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-1 RA) and sodium-glucose co-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 (Lira) and the SGLT2i dapagliflozin (Dapa).Methods and 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 Lira 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. Dapa 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 the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of 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.

Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5–300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46–1.00) for the first round and 0.55 (0.44–1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47–1.00)). Criterion validity showed a 78 (73–84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research.

Background: Myopericardial inflammation, perfusion’s defects and fibrosis are major causes of cardiac disease in scleroderma (SSc). We hypothesized that using inflammation and stress perfusion-fibrosis cardiovascular magnetic resonance (CMR), we can identify the pathophysiology of heart disease in asymptomatic diffuse SSc. Patients-Methods: 46 recently diagnosed, asymptomatic patients with diffuse SSc had a CMR examination using a 1.5T system. ECG gated breath hold cine and short tau inversion recovery (STIR) T2 images were initially acquired. If T2 ratio2 a myocarditis protocol including early (EGE) and late (LGE) gadolinium imaging was applied. SSc patients’ results were compared with age and sex-matched controls and patients with coronary artery disease (CAD). Results: In 2/46 SSc with T2 ratio>2, the myocarditis protocol was positive for acute myocardial inflammation, who developed clinical signs of acute myocarditis shortly after the CMR evaluation. In the rest 44/46 with T2 ratio<2 the stress perfusion-fibrosis CMR identified a significant reduction in Myocardial Perfusion Reserve Index (MPRI) compared with matched controls (0.6±0.4 vs 3.2±0.8, p<0.001), but not with CAD (0.6±0.4 vs 0.86±0.46, p=NS) and correlated only with the presence of digital ulcers (p<0.05). The scar was diffused and greater compared to controls, but did not differ from that assessed in CAD. Two years follow up, available in 11/44 SSc, showed further asymptomatic MPRI deterioration in all and diffuse subendocardial LGE in 8/11, without any change in LV, RV volumes and ejection fractions. Conclusion: 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.

Autoimmune rheumatic diseases (ARDs) involve multiple organs including the heart and vasculature. Despite novel treatments, patients with ARDs still experience a reduced life expectancy, partly caused by the higher prevalence of cardiovascular disease (CVD). This includes CV inflammation, rhythm disturbances, perfusion abnormalities (ischaemia/infarction), dysregulation of vasoreactivity, myocardial fibrosis, coagulation abnormalities, pulmonary hypertension, valvular disease, and side-effects of immunomodulatory therapy. Currently, the evaluation of CV involvement in patients with ARDs is based on the assessment of cardiac symptoms, coupled with electrocardiography, blood testing, and echocardiography. However, CVD may not become overt until late in the course of the disease, thus potentially limiting the therapeutic window for intervention. More recently, cardiovascular magnetic resonance (CMR) has allowed for the early identification of pathophysiologic structural/functional alterations that take place before the onset of clinically overt CVD. CMR allows for detailed evaluation of biventricular function together with tissue characterization of vessels/myocardium in the same examination, yielding a reliable assessment of disease activity that might not be mirrored by blood biomarkers and other imaging modalities. Therefore, CMR provides diagnostic information that enables timely clinical decision-making and facilitates the tailoring of treatment to individual patients. Here we review the role of CMR in the early and accurate diagnosis of CVD in patients with ARDs compared with other non-invasive imaging modalities. Furthermore, we present a consensus-based decision algorithm for when a CMR study could be considered in patients with ARDs, together with a standardized study protocol. Lastly, we discuss the clinical implications of findings from a CMR examination.