Rationale: Atrial fibrillation (AF) and heart failure often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction. Objective: This study investigates the effects and molecular mechanisms of AF on the human LV. Methods and Results: Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca 2+ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca 2+ levels and Ca 2+ transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca 2+ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca 2+ transient amplitude and sarcoplasmic reticulum Ca 2+ load likely because of an increased diastolic sarcoplasmic reticulum Ca 2+ leak. Moreover, cytosolic Na + concentration was elevated, and action potential duration was prolonged after AF simulation. We detected an increased late Na + current as a potential trigger for the detrimentally altered Ca 2+ /Na + -interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca 2+ /calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. CaMKII inhibition and ROS scavenging prevented impaired systolic Ca 2+ handling after AF simulation. Conclusions: AF causes distinct functional remodeling of the human LV via detrimental effects on cardiomyocyte excitation-contraction coupling. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.

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Background Conventional transthoracic echocardiography (TTE) does often not accurately reveal pathologies in patients with acute myocarditis and preserved left ventricular ejection fraction (LVEEF). Therefore, we investigated the diagnostic value of two-dimensional (2D) speckle tracking echocardiography compared to late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) imaging in patients with acute myocarditis and normal global LVEF. Methods and results 31 patients (group 1) with the diagnosis of acute myocarditis confirmed by CMR according to the Lake Louise criteria and 20 healthy controls (group 2) were analyzed including global longitudinal strain (GLS) and regional longitudinal strain (RLS) derived by the bull’s eye plot. Although preserved LVEF was present in both groups, GLS was significantly lower in patients with acute myocarditis (group 1: GLS − 19.1 ± 1.8% vs. group 2: GLS − 22.1 ± 1.7%, p < 0.001). Compared to controls, lower RLS values were detected predominantly in the lateral, inferolateral, and inferior segments in patients with acute myocarditis. Additionally RLS values were significantly lower in segments without LGE. Conclusion In patients with acute myocarditis and preserved LVEF, a significant reduction of GLS compared to healthy subjects was detected. Further RLS adds important information to the localization and extent of myocardial injury. Graphic abstract

Background and objectivesMitraClip implantation is an established therapy for secondary mitral regurgitation (MR) in high-risk patients and has shown to improve several important outcome parameters such as functional capacity. Patient selection is both challenging and crucial for achieving therapeutic success. This study investigated baseline predictors of functional improvement as it was quantified by the six-minute walk distance (6MWD) after transcatheter mitral valve repair. Methods and resultsWe retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation at an academic tertiary care center. Before and four weeks after the procedure, all patients underwent comprehensive clinical assessment, six-minute walk tests and echocardiography. 6MWD significantly improved after MitraClip therapy (295 m vs. 265 m, p < 0.001). A linear regression model including seven clinical baseline variables significantly predicted the change in 6MWD (p = 0.002, R 2 = 0.387). Female gender, diabetes mellitus and arterial hypertension were found to be significant negative predictors of 6MWD improvement. At baseline, female patients had significant higher left ventricular ejection fraction (49% vs. 42%, p = 0.019) and lower 6MWD (240 m vs. 288 m, p = 0.034) than male patients. ConclusionMitraClip implantation in secondary MR significantly improves functional capacity in highrisk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favourable functional outcome. While further validation in a larger cohort is recommended, these parameters may improve patient selection for MitraClip therapy.

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