Prevalence and prognostic meaning of comorbidity in heart failure

Conde-Martel, A.; Hernández-Meneses, M.

doi:10.1016/j.rceng.2015.08.007

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Heart failure" "titulo" => "Prevalence and prognostic meaning of comorbidity in heart failure" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "222" "paginaFinal" => "228" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Conde-Martel, M. Hernández-Meneses" "autores" => array:2 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Conde-Martel" "email" => array:2 [ 0 => "acondemar@telefonica.net" 1 => "alicia.conde@ulpgc.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" => "M." "apellidos" => "Hernández-Meneses" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna. Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Prevalencia y significado pronóstico de la comorbilidad en la insuficiencia cardiaca" ] ] "textoCompleto" => "Heart failure (HF) is a first-order healthcare problem. The condition is associated with considerable morbidity and mortality and is the leading cause of hospitalizations for those older than 65 years in the western world.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In the context of this highly prevalent syndrome, which mainly affects elderly patients, the presence of associated comorbidities has considerable relevance. On one hand, the comorbidities have a high incidence rate and can be the cause or consequence of HF or merely a coincidence. Moreover, comorbidities can hinder the diagnosis of HF by masking or overlapping with some of its symptoms. Comorbidities can also hinder the treatment of these patients<a class="elsevierStyleCrossRef" href="#bib0010">2</a> and have a significant repercussion on the prognosis. Most comorbidities associated with HF lead to a poorer evolution, with more hospitalizations, resource consumption, poorer quality of life and increased mortality.<a class="elsevierStyleCrossRefs" href="#bib0010">2–4</a>Patients with HF typically present several associated comorbidities, the absence of which is unusual. This was made clear in a broad study performed on 122,630 patients older than 65 years with HF. Fifty-five percent of the patients had 4 or more comorbidities, 40% had 5 or more and only 4% had none.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In the last 2 decades, the prevalence of these comorbidities has increased, with the percentage of patients with 5 or more comorbidities increasing from 40% at the end of the 1980s to almost 60% by the end of the 2000.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> This increase coincided with the increase in age of patients with HF; i.e., there has been a change in phenotype toward patients with HF at a more advanced age, with more comorbidities and multiple medications.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Another important issue is that the comorbidities are especially common in patients with HF who have admitted to internal medicine departments. These are elderly patients, predominantly women, with an increased prevalence of hypertension, diabetes, obesity, anemia, chronic obstructive pulmonary disease (COPD) and renal failure. In contrast, more men, younger individuals and those with more ischemic and valvular heart disease are admitted to cardiology departments, as verified in an analysis of more than 27,000 hospital discharges for HF performed in Spain.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>This article reviews the prevalence and prognostic impact of the main comorbidities associated with HF.Prevalence of comorbidities in heart failure registriesWe have data on the prevalence of various comorbidities in the major registries<a class="elsevierStyleCrossRefs" href="#bib0040">8–18</a> that show a more realistic image of clinical practice than the data from clinical trials, in which the presence of comorbidities is considered an exclusion criterion. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> lists the prevalence of the various comorbidities in the large American,<a class="elsevierStyleCrossRefs" href="#bib0050">10,15,18</a> Asian<a class="elsevierStyleCrossRefs" href="#bib0045">9,14</a> and European<a class="elsevierStyleCrossRefs" href="#bib0060">12,16,17</a> registries, including the RICA registry of the Spanish Society of Internal Medicine.<a class="elsevierStyleCrossRefs" href="#bib0065">13,19</a> In addition to the comorbidities typically recorded in the registries and clinical trials (arterial hypertension [AHT], diabetes, chronic kidney disease, anemia, COPD, atrial fibrillation [AF], ischemic heart disease), we should highlight others that are usually underdiagnosed but are important due to their prevalence and repercussion on the prognosis of HF,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> such as depressive syndrome, sleep apnea, cognitive impairment, liver disease, malnutrition, osteoarticular disease and thyroid dysfunction.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>We can deduce that the high prevalence of comorbidity in patients with HF is due to their advanced age, given that the majority of individuals aged 65 years or older have some comorbidity; by the age of 85 years, more than 90% have some comorbidity.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> However, it has been reported that patients with HF have more comorbidity than similarly aged controls.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> This phenomenon is due to several causes. On one hand, comorbidities act as a cause of HF; on the other, they can be a consequence of HF or even coincide; however, many of them contribute to the progression and perpetuation of HF.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Comorbidities as a cause of heart failureHF is a syndrome with multiple causes. Some comorbidities constitute risk factors for developing HF.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In fact, patients with AHT, diabetes, obesity or atherosclerosis are included in stage A of the HF classification of the American Heart Association (AHA).<a class="elsevierStyleCrossRef" href="#bib0110">22</a> These risk factors can behave as etiologic agents; for example, AHT in HF with preserved left ventricular ejection fraction (HFPEF) or arteriosclerosis, through ischemia, in HF with reduced left ventricular ejection fraction (HFREF).These risk factors for the onset of HF are also risk factors for developing chronic kidney disease, whose main causes are diabetes and AHT. Moreover, renal failure can cause heart failure; the so-called cardiorenal syndromes types 3 and 4.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Similarly, anemia associated with kidney disease can trigger or promote the development of HF.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>Sleep apnea (through hypoxia), sympathetic activation, pulmonary and systemic arterial hypertension and arrhythmias contribute to the development of HF.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Moreover, smoking, which is a risk factor for HF, can promote the development of COPD, a disease that also increases the risk of HF.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> These diseases (COPD, diabetes and obesity) cause a systemic inflammatory state, which intervenes in the genesis of HFPEF. A review by Paulus and Tschöpe<a class="elsevierStyleCrossRef" href="#bib0135">27</a> proposed a systemic proinflammatory state generated or induced by comorbidities as a cause of the structural and functional myocardial disorders in patients with HFPEF.Comorbidities as a consequence of heart failureComorbidities can also be the consequence of HF, through the congestion and hypoperfusion that HF causes. In fact, HF can cause renal failure (cardiorenal syndromes types 1 and 2)<a class="elsevierStyleCrossRef" href="#bib0115">23</a> and contributes to the presence of anemia by a dilutional mechanism<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and to hepatic dysfunction. Numerous comorbidities also contribute to the progression of HF, thereby establishing a bidirectional relationship that perpetuates the disease.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3,25,28</a>Finally, some comorbidities can also act as triggers of HF; for example, anemia, atrial fibrillation with rapid ventricular response, hyperthyroidism and infectious processes, mainly of respiratory origin.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Comorbidity and prognosisNumerous comorbidities, considered individually, have been associated with a poorer prognosis for HF.<a class="elsevierStyleCrossRefs" href="#bib0010">2,21,29</a>Renal failure is one of the most relevant comorbidities due to its high prevalence,<a class="elsevierStyleCrossRefs" href="#bib0150">30,31</a> for being a cause and effect of HF,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> hindering its treatment<a class="elsevierStyleCrossRef" href="#bib0150">30</a> and for being an independent predictor of mortality, as has been demonstrated by several studies<a class="elsevierStyleCrossRefs" href="#bib0015">3,31</a> and meta-analyses.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> Renal function impairment has been reported in up to 63% of patients with HF,<a class="elsevierStyleCrossRef" href="#bib0160">32</a> and the prevalence of chronic kidney disease in various HF registries varies from 20%<a class="elsevierStyleCrossRefs" href="#bib0045">9,18</a> to 50%<a class="elsevierStyleCrossRef" href="#bib0075">15</a> or 59%,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> depending on the diagnostic criteria employed.Regarding its prognostic value, a recent meta-analysis that included 57 studies on chronic kidney disease and 28 studies on acute renal function impairment showed that both conditions are associated with increased mortality, both in acute HF and in chronic HF, either HFPEF or HFREF.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>In Spain, the RICA registry has shown a very high prevalence of renal failure (59.5%)<a class="elsevierStyleCrossRef" href="#bib0170">34</a> in patients with HF, both overall<a class="elsevierStyleCrossRef" href="#bib0035">7</a> and specifically in HFPEF,<a class="elsevierStyleCrossRef" href="#bib0175">35</a> and its association with a poorer prognosis, with lower survival as the glomerular filtration rate decreases.Anemia is another of the most common comorbidities. In a meta-analysis of 34 studies that included 153,180 patients with HF, 37.2% of the patients had anemia.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Nevertheless, the prevalence of anemia among various registries varies from 15%<a class="elsevierStyleCrossRef" href="#bib0080">16</a> and 53%,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> mainly due to the varying diagnostic criteria employed. The frequency of anemia increases with the time of HF progression, the NYHA functional class and the degree of renal function impairment.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> Anemia also constitutes a trigger for HF decompensation and is associated with a poorer quality of life and prognosis. There is certain controversy as to the latter point. A number of studies have shown that anemia acts as a factor for poor prognosis (associated with more readmissions and all-cause mortality), regardless of the ejection fraction.<a class="elsevierStyleCrossRefs" href="#bib0180">36–38</a> However, other authors have suggested that anemia is a mere marker of severity, associated with other factors of poor prognosis such as a poorer NYHA functional class and chronic renal failure.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> In fact, it has been reported that anemia loses its independent prognostic value in patients with advanced chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The GESAIC study,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> performed in Spain, observed a prevalence of anemia of 52.7% in patients hospitalized for HF and greater mortality in this patient group, although statistical significance was not reached when considering all-cause mortality. The authors attributed this result to the short follow-up time (1 year) and to the inclusion of patients with initial HF, although the results could also have been affected by the small sample size (211 patients). In this study, however, the patients with anemia and refractory HF did have greater mortality.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>Iron deficiency is very common in patients with HF, even in the absence of anemia. Various studies have shown an improved capacity for exercise and quality of life with iron deficiency correction.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>Diabetes is another very common comorbidity, with a prevalence of 40%,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> which is very similar in all the large American registries (ADHERE,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> OPTIMIZE-HF<a class="elsevierStyleCrossRef" href="#bib0090">18</a> and GWTG-HF<a class="elsevierStyleCrossRef" href="#bib0075">15</a>). In the RICA registry,<a class="elsevierStyleCrossRef" href="#bib0210">42</a> the prevalence of diabetes is 45%.The presence of diabetes in patients with HF worsens the prognosis. Increased mortality,<a class="elsevierStyleCrossRef" href="#bib0215">43</a> longer hospital stays and more readmissions have been observed.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> The DIAMOND study showed lower long-term survival after hospital discharge for patients with diabetes and HF, especially in women.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> Similar results were obtained in a subanalysis of the EVEREST study, with greater cardiovascular mortality and more readmissions for patients with diabetes than for their nondiabetic counterparts.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> The RICA registry confirmed that diabetes is an independent predictor of readmission and all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>COPD is present in 10%<a class="elsevierStyleCrossRef" href="#bib0070">14</a> to 31%<a class="elsevierStyleCrossRef" href="#bib0050">10</a> of patients with HF. Results of observational studies<a class="elsevierStyleCrossRef" href="#bib0235">47</a> and subanalyses of clinical trials<a class="elsevierStyleCrossRef" href="#bib0240">48</a> have shown that the presence of COPD in patients with HF is associated with a poorer prognosis, increased risk of death and hospitalization.The VAlHeft<a class="elsevierStyleCrossRef" href="#bib0240">48</a> study observed an increase in noncardiovascular mortality and hospitalization for patients with HF and COPD compared with patients without COPD. In an observational study with a 5-year follow-up, Rusinaru et al.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> found that the presence of COPD in patients with HF behaves as an independent prognostic factor for mortality at 5 years.Lung function assessed through spirometry has also been related to the prognosis of patients with HF.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> It has therefore been observed that forced expiratory volume in the first second (FEV1) constitutes an independent predictor of all-cause mortality in these patients.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>Moreover, HF also worsens the prognosis of patients with COPD. In the ESMI study,<a class="elsevierStyleCrossRef" href="#bib0250">50</a> which analyzed the comorbidities and short-term prognosis of patients hospitalized for COPD exacerbation, HF was the most common comorbidity and was associated with greater mortality at 90 days.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Respiratory sleep disorders (sleep apnea) have been reported in 50% to 75%<a class="elsevierStyleCrossRef" href="#bib0020">4</a> of patients with HF, although the disorders are often underdiagnosed.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> The presence of these disorders is also associated with a poorer prognosis; specifically, lower survival.<a class="elsevierStyleCrossRefs" href="#bib0255">51–54</a> This lower survival has been reported in obstructive apnea<a class="elsevierStyleCrossRef" href="#bib0270">54</a> and regardless of the type of apnea.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Additionally, several studies have shown longer survival of patients with sleep apnea treated with nocturnal ventilation.<a class="elsevierStyleCrossRefs" href="#bib0255">51–54</a>The prevalence of depression is 2–3 times higher in patients with HF than in the general population<a class="elsevierStyleCrossRef" href="#bib0275">55</a> and varies between 9% and 60%, with an average rate of 21.5% in a meta-analysis of 27 studies.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Depression is often underdiagnosed and undertreated.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> Depression also worsens the prognosis when moderate or severe, and it is associated with greater mortality, more readmissions and greater consumption of healthcare resources.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> Depression also worsens quality of life, which can be improved if the depressive disorder is treated.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> A meta-analysis of 8 cohort studies showed a 2-fold risk of death for patients with HF and with associated depressive symptoms or disorder (RR, 2.1; 95% CI 1.7–2.6).<a class="elsevierStyleCrossRef" href="#bib0280">56</a>Cognitive impairment is more common in patients with HF than in the general populationl<a class="elsevierStyleCrossRef" href="#bib0290">58</a> and often remains underdiagnosed. A prospective study of hospitalized patients older than 65 years, which used the Mini Mental test for screening, detected cognitive impairment in almost half of the patients (46.8%), which had only been previously diagnosed in 22.7% of the patients.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> The presence of cognitive impairment was also associated with a poorer prognosis, a greater risk of readmission and death at 6 months.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Lastly, cognitive impairment hinders self-care and therapeutic compliance.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>Malnutrition is another underdiagnosed condition, with a high prevalence in HF (25–60%),<a class="elsevierStyleCrossRef" href="#bib0305">61</a> and it is associated with greater mortality.<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a> Malnutrition can be present in patients with HF and normal weight and even with excess weight. Gastelurrutia et al.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> found that 53% and 22% of patients with HF and normal weight and excess weight, respectively, were malnourished. Therefore, body mass index is not useful for assessing the nutritional state.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> In fact, a number of authors have postulated that one explanation for the paradox of obesity in patients with HF (i.e., the greater survival of patients with obesity) is partly explained by the lower proportion of malnutrition among these patients.<a class="elsevierStyleCrossRef" href="#bib0320">64</a>Strictly speaking, AF is the only cardiac comorbidity that will be mentioned. AF often coexists with HF, as either the cause or consequence of AF. AF can also act as a trigger, with one negatively affecting the other.<a class="elsevierStyleCrossRef" href="#bib0325">65</a> The prevalence of AF varies between 30% and 40% in the various HF registries,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> increasing with age and HF severity.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> AF increases the risk of stroke and the number of hospitalizations and is associated with a poorer quality of life. Although there is no unanimous agreement, numerous studies have associated AF with lower survival.<a class="elsevierStyleCrossRefs" href="#bib0335">67,68</a>Patients with HF are usually elderly and present geriatric syndromes such as functional impairment, sarcopenia, reduced muscle strength, slower gait and frailty, which various studies have shown to be independent predictors of readmission and mortality.<a class="elsevierStyleCrossRefs" href="#bib0345">69,70</a>The RICA registry analyzed the prognostic value of the baseline functional status, as evaluated using the Barthel index, and found a high prevalence of functional impairment, with severe dependence for basic activities of daily life in 55.9% of the patients.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> The Barthel index prior to hospitalization was shown to be an independent predictor of short-term mortality.<a class="elsevierStyleCrossRef" href="#bib0355">71</a>Associated comorbidities and prognosisAlthough the individual presence of the various comorbidities is associated with a poor prognosis, the coexistence of several of them, as one would expect, determines an even poorer prognosis. A direct relationship has been observed between the number of comorbidities and lower long-term survival, both in outpatients<a class="elsevierStyleCrossRef" href="#bib0105">21</a> and hospitalized patients.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> A direct relationship has also been confirmed between the number of comorbidities and the risk of hospitalization,<a class="elsevierStyleCrossRefs" href="#bib0025">5,73</a> which entails poorer evolution, increased mortality, greater consumption of resources and higher healthcare costs.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>One of the most widely used instruments for assessing overall comorbidity is the Charlson comorbidity index. Its prognostic value has been analyzed in Spain in the SEMI-IC study,<a class="elsevierStyleCrossRef" href="#bib0370">74</a> which included 2127 patients from 51 hospitals. The patients with the highest scores on the Charlson index (≥3 points) had significantly more prior hospitalizations, longer hospital stays and greater mortality.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> The RICA registry has also confirmed the prognostic value of the Charlson index as an independent predictor of mortality or readmission at 1 year.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>The association of comorbidities in profiles or clusters has recently been reported, which helps identify those patients with HF who have a greater risk of death, longer stays and increased hospitalization costs.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> Four profiles have been differentiated: (1) the “common” profile, which has the lowest comorbidity and is related to a lower prevalence of cerebrovascular disease, myocardial infarction, peripheral vascular disorders, depression, kidney disease, AHT and obesity when compared with the other profiles; (2) the “lifestyle” profile, which has a high rate of AHT, uncomplicated diabetes, chronic lung disorders and obesity; (3) the “renal” profile, with high rates of kidney disease, diabetes with complications and electrolyte imbalances; and (4) the “neurovascular” profile, with a high prevalence of cerebrovascular disease, myocardial infarction and peripheral vascular disease. Compared with the common profile, the 3 other profiles are associated with longer hospital stays and higher hospitalization costs. Additionally, the renal and neurovascular profiles are associated with greater mortality.<a class="elsevierStyleCrossRef" href="#bib0375">75</a>For patients with HF, comorbidities are frequently the cause of hospital readmission. In fact, a number of series have observed that only a third or fewer of readmissions are due to HF per se.<a class="elsevierStyleCrossRef" href="#bib0380">76</a> This occurs more frequently in patients with HFPEF,<a class="elsevierStyleCrossRef" href="#bib0365">73</a> in whom mortality is often linked to noncardiovascular diseases, such as malignancies, kidney disease and infections.<a class="elsevierStyleCrossRef" href="#bib0385">77</a>Given the importance of comorbidities in the morbidity and mortality of patients with HF, our attention has recently been focused on the importance of providing overall care for patients with HF instead of restrictive care (i.e., focusing entirely on the heart disease).<a class="elsevierStyleCrossRefs" href="#bib0360">72,78</a>In short, the HF profile in general and especially the type treated in internal medicine departments is that of an elderly patient, with multiple comorbidities that impede their diagnosis and treatment, complicating the evolution, worsening the quality of life and resulting in a poorer prognosis (more hospitalizations, greater consumption of resources and higher mortality).Given that the comorbidities frequently go unnoticed, our approach should consist of an active search for them, to identify them and treat them correctly, as this can improve the evolution and quality of life of patients with HF. It is therefore essential that we approach HF from an overall perspective that is not focused exclusively on the heart disease itself.Conflict of interestsThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Prevalence of comorbidities in heart failure registries" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Comorbidities as a cause of heart failure" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Comorbidities as a consequence of heart failure" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Comorbidity and prognosis" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Associated comorbidities and prognosis" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interests" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-28" "fechaAceptado" => "2015-08-31" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Conde-Martel A, Hernández-Meneses M. Prevalencia y significado pronóstico de la comorbilidad en la insuficiencia cardiaca. Rev Clin Esp. 2016;216:222–228." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "COPD, chronic obstructive pulmonary disease." "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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">ADHERE<a class="elsevierStyleCrossRef" href="#bib0050">10</a> (US) \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">OPTIMIZE-HF<a class="elsevierStyleCrossRef" href="#bib0090">18</a> (US) \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">GWTG-HF<a class="elsevierStyleCrossRef" href="#bib0075">15</a> (US) \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">EHFSII<a class="elsevierStyleCrossRef" href="#bib0080">16</a> (Europe) \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">ADHERE Asia-Pacific<a class="elsevierStyleCrossRef" href="#bib0045">9</a> \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">OFICA<a class="elsevierStyleCrossRef" href="#bib0085">17</a> (France) \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">IN-HF Outcome<a class="elsevierStyleCrossRef" href="#bib0060">12</a> (Italy) \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">ATTEND<a class="elsevierStyleCrossRef" href="#bib0070">14</a> (Japan) \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">RICA<a class="elsevierStyleCrossRefs" href="#bib0065">13,19</a> (Spain) \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">Patients, n \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">105,388 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48,612 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">110,621 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3580 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10,171 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1658 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1855 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4842 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2051 \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">Age (years±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74(62–83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70±13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79(70–86) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">72±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78±7 \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">Women (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \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">Arterial hypertension (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \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">Diabetes mellitus (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44 \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">Chronic kidney disease (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59 \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">Anemia (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45 \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">COPD (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \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">Atrial fibrillation (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \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">Coronary artery disease (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1037753.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Plasma creatinine >2mg/dL or dialysis." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Estimated glomerular filtration rate<30mL/min/1.73m2." ] ] ] "descripcion" => array:1 [ "en" => "Prevalence of comorbidities in heart failure registries." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:78 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical epidemiology of heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. 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Most comorbidities associated with HF lead to a poorer evolution&#44; with more hospitalizations&#44; resource consumption&#44; poorer quality of life and increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Patients with HF typically present several associated comorbidities&#44; the absence of which is unusual&#46; This was made clear in a broad study performed on 122&#44;630 patients older than 65 years with HF&#46; Fifty-five percent of the patients had 4 or more comorbidities&#44; 40&#37; had 5 or more and only 4&#37; had none&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In the last 2 decades&#44; the prevalence of these comorbidities has increased&#44; with the percentage of patients with 5 or more comorbidities increasing from 40&#37; at the end of the 1980s to almost 60&#37; by the end of the 2000&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This increase coincided with the increase in age of patients with HF&#59; i&#46;e&#46;&#44; there has been a change in phenotype toward patients with HF at a more advanced age&#44; with more comorbidities and multiple medications&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Another important issue is that the comorbidities are especially common in patients with HF who have admitted to internal medicine departments&#46; These are elderly patients&#44; predominantly women&#44; with an increased prevalence of hypertension&#44; diabetes&#44; obesity&#44; anemia&#44; chronic obstructive pulmonary disease &#40;COPD&#41; and renal failure&#46; In contrast&#44; more men&#44; younger individuals and those with more ischemic and valvular heart disease are admitted to cardiology departments&#44; as verified in an analysis of more than 27&#44;000 hospital discharges for HF performed in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">This article reviews the prevalence and prognostic impact of the main comorbidities associated with HF&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Prevalence of comorbidities in heart failure registries</span><p id="par0025" class="elsevierStylePara elsevierViewall">We have data on the prevalence of various comorbidities in the major registries<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;18</span></a> that show a more realistic image of clinical practice than the data from clinical trials&#44; in which the presence of comorbidities is considered an exclusion criterion&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> lists the prevalence of the various comorbidities in the large American&#44;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;15&#44;18</span></a> Asian<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;14</span></a> and European<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;16&#44;17</span></a> registries&#44; including the RICA registry of the Spanish Society of Internal Medicine&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;19</span></a> In addition to the comorbidities typically recorded in the registries and clinical trials &#40;arterial hypertension &#91;AHT&#93;&#44; diabetes&#44; chronic kidney disease&#44; anemia&#44; COPD&#44; atrial fibrillation &#91;AF&#93;&#44; ischemic heart disease&#41;&#44; we should highlight others that are usually underdiagnosed but are important due to their prevalence and repercussion on the prognosis of HF&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> such as depressive syndrome&#44; sleep apnea&#44; cognitive impairment&#44; liver disease&#44; malnutrition&#44; osteoarticular disease and thyroid dysfunction&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">We can deduce that the high prevalence of comorbidity in patients with HF is due to their advanced age&#44; given that the majority of individuals aged 65 years or older have some comorbidity&#59; by the age of 85 years&#44; more than 90&#37; have some comorbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> However&#44; it has been reported that patients with HF have more comorbidity than similarly aged controls&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> This phenomenon is due to several causes&#46; 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for example&#44; AHT in HF with preserved left ventricular ejection fraction &#40;HFPEF&#41; or arteriosclerosis&#44; through ischemia&#44; in HF with reduced left ventricular ejection fraction &#40;HFREF&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">These risk factors for the onset of HF are also risk factors for developing chronic kidney disease&#44; whose main causes are diabetes and AHT&#46; Moreover&#44; renal failure can cause heart failure&#59; the so-called cardiorenal syndromes types 3 and 4&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Similarly&#44; anemia associated with kidney disease can trigger or promote the development of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Sleep apnea &#40;through hypoxia&#41;&#44; sympathetic activation&#44; pulmonary and systemic arterial hypertension and arrhythmias contribute to the development of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Moreover&#44; smoking&#44; which is a risk factor for HF&#44; can promote the development of COPD&#44; a disease that also increases the risk of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> These diseases &#40;COPD&#44; diabetes and obesity&#41; cause a systemic inflammatory state&#44; which intervenes in the genesis of HFPEF&#46; A review by Paulus and Tsch&#246;pe<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> proposed a systemic proinflammatory state generated or induced by comorbidities as a cause of the structural and functional myocardial disorders in patients with HFPEF&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Comorbidities as a consequence of heart failure</span><p id="par0050" class="elsevierStylePara elsevierViewall">Comorbidities can also be the consequence of HF&#44; through the congestion and hypoperfusion that HF causes&#46; In fact&#44; HF can cause renal failure &#40;cardiorenal syndromes types 1 and 2&#41;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and contributes to the presence of anemia by a dilutional mechanism<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and to hepatic dysfunction&#46; Numerous comorbidities also contribute to the progression of HF&#44; thereby establishing a bidirectional relationship that perpetuates the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;25&#44;28</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Finally&#44; some comorbidities can also act as triggers of HF&#59; for example&#44; anemia&#44; atrial fibrillation with rapid ventricular response&#44; hyperthyroidism and infectious processes&#44; mainly of respiratory origin&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Comorbidity and prognosis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Numerous comorbidities&#44; considered individually&#44; have been associated with a poorer prognosis for HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;21&#44;29</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Renal failure is one of the most relevant comorbidities due to its high prevalence&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> for being a cause and effect of HF&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> hindering its treatment<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> and for being an independent predictor of mortality&#44; as has been demonstrated by several studies<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;31</span></a> and meta-analyses&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Renal function impairment has been reported in up to 63&#37; of patients with HF&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and the prevalence of chronic kidney disease in various HF registries varies from 20&#37;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;18</span></a> to 50&#37;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> or 59&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> depending on the diagnostic criteria employed&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Regarding its prognostic value&#44; a recent meta-analysis that included 57 studies on chronic kidney disease and 28 studies on acute renal function impairment showed that both conditions are associated with increased mortality&#44; both in acute HF and in chronic HF&#44; either HFPEF or HFREF&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In Spain&#44; the RICA registry has shown a very high prevalence of renal failure &#40;59&#46;5&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> in patients with HF&#44; both overall<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and specifically in HFPEF&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and its association with a poorer prognosis&#44; with lower survival as the glomerular filtration rate decreases&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Anemia is another of the most common comorbidities&#46; In a meta-analysis of 34 studies that included 153&#44;180 patients with HF&#44; 37&#46;2&#37; of the patients had anemia&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Nevertheless&#44; the prevalence of anemia among various registries varies from 15&#37;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and 53&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> mainly due to the varying diagnostic criteria employed&#46; The frequency of anemia increases with the time of HF progression&#44; the NYHA functional class and the degree of renal function impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Anemia also constitutes a trigger for HF decompensation and is associated with a poorer quality of life and prognosis&#46; There is certain controversy as to the latter point&#46; A number of studies have shown that anemia acts as a factor for poor prognosis &#40;associated with more readmissions and all-cause mortality&#41;&#44; regardless of the ejection fraction&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;38</span></a> However&#44; other authors have suggested that anemia is a mere marker of severity&#44; associated with other factors of poor prognosis such as a poorer NYHA functional class and chronic renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In fact&#44; it has been reported that anemia loses its independent prognostic value in patients with advanced chronic kidney disease&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The GESAIC study&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> performed in Spain&#44; observed a prevalence of anemia of 52&#46;7&#37; in patients hospitalized for HF and greater mortality in this patient group&#44; although statistical significance was not reached when considering all-cause mortality&#46; The authors attributed this result to the short follow-up time &#40;1 year&#41; and to the inclusion of patients with initial HF&#44; although the results could also have been affected by the small sample size &#40;211 patients&#41;&#46; In this study&#44; however&#44; the patients with anemia and refractory HF did have greater mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Iron deficiency is very common in patients with HF&#44; even in the absence of anemia&#46; Various studies have shown an improved capacity for exercise and quality of life with iron deficiency correction&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Diabetes is another very common comorbidity&#44; with a prevalence of 40&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> which is very similar in all the large American registries &#40;ADHERE&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> OPTIMIZE-HF<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and GWTG-HF<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#41;&#46; In the RICA registry&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> the prevalence of diabetes is 45&#37;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The presence of diabetes in patients with HF worsens the prognosis&#46; Increased mortality&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> longer hospital stays and more readmissions have been observed&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> The DIAMOND study showed lower long-term survival after hospital discharge for patients with diabetes and HF&#44; especially in women&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Similar results were obtained in a subanalysis of the EVEREST study&#44; with greater cardiovascular mortality and more readmissions for patients with diabetes than for their nondiabetic counterparts&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> The RICA registry confirmed that diabetes is an independent predictor of readmission and all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">COPD is present in 10&#37;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> to 31&#37;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> of patients with HF&#46; Results of observational studies<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> and subanalyses of clinical trials<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> have shown that the presence of COPD in patients with HF is associated with a poorer prognosis&#44; increased risk of death and hospitalization&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The VAlHeft<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> study observed an increase in noncardiovascular mortality and hospitalization for patients with HF and COPD compared with patients without COPD&#46; In an observational study with a 5-year follow-up&#44; Rusinaru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> found that the presence of COPD in patients with HF behaves as an independent prognostic factor for mortality at 5 years&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Lung function assessed through spirometry has also been related to the prognosis of patients with HF&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> It has therefore been observed that forced expiratory volume in the first second &#40;FEV1&#41; constitutes an independent predictor of all-cause mortality in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Moreover&#44; HF also worsens the prognosis of patients with COPD&#46; In the ESMI study&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> which analyzed the comorbidities and short-term prognosis of patients hospitalized for COPD exacerbation&#44; HF was the most common comorbidity and was associated with greater mortality at 90 days&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Respiratory sleep disorders &#40;sleep apnea&#41;</span> have been reported in 50&#37; to 75&#37;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> of patients with HF&#44; although the disorders are often underdiagnosed&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> The presence of these disorders is also associated with a poorer prognosis&#59; specifically&#44; lower survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#8211;54</span></a> This lower survival has been reported in obstructive apnea<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and regardless of the type of apnea&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Additionally&#44; several studies have shown longer survival of patients with sleep apnea treated with nocturnal ventilation&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#8211;54</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The prevalence of <span class="elsevierStyleItalic">depression</span> is 2&#8211;3 times higher in patients with HF than in the general population<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> and varies between 9&#37; and 60&#37;&#44; with an average rate of 21&#46;5&#37; in a meta-analysis of 27 studies&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Depression is often underdiagnosed and undertreated&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Depression also worsens the prognosis when moderate or severe&#44; and it is associated with greater mortality&#44; more readmissions and greater consumption of healthcare resources&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Depression also worsens quality of life&#44; which can be improved if the depressive disorder is treated&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> A meta-analysis of 8 cohort studies showed a 2-fold risk of death for patients with HF and with associated depressive symptoms or disorder &#40;RR&#44; 2&#46;1&#59; 95&#37; CI 1&#46;7&#8211;2&#46;6&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cognitive impairment</span> is more common in patients with HF than in the general populationl<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> and often remains underdiagnosed&#46; A prospective study of hospitalized patients older than 65 years&#44; which used the <span class="elsevierStyleItalic">Mini Mental</span> test for screening&#44; detected cognitive impairment in almost half of the patients &#40;46&#46;8&#37;&#41;&#44; which had only been previously diagnosed in 22&#46;7&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> The presence of cognitive impairment was also associated with a poorer prognosis&#44; a greater risk of readmission and death at 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Lastly&#44; cognitive impairment hinders self-care and therapeutic compliance&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Malnutrition</span> is another underdiagnosed condition&#44; with a high prevalence in HF &#40;25&#8211;60&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> and it is associated with greater mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> Malnutrition can be present in patients with HF and normal weight and even with excess weight&#46; Gastelurrutia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> found that 53&#37; and 22&#37; of patients with HF and normal weight and excess weight&#44; respectively&#44; were malnourished&#46; Therefore&#44; body mass index is not useful for assessing the nutritional state&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> In fact&#44; a number of authors have postulated that one explanation for the paradox of obesity in patients with HF &#40;i&#46;e&#46;&#44; the greater survival of patients with obesity&#41; is partly explained by the lower proportion of malnutrition among these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Strictly speaking&#44; AF is the only cardiac comorbidity that will be mentioned&#46; AF often coexists with HF&#44; as either the cause or consequence of AF&#46; AF can also act as a trigger&#44; with one negatively affecting the other&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> The prevalence of AF varies between 30&#37; and 40&#37; in the various HF registries&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> increasing with age and HF severity&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> AF increases the risk of stroke and the number of hospitalizations and is associated with a poorer quality of life&#46; Although there is no unanimous agreement&#44; numerous studies have associated AF with lower survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">67&#44;68</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Patients with HF are usually elderly and present geriatric syndromes such as functional impairment&#44; sarcopenia&#44; reduced muscle strength&#44; slower gait and frailty&#44; which various studies have shown to be independent predictors of readmission and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;70</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The RICA registry analyzed the prognostic value of the <span class="elsevierStyleItalic">baseline functional status</span>&#44; as evaluated using the Barthel index&#44; and found a high prevalence of functional impairment&#44; with severe dependence for basic activities of daily life in 55&#46;9&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> The Barthel index prior to hospitalization was shown to be an independent predictor of short-term mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Associated comorbidities and prognosis</span><p id="par0160" class="elsevierStylePara elsevierViewall">Although the individual presence of the various comorbidities is associated with a poor prognosis&#44; the coexistence of several of them&#44; as one would expect&#44; determines an even poorer prognosis&#46; A direct relationship has been observed between the number of comorbidities and lower long-term survival&#44; both in outpatients<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and hospitalized patients&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> A direct relationship has also been confirmed between the number of comorbidities and the risk of hospitalization&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;73</span></a> which entails poorer evolution&#44; increased mortality&#44; greater consumption of resources and higher healthcare costs&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">One of the most widely used instruments for assessing overall comorbidity is the Charlson comorbidity index&#46; Its prognostic value has been analyzed in Spain in the SEMI-IC study&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> which included 2127 patients from 51 hospitals&#46; The patients with the highest scores on the Charlson index &#40;&#8805;3 points&#41; had significantly more prior hospitalizations&#44; longer hospital stays and greater mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> The RICA registry has also confirmed the prognostic value of the Charlson index as an independent predictor of mortality or readmission at 1 year&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The association of comorbidities in profiles or clusters has recently been reported&#44; which helps identify those patients with HF who have a greater risk of death&#44; longer stays and increased hospitalization costs&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> Four profiles have been differentiated&#58; &#40;1&#41; the &#8220;common&#8221; profile&#44; which has the lowest comorbidity and is related to a lower prevalence of cerebrovascular disease&#44; myocardial infarction&#44; peripheral vascular disorders&#44; depression&#44; kidney disease&#44; AHT and obesity when compared with the other profiles&#59; &#40;2&#41; the &#8220;lifestyle&#8221; profile&#44; which has a high rate of AHT&#44; uncomplicated diabetes&#44; chronic lung disorders and obesity&#59; &#40;3&#41; the &#8220;renal&#8221; profile&#44; with high rates of kidney disease&#44; diabetes with complications and electrolyte imbalances&#59; and &#40;4&#41; the &#8220;neurovascular&#8221; profile&#44; with a high prevalence of cerebrovascular disease&#44; myocardial infarction and peripheral vascular disease&#46; Compared with the common profile&#44; the 3 other profiles are associated with longer hospital stays and higher hospitalization costs&#46; Additionally&#44; the renal and neurovascular profiles are associated with greater mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">For patients with HF&#44; comorbidities are frequently the cause of hospital readmission&#46; In fact&#44; a number of series have observed that only a third or fewer of readmissions are due to HF per se<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> This occurs more frequently in patients with HFPEF&#44;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> in whom mortality is often linked to noncardiovascular diseases&#44; such as malignancies&#44; kidney disease and infections&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Given the importance of comorbidities in the morbidity and mortality of patients with HF&#44; our attention has recently been focused on the importance of providing overall care for patients with HF instead of restrictive care &#40;i&#46;e&#46;&#44; focusing entirely on the heart disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">72&#44;78</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">In short&#44; the HF profile in general and especially the type treated in internal medicine departments is that of an elderly patient&#44; with multiple comorbidities that impede their diagnosis and treatment&#44; complicating the evolution&#44; worsening the quality of life and resulting in a poorer prognosis &#40;more hospitalizations&#44; greater consumption of resources and higher mortality&#41;&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Given that the comorbidities frequently go unnoticed&#44; our approach should consist of an active search for them&#44; to identify them and treat them correctly&#44; as this can improve the evolution and quality of life of patients with HF&#46; It is therefore essential that we approach HF from an overall perspective that is not focused exclusively on the heart disease itself&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conflict of interests</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Prevalence of comorbidities in heart failure registries"
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          "identificador" => "sec0010"
          "titulo" => "Comorbidities as a cause of heart failure"
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          "identificador" => "sec0015"
          "titulo" => "Comorbidities as a consequence of heart failure"
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          "titulo" => "Comorbidity and prognosis"
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          "titulo" => "Associated comorbidities and prognosis"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Conde-Martel A&#44; Hern&#225;ndez-Meneses M&#46; Prevalencia y significado pron&#243;stico de la comorbilidad en la insuficiencia cardiaca&#46; Rev Clin Esp&#46; 2016&#59;216&#58;222&#8211;228&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">COPD&#44; chronic obstructive pulmonary disease&#46;</p>"
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                  \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="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">ADHERE<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a><br>&#40;US&#41;&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">OPTIMIZE-HF<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a><br>&#40;US&#41;&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">GWTG-HF<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><br>&#40;US&#41;&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">EHFSII<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><br>&#40;Europe&#41;&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">ADHERE Asia-Pacific<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&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">OFICA<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><br>&#40;France&#41;&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">IN-HF Outcome<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><br>&#40;Italy&#41;&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">ATTEND<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><br>&#40;Japan&#41;&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">RICA<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;19</span></a><br>&#40;Spain&#41;&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">Patients&#44; <span class="elsevierStyleItalic">n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">105&#44;388&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#44;612&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">110&#44;621&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3580&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#44;171&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1658&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1855&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4842&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2051&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">Age &#40;years<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74&#40;62&#8211;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&#40;70&#8211;86&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&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">Women &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&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">Arterial hypertension &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&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">Diabetes mellitus &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44&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">Chronic kidney disease &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&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">Anemia &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&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">COPD &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&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">Atrial fibrillation &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&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">Coronary artery disease &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Plasma creatinine &#62;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dL or dialysis&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Prevalence of comorbidities in heart failure registries&#46;</p>"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical epidemiology of heart failure"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "A&#46; Mosterd"
                            1 => "A&#46;W&#46; Hoes"
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                    0 => array:2 [
                      "doi" => "10.1136/hrt.2003.025270"
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                        "tituloSerie" => "Heart"
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                        "volumen" => "93"
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                      "titulo" => "Non-cardiac comorbidities in chronic heart failure"
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                            0 => "C&#46;C&#46; Lang"
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                    0 => array:2 [
                      "doi" => "10.1136/hrt.2005.068296"
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                        "tituloSerie" => "Heart"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16488925"
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