Search

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Background: An elevated resting heart rate is associated with rehospitalization for heart failure and is a modifiable risk factor in heart failure patients. We aimed to examine the association between resting heart rate and incident heart failure in a population-based cohort study of healthy adults without pre-existing overt heart disease., Methods and Results: We studied 4768 men and women aged ≥55 years from the population-based Rotterdam Study. We excluded participants with prevalent heart failure, coronary heart disease, pacemaker, atrial fibrillation, atrioventricular block, and those using β-blockers or calcium channel blockers. We used extended Cox models allowing for time-dependent variation of resting heart rate along follow-up. During a median of 14.6 years of follow-up, 656 participants developed heart failure. The risk of heart failure was higher in men with higher resting heart rate. For each increment of 10 beats per minute, the multivariable adjusted hazard ratios in men were 1.16 (95% confidence interval, 1.05-1.28; P=0.005) in the time-fixed heart rate model and 1.13 (95% confidence interval, 1.02-1.25; P=0.017) in the time-dependent heart rate model. The association could not be demonstrated in women (P for interaction=0.004). Censoring participants for incident coronary heart disease or using time-dependent models to account for the use of β-blockers or calcium channel blockers during follow-up did not alter the results., Conclusions: Baseline or persistent higher resting heart rate is an independent risk factor for the development of heart failure in healthy older men in the general population.

Objectives: The purpose of this study was to determine the association of coronary artery calcification (CAC) with incident heart failure in the elderly and examine its independence of overt coronary heart disease (CHD)., Background: Heart failure is often observed as a first manifestation of coronary atherosclerosis rather than a sequela of overt CHD. Although numerous studies have shown that CAC, an established measure of coronary atherosclerosis, is a strong predictor of CHD, the association between CAC and future heart failure has not been studied prospectively., Methods: In the Rotterdam Study, a population-based cohort, 1,897 asymptomatic participants (mean age, 69.9 years; 58% women) underwent CAC scoring and were followed for the occurrence of heart failure and CHD., Results: During a median follow-up of 6.8 years, there were 78 cases of heart failure and 76 cases of nonfatal CHD. After adjustment for cardiovascular risk factors, increasing CAC scores were associated with heart failure (p for trend = 0.001), with a hazard ratio of 4.1 (95% confidence interval [CI]: 1.7 to 10.1) for CAC scores >400 compared with CAC scores of 0 to 10. After censoring participants for incident nonfatal CHD, increasing extent of CAC remained associated with heart failure (p for trend = 0.046), with a hazard ratio of 2.9 (95% CI: 1.1 to 7.4) for CAC scores >400. Moreover, adding CAC to cardiovascular risk factors resulted in an optimism-corrected increase in the c-statistic by 0.030 (95% CI: 0.001 to 0.050) to 0.734 (95% CI: 0.698 to 0.770) and substantially improved the risk classification of subjects (continuous net reclassification index = 34.0%)., Conclusions: CAC has a clear association with the risk of heart failure, independent of overt CHD. Because heart failure is highly prevalent in the elderly, it might be worthwhile to include heart failure as an outcome in future risk assessment programs incorporating CAC., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the association between unrecognised myocardial infarction (MI) as detected by electrocardiography and the long-term risk of heart failure., Design: The Rotterdam Study is a prospective population-based cohort study of the general population of a suburb of the city of Rotterdam, The Netherlands., Participants: At baseline 2581 men and 3724 women aged > or =55 years were classified on the basis of electrocardiography, interview and clinical data into those with recognised MI, those with ECG-based unrecognised MI and those without MI. The participants were followed-up for incident heart failure, death or end of the study period on 12 October 2006., Results: During a median follow-up time of 13.2 years, 823 cases of heart failure occurred, of which 403 in men. Independently of cardiovascular risk factors, recognised and unrecognised MIs yielded HRs of developing heart failure in men of 2.6 (95% CI 2.0 to 3.3) and 2.1 (95% CI 1.5 to 2.9), respectively. In women, recognised MI was associated with heart failure (HR=2.8; 95% CI 1.9 to 4.1), whereas unrecognised MI was not significantly related to the risk of heart failure (HR=1.1; 95% CI 0.7 to 1.7)., Conclusion: Unrecognised MI detected by electrocardiography yields a long-term risk of heart failure equivalent to recognised MI in men, but is not significantly related to heart failure in women. In the light of the high incidence of both unrecognised MI and heart failure in the elderly, it may be worthwhile for both doctors and patients to improve responsiveness to typical and atypical symptoms of MI.

Aims: Evidence is accumulating that inflammation plays a role in the pathophysiology of heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has pro-inflammatory properties. We investigated whether Lp-PLA2 activity is associated with heart failure., Methods and Results: Lp-PLA2 activity was determined in a random sample of 1820 subjects from the Rotterdam Study, a population-based cohort study among persons aged 55 years and over. During a mean follow-up of 6.7 years, 94 heart failure cases occurred. We excluded participants with heart failure or coronary heart disease at baseline and we accounted for incident coronary heart disease during follow-up. We used Cox proportional hazard models to compute hazard ratios adjusted for age, sex, non-HDL cholesterol, HDL cholesterol, body mass index, systolic blood pressure, diastolic blood pressure, hypertension, diabetes mellitus, smoking, and C-reactive protein. The hazard ratio per unit increase of Lp-PLA2 activity was 1.03 [95% confidence interval (95% CI 1.01-1.05]; P for trend was 0.011. Hazard ratios for the second, third, and fourth quartiles were 1.06 (95% CI 0.55-2.04), 1.43 (95% CI 0.73-2.81), and 2.33 (95% CI 1.21-4.49), respectively, using the lowest quartile of Lp-PLA2 activity as the reference category., Conclusion: This study suggests that Lp-PLA2 activity is independently associated with incident heart failure.

Background: Experimental studies have shown that the known biologic effects of proinflammatory cytokines could explain many aspects of the syndrome of heart failure. The inflammatory marker that presently seems most suitable to assess inflammation is C-reactive protein (CRP). This study was designed to investigate the association between serum CRP levels, as determined by high-sensitivity assay, and the occurrence of heart failure., Methods: Serum CRP levels were available from 6437 men and women without heart failure, aged > or = 55 years, from the prospective population-based Rotterdam Study. Cox proportional hazards analysis was used to determine risk of heart failure for sex-specific quartiles of CRP., Results: C-reactive protein levels in the highest versus the lowest quartile showed increased hazard ratios of incident heart failure. The age- and sex-adjusted hazard ratio was 2.64 (95% CI 2.04-3.43) for all participants. For men, the age adjusted hazard ratio was 4.37 (2.87-6.66), and for women, 1.86 (1.32-2.62). The interaction term of CRP with sex was highly significant. After additional adjustment for established cardiovascular risk factors, the association attenuated slightly in men and substantially in women, becoming 3.73 (2.40-5.78) and 1.42 (0.99-2.03), respectively. Excluding participants with prevalent coronary heart disease and accounting for incident coronary heart disease resulted in a further attenuation of the hazard ratios, which was proportionately larger in men than in women., Conclusions: C-reactive protein is strongly and independently associated with occurrence of heart failure in men. In women, the association is weaker and does not persist after accounting for established cardiovascular risk factors.

Aims: Cardiac angiotensin-I converting enzyme (ACE) activity is influenced by the ACE I/D polymorphism. Evidence suggests that the DD-genotype may be a risk factor for cardiac hypertrophy and heart failure, especially in hypertensive subjects. We assessed the relation between the ACE I/D polymorphism and the risk of incident heart failure in normotensive and hypertensive subjects., Methods and Results: We investigated 4264 normotensive and 2174 hypertensive participants of the Rotterdam Study, a population based prospective cohort study. All subjects were available for follow-up from 1990 until 2000. Incidence rates (IR) of heart failure in normotensive subjects were the same over all genotype strata (10 per 1000 person-years). In hypertensive subjects, the IR increased with the number of D-alleles present (II: IR=13, ID: IR=18 and DD: IR=20 per 1000 person-years). Hypertensive subjects carrying the II-genotype did not have an increased risk of heart failure compared to normotensive II subjects. However, hypertensive subjects carrying one or two copies of the D-allele did have a significantly increased risk of heart failure (ID: RR: 1.4 (1.1-1.9) and DD: RR: 1.5 (1.2-2.1))., Conclusion: Our findings suggest that the ACE I/D polymorphism may play a modifying role in the development of heart failure in hypertensive subjects.

Heart failure is a complex clinical syndrome. There is evidence for a genetic contribution to the pathophysiology of heart failure. Considering the fundamental role of neurohormonal factors in the pathophysiology and progression of cardiac dysfunction and hypertrophy, variants of genes involved in this system are logical candidate genes in heart failure. In this report, genetic polymorphisms of the major neurohormonal systems in heart failure will be discussed. Studies on polymorphisms of the renin-angiotensin-aldosterone system (RAAS), adrenergic receptor polymorphisms, endothelin (receptor) polymorphisms, and a group of miscellaneous polymorphisms that may be involved in the development or phenotypic expression of heart failure will be reviewed. Research on left ventricular hypertrophy is also included. The majority of genetic association studies focused on the ACE I/D polymorphism. Initial genetic associations have often been difficult to replicate, mainly due to problems in study design and lack of power. Promising results have been obtained with genetic polymorphisms of the RAAS and sympathetic system. Considering the evidence so far, a modifying role for these polymorphisms seems more likely than a role of these variants as susceptibility genes. Besides the need for larger studies to examine the effects of single nucleotide polymorphisms and haplotypes, future studies also need to focus on the complexity of these systems and study gene-gene interactions and gene-environment interactions.

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small-scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non-selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) > or = 6.0, the last INR assessment, death, loss to follow-up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR > or = 6.0. The risk of overanticoagulation was 1.66 [95% confidence interval (CI): 1.33-2.07] for cases of prevalent heart failure and 1.91 (95%CI: 1.31-2.79) for incidental cases. The decrease in dose requirements in patients with incidental heart failure showed a significant trend from the fifth INR measurement preceding the date of incidental heart failure to the third measurement after this date. Heart failure is an independent risk factor for overanticoagulation. Therefore, patients with heart failure should be closely monitored to prevent potential bleeding complications., (Copyright 2004 Blackwell Publishing Ltd)

Aims: To determine the prevalence, incidence rate, lifetime risk and prognosis of heart failure., Methods and Results: The Rotterdam Study is a prospective population-based cohort study in 7983 participants aged > or =55. Heart failure was defined according to criteria of the European Society of Cardiology. Prevalence was higher in men and increased with age from 0.9% in subjects aged 55-64 to 17.4% in those aged > or =85. Incidence rate of heart failure was 14.4/1000 person-years (95% CI 13.4-15.5) and was higher in men (17.6/1000 man-years, 95% CI 15.8-19.5) than in women (12.5/1000 woman-years, 95% CI 11.3-13.8). Incidence rate increased with age from 1.4/1000 person-years in those aged 55-59 to 47.4/1000 person-years in those aged > or =90. Lifetime risk was 33% for men and 29% for women at the age of 55. Survival after incident heart failure was 86% at 30 days, 63% at 1 year, 51% at 2 years and 35% at 5 years of follow-up., Conclusion: Prevalence and incidence rates of heart failure are high. In individuals aged 55, almost 1 in 3 will develop heart failure during their remaining lifespan. Heart failure continues to be a fatal disease, with only 35% surviving 5 years after the first diagnosis.

We studied 4,963 participants of the population-based Rotterdam Study and found that a genetically determined chronic exposure to low insulin-like growth factor-I (IGF-I) levels is associated with an increased risk for heart failure in elderly patients.

Heart failure constitutes an increasing public health problem because of the growing incidence and prevalence, poor prognosis and high hospital (re)admission rates. Myocardial infarction is the underlying cause in the majority of patients, followed by hypertension, valvular heart disease and idiopathic cardiomyopathy. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymes cyclo-oxygenase (COX) 1 and 2, have been associated with the occurrence of symptoms of heart failure in several case reports and quantitative studies, mainly in patients with a history of cardiovascular disease or left ventricular impairment. NSAIDs may impair renal function in patients with a decreased effective circulating volume by inhibiting prostaglandin synthesis. Consequently, water and sodium retention, and decreases in renal blood flow and glomerular filtration rate may occur, affecting the unstable cardiovascular homeostasis in these patients. In patients with pre-existing heart failure, this may lead to cardiac decompensation. Putative renal-sparing NSAIDs, such as COX-2 selective inhibitors have similar effects on renal function as the traditional NSAIDs, and can likewise be expected to increase the risk of heart failure in susceptible patients. NSAIDs are frequently prescribed to elderly patients, who are particularly at risk for the renal adverse effects. If treatment with NSAIDs in high risk patients cannot be avoided, intensive monitoring and patient education is important.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with first hospitalization for congestive heart failure (CHF). It is likely, however, that NSAIDs precipitate a relapse but are less likely to induce a first occurrence of (incident) heart failure., Methods: A total of 7277 participants in the Rotterdam Study were followed up from the interview date until the first of the following events: a diagnosis of incident heart failure, death, removal, or end of the follow-up period. Excluded from the study population were all participants with prevalent heart failure at baseline. Exposure to NSAIDs and other medication was calculated on the basis of automated data on filled drug prescriptions in the pharmacies within the study area. In a second analysis, we followed up all participants with incident heart failure until the first relapse or the end of follow-up., Results: Incident heart failure was encountered in 345 participants during follow-up. Current use of NSAIDs was associated with a relative risk of incident heart failure of 1.1 (95% confidence interval [CI], 0.7-1.7), after adjustment for age, sex, and concomitant medication. In patients with prevalent heart failure who filled at least 1 NSAID prescription since diagnosis of heart failure, the univariate and adjusted relative risks of a relapse were 3.8 (95% CI, 1.1-12.7) and 9.9 (95% CI, 1.7-57.0), respectively., Conclusions: The use of NSAIDs is not associated with an increased risk of incident heart failure. In patients with prevalent heart failure, current use of NSAIDs is associated with a substantially increased risk of a relapse.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of heart failure. NSAIDs inhibit the synthesis of renal prostaglandin, which results in a higher total blood volume, cardiac output and preload. The association between recent start of NSAIDs in elderly people and echocardiographic parameters was investigated. Methods In the Rotterdam Study, a population-based cohort study, the effect of NSAIDs on left ventricular end-systolic dimension, left ventricular end-diastolic dimension, fractional shortening and left ventricular systolic function was studied in all participants for whom an echocardiogram was available (n=5307). NSAID use was categorised as current NSAID use on the date of echocardiography, past use and never used before echocardiography during the study period. Current use was divided into short-term NSAID use (=14⇔…days) and long-term NSAID use (>14⇔…days). Associations between drug exposure and echocardiographic measurements were assessed using linear and logistic regression analyses. Results Current NSAID use for <14⇔…days was associated with a significantly higher left ventricular end-systolic dimension (+1.74⇔…mm, 95% CI 0.20 to 3.28), left ventricular end-diastolic dimension (+3.69⇔…mm, 95% CI 1.08 to 6.31) and significantly lower fractional shortening (⇔'6.03%, 95% CI ⇔'9.81% to ⇔'2.26%) compared with non-users. Current NSAID use for >14⇔…days was associated with a higher left end-diastolic dimension (+1.96⇔…mm, 95% CI 0.82 to 3.11) but there was no change in the other echocardiographic parameters. Conclusion This study is the first to investigate the association between NSAIDs and echocardiographic parameters and suggests that there is a transient effect of short-term use of NSAIDs on the left ventricular dimension and function of the heart. [ABSTRACT FROM AUTHOR]