Progress in heart failure management in the Netherlands and beyond:long-term commitment to deliver high-quality research and patient care

Heart failure (HF) remains a major global problem. In the Netherlands, 1.5-2.0% of the total population is diagnosed with HF. Over 30,000 HF patients are admitted annually in the Netherlands, and this number is expected to further increase given the ageing population and the chronic nature of HF. Despite ongoing efforts to reduce the burden of HF, morbidity and mortality rates of this disease remain high. However, several new treatment modalities have become available or are expected to become available in the coming years. This review will provide an overview of HF research conducted in the Netherlands (often in an international setting) that may have clinical consequences for diagnosis, treatment and prevention of HF, and will also evaluate outcomes of larger clinical trials that have been conducted in the Netherlands

Gut-microbe derived TMAO and its association with more progressed forms of AF:Results from the AF-RISK study

Introduction: The importance of gut microbiome in cardiovascular disease has been increasingly recognized. Trimethylamine N-oxide (TMAO) is a gut microbe-derived metabolite that is associated with cardiovascular disease, including atrial fibrillation (AF). The role of TMAO in clinical AF progression however remains unknown. Methods and results: In this study we measured TMAO and its precursor (betaine, choline, and L- carnitine) levels in 78 patients using plasma samples from patients that participated in the AF-RISK study. 56 patients suffered from paroxysmal AF and 22 had a short history of persistent AF. TMAO levels were significantly higher in patients with persistent AF, as compared to those with paroxysmal AF (median [IQR] 5.65 [4.7–9.6] m/z versus 4.31 [3.2–6.2] m/z, p < 0.05), while precursor levels did not differ. In univariate analysis, we observed that for every unit increase in TMAO, the odds for having persistent AF increased with 0.44 [0.14–0.73], p < 0.01. Conclusion: These results suggest that higher levels of TMAO are associated with more progressed forms of AF. We therefore hypothesize that increased TMAO levels may reflect disease progression in humans. Larger studies are required to validate these preliminary findings.Trial Registration number: Clinicaltrials.gov NCT01510210

Multimorbidity prevalence and patterns and their associations with health literacy among chronic kidney disease patients

Background: Health literacy is the ability to deal with information related to one’s health. Patients with low health literacy have poor disease-management skills for chronic diseases, such as chronic kidney disease (CKD). This could influence the number and combination of their diseases. Methods: We included adult patients with CKD stages 1–5 from the Lifelines Study (n = 2,742). We assessed the association between low health literacy and the number and patterns of comorbidities, considering them globally and stratified by age and sex, using multinomial logistic regression and latent class analysis, respectively. Results: Low health literacy was associated with a higher number of comorbidities in the crude models, and after adjustment for age, sex, eGFR, smoking, and BMI. In the crude model, the OR for low health literacy increased from 1.71 (1.25–2.33) for two comorbidities to 2.71 (2.00–3.68) for four comorbidities. In the fully-adjusted model, the associations remained significant with a maximum OR of 1.70 (1.16–2.49) for four comorbidities. The patterns of multimorbidity were similar for low and adequate health literacy, overall and by sex, bur tended to be different for patients older than 65. Older patients with low health literacy had higher comorbidity prevalence and a relatively greater share of cardiovascular, psychiatric, and central nervous system diseases. Conclusions: Among CKD patients, low health literacy is associated with more multimorbidity. Health literacy is not associated with patterns of multimorbidity in younger patients, but a difference was observed in older ones. Improving low health literacy could be an intervention efficient also in decreasing multimorbidity in CKD patients. Graphical abstract: [Figure not available: see fulltext.

Increased plasma levels of NT-proBNP, Troponin T and GDF-15 are driven by persistent AF and associated comorbidities:Data from the AF-RISK study

Atrial fibrillation (AF) is a progressive disease, and early recognition and management may reflect an important strategy to reduce its disease burden. In this study, we evaluated plasma levels of three biomarkers - N-terminal pro-brain natriuretic peptide (NTproBNP), Troponin-T, and growth differentiation factor-15 (GDF-15) - in patients with paroxysmal AF (pAF) (≤7 days of continuous AF, n = 323) and persistent AF ((AF duration &gt; 7 days and &lt; 1 year, n = 84) using patients from AF RISK study (NCT01510210). In this AF-RISK sub-study, patients with persistent AF experienced more symptoms (higher European Heart Rhythm Association class (p &lt; 0.001)), had a higher comorbidity burden (p &lt; 0.001), and had more unfavorable echocardiographic parameters (p &lt; 0.001). All three biomarker levels were significantly higher in patients with persistent AF as compared to those with pAF (p &lt; 0.001). Multivariate linear regression analyses showed that age (beta-coefficient for NTproBNP: 0.21; GDF-15: 0.41; Troponin-T: 0.23) and CHA2DS2-VASc (beta-coefficient for NTproBNP: 0.20; GDF-15: 0.25; Troponin-T: 0.27) were determinants of all three biomarkers, and that persistent AF determined NTproBNP (beta-coefficient: 0.34), but not Troponin-T and GDF-15. More detailed analysis of CHA2DS2-VASc score showed that for all three biomarkers age, coronary artery disease and heart failure were determinants of plasma biomarkers levels, whereas sex determined NTproBNP and Troponin T, and hypertension determined NTproBNP and GDF15. Overall, this study therefore suggests that in AF, Troponin T and GDF15, and especially NTproBNP could be used to detect those patients with more persistent form of AF that may warrant more aggressive treatment of AF and concomitant comorbidities. Future studies, however, are essential to evaluate if more aggressive AF treatment and risk factor management will reduce disease progression and holds a novel therapeutic intervention to reduce the burden of AF.</p

Relationship between body mass index, cardiovascular biomarkers and incident heart failure

BACKGROUND: There are limited data examining whether body-mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF). METHODS AND RESULTS: Thirteen biomarkers representing key HF domains were measured: N-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-A-type natriuretic peptide (MR-proANP), cardiac troponin-T (cTnT), C-reactive protein, procalcitonin, galectin-3, C-terminal pro-endothelin-1 (CT-pro-ET-1), mid-regional pro-adrenomedullin, plasminogen activator inhibitor-1, copeptin, renin, aldosterone and cystatin-C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations. RESULTS: Among 8202 individuals, 41% were overweight (BMI 25-30kg/m2 ), and 16% were obese (BMI≥30kg/m2 ). Mean age of the cohort was 49 years (range 28-75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT-proBNP, MR-proANP, CT-pro-ET-1 and aldosterone whereas positive associations were observed with the remaining biomarkers (Pall ≤0.001). During 11.3±3.1 years follow-up, 357 HF events were recorded. Only NT-proBNP, MR-proANP and cTnT remained associated with incident HF (P0.1). Combined NT-proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC-statistic=0.024; LHRχ2 =38; P<0.001) and in obese (ΔC-statistic=0.020; LHRχ2 =32; P<0.001) individuals. CONCLUSIONS: Plasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT-proBNP, MR-proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT-proBNP and cTnT improves HF risk prediction in overweight and in obese individuals. This article is protected by copyright. All rights reserved

Relative fat mass, a new index of adiposity, is strongly associated with incident heart failure:data from PREVEND

Body-mass index (BMI), waist circumference, and waist-hip ratio are commonly used anthropometric indices of adiposity. However, over the past 10 years, several new anthropometric indices were developed, that more accurately correlated with body fat distribution and total fat mass. They include relative fat mass (RFM), body-roundness index (BRI), weight-adjusted-waist index and body-shape index (BSI). In the current study, we included 8295 adults from the PREVEND (Prevention of Renal and Vascular End-Stage Disease) observational cohort (the Netherlands), and sought to examine associations of novel as well as established adiposity indices with incident heart failure (HF). The mean age of study population was 50 ± 13 years, and approximately 50% (n = 4134) were women. Over a 11 year period, 363 HF events occurred, resulting in an overall incidence rate of 3.88 per 1000 person-years. We found that all indices of adiposity (except BSI) were significantly associated with incident HF in the total population (P &lt; 0.001); these associations were not modified by sex (P interaction &gt; 0.1). Amongst adiposity indices, the strongest association was observed with RFM [hazard ratio (HR) 1.67 per 1 SD increase; 95% confidence interval (CI) 1.37–2.04]. This trend persisted across multiple age groups and BMI categories, and across HF subtypes [HR: 1.76, 95% CI 1.26–2.45 for HF with preserved ejection fraction; HR 1.61, 95% CI 1.25–2.06 for HF with reduced ejection fraction]. We also found that all adiposity indices (except BSI) improved the fit of a clinical HF model; improvements were, however, most evident after adding RFM and BRI (reduction in Akaike information criteria: 24.4 and 26.5 respectively). In conclusion, we report that amongst multiple anthropometric indicators of adiposity, RFM displayed the strongest association with HF risk in Dutch community dwellers. Future studies should examine the value of including RFM in HF risk prediction models.</p

Relative fat mass, a new index of adiposity, is strongly associated with incident heart failure:data from PREVEND

Body-mass index (BMI), waist circumference, and waist-hip ratio are commonly used anthropometric indices of adiposity. However, over the past 10 years, several new anthropometric indices were developed, that more accurately correlated with body fat distribution and total fat mass. They include relative fat mass (RFM), body-roundness index (BRI), weight-adjusted-waist index and body-shape index (BSI). In the current study, we included 8295 adults from the PREVEND (Prevention of Renal and Vascular End-Stage Disease) observational cohort (the Netherlands), and sought to examine associations of novel as well as established adiposity indices with incident heart failure (HF). The mean age of study population was 50 ± 13 years, and approximately 50% (n = 4134) were women. Over a 11 year period, 363 HF events occurred, resulting in an overall incidence rate of 3.88 per 1000 person-years. We found that all indices of adiposity (except BSI) were significantly associated with incident HF in the total population (P &lt; 0.001); these associations were not modified by sex (P interaction &gt; 0.1). Amongst adiposity indices, the strongest association was observed with RFM [hazard ratio (HR) 1.67 per 1 SD increase; 95% confidence interval (CI) 1.37–2.04]. This trend persisted across multiple age groups and BMI categories, and across HF subtypes [HR: 1.76, 95% CI 1.26–2.45 for HF with preserved ejection fraction; HR 1.61, 95% CI 1.25–2.06 for HF with reduced ejection fraction]. We also found that all adiposity indices (except BSI) improved the fit of a clinical HF model; improvements were, however, most evident after adding RFM and BRI (reduction in Akaike information criteria: 24.4 and 26.5 respectively). In conclusion, we report that amongst multiple anthropometric indicators of adiposity, RFM displayed the strongest association with HF risk in Dutch community dwellers. Future studies should examine the value of including RFM in HF risk prediction models.</p

Sex differences in associations of comorbidities with incident cardiovascular disease:Focus on absolute risk

AIM: To examine sex differences in associations of obesity, type-2 diabetes, hypertension, and atrial fibrillation (AF) with incident cardiovascular disease (CVD), focusing on absolute risk measures.METHODS AND RESULTS: We included a total of 7994 individuals (mean age 49.1 years; 51.2% women) without prior CVD from the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort with a median follow-up of 12.5 years. Using Poisson regression, we calculated the increase in absolute as well as relative CVD risk associated with a comorbidity using incidence rate differences (IRD = IR comorbidity-IR no-comorbidity) and incidence rate ratios (IRR = IR comorbidity/IR no-comorbidity), respectively. Sex differences were presented as women-to-men differences (WMD = IRD women-IRD men) and women-to-men ratios (WMR = IRR women/IRR men). Absolute CVD risk was lower in women than in men (IR women: 6.73 vs. IR men: 14.58 per 1000 person-years). While increase in absolute CVD risk associated with prevalent hypertension was lower in women than in men [WMD: -6.12, 95% confidence interval: (-9.84 to -2.40), P = 0.001], increase in absolute CVD risk associated with prevalent obesity [WMD: -4.25 (-9.11 to 0.61), P = 0.087], type-2 diabetes [WMD: -1.04 (-14.36 to 12.29), P = 0.879] and AF [WMD: 18.39 (-39.65 to 76.43), P = 0.535] did not significantly differ between the sexes. Using relative risk measures, prevalent hypertension [WMR: 1.49%, 95% confidence interval: (1.12-1.99), P = 0.006], type-2 diabetes [WMR: 1.73 (1.09-2.73), P = 0.019], and AF [WMR: 2.53 (1.12-5.70), P = 0.025] were all associated with higher CVD risk in women than in men. CONCLUSION: Increase in absolute risk of developing CVD is higher in hypertensive men than in hypertensive women, but no substantial sex-related differences were observed among individuals with obesity, type-2 diabetes and AF. On a relative risk scale, comorbidities, in general, confer a higher CVD risk in women than in men.</p

Sex differences in associations of comorbidities with incident cardiovascular disease: focus on absolute risk

AIM: To examine sex differences in associations of obesity, type-2 diabetes, hypertension, and atrial fibrillation (AF) with incident cardiovascular disease (CVD), focusing on absolute risk measures. METHODS AND RESULTS: We included a total of 7994 individuals (mean age 49.1 years; 51.2% women) without prior CVD from the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort with a median follow-up of 12.5 years. Using Poisson regression, we calculated the increase in absolute as well as relative CVD risk associated with a comorbidity using incidence rate differences (IRD = IR(comorbidity)−IR(no-comorbidity)) and incidence rate ratios (IRR = IR(comorbidity)/IR(no-comorbidity)), respectively. Sex differences were presented as women-to-men differences (WMD = IRD(women)−IRD(men)) and women-to-men ratios (WMR = IRR(women)/IRR(men)). Absolute CVD risk was lower in women than in men (IR(women): 6.73 vs. IR(men): 14.58 per 1000 person-years). While increase in absolute CVD risk associated with prevalent hypertension was lower in women than in men [WMD: −6.12, 95% confidence interval: (−9.84 to −2.40), P = 0.001], increase in absolute CVD risk associated with prevalent obesity [WMD: −4.25 (−9.11 to 0.61), P = 0.087], type-2 diabetes [WMD: −1.04 (−14.36 to 12.29), P = 0.879] and AF [WMD: 18.39 (−39.65 to 76.43), P = 0.535] did not significantly differ between the sexes. Using relative risk measures, prevalent hypertension [WMR: 1.49%, 95% confidence interval: (1.12–1.99), P = 0.006], type-2 diabetes [WMR: 1.73 (1.09–2.73), P = 0.019], and AF [WMR: 2.53 (1.12–5.70), P = 0.025] were all associated with higher CVD risk in women than in men. CONCLUSION: Increase in absolute risk of developing CVD is higher in hypertensive men than in hypertensive women, but no substantial sex-related differences were observed among individuals with obesity, type-2 diabetes and AF. On a relative risk scale, comorbidities, in general, confer a higher CVD risk in women than in men

Sex differences in associations of comorbidities with incident cardiovascular disease:Focus on absolute risk

AIM: To examine sex differences in associations of obesity, type-2 diabetes, hypertension, and atrial fibrillation (AF) with incident cardiovascular disease (CVD), focusing on absolute risk measures.METHODS AND RESULTS: We included a total of 7994 individuals (mean age 49.1 years; 51.2% women) without prior CVD from the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort with a median follow-up of 12.5 years. Using Poisson regression, we calculated the increase in absolute as well as relative CVD risk associated with a comorbidity using incidence rate differences (IRD = IR comorbidity-IR no-comorbidity) and incidence rate ratios (IRR = IR comorbidity/IR no-comorbidity), respectively. Sex differences were presented as women-to-men differences (WMD = IRD women-IRD men) and women-to-men ratios (WMR = IRR women/IRR men). Absolute CVD risk was lower in women than in men (IR women: 6.73 vs. IR men: 14.58 per 1000 person-years). While increase in absolute CVD risk associated with prevalent hypertension was lower in women than in men [WMD: -6.12, 95% confidence interval: (-9.84 to -2.40), P = 0.001], increase in absolute CVD risk associated with prevalent obesity [WMD: -4.25 (-9.11 to 0.61), P = 0.087], type-2 diabetes [WMD: -1.04 (-14.36 to 12.29), P = 0.879] and AF [WMD: 18.39 (-39.65 to 76.43), P = 0.535] did not significantly differ between the sexes. Using relative risk measures, prevalent hypertension [WMR: 1.49%, 95% confidence interval: (1.12-1.99), P = 0.006], type-2 diabetes [WMR: 1.73 (1.09-2.73), P = 0.019], and AF [WMR: 2.53 (1.12-5.70), P = 0.025] were all associated with higher CVD risk in women than in men. CONCLUSION: Increase in absolute risk of developing CVD is higher in hypertensive men than in hypertensive women, but no substantial sex-related differences were observed among individuals with obesity, type-2 diabetes and AF. On a relative risk scale, comorbidities, in general, confer a higher CVD risk in women than in men.</p