Aims: Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods: Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion: The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.

Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. A critical regulator of inflammatory processes represents the mitogen-activated protein kinase–activated protein kinase-2 (MK2). Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice as well as potentially underlying mechanisms in vivo and in vitro. Activation of MK2 (phospho-MK2) was predominantly detected in the endothelium and macrophage-rich plaque areas within aortas of hypercholesterolemic LDL receptor–deficient mice ( ldlr ^−/− ). Systemic MK2 deficiency of hypercholesterolemic ldlr ^−/− mice ( ldlr ^−/− /mk2 ^−/− ) significantly decreased the accumulation of lipids and macrophages in the aorta after feeding an atherogenic diet for 8 and 16 weeks despite a significant increase in proatherogenic plasma lipoproteins compared with ldlr ^−/− mice. Deficiency of MK2 significantly decreased oxLDL-induced foam cell formation in vitro, diet-induced foam cell formation in vivo, and expression of scavenger receptor A in primary macrophages. In addition, systemic MK2 deficiency of hypercholesterolemic ldlr ^−/− mice significantly decreased the aortic expression of the adhesion molecule VCAM-1 and the chemokine MCP-1, key mediators of macrophage recruitment into the vessel wall. Furthermore, silencing of MK2 in endothelial cells by siRNA reduced the IL-1β–induced expression of VCAM-1 and MCP-1. MK2 critically promotes atherogenesis by fostering foam cell formation and recruitment of monocytes/macrophages into the vessel wall. Therefore, MK2 might represent an attractive novel target for the treatment of atherosclerotic cardiovascular disease.

This study aimed to investigate the association of circulating biomarkers with echocardiographic parameters of atrial remodelling and their potential for predicting atrial fibrillation (AF). In patients with and without AF (n = 21 and n = 60) the following serum biomarkers were determined: soluble ST2 (sST2), Galectin−3 (Gal-3), N-terminal pro-brain natriuretic peptide (NT-proBNP), microRNA (miR)−21, −29a, −133a, −146b and −328. Comprehensive transthoracic echocardiography was performed in all participants. Biomarkers were significantly altered in patients with AF. The echocardiographic parameter septal PA-TDI, indicating left atrial (LA) remodelling, correlated with concentrations of sST2 (r = 0.249, p = 0.048), miR−21 (r = −0.277, p = 0.012), miR−29a (r = −0.269, p = 0.015), miR−146b (r = −0.319, p = 0.004) and miR−328 (r = −0.296, p = 0.008). In particular, NT-proBNP showed a strong correlation with echocardiographic markers of LA remodelling and dysfunction (septal PA-TDI: r = 0.444, p < 0.001, LAVI/a’: r = 0.457, p = 0.001, SRa: r = 0.581, p < 0.001). Multivariate Cox regressions analysis highlighted miR−21 and NT-proBNP as predictive markers for AF (miR−21: hazard ratio (HR) 0.16; 95% confidence interval (CI) 0.04–0.7, p = 0.009; NT-proBNP: HR 1.002 95%CI 1.001–1.004, p = 0.006). Combination of NT-proBNP and miR−21 had the best accuracy to discriminate patients with AF from those without AF (area under the curve (AUC)= 0.843). Our findings indicate that miR−21 and NT-proBNP correlate with echocardiographic parameters of atrial remodeling and predict AF, in particular if combined.

Background Subclinical atrial fibrillation (AF) is the underlying cause in a relevant part of patients with embolic stroke of unknown source (ESUS). This pilot study aims to identify novel echocardiographic parameters predicting AF subsequently detected in patients originally hospitalized with ESUS. Methods and results Patients with acute ischemic stroke [baseline diagnosis of ESUS (n = 69), stroke of macro- or microvascular cause (n = 16/25), stroke caused by AF (n = 5)] and controls with paroxysmal AF without acute ischemic stroke (n = 22) as well as healthy controls of young and old age (n = 21/17) in sinus rhythm were included (overall n = 175). Echocardiography was performed in all participants. Prolonged Holter-ECG-monitoring was performed in all stroke patients. In the overall cohort, septal total atrial conduction time (sPA-TDI), left atrial (LA) volume index to tissue Doppler velocity (LAVI/a`) and second negative peak strain rate during LA contraction (SRa), representing echocardiographic parameters of LA remodelling and function, were statistically significant different in patients with and without AF and predictive for subclinical AF (multivariate regression analysis: sPA-TDI: HR 1.06 [1.04–1.08], p < 0.001; LAVI/a`: HR 0.85, [0.74–0.97], p = 0.02; SRa: HR 2.35 [0.9–5.5], p = 0.05). Multivariate Cox regression analysis revealed sPA-TDI as an independent predictor of AF in ESUS patients (sPA-TDI: HR 1.10 [1.04–1.17], p = 0.001). A sPA-TDI of 126 ms strictly discriminated between presence and absence of subclinical AF within 48 h after initiation of Holter-ECG-monitoring in ESUS patients. Conclusions sPA-TDI seems to be a strong independent predictor of subclinical AF in patients hospitalized for ESUS and might support risk-stratified clinical decision making in these patients. Graphic abstract Septal Total Atrial Conduction Time (sPA-TDI) determined by echocardiography for prediction of Atrial Fibrillation in Embolic Stroke of Unknown Source (ESUS).