نبذة مختصرة : Background: Cardiovascular disease is endemic among patients with chronic kidney disease (CKD). Growing evidence suggests the gut microbiome plays an obligatory role in cardiovascular pathogenesis. Trimethylamine-N-oxide (TMAO) is a downstream byproduct of intestinal microbe metabolism of phosphatidylcholine and L-carnitine that may directly promote atherosclerosis formation. Since clearance of this uremic metabolite is dependent on urinary excretion, plasma levels of TMAO increase with decrements in kidney function. Association studies have linked plasma levels of TMAO to adverse cardiovascular outcomes in patients with renal dysfunction; however, the direct effect on the heart itself remains largely unexplored. Objective: The objective of this study was to determine if TMAO alone could acutely alter ex vivo cardiac contractile function on a beat-to-beat basis. Methods: CD1 adult mouse hearts were extracted, attached to a force transducer, oxygenated, and paced within an organ bath. Changes in contractility were measured after infusing TMAO or vehicle into the organ bath. As a follow-up approach, mouse hearts were reverse perfused through the aorta via a modified Langendorff apparatus to facilitate TMAO delivery into the myocardium. Subsequently, to determine if our findings translated to the human heart, we performed contractility experiments using human atrial appendage biopsy tissue, which was retrieved during cardiopulmonary bypass procedures prior to cannula placement. To investigate whether TMAO alters contractile rate, in a separate series of experiments, the atria and sinoatrial node of isolated mouse hearts were kept intact to allow for spontaneous beating without artificial pacing. Changes in contraction rate (in beats per minute) were measured after treatment with TMAO or vehicle. Additionally, calcium imaging was performed on spontaneously beating embryonic (E18) rat cardiomyocytes. Changes in intracellular Ca2+ oscillations were measured, following treatment with 300 µM TMAO or vehicle, using the ...
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