Impact of intestinal microbiota in patients with heart failure: A systematic review

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PRISMA protocol used in this systematic review." ] ] ] "textoCompleto" => "IntroductionHeart failure (HF) is a chronic progressive disorder, with a great impact on the quality of life of patients that causes functional limitations, associates a poor short/long term symptomatic control, a decreased life expectancy and a tendency to hospital readmission.<a class="elsevierStyleCrossRefs" href="#bib0005">1–4</a> Despite the therapeutic advances experienced in the management of HF during the last 2 decades, mortality remains high, even higher than some of the most common cancers, which shows that current treatment options continue to be limited and insufficient.<a class="elsevierStyleCrossRefs" href="#bib0005">1–9</a>In recent years, microbiota, described as the dynamic microbial community that lives in coexistence (symbiosis) with the human host, has been evaluated with increasing interest.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The microorganisms that make it up colonize the surface of the skin and also the respiratory, urogenital and especially gastrointestinal mucous membranes, particularly the colon, whose mainly anaerobic and nutrient-rich environment confers ideal conditions for microbial colonization.<a class="elsevierStyleCrossRefs" href="#bib0050">10–12</a> "Healthy microbiota" is defined as one that preserves and promotes well-being and absence of diseases in the host, especially digestive tract-related conditions.<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a>The possible pathogenic interaction between the human host and the intestinal microbiota is currently under discussion.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> In the specific case of HF, the final common process of various cardiovascular comorbidities, there are hemodynamic changes associated with the disease that can lead to hypoperfusion and, very often, systemic congestion which, due to the involvement of the digestive tract, not only alters the structural morphology, permeability and peristaltic function, but also the growth rate and composition of the intestinal microbiota itself.<a class="elsevierStyleCrossRefs" href="#bib0080">16–19</a> Thus, intestinal wall oedema and impaired intestinal barrier function in HF can promote bacterial translocation.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Trimethylamine N-oxide (TMAO) seems to emerge as a key molecular mediator that would link these alterations in the intestinal microbiota with the risk of developing or maintaining multiple cardiovascular diseases, including HF.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a>In this systematic review, we evaluate the available data regarding these alterations in the composition of intestinal microbiota in HF patients and the importance of TMAO as a pathogenic mechanism in these patients.<a class="elsevierStyleCrossRefs" href="#bib0110">22–25</a>Material and methodsWe have performed a systematic review according to the recommendations of the protocol structured by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, analysing through consecutive stages of identification, screening, eligibility and inclusion all available studies that provided data on the role of intestinal microbiota in HF patients.For this, an extended literature search was initially carried out using the terms shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. This search leads to an exhaustive qualitative analysis of references from various databases and search engines (PubMed/Medline, Scopus, Cochrane), referring to articles published from January 1, 2010 to December 31, 2018. The searches performed in the 3 databases included all the terms in any field. For the management of the references we have used the Mendeley literature manager version 1.17.12. In addition, manual searches of literature references of unidentified reviews during the on-line search have been performed.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>After the systematic search, each article/study has been selected considering the title, the summary and the complete article, according to the inclusion and exclusion criteria reflected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. First, we have identified the references found through the on-line and manual database search. Secondly, we have selected the articles from the 3 databases taking into account the summary and the results of the articles that were related to the study subject, excluding publications related exclusively to animal testing, reviews, editorials and duplicate items. The process of eliminating non-relevant documents according to our exclusion criteria and PRISMA guidelines has been followed in the design of the review. The final result constitutes the number of studies finally included in the review.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Data extraction from the selected studiesArticle data extraction from the selected studies has been carried out by 2 of the authors (Cristiana Isabel Ferreira Teles and Francesc Formiga), and in the case of any conflicting opinion regarding the inclusion or exclusion criteria of all articles, this was resolved through the collaboration of the third author, David Chivite, also an Internal Medicine specialist.In order to express the information explicitly and structurally, we present the results of the review in tabular format, collecting the most relevant data: authors, geographic scope of the study, year of publication, characteristics of the population with evaluated HF, number of subjects included, analysed variables, exclusion criteria, relevant findings and limitations.ResultsThe systematic search led to the identification of 94 articles from databases and 3 from the manual search, of which 11<a class="elsevierStyleCrossRefs" href="#bib0130">26–36</a> met the inclusion criteria and none the exclusion criteria. A flowchart of the final selection of items is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, according to 4-phase PRISMA protocol.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The data contained in these 11 articles were classified in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>, where the main characteristics are presented (study area, year, study design, population characteristics, number of participants, average age, controlled variables, criteria of exclusion, main findings and limitations).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The studies were carried out in different geographical locations: 2 studies in the USA,<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> 2 studies in Norway,<a class="elsevierStyleCrossRefs" href="#bib0140">28,36</a> one study in Italy,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> a study in the United Kingdom,<a class="elsevierStyleCrossRef" href="#bib0150">30</a> a study in North China,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> 2 studies in Japan,<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> a study in Germany<a class="elsevierStyleCrossRef" href="#bib0170">34</a> and a study in Spain.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> All of them were published between 2014 and 2018.DiscussionThe conclusions of most of the studies included in this review support the possibility of a significant association between the presence of abnormalities in the intestinal microbiota and the existence of HF, as well as a possible relationship of the microbiota with the development, course and progression of HF, although there are no longitudinal studies that allow to verify the causality of this association.Changes in the intestinal microbiota of patients with heart failureA repeated finding in the studies analysed is the excessive growth of the pathogenic intestinal flora in most HF patients.<a class="elsevierStyleCrossRefs" href="#bib0145">29,31,33</a> This growth would be partly justified by the fact that the intestinal microbiota is highly sensitive to external and internal environmental alterations.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> External factors include the use of antimicrobials, exposure to other patients and drug-taking.<a class="elsevierStyleCrossRefs" href="#bib0185">37–39</a> Regarding internal factors, hypoxia, gastroparesis, changes in hydroelectrolytic balance, chronic intestinal congestion, intestinal ischemia, alterations in acid-base balance and lack of nutrients are especially relevant.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Hypoxemia seems to act not only by altering the intestinal flora, but also by generating gastric-pyloric dysmotility, increased intestinal mucosa acidosis and compromised intestinal barrier integrity, which leads to increased permeability.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> There are common comorbidities in HF, such as diabetes, which are also associated with the presence of gastroparesis. Also, antimotility agents and acid suppressive therapies can alter the normal intestinal flora, which leads to a pathogenic bacteria overgrowth. Finally, nutrient deprivation that can occur during the hemodynamic instability phases of HF can favour the overgrowth of germs such as Candida, Campylobacter, Shigella and Yersinia, altering the composition of the microbiota,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> with possible detrimental effects on nutritional status mediated by a vitamin B absorption deficiency12 and fat and fat-soluble vitamin malabsorption.Cui et al.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> demonstrated that the composition of the intestinal microbiota in HF patients is significantly different from that of the control groups (p=0.003). The authors analysed enriched cultures of 86 bacteria genera: Ruminococcus, Acinetobacter and Veillonella are more prevalent in HF patients, while Alistipes, Faecalibacterium and Oscillibacter are present to a lesser extent.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> Significantly, C-reactive protein and creatinine levels are associated with the intestinal microbiota characteristic of HF patients. Katsimichas et al.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> proposed in this regard that HF could be the manifestation of a systemic inflammatory state potentially triggered by microbial products that abnormally penetrate the bloodstream through a compromised intestinal mucous barrier. The bacterial communities of both, HF patients and controls, were dominated by phyla Firmicutes and Bacteroidetes, the latter being the most abundant genus in both groups.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>In a study with a relatively small number of HF patients, Luedde et al.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> reassess the composition of the microbiota in relation to controls. With respect to intra-individual bacterial variation, a lower rate of diversity of bacterial genera is reported in cases of HF compared to controls (p=0.01). Changes in bacterial diversity are inferred from the study, mainly due to the significant depletion of Blautia and Collinsella bacterial genera, as well as genera belonging to families Erysipelotrichaceae and Ruminococcaceae.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> This microbial pattern has not been reported as associated with other pathological entities.Kummen et al.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> reported that in HF patients, bacterial richness decreases compared to controls. A significant consequence is the low quantity and depletion of butyrate-producing microbes which, by decreasing, reduce local anti-inflammatory activity in the intestinal mucosa and regulatory T cells stimulation; these 2 alterations could contribute to inflammatory changes.<a class="elsevierStyleCrossRefs" href="#bib0205">41,42</a> This study corroborates an increase in taxa of the family Bacteroides and a depletion in taxa of the family Lachnospiraceae, both related to the CD25T cell activation marker (p=0.001). This study shows that the altered intestinal microbiota in a HF patient generates a persistent activation of T cells that, in turn, could be involved in chronic immune activation.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>In our country, Huntley et al.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> evaluated a cohort of 39HF patients, in order to demonstrate a possible intestinal overgrowth of primary pathogenic gut bacteria, such as Shigella spp., Salmonella spp., Campylobacter spp. and Yersinia enterocolitica. However, unlike previous results,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> this study failed to isolate pathogenic intestinal bacteria in culture, with results being negative for all but one patient (positive for Clostridium difficile B).The role of TMAO as a molecular mediatorTMAO is a metabolite with harmful effects on the myocardium; elevated plasma levels also have predictive capacity for atherosclerosis development.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> In HF patients, high TMAO values have been reported, correlated with a worse NYHA functional class, an ischemic aetiology and the development of adverse health outcomes.<a class="elsevierStyleCrossRefs" href="#bib0130">26–28,30,31</a> Tang et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> investigated the relationship between plasma TMAO concentrations and all-cause mortality in a longitudinal study with long-term follow-up (5 years) in 720 patients with a history of HF. The average values of TMAO in HF patients were significantly higher than those observed in the control cohort (p<0.001). Diabetes mellitus, renal failure and lower levels of HDL cholesterol were often part of the clinical history of these patients with high concentrations of TMAO; however, the history of arterial hypertension, ischemic heart disease, the degree of left ventricular dysfunction, smoking, body mass index or sex did not show this association. Plasma TMAO levels in HF patients were correlated in a weak but inversely significant way, with serum aryl esterase activity (p<0.001), and directly, with serum uric acid levels (p<0.001), of recognized value as a prooxidant factor. The key study finding<a class="elsevierStyleCrossRef" href="#bib0130">26</a> was that high levels of TMAO were associated with an increased risk of mortality in the HF patients cohort (HR 3.42; 95% CI 2.24–5.23; p<0.001); analysing TMAO as a continuous variable, the highest values were also associated with a higher risk of mortality at 5 years, even after adjusting for traditional cardiac risk factors (HR 1.18; 95% CI 1.06–1.31 by SD; p<0.01). Another important aspect of this study is the association between levels of TMAO and brain natriuretic peptide (BNP) and estimated glomerular filtration rate (eGFR).<a class="elsevierStyleCrossRef" href="#bib0130">26</a> After adjustment, patients in the highest quartile of TMAO (>8.5mM) had a significantly higher mortality risk than those in the lower quartile. Elevated fasting TMAO levels were associated with a 2.2-fold increase in mortality risk after adjustment for traditional risk factors and BNP levels (HR 2.20; 95% CI 1.42–3, 43; p<0.01) and a 1.80-fold increase in mortality risk, even after adjustment for traditional risk factors and BNP levels plus eGFR (HR 1.75; 95% CI 1.07–2.86; p<0.05). The authors conclude that this association between high levels of TMAO and mortality in patients with acute HF could indicate that the composition of the intestinal microbiota could play, through TMAO levels, a relevant role in the progression of HF.The same research group conducted a new prospective 5-year cohort study to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in HF patients.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> As expected, patients with a history of diabetes mellitus or renal insufficiency had higher levels of TMAO, choline and betaine compared to those who did not have this history. This study also demonstrates that TMAO levels have a higher prognostic value than choline or betaine in HF patients, independent of that associated with the usual cardiorenal prognostic markers.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> A significant associated finding is the fact that elevated plasma TMAO, choline and betaine concentrations were associated with the presence of left ventricular diastolic dysfunction, but not systolic dysfunction. In light of the findings, the authors conclude that the association between high concentrations of TMAO and the severity of HF reinforces the probable pathogenic link between intestinal microbiota abnormalities and HF.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a>Trøseid et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> also analysed the plasma levels of TMAO and its precursors (choline and betaine) and explored their associations with symptoms and aetiology in HF patients. Plasma levels of TMAO (p=0.01), choline (p<0.001) and betaine (p<0.001) were found to be elevated in patients with chronic HF compared to the control group, with the highest levels being in patients with more advanced functional classes (NYHA III and IV). TMAO levels (but not choline or betaine) were associated with the existence of previous myocardial infarction; TMAO and choline levels (but not betaine) were associated with older age, and betaine levels (but not TMAO or choline) were associated with elevated levels of C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The 3 markers were correlated with the severity of the disease both clinically and hemodynamically or neurohormonally, but only TMAO levels were associated with the development of adverse events over follow-up. The relative lack of correlation between TMAO, choline and betaine and various well-known inflammatory biomarkers, as well as differential relationships with markers of endothelial dysfunction, are indicative that the adverse effects generated by the presence of high concentrations of TMAO follow a possible independent pathophysiological pathway.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>In order to verify the association of circulating TMAO levels with the prognosis in patients admitted to hospital for acute HF, Suzuki et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> conducted a prospective one-year cohort study. The results verify that TMAO levels improve the risk stratification of in-hospital mortality in combination with clinical risk scales (OR≥1.13; p≤0.014). In the tercile analysis, the different categories defined by the concentration of TMAO stratified the risk of adverse health events during follow-up (OR≥1.61; p≤0.004), improving the prediction of the results offered by established biomarkers: the combination of plasma TMAO values with those of the N-terminal fraction of BNP (NT-proBNP) increases (OR≥2.15; p≤0.007) the discriminative power of natriuretic peptides. TMAO values were shown to have an independent predictive value for the development of HF-related deaths, even when adjusting for the presence of traditional risk factors (HR≥1.16; p≤0.037); however, its predictive capacity was weakened when renal function parameters were included. An interesting fact is that once the percentage of total mortality of hospitalized patients was evaluated, elevated levels of TMAO occurred in 75% of patients who died during admission, while elevated NT-proBNP levels were observed in a smaller number (51%) of deaths<a class="elsevierStyleCrossRef" href="#bib0150">30</a>; in the latter case, 78% of the patients also had elevated levels of TMAO.Cui et al.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> observe in their study an elevation of the microbial genes involved in the production of TMAO in the intestinal microbiota of HF patients. Functional changes of the microbial metagenome indicate a correlation between HF and an imbalance of intestinal microbes involved in the metabolism of protective metabolites, such as butyrate, and harmful metabolites, such as TMAO. Alterations of the intestinal microbiota have also been described in HF patients according to age. Kamo et al.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> again verify that the composition of intestinal microbiota in HF patients is different from that of the controls, with Eubacterium rectole and Dorea longicatena being less abundant, but when they analysed this composition according to age they observed that the phylum Bacteroidetes turns out to be less abundant (11.7±2.3% vs. 21.7±4.1%, p=0.047), while Proteobacteria were more prevalent (8.4±2.9% vs. 1.6±0.5%, p=0.046) in the intestinal microbiota of older patients compared to young patients. When they were analysed according to sex and species, the proportion of genus Faecalibacterium, F. prausnitzii and Clostridioforme Clostridium microorganisms decreased (3.1±1.0% vs. 7.5±1.4%, p=0.021, 2.2±0.6% vs. 6.2±1.3%, p=0.013 and 0.7±0.3% vs. 2.3±0.6%, p=0.035, respectively), while that of the genus Lactobacillus and L. salivarius increased (21.4±5.1% vs. 2.0±1.1%, p=0.004 and 14.0±4.7% vs. 0.4±0.4%, p=0.018, respectively) in stool samples from older patients compared to those in younger patients.When assessing the increase in intestinal permeability in HF patients, Pasini et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> verify that said intestinal permeability was normal in the control subjects, but increased by 78.3% of the population with HF. This permeability is emphasized in the more advanced stages of the disease (NYHA III and IV) compared to the initial stages (NYHA I and II).Breath tests are easy methods to identify small intestine bacterial overgrowth. A recent study in our country has shown that the measurement of exhaled hydrogen concentration after the lactulose breath test was associated with HF severity parameters and a worse clinical outcome.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>It is clear that a greater knowledge of intestinal microbiota alterations in HF patients may have therapeutic implications. There are currently no recommendations with a high degree of evidence on whether interventions in intestinal acidity and intestinal peristalsis can be positive with respect to intestinal bacterial burden in HF. Thus, there is a lack of evidence that allows us to know the implications of the use of proton pump inhibitors, or of probiotic treatments, among others, in the prognosis of HF patients.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>LimitationsOne of the most important limitations of the systematic review is that a small number of human studies are available (animal studies have not been included) and, therefore, scientific evidence is still limited. Another important limitation would be that in one of the studies selected for this systematic review the sample size is reduced. It is also essential to highlight that several studies assess the patient globally with different comorbidities involved in changes in the microbiota<a class="elsevierStyleCrossRef" href="#bib0155">31</a> and multiple factors that occur in advanced HF are not excluded<a class="elsevierStyleCrossRefs" href="#bib0155">31,34</a>; nor is there complete information about the patient with HF (NYHA class, dietary habits, among others).<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> In addition, it should be noted that the studies include patients undergoing various treatment regimens for HF which could have influenced the composition of their microbiota, or may have even received antibiotics that, due to obvious reasons, could have significantly altered this composition. Well-designed studies are needed under controlled conditions, of a longitudinal prospective nature, that include homogeneous cohorts and are developed in different geographical areas to avoid selection biases, which allow to correctly identify specific microbiota alterations in HF patients and its possible consequences.<a class="elsevierStyleCrossRefs" href="#bib0130">26,32,34,35</a>In short, a significant anomaly in the composition of the intestinal microbiota in HF patients seems likely. TMAO seems to play a key role as a mediator between these alterations of the intestinal microbiota and the pathogenesis of HF, influencing the prognosis of patients. The improvement in the knowledge of the existing alterations in the heart-intestine axis<a class="elsevierStyleCrossRef" href="#bib0235">47</a> could lead to the development of innovative interventions to improve the clinical course, or even the prognosis, of HF patients.Conflict of interestsThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1268090" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1173794" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1268089" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1173793" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data extraction from the selected studies" ] ] ] 6 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 7 => array:3 [ "identificador" => "sec0025" "titulo" => "Discussion" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Changes in the intestinal microbiota of patients with heart failure" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "The role of TMAO as a molecular mediator" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Limitations" ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-05-21" "fechaAceptado" => "2019-06-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1173794" "palabras" => array:3 [ 0 => "Heart failure" 1 => "Intestinal microbiota" 2 => "Trimethylamine-N-oxide" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1173793" "palabras" => array:3 [ 0 => "Insuficiencia cardíaca" 1 => "Microbiota intestinal" 2 => "N-óxido de trimetilamina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Heart failure (HF) is a chronic disease with significant morbidity and mortality. Substantial haemodynamic changes such as hypoperfusion and intestinal congestion can alter the composition of the intestinal microbiota in patients with HF. The aim of this systematic review is to evaluate the influence of bowel function in patients with HF and the possible role of the intestinal microbiota in the development and evolution of the latter. Eleven studies were included in the review. These studies seem to confirm that HF patients present with substantial abnormalities in the composition of their intestinal microbiota. Trimethylamine N-oxide (TMAO) is identified as a key mediator between the alterations in the intestinal microbiota and HF and correlates with worse prognosis in HF patients. In conclusion, patients with HF present with frequent abnormalities in the characteristics of their intestinal microbiota, which may play a role in the prognosis of the disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La insuficiencia cardiaca (IC) es una enfermedad crónica con importante morbimortalidad asociada. Los pacientes con IC experimentan cambios hemodinámicos sustanciales, generadores de hipoperfusión y congestión esplácnica, que pueden alterar la composición de su microbiota intestinal. El objetivo de esta revisión sistemática es evaluar la influencia de la función intestinal en el paciente con IC, examinando el posible rol de la microbiota intestinal. Se incluyeron en la revisión 11 estudios. Los estudios evaluados ponen de manifiesto la existencia de alteraciones en la composición de la microbiota intestinal en pacientes con IC. El N-óxido de trimetilamina (TMAO) parece actuar como un mediador clave entre estas alteraciones en la microbiota intestinal y la IC; asimismo, su presencia en concentraciones anormales se correlaciona con un peor pronóstico en los pacientes con IC. En conclusión, los pacientes con IC sufren alteraciones en la microbiota intestinal que parecen incidir en el pronóstico de la enfermedad." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Formiga F, Ferreira Teles CI, Chivite D. Impacto de la microbiota intestinal en los pacientes con insuficiencia cardíaca: una revisión sistemática. Med Clin (Barc). 2019;153:402–409." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2069 "Ancho" => 3319 "Tamanyo" => 359428 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Flow chart of the final selection of articles according to the 4-phase PRISMA protocol used in this systematic review." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Database \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Keywords \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results (number of articles) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PubMed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota MeSH Terms] AND heart failure [MeSHTerms] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PubMed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota [Title] AND heart failure [Title] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PubMed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota [Title] AND heart failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PubMed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota AND heart failure [Title] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PubMed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysbiosis [MeSH Terms] and heart failure [MeSH Terms] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scopus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota [Title] AND heart failure [Title] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scopus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysbiosis [Title] and heart failure [Title] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cochrane \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microbiota [MeSH Terms] AND heart failure [MeSH Terms] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cochrane \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysbiosis [Title] and heart failure [Title] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2169052.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Criteria used in the search for articles in PubMed, SCOPUS and Cochrane." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inclusion criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Studies where only human population (any age) is evaluated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Observational Epidemiological Studies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Articles published in quality journals \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Studies that relate intestinal microbiota with HF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exclusion criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Studies of descriptive reviews and systematic reviews \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meta-analysis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Articles not available in English or Spanish \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duplicate citations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Conference communications \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Books, informative material, description of unique cases \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2169053.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Inclusion and exclusion criteria." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "DLP: dyslipidaemia; DM: diabetes mellitus; LVEF: left ventricular ejection fraction; HBP: high blood pressure; HF: heart failure; AHF: acute heart failure; CHF: chronic heart failure; BMI: muscle mass index; RF: renal failure; NYHA: New York Heart Association; NT-proBNP: N-terminal pro-brain natriuretic peptide ; ACS: acute coronary syndrome; TMAO: Trimethylamine N-oxide; LV: left ventricle." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference, study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Geographical area (year) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study design \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Population characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. subjects (test group/control group) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean age (test/control group) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controlled variables/exclusion criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Findings \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limitations \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tang et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study (5 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with stable CHF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,020 (720HF/300 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.20 ± 10years/no data available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with a history of HF who underwent an elective coronary angiographic evaluationExcluded patients with ACS in the previous 30 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High levels of TMAO associated with increased risk of mortality in HFHigh levels of TMAO and increased risk of mortality at 5 years, regardless of cardiorenal factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Single centre studyNo information: NYHA, cachexia or atrial fibrillationOne overnight fast blood test \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tang et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA (2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study (5 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with stable but symptomatic HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">112 HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57teenth ± 14 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Outpatients with stable but symptomatic CHF (LVEF≤35%)Excluded patients with significant primary valve abnormalities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stronger prognostic value of TMAO compared to choline and betaine, independent of cardiorenal factorsCorrelations between t3 metabolites with LV diastolic dysfunction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Samples without an overnight fastNo information on the dietary habits of the study groupNo NYHA class \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trøseid et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Norway (2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stable HF patients during>6 months (NYHA II-IV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">288 (155HF/133 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57±11 years/59.8±2.9 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">History of ACS in the last 6 monthsConcomitant diseases (infection, malignancy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High plasma levels of TMAO, choline and betaine in HF are associated with the severity of the disease, but only TMAO correlates with follow-up. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The influence of diet or antibiotic use has not been consideredCollection of blood samples without fastingFew patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pasini et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Italy (2016) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with HF (NYHA I-IV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80 (60 CHF, 30 NYHA I-II and 30 NYHA III-IV/20 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65±1 years NYHA I-II; 63.20±1 years NYHA III-IV/62.1±1 control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMI <30kg/m<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Concomitant diseasesTreatment with antibiotics and/or probiotics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">When comparing control subjects with HF patients, an excessive growth of Candida, Campylobacter, Shigella and Yersinia is observed. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small sample size \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suzuki et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">United Kingdom (2016) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prospective cohort study (one year) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">972 acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">78±15 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No history of cancer or renal replacement therapy; recent previous surgery; cardiogenic shock, sepsis, pneumonia; ACS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMAO predictive biomarker of death due to corrected HF (HR)≥1.16, p≤0.037). TMAO lost the predictive capacity with the inclusion of renal function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMAO analyses were not strictly time controlled due to emergency admissions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cui et al.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">China (2017) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with acute HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 (53HF/41 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58.08±13.30 years/53.73±5.94 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">History of ACS in the last 6 monthsComorbiditiesUse of antibiotics or probiotics in the previous month \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease in Faecalibacterium prausnitzii and increase of Ruminococcus gnavusImbalance in intestinal microbes involved in the metabolism of protective and harmful metabolites \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cannot be extrapolated to patients without acute HFPatients with comorbidities (HBP, DLP and DM) are not excluded. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kamo et al.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan (2017) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with HF (NYHA II-IV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 (22HF<60 years 12 and>60 years 10/12 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47.4±2.8 years and 73.8±2.8 years/41.4±2.0 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concomitant diseases (active infection, inflammatory disease, neoplasms, renal failure)Treatment with antibiotics, probiotics or immunosuppressants in the previous 2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intestinal dysbiosis varies even more according to ageEubacterium rectole and Dorea longicatena reduced in HFFaecalibacterium prausnitzii and Clostridioforme Clostridium were less abundant in older HF patients, compared to younger \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small sampleCross-sectional study. A longitudinal study is required to explore possible change in the intestinal microbiome during the course of HF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Katsimichas et al.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan (2018) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with reduced HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 (28 reduced HF/37 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51.20±10 years/57.20±9 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adjustment for age, ethnicity, renal function and diet \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Differences in the intestinal microbial communities at the level of basal structure and extensions of the metagenomic transport of metabolic pathways and interactions of bacterial taxa in HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small sample sizeInability to match test and control group by age, renal function and medication \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Luedde et al.3. 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Germany (2017) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with reduced chronic HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 (20HF/20 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65±3.17 years/65.20±3.07 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adjust for age, sex, BMI and smokingConcomitant diseasesAntibiotic/probiotic treatments 3 months prior \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The depletion of the genera Blautia and Collinsella, as well as Erysipelotrichaceae and Ruminococcaceae, could be specific to HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small sample sizeThe influence of the multiple factors that occur in HF, in addition to infections and antibiotic treatment cannot be excluded. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Huntley et al.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spain (2018) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with decompensated HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 CHF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76±9 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concomitant diseases (infection, diarrhoea, ACS, neoplasms)Antibiotic treatment, corticosteroids in the previous month \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No pathogenic intestinal bacteria have been cultured from any patient, except one with Clostridium difficile B) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small cohort sizeSingle centerNon-longitudinal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kummen et al.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Norway (2018) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cohort study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with HF (NYHA II-IV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">350 (84 CHF/266 control) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No available data \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adjustment for age, sex, body mass index, hypertension and diabetes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Depletion of butyrate-producing bacteria in HFInverse correlation between Lachnospiraceae and CD25T cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preliminary data with the need to confirm the results \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2169051.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Articles included in the systematic review." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:47 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiología de la insuficiencia cardiaca en España en los últimos 20 años" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I. 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Impact of intestinal microbiota in patients with heart failure: A systematic review

Impacto de la microbiota intestinal en los pacientes con insuficiencia cardíaca: revisión sistemática

Francesc Formiga

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fformiga@bellvitgehospital.cat

Corresponding author.

, Cristiana Isabel Ferreira Teles, David Chivite

Servicio de Medicina Interna, Hospital Universitario de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure &#40;HF&#41; is a chronic progressive disorder&#44; with a great impact on the quality of life of patients that causes functional limitations&#44; associates a poor short&#47;long term symptomatic control&#44; a decreased life expectancy and a tendency to hospital readmission&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;4</span></a> Despite the therapeutic advances experienced in the management of HF during the last 2 decades&#44; mortality remains high&#44; even higher than some of the most common cancers&#44; which shows that current treatment options continue to be limited and insufficient&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years&#44; microbiota&#44; described as the dynamic microbial community that lives in coexistence &#40;symbiosis&#41; with the human host&#44; has been evaluated with increasing interest&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The microorganisms that make it up colonize the surface of the skin and also the respiratory&#44; urogenital and especially gastrointestinal mucous membranes&#44; particularly the colon&#44; whose mainly anaerobic and nutrient-rich environment confers ideal conditions for microbial colonization&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;12</span></a> &#34;Healthy microbiota&#34; is defined as one that preserves and promotes well-being and absence of diseases in the host&#44; especially digestive tract-related conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The possible pathogenic interaction between the human host and the intestinal microbiota is currently under discussion&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> In the specific case of HF&#44; the final common process of various cardiovascular comorbidities&#44; there are hemodynamic changes associated with the disease that can lead to hypoperfusion and&#44; very often&#44; systemic congestion which&#44; due to the involvement of the digestive tract&#44; not only alters the structural morphology&#44; permeability and peristaltic function&#44; but also the growth rate and composition of the intestinal microbiota itself&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;19</span></a> Thus&#44; intestinal wall oedema and impaired intestinal barrier function in HF can promote bacterial translocation&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Trimethylamine N-oxide &#40;TMAO&#41; seems to emerge as a key molecular mediator that would link these alterations in the intestinal microbiota with the risk of developing or maintaining multiple cardiovascular diseases&#44; including HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this systematic review&#44; we evaluate the available data regarding these alterations in the composition of intestinal microbiota in HF patients and the importance of TMAO as a pathogenic mechanism in these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;25</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">We have performed a systematic review according to the recommendations of the protocol structured by the <span class="elsevierStyleItalic">Preferred Reporting Items for Systematic Reviews and Meta-Analyses</span> &#40;PRISMA&#41; guidelines&#44; analysing through consecutive stages of identification&#44; screening&#44; eligibility and inclusion all available studies that provided data on the role of intestinal microbiota in HF patients&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">For this&#44; an extended literature search was initially carried out using the terms shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; This search leads to an exhaustive qualitative analysis of references from various databases and search engines &#40;PubMed&#47;Medline&#44; Scopus&#44; Cochrane&#41;&#44; referring to articles published from January 1&#44; 2010 to December 31&#44; 2018&#46; The searches performed in the 3 databases included all the terms in any field&#46; For the management of the references we have used the Mendeley literature manager version 1&#46;17&#46;12&#46; In addition&#44; manual searches of literature references of unidentified reviews during the <span class="elsevierStyleItalic">on-line</span> search have been performed&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">After the systematic search&#44; each article&#47;study has been selected considering the title&#44; the summary and the complete article&#44; according to the inclusion and exclusion criteria reflected in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; First&#44; we have identified the references found through the <span class="elsevierStyleItalic">on-line</span> and manual database search&#46; Secondly&#44; we have selected the articles from the 3 databases taking into account the summary and the results of the articles that were related to the study subject&#44; excluding publications related exclusively to animal testing&#44; reviews&#44; editorials and duplicate items&#46; The process of eliminating non-relevant documents according to our exclusion criteria and PRISMA guidelines has been followed in the design of the review&#46; The final result constitutes the number of studies finally included in the review&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Data extraction from the selected studies</span><p id="par0040" class="elsevierStylePara elsevierViewall">Article data extraction from the selected studies has been carried out by 2 of the authors &#40;Cristiana Isabel Ferreira Teles and Francesc Formiga&#41;&#44; and in the case of any conflicting opinion regarding the inclusion or exclusion criteria of all articles&#44; this was resolved through the collaboration of the third author&#44; David Chivite&#44; also an Internal Medicine specialist&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In order to express the information explicitly and structurally&#44; we present the results of the review in tabular format&#44; collecting the most relevant data&#58; authors&#44; geographic scope of the study&#44; year of publication&#44; characteristics of the population with evaluated HF&#44; number of subjects included&#44; analysed variables&#44; exclusion criteria&#44; relevant findings and limitations&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The systematic search led to the identification of 94 articles from databases and 3 from the manual search&#44; of which 11<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;36</span></a> met the inclusion criteria and none the exclusion criteria&#46; A flowchart of the final selection of items is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; according to 4-phase PRISMA protocol&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The data contained in these 11 articles were classified in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#44; where the main characteristics are presented &#40;study area&#44; year&#44; study design&#44; population characteristics&#44; number of participants&#44; average age&#44; controlled variables&#44; criteria of exclusion&#44; main findings and limitations&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The studies were carried out in different geographical locations&#58; 2 studies in the USA&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> 2 studies in Norway&#44;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;36</span></a> one study in Italy&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> a study in the United Kingdom&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> a study in North China&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> 2 studies in Japan&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> a study in Germany<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> and a study in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> All of them were published between 2014 and 2018&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">The conclusions of most of the studies included in this review support the possibility of a significant association between the presence of abnormalities in the intestinal microbiota and the existence of HF&#44; as well as a possible relationship of the microbiota with the development&#44; course and progression of HF&#44; although there are no longitudinal studies that allow to verify the causality of this association&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Changes in the intestinal microbiota of patients with heart failure</span><p id="par0070" class="elsevierStylePara elsevierViewall">A repeated finding in the studies analysed is the excessive growth of the pathogenic intestinal flora in most HF patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;31&#44;33</span></a> This growth would be partly justified by the fact that the intestinal microbiota is highly sensitive to external and internal environmental alterations&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> External factors include the use of antimicrobials&#44; exposure to other patients and drug-taking&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;39</span></a> Regarding internal factors&#44; hypoxia&#44; gastroparesis&#44; changes in hydroelectrolytic balance&#44; chronic intestinal congestion&#44; intestinal ischemia&#44; alterations in acid-base balance and lack of nutrients are especially relevant&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Hypoxemia seems to act not only by altering the intestinal flora&#44; but also by generating gastric-pyloric dysmotility&#44; increased intestinal mucosa acidosis and compromised intestinal barrier integrity&#44; which leads to increased permeability&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> There are common comorbidities in HF&#44; such as diabetes&#44; which are also associated with the presence of gastroparesis&#46; Also&#44; antimotility agents and acid suppressive therapies can alter the normal intestinal flora&#44; which leads to a pathogenic bacteria overgrowth&#46; Finally&#44; nutrient deprivation that can occur during the hemodynamic instability phases of HF can favour the overgrowth of germs such as <span class="elsevierStyleItalic">Candida</span>&#44; <span class="elsevierStyleItalic">Campylobacter</span>&#44; <span class="elsevierStyleItalic">Shigella</span> and <span class="elsevierStyleItalic">Yersinia</span>&#44; altering the composition of the microbiota&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> with possible detrimental effects on nutritional status mediated by a vitamin B absorption deficiency<span class="elsevierStyleInf">12</span> and fat and fat-soluble vitamin malabsorption&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Cui et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> demonstrated that the composition of the intestinal microbiota in HF patients is significantly different from that of the control groups &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; The authors analysed enriched cultures of 86 bacteria genera&#58; <span class="elsevierStyleItalic">Ruminococcus</span>&#44; <span class="elsevierStyleItalic">Acinetobacter</span> and <span class="elsevierStyleItalic">Veillonella</span> are more prevalent in HF patients&#44; while <span class="elsevierStyleItalic">Alistipes</span>&#44; <span class="elsevierStyleItalic">Faecalibacterium</span> and <span class="elsevierStyleItalic">Oscillibacter</span> are present to a lesser extent&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Significantly&#44; C-reactive protein and creatinine levels are associated with the intestinal microbiota characteristic of HF patients&#46; Katsimichas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> proposed in this regard that HF could be the manifestation of a systemic inflammatory state potentially triggered by microbial products that abnormally penetrate the bloodstream through a compromised intestinal mucous barrier&#46; The bacterial communities of both&#44; HF patients and controls&#44; were dominated by <span class="elsevierStyleItalic">phyla Firmicutes</span> and <span class="elsevierStyleItalic">Bacteroidetes</span>&#44; the latter being the most abundant genus in both groups&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In a study with a relatively small number of HF patients&#44; Luedde et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> reassess the composition of the microbiota in relation to controls&#46; With respect to intra-individual bacterial variation&#44; a lower rate of diversity of bacterial genera is reported in cases of HF compared to controls &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Changes in bacterial diversity are inferred from the study&#44; mainly due to the significant depletion of <span class="elsevierStyleItalic">Blautia</span> and <span class="elsevierStyleItalic">Collinsella</span> bacterial genera&#44; as well as genera belonging to families <span class="elsevierStyleItalic">Erysipelotrichaceae</span> and <span class="elsevierStyleItalic">Ruminococcaceae</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> This microbial pattern has not been reported as associated with other pathological entities&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Kummen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> reported that in HF patients&#44; bacterial richness decreases compared to controls&#46; A significant consequence is the low quantity and depletion of butyrate-producing microbes which&#44; by decreasing&#44; reduce local anti-inflammatory activity in the intestinal mucosa and regulatory T cells stimulation&#59; these 2 alterations could contribute to inflammatory changes&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a> This study corroborates an increase in taxa of the family <span class="elsevierStyleItalic">Bacteroides</span> and a depletion in taxa of the family <span class="elsevierStyleItalic">Lachnospiraceae</span>&#44; both related to the CD25<span class="elsevierStyleHsp" style=""></span>T cell activation marker &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; This study shows that the altered intestinal microbiota in a HF patient generates a persistent activation of T cells that&#44; in turn&#44; could be involved in chronic immune activation&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In our country&#44; Huntley et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> evaluated a cohort of 39<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F patients&#44; in order to demonstrate a possible intestinal overgrowth of primary pathogenic gut bacteria&#44; such as <span class="elsevierStyleItalic">Shigella</span> spp&#46;&#44; <span class="elsevierStyleItalic">Salmonella</span> spp&#46;&#44; <span class="elsevierStyleItalic">Campylobacter</span> spp&#46; and <span class="elsevierStyleItalic">Yersinia</span> enterocolitica&#46; However&#44; unlike previous results&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> this study failed to isolate pathogenic intestinal bacteria in culture&#44; with results being negative for all but one patient &#40;positive for <span class="elsevierStyleItalic">Clostridium difficile</span> B&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">The role of TMAO as a molecular mediator</span><p id="par0095" class="elsevierStylePara elsevierViewall">TMAO is a metabolite with harmful effects on the myocardium&#59; elevated plasma levels also have predictive capacity for atherosclerosis development&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> In HF patients&#44; high TMAO values have been reported&#44; correlated with a worse NYHA functional class&#44; an ischemic aetiology and the development of adverse health outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;28&#44;30&#44;31</span></a> Tang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> investigated the relationship between plasma TMAO concentrations and all-cause mortality in a longitudinal study with long-term follow-up &#40;5 years&#41; in 720 patients with a history of HF&#46; The average values of TMAO in HF patients were significantly higher than those observed in the control cohort &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Diabetes mellitus&#44; renal failure and lower levels of HDL cholesterol were often part of the clinical history of these patients with high concentrations of TMAO&#59; however&#44; the history of arterial hypertension&#44; ischemic heart disease&#44; the degree of left ventricular dysfunction&#44; smoking&#44; body mass index or sex did not show this association&#46; Plasma TMAO levels in HF patients were correlated in a weak but inversely significant way&#44; with serum aryl esterase activity &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and directly&#44; with serum uric acid levels &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; of recognized value as a prooxidant factor&#46; The key study finding<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> was that high levels of TMAO were associated with an increased risk of mortality in the HF patients cohort &#40;HR 3&#46;42&#59; 95&#37; CI 2&#46;24&#8211;5&#46;23&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#59; analysing TMAO as a continuous variable&#44; the highest values were also associated with a higher risk of mortality at 5 years&#44; even after adjusting for traditional cardiac risk factors &#40;HR 1&#46;18&#59; 95&#37; CI 1&#46;06&#8211;1&#46;31 by SD&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Another important aspect of this study is the association between levels of TMAO and <span class="elsevierStyleItalic">brain natriuretic peptide</span> &#40;BNP&#41; and estimated glomerular filtration rate &#40;eGFR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> After adjustment&#44; patients in the highest quartile of TMAO &#40;&#62;<span class="elsevierStyleHsp" style=""></span>8&#46;5<span class="elsevierStyleHsp" style=""></span>mM&#41; had a significantly higher mortality risk than those in the lower quartile&#46; Elevated fasting TMAO levels were associated with a 2&#46;2-fold increase in mortality risk after adjustment for traditional risk factors and BNP levels &#40;HR 2&#46;20&#59; 95&#37; CI 1&#46;42&#8211;3&#44; 43&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and a 1&#46;80-fold increase in mortality risk&#44; even after adjustment for traditional risk factors and BNP levels plus eGFR &#40;HR 1&#46;75&#59; 95&#37; CI 1&#46;07&#8211;2&#46;86&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The authors conclude that this association between high levels of TMAO and mortality in patients with acute HF could indicate that the composition of the intestinal microbiota could play&#44; through TMAO levels&#44; a relevant role in the progression of HF&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The same research group conducted a new prospective 5-year cohort study to determine the prognostic value of TMAO and its dietary precursors&#44; choline and betaine&#44; in HF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> As expected&#44; patients with a history of diabetes mellitus or renal insufficiency had higher levels of TMAO&#44; choline and betaine compared to those who did not have this history&#46; This study also demonstrates that TMAO levels have a higher prognostic value than choline or betaine in HF patients&#44; independent of that associated with the usual cardiorenal prognostic markers&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> A significant associated finding is the fact that elevated plasma TMAO&#44; choline and betaine concentrations were associated with the presence of left ventricular diastolic dysfunction&#44; but not systolic dysfunction&#46; In light of the findings&#44; the authors conclude that the association between high concentrations of TMAO and the severity of HF reinforces the probable pathogenic link between intestinal microbiota abnormalities and HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Tr&#248;seid et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> also analysed the plasma levels of TMAO and its precursors &#40;choline and betaine&#41; and explored their associations with symptoms and aetiology in HF patients&#46; Plasma levels of TMAO &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; choline &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and betaine &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; were found to be elevated in patients with chronic HF compared to the control group&#44; with the highest levels being in patients with more advanced functional classes &#40;NYHA III and IV&#41;&#46; TMAO levels &#40;but not choline or betaine&#41; were associated with the existence of previous myocardial infarction&#59; TMAO and choline levels &#40;but not betaine&#41; were associated with older age&#44; and betaine levels &#40;but not TMAO or choline&#41; were associated with elevated levels of C-reactive protein&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The 3 markers were correlated with the severity of the disease both clinically and hemodynamically or neurohormonally&#44; but only TMAO levels were associated with the development of adverse events over follow-up&#46; The relative lack of correlation between TMAO&#44; choline and betaine and various well-known inflammatory biomarkers&#44; as well as differential relationships with markers of endothelial dysfunction&#44; are indicative that the adverse effects generated by the presence of high concentrations of TMAO follow a possible independent pathophysiological pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In order to verify the association of circulating TMAO levels with the prognosis in patients admitted to hospital for acute HF&#44; Suzuki et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> conducted a prospective one-year cohort study&#46; The results verify that TMAO levels improve the risk stratification of in-hospital mortality in combination with clinical risk scales &#40;OR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;13&#59; p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#46; In the tercile analysis&#44; the different categories defined by the concentration of TMAO stratified the risk of adverse health events during follow-up &#40;OR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;61&#59; p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#44; improving the prediction of the results offered by established biomarkers&#58; the combination of plasma TMAO values with those of the N-terminal fraction of BNP &#40;NT-proBNP&#41; increases &#40;OR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2&#46;15&#59; p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; the discriminative power of natriuretic peptides&#46; TMAO values were shown to have an independent predictive value for the development of HF-related deaths&#44; even when adjusting for the presence of traditional risk factors &#40;HR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;16&#59; p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41;&#59; however&#44; its predictive capacity was weakened when renal function parameters were included&#46; An interesting fact is that once the percentage of total mortality of hospitalized patients was evaluated&#44; elevated levels of TMAO occurred in 75&#37; of patients who died during admission&#44; while elevated NT-proBNP levels were observed in a smaller number &#40;51&#37;&#41; of deaths<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#59; in the latter case&#44; 78&#37; of the patients also had elevated levels of TMAO&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Cui et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> observe in their study an elevation of the microbial genes involved in the production of TMAO in the intestinal microbiota of HF patients&#46; Functional changes of the microbial metagenome indicate a correlation between HF and an imbalance of intestinal microbes involved in the metabolism of protective metabolites&#44; such as butyrate&#44; and harmful metabolites&#44; such as TMAO&#46; Alterations of the intestinal microbiota have also been described in HF patients according to age&#46; Kamo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> again verify that the composition of intestinal microbiota in HF patients is different from that of the controls&#44; with <span class="elsevierStyleItalic">Eubacterium rectole</span> and <span class="elsevierStyleItalic">Dorea longicatena</span> being less abundant&#44; but when they analysed this composition according to age they observed that the <span class="elsevierStyleItalic">phylum Bacteroidetes</span> turns out to be less abundant &#40;11&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3&#37; vs&#46; 21&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;1&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#41;&#44; while <span class="elsevierStyleItalic">Proteobacteria</span> were more prevalent &#40;8&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9&#37; vs&#46; 1&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;046&#41; in the intestinal microbiota of older patients compared to young patients&#46; When they were analysed according to sex and species&#44; the proportion of genus <span class="elsevierStyleItalic">Faecalibacterium</span>&#44; <span class="elsevierStyleItalic">F&#46; prausnitzii</span> and <span class="elsevierStyleItalic">Clostridioforme Clostridium</span> microorganisms decreased &#40;3&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;0&#37; vs&#46; 7&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#44; 2&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#37; vs&#46; 6&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013 and 0&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#37; vs&#46; 2&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#44; respectively&#41;&#44; while that of the genus <span class="elsevierStyleItalic">Lactobacillus</span> and <span class="elsevierStyleItalic">L&#46; salivarius</span> increased &#40;21&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;1&#37; vs&#46; 2&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004 and 14&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;7&#37; vs&#46; 0&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;018&#44; respectively&#41; in stool samples from older patients compared to those in younger patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">When assessing the increase in intestinal permeability in HF patients&#44; Pasini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> verify that said intestinal permeability was normal in the control subjects&#44; but increased by 78&#46;3&#37; of the population with HF&#46; This permeability is emphasized in the more advanced stages of the disease &#40;NYHA III and IV&#41; compared to the initial stages &#40;NYHA I and II&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Breath tests are easy methods to identify small intestine bacterial overgrowth&#46; A recent study in our country has shown that the measurement of exhaled hydrogen concentration after the lactulose breath test was associated with HF severity parameters and a worse clinical outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">It is clear that a greater knowledge of intestinal microbiota alterations in HF patients may have therapeutic implications&#46; There are currently no recommendations with a high degree of evidence on whether interventions in intestinal acidity and intestinal peristalsis can be positive with respect to intestinal bacterial burden in HF&#46; Thus&#44; there is a lack of evidence that allows us to know the implications of the use of proton pump inhibitors&#44; or of probiotic treatments&#44; among others&#44; in the prognosis of HF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Limitations</span><p id="par0135" class="elsevierStylePara elsevierViewall">One of the most important limitations of the systematic review is that a small number of human studies are available &#40;animal studies have not been included&#41; and&#44; therefore&#44; scientific evidence is still limited&#46; Another important limitation would be that in one of the studies selected for this systematic review the sample size is reduced&#46; It is also essential to highlight that several studies assess the patient globally with different comorbidities involved in changes in the microbiota<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and multiple factors that occur in advanced HF are not excluded<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;34</span></a>&#59; nor is there complete information about the patient with HF &#40;NYHA class&#44; dietary habits&#44; among others&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> In addition&#44; it should be noted that the studies include patients undergoing various treatment regimens for HF which could have influenced the composition of their microbiota&#44; or may have even received antibiotics that&#44; due to obvious reasons&#44; could have significantly altered this composition&#46; Well-designed studies are needed under controlled conditions&#44; of a longitudinal prospective nature&#44; that include homogeneous cohorts and are developed in different geographical areas to avoid selection biases&#44; which allow to correctly identify specific microbiota alterations in HF patients and its possible consequences&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;32&#44;34&#44;35</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In short&#44; a significant anomaly in the composition of the intestinal microbiota in HF patients seems likely&#46; TMAO seems to play a key role as a mediator between these alterations of the intestinal microbiota and the pathogenesis of HF&#44; influencing the prognosis of patients&#46; The improvement in the knowledge of the existing alterations in the heart-intestine axis<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> could lead to the development of innovative interventions to improve the clinical course&#44; or even the prognosis&#44; of HF patients&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflict of interests</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Material and methods"
          "secciones" => array:1 [
            0 => array:2 [
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              "titulo" => "Data extraction from the selected studies"
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          "titulo" => "Discussion"
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              "identificador" => "sec0030"
              "titulo" => "Changes in the intestinal microbiota of patients with heart failure"
            ]
            1 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "The role of TMAO as a molecular mediator"
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            2 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Limitations"
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          "titulo" => "Conflict of interests"
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    "fechaRecibido" => "2019-05-21"
    "fechaAceptado" => "2019-06-22"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1173794"
          "palabras" => array:3 [
            0 => "Heart failure"
            1 => "Intestinal microbiota"
            2 => "Trimethylamine-N-oxide"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1173793"
          "palabras" => array:3 [
            0 => "Insuficiencia card&#237;aca"
            1 => "Microbiota intestinal"
            2 => "N-&#243;xido de trimetilamina"
          ]
        ]
      ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Heart failure &#40;HF&#41; is a chronic disease with significant morbidity and mortality&#46; Substantial haemodynamic changes such as hypoperfusion and intestinal congestion can alter the composition of the intestinal microbiota in patients with HF&#46; The aim of this systematic review is to evaluate the influence of bowel function in patients with HF and the possible role of the intestinal microbiota in the development and evolution of the latter&#46; Eleven studies were included in the review&#46; These studies seem to confirm that HF patients present with substantial abnormalities in the composition of their intestinal microbiota&#46; Trimethylamine N-oxide &#40;TMAO&#41; is identified as a key mediator between the alterations in the intestinal microbiota and HF and correlates with worse prognosis in HF patients&#46; In conclusion&#44; patients with HF present with frequent abnormalities in the characteristics of their intestinal microbiota&#44; which may play a role in the prognosis of the disease&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La insuficiencia cardiaca &#40;IC&#41; es una enfermedad cr&#243;nica con importante morbimortalidad asociada&#46; Los pacientes con IC experimentan cambios hemodin&#225;micos sustanciales&#44; generadores de hipoperfusi&#243;n y congesti&#243;n espl&#225;cnica&#44; que pueden alterar la composici&#243;n de su microbiota intestinal&#46; El objetivo de esta revisi&#243;n sistem&#225;tica es evaluar la influencia de la funci&#243;n intestinal en el paciente con IC&#44; examinando el posible rol de la microbiota intestinal&#46; Se incluyeron en la revisi&#243;n 11 estudios&#46; Los estudios evaluados ponen de manifiesto la existencia de alteraciones en la composici&#243;n de la microbiota intestinal en pacientes con IC&#46; El N-&#243;xido de trimetilamina &#40;TMAO&#41; parece actuar como un mediador clave entre estas alteraciones en la microbiota intestinal y la IC&#59; asimismo&#44; su presencia en concentraciones anormales se correlaciona con un peor pron&#243;stico en los pacientes con IC&#46; En conclusi&#243;n&#44; los pacientes con IC sufren alteraciones en la microbiota intestinal que parecen incidir en el pron&#243;stico de la enfermedad&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Formiga F&#44; Ferreira Teles CI&#44; Chivite D&#46; Impacto de la microbiota intestinal en los pacientes con insuficiencia card&#237;aca&#58; una revisi&#243;n sistem&#225;tica&#46; Med Clin &#40;Barc&#41;&#46; 2019&#59;153&#58;402&#8211;409&#46;</p>"
      ]
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                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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Database&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Keywords&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results &#40;number of articles&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PubMed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota MeSH Terms&#93; AND heart failure &#91;MeSHTerms&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PubMed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota &#91;Title&#93; AND heart failure &#91;Title&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PubMed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota &#91;Title&#93; AND heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PubMed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota AND heart failure &#91;Title&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PubMed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysbiosis &#91;MeSH Terms&#93; and heart failure &#91;MeSH Terms&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scopus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota &#91;Title&#93; AND heart failure &#91;Title&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scopus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysbiosis &#91;Title&#93; and heart failure &#91;Title&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cochrane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microbiota &#91;MeSH Terms&#93; AND heart failure &#91;MeSH Terms&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cochrane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysbiosis &#91;Title&#93; and heart failure &#91;Title&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Inclusion criteria</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Studies where only human population &#40;any age&#41; is evaluated&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Observational Epidemiological Studies&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Articles published in quality journals&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Studies that relate intestinal microbiota with HF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exclusion criteria</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Studies of descriptive reviews and systematic reviews&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Meta-analysis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Articles not available in English or Spanish&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Duplicate citations&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Conference communications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Books&#44; informative material&#44; description of unique cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference&#44; study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Geographical area &#40;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Population characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; subjects &#40;test group&#47;control group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean age &#40;test&#47;control group&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controlled variables&#47;exclusion criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Limitations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA &#40;2014&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prospective cohort study &#40;5 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with stable CHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;020 &#40;720<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F&#47;300 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;20 &#177; <span class="elsevierStyleHsp" style=""></span>10years&#47;no data available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with a history of HF who underwent an elective coronary angiographic evaluationExcluded patients with ACS in the previous 30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High levels of TMAO associated with increased risk of mortality in HFHigh levels of TMAO and increased risk of mortality at 5 years&#44; regardless of cardiorenal factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Single centre studyNo information&#58; NYHA&#44; cachexia or atrial fibrillationOne overnight fast blood test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA &#40;2015&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prospective cohort study &#40;5 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with stable but symptomatic HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">112 HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57teenth &#177; <span class="elsevierStyleHsp" style=""></span>14 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Outpatients with stable but symptomatic CHF &#40;LVEF<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>35&#37;&#41;Excluded patients with significant primary valve abnormalities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stronger prognostic value of TMAO compared to choline and betaine&#44; independent of cardiorenal factorsCorrelations between t3 metabolites with LV diastolic dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Samples without an overnight fastNo information on the dietary habits of the study groupNo NYHA class&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tr&#248;seid et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Norway &#40;2015&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prospective observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stable HF patients during<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>6 months &#40;NYHA II-IV&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">288 &#40;155<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F&#47;133 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11 years&#47;59&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">History of ACS in the last 6 monthsConcomitant diseases &#40;infection&#44; malignancy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High plasma levels of TMAO&#44; choline and betaine in HF are associated with the severity of the disease&#44; but only TMAO correlates with follow-up&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The influence of diet or antibiotic use has not been consideredCollection of blood samples without fastingFew patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pasini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Italy &#40;2016&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with HF &#40;NYHA I-IV&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#40;60 CHF&#44; 30 NYHA I-II and 30 NYHA III-IV&#47;20 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1 years NYHA I-II&#59; 63&#46;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1 years NYHA III-IV&#47;62&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1 control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI<span class="elsevierStyleHsp" style=""></span> &#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>Concomitant diseasesTreatment with antibiotics and&#47;or probiotics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">When comparing control subjects with HF patients&#44; an excessive growth of <span class="elsevierStyleItalic">Candida</span>&#44; <span class="elsevierStyleItalic">Campylobacter</span>&#44; <span class="elsevierStyleItalic">Shigella</span> and <span class="elsevierStyleItalic">Yersinia</span> is observed&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small sample size&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suzuki et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">United Kingdom &#40;2016&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prospective cohort study &#40;one year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">972 acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No history of cancer or renal replacement therapy&#59; recent previous surgery&#59; cardiogenic <span class="elsevierStyleItalic">shock</span>&#44; sepsis&#44; pneumonia&#59; ACS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMAO predictive biomarker of death due to corrected HF &#40;HR&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;16&#44; p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41;&#46; TMAO lost the predictive capacity with the inclusion of renal function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMAO analyses were not strictly time controlled due to emergency admissions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cui et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">China &#40;2017&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with acute HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94 &#40;53<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F&#47;41 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#46;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;30 years&#47;53&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;94 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">History of ACS in the last 6 monthsComorbiditiesUse of antibiotics or probiotics in the previous month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decrease in <span class="elsevierStyleItalic">Faecalibacterium prausnitzii</span> and increase of <span class="elsevierStyleItalic">Ruminococcus gnavus</span>Imbalance in intestinal microbes involved in the metabolism of protective and harmful metabolites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cannot be extrapolated to patients without acute HFPatients with comorbidities &#40;HBP&#44; DLP and DM&#41; are not excluded&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kamo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan &#40;2017&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with HF &#40;NYHA II-IV&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;22<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60 years 12 and<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60 years 10&#47;12 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8 years and 73&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;8 years&#47;41&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant diseases &#40;active infection&#44; inflammatory disease&#44; neoplasms&#44; renal failure&#41;Treatment with antibiotics&#44; probiotics or immunosuppressants in the previous 2 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intestinal dysbiosis varies even more according to age<span class="elsevierStyleItalic">Eubacterium rectole</span> and <span class="elsevierStyleItalic">Dorea longicatena</span> reduced in HF<span class="elsevierStyleItalic">Faecalibacterium prausnitzii</span> and <span class="elsevierStyleItalic">Clostridioforme Clostridium</span> were less abundant in older HF patients&#44; compared to younger&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small sampleCross-sectional study&#46; A longitudinal study is required to explore possible change in the intestinal microbiome during the course of HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Katsimichas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with reduced HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65 &#40;28 reduced HF&#47;37 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10 years&#47;57&#46;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adjustment for age&#44; ethnicity&#44; renal function and diet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Differences in the intestinal microbial communities at the level of basal structure and extensions of the metagenomic transport of metabolic pathways and interactions of bacterial taxa in HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small sample sizeInability to match test and control group by age&#44; renal function and medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Luedde et al&#46;<span class="elsevierStyleSup">3&#46; 4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Germany &#40;2017&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with reduced chronic HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;20<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleHsp" style=""></span>F&#47;20 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;17 years&#47;65&#46;20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;07 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adjust for age&#44; sex&#44; BMI and smokingConcomitant diseasesAntibiotic&#47;probiotic treatments 3 months prior&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The depletion of the genera <span class="elsevierStyleItalic">Blautia</span> and <span class="elsevierStyleItalic">Collinsella</span>&#44; as well as <span class="elsevierStyleItalic">Erysipelotrichaceae</span> and <span class="elsevierStyleItalic">Ruminococcaceae</span>&#44; could be specific to HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small sample sizeThe influence of the multiple factors that occur in HF&#44; in addition to infections and antibiotic treatment cannot be excluded&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Huntley et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Spain &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with decompensated HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 CHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant diseases &#40;infection&#44; diarrhoea&#44; ACS&#44; neoplasms&#41;Antibiotic treatment&#44; corticosteroids in the previous month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No pathogenic intestinal bacteria have been cultured from any patient&#44; except one with <span class="elsevierStyleItalic">Clostridium difficile</span> B&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small cohort sizeSingle centerNon-longitudinal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kummen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Norway &#40;2018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with HF &#40;NYHA II-IV&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">350 &#40;84 CHF&#47;266 control&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No available data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adjustment for age&#44; sex&#44; body mass index&#44; hypertension and diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Depletion of butyrate-producing bacteria in HFInverse correlation between <span class="elsevierStyleItalic">Lachnospiraceae</span> and CD25<span class="elsevierStyleHsp" style=""></span>T cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preliminary data with the need to confirm the results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Articles included in the systematic review&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:47 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiolog&#237;a de la insuficiencia cardiaca en Espa&#241;a en los &#250;ltimos 20 a&#241;os"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "I&#46; Sayago-Silva"
                            1 => "F&#46; Garc&#237;a-L&#243;pez"
                            2 => "J&#46; Segovia-Cubero"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.rec.2013.03.012"
                      "Revista" => array:7 [
                        "tituloSerie" => "Rev Esp Cardiol&#46;"
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                        "volumen" => "66"
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                        "paginaFinal" => "736"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24776334"
                            "web" => "Medline"
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                        "itemHostRev" => array:3 [
                          "pii" => "S0890856709603427"
                          "estado" => "S300"
                          "issn" => "08908567"
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            1 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mensajes clave para la atenci&#243;n inicial del anciano con insuficiencia cardiaca aguda"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "F&#46;J&#46; Mart&#237;n-S&#225;nchez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.regg.2015.02.005"
                      "Revista" => array:6 [
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                        "link" => array:1 [
                          0 => array:2 [
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              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and mortality of heart failure&#58; a community-based study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;M&#46; Gomez-Soto"
                            1 => "J&#46;L&#46; Andrey"
                            2 => "A&#46;A&#46; Garcia-Egido"
                            3 => "M&#46;A&#46; Escobar"
                            4 => "S&#46;P&#46; Romero"
                            5 => "R&#46; Garcia-Arjona"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2010.04.055"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol&#46;"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20471122"
                            "web" => "Medline"
                          ]
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                  ]
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              ]
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            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Trends in comorbidity&#44; disability&#44; and polypharmacy in heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "C&#46;Y&#46; Wong"
                            1 => "S&#46;I&#46; Chaudhry"
                            2 => "M&#46;M&#46; Desai"
                            3 => "H&#46;M&#46; Krumholz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjmed.2010.08.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med&#46;"
                        "fecha" => "2011"
                        "volumen" => "124"
                        "paginaInicial" => "136"
                        "paginaFinal" => "143"
                        "link" => array:1 [
                          0 => array:2 [
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                ]
              ]
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              "identificador" => "bib0025"
              "etiqueta" => "5"
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                    0 => array:2 [
                      "titulo" => "Insuficiencia card&#237;aca cr&#243;nica en el paciente anciano"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46; Chivite"
                            1 => "J&#46; Franco"
                            2 => "F&#46; Formiga"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.regg.2015.02.010"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Esp Geriatr Gerontol&#46;"
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                        "volumen" => "50"
                        "paginaInicial" => "209"
                        "paginaFinal" => "260"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25881763"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology and risk profile of heart failure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;L&#46; Bui"
                            1 => "T&#46;B&#46; Horwich"
                            2 => "G&#46;C&#46; Fonarow"
                          ]
                        ]
                      ]
                    ]
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