The Acute Chronotropic Effect of the Uremic Metabolite, Trimethylamine‐N‐Oxide (TMAO), on Mouse Cardiac Muscle

Abstract

BackgroundWhile it is understood that patients with chronic kidney disease (CKD) have an increased propensity for developing cardiovascular disease, the exact mechanisms remain unclear. Growing evidence suggests that the gut microbiome and its byproducts, such as TMAO, may be important contributors to this pathologic process. This uremic metabolite is cleared through renal excretion, which is compromised in CKD patients. Therefore, CKD patients often possess elevated plasma levels of this substance. In a previous study, we found that TMAO at pathological concentrations directly increases cardiac contractility in isolated, paced hearts. In this study, we sought to determine if TMAO also has chronotropic effects on isolated, spontaneously beating mouse hearts.MethodsWhole mouse hearts were extracted from anesthetized CD1 adult mice and subsequently connected to a force transducer and bubbled with oxygen inside an organ bath. The atria and sinoatrial node were kept intact to allow for spontaneous beating without artificial pacing. Changes in heart rate (in beats per minute) were measured after treatment with TMAO (3,000 μM) or vehicle (Ringer's solution). Additionally, calcium imaging was performed on cultured spontaneously beating embryonic rat cardiomyocytes. Intracellular Ca2+ responses in rat primary cardiomyocytes were measured with the fluorescent Ca2+ indicator Fura‐2 AM in response to vehicle and TMAO (3,000 uM).ResultsAverage beating frequency (in beats per minutes) of isolated hearts increased by 27% following treatment with 3,000 μM TMAO (P < 0.05, n =3) while there was no change with vehicle. Regarding isolated myocytes, TMAO was found to have a direct chronotropic effect as it increased beating frequency (as measured by calcium waves) by 13% compared to vehicle treatment (P < 0.05, n =4–5).ConclusionsIn addition to our previously described inotropic effects in the mouse heart, pathologic concentrations of TMAO also have a direct and positive chronotropic effect. The direct effects we have observed on the heart may increase cardiac output in early stages of CKD. However, cardiac remodeling as a result of increased beating frequency and contractility may have pathologic consequences in those with chronic disease. Further research is needed in order to elucidate the effect that TMAO has on cardiovascular function and pathology during CKD.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.