Bayesian integration of genetics and epigenetics detects causal regulatory SNPs underlying expression variability.

The standard expression quantitative trait loci (eQTL) detects polymorphisms associated with gene expression without revealing causality. We introduce a coupled Bayesian regression approach--eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combination of regulatory single-nucleotide polymorphisms (SNPs) that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance but also predicts gene expression more accurately than other methods. Based on realistic simulated data, we demonstrate that eQTeL accurately detects causal regulatory SNPs, including those with small effect sizes. Using various functional data, we show that SNPs detected by eQTeL are enriched for allele-specific protein binding and histone modifications, which potentially disrupt binding of core cardiac transcription factors and are spatially proximal to their target. eQTeL SNPs capture a substantial proportion of genetic determinants of expression variance and we estimate that 58% of these SNPs are putatively causal.

Patient-reported selective adherence to heart failure self-care recommendations: a prospective cohort study: the Atlanta Cardiomyopathy Consortium.

Simultaneous adherence with multiple self-care instructions among heart failure (HF) patients is not well described. Patient-reported adherence to 8 recommendations related to exercise, alcohol, medications, smoking, diet, weight, and symptoms was assessed among 308 HF patients using the Medical Outcomes Study Specific Adherence Scale questionnaire (0="never" to 5="always," maximum score=40). A baseline cumulative score of ≥32/40 (average ≥80%) defined good adherence. Clinical events (death/transplantation/ventricular assist device), resource utilization, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were compared among patients with and without good adherence. The mean follow-up was 2.0±1.0 years, and adherence ranged from 26.3% (exercise) to 89.9% (medications). A cumulative score indicating good adherence was reported by 35.7%, whereas good adherence with every behavior was reported by 9.1% of patients. Good adherence was associated with fewer hospitalizations (all-cause 87.8 vs 107.6; P=.018; HF 29.6 vs 43.8; P=.007) and hospitalized days (all-cause 422 vs 465; P=.015; HF 228 vs 282; P<.001) per 100-person-years and better health status (KCCQ overall score 70.1±24.6 vs 63.8±22.8; P=.011). Adherence was not associated with clinical events or functional capacity. Patient-reported adherence with HF self-care recommendations is alarmingly low and selective. Good adherence was associated with lower resource utilization and better health status.

Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension.

Circulating cardiac troponins are markers of myocardial injury. We sought to determine whether cardiac troponin I (cTnI), measured by a sensitive assay, is associated with disease severity and prognosis in pulmonary arterial hypertension (PAH). cTnI was measured in 68 patients with PAH diagnostic category 1 in a research-based sensitive immunoanalyser with a lower limit of detection of 0.008 ng · mL(-1). The associations between cTnI and PAH severity and clinical outcomes were assessed using Chi-squared and Wilcoxon rank sum tests, Kaplan-Meier analysis and Cox regression models. cTnI was detected in 25% of patients. Patients with detectable cTnI had more advanced functional class symptoms, a shorter 6-min walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels. 36-month transplant-free survival was 44% in patients with detectable cTnI versus 85% in those with undetectable cTnI. cTnI was associated with a 4.7-fold increased risk of death related to right ventricular failure or transplant (hazard ratio 4.74, 95% CI 1.89-11.89; p<0.001), even when adjusted individually for known parameters of PAH severity. Elevated plasma cTnI, even at subclinically detectable levels, is associated with more severe disease and worse outcomes in patients with PAH.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Current and novel pharmacological approaches to renal insufficiency in heart failure.

Renal insufficiency is becoming an increasingly common and devastating comorbidity in both acute and chronic heart failure settings. Part of the problem is due to the lack of insight into the underlying pathophysiology of salt and water balance leading to the congestive states. This review summarizes our current understanding regarding the cause and consequences of renal insufficiency in patients with heart failure, and addresses some of the limitations of current therapeutic strategies. Based on these limitations, this paper will explore the ongoing efforts to develop novel drug therapeutics to prevent or ameliorate renal impairment in patients with heart failure. These include natriuretic peptides and other vasodilators, adenosine receptor antagonists, and vasopressin receptor antagonists all currently undergoing late-stage clinical trials.

Clinical outcomes of patients with impaired left ventricular ejection fraction undergoing autologous bone marrow transplantation: can we safely transplant patients with impaired ejection fraction?

Experience with autologous bone marrow transplantation (ABMT) in patients with impaired left ventricular ejection fraction (LVEF) or heart failure (HF) is limited. We identified 308 consecutive patients who underwent ABMT for Hodgkin's or non-Hodgkin's lymphoma at our institution (1996-2003). Patient characteristics, clinical course and overall survival were compared between patients with preserved ( > or = 50%) or impaired ( < 50%) LVEF. Of the 308 patients identified, 20 had baseline impaired LVEF (four with LVEF < or = 40%, all NYHA class I-II HF). None of the patients with post-ABMT echocardiogram had worsened LVEF (n = 7). Among the 20 patients with impaired LVEF, four patients had reversible cardiac complications post-ABMT (including worsening HF). The two deaths observed in the impaired LVEF group were both due to noncardiac causes. The 5-year survival was similar between patients with preserved and impaired LVEF (P = 0.43). Careful selection of patients with stable, mild-to-moderate HF and impaired LVEF for ABMT can achieve similar long-term survival. As medical care for HF and ABMT improves, the exclusion criteria for ABMT with regard to HF and impaired LVEF should be re-examined.