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1.  Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy 
European Journal of Heart Failure  2013;15(7):724-729.
Anti-beta-1-adrenergic receptor antibodies (anti-β1AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the β1AR to promote pathological cardiac remodelling and β1AR desensitization and downregulation. The prevalence of anti-β1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-β1AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-β1AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-β1AR Abs and highlight the opportunity for further research and development in this area.
PMCID: PMC3707431  PMID: 23639780
Cardiomyopathy; Antibodies; Beta-1-adrenergic receptors; Immunoglobulins; Immunoadsorption
2.  Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study 
European Journal of Heart Failure  2013;15(7):742-746.
Reduced physical activity is associated with increased risk of heart failure (HF) in middle-aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF).
Methods and results
We evaluated 1142 elderly participants (mean age 76 years) from the Framingham Study without prior myocardial infarction and who attended a routine examination when daily physical activity was assessed systematically with a questionnaire. A composite score, the physical activity index (PAI), was calculated and modelled as tertiles, and related to incidence of HF, HFPEF, and HFREF on follow-up using proportional hazards regression models adjusting for age and sex, and then additionally for standard HF risk factors. Participants with HF and EF <45% vs. ≥45% were categorized as HFREF and HFPEF, respectively. On follow-up (mean 10 years), 250 participants developed HF (108 with HFPEF, 106 with HFREF, 36 with unavailable EF). In age- and sex-adjusted models, the middle and highest PAI tertiles were associated with a 15–56% lower risk of any HF, of HFREF, and of HFPEF, with a graded response across tertiles. In multivariable models, the association of higher PAI with lower risk of any HF and with HFPEF was maintained, whereas the association with HFREF was attenuated.
Our study of an older community-based sample extends to the elderly and to HFPEF previous findings of a protective effect of physical activity on HF risk.
PMCID: PMC3857918  PMID: 23435761
Physical activity; Heart failure; Elderly
3.  Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction 
European Journal of Heart Failure  2013;15(7):776-785.
Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), yet its mechanisms remain unclear. The current study sought to determine whether increases in cardiac output (CO) during exercise are appropriately matched to metabolic demands in HFpEF.
Methods and results
Patients with HFpEF (n = 109) and controls (n = 73) exercised to volitional fatigue with simultaneous invasive (n = 96) or non-invasive (n = 86) haemodynamic assessment and expired gas analysis to determine oxygen consumption (VO2) during upright or supine exercise. At rest, HFpEF patients had higher LV filling pressures but similar heart rate, stroke volume, EF, and CO. During supine and upright exercise, HFpEF patients displayed lower peak VO2 coupled with blunted increases in heart rate, stroke volume, EF, and CO compared with controls. LV filling pressures increased dramatically in HFpEF patients, with secondary elevation in pulmonary artery pressures. Reduced peak VO2 in HFpEF patients was predominantly attributable to CO limitation, as the slope of the increase in CO relative to VO2 was 20% lower in HFpEF patients (5.9 ± 2.5 vs. 7.4 ± 2.6 L blood/L O2, P = 0.0005). While absolute increases in arterial–venous O2 difference with exercise were similar in HFpEF patients and controls, augmentation in arterial–venous O2 difference relative to VO2 was greater in HFpEF patients (8.9 ± 3.4 vs. 5.5 ± 2.0 min/dL, P < 0.0001). These differences were observed in the total cohort and when upright and supine exercise modalities were examined individually.
While diastolic dysfunction promotes congestion and pulmonary hypertension with stress in HFpEF, reduction in exercise capacity is predominantly related to inadequate CO relative to metabolic needs.
PMCID: PMC3857919  PMID: 23426022
Diastolic heart failure; Exercise; Oxygen consumption; Cardiac output; Stroke volume; Heart rate
4.  Primary proteasome inhibition results in cardiac dysfunction 
European Journal of Heart Failure  2013;15(6):614-623.
The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart.
Methods and results
Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P < 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P < 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P < 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI.
The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic–restrictive cardiomyopathy phenotype.
PMCID: PMC3661018  PMID: 23616520
Cardiomyopathy; Heart failure; Proteasome
6.  Double dose vs. standard dose influenza vaccination in patients with heart failure: a pilot study 
European Journal of Heart Failure  2013;15(5):560-564.
Influenza infection leads to increased morbidity and mortality in those with heart failure, and individuals with heart failure exhibit reduced antibody responses to influenza vaccine. We hypothesized that patients with heart failure randomized to double dose (DD) influenza vaccine will mount more vigorous humoral immune responses compared with those given standard dose (SD) vaccine.
Methods and results
We randomized 28 heart failure patients to DD (30 μg/strain) or SD (15 μg/strain) influenza vaccine. We assessed antibody production by haemagglutination inhibition assay (reported as log haemagglutination units) prior to, at 2–4 weeks and at 4–6 months following vaccination. Baseline antibody titres between DD (n = 12, mean age 64 ± 10 years) and SD (n = 16, mean age 63 ± 9 years) did not differ significantly. At 2–4 weeks, DD haemagglutination unit changes were significantly higher than those of SD (3.3 vs. 1.6 for A/H3N2, P < 0.001; 1.9 and 1.1 for A/H1N1, P = 0.009; and 1.7 and 1 for B-type, P = 0.02). At 4–6 weeks, there were no differences in titres in any of the virus types between treatment groups and, although titres decreased, levels remained above the seroprotective threshold.
Higher influenza vaccine doses may elicit increased antibody-mediated responses in patients with heart failure; further studies should assess whether clinical outcomes are improved with this strategy.
PMCID: PMC3631764  PMID: 23291729
Influenza vaccine; Heart failure; Immune system
7.  Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial† 
European Journal of Heart Failure  2013;15(5):551-559.
In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up.
Methods and results
In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III–IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III–IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57–0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53–0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57–0.75; P < 0.001). Digoxin-associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III–IV, LVEF <25%, and CTR >55% were 0.88 (0.80–0.97; P = 0.012), 0.84 (0.76–0.93; P = 0.001), and 0.85 (0.77–0.94; P = 0.002), respectively.
Digoxin improves outcomes in chronic HF patients with NYHA class III–IV, LVEF <25%, or CTR >55%, and should be considered in these patients.
PMCID: PMC3707428  PMID: 23355060
Digoxin; Heart Failure; High risk; Morbidity; Mortality
8.  Predictors of early dyspnoea relief in acute heart failure and the association with 30-day outcomes: findings from ASCEND-HF 
European Journal of Heart Failure  2012;15(4):456-464.
To examine the characteristics associated with early dyspnoea relief during acute heart failure (HF) hospitalization, and its association with 30-day outcomes.
Methods and results
ASCEND-HF was a randomized trial of nesiritide vs. placebo in 7141 patients hospitalized with acute HF in which dyspnoea relief at 6 h was measured on a 7-point Likert scale. Patients were classified as having early dyspnoea relief if they experienced moderate or marked dyspnoea improvement at 6 h. We analysed the clinical characteristics, geographical variation, and outcomes (mortality, mortality/HF hospitalization, and mortality/hospitalization at 30 days) associated with early dyspnoea relief. Early dyspnoea relief occurred in 2984 patients (43%). In multivariable analyses, predictors of dyspnoea relief included older age and oedema on chest radiograph; higher systolic blood pressure, respiratory rate, and natriuretic peptide level; and lower serum blood urea nitrogen (BUN), sodium, and haemoglobin (model mean C index = 0.590). Dyspnoea relief varied markedly across countries, with patients enrolled from Central Europe having the lowest risk-adjusted likelihood of improvement. Early dyspnoea relief was associated with lower risk-adjusted 30-day mortality/HF hospitalization [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68–0.96] and mortality/hospitalization (HR 0.85; 95% CI 0.74–0.99), but similar mortality.
Clinical characteristics such as respiratory rate, pulmonary oedema, renal function, and natriuretic peptide levels are associated with early dyspnoea relief, and moderate or marked improvement in dyspnoea was associated with a lower risk for 30-day outcomes.
PMCID: PMC3605752  PMID: 23159547
Acute heart failure; Dyspnoea relief; Prognosis; Outcomes
9.  Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study 
European Journal of Heart Failure  2012;15(4):394-399.
To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.
Methods and results
In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25–1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01–1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.
An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
PMCID: PMC3707430  PMID: 23223158
Epidemiology; Adiposity; Heart failure; Fatty acid-binding protein 4
10.  Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study 
European Journal of Heart Failure  2012;15(3):277-283.
Elevated levels of the mineralocorticoid hormone aldosterone are recognized as a modifiable contributor to the pathophysiology of select cardiovascular diseases due to left heart failure. In pulmonary arterial hypertension (PAH), pulmonary vascular remodelling induces right ventricular dysfunction and heart failure in the absence of left ventricular (LV) dysfunction. Hyperaldosteronism has emerged as a promoter of pulmonary vascular disease in experimental animal models of PAH; however, the extent to which hyperaldosteronism is associated with PAH in patients is unknown. Thus, the central aim of the current study is to determine if hyperaldosteronism is an unrecognized component of the PAH clinical syndrome.
Methods and results
Plasma aldosterone levels and invasive cardiopulmonary haemodynamic measurements were obtained for 25 patients referred for evaluation of unexplained dyspnoea or pulmonary hypertension. Compared with controls (n = 5), patients with PAH (n = 18) demonstrated significantly increased plasma aldosterone levels (1200.4 ± 423.9 vs. 5959.1 ± 2817.9 pg/mL, P < 0.02), mean pulmonary artery pressure (21.4 ± 5.0 vs. 45.5 ± 10.4 mmHg, P < 0.002), and pulmonary vascular resistance (PVR) (1.41 ± 0.6 vs. 7.3 ± 3.8 Wood units, P < 0.003) without differences in LV ejection fraction or pulmonary capillary wedge pressure between groups. Among patients not prescribed PAH-specific pharmacotherapy prior to cardiac catheterization, a subgroup of the cohort with severe pulmonary hypertension, aldosterone levels correlated positively with PVR (r = 0.72, P < 0.02) and transpulmonary gradient (r = 0.69, P < 0.02), but correlated inversely with cardiac output (r = –0.79, P < 0.005).
These data demonstrate a novel cardiopulmonary haemodynamic profile associated with hyperaldosteronism in patients: diminished cardiac output due to pulmonary vascular disease in the absence of LV heart failure.
PMCID: PMC3576899  PMID: 23111998
Aldosterone; Pulmonary hypertension; Right ventricle; Heart failure
11.  Genetic polymorphisms confer risk of atrial fibrillation in patients with heart failure: a population-based study 
European Journal of Heart Failure  2012;15(3):250-257.
Atrial fibrillation (AF) is a frequent co-morbidity in heart failure (HF) associated with increased mortality, but little is known about the mechanisms underlying AF onset in HF patients. We evaluated the association of cardiovascular and genetic risk factors with AF in HF patients.
Methods and results
Individuals hospitalized for HF (n = 1040; 500 with AF) were identified from a large, population-based cohort study (n = 30 447; 2339 with AF). Genetic polymorphisms in the chromosomal regions 4q25 (rs2200733) and 16q22 (rs2106261) associated with AF in genome-wide association studies were genotyped. Association of cardiovascular risk factors and polymorphisms with AF was tested in HF patients and the entire cohort using both prospective and non-time-dependent models. Cardiovascular risk factors—hypertension, body mass index, sex, smoking, diabetes, and myocardial infarction—were associated with AF in the entire cohort but not in HF patients. In contrast, polymorphisms on chromosomes 16q22 and 4q25 were associated with AF both in the entire cohort and in HF patients, conferring 75% [95% confidence interval (CI) 35–126, P = 2 × 10−5] and 57% (95% CI 18–109, P = 0.002) increased risk of AF per copy in HF patients, respectively. In the entire cohort, AF risk in the presence of HF was multiplicatively magnified by genotype for 16q22 (P for interaction = 7 × 10−4) but not 4q25 (P = 0.83). In prospective analyses excluding patients with AF diagnosis prior to or simultaneously with HF diagnosis, 16q22 but not 4q25 remained robustly associated with AF (hazard ratio 1.96, 95% CI 1.40–2.73, P = 8 × 10−5). The proportion of AF diagnoses in HF patients attributable to polymorphisms was 19% and 12%, respectively.
A polymorphism in the ZFHX3 gene, encoding a cardiac transcription factor, was associated with increased AF risk in HF patients, and the genetic association with AF was more pronounced in HF patients than in the general population.
PMCID: PMC3576900  PMID: 23132824
Atrial fibrillation; Heart failure; Genetic association; Risk factors; Genetic predisposition
12.  Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation 
European Journal of Heart Failure  2012;15(3):324-333.
There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST).
Methods and results
A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (β1389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤80 b.p.m., there were no treatment effects on events in either group. β1389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in β1389-Arg homozygotes.
In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤80 b.p.m. and nominally in those with the β1389-Arg homozygous genotype.
PMCID: PMC3576901  PMID: 23223178
Atrial fibrillation; Heart failure; Bucindolol; Beta-blocker; Beta1-adrenergic receptor polymorphism
13.  Association between adrenergic receptor genotypes and beta-blocker dose in heart failure patients: analysis from the HF-ACTION DNA substudy 
European Journal of Heart Failure  2012;15(3):258-266.
Beta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction. However, there is heterogeneity in the response to these drugs, perhaps due to genetic variations in the β1-adrenergic receptor (ADRβ1). We examined whether the Arg389Gly polymorphism in ADRβ1 interacts with the dose requirements of beta-blockers in patients with systolic HF.
Methods and results
HF-ACTION was a randomized, multicentre trial of ambulatory HF patients with systolic dysfunction who were randomized to exercise training or usual care. A subset of patients provided DNA. The relationships among beta-blocker dose, ADRβ1–389 genotype, and outcomes were assessed using the Cox proportional hazards regression model. The interaction between beta-blocker dose and the ADRβ1–389 genotype was tested. DNA information was available for 957 patients. The alleles did not deviate from Hardy–Weinberg equilibrium. Patients with the ADRβ1–389 Arg/Arg genotype receiving low-dose beta-blockers had a two-fold increase in the risk of death compared with those receiving a high dose (hazard ratio 2.09; P = 0.015); this was not conferred in Gly carriers. There was also an interaction between improvements in Kansas City Cardiomyopathy Questionnaire score and beta-blocker dose by genotype, suggesting that higher doses of beta-blockade might be needed to achieve benefit in Arg/Arg genotype patients.
There was a gene–dose interaction with the ADRβ1–389 Arg/Arg vs. Gly carrier genotype and beta-blocker dose, suggesting that patients with the Arg/Arg genotype might require a higher dose of beta-blockade to achieve a treatment response similar to that of Gly carriers.
PMCID: PMC3707429  PMID: 23115322
Adrenergic receptor polymorphisms; Genotypes; Heart failure; Beta-blockers; Dose
14.  Chronic kidney disease and cardiac remodelling in patients with mild heart failure: results from the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) study 
European Journal of Heart Failure  2012;14(12):1420-1428.
Chronic kidney disease (CKD) is a risk factor for left ventricular hypertrophy (LVH) and heart failure. We evaluated the effect of CKD on left ventricular (LV) remodelling among patients with mild heart failure.
Methods and results
REVERSE was a randomized, controlled trial evaluating cardiac resynchronization therapy (CRT) in patients with New York Heart Association (NYHA) class I/II heart failure. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. We compared changes in LV function and size over the course of 12 months by CKD status using linear mixed models adjusted for demographics, co-morbidities, medications, cardiomyopathy aetiology, and CRT status. Finally, we evaluated the effect of CKD on cardiac remodelling among patients randomized to CRT on or off. CKD was associated with worsening LV function and dilation compared with the non-CKD group {adjusted, 12-month β coefficients for the CKD group compared with the non-CKD referent group: LV ejection fraction (%) [–1.80, 95% confidence interval (CI) –3.36 to –0.24], LV end-systolic volume (mL) (14.16, 95% CI 3.96–24.36), LV end-diastolic volume (mL) (14.88, 95% CI 2.88–26.76), LV end-systolic diameter (cm) (0.36, 95% CI 0.12–0.48), LV end-diastolic diameter (cm) (0.24, 95% CI 0.012–0.36), mitral regurgitation (%) (3.12, 95% CI 0.48–5.76), and LV shape (0.036, 95% CI 0.012–0.060)}. In participants assigned to CRT, those without CKD had significantly greater improvements in LV structural parameters compared with the CKD group.
In comparison with participants with normal kidney function, CKD is an independent risk factor for ventricular dysfunction and dilation. CRT improves LV function and structure to a lesser extent in patients with CKD than in those with normal kidney function.
PMCID: PMC3506959  PMID: 22956574
Chronic kidney disease; Heart failure; Cardiac resynchronization therapy
15.  Dynamics of bone turnover markers in patients with heart failure and following haemodynamic improvement through ventricular assist device implantation 
European Journal of Heart Failure  2012;14(12):1356-1365.
Abnormal bone metabolism and progressive demineralization have been described in patients with heart failure (HF). We hypothesized that mechanical unloading through implantation of a ventricular assist device (VAD) with subsequent haemodynamic improvement would correct abnormal bone metabolism in patients with advanced HF.
Methods and results
Serum was collected from 14 controls, 20 patients with moderate HF, 34 patients with advanced HF undergoing VAD implantation, and 34 patients at the time of VAD explantation (mean duration: 169 ± 125 days). Bone metabolism markers were measured using enzyme-linked immunosorption assay (ELISA) or chemiluminescence immunoassay (CLIA). Compared with controls, HF patients showed increased parathyroid hormone (PTH: 42 ± 19 vs. 117 ± 117 pg/mL in HF; P < 0.02) with decreased 25-hydroxyvitamin D [25(OH)D: 29 ± 14 vs. 21 ± 11 ng/mL in HF; P = 0.05]. While procollagen-1 N-terminal peptide (P1NP) and osteocalcin were similar, cross-linked C- and N-telopeptides of type I collagen (CTX and NTX) were both higher in HF (NTX: 14 ± 6 vs. 20 ± 11 ng/mL; P < 0.05; CTX: 0.35 ± 0.13 vs. 1.05 ± 0.78 ng/mL; P < 0.01 for controls and HF, respectively). P1NP increased markedly after VAD implantation (49 ± 37 vs. 121 ± 62 ng/mL; P < 0.0001), with a mild decrease in CTX and NTX levels indicating a shift towards anabolic bone formation. Serum PTH correlated with estimated glomerular filtration rate (r = –0.245, P < 0.05).
Patients with advanced HF are characterized by increased levels of biochemical markers of bone resorption potentially as a result of secondary hyperparathyroidism and uncoupling of bone remodelling. Haemodynamic improvement and mechanical unloading after VAD implantation lead to correction of bone metabolism and increased levels of anabolic bone formation markers.
PMCID: PMC3598377  PMID: 22989867
Heart failure; Bone metabolism; Ventricular assist; Device
16.  Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy 
European Journal of Heart Failure  2012;14(11):1199-1207.
To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).
Methods and results
We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 % ) ARVC patients and in 39 (15 % ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del– DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 % ) R14del+ ARVC samples, but in only one of nine (11 % ) R14del+ DCM samples (P = 0.03).
The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of ‘arrhythmogenic cardiomyopathy’.
PMCID: PMC3475434  PMID: 22820313
Arrhythmia; Arrhythmogenic cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy; Dilated cardiomyopathy; Genetics
17.  Association of QRS duration with left ventricular structure and function and risk of heart failure in middle-aged and older adults: the Multi-Ethnic Study of Atherosclerosis (MESA) 
European Journal of Heart Failure  2012;14(11):1285-1292.
Prolonged QRS duration (QRSd) on the electrocardiogram (ECG) has been associated with cardiac structural and functional abnormalities by echocardiography and an increased risk of heart failure (HF). Data are sparse on these relationships in middle-aged and elderly individuals free of baseline cardiovascular disease with respect to cardiac magnetic resonance imaging (MRI). We sought to determine whether QRSd is associated with incident HF and measures of cardiac structure and function by cardiac MRI.
Methods and results
We analysed baseline ECGs in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether QRSd >100 ms was associated with incident HF. We adjusted for demographic and clinical risk factors, as well as MRI measures of left ventricular (LV) structure and function. Among 4591 eligible participants (51% women; 39% white; mean age 61 years), 75 developed incident HF over a mean follow-up of 7.1 years. QRSd >100 ms was significantly associated with MRI measures of cardiac structure and function, as well as incident HF, even after adjustment for demographic covariates [hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.29–3.42; P = 0.003] and clinical risk factors (HR 1.86, 95% CI 1.14–3.03; P = 0.01). With further adjustment for individual LV structural measures, findings were attenuated to non-significance. Separate adjustment for LV functional measures yielded only mild attenuation.
In middle-aged and older adults without cardiovascular disease, a QRSd >100 ms was significantly associated with incident HF. After adjustment for LV structural measures, the association was attenuated to non-significance, suggesting that prolonged QRSd is potentially a useful marker of LV structure that may predispose to HF risk.
PMCID: PMC3530347  PMID: 22791081
Electrocardiogram; Heart failure; Magnetic resonance imaging; QRS duration
18.  Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study 
European Journal of Heart Failure  2012;14(10):1179-1188.
To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF-PEF).
Methods and results
Of the 10 570 hospitalized HF-PEF patients, aged ≥65 years, EF ≥40%, in OPTIMIZE-HF (2003–2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin-converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow-up, the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74–1.06; P = 0.179]. ARB use had no association with individual endpoints of all-cause mortality (HR 0.93, 95% CI 0.76–1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72–1.14; P = 0.389), or all-cause hospitalization (HR 0.91, 95% CI 0.77–1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non-use in a separately assembled propensity-matched cohort of 1137 pairs of HF-PEF patients.
In real-world older HF-PEF patients, ARB use was not associated with improved clinical outcomes.
PMCID: PMC3448391  PMID: 22759445
Angiotensin receptor blockers; Heart failure; Preserved ejection fraction
19.  Elevated urinary neutrophil gelatinase-associated lipocalcin after acute heart failure treatment is associated with worsening renal function and adverse events 
European Journal of Heart Failure  2012;14(9):1020-1029.
Reliable detectors of worsening renal function (WRF) in Emergency Department (ED) patients with acute heart failure (AHF) are limited. We hypothesized that initial urinary neutrophil gelatinase-associated lipocalcin (NGAL) levels, and changes in urinary NGAL levels after initial ED AHF therapy, would be associated with WRF and adverse events.
Methods and results
Urinary NGAL upon ED presentation and 12–24 h after ED treatment was measured in a cohort of ED patients with AHF. NGAL was corrected for urinary creatinine (uCr). WRF was defined as RIFLE stages 1, 2, or 3, or a creatinine increase of ≥0.3 mg/dL. Patients were prospectively followed for 5- and 30-day adverse cardiovascular events. The 399 patients had a median age of 63 years, 50% were Caucasian, and 62% were male. Those with WRF at 72–96 h were more likely to have a higher initial NGAL value (71 vs. 32 ng NGAL/mg uCr) (P = 0.005), and a higher NGAL level at 12–24 h after ED therapy (107 vs. 25ng NGAL/mg uCr, P < 0.001). In a multivariable model, NGAL at 12–24 h remained a significant predictor of WRF (P = 0.012). Of all variables available 12–24 h after initial therapy, the only significant predictor of 30-day events was an elevated urinary NGAL level (P = 0.02).
Urinary NGAL levels determined 12–24 h after ED therapy are significantly associated with both WRF at 72–96 h and 30-day adverse events. This suggests that early management strategies may have an impact on subsequent WRF and outcomes. If confirmed, NGAL may have a role for guiding therapeutic decisions.
PMCID: PMC3423948  PMID: 22733980
Heart failure; NGAL; Outcomes; ED
20.  Differential mortality association of loop diuretic dosage according to blood urea nitrogen and carbohydrate antigen 125 following a hospitalization for acute heart failure 
European Journal of Heart Failure  2012;14(9):974-984.
Recent observations in chronic stable heart failure suggest that high-dose loop diuretics (HDLDs) have detrimental prognostic effects in patients with high blood urea nitrogen (BUN), but recent findings have also indicated that diuretics may improve renal function. Carbohydrate antigen 125 (CA125) has been shown to be a surrogate of systemic congestion. We sought to explore whether BUN and CA125 modulate the mortality risk associated with HDLDs following a hospitalization for acute heart failure (AHF).
Methods and results
We analysed 1389 consecutive patients discharged for AHF. CA125 and BUN were measured at a mean of 72 ± 12 h after admission. HDLDs (≥120 mg/day in furosemide equivalent dose) were interacted to a four-level variable according to CA125 (>35 U/mL) and BUN (above the median), and related to all-cause mortality. At a median follow-up of 21 months, 561 (40.4%) patients died. The use of HDLDs was independently associated with increased mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01–1.50], but this association was not homogeneous across CA125–BUN categories (P for interaction <0.001). In patients with normal CA125, use of HDLDs was associated with high mortality if BUN was above the median (HR 2.29, 95% 1.51–3.46), but not in those with BUN below the median (HR 1.22, 95% CI 0.73–2.04). Conversely, in patients with high CA125, HDLDs showed an association with increased survival if BUN was above the median (HR 0.73, 95% CI 0.55–0.98) but was associated with increased mortality in those with BUN below the median (HR 1.94, 95% CI 1.36–2.76).
The risk associated with HDLDs in patients after hospitalization for AHF was dependent on the levels of BUN and CA125. The information provided by these two biomarkers may be helpful in tailoring the dose of loop diuretics at discharge for AHF.
PMCID: PMC3423949  PMID: 22700856
Loop diuretics; Mortality; Acute heart failure; Carbohydrate antigen 125; Blood urea nitrogen
21.  Increased Rho kinase activity in congestive heart failure 
European Journal of Heart Failure  2012;14(9):965-973.
Rho kinases (ROCKs) are the best characterized effectors of the small G-protein RhoA, and play a role in enhanced vasoconstriction in animal models of congestive heart failure (CHF). This study examined if ROCK activity is increased in CHF and how it is associated with the outcome in CHF.
Methods and results
Patients admitted with CHF (n =178), disease controls (n =31), and normal subjects (n =30) were studied. Baseline ROCK activity was measured by phosphorylation of themyosin-binding subunit in peripheral leucocytes. The patients were followed up for 14.4 ± 7.2 months (range 0.5–26 months) or until the occurrence of cardiac death. The ROCK activity in CHF patients (2.93 ± 0.87) was significantly higher than that of the disease control (2.06 ± 0.38, P < 0.001) and normal control (1.57 ± 0.43, P < 0.001) groups. Similarly, protein levels of ROCK1 and ROCK2 as well as the activity of RhoA in CHF were significantly higher than in disease controls and normal controls (all P < 0.05). Dyspnoea at rest (β =0.338, P < 0.001), low left ventricular ejection fraction (β = –0.277, P < 0.001), and high creatinine (β =0.202, P =0.006) were independent predictors of the baseline ROCK activity in CHF. Forty-five patients died within 2 years follow-up (25.3%). Combining ROCK activity and N-terminal pro brain natriuretic peptide (NT-proBNP) had an incremental value (log rank χ2 =11.62) in predicting long-term mortality when compared with only NT-proBNP (log rank χ2 =5.16, P < 0.05).
ROCK activity is increased in CHF and it might be associated with the mortality in CHF. ROCK activity might be a complementary biomarker to CHF risk stratification.
PMCID: PMC3707433  PMID: 22588320
Rho kinases; Congestive heart failure; Mortality
22.  Reducing heart failure admission rates in England 2004–2011 are not related to changes in primary care quality: national observational study 
European Journal of Heart Failure  2013;15(12):1335-1342.
Heart failure (HF) is an important clinical problem. Expert consensus has defined HF as a primary care-sensitive condition for which the risk of unplanned admissions may be reduced by high quality primary care, but there is little supporting evidence. We analysed time trends in HF admission rates in England and risk and protective factors for admission.
Methods and results
We used Hospital Episodes Statistics to produce indirectly standardized HF admission counts by general practice for 2004–2011. Clustered negative binomial regression analysis produced admission risk ratios and assessed the significance of potential explanatory covariates. These included population factors (deprivation; HF, coronary heart disease, and smoking prevalence), primary care resourcing [access; general practitioner (GP) supply], and primary care quality (‘Quality and Outcomes Framework’ indicator.) There were 327 756 HF admissions of patients registered with 8405 practices over the study period. There was a significant reduction in admissions over time, from 6.96/100 000 in 2004 to 5.60/100 000 in 2010 (P < 0.001). Deprivation and HF prevalence were risk factors for admission. GP supply and access protected against admission. However, these effects were small and did not explain the large and highly significant annual trend in falling admission rates.
The observed fall in admissions over time cannot be explained by the primary care covariates we included. This analysis suggests that the potential for further significant reduction in emergency HF admissions by improving clinical quality of primary care (as currently measured) may be limited. Further work is required to identify the reasons for the reduction in admissions.
PMCID: PMC3834843  PMID: 23845798
Heart failure; Epidemiology; Hospital admission; Healthcare quality
23.  Double jeopardy: the influence of excessive daytime sleepiness and impaired cognition on health-related quality of life in adults with heart failure 
European Journal of Heart Failure  2012;14(7):730-736.
To determine how excessive daytime sleepiness (EDS) and impaired cognition contribute to health-related quality of life (HRQL) in heart failure (HF).
Methods and results
Adults with chronic HF were enrolled into a prospective cohort study. Data were obtained from 280 subjects enrolled from three sites in the northeastern USA; 242 completed the 6-month study. At baseline, cohorts with and without EDS were identified using the Epworth Sleepiness Scale. Each EDS group was further subdivided into those with and without impaired cognition using a battery of five neuropsychological tests. Two disease-specific measures, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Outcomes of Sleep Questionnaire (FOSQ), were used to measure HRQL. General linear modelling of square-transformed variables was used to test the hypothesis that cohort membership was a significant predictor of HRQL. At 6 months the remaining sample was 62.5 [standard deviation (SD) 12] years old, mostly male (63%), white (65%), and functionally compromised [72% New York Heart Association (NYHA) class III/IV]. The cohort with both EDS and impaired cognition had the lowest KCCQ overall summary score (60.5 ± 22.5) compared with the cohort without EDS or impaired cognition (74.6 ± 17.4, P ≤ 0.001). A similar effect was seen on the FOSQ (16.0 ± 2.8 vs. 18.5 ± 2.2, P < 0.001).
Impaired cognition alone did not explain poor HRQL, but the addition of EDS poses a significant risk for poor HRQL. Interventions designed to influence EDS may improve HRQL in this population.
PMCID: PMC3380544  PMID: 22510422
Heart failure; Quality of life; Sleep; Cognition
24.  Social isolation, vital exhaustion, and incident heart failure: findings from the Atherosclerosis Risk in Communities Study 
European Journal of Heart Failure  2012;14(7):748-753.
Prospective studies have shown that social isolation (i.e. lack of social contacts) predicts incident coronary heart disease (CHD), but it is unclear whether it predicts incident heart failure (HF) and what factors might mediate this association. HF patients may be more susceptible to social isolation as they tend to be older and may have disrupted social relationships due to life course factors (e.g. retirement or bereavement). We prospectively examined whether individuals with higher vs. low social isolation have a higher incidence of HF and determined whether this association is mediated by vital exhaustion.
Methods and results
We estimated incident HF hospitalization or death among 14 348 participants from Visit 2 (1990–1992) in the Atherosclerosis Risk in Communities (ARIC) study using Cox proportional hazard models which were sequentially adjusted for age, race/study community, gender, current smoking, alcohol use, and co-morbidities. We conducted mediation analyses according to the Baron and Kenny method. After a median follow-up of 16.9 person-years, 1727 (13.0%) incident HF events occurred. The adjusted hazard of incident HF was greater for those in the higher vs. low social isolation risk group (hazard ratio 1.21, 95% confidence interval 1.08–1.35). Our data suggest that vital exhaustion strongly mediates the association between higher social isolation and incident HF (the percentage change in beta coefficient for higher vs. low social isolation groups after adjusting for vital exhaustion was 36%).
These data suggest that greater social isolation is an independent risk factor for incident HF, and this association appears to be strongly mediated by vital exhaustion.
PMCID: PMC3380545  PMID: 22588323
Social isolation • Heart failure • Psychological distress • Prospective cohort study
25.  Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial 
European Journal of Heart Failure  2013;15(11):1267-1276.
Therapy with i.v. iron in patients with chronic heart failure (CHF) and iron deficiency (ID) improves symptoms, functional capacity, and quality of life. We sought to investigate whether these beneficial outcomes are independent of anaemia.
Methods and results
FAIR-HF randomized 459 patients with CHF [NYHA class II or III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III)] and ID to i.v. iron as ferric carboxymaltose (FCM) or placebo in a 2:1 ratio. We analysed the efficacy and safety according to the presence or absence of anaemia (haemoglobin ≤120 g/L) at baseline. Of 459 patients, 232 had anaemia at baseline (51%). The effect of FCM on the primary endpoints of self-reported Patient Global Assessment (PGA) and NYHA class at week 24 was similar in patients with and without anaemia [odds ratio (OR) for improvement, 2.48 vs. 2.60, P = 0.97 for PGA and 1.90 vs. 3.39, P = 0.51 for NYHA). Results were also similar for the secondary endpoints, including PGA and NYHA at weeks 4 and 12, 6 min walk test distance, Kansas City Cardiomyopathy Questionnaire overall score, and European Quality of Life-5 Dimensions Visual Analogue Scale at most time points. Regarding safety, no differences were noticed in the rates of death or first hospitalization between FCM and placebo both in anaemic and in non-anaemic patients.
Treatment of ID with FCM in patients with CHF is equally efficacious and shows a similar favourable safety profile irrespective of anaemia. Iron status should be assessed in symptomatic CHF patients both with and without anaemia and treatment of ID should be considered.
PMCID: PMC3806282  PMID: 23787722
Anaemia; Iron deficiency; Heart failure; Intravenous iron; Ferric carboxymaltose

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