Single-Center Outcomes of WATCHMAN™ Implantation with Comparison to Oral Anticoagulant and Dual Antiplatelet Therapy.

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.

Sarcolipin haploinsufficiency prevents dystrophic cardiomyopathy in mdx mice.

Sarcolipin (SLN) is an inhibitor of sarco/endoplasmic reticulum (SR) Ca2+-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 Ca2+ (Ca2+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 Ca2+i handling were determined by Ca2+ uptake assays and by measuring single-cell Ca2+ 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 Ca2+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 Ca2+i cycling and prevent cardiomyopathy in mdx mice.NEW & NOTEWORTHY First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca2+ uptake and intracellular Ca2+ 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.

Long-term clinical outcomes and prognostic indicators for focal impulse and rotor modulation guided ablation: A single-center observational study.

BACKGROUND: Electrophysiologists have developed a computational mapping approach to localize sources that may perpetuate persistent atrial fibrillation (AF). Focal impulse and rotor modulation (FIRM)-guided ablation of these sources have produced variable results. The current study further assesses single-procedure success rates of FIRM-guided ablation for preventing AF or atrial tachyarrhythmia recurrence and analyzes different baseline characteristics as prognostic indicators for individuals experiencing these undesired outcomes. METHODS: Seventy-one consecutive patients (mean age 64.58 ± 9.05 years and 36.6% female) with drug-refractory persistent AF with and without prior history of pulmonary vein antral isolation (PVAI) underwent FIRM-guided ablation. Patients without prior history of PVAI underwent FIRM-guided ablation in addition to de novo PVAI. Patients with prior history of PVAI had the pulmonary veins reassessed at the time of FIRM-guided ablation for reconnection as well as re-isolation, when necessary. These patients were then prospectively followed for AF and atrial tachyarrhythmia recurrence. RESULTS: FIRM analysis revealed rotors in the right atrium in 66.2% (1.77 ± 1.53 mean rotors per patient) and in the left atrium in 85.9% (2.65 ± 1.52 mean rotors per patient) of patients analyzed in the current study. After a single FIRM-guided ablation procedure, AF and atrial tachyarrhythmia recurrence was demonstrated in 21.1% (15/71) and 33.8% (24/71) of patients, respectively. The entire cohort of patients were followed for a mean duration of 23.20 ± 8.38 months with the mean time to AF recurrence found to be 12.35 ± 10.44 months. Furthermore, valvular heart disease (i.e. moderate mitral or tricuspid regurgitation) was found to be a statistically significant independent predictor for AF recurrence following FIRM-guided ablation (p = .033). CONCLUSIONS: FIRM-guided ablation in combination with PVAI is a suitable and effective approach for symptomatic individuals with drug-refractory persistent AF with and without prior history of PVAI. Randomized controlled studies are warranted.

Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice.

Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ 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.

A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion.

A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-ß-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation.

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance.

The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (ß-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.

Overexpression of Cardiomyocyte α1A-Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling.

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.

Inhibition of adenylyl cyclase type 5 increases longevity and healthful aging through oxidative stress protection.

Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5's action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms.

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice.

Our review of the literature of the major cardiovascular journals for the past three years showed that for all studies using anesthesia for mouse echocardiography, the predominant anesthetic was isoflurane, which was used in 76% of the studies. The goal of this investigation was to determine if isoflurane is indeed the best anesthetic. Accordingly, we compared isoflurane with 2,2,2-tribromoethanol (Avertin), ketamine-xylazine, and ketamine on different days in the same 14 mice, also studied in the conscious state without anesthesia. A randomized crossover study design was employed to compare the effects on left ventricular (LV) systolic function and heart rate of the four different anesthetic agents assessed by transthoracic echocardiography. As expected, each anesthetic depressed LV ejection fraction and heart rate when compared with values in conscious mice. Surprisingly, isoflurane was not the best, but actually second to last in maintaining normal LV function and heart rate. The anesthetic with the least effect on LV function and heart rate was ketamine alone at a dose of 150 mg/kg, followed by Avertin at 290 mg/kg, isoflurane at 3% induction and 1 to 2% maintenance, and lastly ketamine-xylazine at 100 and 10 mg/kg, respectively. In summary, these results indicate that ketamine alone exerts the least depressant effects on LV function and heart rate, with Avertin second, suggesting that these anesthetics should be used when it is not feasible to study the animals in the conscious state as opposed to the most commonly used anesthetic, isoflurane.

Cardiac specific expression of threonine 5 to alanine mutant sarcolipin results in structural remodeling and diastolic dysfunction.

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.

Sudden cardiac death as a presentation of anomalous origin of the left coronary artery from pulmonary artery in a young adult.

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.