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Background The WATCHMAN™ device is a Food and Drug Administration (FDA)-approved device that reduces the risk of stroke from atrial fibrillation (AF) in those who have a contraindication to taking oral anticoagulation. A key aspect of this device implantation is the choice of medical therapy in the months after device implantation with Vitamin K antagonist oral anticoagulants (OAC) being the mainstay of therapy but dual antiplatelet therapy (DAPT) poses as a potential alternative to patients who have a contraindication to OAC use. Methods Our single-center study retroactively followed 150 patients post-WATCHMAN™ implantation and evaluated outcomes at 12 months post-implantation in two cohorts, those treated with OAC or DAPT. Our results were obtained via chart review of a single-center electronic medical records system. Results In our study, 67.33% of study patients were males and 49.33% were on OAC compared to 36.00% that were on DAPT. Ten patients were not able to undergo device implantation. With this analysis, we found similarly low rates of complications such as stroke and device-associated thrombosis (DAT) in both groups. Our DAPT cohort did have a higher number of gastrointestinal (GI) bleeding but this was not significant in our analysis. Discussion Our study compares to larger trials that show similar outcomes between OAC and DAPT post-implantation of the WATCHMAN™ device. The increased number of GI bleeding in our DAPT cohort could be the result of the underlying advanced age and comorbidity of that patient cohort. Conclusion Our results suggest that DAPT is a safe alternative to OAC for patients undergoing WATCHMAN™ implantation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Demiraj et al.)

Sarcolipin (SLN) is an inhibitor of sarco/endoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA) and expressed at high levels in the ventricles of animal models for and patients with Duchenne muscular dystrophy (DMD). The goal of this study was to determine whether the germline ablation of SLN expression improves cardiac SERCA function and intracellular Ca 2+ (Ca 2+ i ) handling and prevents cardiomyopathy in the mdx mouse model of DMD. Wild-type, mdx , SLN-haploinsufficient mdx ( mdx:sln +/- ), and SLN-deficient mdx ( mdx:sln -/- ) mice were used for this study. SERCA function and Ca 2+ i handling were determined by Ca 2+ uptake assays and by measuring single-cell Ca 2+ transients, respectively. Age-dependent disease progression was determined by histopathological examinations and by echocardiography in 6-, 12-, and 20-mo-old mice. Gene expression changes in the ventricles of mdx:sln +/- mice were determined by RNA-Seq analysis. SERCA function and Ca 2+ i cycling were improved in the ventricles of mdx:sln +/- mice. Fibrosis and necrosis were significantly decreased, and cardiac function was enhanced in the mdx:sln +/- mice until the study endpoint. The mdx:sln -/- mice also exhibited similar beneficial effects. RNA-Seq analysis identified distinct gene expression changes including the activation of the apelin pathway in the ventricles of mdx:sln +/- mice. Our findings suggest that reducing SLN expression is sufficient to improve cardiac SERCA function and Ca 2+ i cycling and prevent cardiomyopathy in mdx mice. NEW & NOTEWORTHY First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca 2+ uptake and intracellular Ca 2+ handling and prevents cardiomyopathy in mdx mice. Second, reducing SLN expression prevents diastolic dysfunction and improves cardiac contractility in mdx mice Third, reducing SLN expression activates apelin-mediated cardioprotective signaling pathways in mdx heart.

Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca 2+ ATPase (SERCA) and is abnormally elevated in the muscle of Duchenne muscular dystrophy (DMD) patients and animal models. Here we show that reducing SLN levels ameliorates dystrophic pathology in the severe dystrophin/utrophin double mutant (mdx:utr -/- ) mouse model of DMD. Germline inactivation of one allele of the SLN gene normalizes SLN expression, restores SERCA function, mitigates skeletal muscle and cardiac pathology, improves muscle regeneration, and extends the lifespan. To translate our findings into a therapeutic strategy, we knock down SLN expression in 1-month old mdx:utr -/- mice via adeno-associated virus (AAV) 9-mediated RNA interference. The AAV treatment markedly reduces SLN expression, attenuates muscle pathology and improves diaphragm, skeletal muscle and cardiac function. Taken together, our findings suggest that SLN reduction is a promising therapeutic approach for DMD.

Sudden cardiac death in 5-10% of cases is explained by patients with congenital abnormalities that include coronary artery malformations such as anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). We report a case of sudden cardiac death as the first presentation of ALCAPA in a young female with no history of hypertrophic cardiomyopathy., (© The European Society of Cardiology 2014.)

Objective: Stimulation of cardiac α1A-adrenergic receptors (α1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis., Approach and Results: Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor., Conclusion: Cardiomyocyte-specific overexpression of the α1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion., (© 2015 American Heart Association, Inc.)

The functional importance of threonine 5 (T5) in modulating the activity of sarcolipin (SLN), a key regulator of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pump was studied using a transgenic mouse model with cardiac specific expression of threonine 5 to alanine mutant SLN (SLNT5A). In these transgenic mice, the SLNT5A protein replaces the endogenous SLN in atria, while maintaining the total SLN content. The cardiac specific expression of SLNT5A results in severe cardiac structural remodeling accompanied by bi-atrial enlargement. Biochemical analyses reveal a selective downregulation of SR Ca2+ handling proteins and a reduced SR Ca2+ uptake both in atria and in the ventricles. Optical mapping analysis shows slower action potential propagation in the transgenic mice atria. Doppler echocardiography and hemodynamic measurements demonstrate a reduced atrial contractility and an impaired diastolic function. Together, these findings suggest that threonine 5 plays an important role in modulating SLN function in the heart. Furthermore, our studies suggest that alteration in SLN function can cause abnormal Ca2+ handling and subsequent cardiac remodeling and dysfunction.