Genetics in heart failure:where are we headed?

Heart failure is a complex disease with many precipitating factors. Novel insights into the genetic background of heart failure have boosted new areas of research that gave rise to the concept of genetic predisposition for heart failure. Various genetic defects and variances have been identified and subsequently linked to the onset of or progression to heart failure. Nevertheless, our understanding of the genetic basis for heart failure is incomplete because we lack knowledge of the functionality of genetic variances. We also do not understand the impact of genetic variances in noncoding DNA because of logistic problems in performing whole-genome scans and difficulties in statistical evaluation of large amounts of data generated by the genetic boom. It is expected that in the future we will be able to overcome these problems and apply the knowledge gained by genetic analyses to target and optimize treatment.</p

A Role for CETP TaqIB Polymorphism in Determining Susceptibility to Atrial Fibrillation: A Nested Case Control Study

Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included

Pretreatment with ACE inhibitors improves acute outcome of electrical cardioversion in patients with persistent atrial fibrillation

BACKGROUND: Persistent atrial fibrillation (AF) is difficult to treat. In the absence of class I or III antiarrhythmic drugs sinus rhythm is maintained in only 30% of patients during the first year after electrical cardioversion (ECV). One of the remodeling processes induced by AF is fibrosis, which relates to inducibility and maintenance of AF. The renin-angiotensin system may play a important role in this. The aim of this study was to investigate the role of angiotensin-converting enzyme (ACE) inhibitor use on efficacy of ECV, and occurrence of subacute recurrences. METHODS: One hundred-seven consecutive patients with persistent AF underwent ECV. In twenty-eight (26%) patients ACE inhibitors had been started before initiation of the present episode of AF ('pre-treated' patients). RESULTS: ECV was successful in 96% of patients who were on ACE inhibitors before start of the present episode of AF compared to 80% of the patients not pre-treated (p = 0.04). After 1 month of follow-up 49% of the pre-treated patients and 50% of those not pre-treated with ACE inhibition were still in sinus rhythm (p=ns). Multivariate analysis showed that pre-treatment with ACE inhibitors and a smaller left atrial size were independent predictors of successful ECV (OR = 5.8, C.I. 1.3–26.1, and OR = 5.6, C.I. 1.2–25.3, respectively). CONCLUSIONS: Pre-treatment with ACE inhibitors may improve acute success of ECV but does not prevend AF recurrences

SCN5A-1795insD founder variant:a unique Dutch experience spanning 7 decades

The SCN5A-1795insD founder variant is a unique SCN5A gene variant found in a large Dutch pedigree that first came to attention in the late 1950s. To date, this is still one of the largest and best described SCN5A founder families worldwide. It was the first time that a single pathogenic variant in SCN5A proved to be sufficient to cause a sodium channel overlap syndrome. Affected family members displayed features of Brugada syndrome, cardiac conduction disease and long QT syndrome type 3, thus encompassing features of both loss and gain of sodium channel function. This brief summary takes us past 70 years of clinical experience and over 2 decades of research. It is remarkable to what extent researchers and clinicians have managed to gain understanding of this complex phenotype in a relatively short time. Extensive clinical, genetic, electrophysiological and molecular studies have provided fundamental insights into SCN5A and the cardiac sodium channel Nav1.5.</p

Predictors of non-pharmacological intervention in patients with paroxysmal atrial fibrillation:Value of neuroticism

Background: Non-pharmacological intervention is gaining increasing popularity in the treatment of patients with paroxysmal atrial fibrillation. We sought to investigate which factors play a role in the choice for non-pharmacological intervention with a particular focus on neuroticism. Methods: The study group comprised 73 patients with paroxysmal atrial fibrillation (mean age 55 13 years, 50 males). On average, patients had a 3-year-history of one symptomatic paroxysm per week lasting 2 It. The degree of neuroticism was assessed using the short scale Eysenck Personality Questionnaire. Results: During a mean follow-up period of 7.0 +/- 0.6 years, 20 patients (27%) underwent a non-pharmacological intervention for atria] fibrillation including His bundle ablation (n=1), maze operation (n=4), DDDR-pacemaker (n=10), pulmonary vein ablation (n=5). Multivariate regression analysis showed that age <55 years (odds ratio 5.3, 95% CI 1.1-24.5), frequency of paroxysms of atrial fibrillation > 1 per week (odds ratio 5.9, 95% CI 1.2-28.5) and total number of anti-arrhythmic drugs (class I and III) used > 2 (odds ratio 3.4, 95% CI 1.6-6.9) were predictive of non-pharmacological intervention (all p <0.05). In contrast, the degree of neuroticism was similar in patients who underwent non-pharmacological intervention as opposed to patients who did not undergo non-pharmacological intervention (4.5 +/- 3.3 vs. 4.0 +/- 2.9, p = NS). Conclusions: On the basis of this small study, neuroticism would not appear to play an important role in the decision to perform a nonpharmacological intervention. Instead, the data indicate that younger patients with pharmacologically refractory atrial fibrillation more often undergo non-pharmacological intervention. (c) 2005 Elsevier Ireland Ltd. All rights reserved

HLA-DR expression on monocytes and systemic inflammation in patients with ruptured abdominal aortic aneurysms

INTRODUCTION: Mortality from ruptured abdominal aortic aneurysms (RAAA) remains high. Severe systemic inflammation, leading to multi-organ failure, often occurs in these patients. In this study we describe the level of HLA-DR expression in a consecutive group of patients following surgery for RAAA and compare results between survivors and non-survivors. A similar comparison is made for IL-6 and IL-10 levels and Sequential Organ Failure Assessment (SOFA) scores. METHODS: This is a prospective observational study. Patients with RAAA were prospectively analysed. Blood samples were collected on days 1, 3, 5, 7, 10 and 14. The fraction of CD-14 positive monocytes expressing HLA-DR was measured by flow-cytometry. IL-6 and IL-10 levels were measured by ELISA. RESULTS: The study included 30 patients with a median age of 70 years, of which 27 (90%) were men. Six patients died from multiple organ failure, all other patients survived. The SOFA scores were significantly higher in non-survivors on days 1 through 14. HLA-DR expression on monocytes was significantly lower on days 3, 5, 7, 10 and 14 in non-survivors. IL-6 and IL-10 levels were significantly higher in non-survivors on day 1 and days 1 and 3, respectively. CONCLUSION: HLA-DR expression on monocytes was decreased, especially in non-survivors. All patients with RAAA displayed a severe inflammatory and anti-inflammatory response with an increased production of IL-6 and IL-10. Poor outcome is associated with high levels of IL-6 and IL-10 and a high SOFA score in the first three days after surgery, while low levels of HLA-DR expression are observed from day three after RAAA repair

Cardiac Transthyretin-derived Amyloidosis:An Emerging Target in Heart Failure with Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful