Pathophysiology of acute heart failure: A world to know

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Heart Failure" "titulo" => "Pathophysiology of acute heart failure: A world to know" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "38" "paginaFinal" => "46" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Sánchez-Marteles, J. Rubio Gracia, I. Giménez López" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Sánchez-Marteles" "email" => array:1 [ 0 => "marta.sanchez15@yahoo.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Rubio Gracia" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "I." 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Abbreviations: IL-6, interleukins 6; NO, nitric oxide; TNF-α, tumor necrosis factor α." ] ] ] "textoCompleto" => "Introduction and concept of acute heart failureHeart failure (HF) is a clinical syndrome that is common to various diseases and that causes a reduction in cardiac function by mechanisms that are not completely understood. As a result, either the tissues’ metabolic needs cannot be met or they are met at the cost of an increased heart rate and/or an abnormally high diastolic volume.<a class="elsevierStyleCrossRefs" href="#bib0305">1,2</a>Approximately 1–2% of the adult population in developed countries experience HF, a percentage that rises with age and reaches more than 10% of the population aged over 70 years and up to almost 20% of those older than 80 years. The natural progression of this syndrome is the progressive onset of signs and symptoms that cause a decline in the patient's vital and functional capacity, with hospitalizations for decompensations and, ultimately, death due to refractory HF, pump failure or ventricular arrhythmia.<a class="elsevierStyleCrossRefs" href="#bib0305">1,2</a> A number of population registries have recorded a 20% readmission rate in the 30 days following discharge and an annual mortality of 30%.<a class="elsevierStyleCrossRef" href="#bib0315">3</a> This makes HF a growing and first-order healthcare and financial problem.The differences between acute and chronic HF are based on the speed with which symptoms start. Although both terms are widely used in clinical practice, there are no specific definitions on the duration that should be used to separate the two concepts. In 2010, the American Heart Association and the American College of Cardiology defined acute HF as that which develops within 24–48h.<a class="elsevierStyleCrossRef" href="#bib0320">4</a> As new items in their latest guidelines, distinct acute HF subgroups have been identified, such as those resulting from acute coronary syndrome, hypertensive emergency, sudden right ventricular failure, shock and decompensations in patients with already known chronic HF.<a class="elsevierStyleCrossRef" href="#bib0310">2</a> Along these lines, the European Society of Cardiology differentiates decompensations resulting from chronic HF from those caused by de novo HF.<a class="elsevierStyleCrossRef" href="#bib0305">1</a>From the physiological point of view, HF has classically been divided into two types: systolic and diastolic. This difference refers to whether the main heart anomaly is the left ventricle's (LV) inability to contract normally and expel sufficient blood (systolic HF) or in the difficulty in ventricular relaxation and filling (diastolic HF). However, the application of this classification in clinical practice has not been easy. First, there are diagnostic problems. According to the European Society of Cardiology, diagnosing HF as diastolic requires the presence not only of HF signs and symptoms with a LV ejection fraction (LVEF) >50% but also the echocardiographic demonstration or (better yet) the hemodynamics of diastolic dysfunction, which cannot always be obtained.<a class="elsevierStyleCrossRefs" href="#bib0305">1,5,6</a> It has been shown that an LVEF <50% does not always correspond to systolic dysfunction. This occurs particularly in the LVEF range of 40–50%, which remains a gray area in which the patient's background (ischemic vs. hypertensive) is assessed in order to assign it to one type of HF or the other.<a class="elsevierStyleCrossRef" href="#bib0305">1</a>In order to adopt a more pragmatic approach, one that has already been accepted by both the European and American HF guidelines, the terms HF with reduced or preserved LVEF (HFREF and HFPEF, respectively) have been adopted,<a class="elsevierStyleCrossRefs" href="#bib0305">1,2</a> the latter term designated to the type of HF initially categorized as diastolic HF. Although HFPEF is occasionally assimilated into diastolic HF, they are not strictly comparable terms.The various ejection fraction-based HF phenotypes detected in recent population registries have led to in-depth research into their pathophysiology and to the still unresolved debate on whether this involves 1 or 2 separate syndromes.<a class="elsevierStyleCrossRefs" href="#bib0325">5,7,8</a>In this article, we review the basic and known issues of acute HF regarding acute chronic HF decompensation.The mechanisms underlying acute HF are complex and still unclear. The understanding of neurohormonal mechanisms has been added to the merely hemodynamic viewpoint in which HF is regarded as pump failure. Based on this understanding, a number of drugs have been suggested as the cornerstones of treatment: angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.<a class="elsevierStyleCrossRef" href="#bib0345">9</a>Other phenomena (such as congestion, interstitial involvement, extracellular matrix modification, inflammation, remodeling, genetics, molecular biology and multiple organ interaction) are increasingly gaining relevance in the pathophysiology of HF, prompting the consideration of an inclusive vision in which all of these conditions participate to a greater of lesser extent (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0350">10,11</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Hemodynamic overload and adaptationThe initial and classical vision of HF was based on the body's need to maintain an adequate cardiac output that covers the tissue's metabolic needs.In conditions of myocardial deficit (loss of contractility, intrinsic problems in the myocardium and valve failure), there is a decrease in ejection fraction and an increase in end-diastolic volume and end-diastolic pressure in the LV, which causes an increase in atrial contraction in order to exploit the cardiac reserve. Furthermore, the Frank–Starling mechanism starts within a few moments, along with sympathetic system activation, resulting in an increase in contractility that in turn results in an immediate improvement in the conditions generated by the initial aggression.<a class="elsevierStyleCrossRefs" href="#bib0345">9,12</a> When this condition persists, the adaptive response becomes adverse and leads to changes in the form and function of the LV, a phenomenon known as ventricular remodeling. The remodeling changes the electrical conduction and ventricular function and ultimately leads to the development of HF.<a class="elsevierStyleCrossRef" href="#bib0345">9</a>This hemodynamic explanation is straightforward and useful, but it is tied primarily to ventricular dysfunction and is simplistic. The myocardium and both ventricles interact and should be considered a continuum in which the dysfunction and overloading of one element affects the others. The right ventricle (RV) differs from the left in a number of ways. The RV wall is thinner (8–11mm vs. 2–3mm). Structurally, there is a different proportion of alpha myosin in the myofibrils, and the response to adrenergic stimulus and coronary irrigation is different. This confers a considerable adaptive capacity on the RV, making it the great “shock absorber” of volume changes and venous return, which are continuously produced by changes in blood pressure and posture, vascular repletion, respiration and Valsalva maneuvers, among others.<a class="elsevierStyleCrossRef" href="#bib0365">13</a>Acute RV overload (e.g., tamponade, pulmonary thromboembolism, acute valvular heart disease) hinders proper left ventricular filling, which results in reduced cardiac output. This in turn results in hypoxemia and poor RV perfusion, which increases its dysfunction and generates a vicious pathological cycle that can rapidly lead to death (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0365">13</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>The regulatory role of RV is significant. In fact, its dysfunction has been revealed in recent years as a key pathophysiological and prognostic factor, especially in patients with HFPEF.<a class="elsevierStyleCrossRef" href="#bib0370">14</a> Despite the difficulty of studying RV disorders, there are already significant data, both populational<a class="elsevierStyleCrossRef" href="#bib0375">15</a> and from selected patient cohorts, on its prognostic value.<a class="elsevierStyleCrossRefs" href="#bib0380">16,17</a> An example of this is a recent case–control study of patients with HF and preserved LVEF, which showed how pressure increases, dysfunction and changes in RV dimensions were directly related to mortality.<a class="elsevierStyleCrossRef" href="#bib0380">16</a>In the patients with HFPEF, histopathological changes in the pulmonary vascular tree (intimal hypertrophy and adventitial fibrosis in the small vessels) and thickening of the alveolar-capillary membrane, along with inflammatory phenomena, provoke long-term pulmonary hypertension and structural changes, with subsequent RV dysfunction.<a class="elsevierStyleCrossRef" href="#bib0390">18</a>Systemic congestionThe presence of signs and symptoms such as dyspnea, orthopnea, edema, jugular venous distention, ascites, hepatomegaly and lung crackles during an episode of acute HF signal the presence of congestion. Congestion reflects an increase in central venous pressure (CVP) and circulating volume, whose most important reservoir, due to its involvement in acute HF, is splanchnic venous circulation.<a class="elsevierStyleCrossRefs" href="#bib0395">19–21</a>There are two fundamental theories that explain the genesis of congestion in acute HF. The classical theory explains congestion by sodium and water retention, which results in an accumulation of extracellular liquid, and an increase in weight and effective circulatory volume, with prominent renal dysfunction.<a class="elsevierStyleCrossRef" href="#bib0350">10</a> The second more recent interpretation explains congestion as the consequence of a sudden displacement of the splanchnic reservoir to the general circulation, due to the increase in sympathetic stimulation from the cardiac decompensation. The sustained stimulation of the sympathetic nervous system, resulting from tissue hypoperfusion, is accompanied by a reduction or depletion of the inhibitory response of the carotid baroreflexes. In this context, a small increase in sympathetic tone at the start of a cardiac decompensation will move a sizeable volume of blood from the splanchnic reservoir to the general circulation, which explains the volume overload and congestive symptoms. According to the second theory, there is no exogenous fluid retention nor is there weight gain preceding the decompensations.<a class="elsevierStyleCrossRef" href="#bib0350">10</a>Venous congestion is not only a consequence of HF associated with a poorer prognosis but also an important pathophysiological factor, especially for the genesis of renal damage during HF exacerbations.<a class="elsevierStyleCrossRef" href="#bib0410">22</a>The negative effect of venous congestion on renal function has been known for more than a century. Experiments in 1860<a class="elsevierStyleCrossRef" href="#bib0415">23</a> showed that partial occlusion of the renal vein causes an immediate reduction in renal blood flow, glomerular filtration and sodium excretion, which are resolved after the vein is decompressed.Despite those initial studies, the pathophysiological role of venous congestion remained hidden until recently and was interpreted as a mere epiphenomenon of retrograde heart failure secondary to reduced cardiac output. However, recent research has focused attention on venous congestion as a core factor in the incidence of cardiorenal syndrome and acute HF itself.<a class="elsevierStyleCrossRef" href="#bib0420">24</a>In one of these studies, Mullens et al. showed that patients with HF with reduced LVEF who developed functional renal failure (FRF) had, after intensive diuretic treatment, a baseline CVP greater than those in whom FRF did not occur.<a class="elsevierStyleCrossRef" href="#bib0420">24</a> Additionally, FRF was rare among the patients who decreased their CVP below 8mmHg, and the relationship between CVP and risk of FRF remained independent of the other patient characteristics (blood pressure, pulmonary capillary wedge pressure, cardiac index and glomerular filtration rate). The authors concluded that the hemodynamic factor that most predisposes patients to FRF in exacerbated HF is venous congestion, measured by CVP, a phenomenon for which they suggested the term “congestive renal failure congestive”.<a class="elsevierStyleCrossRef" href="#bib0420">24</a> There are data from extensive epidemiological registries (such as ADHERE) that support this interpretation.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> Fifty percent of the patients in this registry, hospitalized for HF decompensation, had systolic blood pressures >140mmHg, while only 2% had readings <90mmHg.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> This finding reflects the importance of congestion, pulmonary in this case, at the expense of reduced cardiac output.<a class="elsevierStyleCrossRef" href="#bib0430">26</a>Renal blood flow is also determined by abdominal perfusion pressure, which is directly related to blood pressure and inversely related to intraabdominal pressure (IAP). Normal IAP is approximately 5–7mmHg. Intestinal distension, ascites, urinary retention and obesity can cause an increase in IAP. Pressures greater than 8mmHg have been related to an increased incidence of FRF. To all of this we must add that renal perfusion does not depend only on the flow and pressure in the renal artery but also on the so-called transrenal perfusion pressure resulting from the difference between the CVP and blood pressure. Changes in both, which are common in acute HF, will therefore affect renal filtration.<a class="elsevierStyleCrossRef" href="#bib0435">27</a>However, beyond their influence on renal dysfunction, the data indicate that systemic congestion and IAP, per se, play a fundamental but still not completely understood role in the pathophysiology of HF.<a class="elsevierStyleCrossRefs" href="#bib0350">10,21,28,29</a> It also seems that there is a complex network in which proinflammatory, oxidative stress, neurohormonal and hemodynamic phenomena (among others) are interwoven and interact (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0450">30,31</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>The accurate measurement of systemic congestion is still problematic. It appears that the combination of signs and symptoms of congestion (edema, ascites and jugular venous distention) and the related echocardiographic parameters (LVEF, diameter and collapse of the inferior vena cava and systolic pulmonary artery pressure) are associated with greater mortality and readmissions in these patients, even if FRF does not develop. The measurement and use of these parameters could be of use in the early identification of those patients with HF who are at risk of developing renal failure.<a class="elsevierStyleCrossRef" href="#bib0460">32</a>In terms of biomarkers for estimating systemic congestion, carbohydrate antigen 125 (CA125) appears to have the most appropriate profile.<a class="elsevierStyleCrossRef" href="#bib0465">33</a> CA125 is a glycoprotein synthesized by serous epithelial cells, has a complex structure and high molecular weight and is widely used in the follow-up of ovarian cancer. As in ovarian cancer, serum CA125 concentrations can be increased in hepatic cirrhosis, nephrotic syndrome, pelvic inflammatory disease and tuberculosis. HF has been postulated as a useful marker due to its correlation with prognostic and congestion parameters.<a class="elsevierStyleCrossRef" href="#bib0460">32</a> The pathophysiological mechanisms by which CA125 concentrations are increased in acute HF are not known. However, it has been postulated that there are inflammatory factors that trigger its production in serum in response to congestion and interstitial fluid accumulation.<a class="elsevierStyleCrossRef" href="#bib0470">34</a>Neurohormonal system and natriuretic peptidesIn addition to the changes in pressure and contractility, myocardial stress activates various neurohormonal pathways to counter the vascular congestion and hypoperfusion caused by myocardial dysfunction.<a class="elsevierStyleCrossRefs" href="#bib0475">35,36</a>Activation of the sympathetic system helps increase contractility, heart rate and vasoconstriction through the release norepinephrine and also promotes the release of renin. However, a high and sustained concentration of norepinephrine is associated with a poorer prognosis and increased mortality.<a class="elsevierStyleCrossRefs" href="#bib0360">12,35</a>Another fundamental response system is the renin–angiotensin–aldosterone system. This system is activated in response to renal hypoperfusion, producing an increase in renin and, consequently, angiotensin II, with efferent arteriolar vasoconstriction, which increases the filtration fraction and maintains a minimum glomerular filtration rate. There is a simultaneous increase in aldosterone concentrations, which translates into water and sodium retention. This system, although effective in the short term, increases myocardial dysfunction and mortality when prolonged.Aldosterone has a role beyond water retention, with important actions on metalloproteinases and thus on fibrosis and ventricular remodeling.<a class="elsevierStyleCrossRefs" href="#bib0475">35,37</a> A few decades ago, drugs were developed that are today the basis of treatment for HF with reduced LVEF: angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and mineralocorticoid receptor blockers whose efficacy has been demonstrated in numerous clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0360">12,36,38</a>Vasopressin and antidiuretic hormone are also secreted in acute HF. The increase in osmolarity resulting from sodium absorption generated by aldosterone directly results in the release of antidiuretic hormone. The antidiuretic hormone is a neurohypophyseal peptide that intervenes in free water absorption, thereby controlling blood volume and pressure.<a class="elsevierStyleCrossRefs" href="#bib0360">12,35,39,40</a>Lastly, natriuretic peptides have a fundamental and compensatory role in this complex neurohormonal network. The family of natriuretic peptides includes at least five subtypes: atrial natriuretic peptide (type A), brain natriuretic peptide (BNP or type B) and types C, D and V.<a class="elsevierStyleCrossRef" href="#bib0505">41</a> The most well known from the pathophysiological point of view are the atrial natriuretic peptide and BNP. Both are released in conditions of stress on the atrial and ventricular wall, respectively, triggered by stimuli such as volume overload and ischemia, in the case of BNP. Their speed of action varies and produces a host of actions on the kidney and vascular and sympathetic systems, which translates into venous and arterial vasodilation. Vasodilation in the afferent renal arteriole and vasoconstriction in the efferent, along with complex interactions in the interstitium and renal tubules, cause an increase in glomerular filtration.<a class="elsevierStyleCrossRefs" href="#bib0510">42,43</a> They also act on mesangial cyclic guanosine monophosphate, promoting an increase in filtration surface and act directly on the distal convoluted tubule. The ultimate consequence of this is an effective increase in diuresis and natriuresis.<a class="elsevierStyleCrossRefs" href="#bib0520">44,45</a>Recent data suggest that, in addition to the release of the peptide, myocardial stress causes a cascade reaction that increases BNP deglycosylation and furin production, one of the fundamental enzymes for excision of the propeptide in its active form and its aminoterminal fraction,<a class="elsevierStyleCrossRef" href="#bib0530">46</a> thereby promoting faster biological action.Inflammatory damage and oxidative stressHemodynamic disorders (hypoperfusion and congestion) can be considered the main consequence of HF, followed by neurohormonal disorders that result from the attempt to counter the former's effects. However, the chronicity of HF and the simultaneous involvement of other organs activates inflammation, oxidative stress and endothelial dysfunction, which contribute to the pathophysiology of HF.<a class="elsevierStyleCrossRefs" href="#bib0435">27,47</a>C-reactive protein was the first inflammatory molecule to be related to HF, whose prognosis worsens in those patients who show high and sustained concentrations of C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> Other inflammatory molecules have since been implicated, such as tumor necrosis factor α and a number of interleukins (mainly IL-1, IL-6 and IL-18), which act on the cardiomyocyte, activating mechanisms of apoptosis and necrosis.<a class="elsevierStyleCrossRef" href="#bib0475">35</a>The endothelium plays a central role in the inflammatory response, because its response to congestion includes the production of free radicals (oxidative stress) and the release of proinflammatory factors and vasoactive peptides.<a class="elsevierStyleCrossRef" href="#bib0435">27</a> Recent studies on human models of venous congestion have shown that brief increases (75min) in venous pressure of 30mmHg above normal pressure are sufficient to trigger the endothelium and increase the release of inflammatory cytokines (IL-1β, tumor necrosis factor-α and IL-6), vasoactive peptides (ET-1, ATII), endothelial adhesion molecules (VCAM-1, ICAM-1) and coagulation factors (vWF).<a class="elsevierStyleCrossRefs" href="#bib0455">31,47</a>The latent and systemic inflammatory state is accompanied by an increase in oxidative stress. The increased production of reactive oxygen species and the reduction in free radical scavenger systems, such as glutathione peroxidase, produce oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0540">48,49</a> A significant consequence of the sustained inflammatory state is the reduced bioavailability of nitric oxide (NO), a potent vasodilator. Additionally, the excess of reactive oxygen species and the reduction in NO promote the emergence of a proinflammatory and profibrotic phenotype, which intensifies myocardial necrosis<a class="elsevierStyleCrossRefs" href="#bib0360">12,35</a> and promotes remodeling.<a class="elsevierStyleCrossRefs" href="#bib0550">50,51</a> The result is a vicious cycle that perpetuates hemodynamic and neurohormonal disorders, with harmful effects on the heart itself (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>) and the consequent progression of HF.<a class="elsevierStyleCrossRef" href="#bib0325">5</a>Moreover, oxidative stress intensifies due to the dysfunction of other organs and some metabolic disorders. Increases in serum uric acid levels boost the enzymatic activity of xanthine-oxidase and intensify the oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0560">52</a> In addition to the reduction in NO, the pro-oxidant state can cause increased lipid oxidation. Tang et al. showed that isoprostanoid concentrations correlate with HF severity and are an independent predictor of mortality.<a class="elsevierStyleCrossRef" href="#bib0560">52</a>The extension of the inflammation and the activation of the endothelium in various territories would explain not only the myocardial impairment itself but also the involvement of other organs that accompany the HF exacerbation.<a class="elsevierStyleCrossRef" href="#bib0565">53</a>In the kidneys, the inflammation and oxidative stress generated in the endothelium translates into reduced glomerular filtration, tubular damage and increased renin release. In the lungs, the inflammatory factors not only promote pulmonary hypertension and the onset of congestive symptoms but are also probably shared with the pathophysiology of chronic obstructive pulmonary disease in patients in whom both conditions are present.<a class="elsevierStyleCrossRef" href="#bib0570">54</a>Endothelial participation in the pathophysiology of decompensated HF and its complications has prompted the search for new therapeutic targets (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), most of which attempt to restore the beneficial effects of NO. However, studies whose objective was to demonstrate a positive effect from the administration of antioxidants have had negative or contradictory results.<a class="elsevierStyleCrossRef" href="#bib0540">48</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Pathological remodelingMyocardial structural abnormalities in HF are well known. Cardiac remodeling is the process by which morphological and structural changes are accompanied by functional impairment. Thus, perpetuated conditions of arterial hypertension produce left ventricular hypertrophy, and the acute ischemic lesions that cause necrosis and posterior fibrosis are followed by ventricular wall thinning, which can ultimately lead to dilated cardiomyopathy.<a class="elsevierStyleCrossRefs" href="#bib0345">9,10,12</a>However, this classical concept has been superseded in recent years by basic science research. It is therefore known that “pathological remodeling” goes beyond the macroscopic. This type of remodeling produces abnormalities in the extracellular matrix, in the molecules that regulate it, in the myocytes and its myofibrils, in the proteins that regulate folding and, probably, in the genetics, making it an open field for research and a future therapeutic target for patients with HF.There are two fundamental elements that maintain and regulate ventricular stiffness: the extracellular matrix and cardiomyocytes. The extracellular matrix is basically composed of collagen, especially type I. Several proteolytic enzymes (known as metalloproteinases) and their inhibitors (TIMP) are involved in collagen synthesis and degradation, creating a complex equilibrium between the synthesis and degradation of procollagen and type I collagen in the extracellular matrix.<a class="elsevierStyleCrossRefs" href="#bib0325">5,37,55</a>Studies performed on myocardial biopsies have shown that the increase in activity of metalloproteinases leads to greater degradation of the extracellular matrix, with ventricular remodeling leading to chamber dilation, with the subsequent systolic dysfunction. Moreover, the predominance of the action of proteolytic inhibitors (TIMP) produces lower collagen degradation, with accentuation of fibrosis in patients with HFPEF.<a class="elsevierStyleCrossRefs" href="#bib0485">37,55</a>With regard to the cardiomyocytes, their stiffness has been related to titin, one of the cytoskeleton proteins. Titin has two isoforms: N2B (which is more rigid) and N2BA (which is more distensible). As a result of the degree of phosphorylation and oxidative stress, the expression of one or another isoform predominates, leading to a different cardiac remodeling.<a class="elsevierStyleCrossRef" href="#bib0325">5</a> Research is also being conducted on the influence of folding variations and the binding bridges and phosphorylation of myosin on diastolic function and inotropism.<a class="elsevierStyleCrossRefs" href="#bib0580">56–58</a>A step further in this entire complex network of protein action and expression are chaperones, which seem to have an important role in HF. Chaperones are a class of proteins that participate in the regulation of protein folding and maintain an appropriate equilibrium between the synthesis and degradation of cellular proteins. Various families of chaperones have already been implicated in myocardial disorders. For example, Grp78 (78kDa glucose-regulated protein) intervenes in protein folding and increases its expression in patients with HF. The overexpression of HspB8/Hsp22 (heat shock 22kDa protein 8) leads to concentric hypertrophy, while its cancelation, in contrast, leads to the development of ventricular dilation.<a class="elsevierStyleCrossRef" href="#bib0595">59</a> However, the studies are mainly in vitro, and little is known about these chaperones’ exact correlation with the symptoms.In a number of cardiomyopathies, such as the cardiac phenotype of Fabry disease, chaperones have been administered as experimental therapy, with good results. This leads us to consider their potential usefulness in HF and makes them attractive therapeutic targets for the future.<a class="elsevierStyleCrossRef" href="#bib0600">60</a>ConclusionsThe pathophysiology of acute HF consists of a network of mechanisms that, starting at the molecular level and interacting with each other, configure a hemodynamic and humoral response that attempts to restore proper tissue perfusion. The mechanisms are complex and still unclear. The deepening of our understanding of these mechanisms will surely lead to a better understanding of the clinical phenomena and thus to potential new therapeutic targets.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres599583" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec613972" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres599584" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec613973" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction and concept of acute heart failure" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Hemodynamic overload and adaptation" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Systemic congestion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Neurohormonal system and natriuretic peptides" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Inflammatory damage and oxidative stress" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Pathological remodeling" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-17" "fechaAceptado" => "2015-09-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec613972" "palabras" => array:6 [ 0 => "Acute heart failure" 1 => "Pathophysiology" 2 => "Cardiorenal syndrome" 3 => "Venous congestion" 4 => "Inflammation" 5 => "Remodeling" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec613973" "palabras" => array:6 [ 0 => "Insuficiencia cardiaca aguda" 1 => "Fisiopatología" 2 => "Síndrome cardiorrenal" 3 => "Congestión venosa" 4 => "Inflamación" 5 => "Remodelado" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Our understanding of the pathophysiological mechanisms of heart failure (HF) has changed considerably in recent years, progressing from a merely hemodynamic viewpoint to a concept of systemic and multifactorial involvement in which numerous mechanisms interact and concatenate. The effects of these mechanisms go beyond the heart itself, to other organs of vital importance such as the kidneys, liver and lungs. Despite this, the pathophysiology of acute HF still has aspects that elude our deeper understanding.Hemodynamic overload, venous congestion, neurohormonal systems, natriuretic peptides, inflammation, oxidative stress and its repercussion on cardiac and vascular remodeling are currently considered the main players in acute HF.Starting with the concept of acute HF, this review provides updates on the various mechanisms involved in this disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La comprensión de los mecanismos fisiopatológicos de la insuficiencia cardiaca (IC) ha evolucionado mucho en los últimos años, pasando de una visión meramente hemodinámica a un concepto de afectación sistémica y multifactorial en la que interaccionan y se concatenan múltiples mecanismos, con efectos más allá del propio corazón, en órganos de vital importancia como el riñón, el hígado o el pulmón. A pesar de lo anterior, la fisiopatología de la IC aguda presenta todavía aspectos que escapan a una profunda comprensión.La sobrecarga hemodinámica, la congestión venosa, los sistemas neurohormonales, los péptidos natriuréticos, la inflamación, el estrés oxidativo y su repercusión sobre el remodelado cardiaco y vascular se consideran hoy actores principales en la IC aguda.Partiendo del concepto de IC aguda, en esta revisión se actualizan los distintos mecanismos implicados en la misma." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sánchez-Marteles M, Rubio Gracia J, Giménez López I. Fisiopatología de la insuficiencia cardiaca aguda: un mundo por conocer. Rev Clin Esp. 2016;216:38–46." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1544 "Ancho" => 1649 "Tamanyo" => 160711 ] ] "descripcion" => array:1 [ "en" => "Phenomena involved in the pathophysiology of heart failure." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1469 "Ancho" => 1432 "Tamanyo" => 78511 ] ] "descripcion" => array:1 [ "en" => "Hemodynamic disorders of acute right ventricular dysfunction." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1012 "Ancho" => 1650 "Tamanyo" => 93313 ] ] "descripcion" => array:1 [ "en" => "Congestion and renal dysfunction. Abbreviations: IL-6, interleukins 6; NO, nitric oxide; TNF-α, tumor necrosis factor α." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Lim et al.<a class="elsevierStyleCrossRef" href="#bib0555">51</a>" "tabla" => array:2 [ "leyenda" => "Abbreviations: A-HeFT, African-American Heart Failure Trial; AHU377, sacubitril; cGMP, cyclic guanosine monophosphate; ET-1, endothelin-1; LCZ 696, combination of sacubitril and valsartan; NO, nitric oxide; RXFP, relaxin family peptide; V-HeFT I, vasodilator heart failure trial." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic target \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic agent \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Trials ongoing* \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical status \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Limitations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NO agonists \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Organic nitrates and NO donors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">cGMP intracellular increase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vasodilation, antioxidant, anti-inflammatory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">V-HeFT IIA-HeFT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In use (nitroprusside, isosorbide dinitrate)Combined with hydralazine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tolerance, resistance, formation of peroxynitrite \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phosphodiesterase-5 (PDE-5) inhibition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sildenafil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase in intracellular cGMP levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vasodilation, antioxidant, anti-inflammatory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not in widespread use. For special indications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Failure in multicenter studies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Soluble guanylate cyclase agonists (sGC) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">sGC stimulants (riociguat) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sensitizes sGC to NO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Potent vasodilators, cardioprotectors and renoprotectors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DILATE-1SOCRATES* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">sGC activators (cinaciguat) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Direct activation of sGC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Potent vasodilators, renoprotectors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Excessive hypotension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neprilysin inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AHU377LCZ 696 (combination of AHU377 and valsartan) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases bioavailability of natriuretic peptides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Natriuresis, diuresis, vasodilation, myocardial relaxation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PARADIGM-HFPARAMOUNTPARAGON-HF*(LCZ 696) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Relaxin-2 agonists \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Serelaxin (recombinant human relaxin-2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activation of RXFP receptors of the cardiovascular system and kidneys, NO release, ET-1 reduction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Vasodilation, reduced preload \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RELAX-AHF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Physical exercise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increases NO bioavailability by hemodynamic stressImproves metabolism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HF-ACTION was negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low adherence \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neuregulin-1 (NRG-1) agonists \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NRG-1 human recombinant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Stimulation via NRG-1, includes NO release, negative inotropism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Improves ventricular function and remodeling \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Various ongoing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activation of neoplastic pathways \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab980921.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Strategies for treating endothelial dysfunction." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. 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Symposium. Heart Failure

Pathophysiology of acute heart failure: A world to know

Fisiopatología de la insuficiencia cardiaca aguda: un mundo por conocer

M. Sánchez-Martelesa,b,

Corresponding author

marta.sanchez15@yahoo.es

Corresponding author.

, J. Rubio Graciaa,b, I. Giménez Lópezc,d

a Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

b Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain

c Departamento de Farmacología y Fisiología, Universidad de Zaragoza, Zaragoza, Spain

d Instituto Aragonés de Ciencias de la Salud, Instituto de Investigación Sanitaria de Aragón, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction and concept of acute heart failure</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure &#40;HF&#41; is a clinical syndrome that is common to various diseases and that causes a reduction in cardiac function by mechanisms that are not completely understood&#46; As a result&#44; either the tissues&#8217; metabolic needs cannot be met or they are met at the cost of an increased heart rate and&#47;or an abnormally high diastolic volume&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Approximately 1&#8211;2&#37; of the adult population in developed countries experience HF&#44; a percentage that rises with age and reaches more than 10&#37; of the population aged over 70 years and up to almost 20&#37; of those older than 80 years&#46; The natural progression of this syndrome is the progressive onset of signs and symptoms that cause a decline in the patient&#39;s vital and functional capacity&#44; with hospitalizations for decompensations and&#44; ultimately&#44; death due to refractory HF&#44; pump failure or ventricular arrhythmia&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a> A number of population registries have recorded a 20&#37; readmission rate in the 30 days following discharge and an annual mortality of 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> This makes HF a growing and first-order healthcare and financial problem&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The differences between acute and chronic HF are based on the speed with which symptoms start&#46; Although both terms are widely used in clinical practice&#44; there are no specific definitions on the duration that should be used to separate the two concepts&#46; In 2010&#44; the American Heart Association and the American College of Cardiology defined acute HF as that which develops within 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> As new items in their latest guidelines&#44; distinct acute HF subgroups have been identified&#44; such as those resulting from acute coronary syndrome&#44; hypertensive emergency&#44; sudden right ventricular failure&#44; shock and decompensations in patients with already known chronic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> Along these lines&#44; the European Society of Cardiology differentiates decompensations resulting from chronic HF from those caused by de novo HF&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">From the physiological point of view&#44; HF has classically been divided into two types&#58; systolic and diastolic&#46; This difference refers to whether the main heart anomaly is the left ventricle&#39;s &#40;LV&#41; inability to contract normally and expel sufficient blood &#40;systolic HF&#41; or in the difficulty in ventricular relaxation and filling &#40;diastolic HF&#41;&#46; However&#44; the application of this classification in clinical practice has not been easy&#46; First&#44; there are diagnostic problems&#46; According to the European Society of Cardiology&#44; diagnosing HF as diastolic requires the presence not only of HF signs and symptoms with a LV ejection fraction &#40;LVEF&#41; &#62;50&#37; but also the echocardiographic demonstration or &#40;better yet&#41; the hemodynamics of diastolic dysfunction&#44; which cannot always be obtained&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;5&#44;6</span></a> It has been shown that an LVEF &#60;50&#37; does not always correspond to systolic dysfunction&#46; This occurs particularly in the LVEF range of 40&#8211;50&#37;&#44; which remains a gray area in which the patient&#39;s background &#40;ischemic vs&#46; hypertensive&#41; is assessed in order to assign it to one type of HF or the other&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In order to adopt a more pragmatic approach&#44; one that has already been accepted by both the European and American HF guidelines&#44; the terms HF with reduced or preserved LVEF &#40;HFREF and HFPEF&#44; respectively&#41; have been adopted&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a> the latter term designated to the type of HF initially categorized as diastolic HF&#46; Although HFPEF is occasionally assimilated into diastolic HF&#44; they are not strictly comparable terms&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The various ejection fraction-based HF phenotypes detected in recent population registries have led to in-depth research into their pathophysiology and to the still unresolved debate on whether this involves 1 or 2 separate syndromes&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a>In this article&#44; we review the basic and known issues of acute HF regarding acute chronic HF decompensation&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The mechanisms underlying acute HF are complex and still unclear&#46; The understanding of neurohormonal mechanisms has been added to the merely hemodynamic viewpoint in which HF is regarded as pump failure&#46; Based on this understanding&#44; a number of drugs have been suggested as the cornerstones of treatment&#58; angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Other phenomena &#40;such as congestion&#44; interstitial involvement&#44; extracellular matrix modification&#44; inflammation&#44; remodeling&#44; genetics&#44; molecular biology and multiple organ interaction&#41; are increasingly gaining relevance in the pathophysiology of HF&#44; prompting the consideration of an inclusive vision in which all of these conditions participate to a greater of lesser extent &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">10&#44;11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hemodynamic overload and adaptation</span><p id="par0045" class="elsevierStylePara elsevierViewall">The initial and classical vision of HF was based on the body&#39;s need to maintain an adequate cardiac output that covers the tissue&#39;s metabolic needs&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In conditions of myocardial deficit &#40;loss of contractility&#44; intrinsic problems in the myocardium and valve failure&#41;&#44; there is a decrease in ejection fraction and an increase in end-diastolic volume and end-diastolic pressure in the LV&#44; which causes an increase in atrial contraction in order to exploit the cardiac reserve&#46; Furthermore&#44; the Frank&#8211;Starling mechanism starts within a few moments&#44; along with sympathetic system activation&#44; resulting in an increase in contractility that in turn results in an immediate improvement in the conditions generated by the initial aggression&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;12</span></a> When this condition persists&#44; the adaptive response becomes adverse and leads to changes in the form and function of the LV&#44; a phenomenon known as ventricular remodeling&#46; The remodeling changes the electrical conduction and ventricular function and ultimately leads to the development of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">This hemodynamic explanation is straightforward and useful&#44; but it is tied primarily to ventricular dysfunction and is simplistic&#46; The myocardium and both ventricles interact and should be considered a continuum in which the dysfunction and overloading of one element affects the others&#46; The right ventricle &#40;RV&#41; differs from the left in a number of ways&#46; The RV wall is thinner &#40;8&#8211;11<span class="elsevierStyleHsp" style=""></span>mm vs&#46; 2&#8211;3<span class="elsevierStyleHsp" style=""></span>mm&#41;&#46; Structurally&#44; there is a different proportion of alpha myosin in the myofibrils&#44; and the response to adrenergic stimulus and coronary irrigation is different&#46; This confers a considerable adaptive capacity on the RV&#44; making it the great &#8220;shock absorber&#8221; of volume changes and venous return&#44; which are continuously produced by changes in blood pressure and posture&#44; vascular repletion&#44; respiration and Valsalva maneuvers&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Acute RV overload &#40;e&#46;g&#46;&#44; tamponade&#44; pulmonary thromboembolism&#44; acute valvular heart disease&#41; hinders proper left ventricular filling&#44; which results in reduced cardiac output&#46; This in turn results in hypoxemia and poor RV perfusion&#44; which increases its dysfunction and generates a vicious pathological cycle that can rapidly lead to death &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The regulatory role of RV is significant&#46; In fact&#44; its dysfunction has been revealed in recent years as a key pathophysiological and prognostic factor&#44; especially in patients with HFPEF&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> Despite the difficulty of studying RV disorders&#44; there are already significant data&#44; both populational<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> and from selected patient cohorts&#44; on its prognostic value&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;17</span></a> An example of this is a recent case&#8211;control study of patients with HF and preserved LVEF&#44; which showed how pressure increases&#44; dysfunction and changes in RV dimensions were directly related to mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the patients with HFPEF&#44; histopathological changes in the pulmonary vascular tree &#40;intimal hypertrophy and adventitial fibrosis in the small vessels&#41; and thickening of the alveolar-capillary membrane&#44; along with inflammatory phenomena&#44; provoke long-term pulmonary hypertension and structural changes&#44; with subsequent RV dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Systemic congestion</span><p id="par0075" class="elsevierStylePara elsevierViewall">The presence of signs and symptoms such as dyspnea&#44; orthopnea&#44; edema&#44; jugular venous distention&#44; ascites&#44; hepatomegaly and lung crackles during an episode of acute HF signal the presence of congestion&#46; Congestion reflects an increase in central venous pressure &#40;CVP&#41; and circulating volume&#44; whose most important reservoir&#44; due to its involvement in acute HF&#44; is splanchnic venous circulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">19&#8211;21</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">There are two fundamental theories that explain the genesis of congestion in acute HF&#46; The classical theory explains congestion by sodium and water retention&#44; which results in an accumulation of extracellular liquid&#44; and an increase in weight and effective circulatory volume&#44; with prominent renal dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> The second more recent interpretation explains congestion as the consequence of a sudden displacement of the splanchnic reservoir to the general circulation&#44; due to the increase in sympathetic stimulation from the cardiac decompensation&#46; The sustained stimulation of the sympathetic nervous system&#44; resulting from tissue hypoperfusion&#44; is accompanied by a reduction or depletion of the inhibitory response of the carotid baroreflexes&#46; In this context&#44; a small increase in sympathetic tone at the start of a cardiac decompensation will move a sizeable volume of blood from the splanchnic reservoir to the general circulation&#44; which explains the volume overload and congestive symptoms&#46; According to the second theory&#44; there is no exogenous fluid retention nor is there weight gain preceding the decompensations&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Venous congestion is not only a consequence of HF associated with a poorer prognosis but also an important pathophysiological factor&#44; especially for the genesis of renal damage during HF exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The negative effect of venous congestion on renal function has been known for more than a century&#46; Experiments in 1860<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> showed that partial occlusion of the renal vein causes an immediate reduction in renal blood flow&#44; glomerular filtration and sodium excretion&#44; which are resolved after the vein is decompressed&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Despite those initial studies&#44; the pathophysiological role of venous congestion remained hidden until recently and was interpreted as a mere epiphenomenon of retrograde heart failure secondary to reduced cardiac output&#46; However&#44; recent research has focused attention on venous congestion as a core factor in the incidence of cardiorenal syndrome and acute HF itself&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In one of these studies&#44; Mullens et al&#46; showed that patients with HF with reduced LVEF who developed functional renal failure &#40;FRF&#41; had&#44; after intensive diuretic treatment&#44; a baseline CVP greater than those in whom FRF did not occur&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a> Additionally&#44; FRF was rare among the patients who decreased their CVP below 8<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg&#44; and the relationship between CVP and risk of FRF remained independent of the other patient characteristics &#40;blood pressure&#44; pulmonary capillary wedge pressure&#44; cardiac index and glomerular filtration rate&#41;&#46; The authors concluded that the hemodynamic factor that most predisposes patients to FRF in exacerbated HF is venous congestion&#44; measured by CVP&#44; a phenomenon for which they suggested the term &#8220;congestive renal failure congestive&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a> There are data from extensive epidemiological registries &#40;such as ADHERE&#41; that support this interpretation&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> Fifty percent of the patients in this registry&#44; hospitalized for HF decompensation&#44; had systolic blood pressures &#62;140<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg&#44; while only 2&#37; had readings &#60;90<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> This finding reflects the importance of congestion&#44; pulmonary in this case&#44; at the expense of reduced cardiac output&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Renal blood flow is also determined by abdominal perfusion pressure&#44; which is directly related to blood pressure and inversely related to intraabdominal pressure &#40;IAP&#41;&#46; Normal IAP is approximately 5&#8211;7<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg&#46; Intestinal distension&#44; ascites&#44; urinary retention and obesity can cause an increase in IAP&#46; Pressures greater than 8<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg have been related to an increased incidence of FRF&#46; To all of this we must add that renal perfusion does not depend only on the flow and pressure in the renal artery but also on the so-called transrenal perfusion pressure resulting from the difference between the CVP and blood pressure&#46; Changes in both&#44; which are common in acute HF&#44; will therefore affect renal filtration&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">However&#44; beyond their influence on renal dysfunction&#44; the data indicate that systemic congestion and IAP&#44; per se&#44; play a fundamental but still not completely understood role in the pathophysiology of HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">10&#44;21&#44;28&#44;29</span></a> It also seems that there is a complex network in which proinflammatory&#44; oxidative stress&#44; neurohormonal and hemodynamic phenomena &#40;among others&#41; are interwoven and interact &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">30&#44;31</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">The accurate measurement of systemic congestion is still problematic&#46; It appears that the combination of signs and symptoms of congestion &#40;edema&#44; ascites and jugular venous distention&#41; and the related echocardiographic parameters &#40;LVEF&#44; diameter and collapse of the inferior vena cava and systolic pulmonary artery pressure&#41; are associated with greater mortality and readmissions in these patients&#44; even if FRF does not develop&#46; The measurement and use of these parameters could be of use in the early identification of those patients with HF who are at risk of developing renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In terms of biomarkers for estimating systemic congestion&#44; carbohydrate antigen 125 &#40;CA125&#41; appears to have the most appropriate profile&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a> CA125 is a glycoprotein synthesized by serous epithelial cells&#44; has a complex structure and high molecular weight and is widely used in the follow-up of ovarian cancer&#46; As in ovarian cancer&#44; serum CA125 concentrations can be increased in hepatic cirrhosis&#44; nephrotic syndrome&#44; pelvic inflammatory disease and tuberculosis&#46; HF has been postulated as a useful marker due to its correlation with prognostic and congestion parameters&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> The pathophysiological mechanisms by which CA125 concentrations are increased in acute HF are not known&#46; However&#44; it has been postulated that there are inflammatory factors that trigger its production in serum in response to congestion and interstitial fluid accumulation&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Neurohormonal system and natriuretic peptides</span><p id="par0125" class="elsevierStylePara elsevierViewall">In addition to the changes in pressure and contractility&#44; myocardial stress activates various neurohormonal pathways to counter the vascular congestion and hypoperfusion caused by myocardial dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#44;36</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Activation of the sympathetic system helps increase contractility&#44; heart rate and vasoconstriction through the release norepinephrine and also promotes the release of renin&#46; However&#44; a high and sustained concentration of norepinephrine is associated with a poorer prognosis and increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">12&#44;35</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Another fundamental response system is the renin&#8211;angiotensin&#8211;aldosterone system&#46; This system is activated in response to renal hypoperfusion&#44; producing an increase in renin and&#44; consequently&#44; angiotensin II&#44; with efferent arteriolar vasoconstriction&#44; which increases the filtration fraction and maintains a minimum glomerular filtration rate&#46; There is a simultaneous increase in aldosterone concentrations&#44; which translates into water and sodium retention&#46; This system&#44; although effective in the short term&#44; increases myocardial dysfunction and mortality when prolonged&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Aldosterone has a role beyond water retention&#44; with important actions on metalloproteinases and thus on fibrosis and ventricular remodeling&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">35&#44;37</span></a> A few decades ago&#44; drugs were developed that are today the basis of treatment for HF with reduced LVEF&#58; angiotensin-converting enzyme inhibitors&#44; angiotensin II receptor antagonists and mineralocorticoid receptor blockers whose efficacy has been demonstrated in numerous clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">12&#44;36&#44;38</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Vasopressin and antidiuretic hormone are also secreted in acute HF&#46; The increase in osmolarity resulting from sodium absorption generated by aldosterone directly results in the release of antidiuretic hormone&#46; The antidiuretic hormone is a neurohypophyseal peptide that intervenes in free water absorption&#44; thereby controlling blood volume and pressure&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">12&#44;35&#44;39&#44;40</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Lastly&#44; natriuretic peptides have a fundamental and compensatory role in this complex neurohormonal network&#46; The family of natriuretic peptides includes at least five subtypes&#58; atrial natriuretic peptide &#40;type A&#41;&#44; brain natriuretic peptide &#40;BNP or type B&#41; and types C&#44; D and V&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> The most well known from the pathophysiological point of view are the atrial natriuretic peptide and BNP&#46; Both are released in conditions of stress on the atrial and ventricular wall&#44; respectively&#44; triggered by stimuli such as volume overload and ischemia&#44; in the case of BNP&#46; Their speed of action varies and produces a host of actions on the kidney and vascular and sympathetic systems&#44; which translates into venous and arterial vasodilation&#46; Vasodilation in the afferent renal arteriole and vasoconstriction in the efferent&#44; along with complex interactions in the interstitium and renal tubules&#44; cause an increase in glomerular filtration&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">42&#44;43</span></a> They also act on mesangial cyclic guanosine monophosphate&#44; promoting an increase in filtration surface and act directly on the distal convoluted tubule&#46; The ultimate consequence of this is an effective increase in diuresis and natriuresis&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">44&#44;45</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Recent data suggest that&#44; in addition to the release of the peptide&#44; myocardial stress causes a cascade reaction that increases BNP deglycosylation and furin production&#44; one of the fundamental enzymes for excision of the propeptide in its active form and its aminoterminal fraction&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> thereby promoting faster biological action&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Inflammatory damage and oxidative stress</span><p id="par0160" class="elsevierStylePara elsevierViewall">Hemodynamic disorders &#40;hypoperfusion and congestion&#41; can be considered the main consequence of HF&#44; followed by neurohormonal disorders that result from the attempt to counter the former&#39;s effects&#46; However&#44; the chronicity of HF and the simultaneous involvement of other organs activates inflammation&#44; oxidative stress and endothelial dysfunction&#44; which contribute to the pathophysiology of HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">27&#44;47</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">C-reactive protein was the first inflammatory molecule to be related to HF&#44; whose prognosis worsens in those patients who show high and sustained concentrations of C-reactive protein&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> Other inflammatory molecules have since been implicated&#44; such as tumor necrosis factor &#945; and a number of interleukins &#40;mainly IL-1&#44; IL-6 and IL-18&#41;&#44; which act on the cardiomyocyte&#44; activating mechanisms of apoptosis and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The endothelium plays a central role in the inflammatory response&#44; because its response to congestion includes the production of free radicals &#40;oxidative stress&#41; and the release of proinflammatory factors and vasoactive peptides&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> Recent studies on human models of venous congestion have shown that brief increases &#40;75<span class="elsevierStyleHsp" style=""></span>min&#41; in venous pressure of 30<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>Hg above normal pressure are sufficient to trigger the endothelium and increase the release of inflammatory cytokines &#40;IL-1&#946;&#44; tumor necrosis factor-&#945; and IL-6&#41;&#44; vasoactive peptides &#40;ET-1&#44; ATII&#41;&#44; endothelial adhesion molecules &#40;VCAM-1&#44; ICAM-1&#41; and coagulation factors &#40;vWF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">31&#44;47</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The latent and systemic inflammatory state is accompanied by an increase in oxidative stress&#46; The increased production of reactive oxygen species and the reduction in free radical scavenger systems&#44; such as glutathione peroxidase&#44; produce oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#44;49</span></a> A significant consequence of the sustained inflammatory state is the reduced bioavailability of nitric oxide &#40;NO&#41;&#44; a potent vasodilator&#46; Additionally&#44; the excess of reactive oxygen species and the reduction in NO promote the emergence of a proinflammatory and profibrotic phenotype&#44; which intensifies myocardial necrosis<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">12&#44;35</span></a> and promotes remodeling&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">50&#44;51</span></a> The result is a vicious cycle that perpetuates hemodynamic and neurohormonal disorders&#44; with harmful effects on the heart itself &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41; and the consequent progression of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Moreover&#44; oxidative stress intensifies due to the dysfunction of other organs and some metabolic disorders&#46; Increases in serum uric acid levels boost the enzymatic activity of xanthine-oxidase and intensify the oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> In addition to the reduction in NO&#44; the pro-oxidant state can cause increased lipid oxidation&#46; Tang et al&#46; showed that isoprostanoid concentrations correlate with HF severity and are an independent predictor of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The extension of the inflammation and the activation of the endothelium in various territories would explain not only the myocardial impairment itself but also the involvement of other organs that accompany the HF exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">In the kidneys&#44; the inflammation and oxidative stress generated in the endothelium translates into reduced glomerular filtration&#44; tubular damage and increased renin release&#46; In the lungs&#44; the inflammatory factors not only promote pulmonary hypertension and the onset of congestive symptoms but are also probably shared with the pathophysiology of chronic obstructive pulmonary disease in patients in whom both conditions are present&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Endothelial participation in the pathophysiology of decompensated HF and its complications has prompted the search for new therapeutic targets &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; most of which attempt to restore the beneficial effects of NO&#46; However&#44; studies whose objective was to demonstrate a positive effect from the administration of antioxidants have had negative or contradictory results&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pathological remodeling</span><p id="par0200" class="elsevierStylePara elsevierViewall">Myocardial structural abnormalities in HF are well known&#46; Cardiac remodeling is the process by which morphological and structural changes are accompanied by functional impairment&#46; Thus&#44; perpetuated conditions of arterial hypertension produce left ventricular hypertrophy&#44; and the acute ischemic lesions that cause necrosis and posterior fibrosis are followed by ventricular wall thinning&#44; which can ultimately lead to dilated cardiomyopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;10&#44;12</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">However&#44; this classical concept has been superseded in recent years by basic science research&#46; It is therefore known that &#8220;pathological remodeling&#8221; goes beyond the macroscopic&#46; This type of remodeling produces abnormalities in the extracellular matrix&#44; in the molecules that regulate it&#44; in the myocytes and its myofibrils&#44; in the proteins that regulate folding and&#44; probably&#44; in the genetics&#44; making it an open field for research and a future therapeutic target for patients with HF&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">There are two fundamental elements that maintain and regulate ventricular stiffness&#58; the extracellular matrix and cardiomyocytes&#46; The extracellular matrix is basically composed of collagen&#44; especially type I&#46; Several proteolytic enzymes &#40;known as metalloproteinases&#41; and their inhibitors &#40;TIMP&#41; are involved in collagen synthesis and degradation&#44; creating a complex equilibrium between the synthesis and degradation of procollagen and type I collagen in the extracellular matrix&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#44;37&#44;55</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Studies performed on myocardial biopsies have shown that the increase in activity of metalloproteinases leads to greater degradation of the extracellular matrix&#44; with ventricular remodeling leading to chamber dilation&#44; with the subsequent systolic dysfunction&#46; Moreover&#44; the predominance of the action of proteolytic inhibitors &#40;TIMP&#41; produces lower collagen degradation&#44; with accentuation of fibrosis in patients with HFPEF&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">37&#44;55</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">With regard to the cardiomyocytes&#44; their stiffness has been related to titin&#44; one of the cytoskeleton proteins&#46; Titin has two isoforms&#58; N2B &#40;which is more rigid&#41; and N2BA &#40;which is more distensible&#41;&#46; As a result of the degree of phosphorylation and oxidative stress&#44; the expression of one or another isoform predominates&#44; leading to a different cardiac remodeling&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> Research is also being conducted on the influence of folding variations and the binding bridges and phosphorylation of myosin on diastolic function and inotropism&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">56&#8211;58</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">A step further in this entire complex network of protein action and expression are chaperones&#44; which seem to have an important role in HF&#46; Chaperones are a class of proteins that participate in the regulation of protein folding and maintain an appropriate equilibrium between the synthesis and degradation of cellular proteins&#46; Various families of chaperones have already been implicated in myocardial disorders&#46; For example&#44; Grp78 &#40;78<span class="elsevierStyleHsp" style=""></span>kDa glucose-regulated protein&#41; intervenes in protein folding and increases its expression in patients with HF&#46; The overexpression of HspB8&#47;Hsp22 &#40;heat shock 22<span class="elsevierStyleHsp" style=""></span>kDa protein 8&#41; leads to concentric hypertrophy&#44; while its cancelation&#44; in contrast&#44; leads to the development of ventricular dilation&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> However&#44; the studies are mainly in vitro&#44; and little is known about these chaperones&#8217; exact correlation with the symptoms&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">In a number of cardiomyopathies&#44; such as the cardiac phenotype of Fabry disease&#44; chaperones have been administered as experimental therapy&#44; with good results&#46; This leads us to consider their potential usefulness in HF and makes them attractive therapeutic targets for the future&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0235" class="elsevierStylePara elsevierViewall">The pathophysiology of acute HF consists of a network of mechanisms that&#44; starting at the molecular level and interacting with each other&#44; configure a hemodynamic and humoral response that attempts to restore proper tissue perfusion&#46; The mechanisms are complex and still unclear&#46; The deepening of our understanding of these mechanisms will surely lead to a better understanding of the clinical phenomena and thus to potential new therapeutic targets&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres599583"
          "titulo" => "Abstract"
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          "identificador" => "xpalclavsec613972"
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          "identificador" => "xres599584"
          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction and concept of acute heart failure"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Hemodynamic overload and adaptation"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Systemic congestion"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Neurohormonal system and natriuretic peptides"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Inflammatory damage and oxidative stress"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Pathological remodeling"
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        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Conclusions"
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        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflict of interest"
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        12 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2015-07-17"
    "fechaAceptado" => "2015-09-22"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec613972"
          "palabras" => array:6 [
            0 => "Acute heart failure"
            1 => "Pathophysiology"
            2 => "Cardiorenal syndrome"
            3 => "Venous congestion"
            4 => "Inflammation"
            5 => "Remodeling"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec613973"
          "palabras" => array:6 [
            0 => "Insuficiencia cardiaca aguda"
            1 => "Fisiopatolog&#237;a"
            2 => "S&#237;ndrome cardiorrenal"
            3 => "Congesti&#243;n venosa"
            4 => "Inflamaci&#243;n"
            5 => "Remodelado"
          ]
        ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Our understanding of the pathophysiological mechanisms of heart failure &#40;HF&#41; has changed considerably in recent years&#44; progressing from a merely hemodynamic viewpoint to a concept of systemic and multifactorial involvement in which numerous mechanisms interact and concatenate&#46; The effects of these mechanisms go beyond the heart itself&#44; to other organs of vital importance such as the kidneys&#44; liver and lungs&#46; Despite this&#44; the pathophysiology of acute HF still has aspects that elude our deeper understanding&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Hemodynamic overload&#44; venous congestion&#44; neurohormonal systems&#44; natriuretic peptides&#44; inflammation&#44; oxidative stress and its repercussion on cardiac and vascular remodeling are currently considered the main players in acute HF&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Starting with the concept of acute HF&#44; this review provides updates on the various mechanisms involved in this disease&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La comprensi&#243;n de los mecanismos fisiopatol&#243;gicos de la insuficiencia cardiaca &#40;IC&#41; ha evolucionado mucho en los &#250;ltimos a&#241;os&#44; pasando de una visi&#243;n meramente hemodin&#225;mica a un concepto de afectaci&#243;n sist&#233;mica y multifactorial en la que interaccionan y se concatenan m&#250;ltiples mecanismos&#44; con efectos m&#225;s all&#225; del propio coraz&#243;n&#44; en &#243;rganos de vital importancia como el ri&#241;&#243;n&#44; el h&#237;gado o el pulm&#243;n&#46; A pesar de lo anterior&#44; la fisiopatolog&#237;a de la IC aguda presenta todav&#237;a aspectos que escapan a una profunda comprensi&#243;n&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La sobrecarga hemodin&#225;mica&#44; la congesti&#243;n venosa&#44; los sistemas neurohormonales&#44; los p&#233;ptidos natriur&#233;ticos&#44; la inflamaci&#243;n&#44; el estr&#233;s oxidativo y su repercusi&#243;n sobre el remodelado cardiaco y vascular se consideran hoy actores principales en la IC aguda&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Partiendo del concepto de IC aguda&#44; en esta revisi&#243;n se actualizan los distintos mecanismos implicados en la misma&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; S&#225;nchez-Marteles M&#44; Rubio Gracia J&#44; Gim&#233;nez L&#243;pez I&#46; Fisiopatolog&#237;a de la insuficiencia cardiaca aguda&#58; un mundo por conocer&#46; Rev Clin Esp&#46; 2016&#59;216&#58;38&#8211;46&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Phenomena involved in the pathophysiology of heart failure&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Hemodynamic disorders of acute right ventricular dysfunction&#46;</p>"
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      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Congestion and renal dysfunction&#46; Abbreviations&#58; IL-6&#44; interleukins 6&#59; NO&#44; nitric oxide&#59; TNF-&#945;&#44; tumor necrosis factor &#945;&#46;</p>"
        ]
      ]
      3 => array:8 [
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        "tipo" => "MULTIMEDIATABLA"
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Lim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; A-HeFT&#44; African-American Heart Failure Trial&#59; AHU377&#44; sacubitril&#59; cGMP&#44; cyclic guanosine monophosphate&#59; ET-1&#44; endothelin-1&#59; LCZ 696&#44; combination of sacubitril and valsartan&#59; NO&#44; nitric oxide&#59; RXFP&#44; relaxin family peptide&#59; V-HeFT I&#44; vasodilator heart failure trial&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic agent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Trials ongoing&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Limitations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NO agonists&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Organic nitrates and NO donors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">cGMP intracellular increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vasodilation&#44; antioxidant&#44; anti-inflammatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">V</span>-HeFT I<span class="elsevierStyleSmallCaps">I</span>A-HeFT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In use &#40;nitroprusside&#44; isosorbide dinitrate&#41;Combined with hydralazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tolerance&#44; resistance&#44; formation of peroxynitrite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Phosphodiesterase-5 &#40;PDE-5&#41; inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sildenafil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increase in intracellular cGMP levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vasodilation&#44; antioxidant&#44; anti-inflammatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not in widespread use&#46; For special indications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Failure in multicenter studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Soluble guanylate cyclase agonists &#40;sGC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">sGC stimulants &#40;riociguat&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sensitizes sGC to NO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Potent vasodilators&#44; cardioprotectors and renoprotectors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DILATE-1SOCRATES&#42;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">sGC activators &#40;cinaciguat&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct activation of sGC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Potent vasodilators&#44; renoprotectors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Excessive hypotension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neprilysin inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AHU377LCZ 696 &#40;combination of AHU377 and valsartan&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases bioavailability of natriuretic peptides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Natriuresis&#44; diuresis&#44; vasodilation&#44; myocardial relaxation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PARADIGM-HFPARAMOUNTPARAGON-HF&#42;&#40;LCZ 696&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Relaxin-2 agonists&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Serelaxin &#40;recombinant human relaxin-2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activation of RXFP receptors of the cardiovascular system and kidneys&#44; NO release&#44; ET-1 reduction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vasodilation&#44; reduced preload&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RELAX-AHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Physical exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increases NO bioavailability by hemodynamic stressImproves metabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HF-ACTION was negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low adherence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neuregulin-1 &#40;NRG-1&#41; agonists&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NRG-1 human recombinant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Stimulation via NRG-1&#44; includes NO release&#44; negative inotropism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improves ventricular function and remodeling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Various ongoing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activation of neoplastic pathways&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2015.09.007

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