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Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

Serial measurement of natriuretic peptides may guide management in heart failure (HF) patients. In previous trials, natriuretic peptides were infrequently monitored, which may undervalue the benefit of this approach.HOME was an adaptive three-arm randomized clinical study to test whether home monitoring of BNP could reduce HF-related death, hospitalization due to acute decompensated HF (ADHF), and ADHF treated with intravenous diuretics in the emergency department or outpatient setting. Enrolment was terminated early because of slow enrolment, low event rates, and the belief that an algorithm for assessing BNP trends was needed. Justification for pooling data from all study arms was made and analysis as a single observational study was performed. The analysis resulted in 107 patients who were monitored for a median of 172 days with BNP measures on a median of 74% of days. BNP values were highly variable within a patient. Dispersion between serial BNPs was calculated to be 39.3%, 57.7%, and 73.6% for 1, 60, and 120 days between measures, respectively. A moving average filter (fBNP) was calculated to reduce day-to-day fluctuations and track changes from week to week. There were 27 primary events in 17 362 patient days of monitoring; the hazard ratio for time-varying fBNP was 2.22 (95% confidence interval 1.48-3.34) per unit natural log (corresponding to a 2.72-fold change in fBNP level).The HOME HF study demonstrates the feasibility of home BNP measurement and shows the potential value of fBNP as an index of emerging clinical deterioration. Assessment of the clinical value of this is required.

Heart transplantation is without doubt a very effective treatment for patients’ whose lives and well- being are threatened by their failing heart. We previously categorized our concerns into four areas or Ds: Donor availability, Disorganization, Disillusionment (of clinicians) and Disaffection (of tomorrow’s clinicians). After a decade, this is a timely reflection on this crisis of cardiac transplantation. It is also appropriate to set this in the context of a fifth D, the Demand for heart transplantation. In this reflective analysis, we use the 5 Ds to explore the current climate in heart transplantation, with particular reference to the situation in the UK.

Introduction: Current US and European guidelines recommend that patients hospitalized with heart failure (HF) are followed up after discharge, but do not specify whether or not this should be with HF specialist services. We investigated referral patterns to specialist services amongst hospitals in England and Wales and assessed whether these differences were associated with 30-day mortality. Methods: We used data from the National Heart Failure Audit, which included 84647 HF patients from 176 hospitals. Vital status was obtained from the UK national death registry. Using hierarchical statistical models and instrumental variable analysis, we estimated whether different types of follow-up (cardiologist, HF nurse or geriatrician) were associated with 30-day mortality, adjusting for case mix. Results: At the hospital level, rates of referral to cardiologists for follow up varied from 4% to 94%, to HF nurses from 0% to 97% and to geriatricians from 0% to 65%. When heart failure patients were referred for follow-up to a heart failure nurse, to a geriatrician, or to a cardiologist, they were 15%, 15% and 47% less likely to die than patients who were not referred to these specialists (odds ratio [OR] = 0.85, p Conclusion: Referral at discharge to cardiology services for follow-up varies considerably amongst UK hospitals. At both an individual patient and at a hospital level, referral to cardiology for follow-up is a major determinant of 30-day mortality.

The originally published version of this paper was incorrect. In the table on page 1816, the Class of recommendation and Level of evidence for ‘The patient is pacemaker dependent as a result of AV nodal ablation’ should have read ‘IIa’ and ‘B’ respectively. Appendix: six tables ([3][1

Whether beta-blockers reduce atrial arrhythmias and, when added to an angiotensin-converting enzyme (ACE) inhibitor, ventricular arrhythmia is unknown.Ventricular and atrial arrhythmias are common after acute myocardial infarction (AMI) and are associated with a poor prognosis. Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia.The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, which enrolled 1,959 patients with reduced left ventricular systolic function after AMI, 98% of whom were treated with an ACE inhibitor.The incidence of atrial fibrillation/flutter was 53 to 984 (5.4%) in the placebo group and 22 to 975 (2.3%) in the carvedilol group, giving a carvedilol/placebo hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.25 to 0.68; p = 0.0003). The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 (3.9%) and 9 to 975 (0.9%) (HR 0.24, 95% CI 0.11 to 0.49; p0.0001).Carvedilol has a powerful antiarrhythmic effect after AMI, even in patients already treated with an ACE inhibitor. Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients.

Background — In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. Methods and Results — A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. Conclusions — Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.

Heart failure (HF), defined in its broadest sense as a syndromecharacterized by symptoms and signs of ventricular dysfunction inthe presence of structural and or functional abnormalities of heartfunction, affects millions of people worldwide; in addition, a substantialnumber of individuals have asymptomatic abnormalitiesof heart function that predispose them to symptomatic HF in laterlife. Coronary artery disease and hypertension are by far the most common causes of HF, but a substantial minority of cases arecaused by a heterogeneous group of heart muscle diseases, the cardiomyopathies.These disorders differ in several important respectsfrom other causes of HF in that they are often familial and presentthroughout life. With recent advances in the understanding of themolecular genetics of cardiomyopathies, cardiologists are havingto adapt diagnostic and treatment protocols in order to optimizemanagement of individual patients and their families. In thischapter we review the clinical presentation and pathophysiology ofthe most common monogenic cardiomyopathies and the cardiovascularmanifestations of mutations in the genes controlling therespiratory chain (mitochondrial diseases).