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

Abstract

BackgroundCardiovascular disease is endemic among patients with chronic kidney disease (CKD). Growing evidence suggests the gut microbiome plays an obligatory role in cardiovascular pathogenesis. 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, to our knowledge, we are the first to investigate whether TMAO alone has any direct effect on cardiac contractility. In prior studies, we found TMAO to acutely increase contractile force in mouse hearts ex vivo. The objective of the current investigation was to determine if our findings translated to human heart tissue.MethodsHuman right atrial appendage biopsy tissue was retrieved during cardiopulmonary bypass procedures, prior to cannula placement. The cardiac muscle samples were attached to a force transducer and bubbled with oxygen inside an organ bath. Changes in contractility were measured after treatment with TMAO or vehicle (Ringer's solution).ResultsIn our previous studies using mouse hearts, we found acute treatment with TMAO in the organ bath increased average contraction amplitude 20% and 41% at 300 μM and 3000 μM, respectively (P < 0.05, n = 6–7 animals). Langendorff reverse perfusion of hearts with 300 μM TMAO generated an even greater response than incubation and increased isometric force 32% (P < 0.05, n = 2–3). Consistent with what we observed in the animal model, incubation of human atrial muscle tissue with TMAO at 3,000 μM increased isometric tension 31% compared to vehicle (P < 0.05, n = 4–5).ConclusionsTMAO, at pathological concentrations, directly increases cardiac contractility in both animal and human hearts. Initially, this inotropic effect may be beneficial or adaptive during CKD; however, chronic increases in cardiac contractility can promote cardiac remodeling and left ventricular hypertrophy. Further in vivo studies are needed to determine how chronic exposure to TMAO may contribute to cardiac pathology in CKD and to examine if TMAO represents a therapeutic target for reducing cardiovascular mortality in CKD patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.