Utility of B-type natriuretic peptide measurement in outpatients with heart failure with preserved ejection fraction | Revista Portuguesa de Cardiologia (English edition)

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"titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Utilidade do doseamento do peptídeo natriurético tipo B em doentes ambulatórios com insuficiência cardíaca com fração de ejeção preservada" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1848 "Ancho" => 2375 "Tamanyo" => 171823 ] ] "descripcion" => array:1 [ "en" => "Receiver-operator characteristic curve identifying the best cutoff for B-type natriuretic peptide to diagnose heart failure with preserved ejection fraction in outpatients. AUC: area under the curve; CI: confidence interval." ] ] ] "textoCompleto" => "IntroductionHeart failure (HF) is a major public health problem worldwide – one in five people aged over 40 will develop HF at some stage – and in Brazil it is the leading cause of hospitalization in those aged over 60.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Over half of these patients are classified as having HF with preserved ejection fraction (HFPEF)<a class="elsevierStyleCrossRef" href="#bib0010">2</a>; this proportion is growing in both developed and developing countries due to ageing populations and increased awareness among physicians of the syndrome, which predominantly affects women and those with multiple comorbidities.<a class="elsevierStyleCrossRefs" href="#bib0015">3–5</a> The costs associated with HF are high, for both hospitalization and outpatient care, irrespective of left ventricular ejection fraction (LVEF). A simple exam would thus be useful for screening these patients with a view to more thorough investigation.<a class="elsevierStyleCrossRefs" href="#bib0010">2–6</a>B-type natriuretic peptide (BNP) is released in response to increased left ventricular (LV) filling pressure<a class="elsevierStyleCrossRef" href="#bib0035">7</a> and end-diastolic wall stress,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and plasma BNP levels can help in both diagnosis (confirming or excluding HF) and prognostic assessment of HF.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a>Paulus et al.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> proposed criteria for the diagnosis of HFPEF that included Doppler echocardiographic parameters and BNP measurement. The BNP cutoff used was based on data from a study by Maisel et al. of patients admitted to the emergency room with acute HF.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>However, BNP assessment in outpatients show lower values than those suggested by Paulus et al. for a diagnosis of HFPEF, although with different Doppler echocardiographic criteria for diagnostic confirmation.<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>The use of the BNP cutoff proposed by Paulus et al. has not been validated in clinical practice for outpatients, but BNP measurement, an inexpensive exam, may help to exclude HFPEF and thus direct investigation of a patient's symptoms to other areas.The aim of this study was to determine the diagnostic accuracy of BNP measurement and the best cutoff to confirm or exclude HFPEF in outpatients using the criteria proposed by Paulus et al.MethodsPopulationThis prospective, observational, cross-sectional study enrolled 161 consecutive outpatients (mean age 68.1±11.5 years; 72% female) with suspected HF. All were in New York Heart Association (NYHA) functional class II or III. HFPEF was defined in accordance with the European Society of Cardiology (ESC) criteria, which include signs or symptoms of HF, LVEF >50%, LV end-diastolic volume index <97 ml/m2 and diastolic LV dysfunction.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Diagnostic evidence of diastolic dysfunction was obtained by tissue Doppler echocardiography showing an E/E’ ratio of >15. According to the ESC guidelines, if the E/E’ ratio is suggestive of diastolic dysfunction (8-15), other echocardiographic measures should be used to confirm the diagnosis such as LV mass index (>122 and >149 g/m2 for women and men, respectively), left atrial volume index (LAVI) (>40 ml/m2), and E/A ratio <0.5 with E deceleration time >280 ms. An electrocardiogram showing atrial fibrillation with an E/E’ ratio of 8-15 also confirms the diagnosis of HFPEF.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Patients with severe valve disease, permanent pacemaker or chronic obstructive pulmonary disease, as well as those who had undergone cardiac surgery in the previous six months, were excluded. The study was conducted in accordance with the Helsinki declaration and the protocol was approved by the institution's ethics committee (no. 00410.258.000-08); all patients gave their written informed consent to inclusion in the study.Conventional and tissue Doppler echocardiographyDoppler echocardiography was performed on a VIVID 7 ultrasound system (GE®, USA), and the images analyzed in EchoPac software by an experienced investigator blinded to the results of other exams. The exam was carried out in accordance with the recommendations for chamber quantification of the American Society of Echocardiography/European Association of Echocadiography.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Systolic function was assessed by estimation of LVEF and longitudinal strain (S’) by tissue Doppler.LAVI was calculated by Simpson's biplane method based on apical 2- and 4-chamber views in LV end-systole, indexed to body surface area. Diastolic function was estimated on the basis of the mean of five consecutive cycles. Early (E) and late (A) transmitral flow and E-wave deceleration time were measured. Myocardial relaxation velocity at beginning diastole (E’) was measured by tissue Doppler at the septal and lateral segments of the mitral annulus and the mean used in the analysis. All exams were recorded in digital form for subsequent analysis and review.ElectrocardiographyAll patients underwent 12-lead resting ECG to screen for atrial fibrillation.B-type natriuretic peptidePlasma BNP was measured by the Triage BNP test (Biosite USA), a rapid fluorescence immunoassay for quantitative BNP measurement using the Triage meter. BNP values were expressed in pg/ml.Statistical analysisThe statistical analysis was performed using SPSS® version 15.0. Continuous variables with normal distribution were expressed as means ± standard deviation, and the remainder as medians. ANOVA and the chi-square test were used to determine differences in means between the continuous variables with normal distribution, between those with abnormal distribution and between categorical variables, respectively. Spearman's correlation (r) was used to measure the association between BNP levels and clinical and echocardiographic variables. A receiver-operator characteristic (ROC) curve was constructed to determine the sensitivity and specificity of BNP for a diagnosis of HFPEF. A level of statistical significance of 0.05 was adopted.ResultsThe demographic, clinical, laboratory and echocardiographic characteristics of the study population are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, from which it can be seen that patients with HFPEF were older, and had a higher prevalence of hypertension, diabetes and atrial fibrillation and lower glomerular filtration rate (GFR) than those without HFPEF. LV function assessed by Doppler echocardiography showed more marked systolic and diastolic dysfunction in the group with HFPEF.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>BNP levels were significantly different between those with and without HFPEF (mean 144.4 pg/ml, median 113 pg/ml vs. mean 27.6 pg/ml, median 16.7 pg/ml, respectively, p<0.0001).<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the correlations between BNP and clinical and echocardiographic variables. There was a direct correlation between BNP and LAVI, age and E/E’ ratio and an indirect correlation with estimated GFR.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The area under the ROC curve for BNP to detect HFPEF was 0.92 (95% confidence interval [CI] 0.87-0.96, p<0.0001) (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>), and 51 pg/ml was the most appropriate cutoff to detect HFPEF, with sensitivity of 86%, specificity of 86%, positive predictive value of 93%, negative predictive value of 72%, and diagnostic accuracy of 86%.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiscussionThis is the first prospective study to use the ESC criteria<a class="elsevierStyleCrossRef" href="#bib0030">6</a> for the diagnosis of HFPEF in outpatients and to demonstrate that HFPEF patients present high BNP values, although lower than those found in emergency room patients. Our results suggest that BNP cutoffs for a diagnosis of HFPEF in outpatients may be lower than those in the ESC consensus statement, which was based on studies in patients presenting with acute HF.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>In the emergency room, signs and symptoms of congestive HF are usually present and since many patients are hospitalized due to acute pulmonary edema, BNP levels are higher than in outpatients, as demonstrated in a study of 1586 emergency room patients, in whom a BNP cutoff of 100 pg/ml had sensitivity of 90% and specificity of 76%, irrespective of LVEF, for differentiating acute HF from other causes of dyspnea.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Exertional dyspnea may be the only symptom in out-patients with HFPEF, with no sign of congestion, and those most commonly affected are women, the elderly, the obese, and those with multiple comorbidities.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> The diagnosis of HFPEF in such cases is a challenge to physicians and a biomarker such as BNP may be useful in identifying these patients, but based on lower BNP levels than in emergency room patients.Our results show that patients with HFPEF present significant diastolic dysfunction, characterized by alterations in ventricular relaxation (E’) and increased LV filling pressures (as shown by LAVI and E/E’ ratio) but normal LVEF. The correlation observed between BNP values and echocardiographic parameters reflects the association between BNP and LV diastolic function, and BNP measurement is thus a useful and simple exam to assess dyspnea in outpatients with suspected HF.Arques et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> studied 26 outpatients presenting chronic dyspnea as the only manifestation of HF who underwent cardiac catheterization, which is considered the gold standard exam to confirm a diagnosis of HFPEF.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The study showed that BNP of 31 pg/ml was predictive of HFPEF (p=0.003), with 67% sensitivity and 73% specificity (area under the ROC curve 0.76, 95% CI: 0.55-0.90; p=0.007).<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Penicka et al.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> assessed 30 outpatients (73% female) with unexplained chronic dyspnea, in NYHA functional class II or III and LVEF >50%, who underwent cardiac catheterization. HFPEF was defined as LV end-diastolic pressure of >16 mmHg at rest during hemodynamic study, and HFPEF was confirmed in 20 of these patients (66%). BNP was higher in the HFPEF group than in controls (68 pg/ml vs. 21 pg/ml, p=0.09), but only three patients had BNP levels above the cutoff recommended by Paulus et al. (200 pg/ml) for a diagnosis of HFPEF.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Kitzman et al.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> assessed 147 outpatients, of whom 59 had HFPEF; mean BNP in this group was 56±30 pg/ml.Our findings are consistent with the results of the above studies<a class="elsevierStyleCrossRefs" href="#bib0065">13,17,19</a> in terms of BNP cutoff points in patients with HFPEF, and confirm that outpatients with HFPEF can have BNP levels well below the cutoffs established by the ESC.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Determining a more appropriate BNP cutoff than those currently used could help in screening outpatients with suspected HFPEF. Zuber et al. studied 384 primary care patients to assess the accuracy of BNP for diagnosing HF as determined by clinical and echocardiographic data and found that 31 (8%) had HFPEF and 193 (50%) had systolic HF with reduced ejection fraction. The recommended BNP cutoff of 100 pg/ml was used to diagnose or exclude HF, which gave a false negative result in 25% of patients with HF. The study concluded that this cutoff failed to exclude HF in primary care patients.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>The latest ESC guidelines for the diagnosis and treatment of acute and chronic HF<a class="elsevierStyleCrossRef" href="#bib0105">21</a> propose a new BNP cutoff of 35 pg/ml to exclude HF (with reduced or preserved ejection fraction) in outpatients, which may reduce the number of false negatives and unnecessary echocardiographic exams. This cutoff was based on data from eight studies<a class="elsevierStyleCrossRefs" href="#bib0110">22–29</a> that analyzed patients with suspected HF or at risk of developing HF due to ventricular dysfunction. The cutoff of 51 pg/ml determined in our study is specific to HFPEF and showed a positive predictive value of 93% and negative predictive value of 72%, making it useful to confirm or exclude HFPEF in outpatients.In view of the ageing of populations, which will increase the number of cases of HFPEF, BNP measurement could be a less costly and simpler way to screen outpatients for suspected HF than echocardiography.Certain limitations of our study should be borne in mind. As the absolute number of patients in whom HFPEF was confirmed was small, and given the heterogeneous nature of the syndrome, and the fact that comorbidities can effect BNP levels, further studies involving large samples of outpatients will be required to validate our findings.ConclusionsBNP levels in outpatients with HFPEF, as diagnosed by ESC criteria, are higher than in those without HFPEF. In the study population, a cutoff of 51 pg/ml had the best diagnostic accuracy to identify HFPEF in outpatients.Ethical disclosuresProtection of human and animal subjectsThe authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).Confidentiality of dataThe authors declare that they have followed the protocols of their work center on the publication of patient data and that all the patients included in the study received sufficient information and gave their written informed consent to participate in the study.Right to privacy and informed consentThe authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres296965" "titulo" => array:4 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods and Results" 3 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec280629" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres296964" "titulo" => array:3 [ 0 => "Resumo" 1 => "Métodos/resultados" 2 => "Conclusão" ] ] 3 => array:2 [ "identificador" => "xpalclavsec280630" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Conventional and tissue Doppler echocardiography" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Electrocardiography" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "B-type natriuretic peptide" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions" ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-06-14" "fechaAceptado" => "2012-10-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec280629" "palabras" => array:4 [ 0 => "B-type natriuretic peptide" 1 => "Heart failure" 2 => "Diastole" 3 => "Outpatients" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec280630" "palabras" => array:4 [ 0 => "Peptídeo natriurético tipo B" 1 => "Insuficiência cardíaca" 2 => "Diástole" 3 => "Doentes ambulatórios" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionHeart failure with preserved ejection fraction (HFPEF) is a highly prevalent syndrome that is difficult to diagnose in outpatients. The measurement of B-type natriuretic peptide (BNP) may be useful in the diagnosis of HFPEF, but with a different cutoff from that used in the emergency room. The aim of this study was to identify the BNP cutoff for a diagnosis of HFPEF in outpatients. Methods and ResultsThis prospective, observational study enrolled 161 outpatients (aged 68.1±11.5 years, 72% female) with suspected HFPEF. Patients underwent ECG, tissue Doppler imaging, and plasma BNP measurement, and were classified in accordance with algorithms for the diagnosis of HFPEF. HFPEF was confirmed in 49 patients, who presented higher BNP values (mean 144.4 pg/ml, median 113 pg/ml, vs. mean 27.6 pg/ml, median 16.7 pg/ml, p<0.0001). The results showed a significant correlation between BNP levels and left atrial volume index (r=0.554, p<0.0001), age (r=0.452; p<0.0001) and E/E′ ratio (r=0.345, p<0.0001). The area under the ROC curve for BNP to detect HFPEF was 0.92 (95% confidence interval: 0.87-0.96; p<0.001), and 51 pg/ml was identified as the best cutoff to detect HFPEF, with sensitivity of 86%, specificity of 86% and accuracy of 86%. ConclusionsBNP levels in outpatients with HFPEF are significantly higher than in those without. A cutoff value of 51 pg/ml had the best diagnostic accuracy in outpatients." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "Insuficiência cardíaca com fração de ejeção preservada (ICFEP) é uma síndrome de alta prevalência e difícil diagnóstico no ambulatório. O doseamento de peptídeo natriurético tipo B (BNP) pode ser útil no diagnóstico de ICFEP, porém com valor de corte diferente daquele utilizado na sala de emergência. O objetivo desse estudo foi identificar o ponto de corte do BNP em doentes ambulatórios para diagnóstico de ICFEP. Métodos/resultadosEstudo prospectivo observacional envolvendo 161 doentes ambulatórios (68,1 ± 11,5 anos, 72% mulheres) com suspeita de ICFEP. Doentes foram submetidos a exame clínico, eletrocardiograma, ecocardiograma com Doppler tecidual e doseamento de BNP e classificados de acordo com critérios propostos por Paulus et al. para diagnóstico de ICFEP. ICFEP foi confirmada em 49 doentes que apresentavam valores mais elevados de BNP (144,4 pg/mL mediana 113 pg/mL versus 27,6 pg/mL mediana 16,7 pg/mL p < 0,0001). Uma correlação significativa foi mostrada entre BNP e volume da aurícula esquerda indexada (rho = 0,554, p < 0,0001), idade (rho = 0,452, p < 0,0001) e relação E/E’ (rho = 0,345, p < 0,0001). A área sob a curva ROC para BNP detectar ICFEP foi 0,92 (95% IC, 0,87-0,96, p < 0,0001) e o valor de corte de 51 pg/mL foi o que melhor se correlacionou com o diagnóstico de ICFEP (sensibilidade 86%, especificidade 86%, acuidade de 86%). ConclusãoValores de BNP em doentes ambulatórios com ICFEP são significativamente mais elevados que os valores dos doentes sem ICFEP. O valor de corte do BNP de 51 pg/mL apresentou melhor acuidade diagnóstica para ICFEP em doentes ambulatórios." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Lagoeiro Jorge AJ, Di Calafiori Freire M, Ribeiro ML, et al. Utilidade do doseamento do peptídeo natriurético tipo B em doentes ambulatórios com insuficiência cardíaca com fração de ejeção preservada. Rev Port Cardiol. 2013;32:647–652." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1848 "Ancho" => 2375 "Tamanyo" => 171823 ] ] "descripcion" => array:1 [ "en" => "Receiver-operator characteristic curve identifying the best cutoff for B-type natriuretic peptide to diagnose heart failure with preserved ejection fraction in outpatients. AUC: area under the curve; CI: confidence interval." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "BMI: body mass index; BNP: B-type natriuretic peptide; GFR: glomerular filtration rate; HR: heart rate; hsCRP: high sensitivity C-reactive protein; LAVI: left atrial volume index; LV: left ventricular; LVEF: left ventricular ejection fraction; SBP: systolic blood pressure. Categorical variables – Pearson's chi-square; Numerical variables – ANOVA; a median; b not assessed in patients with atrial fibrillation (n=143). Significant differences between the groups for p<0.05." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Total (n=161) \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">With HFPEF (n=49) \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Without HFPEF (n=112) \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><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">BNP (pg/ml)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">63.1 (28.3) \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">144.4 (113) \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">27.6 (16.7) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">Age (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">68.1±11.5 \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">74.7±11.5 \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±10.4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">Female (%) \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">72 \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 \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">69 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.110 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">HR (bpm) \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">77±16 \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">83±21 \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">74±14 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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 (kg/m2) \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">29.4±6.0 \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">28.9±6.7 \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">29.6±5.7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.546 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">hsCRP (mg/dl)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">0.54 (0.30) \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">0.48 (0.30) \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">0.57 (0.32) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.527 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><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">Hypertension (%) \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">90 \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 \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">88 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.221 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">SBP (mmHg) \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">153±26 \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">159±28 \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">150±24 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.036 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><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">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">29 \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">41 \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">23 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.020 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">Blood glucose (mg/dl) \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">106±30 \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±37 \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">103±25 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.072 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><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">Atrial fibrillation (%) \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><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">31 \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><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal function</td></tr><tr title="table-row"><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">Creatinine (mg/dl) \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">0.91±0.27 \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">0.95±0.24 \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">0.88±0.28 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.135 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">GFR (ml/min) \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">87.1±40.3 \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">71.2±33.3 \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">94.1±41.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systolic function</td></tr><tr title="table-row"><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">LVEF (%) \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">73±8 \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">71±9 \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">74±8 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.028 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">S’ (cm/s) \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">8.9±2.4 \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">7.6±2.2 \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">9.4±2.3 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diastolic function</td></tr><tr title="table-row"><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">E’ (cm/s) \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">8.9±2.7 \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">7.8±2.6 \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">9.4±2.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">E/E’ ratio \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">9.5±4.8 \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">14.0±6.1 \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">7.6±2.2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">LAVI (ml/m2) \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">33.4±12.0 \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">44.5±12.8 \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">28.5±7.6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">E/A ratiob \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">0.88±0.47 \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">1.1±0.76 \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">0.83±0.31 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.006 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">LV mass index (g/m2) \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">90.1±24.2 \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">96.4±25.0 \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">87.7±23.4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.022 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab433157.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic, clinical and laboratory characteristics of the study population, and systolic and diastolic function by Doppler echocardiography and tissue Doppler." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "BNP: B-type natriuretic peptide; GFR: glomerular filtration rate estimated by the Cockcroft-Gault formula; HR: heart rate; LAVI: left atrial volume index; LV: left ventricular; LVEF: left ventricular ejection fraction; SBP: systolic blood pressure. Significant correlation with p=0.05." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Spearman (r) \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><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">Age (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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.452 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">SBP (mmHg) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-0.012 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.880 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">HR (bpm) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.045 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.570 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">GFR (ml/min) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-0.329 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">LVEF (%) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.049 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.535 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">S’ (cm/s) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-0.203 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.011 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">E’ (cm/s) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-0.147 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.062 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">E/E’ ratio \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.345 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">LAVI (ml/m2) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.554 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">E/A ratio \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-0.077 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.363 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><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">LV mass index (g/m2) \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.059 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.455 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => 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Utility of B-type natriuretic peptide measurement in outpatients with heart failure with preserved ejection fraction

Utilidade do doseamento do peptídeo natriurético tipo B em doentes ambulatórios com insuficiência cardíaca com fração de ejeção preservada

Antonio José Lagoeiro Jorge

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lagoeiro@globo.com

Corresponding author.

, Monica Di Calafiori Freire, Mário Luiz Ribeiro, Luiz Cláudio Maluhy Fernandes, Pedro Gemal Lanzieri, Bruno Afonso Lagoeiro Jorge, João Gabriel B Lage, Maria Luiza Garcia Rosa, Evandro Tinoco Mesquita

Departamento de Medicina Clínica, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil

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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Receiver-operator characteristic curve identifying the best cutoff for B-type natriuretic peptide to diagnose heart failure with preserved ejection fraction in outpatients&#46; AUC&#58; area under the curve&#59; CI&#58; confidence interval&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure &#40;HF&#41; is a major public health problem worldwide &#8211; one in five people aged over 40 will develop HF at some stage &#8211; and in Brazil it is the leading cause of hospitalization in those aged over 60&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Over half of these patients are classified as having HF with preserved ejection fraction &#40;HFPEF&#41;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#59; this proportion is growing in both developed and developing countries due to ageing populations and increased awareness among physicians of the syndrome&#44; which predominantly affects women and those with multiple comorbidities&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> The costs associated with HF are high&#44; for both hospitalization and outpatient care&#44; irrespective of left ventricular ejection fraction &#40;LVEF&#41;&#46; A simple exam would thus be useful for screening these patients with a view to more thorough investigation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide &#40;BNP&#41; is released in response to increased left ventricular &#40;LV&#41; filling pressure<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and end-diastolic wall stress&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and plasma BNP levels can help in both diagnosis &#40;confirming or excluding HF&#41; and prognostic assessment of HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Paulus et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> proposed criteria for the diagnosis of HFPEF that included Doppler echocardiographic parameters and BNP measurement&#46; The BNP cutoff used was based on data from a study by Maisel et al&#46; of patients admitted to the emergency room with acute HF&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; BNP assessment in outpatients show lower values than those suggested by Paulus et al&#46; for a diagnosis of HFPEF&#44; although with different Doppler echocardiographic criteria for diagnostic confirmation&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The use of the BNP cutoff proposed by Paulus et al&#46; has not been validated in clinical practice for outpatients&#44; but BNP measurement&#44; an inexpensive exam&#44; may help to exclude HFPEF and thus direct investigation of a patient&#39;s symptoms to other areas&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The aim of this study was to determine the diagnostic accuracy of BNP measurement and the best cutoff to confirm or exclude HFPEF in outpatients using the criteria proposed by Paulus et al&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Population</span><p id="par0040" class="elsevierStylePara elsevierViewall">This prospective&#44; observational&#44; cross-sectional study enrolled 161 consecutive outpatients &#40;mean age 68&#46;1&#177;11&#46;5 years&#59; 72&#37; female&#41; with suspected HF&#46; All were in New York Heart Association &#40;NYHA&#41; functional class II or III&#46; HFPEF was defined in accordance with the European Society of Cardiology &#40;ESC&#41; criteria&#44; which include signs or symptoms of HF&#44; LVEF &#62;50&#37;&#44; LV end-diastolic volume index &#60;97 ml&#47;m<span class="elsevierStyleSup">2</span> and diastolic LV dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Diagnostic evidence of diastolic dysfunction was obtained by tissue Doppler echocardiography showing an E&#47;E&#8217; ratio of &#62;15&#46; According to the ESC guidelines&#44; if the E&#47;E&#8217; ratio is suggestive of diastolic dysfunction &#40;8-15&#41;&#44; other echocardiographic measures should be used to confirm the diagnosis such as LV mass index &#40;&#62;122 and &#62;149 g&#47;m<span class="elsevierStyleSup">2</span> for women and men&#44; respectively&#41;&#44; left atrial volume index &#40;LAVI&#41; &#40;&#62;40 ml&#47;m<span class="elsevierStyleSup">2</span>&#41;&#44; and E&#47;A ratio &#60;0&#46;5 with E deceleration time &#62;280 ms&#46; An electrocardiogram showing atrial fibrillation with an E&#47;E&#8217; ratio of 8-15 also confirms the diagnosis of HFPEF&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Patients with severe valve disease&#44; permanent pacemaker or chronic obstructive pulmonary disease&#44; as well as those who had undergone cardiac surgery in the previous six months&#44; were excluded&#46; The study was conducted in accordance with the Helsinki declaration and the protocol was approved by the institution&#39;s ethics committee &#40;no&#46; 00410&#46;258&#46;000-08&#41;&#59; all patients gave their written informed consent to inclusion in the study&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conventional and tissue Doppler echocardiography</span><p id="par0055" class="elsevierStylePara elsevierViewall">Doppler echocardiography was performed on a VIVID 7 ultrasound system &#40;GE&#174;&#44; USA&#41;&#44; and the images analyzed in EchoPac software by an experienced investigator blinded to the results of other exams&#46; The exam was carried out in accordance with the recommendations for chamber quantification of the American Society of Echocardiography&#47;European Association of Echocadiography&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Systolic function was assessed by estimation of LVEF and longitudinal strain &#40;S&#8217;&#41; by tissue Doppler&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">LAVI was calculated by Simpson&#39;s biplane method based on apical 2- and 4-chamber views in LV end-systole&#44; indexed to body surface area&#46; Diastolic function was estimated on the basis of the mean of five consecutive cycles&#46; Early &#40;E&#41; and late &#40;A&#41; transmitral flow and E-wave deceleration time were measured&#46; Myocardial relaxation velocity at beginning diastole &#40;E&#8217;&#41; was measured by tissue Doppler at the septal and lateral segments of the mitral annulus and the mean used in the analysis&#46; All exams were recorded in digital form for subsequent analysis and review&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Electrocardiography</span><p id="par0070" class="elsevierStylePara elsevierViewall">All patients underwent 12-lead resting ECG to screen for atrial fibrillation&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">B-type natriuretic peptide</span><p id="par0075" class="elsevierStylePara elsevierViewall">Plasma BNP was measured by the Triage BNP test &#40;Biosite USA&#41;&#44; a rapid fluorescence immunoassay for quantitative BNP measurement using the Triage meter&#46; BNP values were expressed in pg&#47;ml&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The statistical analysis was performed using SPSS<span class="elsevierStyleSup">&#174;</span> version 15&#46;0&#46; Continuous variables with normal distribution were expressed as means &#177; standard deviation&#44; and the remainder as medians&#46; ANOVA and the chi-square test were used to determine differences in means between the continuous variables with normal distribution&#44; between those with abnormal distribution and between categorical variables&#44; respectively&#46; Spearman&#39;s correlation &#40;r&#41; was used to measure the association between BNP levels and clinical and echocardiographic variables&#46; A receiver-operator characteristic &#40;ROC&#41; curve was constructed to determine the sensitivity and specificity of BNP for a diagnosis of HFPEF&#46; A level of statistical significance of 0&#46;05 was adopted&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0085" class="elsevierStylePara elsevierViewall">The demographic&#44; clinical&#44; laboratory and echocardiographic characteristics of the study population are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; from which it can be seen that patients with HFPEF were older&#44; and had a higher prevalence of hypertension&#44; diabetes and atrial fibrillation and lower glomerular filtration rate &#40;GFR&#41; than those without HFPEF&#46; LV function assessed by Doppler echocardiography showed more marked systolic and diastolic dysfunction in the group with HFPEF&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">BNP levels were significantly different between those with and without HFPEF &#40;mean 144&#46;4 pg&#47;ml&#44; median 113 pg&#47;ml vs&#46; mean 27&#46;6 pg&#47;ml&#44; median 16&#46;7 pg&#47;ml&#44; respectively&#44; p&#60;0&#46;0001&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the correlations between BNP and clinical and echocardiographic variables&#46; There was a direct correlation between BNP and LAVI&#44; age and E&#47;E&#8217; ratio and an indirect correlation with estimated GFR&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">The area under the ROC curve for BNP to detect HFPEF was 0&#46;92 &#40;95&#37; confidence interval &#91;CI&#93; 0&#46;87-0&#46;96&#44; p&#60;0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#44; and 51 pg&#47;ml was the most appropriate cutoff to detect HFPEF&#44; with sensitivity of 86&#37;&#44; specificity of 86&#37;&#44; positive predictive value of 93&#37;&#44; negative predictive value of 72&#37;&#44; and diagnostic accuracy of 86&#37;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">This is the first prospective study to use the ESC criteria<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> for the diagnosis of HFPEF in outpatients and to demonstrate that HFPEF patients present high BNP values&#44; although lower than those found in emergency room patients&#46; Our results suggest that BNP cutoffs for a diagnosis of HFPEF in outpatients may be lower than those in the ESC consensus statement&#44; which was based on studies in patients presenting with acute HF&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In the emergency room&#44; signs and symptoms of congestive HF are usually present and since many patients are hospitalized due to acute pulmonary edema&#44; BNP levels are higher than in outpatients&#44; as demonstrated in a study of 1586 emergency room patients&#44; in whom a BNP cutoff of 100 pg&#47;ml had sensitivity of 90&#37; and specificity of 76&#37;&#44; irrespective of LVEF&#44; for differentiating acute HF from other causes of dyspnea&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Exertional dyspnea may be the only symptom in out-patients with HFPEF&#44; with no sign of congestion&#44; and those most commonly affected are women&#44; the elderly&#44; the obese&#44; and those with multiple comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The diagnosis of HFPEF in such cases is a challenge to physicians and a biomarker such as BNP may be useful in identifying these patients&#44; but based on lower BNP levels than in emergency room patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Our results show that patients with HFPEF present significant diastolic dysfunction&#44; characterized by alterations in ventricular relaxation &#40;E&#8217;&#41; and increased LV filling pressures &#40;as shown by LAVI and E&#47;E&#8217; ratio&#41; but normal LVEF&#46; The correlation observed between BNP values and echocardiographic parameters reflects the association between BNP and LV diastolic function&#44; and BNP measurement is thus a useful and simple exam to assess dyspnea in outpatients with suspected HF&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Arques et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> studied 26 outpatients presenting chronic dyspnea as the only manifestation of HF who underwent cardiac catheterization&#44; which is considered the gold standard exam to confirm a diagnosis of HFPEF&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The study showed that BNP of 31 pg&#47;ml was predictive of HFPEF &#40;p&#61;0&#46;003&#41;&#44; with 67&#37; sensitivity and 73&#37; specificity &#40;area under the ROC curve 0&#46;76&#44; 95&#37; CI&#58; 0&#46;55-0&#46;90&#59; p&#61;0&#46;007&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Penicka et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> assessed 30 outpatients &#40;73&#37; female&#41; with unexplained chronic dyspnea&#44; in NYHA functional class II or III and LVEF &#62;50&#37;&#44; who underwent cardiac catheterization&#46; HFPEF was defined as LV end-diastolic pressure of &#62;16 mmHg at rest during hemodynamic study&#44; and HFPEF was confirmed in 20 of these patients &#40;66&#37;&#41;&#46; BNP was higher in the HFPEF group than in controls &#40;68 pg&#47;ml vs&#46; 21 pg&#47;ml&#44; p&#61;0&#46;09&#41;&#44; but only three patients had BNP levels above the cutoff recommended by Paulus et al&#46; &#40;200 pg&#47;ml&#41; for a diagnosis of HFPEF&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Kitzman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> assessed 147 outpatients&#44; of whom 59 had HFPEF&#59; mean BNP in this group was 56&#177;30 pg&#47;ml&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Our findings are consistent with the results of the above studies<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;17&#44;19</span></a> in terms of BNP cutoff points in patients with HFPEF&#44; and confirm that outpatients with HFPEF can have BNP levels well below the cutoffs established by the ESC&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Determining a more appropriate BNP cutoff than those currently used could help in screening outpatients with suspected HFPEF&#46; Zuber et al&#46; studied 384 primary care patients to assess the accuracy of BNP for diagnosing HF as determined by clinical and echocardiographic data and found that 31 &#40;8&#37;&#41; had HFPEF and 193 &#40;50&#37;&#41; had systolic HF with reduced ejection fraction&#46; The recommended BNP cutoff of 100 pg&#47;ml was used to diagnose or exclude HF&#44; which gave a false negative result in 25&#37; of patients with HF&#46; The study concluded that this cutoff failed to exclude HF in primary care patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The latest ESC guidelines for the diagnosis and treatment of acute and chronic HF<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> propose a new BNP cutoff of 35 pg&#47;ml to exclude HF &#40;with reduced or preserved ejection fraction&#41; in outpatients&#44; which may reduce the number of false negatives and unnecessary echocardiographic exams&#46; This cutoff was based on data from eight studies<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;29</span></a> that analyzed patients with suspected HF or at risk of developing HF due to ventricular dysfunction&#46; The cutoff of 51 pg&#47;ml determined in our study is specific to HFPEF and showed a positive predictive value of 93&#37; and negative predictive value of 72&#37;&#44; making it useful to confirm or exclude HFPEF in outpatients&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In view of the ageing of populations&#44; which will increase the number of cases of HFPEF&#44; BNP measurement could be a less costly and simpler way to screen outpatients for suspected HF than echocardiography&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Certain limitations of our study should be borne in mind&#46; As the absolute number of patients in whom HFPEF was confirmed was small&#44; and given the heterogeneous nature of the syndrome&#44; and the fact that comorbidities can effect BNP levels&#44; further studies involving large samples of outpatients will be required to validate our findings&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0165" class="elsevierStylePara elsevierViewall">BNP levels in outpatients with HFPEF&#44; as diagnosed by ESC criteria&#44; are higher than in those without HFPEF&#46; In the study population&#44; a cutoff of 51 pg&#47;ml had the best diagnostic accuracy to identify HFPEF in outpatients&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical disclosures</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Protection of human and animal subjects</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Confidentiality of data</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data and that all the patients included in the study received sufficient information and gave their written informed consent to participate in the study&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Keywords"
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              "titulo" => "Conventional and tissue Doppler echocardiography"
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              "titulo" => "Electrocardiography"
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              "identificador" => "sec0030"
              "titulo" => "B-type natriuretic peptide"
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              "titulo" => "Right to privacy and informed consent"
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    "fechaRecibido" => "2012-06-14"
    "fechaAceptado" => "2012-10-11"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec280629"
          "palabras" => array:4 [
            0 => "B-type natriuretic peptide"
            1 => "Heart failure"
            2 => "Diastole"
            3 => "Outpatients"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec280630"
          "palabras" => array:4 [
            0 => "Pept&#237;deo natriur&#233;tico tipo B"
            1 => "Insufici&#234;ncia card&#237;aca"
            2 => "Di&#225;stole"
            3 => "Doentes ambulat&#243;rios"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Heart failure with preserved ejection fraction &#40;HFPEF&#41; is a highly prevalent syndrome that is difficult to diagnose in outpatients&#46; The measurement of B-type natriuretic peptide &#40;BNP&#41; may be useful in the diagnosis of HFPEF&#44; but with a different cutoff from that used in the emergency room&#46; The aim of this study was to identify the BNP cutoff for a diagnosis of HFPEF in outpatients&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods and Results</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This prospective&#44; observational study enrolled 161 outpatients &#40;aged 68&#46;1&#177;11&#46;5 years&#44; 72&#37; female&#41; with suspected HFPEF&#46; Patients underwent ECG&#44; tissue Doppler imaging&#44; and plasma BNP measurement&#44; and were classified in accordance with algorithms for the diagnosis of HFPEF&#46; HFPEF was confirmed in 49 patients&#44; who presented higher BNP values &#40;mean 144&#46;4 pg&#47;ml&#44; median 113 pg&#47;ml&#44; vs&#46; mean 27&#46;6 pg&#47;ml&#44; median 16&#46;7 pg&#47;ml&#44; p&#60;0&#46;0001&#41;&#46; The results showed a significant correlation between BNP levels and left atrial volume index &#40;r&#61;0&#46;554&#44; p&#60;0&#46;0001&#41;&#44; age &#40;r&#61;0&#46;452&#59; p&#60;0&#46;0001&#41; and E&#47;E&#8242; ratio &#40;r&#61;0&#46;345&#44; p&#60;0&#46;0001&#41;&#46; The area under the ROC curve for BNP to detect HFPEF was 0&#46;92 &#40;95&#37; confidence interval&#58; 0&#46;87-0&#46;96&#59; p&#60;0&#46;001&#41;&#44; and 51 pg&#47;ml was identified as the best cutoff to detect HFPEF&#44; with sensitivity of 86&#37;&#44; specificity of 86&#37; and accuracy of 86&#37;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">BNP levels in outpatients with HFPEF are significantly higher than in those without&#46; A cutoff value of 51 pg&#47;ml had the best diagnostic accuracy in outpatients&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Insufici&#234;ncia card&#237;aca com fra&#231;&#227;o de eje&#231;&#227;o preservada &#40;ICFEP&#41; &#233; uma s&#237;ndrome de alta preval&#234;ncia e dif&#237;cil diagn&#243;stico no ambulat&#243;rio&#46; O doseamento de pept&#237;deo natriur&#233;tico tipo B &#40;BNP&#41; pode ser &#250;til no diagn&#243;stico de ICFEP&#44; por&#233;m com valor de corte diferente daquele utilizado na sala de emerg&#234;ncia&#46; O objetivo desse estudo foi identificar o ponto de corte do BNP em doentes ambulat&#243;rios para diagn&#243;stico de ICFEP&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0030">M&#233;todos&#47;resultados</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudo prospectivo observacional envolvendo 161 doentes ambulat&#243;rios &#40;68&#44;1 &#177; 11&#44;5 anos&#44; 72&#37; mulheres&#41; com suspeita de ICFEP&#46; Doentes foram submetidos a exame cl&#237;nico&#44; eletrocardiograma&#44; ecocardiograma com Doppler tecidual e doseamento de BNP e classificados de acordo com crit&#233;rios propostos por Paulus et al&#46; para diagn&#243;stico de ICFEP&#46; ICFEP foi confirmada em 49 doentes que apresentavam valores mais elevados de BNP &#40;144&#44;4 pg&#47;mL mediana 113 pg&#47;mL <span class="elsevierStyleItalic">versus</span> 27&#44;6 pg&#47;mL mediana 16&#44;7 pg&#47;mL p &#60; 0&#44;0001&#41;&#46; Uma correla&#231;&#227;o significativa foi mostrada entre BNP e volume da aur&#237;cula esquerda indexada &#40;rho &#61; 0&#44;554&#44; p &#60; 0&#44;0001&#41;&#44; idade &#40;rho &#61; 0&#44;452&#44; p &#60; 0&#44;0001&#41; e rela&#231;&#227;o E&#47;E&#8217; &#40;rho &#61; 0&#44;345&#44; p &#60; 0&#44;0001&#41;&#46; A &#225;rea sob a curva ROC para BNP detectar ICFEP foi 0&#44;92 &#40;95&#37; IC&#44; 0&#44;87-0&#44;96&#44; p &#60; 0&#44;0001&#41; e o valor de corte de 51 pg&#47;mL foi o que melhor se correlacionou com o diagn&#243;stico de ICFEP &#40;sensibilidade 86&#37;&#44; especificidade 86&#37;&#44; acuidade de 86&#37;&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Valores de BNP em doentes ambulat&#243;rios com ICFEP s&#227;o significativamente mais elevados que os valores dos doentes sem ICFEP&#46; O valor de corte do BNP de 51 pg&#47;mL apresentou melhor acuidade diagn&#243;stica para ICFEP em doentes ambulat&#243;rios&#46;</p>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Lagoeiro Jorge AJ&#44; Di Calafiori Freire M&#44; Ribeiro ML&#44; et al&#46; Utilidade do doseamento do pept&#237;deo natriur&#233;tico tipo B em doentes ambulat&#243;rios com insufici&#234;ncia card&#237;aca com fra&#231;&#227;o de eje&#231;&#227;o preservada&#46; Rev Port Cardiol&#46; 2013&#59;32&#58;647&#8211;652&#46;</p>"
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    ]
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        "tipo" => "MULTIMEDIAFIGURA"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Receiver-operator characteristic curve identifying the best cutoff for B-type natriuretic peptide to diagnose heart failure with preserved ejection fraction in outpatients&#46; AUC&#58; area under the curve&#59; CI&#58; confidence interval&#46;</p>"
        ]
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">BMI&#58; body mass index&#59; BNP&#58; B-type natriuretic peptide&#59; GFR&#58; glomerular filtration rate&#59; HR&#58; heart rate&#59; hsCRP&#58; high sensitivity C-reactive protein&#59; LAVI&#58; left atrial volume index&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; SBP&#58; systolic blood pressure&#46; Categorical variables &#8211; Pearson&#39;s chi-square&#59; Numerical variables &#8211; ANOVA&#59; <span class="elsevierStyleSup">a</span> median&#59; <span class="elsevierStyleSup">b</span> not assessed in patients with atrial fibrillation &#40;n&#61;143&#41;&#46; Significant differences between the groups for p&#60;0&#46;05&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Total &#40;n&#61;161&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">With HFPEF &#40;n&#61;49&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Without HFPEF &#40;n&#61;112&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">BNP &#40;pg&#47;ml&#41;</span><span class="elsevierStyleSup">a</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">63&#46;1 &#40;28&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">144&#46;4 &#40;113&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">27&#46;6 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">68&#46;1&#177;11&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">74&#46;7&#177;11&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">65&#46;3&#177;10&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Female &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">72&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">80&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">HR &#40;bpm&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">74&#177;14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;002&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">BMI &#40;kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">28&#46;9&#177;6&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">29&#46;6&#177;5&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SBP &#40;mmHg&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>GFR &#40;ml&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LVEF &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#8217; &#40;cm&#47;s&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>E&#8217; &#40;cm&#47;s&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>E&#47;E&#8217; ratio&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">33&#46;4&#177;12&#46;0&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">BNP&#58; B-type natriuretic peptide&#59; GFR&#58; glomerular filtration rate estimated by the Cockcroft-Gault formula&#59; HR&#58; heart rate&#59; LAVI&#58; left atrial volume index&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; SBP&#58; systolic blood pressure&#46; Significant correlation with p&#61;0&#46;05&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Correlation between BNP and clinical&#44; laboratory and Doppler echocardiographic variables&#46;</p>"
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                      "titulo" => "Doen&#231;as cr&#244;nicas n&#227;o transmiss&#237;veis no Brasil&#58; carga e desafios atuais"
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                          "etal" => true
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                      "doi" => "10.1016/S0140-6736(11)60135-9"
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                        "tituloSerie" => "The Lancet"
                        "fecha" => "2011"
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                0 => array:2 [
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                      "titulo" => "Insufici&#234;ncia card&#237;aca com fra&#231;&#227;o de eje&#231;&#227;o preservada e com disfun&#231;&#227;o sist&#243;lica na comunidade"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46;A&#46;E&#46; Moutinho"
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                            2 => "V&#46; Alcoforado"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arq Bras Cardiol"
                        "fecha" => "2008"
                        "volumen" => "90"
                        "paginaInicial" => "145"
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                      ]
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              "identificador" => "bib0015"
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              "referencia" => array:1 [
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                      "titulo" => "Trends in prevalence and outcome of heart failure with preserved ejection fraction"
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                          "etal" => true
                          "autores" => array:3 [
                            0 => "T&#46;E&#46; Owan"
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa052256"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2006"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2013.10.013

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	5	3	8
2024 October	42	24	66
2024 September	44	22	66
2024 August	40	22	62
2024 July	32	22	54
2024 June	26	19	45
2024 May	58	20	78
2024 April	27	19	46
2024 March	27	16	43
2024 February	23	19	42
2024 January	28	30	58
2023 December	25	22	47
2023 November	29	24	53
2023 October	22	25	47
2023 September	22	17	39
2023 August	29	12	41
2023 July	24	10	34
2023 June	28	15	43
2023 May	40	26	66
2023 April	24	1	25
2023 March	49	24	73
2023 February	40	20	60
2023 January	25	10	35
2022 December	44	22	66
2022 November	42	16	58
2022 October	24	21	45
2022 September	24	22	46
2022 August	32	24	56
2022 July	39	35	74
2022 June	22	21	43
2022 May	26	29	55
2022 April	36	19	55
2022 March	35	25	60
2022 February	41	15	56
2022 January	30	13	43
2021 December	18	25	43
2021 November	38	33	71
2021 October	27	34	61
2021 September	28	16	44
2021 August	20	23	43
2021 July	27	30	57
2021 June	19	14	33
2021 May	45	34	79
2021 April	54	24	78
2021 March	59	18	77
2021 February	52	7	59
2021 January	69	10	79
2020 December	22	5	27
2020 November	28	6	34
2020 October	19	9	28
2020 September	49	9	58
2020 August	22	10	32
2020 July	34	12	46
2020 June	38	5	43
2020 May	33	10	43
2020 April	35	16	51
2020 March	51	13	64
2020 February	38	45	83
2020 January	33	4	37
2019 December	50	9	59
2019 November	37	6	43
2019 October	38	6	44
2019 September	29	5	34
2019 August	23	5	28
2019 July	39	8	47
2019 June	33	8	41
2019 May	38	5	43
2019 April	17	15	32
2019 March	99	10	109
2019 February	94	12	106
2019 January	45	9	54
2018 December	45	9	54
2018 November	83	8	91
2018 October	114	12	126
2018 September	40	20	60
2018 August	37	11	48
2018 July	29	6	35
2018 June	51	12	63
2018 May	67	12	79
2018 April	97	2	99
2018 March	75	13	88
2018 February	39	4	43
2018 January	99	8	107
2017 December	114	0	114
2017 November	65	8	73
2017 October	41	16	57
2017 September	34	17	51
2017 August	41	13	54
2017 July	42	9	51
2017 June	42	7	49
2017 May	53	5	58
2017 April	36	17	53
2017 March	35	30	65
2017 February	31	4	35
2017 January	28	5	33
2016 December	43	9	52
2016 November	28	1	29
2016 October	31	9	40
2016 September	29	10	39
2016 August	24	6	30
2016 July	15	8	23
2016 June	6	9	15
2016 May	6	10	16
2016 April	30	1	31
2016 March	50	11	61
2016 February	77	25	102
2016 January	55	10	65
2015 December	45	9	54
2015 November	45	10	55
2015 October	55	13	68
2015 September	52	15	67
2015 August	57	16	73
2015 July	36	8	44
2015 June	32	2	34
2015 May	45	7	52
2015 April	39	8	47
2015 March	31	10	41
2015 February	43	4	47
2015 January	41	11	52
2014 December	50	11	61
2014 November	38	10	48
2014 October	48	13	61
2014 September	45	9	54
2014 August	39	12	51
2014 July	44	17	61
2014 June	38	6	44
2014 May	40	18	58
2014 April	29	7	36
2014 March	60	14	74
2014 February	65	21	86
2014 January	60	15	75
2013 December	39	17	56

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