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The Uremic Metabolite, Trimethylamine‐N‐Oxide (TMAO), Directly Alters Cardiac Contractile Function
Author(s) -
Oakley Carlee,
Hendrix Matt,
Grillo Michael,
McCarthy Darla,
Stubbs Jason R.,
Wacker Michael J.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.688.3
Subject(s) - contractility , chemistry , metabolite , medicine , endocrinology , contraction (grammar) , myocyte , perfusion , cardiac function curve , heart failure , biochemistry
Background TMAO is produced by intestinal microbial metabolism of phosphatidylcholine. Clearance of this uremic metabolite is dependent on urinary excretion. Therefore, as kidney function declines during chronic kidney disease (CKD), plasma levels of TMAO increase. Recently, elevated TMAO plasma levels have been reported to show concentration‐dependent associations with cardiovascular disease. However, there have been no experiments to determine the direct effect of TMAO on cardiac muscle. Therefore, our objective in this study was to determine if TMAO directly alters cardiac contractility and intracellular calcium levels. 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 diffusing TMAO through the organ bath. As a follow‐up approach, mouse hearts were reverse perfused through the aorta via a modified Langendorff apparatus to facilitate TMAO tissue perfusion. To further explore a mechanism of action, embryonic cardiac myocytes were isolated and cultured to conduct epifluorescence calcium imaging experiments. Results Acute treatment with TMAO, in the diffusion‐based model, increased contraction amplitude of ventricular muscle 17% and 46% at 300 μM (P=0.08) and 3000 μM (P<0.05), respectively. TMAO also increased the slope and area under the curve of the contractile waveform compared to vehicle (n=4–6). Langendorff perfusion of hearts with 300 μM TMAO generated a greater response and increased average contraction height 34% (P<0.05; n=3). TMAO, at 300 and 3000 μM, also increased intracellular calcium levels in spontaneously beating cardiomyocytes. Conclusions TMAO directly increases cardiac contractility and intracelluar calcium levels. Acutely, these actions may be an adaptive response. Chronically, however, increases in intracellular calcium and cardiac stress promote cardiac remodeling and heart disease. Therefore, TMAO may be a novel contributor in the development of heart disease in CKD and thus an important therapeutic target for reducing morbidity and mortality.