Aims Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)‐α were largely unsuccessful. Interleukin (IL)‐6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL‐6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. Methods and results Interleukin‐6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT‐CHF cohort. The primary outcome was all‐cause mortality and HF hospitalization during 2 years, with all‐cause, cardiovascular (CV), and non‐CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL‐6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N‐terminal pro‐brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF‐α/IL‐1‐related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL‐6 levels. IL‐6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P < 0.001], all‐cause mortality [1.22 (1.16–1.29), P < 0.001] and CV as well as non‐CV mortality [1.16 (1.09–1.24), P < 0.001; 1.31 (1.18–1.45), P < 0.001], but did not improve discrimination in previously published risk models. Conclusions In a large, heterogeneous cohort of HF patients, elevated IL‐6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL‐6 as a potential therapeutic target in specific HF subpopulations.

Aims Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods & Results Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF. Translational Perspective The failure of many treatment modalities for HFpEF may –at least in part– be explained by the lack of an adequate animal model. The diverse etiology of HFpEF is still largely neglected in pre-clinical research. In this study we developed a murine model that includes advanced age, female sex, in concert with co-morbidities: elevated blood pressure, obesity and T2DM. We demonstrate that this model recapitulates the human cardiometabolic HFpEF phenotype. We showed that contemporary glucose lowering drugs, liraglutide and dapagliflozin, which are both under study for HFpEF, have positive results. Our model may be useful to evaluate novel cardiometabolic, anti-fibrotic, and anti-inflammatory treatments for HFpEF.

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation, not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction, heart block or malignant arrhythmias. Not only DMD/BMD patients, but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent, due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects, arrhythmias (supraventricular or ventricular), hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction, independently of age of onset or mutation groups. Cardiovascular magnetic resonance (CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies' patients and carriers that can be observed even if overt muscular disease is absent. Recently, new CMR techniques, such as postcontrast myocardial T1 mapping, have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications.

CMR may reveal severe cardiac involvement in early, asymptomatic diffuse SSc with normal routine cardiac evaluation, presenting either as myocardial inflammation or as severe reduction of MPRI and diffuse fibrosis with further deterioration in the long term follow up.