Increased epicardial adipose tissue is associated with left atrial mechanical dysfunction in patients with heart failure with mildly reduced and preserved ejection fraction.

INTRODUCTION: Heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF) is often accompanied by atrial dysfunction. It has been suggested that specific ectopic fat depots, such as epicardial adipose tissue (EAT), may directly influence the myocardial cells and, therefore, be involved in the pathophysiology of atrial mechanical dysfunction. In this study, we aimed to investigate the association between EAT and left atrial (LA) mechanical dysfunction. METHODS AND RESULTS: In total, 82 patients with symptomatic HF and left ventricular ejection fraction > 40% were prospectively enrolled. All patients underwent CMR while in sinus rhythm. LA mechanical dysfunction was defined as the presence of LA end-systolic volume index > 52 mL/m2 and LA reservoir strain < 23%. EAT volume was indexed for body surface area. Mean age was 69 ± 10 years, 42 (51%) were women and mean body mass index (BMI) was 29 ± 6 kg/m2. Mean LVEF was 55 ± 9% and 34 (41%) patients had LA mechanical dysfunction. In patients with LA mechanical dysfunction, the EAT volume was significantly higher than in patients without LA mechanical dysfunction (90 vs 105 mL/m2, p = 0.02) while BMI was similar. In multivariable logistic regression analyses, increased EAT remained significantly associated with LA mechanical dysfunction (OR 1.31, 95% CI 1.03-1.66, p = 0.03). CONCLUSION: Increased EAT was associated with LA mechanical dysfunction in patients with HFmrEF and HFpEF. Further research is needed to elucidate the exact mechanisms that underlie this association.

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Apoptosis during CABG surgery with the use of cardiopulmonary bypass is prominent in ventricular but not in atrial myocardium.

Objectives. We aimed to compare the rate of apoptosis after cardiopulmonary bypass (CPB) and cardioplegic arrest during coronary artery bypass grafting (CABG) surgery between atrial and ventricular tissue.Methods. During CABG surgery with CPB and cardioplegic arrest, sequential biopsies were taken from the right atrial appendage and left ventricular anterior wall before CPB and after aortic cross clamp release. Change in number of apoptotic cells and biochemical markers of myocardial ischaemia and renal dysfunction were assessed.Results. CPB was associated with a transient small, but significant increase in CK (1091+/-374%), CK-MB (128+/-38%), troponin-T (102+/-13%) and NT-proBNP (1308+/-372%) levels (all: p<0.05). A higher number of apoptotic cells as assessed by caspase-3 staining was found in the ventricular biopsies taken after aortic cross clamp release compared with the biopsies taken before CPB (5.3+/-0.6 vs. 14.0+/-1.5 cells/microscopic field, p<0.01). The number of apoptotic cells in the atrial appendage was not altered during CPB. Correlation between the duration of aortic cross clamp time and the change in caspase-3 positive cells in the left ventricular wall was of borderline significance (r of 0.58, p=0.08). Similar results were obtained from TUNEL staining for apoptosis.Conclusion. CABG surgery with CPB and cardioplegic arrest is associated with an elevated rate of apoptosis in ventricular but not in atrial myocardial tissue. Ventricular tissue may be more sensitive to detect changes than atrial tissue, and may be more useful to investigate the protective effects of therapeutic intervention. (Neth Heart J 2010;18:236-42.).

Systemic and local interferon-gamma production following Mycobacterium ulcerans infection.

Buruli ulcer disease (BUD) is an emerging predominantly tropical disease caused by Mycobacterium ulcerans. The initial pre-ulcerative skin lesion often breaks down into an ulcer with undermined edges. Healing is common but may require considerable time, and scarring often results in functional limitations. Considerable evidence has now emerged that patients with early BUD cannot mount a sufficient protective T helper 1 (Th1) cell response to M. ulcerans, but uncertainty remains as to whether immune protection is restored over time. This study investigates the Th1 cell response of patients with various stages of BUD on mycobacterial antigens. We measured interferon (IFN)-gamma levels after ex vivo whole blood stimulation with tuberculin purified protein derivative (PPD), and compared the Th1 cell response of individuals with pre-ulcerative, ulcerative and healed BUD as well as healthy controls. Moreover, the systemic Th1 cell response was related to histopathological features in the various stages of surgically resected BUD lesions. We show that patients with ulcerative and healed BUD produce significantly higher IFN-gamma levels after mycobacterial ex vivo whole blood stimulation than healthy controls, and that patients with a granulomatous tissue response produce higher IFN-gamma levels than individuals without. We therefore suggest that the mounted Th1 cell response in ulcerative BUD patients might be related to their histopathological tissue response.