59 research outputs found

    Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism Role of Neuronal Nitric Oxide Synthase

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    ObjectivesThe aim of this study was to determine whether activation of Ī²3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload.BackgroundĪ²3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike Ī²1- and Ī²2-ARs, Ī²3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a ā€œbrakeā€ to protect the heart from catecholamine overstimulation.MethodsC57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (Ī²3 agonist, BRL 0.1 mg/kg/h), or both.ResultsThree weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOSā€“/ā€“ mice.ConclusionsThese results are the first to show in vivo cardioprotective effects of Ī²3-ARā€“specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart

    Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform

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    Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total success. Since this likely relates to cell immaturity, efforts are underway to use biochemical and biophysical cues to improve many of the ~ 30 structural and functional properties of hPSC-CMs towards those seen in adult CMs. Other developments needed for widespread hPSC-CM utility include subtype specification, cost reduction of large scale differentiation and elimination of the phenotyping bottleneck. This review will consider these factors in the evolution of hPSC-CM technologies, as well as their integration into high content industrial platforms that assess structure, mitochondrial function, electrophysiology, calcium transients and contractility. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel

    The pulmonary vein that stumped us

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    The Maine vein of Marshall ethanol experience: learning curve and safety

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    BACKGROUND: The marginal benefit of ethanol infusion into the vein of Marshall (VOM) as an adjunct to atrial fibrillation ablation has shown promise in a single randomized study and case series from very experienced centers. However, adoption has not been widespread and the impact on real-world outcomes outside of leading centers is not established. The objective in this study is to understand the learning curve, and explore procedural outcomes and safety with VOM ethanol infusion from a large single medical center. METHODS: One hundred twenty nine atrial ablation cases wherein VOM ethanol infusion was attempted were identified from the time of the program\u27s inception in 2019 at Maine Medical Center (Portland, ME). Our technical approach, procedural success, and complications were adjudicated from the medical record. RESULTS: The overall VOM ethanol infusion success was 90%. Infusion success rates improved and fluoroscopy utilization decreased with experience. Arrhythmia recurrence was 14% after a mean follow-up of 9.5 months. Complications occurred in 5.4% of patients, including a 3.1% risk of delayed tamponade. CONCLUSION: In our single center experience, VOM ethanol infusion was feasible with a high technical success rate. These positive results are balanced against a concerning rate of delayed tamponade

    Atrioesophageal Fistula Rates Before and After Adoption of Active Esophageal Cooling During Atrial Fibrillation Ablation

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    BACKGROUND: Active esophageal cooling reduces the incidence of endoscopically identified severe esophageal lesions during radiofrequency (RF) catheter ablation of the left atrium for the treatment of atrial fibrillation. A formal analysis of the atrioesophageal fistula (AEF) rate with active esophageal cooling has not previously been performed. OBJECTIVES: The authors aimed to compare AEF rates before and after the adoption of active esophageal cooling. METHODS: This institutional review board (IRB)-approved study was a prospective analysis of retrospective data, designed before collecting and analyzing the real-world data. The number of AEFs occurring in equivalent time frames before and after adoption of cooling using a dedicated esophageal cooling device (ensoETM, Attune Medical) were quantified across 25 prespecified hospital systems. AEF rates were then compared using generalized estimating equations robust to cluster correlation. RESULTS: A total of 14,224 patients received active esophageal cooling during RF ablation across the 25 hospital systems, which included a total of 30 separate hospitals. In the time frames before adoption of active cooling, a total of 10,962 patients received primarily luminal esophageal temperature (LET) monitoring during their RF ablations. In the preadoption cohort, a total of 16 AEFs occurred, for an AEF rate of 0.146%, in line with other published estimates for procedures using LET monitoring. In the postadoption cohort, no AEFs were found in the prespecified sites, yielding an AEF rate of 0% (P \u3c 0.0001). CONCLUSIONS: Adoption of active esophageal cooling during RF ablation of the left atrium for the treatment of atrial fibrillation was associated with a significant reduction in AEF rate

    Rapid Cellular Phenotyping of Human Pluripotent Stem Cell-Derived Cardiomyocytes using a Genetically Encoded Fluorescent Voltage Sensor

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    In addition to their promise in regenerative medicine, pluripotent stem cells have proved to be faithful models of many human diseases. In particular, patient-specific stem cell-derived cardiomyocytes recapitulate key features of several life-threatening cardiac arrhythmia syndromes. For both modeling and regenerative approaches, phenotyping of stem cell-derived tissues is critical. Cellular phenotyping has largely relied upon expression of lineage markers rather than physiologic attributes. This is especially true for cardiomyocytes, in part because electrophysiological recordings are labor intensive. Likewise, most optical voltage indicators suffer from phototoxicity, which damages cells and degrades signal quality. Here we present the use of a genetically encoded fluorescent voltage indicator, ArcLight, which we demonstrate can faithfully report transmembrane potentials in human stem cell-derived cardiomyocytes. We demonstrate the application of this fluorescent sensor in high-throughput, serial phenotyping of differentiating cardiomyocyte populations and in screening for drug-induced cardiotoxicity
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