Moderate Heart Failure Research Articles

Low Atrial Fibrillatory Rate Is Associated With Poor Outcome in Patients With Mild to Moderate Heart Failure

Atrial fibrillatory rate (AFR) is a measure of atrial remodeling caused by atrial fibrillation (AF), and its acceleration negatively affects outcome of interventions for persistent AF. However, the prognostic value of AFR in patients with congestive heart failure (CHF) has not been studied. We sought to evaluate whether AFR can predict outcome in patients with mild to moderate (New York Health Association II-III) CHF. High-resolution 20-minute long Holter ECGs obtained from 169 CHF patients with AF at enrollment were analyzed. AFR was estimated using spatiotemporal QRST cancellation and time-frequency analysis. The patients were followed for a median of 44 months, with primary end point defined as total mortality and secondary end points as sudden death and heart failure death. Atrial signal quality was sufficient for AFR estimation in 142 patients (mean age 69±11 years, 101 male). Of those, 48 patients died during follow-up, including 18 because of CHF progression. Mean AFR was 390±60 fpm and decreased with age (r=-0.3, P<0.001). Patients with AFR ≤371 fpm (lower tertile) had 44% 3-year mortality as compared with 26% with higher AFR. Lower AFR was an independent predictor of all cause mortality (HR=1.99, 95% CI=1.09-3.63, P=0.025) and CHF death (HR=3.74, 95% CI=1.38-10.14, P=0.010) after adjustment for significant clinical covariates in multivariable Cox analysis. In CHF patients with AF, reduced AFR assessed using noninvasive approach is associated with increased risk of death because of heart failure progression, and may be considered a predictor of outcome.

The Prognostic Value of Estimated Glomerular Filtration Rate, Amino-Terminal Portion of the Pro-Hormone B-Type Natriuretic Peptide and Parameters of Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure

The aim of this study was to evaluate the prognostic value of renal function in relation to amino-terminal portion of the pro-hormone B-type natriuretic peptide (NT-proBNP) and parameters of cardiopulmonary exercise testing in predicting mortality and morbidity in patients with moderate chronic heart failure (CHF). Sixty-one CHF patients were included in the study. Patients' characteristics were: age 64.3±11.6 years; New York Heart Association class I/II/III: 14/37/10; left ventricular ejection fraction: 0.30±0.13 (%); NT-proBNP: 252.2±348.0 (ng/L); estimated creatinine clearance (e-CC): 73.6±31.4 (mL/min); estimated glomerular filtration rate (e-GFR): 66.1±24.6 (mL/min/1.73 m2); the highest O2 uptake during exercise (VO2-peak): 1.24±0.12 mL/kg/min; VO2/workload: 8.52±1.81 (mL/min/W)]. During follow up (59.5±4.0 months) there were 15 cardiac deaths and 16 patients were hospitalized due to progression of heart failure. NT-proBNP and VO2/workload were independently associated with cardiac death (P=0.007 and P=0.006, respectively). Hospitalization for progressive CHF was only associated with NT-proBNP (P=0.002). The combined cardiac events (cardiac death and hospitalization) were associated with NT-proBNP and VO2/ workload (P=0.007 and P=0.005, respectively). The addition of estimates of renal function (neither serum creatinine nor e-GFR) did not improve the prognostic value for any of the models.In conclusion, in patients with moderate CHF, increased NT-proBNP and reduced VO2/ work-load identify those with increased mortality and morbidity, irrespective of estimates of renal function.

A trial-based economic evaluation of 2 nurse-led disease management programs in heart failure

Although previously conducted meta-analyses suggest that nurse-led disease management programs in heart failure (HF) can improve patient outcomes, uncertainty regarding the cost-effectiveness of such programs remains. To compare the relative merits of 2 variants of a nurse-led disease management program (basic or intensive support by a nurse specialized in the management of patients with HF) against care as usual (routine follow-up by a cardiologist), a trial-based economic evaluation was conducted alongside the COACH study. In terms of costs per life-year, basic support was found to dominate care as usual, whereas the incremental cost-effectiveness ratio between intensive support and basic support was found to be equal to €532,762 per life-year; in terms of costs per quality-adjusted life-year (QALY), basic support was found to dominate both care as usual and intensive support. An assessment of the uncertainty surrounding these findings showed that, at a threshold value of €20,000 per life-year/€20,000 per QALY, basic support was found to have a probability of 69/62% of being optimal against 17/30% and 14/8% for care as usual and intensive support, respectively. The results of our subgroup analysis suggest that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF would be optimal if the willingness-to-pay threshold exceeds €45,345 per life-year/€59,289 per QALY. Although the differences in costs and effects among the 3 study groups were not statistically significant, from a decision-making perspective, basic support still had a relatively large probability of generating the highest health outcomes at the lowest costs. Our results also substantiated that a stratified approach based on offering basic support to patients with mild to moderate HF and intensive support to patients with severe HF could further improve health outcomes at slightly higher costs.

Abstract 8980: Effective Cardiac Resynchronization Therapy May Normalize Longitudinal Dyssynchrony Evaluated by 3-Dimentional Speckle Tracking Imaging

Background: Cardiac resynchronization therapy (CRT) becomes standard therapy for severe heart failure and its indication is now spreading to mild to moderate heart failure. However there remains approximately 30% non-responders and the mechanism of reverse remodeling induced by CRT is still unclear. Thereby we investigated which kind of dyssynchrony parameter, existing during own beat, was improved by CRT-on. Methods: We investigated 43 patients by 3-dimentional speckle tracking imaging (3DSTI) (ARTIDA, TOSHIBA Medical System): 12 CRT responders, defined as left ventricular end-systolic volume reduction &gt;15% at 6 months after CRT, 14 CRT non-responders and age matched 17 healthy normal controls. Radial strain, longitudinal strain and circumferential strain were investigated and we calculated the following 3DSTI parameter: strain delay index (SDI) which was defined as the sum of the difference between peak and end-systolic each parameter across 16 segments. 3DSTI was investigated at &gt;6months after CRT implantation and evaluated during CRT-off as own beat and CRT-on for responders and non-responders and during sinus rhythm for normal controls to estimate CRT effect at chronic phase. Results: During CRT-off, radial and longitudinal SDI were significantly higher in responders than non-responders, but circumferential SDI was not significantly different. After turning CRT-on, radial and longitudinal SDI were improved to lose significant difference, but circumferential SDI showed significant difference. Turning CRT-on, longitudinal SDI of responders had no more significant difference with normal controls (figure). Conclusions: Effective CRT pacing at chronic phase improves radial and longitudinal dyssynchrony, especially longitudinal SDI tend to be normalized. Reverse remodeling after CRT might be induced by improvement of longitudinal dyssynchrony.

Long-Term Prognostic Value of CA 125 Serum Levels in Mild to Moderate Heart Failure Patients

BackgroundPlasma levels of tumor marker carbohydrate 125 antigen (CA 125) have been found elevated among patients with advanced heart failure (HF). We evaluated the prognostic value of CA125 in a population of patients with mild to moderate HF. Methods and ResultsSerum levels of CA 125 were obtained in 102 patients with mild to moderate HF from idiopathic (48%) or ischemic (52%) dilated cardiomyopathy (age 64 ± 10.4 years, left ventricular ejection fraction: 34.4 ± 8.5%), under optimized medical therapy. During follow-up (43 ± 15 months), 16 (15.7%) cardiovascular deaths and 23 (22.5%) cardiovascular deaths + HF hospitalizations were recorded. Considering cardiac death, comparison of Kaplan-Meier survival curves by the log-rank test showed that patients with CA 125 levels higher than the cut-off value (30 U/mL) had a worse survival (P < .0001). This was observed also when considering cardiovascular death+ HF hospitalizations as the secondary end point (P = .0003). Event-free survival was assessed by Kaplan-Meier method and log-rank test. Multivariable Cox proportional stepwise hazards regression analysis was performed and showed that CA 125 and systolic pulmonary artery pressure (sPAP) were significantly associated with the risk of cardiovascular deaths + HF hospitalizations (HR 1.01, 95% CI 1.02–1.06, and HR 1.07, 95% CI 1.02–1.1, P < .001, respectively). ConclusionsIn mild-to-moderate HF patients under optimized therapy, higher plasma CA 125 levels are an effective long-term prognostic marker in forecasting cardiovascular events and HF hospitalization and may contribute to a better risk stratification.

ORAL PRESENTATION

ORAL PRESENTATION

Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure

1. Chronic heart failure (CHF) is a common disabling disorder associated with thromboembolic events, the genesis of which is not yet fully understood. Nitric oxide (NO), derived from the vascular endothelium and platelets, has an important role in the physiological regulation of blood flow. It is generated from the amino acid L-arginine via NO synthase (NOS). 2. The main objective of the present study was to investigate NO production and its relationship with platelet aggregation, oxidative stress, inflammation and related amino acids in patients with moderate CHF. The expression and activity of NOS isoforms were analysed by western blotting and conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline, respectively, in CHF patients (n = 12) and healthy controls (n = 15). Collagen- and ADP-induced platelet aggregation, oxidative stress (thiobarbituric acid-reactive substances (TBARS) formation and superoxide dismutase (SOD) activity) and plasma levels of amino acids and inflammatory markers (fibrinogen and C-reactive protein (CRP)) were also determined. 3. Both collagen- and ADP-induced platelet aggregation were increased in CHF patients compared with controls. Platelets from CHF patients did not show any changes in NOS activity in the presence of overexpression of inducible NOS. Systemic and intraplatelet TBARS production was elevated, whereas SOD activity was decreased in CHF patients. l-arginine plasma concentrations were lower in CHF patients than in controls. Systemic levels of CRP and fibrinogen were increased in CHF patients. 4. The results show that, in patients with moderate CHF, there is platelet activation and reduced intraplatelet NO bioavailability due to oxidative stress, which suggests a role for platelets in the prothrombotic state.

N-Terminal Pro–Atrial Natriuretic Peptide Measurement in Plasma Suggests Covalent Modification

The N-terminal fragment of cardiac-derived pro-B-type natriuretic peptide is a glycosylated polypeptide. It is unknown whether N-terminal pro-atrial natriuretic peptide (proANP) fragments are also covalently modified. We therefore evaluated the clinical performance of 2 distinctly different proANP assays on clinical outcome. We examined 474 elderly patients with symptoms of heart failure presenting in a primary healthcare setting. Samples were analyzed with an automated immunoluminometric midregion proANP (MR-proANP) assay and a new processing-independent assay (PIA) developed in our laboratory. The results were compared with Bland-Altman plots, and clinical performance was assessed by generating ROC curves for different clinical outcomes. Despite linear regression results indicating a good correlation (r = 0.85; P < 0.0001), the PIA measured considerably more proANP than the MR-proANP assay (mean difference, 663 pmol/L; SD, 478 pmol/L). In contrast, the clinical performances of the 2 assays [as assessed by the area under the ROC curve (AUC)] in detecting left ventricular dysfunction were similar [proANP PIA, 0.71 (95% CI, 0.63-0.79); MR-proANP assay, 0.74 (95% CI, 0.66-0.81); P = 0.32]. The prognostic ability to report cardiovascular mortality during a 10-year follow-up revealed AUC values of 0.66 (95% CI, 0.60-0.71) for the proANP PIA and 0.69 (95% CI, 0.63-0.74) for the MR-proANP assay (P = 0.08, for comparing the 2 assays). Our data suggest that N-terminal proANP fragments in patient plasma differ from the calibrator peptides used but that the difference does not affect ROC curves in an elderly cohort of patients with mild to moderate heart failure. We suggest that human N-terminal proANP fragments can be covalently modified.

Continuous Hemodynamic Monitoring in Patients With Mild to Moderate Heart Failure: Results of the Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic Heart Failure (REDUCEhf) Trial

Clinical trial results support the hypothesis that implantable hemodynamic monitoring (IHM) systems may reduce hospitalizations among patients with chronic heart failure (HF). The Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic Heart Failure (REDUCE hf ) study was a prospective, randomized, multicenter, single-blinded trial that enrolled patients with New York Heart Association class II or III symptoms, an indication for an implantable cardioverter-defibrillator (ICD), and a previous HF hospitalization. A combination IHM-ICD was implanted and patients were randomly assigned to a treatment group in which hemodynamic information was used or a control group in which hemodynamic information was not available. Patients were followed for 12 months to evaluate the primary efficacy end point of HF hospitalizations, emergency department visits, or urgent clinic visits. The trial was designed to enroll 1300 patients, but stopped at 400 patients because of IHM lead failures experienced from previous trials. A total of 202 treatment patients and 198 controls were randomized for 12-month follow-up. The primary safety end point was met, but the rate of HF equivalents was not different between groups. REDUCE hf was unable to test clinical efficacy end points adequately. The device combining IHM-ICD technology was safe and functioned appropriately. Patients at high risk for decompensated HF have high baseline filling pressures and demonstrate consistent increases as the process of congestion worsens to the time of hospitalization.

The Benefit of Cardiac Resynchronization Therapy and QRS Duration: A Meta‐Analysis

Cardiac resynchronization therapy (CRT) improves outcomes in patients with heart failure (HF) because of reduced left ventricular systolic function and a wide QRS complex. Whether this benefit is consistent across all degrees of QRS widening is unclear. We performed a meta-analysis of randomized clinical trials to evaluate the impact of QRS duration on the efficacy of CRT. We searched MEDLINE and EMBASE databases for studies evaluating the efficacy of CRT in patients with HF. Only trials that reported subgroup data according to QRS duration were included. Hazard ratios (HR) with 95% confidence interval (CI) were calculated using a random effects model. Five trials involving 6,501 patients (4,437 with QRS ≥ 150 ms and 2,064 with QRS < 150 ms) were included. Three trials, enrolling patients with mild to moderate HF, compared CRT-implantable cardioverter defibrillator with CRT, whereas CRT versus medical therapy was compared in the other 2 trials, which included patients with advanced HF. Based on the pooled estimate across the 5 studies, CRT significantly decreased the primary endpoint of death or hospitalization for HF in patients with QRS ≥ 150 ms (HR = 0.58, 95% CI: 0.50-0.68; P < 0.00001), but not in patients with QRS < 150 ms (HR = 0.95, 95% CI: 0.83-1.10; P = 0.51). These results were consistent across all degrees of HF severity. The benefit of CRT seems to be dependent on QRS duration. Available data suggest a significant benefit associated with CRT in patients with QRS ≥ 150 ms, but not in patients with QRS < 150 ms. Further studies are needed to identify patients with QRS < 150 ms who might benefit from CRT.

Epicardial Fat Volume in Patients With Left Ventricular Systolic Dysfunction

Epicardial adipose tissue has been linked to cardiovascular metabolism and inflammation and has been shown to predict prevalence and progression of coronary artery disease. Only limited data are available on the role of epicardial fat in patients with heart failure (HF). We analyzed cardiac adiposity and its relation to markers of morbidity and clinical outcome in patients with normal and impaired left ventricular (LV) function. Epicardial fat volume (EFV) and coronary artery calcium were measured in 381 patients (210 women and 171 men, mean age 55 ± 10 years) who underwent low-dose computed tomography. HF was defined by LV ejection fraction (EF) <55%. Three hundred twenty-one patients had an EF >55% (mean 63 ± 6) and 60 patients had an EF <55% (mean 41 ± 12). Subgroup analysis was performed according to degree of LV dysfunction in patients with HF (LVEF 35% to 55% or <35%). Mean EFVs were 114.5 ± 98.5 cm(3) in patients with normal EF and 83.5 ± 67.1 cm(3) in those with decreased EF (p <0.05). Mean EFVs were 96.1 ± 73.9 cm(3) in patients with moderate HF and 52.2 ± 29.7 cm(3) in patients with severe HF (p <0.05). Subgroup analysis revealed a persistently smaller EFV in patients with HF regardless of coronary artery calcium scores, markers of renal function, lipid metabolism, fasting blood glucose, or body mass index. In conclusion, our data demonstrate a stepwise decrease in EFV in patients with impaired cardiac function.

Heart Failure Severity Scoring System and Medical- and Health-Related Quality-of-Life Outcomes: The HEMO Study

Cardiac disease is the leading cause of death in US prevalent hemodialysis (HD) patients. There is a lack of data about the impact of the severity of heart failure (HF) on outcomes and health-related quality of life (HRQoL) in HD patients. We aimed to determine the prognostic importance of the Index of Disease Severity (IDS) of the Index of Coexistent Disease (ICED) scoring system as an HF severity measure. Subanalysis of the Hemodialysis (HEMO) Study, a randomized controlled trial. Relationships between HF severity and mortality and cardiac hospitalizations were determined using Cox proportional hazards models. The relationship between HF severity and HRQoL scores was modeled using linear regression and generalized estimating equations. 1,846 long-term HD patients at 15 clinical centers including 72 dialysis units. HF severity classified using the IDS of the ICED scoring system. Mortality (all cause and cause specific), cardiac hospitalizations, and HRQoL. All-cause, cardiac, and infectious deaths; cardiac hospitalizations; and HRQoL scores from the Kidney Disease Quality of Life-Long Form. HF was present in 40% of HD patients. Increasing severity of HF was associated with older age, greater likelihood of diabetes, and lower serum albumin level (all P < 0.001). Adjusted HRs for all-cause mortality were 1.31 (95% CI, 1.12-1.53), 1.48 (95% CI, 1.19-1.85), and 2.11 (95% CI, 1.43-3.11) for mild, moderate, and severe HF, respectively (P < 0.001). All-cause, cardiac, and infectious mortality and cardiac hospitalizations increased with increasing severity of HF. Increasing HF severity was associated with decreases in HRQoL, particularly in physical functioning and sleep quality. This study is limited by the small sample size in the most severe HF group. Increasing severity of HF is associated with increased mortality and cardiac hospitalizations and worse HRQoL, especially in perceived physical limitations. These findings emphasize the utility of the IDS of the ICED score as a valid prognostic tool for medical and HRQoL outcomes in the HD population with HF.

QT variability index on 24-hour Holter independently predicts mortality in patients with heart failure: analysis of Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) trial

Increased temporal variability of repolarization, as reflected by QT interval variability measured over 10-15 minutes, predicted spontaneous ventricular arrhythmias and death in implantable cardioverter-defibrillator patients in mild to moderate heart failure (HF). The purpose of this study was to test our hypothesis that increased mean QT variability over 24 hours would be associated with increased cardiovascular (CV) mortality in a heterogeneous HF population. The Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure trial prospectively enrolled subjects with HF of any cause. Twenty-four-hour Holter recordings from 268 subjects were analyzed using a template-matching, semiautomatic algorithm to measure QT and heart rate time series in sequential 5-minute epochs over 24 hours. The QT variability index (QTVI) was expressed as the log ratio of the normalized QT variance over normalized heart rate variance. Total and CV mortality were assessed as a function of continuous and dichotomous QTVI (>-0.84) in univariate and multivariable Cox proportional hazards models, adjusting for significant clinical predictors. After a median of 47 months, there were 53 deaths, of which 44 were from CV causes. A significant association with the outcome was found for QTVI both as continuous and dichotomous variables after adjustment for clinical covariates (age >70, New York Heart Association class III-IV, left ventricular ejection fraction, nonsustained ventricular tachycardia, creatinine): QTVI hazard ratio (HR) 4.0 (confidence interval [CI] 1.8-88; P = .008) for total and 4.4 (CI 1.9-10.1; P = .0006) for CV mortality; QTVI >-0.84 HR 2.0 (CI 1.1-3.6; P = .02) for total and 2.1 (CI 1.1-3.8; P = .02) for CV mortality. Increased repolarization lability, as reflected in QTVI measured over 24 hours, is associated with increased risk for total and CV mortality in a heterogeneous population with chronic HF.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP ≤ 120 mm Hg. Propensity scores for SBP ≤ 120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP ≤ 120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤ 120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP ≤ 120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP ≤ 120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs ≤ 120 and > 120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP ≤ 120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP ≤ 120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics.

Absence of obesity paradox in patients with chronic heart failure and diabetes mellitus: a propensity‐matched study

Obesity is paradoxically associated with survival benefit in patients with chronic heart failure (HF). However, obesity complicates the management of diabetes mellitus (DM), which is common in HF. Yet, little is known about the impact of obesity in HF patients with DM. Therefore, we examined the association between obesity and outcomes in propensity-matched cohorts of HF patient with and without DM. Of the 7788 participants with chronic mild to moderate HF in the Digitalis Investigation Group trial, 7379 were non-cachectic [body mass index (BMI) ≥ 20 kg/m²] at baseline. Of these, 2153 (29%) had DM, of whom 798 (37%) were obese (BMI ≥ 30 kg/m²). Of the 5226 patients without DM, 1162 (22%) were obese. Propensity scores for obesity were used to separately assemble 636 pairs of obese and non-obese patients with DM and 770 pairs of obese and non-obese patients without DM, who were balanced on 32 baseline characteristics. Among matched patients with DM, all-cause mortality occurred in 38 and 39% of obese and non-obese patients, respectively [hazard ratio (HR) when obesity was compared with no obesity 0.99; 95% confidence interval (CI) 0.80-1.22; P = 0.915]. Among matched patients without DM, all-cause mortality occurred in 23 and 27% obese and non-obese patients, respectively (HR associated with obesity 0.77; 95% CI 0.61-0.97; P = 0.025). In patients with chronic mild to moderate HF and DM, obesity confers no paradoxical survival benefit. Whether intentional weight loss may improve outcomes in these patients needs to be investigated in future prospective studies.

Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials

Studies of cardiac resynchronization therapy in addition to an implantable cardioverter defibrillator in patients with mild to moderate congestive heart failure had not been shown to reduce mortality until the recent RAFT trial (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial). We performed a meta-analysis including the RAFT trial to determine the effect of cardiac resynchronization therapy with or without an implantable defibrillator on mortality. We searched electronic databases and other sources for reports of randomized trials using a parallel or crossover design. We included studies involving patients with heart failure receiving optimal medical therapy that compared cardiac resynchronization therapy with optimal medical therapy alone, or cardiac resynchronization therapy plus an implantable defibrillator with a standard implantable defibrillator. The primary outcome was mortality. The optimum information size was considered to assess the minimum amount of information required in the literature to reach reliable conclusions about cardiac resynchronization therapy. Of 3071 reports identified, 12 studies (n = 7538) were included in our meta-analysis. Compared with optimal medical therapy alone, cardiac resynchronization therapy plus optimal medical therapy significantly reduced mortality (relative risk [RR] 0.73, 95% confidence interval [CI] 0.62-0.85). Compared with an implantable defibrillator alone, cardiac resynchronization therapy plus an implantable defibrillator significantly reduced mortality (RR 0.83, 95% CI 0.72-0.96). This last finding remained significant among patients with New York Heart Association (NYHA) class I or II disease (RR 0.80, 95% CI 0.67-0.96) but not among those with class III or IV disease (RR 0.84, 95% CI 0.69-1.07). Analysis of the optimum information size showed that the sequential monitoring boundary was crossed, which suggests no need for further clinical trials. The cumulative evidence is now conclusive that the addition of cardiac resynchronization to optimal medical therapy or defibrillator therapy significantly reduces mortality among patients with heart failure.

Functional and molecular effects of imidazoline receptor activation in heart failure

Aims Heart failure is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. The benefit of inhibition of sympathetic activity by moxonidine, a centrally acting imidazoline receptor agonist, was questioned based on the outcome of a failing clinical trial. The following studies measured cardiac structure and hemodynamics and mechanisms underlying moxonidine-induced changes, in cardiomyopathic hamsters, where the stage of the disease, dose, and compliance were controlled. Main methods Male BIO 14.6 hamsters (6 and 10 months old, with moderate and advanced heart failure, respectively) received moxonidine at 2 concentrations: low (2.4 mg/kg/day) and high (9.6 mg/kg/day), or vehicle, subcutaneously, for 1 month. Cardiac function was measured by echocardiography, plasma and hearts were collected for histological determination of fibrosis and apoptosis, as well as for measurement cytokines by Elisa and cardiac proteins by Western blotting. Key findings Compared to age-matched vehicle-treated BIO 14.6, moxonidine did not reduce blood pressure but significantly reduced heart rate and improved cardiac performance. Moxonidine exerted anti-apoptotic effect with differential inflammatory/anti-inflammatory responses that culminate in attenuated cardiac apoptosis and fibrosis and altered protein expression of collagen types. Some effects were observed regardless of treatment onset, although the changes were more significant in the younger group. Interestingly, moxonidine resulted in upregulation of cardiac imidazoline receptors. Significance These studies imply that in addition to centrally mediated sympathetic inhibition, the effects of moxonidine may, at least in part, be mediated by direct actions on the heart. Further investigation of imidazolines/imidazoline receptors in cardiovascular diseases is warranted.

Myocardial transfection with naked DNA plasmid encoding hepatocyte growth factor prevents the progression of heart failure in dogs

This study examined the effects of localized intramyocardial injections of hepatocyte growth factor (HGF) naked DNA plasmid on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Twenty-one dogs with intracoronary microembolization-induced HF [LV ejection fraction (EF) = 35-40%] were randomized into three treatment groups, namely, high-dose HGF plasmid (4.0 mg, n = 7), low-dose HGF plasmid (0.4 mg, n = 7), and sham-operated controls treated with normal saline (n = 7). A total of 10-15 injections of HGF plasmid or saline were made directly into the anterior wall of LV. LV EF and end-systolic volume (ESV) were measured before randomization (pretreatment) and at the end of 3 mo of follow-up (posttreatment). Treatment effect (Δ) was calculated as the change from pre- to posttreatment. Protein expression of sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins was determined in LV tissue obtained from the sites of HGF injection and remote areas. Low-dose HGF attenuated the decline in EF (ΔEF: -3 ± 1 vs. -8 ± 1%, P < 0.05) and the increase in ESV (ΔESV: 6 ± 2 vs. 10 ± 1 ml, P < 0.05) seen in control sham-operated dogs, whereas high-dose HGF significantly increased EF (ΔEF: 4 ± 1 vs. -8 ± 1%, P < 0.05) and prevented the increase in ΔESV (ESV: -1 ± 1 vs. 10 ± 1 ml, P < 0.05) compared with control dogs. Treatment with high- and low-dose HGF improved the expression of the SR Ca(2+)-cycling proteins compared with controls. In conclusion, regional intramyocardial injections of HGF naked DNA plasmid improve regional and global LV function and prevent progressive LV remodeling.

Obesity paradox and risk of sudden death in heart failure: Results from the MUerte Subita en Insuficiencia Cardiaca (MUSIC) Study

among patients with heart failure (HF), body mass index (BMI) has been inversely associated with mortality, giving rise to the so-called obesity paradox. The aim of this study was to examine the relationship between BMI and two modes of cardiac death: pump failure death and sudden death.nine hundred seventy-nine patients with mild to moderate chronic symptomatic HF from the MUSIC (MUerte Subita en Insuficiencia Cardiaca) Study, a prospective, multicenter, and longitudinal study designed to assess risk predictors of cardiac mortality, were followed up during a median of 44 months. Independent predictors of death were identified by a multivariable Cox proportional hazards model.higher BMI emerged as an independent predictor of all-cause mortality (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.91-0.97, P = .0003) and pump failure death (HR = 0.93, 95% CI = 0.88-0.98, P = .004). Sudden death accounted for 45% of deaths in obese patients, 53% in overweight patients, and 37% in lean patients. No significant relationship between BMI and sudden death was observed (HR = 0.97, 95% CI = 0.92-1.02, P = .28). The only independent predictors of sudden death were prior history of myocardial infarction (HR = 1.89, 95% CI = 1.23-2.90, P = .004), hypertension (HR = 1.66, 95% CI = 1.05-2.63, P = .03), left ventricular ejection fraction (HR = 0.88, 95% CI = 0.79-0.96, P = .006), and N-terminal pro-B-type natriuretic peptide (HR = 1.01, 95% CI = 1.00-1.02, P = .048).the obesity paradox in HF affects all-cause mortality and pump failure death but not sudden death. The risk of dying suddenly was similar across BMI categories in this cohort of ambulatory patients with HF.

Slow Cardiac Myosin Regulatory Light Chain 2 (MYL2) was Down‐Expressed in Chronic Heart Failure Patients

Genetic studies have shown that many slow cardiac myosin regulatory light chain 2 (MYL2) gene mutations can cause hypertrophic cardiomyopathy, which is one of the most common causes of heart failure (HF). But until now there has been no pathological or histological evidence that MYL2 may be associated with HF development. Recent microarray studies indicated that myosin heavy chain expression changed in the pathological process of HF. Because MYL2 is a regulatory component of myosin heavy polypeptide, the role of MYL2 protein in HF needs to be studied. The level of expression of MYL2 may change in the heart tissue of patients with chronic HF. We collected 28 human right auricle samples, 16 from chronic HF patients and 12 from healthy control subjects. Immunohistochemistry was carried out to observe the tissue-expression pattern of the MYL2 protein and Western blot methods were performed to quantify the relative MYL2 expression level. In chronic HF patients, the MYL2 protein level decreased significantly compared with normal controls (t test P < 0.05). Among the 16 HF patients, MYL2 expression in the severe HF group (New York Heart Association [NYHA] class III or IV) was even lower than that of the moderate HF group (NYHA class II) (t test P < 0.05). MYL2 was down-expressed in HF tissues, and our findings suggested that MYL2 may play a role in the development and progression of chronic HF.