Heart failure: focus on co-morbidities, inflammation, and heart rate.

Abstract

In spite of recent progress made in the management of heart failure as outlined in current guidelines, patients often remain symptomatic, and the event rate, even on optimal therapy and with devices, is still high. Besides pump failure itself, co-morbidities contribute importantly to the disease burden in heart failure patients. Besides renal failure and diabetes, many patients with heart failure have an iron deficiency, probably due to chronic inflammation associated with the disease process. Accordingly, the first manuscript, by Piotr Ponikowski from the Clinical Military Hospital in Wroclaw, Poland, is an ESC FAST TRACK manuscript entitled ‘Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency’ accompanied by a critical Editorial by Harry Crijns from the University Hospital Maastricht in the Netherlands. The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in 304 iron-deficient patients with heart failure and a reduced left ventricular ejection fraction and elevated natriuretic peptides enrolled in CONFIRM-HF and randomized to i.v. ferric carboxymaltose or placebo. The primary endpoint was the change in 6 min walk test distance from baseline at 4 months. Secondary endpoints included changes in New York Heart Association (NYHA) class, Patient Global Assessment, health-related quality of life, fatigue score, and hospitalization for worsening heart failure. Ferric carboxymaltose prolonged the 6 min walk distance beyond 1 year. Furthermore, ferric carboxymaltose improved NYHA class, Patient Global Assessment, quality of life, and fatigue score, and reduced hospitalizations for heart failure, while deaths and adverse events were comparable between groups. The authors conclude that treatment of symptomatic, iron-deficient heart failure patients with ferric carboxymaltose over 1 year results in a sustained improvement in functional capacity, symptoms, andqualityof life, aswell in a reduction of hospitalization for heart failure. It remains unknown, however, whether iron substitution beyond symptomatic benefit also provides protection from premature death in these patients. A large randomized trial certainly is an unmet need in this patient population. In addition to co-morbidities, baseline heart rate has been recognized as a risk factor in heart failure, while its modulation over time has not been studied. The second manuscript, by Scott Solomon et al. from the Brigham and Women’s Hospital in Boston USA, accompanied by a thought-provoking Editorial by Michel Komajda from the CHU Pitie-Salpetriere, Paris, France, is entitled ‘Prognostic importance of temporal changes in resting heart rate in heart failure patients: an analysis of the CHARM programme’. The authors explored the relationship between changes in heart rate from a preceding visit, time-updated heart rate (i.e. most-recent available heart rate value), and outcomes in 7599 patients with chronic heart failure recruited in the CHARM programme. Of note, an increase in heart rate from a preceding visit was associated with higher all-cause mortality and the composite of cardiovascular death or hospitalization for heart failure, while lowering of heart rate was associated with reduced risk. The authors showed for the first time that heart rate at follow-up, as well as a change or time-updated heart rate, predicts outcome in chronic heart failure. They further suggest that frequent outpatient monitoring of heart rate, and identification of changes over time, possibly with remote technologies, may identify patients at increased risk of re-hospitalization or death. With the help of modern devices, remote monitoring is already possible and may eventually find its way into the everyday management of patients with heart failure. Inflammation is associated not only with atherosclerosis but also with heart failure. On the other hand, myocardial inflammation can severely impair left ventricular function, for instance in myocarditis. It is of note that chemokines and cytokines may not only be damaging, but may also be protective. The third manuscript, by Konrad Hoetzenecker from the Medical University of Vienna in Austria, accompanied by an enlightening Editorial by Heinz-Peter Schultheiss from the Charite University in Berlin, Germany, reports on ‘Mononuclear cell secretome protects from experimental autoimmune myocarditis’. The authors investigated in the supernatants of serum-free cultured mononuclear cells a mix of immunomodulating factors (i.e. the so-called secretome), which is able to attenuate inflammatory responses in myocardial ischaemia. In this study, the authors aimed to characterize the influence of the mononuclear secretome on myocardial inflammation in an experimental model of a-myosin heavy chain autoimmune myocarditis. A single high-dose injection of the mononuclear secretome at day 14 attenuated myocardial inflammation. Mechanistically, the mononuclear secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells. Thus, the authors conclude that the mononuclear secretome is able to