloSerie" => "Nat Rev Endocrinol" "fecha" => "2015" "volumen" => "11" "paginaInicial" => "363" "link" => array:1 [ …1] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary heart disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10517-017-3860-5" "Revista" => array:5 [ "tituloSerie" => "Bull Exp Biol Med" "fecha" => "2017" "volumen" => "163" "paginaInicial" => "608" "link" => array:1 [ …1] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inflammatory profile in subcutaneous and epicardial adipose tissue in men with and without diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Heart Vessels" "fecha" => "2014" "volumen" => "29" "paginaInicial" => "8" "paginaFinal" => "42" ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure epicardial fat increases atrial arrhythmogenesis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2011.12.035" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2013" "volumen" => "167" "paginaInicial" => "197" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of epicardial and peri-atrial adiposity with the presence and severity of non-valvular atrial fibrillation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10554-014-0579-5" "Revista" => array:5 [ "tituloSerie" => "Int J Cardiovasc Imaging" "fecha" => "2017" "volumen" => "31" "paginaInicial" => "649" "link" => array:1 [ …1] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2006.04.016" "Revista" => array:5 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2007" "volumen" => "115" "paginaInicial" => "272" "link" => array:1 [ …1] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of atorvastatin (80 mg) therapy on quantity of epicardial adipose tissue in patients undergoing pulmonary vein isolation for atrial fibrillation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Cardiol" "fecha" => "2015" "volumen" => "116" "paginaInicial" => "144" "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin therapy reduces inflammatory markers in hypercholesterolemic patients with high baseline levels" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Atheroscler Thromb" "fecha" => "2010" "volumen" => "17" "paginaInicial" => "722" ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S2213-8587(14)70217-7" "Revista" => array:6 [ "tituloSerie" => "Lancet Diabetes Endocrinol" "fecha" => "2015" "volumen" => "3" "paginaInicial" => "6" "paginaFinal" => "356" "link" => array:1 [ …1] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacologic agents for type 2 diabetes therapy and regulation of adipogenesis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Arch Physiol Biochem" "fecha" => "2013" "volumen" => "119" "paginaInicial" => "139" ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-inflammatory effects of metformin irrespective of diabetes status" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCRESAHA.116.308445" "Revista" => array:5 [ "tituloSerie" => "Circ Res" "fecha" => "2016" "volumen" => "119" "paginaInicial" => "652" "link" => array:1 [ …1] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Nutr Diabetes" "fecha" => "2014" "volumen" => "7" ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antidiabetic agents and endothelial dysfunction — beyond glucose control" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bcpt.12402" "Revista" => array:5 [ "tituloSerie" => "Basic Clin Pharmacol Toxicol" "fecha" => "2015" "volumen" => "117" "paginaInicial" => "15" "link" => array:1 [ …1] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic cardiomyopathy — fact or fiction?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00059-011-3429-4" "Revista" => array:5 [ "tituloSerie" => "Herz" "fecha" => "2011" "volumen" => "36" "paginaInicial" => "102" "link" => array:1 [ …1] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0375" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCHEARTFAILURE.111.965848" "Revista" => array:6 [ "tituloSerie" => "Circ Heart Fail" "fecha" => "2012" "volumen" => "5" "paginaInicial" => "6" "paginaFinal" => "720" "link" => array:1 [ …1] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0380" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2008" "volumen" => "117" "paginaInicial" => "43" "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0385" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Myocardial structure and function differ in systolic and diastolic heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Circulation" "fecha" => "2006" "volumen" => "113" "paginaInicial" => "19" ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0390" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2011" "volumen" => "123" "paginaInicial" => "19" "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0395" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Left and right atrial phasic function and deformation in untreated patients with prediabetes and type 2 diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10554-014-0512-y" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiovasc Imaging" "fecha" => "2015" "volumen" => "31" "paginaInicial" => "7" "paginaFinal" => "65" "link" => array:1 [ …1] ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0400" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Am Soc Echocardiogr" "fecha" => "2014" "volumen" => "27" "paginaInicial" => "479" ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0405" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved myocardial tagging contrast" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/mrm.1910300207" "Revista" => array:5 [ "tituloSerie" => "Magn Reson Med" "fecha" => "1993" "volumen" => "30" "paginaInicial" => "191" "link" => array:1 [ …1] ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0410" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehw128" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2016" "volumen" => "37" "paginaInicial" => "2129" "paginaFinal" => "2200m" "link" => array:1 [ …1] ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0415" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiotrophin-1 induces sarcoplasmic reticulum Ca(2+) leak and arrhythmogenesis in adult rat ventricular myocytes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cvr/cvs245" "Revista" => array:7 [ "tituloSerie" => "Cardiovasc Res" "fecha" => "2012" "volumen" => "96" "numero" => "1" "paginaInicial" => "9" "paginaFinal" => "81" "link" => array:1 [ …1] ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0420" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12933-018-0787-8" "Revista" => array:5 [ "tituloSerie" => "Cardiovasc Diabetol" "fecha" => "2013" "volumen" => "17" "paginaInicial" => "150" "link" => array:1 [ …1] ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0425" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum heart type fatty acid binding protein levels in metabolic syndrome" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12020-009-9243-6" "Revista" => array:5 [ "tituloSerie" => "Endocrine" "fecha" => "2009" "volumen" => "36" "paginaInicial" => "433" "link" => array:1 [ …1] ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0430" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased expression of fatty-acid and calcium metabolism genes in failing human heart" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "PLoS One" "fecha" => "2012" …1 ] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0435" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of serum biomarkers in early detection of diabetic cardiomyopathy in the West Virginian Population" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7150/ijms.14141" "Revista" => array:5 [ …5] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0440" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum carboxy-terminal propeptide of type I procollagen (PIP) is a marker of diastolic dysfunction in patients with early type 2 diabetes mellitus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ …3] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0445" "etiqueta" => "89" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.diabres.2010.01.004" "Revista" => array:6 [ …6] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0450" "etiqueta" => "90" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognostic usefulness of insulin-like growth factor-binding protein 7 in heart failure with reduced ejection fraction: a novel biomarker of myocardial diastolic function?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0455" "etiqueta" => "91" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib0460" "etiqueta" => "92" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mechanism of action of metformin: old or new insights?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-013-2991-0" "Revista" => array:5 [ …5] ] ] ] ] ] 92 => array:3 [ "identificador" => "bib0465" "etiqueta" => "93" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 93 => array:3 [ "identificador" => "bib0470" "etiqueta" => "94" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metformin therapy and outcomes in patients with advanced systolic heart failure and diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cardfail.2009.10.022" "Revista" => array:5 [ …5] ] ] ] ] ] 94 => array:3 [ "identificador" => "bib0475" "etiqueta" => "95" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature05894" "Revista" => array:6 [ …6] ] ] ] ] ] 95 => array:3 [ "identificador" => "bib0480" "etiqueta" => "96" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Review: peroxisome proliferator-activated receptor gamma and adipose tissue — understanding obesity-related changes in regulation of lipid and glucose metabolism" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2006-1268" "Revista" => array:5 [ …5] ] ] ] ] ] 96 => array:3 [ "identificador" => "bib0485" "etiqueta" => "97" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehp604" "Revista" => array:5 [ …5] ] ] ] ] ] 97 => array:3 [ "identificador" => "bib0490" "etiqueta" => "98" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pro. I. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08)" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 98 => array:3 [ "identificador" => "bib0495" "etiqueta" => "99" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diabetes.54.1.146" "Revista" => array:5 [ …5] ] ] ] ] ] 99 => array:3 [ "identificador" => "bib0500" "etiqueta" => "100" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 100 => array:3 [ "identificador" => "bib0505" "etiqueta" => "101" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liraglutide and cardiovascular outcomes in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1603827" "Revista" => array:6 [ …6] ] ] ] ] ] 101 => array:3 [ "identificador" => "bib0510" "etiqueta" => "102" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Semaglutide and cardiovascular outcomes in patients with type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 102 => array:3 [ "identificador" => "bib0515" "etiqueta" => "103" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1501352" "Revista" => array:5 [ …5] ] ] ] ] ] 103 => array:3 [ "identificador" => "bib0520" "etiqueta" => "104" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 104 => array:3 [ "identificador" => "bib0525" "etiqueta" => "105" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-016-3956-x" "Revista" => array:5 [ …5] ] ] ] ] ] 105 => array:3 [ "identificador" => "bib0530" "etiqueta" => "106" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 106 => array:3 [ "identificador" => "bib0535" "etiqueta" => "107" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-017-4509-7" "Revista" => array:5 [ …5] ] ] ] ] ] 107 => array:3 [ "identificador" => "bib0540" "etiqueta" => "108" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ …4] ] ] ] ] ] 108 => array:3 [ "identificador" => "bib0545" "etiqueta" => "109" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of dapagliflozin treatment on epicardial adipose tissue volume" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/s12933-017-0658-8" "Revista" => array:5 [ …5] ] ] ] ] ] 109 => array:3 [ "identificador" => "bib0550" "etiqueta" => "110" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1504720" "Revista" => array:6 [ …6] ] ] ] ] ] 110 => array:3 [ "identificador" => "bib0555" "etiqueta" => "111" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 Randomized Clinical Trial" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.119.042375" "Revista" => array:6 [ …6] ] ] ] ] ] 111 => array:3 [ "identificador" => "bib0560" "etiqueta" => "112" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ …3] ] ] ] ] ] 112 => array:3 [ "identificador" => "bib0565" "etiqueta" => "113" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dapagliflozin in patients with heart failure and reduced ejection fraction" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1911303" "Revista" => array:7 [ …7] ] ] ] ] ] 113 => array:3 [ "identificador" => "bib0570" "etiqueta" => "114" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/11.suppl_h.4" "Revista" => array:7 [ …7] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/22548874/0000022200000002/v1_202202020644/S225488742030103X/v1_202202020644/en/main.assets" "Apartado" => array:4 [ "identificador" => "48740" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/22548874/0000022200000002/v1_202202020644/S225488742030103X/v1_202202020644/en/main.pdf?idApp=WRCEE&text.app=https://revclinesp.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S225488742030103X?idApp=WRCEE"]

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Review

Diabetic cardiomyopathy

Miocardiopatía diabética

A. Lorenzo-Almorósa,

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atos2904@yahoo.es

Corresponding author.

, J.M. Cepeda-Rodrigob, Ó. Lorenzoc

a Servicio de Medicina Interna, Fundación Jiménez Díaz, Madrid, Spain

b Servicio de Medicina Interna, Hospital Vega Baja, Orihuela, Alicante, Spain

c Laboratorio de Renal, Vascular y Diabetes, IIS Fundación Jiménez-Díaz, Universidad Autónoma de Madrid, Madrid, Spain

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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Metabolic disorders in diabetes&#46; There is a reduction in the expression of glucose transporters to the cell interior&#44; especially GLUT-4&#44; resulting in increased expression of the peroxisome proliferator-activated receptor-&#945; &#40;PPAR-&#945;&#41;&#44; which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance&#46; In this process&#44; free fatty acids are employed over glucose&#46; PPAR-&#945; activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3&#46; Resulting in less efficient ATP production&#46; The excess of fatty acids also saturates the &#946;-oxidation&#44; producing an excess of ceramides&#44; diacylglycerol and reactive oxygen species &#40;ROS&#41;&#44; which are accumulated in the cytoplasm increasing lipotoxicity&#46; Moreover&#44; the excess glucose generates polyols and hexosamine&#44; which activate pro-oxidant and proinflammatory pathways and generate advanced glycation end products &#40;AGE&#41;&#44; thereby increasing the glucotoxicity&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The arrows indicate the metabolic changes&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ATP&#47;O2&#44; adenosine triphosphate&#47;oxygen ratio&#59; &#946;-ox&#44; beta-oxidation&#44; ETC&#44; electron transport chain&#59; G6P&#44; glucose 6 phosphate&#59; TAG&#44; triacylglycerides&#59; TCA&#44; tricarboxylic acid&#46;</p>"
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HF with reduced ejection fraction &#40;HFrEF&#41; and in the presence of microvascular complications&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Since then&#44; there have been various definitions for DCM&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> but there is still a lack of universally accepted criteria for the condition&#46; Most definitions are based on clinical criteria and require the absence of other conditions for the diagnosis of DCM&#46; Some definitions require the absence of coronary artery disease&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> while others also require the absence of arterial hypertension&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> Other definitions require the absence of other cardiovascular diseases &#40;in addition to coronary artery disease and arterial hypertension&#41; such as valvular heart disease<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> and congenital heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In contrast&#44; definitions proposed by other authors mention pathophysiological criteria such as ventricular dilation or hypertrophy&#44; interstitial fibrosis and diastolic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In 2018&#44; the European Society of Cardiology<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> stated that there was no definition for DCM&#46; Thus&#44; the most widespread definition refers to myocardial dysfunction that occurs in the absence of other cardiovascular diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> Nevertheless&#44; this definition seems unrealistic&#44; given that diabetes typically coexists with other cardiovascular diseases such as arterial hypertension and ischemic heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> For this reason&#44; some authors have proposed defining DCM as cardiac disorders that are not explained by other cardiovascular or noncardiovascular diseases and that can be attributed to diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology and prevalence</span><p id="par0015" class="elsevierStylePara elsevierViewall">Given the lack of consensus on the definition of DCM&#44; we cannot accurately determine the prevalence or incidence of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Nevertheless&#44; clinical trials with patients with type 2 diabetes &#40;DM2&#41; found a prevalence of HF of 10&#8211;30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In the Reykjavik study&#44; the prevalence of HF in patients with diabetes in the general population was estimated at approximately 12&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In contrast&#44; the number of patients with a diabetic etiology in clinical trials of HFrEF &#40;according to the researchers&#8217; assignment&#44; which could be interpreted as DCM&#41; has been estimated at &#60;1&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> However&#44; the presence of possible DCM was reported in a US cohort of patients with dilated cardiomyopathy with the HFrEF phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Moreover&#44; clinical trials with patients with HF have found an estimated prevalence of diabetes of approximately 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In the Kaiser Permanent study population&#44; the patients with DM2 younger than 75 years had a 3&#8211;4-fold greater risk of HF than the patients without diabetes&#46; For those older than 75 years&#44; the risk was double&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> DM2 also worsens the prognosis of patients with HFrEF and is even more deleterious for those with HF with preserved ejection fraction &#40;HFpEF&#41;&#44; for whom the mortality and hospitalization risk is increased&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Thus&#44; patients with DM2 are estimated to have a 75&#37; greater cardiovascular mortality risk and risk of hospitalization for HF compared with patients without diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> For patients with diabetes and HF who are older than 65 years&#44; the mortality risk increases 10 fold&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In general&#44; a 1&#37; reduction in glycated hemoglobin is estimated to reduce the risk of HF by 16&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathophysiology and clinical presentation of the disease</span><p id="par0025" class="elsevierStylePara elsevierViewall">There is an interrelationship between diabetes and HF&#44; where each affects the other&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> HF entails the activation of 2 neurohormonal systems&#58; the renin-angiotensin-aldosterone system and the sympathetic nervous system&#46; The first increases sodium and water retention&#44; while the second activates hepatic lipolysis&#44; lipogenesis and gluconeogenesis&#44; contributing to insulin resistance and consequently diabetes&#46; Hyperglycemia in diabetes is in turn responsible for the microvascular and macrovascular complications&#46; For macrovascular complications&#44; the increase in blood glucose produces coronary disorders and loss of cardiomyocytes&#44; which leads to ischemic heart disease and HFrEF&#44; while sarcomere stiffness and fibrosis are responsible for left ventricular restriction and HFpEF&#46; Inflammation has a marked influence on both mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Therefore&#44; HF in diabetes can be due to macroangiopathy&#44; with impairment of the coronary arteries&#44; causing myocardial ischemia&#44; or through primary impairment of the cardiac muscle &#40;cardiomyopathy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Numerous mechanisms have been proposed to explain myocardial dysfunction in DCM&#46; Cardiac mechanisms are therefore not the sole influence&#59; vascular and systemic methods also play a role&#44; considering that dysfunction in obtaining energy and contractility disorders play a critical role in DCM&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Energy substrate disorder</span><p id="par0035" class="elsevierStylePara elsevierViewall">Under normal conditions&#44; the myocardium consumes free fatty acids &#40;70&#37;&#41; and glucose &#40;30&#37;&#41; as fuel&#46; However&#44; the heart is a highly flexible metabolic organ and can change energy sources according to their availability&#46; The heart can even use lactate&#44; pyruvate&#44; glycerol&#44; and beta-hydroxybutyrate during fasting&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> This process is regulated by the Randle cycle&#44; in which the key factor for employing a certain substrate in the heart is glucose availability&#58; high blood glucose levels decrease the oxidation rate of free fatty acids and vice versa&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In HF&#44; abnormalities occur in the processing of energy at the mitochondrial level&#46; Thus&#44; despite the increasing levels of free fatty acids and glucose &#40;as well as their uptake in cardiomyocytes&#41;&#44; these cannot be metabolized as free fatty acids and pyruvate&#44; respectively&#44; due to the blocking of the pyruvate dehydrogenase complex&#44; which leads to their accumulation in the cell&#8217;s cytosol&#46; This causes a detour towards the generation of intermediate metabolites that induce altered signaling&#44; lipotoxicity&#44; and glucotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The change in energy substrate oxidation entails reduced activity of the Krebs cycle&#44; which produces the electron donors NADH and FADH<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> in the electron transport chain&#44; thereby reducing the phosphocreatine&#47;adenosine triphosphate &#40;ATP&#41; flow&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The myocardium could be said to function in HF as <span class="elsevierStyleItalic">&#8220;</span>an engine out of fuel&#8221;&#44; especially in conditions of increased energy demand such as exercise &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In diabetes&#44; in contrast&#44; there is a loss of energy flexibility&#44; with reduced expression of glucose transporters &#40;GLUT1 and especially GLUT4&#41; to the cell interior&#44; resulting in increased expression of the peroxisome proliferator-activated receptor-alpha &#945; &#40;PPAR-&#945;&#41;&#44; which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance&#46; In this process&#44; free fatty acids are employed over glucose&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;32</span></a> In the long term&#44; this process favors mitochondrial uncoupling&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> which requires a greater quantity of oxygen for each ATP molecule generated&#46; This energy inefficiency occurs due to 2 mechanisms&#58; 1&#41; fatty acid oxidation requires 8&#8211;11&#37; more oxygen for each carbon than glucose oxidation<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;34</span></a>&#44; and 2&#41; PPAR-&#945; activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Both mechanisms promote mitochondrial uncoupling and the disappearance of the proton gradient&#44; resulting in less efficient ATP production&#46; The excess of fatty acids also saturates beta-oxidation&#44; producing an excess of ceramide&#44; diacylglycerol&#44; and reactive oxygen species &#40;ROS&#41; that accumulate in the cytoplasm of the cardiomyocyte&#44; contributing to cardiac steatosis and oxidative stress&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> which increase lipotoxicity&#46; In turn&#44; the excess circulating glucose that cannot be assimilated due to the lack of GLUT receptors generates polyols and hexosamine&#44; which activate pro-oxidant and proinflammatory pathways<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and create advanced glycation end products &#40;AGEs&#41;&#44; thereby increasing glucotoxicity &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">When there is a lack of useful fuel&#44; ketone production &#40;mainly of D-beta-hydroxybutyrate&#41; is increased&#44; thereby providing a potential alternative fuel for oxidative phosphorylation&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> which could improve the energy efficiency by approximately 24&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Ketones are typically produced in fasting conditions when they are released by adipose tissue through incomplete oxidation of free fatty acids&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Ketone bodies are therefore found in greater numbers in HF when the availability of other fuels &#40;glucose and fatty acids&#41; decreases&#46; However&#44; it is not known whether the presence of ketone bodies constitutes a cause&#44; consequence&#44; or compensatory mechanism in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Ketones increase the uptake of free fatty acids in cardiomyocytes&#44; thereby improving energy efficiency&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Calcium and sodium homeostasis disorder</span><p id="par0055" class="elsevierStylePara elsevierViewall">in vitro overexpression of calcium&#47;calmodulin-dependent protein kinase II has been reported in DM2 and HF&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> which causes a reduction in the calcium &#40;Ca&#178;<span class="elsevierStyleSup">&#43;</span>&#41; of the sarcoplasmic reticulum and a reduction in the cytosolic Ca&#178;<span class="elsevierStyleSup">&#43;</span> transient amplitude&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> This process contributes to contractile dysfunction and the generation of arrhythmias<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> through the reduced activity of actin-myosin-troponin complexes&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> As a result of the parallel increase in activity of the sodium&#8211;hydrogen antiporter 1 &#40;NHE-1&#41;&#44; which regulates pH and prevents cell damage by ischemia-reperfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> there is an increase in intracellular sodium &#40;Na<span class="elsevierStyleSup">&#43;</span>&#41; in the cardiomyocyte&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> It has been reported that obesity and insulin produce NHE activation&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a> while mineralocorticoid receptor antagonists block NHE activation&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> In HFrEF&#44; disorders in the transport of cytoplasmic Na<span class="elsevierStyleSup">&#43;</span>&#8211;Ca&#178;<span class="elsevierStyleSup">&#43;</span> hinder its use by mitochondria&#44; promoting oxidative stress and energy deficiency&#44; thereby affecting cell contractility&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In turn&#44; the lack of useful fuel and the generation of lipotoxicity&#47;glucotoxicity promotes calcium imbalance&#44; mitochondrial and sarcoplasmic reticulum failure&#44; apoptosis&#44; and inflammation&#44; leading to cardiomyocyte dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Insulin resistance</span><p id="par0065" class="elsevierStylePara elsevierViewall">The myocardium in HF presents insulin resistance due to the increase in adrenergic tone&#44; the presence of inflammatory molecules&#44; oxidative stress&#44; and tissue hypoperfusion&#44; among other factors&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Insulin resistance is associated with increased hepatic lipolysis&#44; lipogenesis&#44; and gluconeogenesis&#44; to provide the cardiomyocyte with fuel&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> However&#44; excess fuel contributes to the generation of lipotoxicity&#47;glucotoxicity&#44; the reduced availability of nitric oxide&#44; and the generation of ROS&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Insulin resistance also affects other signaling pathways&#44; such as the phosphatidylinositol 3-kinase&#47;protein kinase B &#40;PI3K&#47;Akt&#41;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> and titin pathways&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> which promote cardiomyocyte hypertrophy and reduced distensibility &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In fact&#44; insulin resistance is an independent risk factor for mortality in stable patients with chronic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> It is not known&#44; however&#44; whether reducing insulin resistance improves the prognosis through the recovery of contractility&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Potential role of epicardial fat</span><p id="par0070" class="elsevierStylePara elsevierViewall">Obesity increases the risk of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The deleterious effect of obesity at the cardiovascular level has classically been thought to occur through hemodynamic mechanisms of ventricular overload&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> However&#44; most patients with obesity have slightly larger ventricles&#44; low natriuretic peptide levels&#44; and renal function impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Thus&#44; the proposed pathophysiological mechanism would be the reduction in myocardial distensibility&#44; while the main phenotype would be HFpEF&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Obesity promotes chronic systemic inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> which in turn is accompanied by an increase in epicardial fat and especially perivascular fat&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Due to its unique properties as a neuroendocrine organ and in intimate contact with the myocardium&#44;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a> epicardial fat assumes an active role in obesity&#44; changing its biological characteristics towards adipogenesis<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> and promoting the secretion of fatty acids and proinflammatory cytokines &#40;leptin&#44; tumor necrosis factor-alpha&#44; interleukin-1-beta and interleukin-6&#41;&#44; as well as reducing the anti-inflammatory cytokine adiponectin&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#44;63</span></a> In addition&#44; the secretion of the previously mentioned cytokines promotes the infiltration of macrophages and the generation of fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> Epicardial fat has also been linked to the onset of atrial arrhythmias due to the generation of fibrosis&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;65</span></a> with diastolic abnormalities<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> and multiple organ dysfunction due to the systemic release of inflammatory mediators &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Statins have been related to the reduction in epicardial fat&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> and a pleiotropic effect at this level is speculated beyond their lipid-lowering role&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> In contrast&#44; antidiabetic treatments that cause weight gain have shown an increased risk of HF in clinical trials&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> with the potential role occurring through an increase in epicardial fat&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> In contrast&#44; metformin and sodium&#8211;glucose co-transporter-2 inhibitors not only reduce epicardial fat but also decrease inflammation and improve the ventricular dynamic in animal studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#44;72</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Endothelial dysfunction</span><p id="par0085" class="elsevierStylePara elsevierViewall">Diabetes is associated with endothelial dysfunction through the reduction in nitric oxide&#44; among other factors&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Several antidiabetic drugs act by activating PI3K&#44; which controls the activity of endothelial nitric oxide synthase&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In fact&#44; intensive glycemic control reduces the microvascular but not the macrovascular complications&#44; indicating a probable protective effect at the endothelial level beyond the glycemic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Therefore&#44; DCM would be the result of not just cardiac disorders but complex systemic phenomena&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Some authors &#40;such as Maisch and Alter&#41; initially supported the presence of 4 progressive stages in DCM&#44; with the progressive addition of microscopic and macroscopic disorders&#46; Thus&#44; stage 1 of DCM would include asymptomatic patients with diastolic dysfunction&#59; stages 2 and 3 would be defined by diastolic dysfunction&#59; and stage 4 would be defined by symptomatic HF&#44; fibrosis and left ventricular dilation&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> However&#44; this theory has been criticized because the various stages often coexist in the same patient and that there are currently no diagnostic means for determining whether the abnormalities encountered are attributable exclusively to diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In addition&#44; the clinical evidence that HFpEF progresses to HFrEF is limited and has been reported subsequent to a myocardial ischemic event or in patients older than 80 years but not in diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> This classification was not developed in patient cohorts but rather experimentally&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although the disease was initially reported with the HFrEF phenotype&#44; an increasing number of authors &#40;such as Seferovi&#263;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#41; support the presence of 2 independent phenotypes in DCM &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; Thus&#44; HFpEF and HFrEF are the results of different mechanisms responsible for restrictive and dilated cardiac remodeling&#46; Nevertheless&#44; the factors that determine the development of a dominant phenotype are not known&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> At the structural level&#44; the onset of DCM with the restrictive&#47;HFpEF phenotype is completely different from the dilated&#47;HFrEF phenotype&#44;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#44;77</span></a> as are the pathophysiological mechanisms underlying each phenotype&#46; Numerous potential mechanisms that could contribute to myocardial dysfunction in DCM have been described&#46; However&#44; hyperglycemia&#44; lipotoxicity&#44; and insulin resistance would be the mechanisms most related to the restrictive&#47;HFpEF phenotype&#44; while autoimmunity phenomena would be the most influential for the dilated&#47;HFrEF phenotype&#46; Both phenotypes would also experience coronary microvascular rarefaction&#44; defined as the reduction in the capillary surface in proportion to the cardiomyocyte&#8217;s surface&#44; as well as the deposit of AGEs&#46; Hyperglycemia increases protein kinase-C activity in fibroblasts&#44; promoting fibrosis in both phenotypes&#46; The presence of diabetes would therefore have a key effect in increasing left ventricular stiffness&#44; which would affect the generation of diastolic dysfunction&#44; both in HFrEF and HFpEF&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">In the restrictive&#47;HFpEF phenotype&#44; the left ventricle is not dilated but rather hypertrophied and rigid&#46; Cardiomyocytes are also hypertrophied&#44; with a normal sarcomeric structure but high resting tension and reactive fibrosis &#40;increased collagen deposit among the cardiomyocytes&#41;&#46; In this phenotype&#44; endothelial dysfunction predominates in the coronary microvasculature&#44; triggered by the subclinical inflammation related to the comorbidities and directly by the hyperglycemia&#44; lipotoxicity&#44; and microvascular rarefaction&#46; This endothelial dysfunction affects the cardiac remodeling and reduces nitric oxide availability&#44; which in turn decreases protein kinase-G activity&#46; This decrease produces a reduction in distensibility and increases cardiomyocyte stiffness by the hyperphosphorylation of cytoskeletal proteins such as titin&#46; In the dilated&#47;HFrEF phenotype&#44; in contrast&#44; the loss of cardiomyocytes by ischemia or toxicity predominates&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> a loss triggered by inflammation&#47;autoimmunity&#44; hyperglycemia&#44; and lipotoxicity&#44; which results in oxidative stress by tissue hypoxia&#46; The left ventricle is increased in size&#44; with sarcomeric damage and replacement fibrosis &#40;deposit of collagen fibers not only between cardiomyocytes but also in extensive areas replacing the lost cardiomyocytes&#41;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnosis of diabetic cardiomyopathy</span><p id="par0110" class="elsevierStylePara elsevierViewall">For patients with diabetes&#44; the suspected diagnosis in DCM is established with signs and symptoms consistent with HF&#44; ruling out the presence of coronary artery disease&#44; valve disease&#44; congenital heart disease&#44; hypertension&#44; and infiltration disease&#44; as well as with increased natriuretic peptide levels&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The definitive diagnosis would be reached through endomyocardial biopsy&#44; which would histologically report the typical findings described above&#46; Nevertheless&#44; the invasive nature of the procedure and its associated risks require alternative techniques&#44; with biopsy relegated to experimental studies<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> or&#44; in the event of suspected infiltration disease&#44; when not assessable by other diagnostic techniques&#46; Imaging techniques are useful for describing the structural abnormalities of HF&#44; although they do not describe the pathognomonic abnormalities of diabetes or of DCM&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;15</span></a> The most noteworthy of these techniques is echocardiography&#44; specifically the speckle-tracking technique&#44; which can measure myocardial deformation during the cardiac cycle in 3 axes&#58; radial&#44; longitudinal and circumferential&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Patients with diabetes have myocardial deformation abnormalities in all directions&#44; and longitudinal deformation abnormalities have been reported in patients with prediabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a> Furthermore&#44; the reduction in longitudinal deformation has been associated with cardiovascular events at 10 years in patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> Magnetic resonance imaging &#40;MRI&#41; can be useful for DCM&#44; especially for detecting associated deposit disease&#44; fibrosis&#44; or underlying ischemia&#46; In particular&#44; tagged MRI is useful for measuring the deformation during the cardiac cycle and thereby diagnosing DCM in its initial stages&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> According to the recommendations of international guidelines&#44; physicians should search for the typical disorders of each HF phenotype &#40;HFrEF and HFpEF&#41; using these techniques&#44; especially ultrasonography&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">To diagnose DCM&#44; other entities that can cause HF need to be ruled out&#44; such as ischemic heart disease&#44; valvular heart disease&#44; and congenital heart disease&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Numerous circulating biomarkers have been studied for diagnosing DCM&#44; most of which are from experimental studies&#46; The detection of DCM would be a reflection of the disease&#8217;s processes&#44; such as steatosis&#44; contractility disorder&#44; and fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The most noteworthy biomarkers in human studies are listed below &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Cardiotrophin 1&#44; a member of the family of glycoprotein 130 cytokines that is released in response to oxidative stress to modulate hypertrophy&#44; contractility&#44; fibrosis and ischemia&#44; as well as the cardiac remodeling in DCM&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Activin A&#44; a member of the transforming growth factor-beta &#40;TGF-&#946;&#41; family&#44; released by epicardial fat to promote the entry of glucose into the cell through Akt phosphorylation&#46; High activin A levels have been related to left ventricular hypertrophy in patients with DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0135" class="elsevierStylePara elsevierViewall">Heart-type fatty acid-binding protein &#40;HFABP&#41;&#44; a cardiac cytosolic protein that transports fatty acids to the mitochondria for degradation and generation of ATP&#46; HFABP levels are undetectable in healthy patients&#44; but it is released into the blood when there is cardiac damage and in DM2&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">TGF-&#946;&#44; a protein that activates Smad signaling&#44; which increases extracellular matrix protein expression&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> High TGF-&#946; levels have been found in patients with DM2 with or without diastolic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a></p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">Procollagen type I N-terminal propeptide &#40;PINP&#41; and matrix metalloproteinase-7 &#40;MMP-7&#41;&#58; proteins related to the accumulation and degradation of the extracellular matrix&#46; An increase in the PINP&#47;MMP-7 ratio favors the development of cardiac fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">88&#44;89</span></a></p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Insulin-like growth factor binding protein-7 &#40;IGFBP-7&#41;&#44; a modulator of insulin receptor activity&#46; IGFBP-7 levels are high in patients with diabetes with systolic dysfunction and cardiac fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a></p></li></ul></p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">However&#44; further studies are needed with patient cohorts specifically diagnosed with DCM to determine not only the diagnostic and prognostic utility of these and other biomarkers but also to determine their normal ranges and thereby establish early therapeutic strategies to prevent disease progression&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of diabetic cardiomyopathy</span><p id="par0160" class="elsevierStylePara elsevierViewall">To date&#44; there are no specific treatments for DCM&#46; Ideally&#44; treatment for DCM should reverse the pathophysiological disorders reported in the disease&#46; Therapies commonly employed for treating diabetes could therefore have a potential role in DCM&#46; Once again&#44; however&#44; most results come from experimental studies&#46; Studies in patients diagnosed with DCM are therefore needed to investigate the potential role of these and other new drugs in the disease&#46; Once the findings indicate HF &#40;both the HFrEF and HFpEF phenotypes&#41;&#44; the treatments should follow the recommendations of international clinical guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The main therapies currently available for DM2 and their potential role in DCM are listed below&#46;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Metformin&#46; Acts by inhibiting the enzymes of the mitochondrial respiratory chain &#40;complex <span class="elsevierStyleSmallCaps">I</span>&#41;&#44; reducing ATP production&#44; and increasing AMP production&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> The drug&#44; therefore&#44; has a potential role in obtaining mitochondrial energy&#46; Moreover&#44; AMP activates the AMP-activated protein kinase &#40;AMPK&#41;&#44; inhibiting the synthesis of cholesterol and lipids and reducing hepatic gluconeogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> Through AMPK&#44; metformin also increases the availability of nitric oxide&#44; thereby improving endothelial function&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Although there are no clinical trials with metformin in patients with DM2 and HF&#44; cohort and case-control studies&#44; reviews and meta-analyses have shown that metformin reduces mortality and readmissions due to HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">93&#44;94</span></a> Currently&#44; the recommendation is to employ metformin as first-line therapy for patients with DM2 and HF&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Glitazones and thiazolidinediones&#46; These insulin-sensitizing agents activate the nuclear receptor PPAR-¿&#44; which has beneficial effects on the storage of free fatty acids in adipose tissue for re-establishing glucose as a source of cell energy&#46; These agents also improve nitric oxide-dependent vasodilation and have positive effects on inflammation and vascular remodeling&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">95&#44;96</span></a> However&#44; these agents cause sodium and water retention&#44; and some studies have shown an increased risk of HF&#44; in particular with rosiglitazone<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> and pioglitazone&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a> Glitazones are therefore currently contraindicated for HF&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Glucagon-like peptide-1 receptor agonists&#46; These agents decrease blood glucose by increasing insulin secretion&#44; reducing glucagon&#44; and decreasing body weight&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Numerous effects have been demonstrated in animals&#44; including reduced damage in ischemia&#47;reperfusion&#44; improved remodeling&#44; and improved endothelial function due to the increase in nitric oxide&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">99&#44;100</span></a> In clinical trials&#44; liraglutide<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> and semaglutide<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> decreased the combined event of cardiovascular mortality&#44; nonfatal myocardial infarction&#44; and nonfatal stroke in patients with high-risk DM2 and a history of cardiovascular events&#44; acting in secondary prevention&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Dipeptidyl peptidase 4 inhibitors&#46; These agents exert their hypoglycemic effect by increasing insulin secretion and reducing glucagon secretion&#44; as with glucagon-like peptide-1 agonists&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> These agents have demonstrated neutral cardiovascular effects&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> except for saxagliptin&#44; which in the SAVOR-TIMI trial showed a 27&#37; increase in the risk of hospitalization for HF<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> and is&#44; therefore&#44; contraindicated in these patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Sodium&#8211;glucose cotransporter 2 inhibitors&#46; These hypoglycemic agents produce the inhibition of sodium&#47;glucose cotransporter 2 of the proximal convoluted renal tubule&#44; thereby promoting the renal elimination of glucose &#40;glycosuria&#41; and sodium independently of insulin secretion&#46; These agents are also responsible for other beneficial hemodynamic effects such as increased diuresis &#40;diuretic effect&#41;&#44; reduced systolic blood pressure and reduced intravascular volume&#44; as well as reduced cardiac preload and afterload&#44; thereby improving the myocardial oxygen supply&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> These agents also exert metabolic effects on cardiomyocytes&#44; reported mostly in experimental studies&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> such as the increase in ketone bodies&#44; in fatty acids and in glucagon and reduced intracellular sodium through NHE inhibition&#44; which could mediate an anti-inflammatory and antioxidant effect&#46; These studies have related SGLT-2 inhibitors to improved obtention of mitochondrial energy&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> reversal of the Na<span class="elsevierStyleSup">&#43;</span>&#47;Ca&#178;<span class="elsevierStyleSup">&#43;</span> imbalance&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> and reduction of epicardial fat&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108&#44;109</span></a> In the EMPA-REG OUTCOME study&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> empagliflozin decreased the combined event of cardiovascular death&#44; nonfatal myocardial infarction&#44; and nonfatal stroke by 38&#37; and reduced the risk of hospitalization for HF by 35&#37;&#44; although only 10&#37; of the study patients had a previous history of HF&#46; Recently&#44; the EMPA-HEART study<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">111</span></a> employed cardiac MRI to investigate the potential role of empagliflozin in left ventricular remodeling &#40;at baseline and at 6 months&#41; in 97 patients with DM2 and stable coronary artery disease&#46; Empagliflozin reduced the ventricular mass&#44; especially in those patients with a higher grade of baseline hypertrophy&#46; Studies with small numbers of patients have reported improvements in diastolic function at 3 months in patients with diabetes undergoing treatment with empagliflozin&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> Recently&#44; the DAPA-HF trial<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">113</span></a> studied the effect of dapagliflozin added to standard therapy for patients with HFrEF &#40;with or without DM2&#41; and showed a reduction in cardiovascular mortality and hospitalizations for HF&#44; as well as improved quality of life for the active treatment group&#44; both in the presence and absence of diabetes&#46; Dapagliflozin was also well-tolerated&#44; without a higher rate of treatment withdrawal&#46; This study&#8217;s results opened the door to potential treatments for HF and DCM with this pharmacological group&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Insulin&#46; The intensive use of insulin has failed to demonstrate an improvement in diastolic function in DCM with the HFpEF phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> Treatment with insulin&#44; far from reversing the metabolic disorders of diabetes&#44; is associated with weight gain and sodium and water retention&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Other treatments&#44; such as zinc supplements&#44; copper chelators&#44; AGE blockers&#44; and beta-blockers&#44; have been tested in animal studies&#44; with apparently beneficial results&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0205" class="elsevierStylePara elsevierViewall">Although the consideration of DCM as a separate entity and attributed exclusively to diabetes has been questioned and is currently the subject of controversy&#44; studies conducted with patients with diabetes suggest the presence of a characteristic cardiac impairment&#44; with pathophysiology differentiated from that of other entities&#44; systemic and complex&#46; Studies conducted with diabetic treatments such as SGLT-2 inhibitors suggest a potential role in diabetic cardiomyopathy&#46; Nevertheless&#44; a consensus definition might be needed in order to design clinical trials with patients with DCM and thereby advance our understanding&#44; diagnosis and treatment of this condition&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0210" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Epidemiology and prevalence"
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        6 => array:3 [
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          "titulo" => "Pathophysiology and clinical presentation of the disease"
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              "titulo" => "Energy substrate disorder"
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            1 => array:2 [
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              "titulo" => "Calcium and sodium homeostasis disorder"
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            2 => array:2 [
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              "titulo" => "Insulin resistance"
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              "titulo" => "Endothelial dysfunction"
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          "titulo" => "Diagnosis of diabetic cardiomyopathy"
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          "titulo" => "Treatment of diabetic cardiomyopathy"
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            0 => "Diabetic cardiomyopathy"
            1 => "Diabetes"
            2 => "Heart failure"
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            0 => "Miocardiopat&#237;a diab&#233;tica"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The relationship between diabetes and heart failure is complex and bidirectional&#46; Nevertheless&#44; the existence of a cardiomyopathy attributable exclusively to diabetes has been and is still the subject of controversy&#44; due&#44; among other reasons&#44; to a lack of a consensus definition&#46; There is also no unanimous agreement in terms of the physiopathogenic findings that need to be present in the definition of diabetic cardiomyopathy or on its classification&#44; which&#44; added to the lack of diagnostic methods and treatments specific for this disease&#44; limits its general understanding&#46; Studies conducted on diabetic cardiomyopathy&#44; however&#44; suggest a unique physiopathogenesis different from that of other diseases&#46; Similarly&#44; new treatments have been shown to play a potential role in this disease&#46; The following review provides an update on diabetic cardiomyopathy&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La relaci&#243;n entre la diabetes y la insuficiencia card&#769;iaca es compleja y bidireccional&#46; No obstante&#44; la existencia de una miocardiopat&#237;a como entidad propia y atribuible exclusivamente a la diabetes ha sido y es motivo de controversia hoy d&#237;a&#46; Esto es debido&#44; entre otros motivos&#44; a la ausencia de una definici&#243;n de consenso&#46; Tampoco existe unanimidad en cuanto a los hallazgos fisiopatog&#233;nicos presentes en la miocardiopat&#237;a diab&#233;tica ni en su clasificaci&#243;n&#46; Esto&#44; a&#241;adido a la ausencia de m&#233;todos diagn&#243;sticos propios o de tratamientos espec&#237;ficos en la enfermedad&#44; limita el conocimiento general de la patolog&#237;a&#46; Sin embargo&#44; los estudios realizados en miocardiopat&#237;a diab&#233;tica sugieren una fisiopatogenia propia diferenciada de la de otras entidades&#46; De la misma manera&#44; nuevos tratamientos han demostrado tener un papel potencial en esta enfermedad&#46; En la siguiente revisi&#243;n realizamos una actualizaci&#243;n de la miocardiopat&#237;a diab&#233;tica&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Lorenzo-Almor&#243;s A&#44; Cepeda-Rodrigo JM&#44; Lorenzo &#211;&#46; Miocardiopat&#237;a diab&#233;tica&#46; Rev Clin Esp&#46; 2022&#59;222&#58;100&#8211;111&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Metabolic disorders in heart failure&#46; Despite increasing free fatty acid and glucose levels&#44; as well as their uptake&#44; these cannot be metabolized as free fatty acids and pyruvate&#44; respectively&#44; by blocking PDC&#44; which leads to its accumulation in cytosol&#46; This causes a detour towards the generation of intermediate metabolites that induce lipotoxicity and glucotoxicity&#46; The change in energy substrate oxidation entails reduced activity of the Krebs cycle&#44; thereby reducing the phosphocreatine&#47;adenosine triphosphate flow&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The arrows indicate the metabolic changes&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AGE&#59; advanced glycosylation end products&#59; ATP&#47;O2&#44; adenosine triphosphate&#47;oxygen ratio&#59; &#946;-ox&#44; beta-oxidation&#44; ETC&#44; electron transport chain&#59; G6P&#44; glucose 6 phosphate&#59; PDC&#44; pyruvate dehydrogenase complex&#59; TAG&#44; triacylglycerides&#59; TCA&#44; tricarboxylic acid&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Metabolic disorders in diabetes&#46; There is a reduction in the expression of glucose transporters to the cell interior&#44; especially GLUT-4&#44; resulting in increased expression of the peroxisome proliferator-activated receptor-&#945; &#40;PPAR-&#945;&#41;&#44; which in turn induces an increase in fatty acid degradation enzymes and an increase in insulin resistance&#46; In this process&#44; free fatty acids are employed over glucose&#46; PPAR-&#945; activation due to the increase in fatty acids leads to increased expression of the mitochondrial uncoupling protein UCP3&#46; Resulting in less efficient ATP production&#46; The excess of fatty acids also saturates the &#946;-oxidation&#44; producing an excess of ceramides&#44; diacylglycerol and reactive oxygen species &#40;ROS&#41;&#44; which are accumulated in the cytoplasm increasing lipotoxicity&#46; Moreover&#44; the excess glucose generates polyols and hexosamine&#44; which activate pro-oxidant and proinflammatory pathways and generate advanced glycation end products &#40;AGE&#41;&#44; thereby increasing the glucotoxicity&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The arrows indicate the metabolic changes&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ATP&#47;O2&#44; adenosine triphosphate&#47;oxygen ratio&#59; &#946;-ox&#44; beta-oxidation&#44; ETC&#44; electron transport chain&#59; G6P&#44; glucose 6 phosphate&#59; TAG&#44; triacylglycerides&#59; TCA&#44; tricarboxylic acid&#46;</p>"
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                      "titulo" => "Asthma and diabetes mellitus"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Zeitschr Klin Med"
                        "fecha" => "1881"
                        "volumen" => "3"
                        "paginaInicial" => "358"
                        "paginaFinal" => "364"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic angiopathy&#58; a specific vascular disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0140-6736(54)90924-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1954"
                        "volumen" => "266"
                        "paginaInicial" => "377"
                        "paginaFinal" => "379"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is there a diabetic cardiopathy&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Pathogenetische Fakt des Myokardinfarkts"
                        "fecha" => "1969"
                        "paginaInicial" => "63"
                        "paginaFinal" => "71"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New type of cardiomyopathy associated with diabetic glomerulosclerosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0002-9149(72)90595-4"
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "1972"
                        "volumen" => "30"
                        "paginaInicial" => "595"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnostic approaches for diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Cardiovasc Diabetol"
                        "fecha" => "2017"
                        "volumen" => "16"
                        "paginaInicial" => "28"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy and its mechanisms&#58; role of oxidative stress and damage"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Diabetes Investig"
                        "fecha" => "2014"
                        "volumen" => "5"
                        "paginaInicial" => "623"
                        "paginaFinal" => "634"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy revisited"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2007"
                        "volumen" => "115"
                        "numero" => "25"
                        "paginaInicial" => "32"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ESC guidelines on diabetes&#44; pre-diabetes&#44; and cardiovascular diseases developed in collaboration with the EASD"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/eht108"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2013"
                        "volumen" => "34"
                        "paginaInicial" => "3035"
                        "paginaFinal" => "3087"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy&#58; insights into pathogenesis&#44; diagnostic challenges&#44; and therapeutic options"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjmed.2008.03.046"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "2008"
                        "volumen" => "121"
                        "paginaInicial" => "748"
                        "paginaFinal" => "757"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00592-010-0180-x"
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Diabetol"
                        "fecha" => "2011"
                        "volumen" => "48"
                        "paginaInicial" => "173"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Second in a series on diabetes and the heart&#58; diabetic cardiomyopathy &#8212; mechanisms and mode of diagnosis&#46; E-Journal-of-Cardiology-Practice&#47;Volume-14&#47;Second-in-a-series-on-diabetes-and-the-heart-diabetic-cardiomyopathy-mechanisms-and-mode-of-diagnosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "E J Clin Pract ESC"
                        "fecha" => "2016"
                        "volumen" => "14"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy&#58; from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Vasc Health Risk Manag"
                        "fecha" => "2010"
                        "volumen" => "21"
                        "paginaInicial" => "883"
                        "paginaFinal" => "889"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Type 2 diabetes mellitus and heart failure&#58; a position statement from the Heart Failure Association of the European Society of Cardiology"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ejhf.1170"
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur J Heart Fail"
                        "fecha" => "2018"
                        "volumen" => "20"
                        "paginaInicial" => "853"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myocardial dysfunction and cardiovascular disease in type 2 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/00365513.2016.1155230"
                      "Revista" => array:5 [
                        "tituloSerie" => "Scand J Clin Lab Invest"
                        "fecha" => "2016"
                        "volumen" => "76"
                        "paginaInicial" => "271"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Heart heartjnl-2"
                        "fecha" => "2018"
                        "volumen" => "105"
                        "paginaInicial" => "337"
                        "paginaFinal" => "345"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The association between glucose abnormalities and heart failure in the population-based Reykjavik study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.28.3.612"
                      "Revista" => array:5 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2005"
                        "volumen" => "28"
                        "paginaInicial" => "612"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial &#40;PARADIGM-HF&#41;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur J Heart Fail"
                        "fecha" => "2014"
                        "volumen" => "16"
                        "paginaInicial" => "817"
                        "paginaFinal" => "825"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of candesartan in patientswith chronic heart failure and reduced left-ventricular systolicfunction taking angiotensin-converting-enzyme inhibitors&#58; the CHARM-Added trial"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(03)14283-3"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2003"
                        "volumen" => "362"
                        "paginaInicial" => "767"
                        "paginaFinal" => "771"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes and idiopathic cardiomyopathy&#58; a nationwide case-control study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.26.2.279"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2003"
                        "volumen" => "26"
                        "paginaInicial" => "279"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Congestive heart failure in type 2 diabetes&#58; prevalence&#44; incidence&#44; and risk factors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.24.9.1614"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2001"
                        "volumen" => "24"
                        "paginaInicial" => "1614"
                        "paginaFinal" => "1619"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure&#58; findings from the EVEREST trial"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2013"
                        "volumen" => "15"
                        "paginaInicial" => "194"
                        "paginaFinal" => "202"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction&#58; a report from the I-preserve trial &#40;Irbesartan in Heart Failure with preserved ejection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.116.024593"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2017"
                        "volumen" => "135"
                        "paginaInicial" => "724"
                        "paginaFinal" => "735"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heart failure prevalence&#44; incidence&#44; and mortality in the elderly with diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.27.3.699"
                      "Revista" => array:5 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2004"
                        "volumen" => "27"
                        "paginaInicial" => "699"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes &#40;UKPDS 35&#41;&#58; prospective observational study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2000"
                        "volumen" => "321"
                        "paginaInicial" => "405"
                        "paginaFinal" => "412"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Concomitant diabetes mellitus and heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cpcardiol.2014.09.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Probl Cardiol"
                        "fecha" => "2015"
                        "volumen" => "40"
                        "paginaInicial" => "7"
                        "paginaFinal" => "43"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heart failure and diabetes&#58; metabolic alterations and therapeutic interventions&#58; a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2018"
                        "volumen" => "39"
                        "paginaInicial" => "424"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical diabetic cardiomyopathy&#58; a two-faced disease with restrictive and dilated phenotypes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2015"
                        "volumen" => "36"
                        "paginaInicial" => "171"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CV protection in the EMPA-REG OUTCOME trial&#58; a &#8216;Thrifty Substrate&#8217; hypothesis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2016"
                        "volumen" => "39"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The glucose fatty-acid cycle&#46; Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1963"
                        "volumen" => "1"
                        "paginaInicial" => "78"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metabolic remodelling in heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41569-018-0044-6"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Rev Cardiol"
                        "fecha" => "2018"
                        "volumen" => "15"
                        "paginaInicial" => "457"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The failing heart &#8212; an engine out of fuel"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa060096"
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2007"
                        "volumen" => "356"
                        "paginaInicial" => "11"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular mechanisms of diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "2014"
                        "volumen" => "57"
                        "paginaInicial" => "660"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mitochondrial uncoupling&#44; ROS generation and cardioprotection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Biochim Biophys Acta Bioenerg"
                        "fecha" => "2018"
                        "volumen" => "1859"
                        "paginaInicial" => "94"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myocardial fatty acid metabolism in health and disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Physiol Rev"
                        "fecha" => "2010"
                        "volumen" => "90"
                        "paginaInicial" => "207"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor &#40;alpha&#41; in the adult rodent heart"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.00-0351com"
                      "Revista" => array:5 [
                        "tituloSerie" => "FASEB J"
                        "fecha" => "2001"
                        "volumen" => "15"
                        "paginaInicial" => "833"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nutritional ketosis alters fuel preference and thereby endurance performance in athletes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cmet.2016.07.010"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cell metab"
                        "fecha" => "2016"
                        "volumen" => "24"
                        "paginaInicial" => "256"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ketone bodies as a fuel for the brain during starvation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Biochem Mol Biol Educ"
                        "fecha" => "2005"
                        "volumen" => "33"
                        "paginaInicial" => "246"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Failing heart and starving brain&#58; ketone bodies to the rescue"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.116.022141"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2016"
                        "volumen" => "134"
                        "paginaInicial" => "265"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Empagliflozin reduces Ca&#47;calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ehf2.12336"
                      "Revista" => array:6 [
                        "tituloSerie" => "ESC Heart Fail"
                        "fecha" => "2018"
                        "volumen" => "5"
                        "paginaInicial" => "642"
                        "paginaFinal" => "646"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Calcium signaling in diabetic cardiomyocytes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Cell Calcium"
                        "fecha" => "2014"
                        "volumen" => "56"
                        "paginaInicial" => "372"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Activation of Na&#43;&#47;H&#43; exchanger 1 is sufficient to generate Ca2&#43; signals that induce cardiac hypertrophy and heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCRESAHA.108.175141"
                      "Revista" => array:5 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2008"
                        "volumen" => "103"
                        "paginaInicial" => "891"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intracellular Na&#43; concentration &#40;&#91;Na&#43;&#93;i&#41; is elevated in diabetic hearts due to enhanced Na&#43;-glucose cotransport"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "J Am Heart Assoc"
                        "fecha" => "2015"
                        "volumen" => "4"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Translocation of the Na&#43;&#47;H&#43; exchanger 1 &#40;NHE1&#41; in cardiomyocyte responses to insulin and energy-status signalling"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1042/BJ20100717"
                      "Revista" => array:5 [
                        "tituloSerie" => "Biochem J"
                        "fecha" => "2010"
                        "volumen" => "432"
                        "paginaInicial" => "515"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of leptin on Na&#40;&#43;&#41;-H&#40;&#43;&#41; antiport &#40;NHE 1&#41; activity of obese and normal subjects erythrocytes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Mol Cell Endocrinol"
                        "fecha" => "2001"
                        "volumen" => "183"
                        "numero" => "1&#8211;2"
                        "paginaInicial" => "1"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.HYP.0000102863.23854.0B"
                      "Revista" => array:5 [
                        "tituloSerie" => "Hypertension"
                        "fecha" => "2003"
                        "volumen" => "42"
                        "paginaInicial" => "1171"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Calcium signaling and reactive oxygen species in mitochondria"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCRESAHA.117.312287"
                      "Revista" => array:5 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2018"
                        "volumen" => "122"
                        "paginaInicial" => "14"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myocardial cell death in human diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.res.87.2.112"
                      "Revista" => array:5 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2010"
                        "volumen" => "87"
                        "paginaInicial" => "112"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metabolic impairment in heart failure&#58; the myocardial and systemic perspective"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2014"
                        "volumen" => "64"
                        "paginaInicial" => "138"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adaptation and maladaptation of the heart in diabetes&#58; part I"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.cir.0000012466.50373.e8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2002"
                        "volumen" => "105"
                        "paginaInicial" => "1727"
                        "paginaFinal" => "1731"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel paradigm for heart failure with preserved ejection fraction&#58; comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2013.02.092"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2013"
                        "volumen" => "62"
                        "paginaInicial" => "263"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "PKB&#47;Akt&#58; a key mediator of cell prolife-ration&#44; survival and insulin responses&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Cell Sci"
                        "fecha" => "2001"
                        "volumen" => "114"
                        "numero" => "Pt 16"
                        "paginaInicial" => "2903"
                        "paginaFinal" => "2910"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.yjmcc.2010.02.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Mol Cell Cardiol"
                        "fecha" => "2010"
                        "volumen" => "48"
                        "paginaInicial" => "910"
                        "paginaFinal" => "916"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2005.02.093"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2005"
                        "volumen" => "46"
                        "paginaInicial" => "1019"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Obesity and the risk of heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa020245"
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2002"
                        "volumen" => "347"
                        "paginaInicial" => "305"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Leptin-aldosterone-neprilysin axis&#58; identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2018"
                        "volumen" => "137"
                        "paginaInicial" => "16"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence Supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2017"
                        "volumen" => "136"
                        "paginaInicial" => "1"
                        "paginaFinal" => "6"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The HFpEF obesity phenotype&#58; the elephant in the Room&#46;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2016"
                        "volumen" => "68"
                        "paginaInicial" => "200"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adipose tissue&#44; inflammation&#44; and cardiovascular disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/01.RES.0000163635.62927.34"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2005"
                        "volumen" => "96"
                        "paginaInicial" => "939"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Local adipose tissue depots as cardiovascular risk factors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cardiores.2007.03.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cardiovasc Res"
                        "fecha" => "2007"
                        "volumen" => "75"
                        "paginaInicial" => "690"
                        "paginaFinal" => "701"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The double role of epicardial adipose tissue as pro- and anti-inflammatory organ"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-2008-1062724"
                      "Revista" => array:5 [
                        "tituloSerie" => "Horm Metab Res"
                        "fecha" => "2008"
                        "volumen" => "40"
                        "paginaInicial" => "442"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Local and systemic effects of the multifaceted epicardial adipose tissue depot"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrendo.2015.58"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Rev Endocrinol"
                        "fecha" => "2015"
                        "volumen" => "11"
                        "paginaInicial" => "363"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary heart disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10517-017-3860-5"
                      "Revista" => array:5 [
                        "tituloSerie" => "Bull Exp Biol Med"
                        "fecha" => "2017"
                        "volumen" => "163"
                        "paginaInicial" => "608"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inflammatory profile in subcutaneous and epicardial adipose tissue in men with and without diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Heart Vessels"
                        "fecha" => "2014"
                        "volumen" => "29"
                        "paginaInicial" => "8"
                        "paginaFinal" => "42"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Heart failure epicardial fat increases atrial arrhythmogenesis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2011.12.035"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2013"
                        "volumen" => "167"
                        "paginaInicial" => "197"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of epicardial and peri-atrial adiposity with the presence and severity of non-valvular atrial fibrillation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10554-014-0579-5"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Cardiovasc Imaging"
                        "fecha" => "2017"
                        "volumen" => "31"
                        "paginaInicial" => "649"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2006.04.016"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2007"
                        "volumen" => "115"
                        "paginaInicial" => "272"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of atorvastatin &#40;80 mg&#41; therapy on quantity of epicardial adipose tissue in patients undergoing pulmonary vein isolation for atrial fibrillation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "2015"
                        "volumen" => "116"
                        "paginaInicial" => "144"
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Statin therapy reduces inflammatory markers in hypercholesterolemic patients with high baseline levels"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Atheroscler Thromb"
                        "fecha" => "2010"
                        "volumen" => "17"
                        "paginaInicial" => "722"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes&#58; a meta-analysis of randomised controlled trials"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-8587(14)70217-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Diabetes Endocrinol"
                        "fecha" => "2015"
                        "volumen" => "3"
                        "paginaInicial" => "6"
                        "paginaFinal" => "356"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacologic agents for type 2 diabetes therapy and regulation of adipogenesis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Arch Physiol Biochem"
                        "fecha" => "2013"
                        "volumen" => "119"
                        "paginaInicial" => "139"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-inflammatory effects of metformin irrespective of diabetes status"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCRESAHA.116.308445"
                      "Revista" => array:5 [
                        "tituloSerie" => "Circ Res"
                        "fecha" => "2016"
                        "volumen" => "119"
                        "paginaInicial" => "652"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tofogliflozin&#44; a sodium&#47;glucose cotransporter 2 inhibitor&#44; attenuates body weight gain and fat accumulation in diabetic and obese animal models"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Nutr Diabetes"
                        "fecha" => "2014"
                        "volumen" => "7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antidiabetic agents and endothelial dysfunction &#8212; beyond glucose control"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/bcpt.12402"
                      "Revista" => array:5 [
                        "tituloSerie" => "Basic Clin Pharmacol Toxicol"
                        "fecha" => "2015"
                        "volumen" => "117"
                        "paginaInicial" => "15"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic cardiomyopathy &#8212; fact or fiction&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00059-011-3429-4"
                      "Revista" => array:5 [
                        "tituloSerie" => "Herz"
                        "fecha" => "2011"
                        "volumen" => "36"
                        "paginaInicial" => "102"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCHEARTFAILURE.111.965848"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circ Heart Fail"
                        "fecha" => "2012"
                        "volumen" => "5"
                        "paginaInicial" => "6"
                        "paginaFinal" => "720"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diastolic stiffness of the failing diabetic heart&#58; importance of fibrosis&#44; advanced glycation end products&#44; and myocyte resting tension"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2008"
                        "volumen" => "117"
                        "paginaInicial" => "43"
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Myocardial structure and function differ in systolic and diastolic heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2006"
                        "volumen" => "113"
                        "paginaInicial" => "19"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2011"
                        "volumen" => "123"
                        "paginaInicial" => "19"
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Left and right atrial phasic function and deformation in untreated patients with prediabetes and type 2 diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10554-014-0512-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiovasc Imaging"
                        "fecha" => "2015"
                        "volumen" => "31"
                        "paginaInicial" => "7"
                        "paginaFinal" => "65"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Am Soc Echocardiogr"
                        "fecha" => "2014"
                        "volumen" => "27"
                        "paginaInicial" => "479"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved myocardial tagging contrast"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/mrm.1910300207"
                      "Revista" => array:5 [
                        "tituloSerie" => "Magn Reson Med"
                        "fecha" => "1993"
                        "volumen" => "30"
                        "paginaInicial" => "191"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehw128"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2016"
                        "volumen" => "37"
                        "paginaInicial" => "2129"
                        "paginaFinal" => "2200m"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiotrophin-1 induces sarcoplasmic reticulum Ca&#40;2&#43;&#41; leak and arrhythmogenesis in adult rat ventricular myocytes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/cvr/cvs245"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cardiovasc Res"
                        "fecha" => "2012"
                        "volumen" => "96"
                        "numero" => "1"
                        "paginaInicial" => "9"
                        "paginaFinal" => "81"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12933-018-0787-8"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cardiovasc Diabetol"
                        "fecha" => "2013"
                        "volumen" => "17"
                        "paginaInicial" => "150"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum heart type fatty acid binding protein levels in metabolic syndrome"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12020-009-9243-6"
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrine"
                        "fecha" => "2009"
                        "volumen" => "36"
                        "paginaInicial" => "433"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased expression of fatty-acid and calcium metabolism genes in failing human heart"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "PLoS One"
                        "fecha" => "2012"
                         …1
                      ]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of serum biomarkers in early detection of diabetic cardiomyopathy in the West Virginian Population"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7150/ijms.14141"
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum carboxy-terminal propeptide of type I procollagen &#40;PIP&#41; is a marker of diastolic dysfunction in patients with early type 2 diabetes mellitus"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [ …3]
                    ]
                  ]
                ]
              ]
            ]
            88 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "89"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.diabres.2010.01.004"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            89 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "90"
              "referencia" => array:1 [
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2019.10.012

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