Trimethylamine-N-oxide acutely increases cardiac muscle contractility

Area of Science:

• Cardiovascular Physiology
• Nephrology
• Biochemistry

Background:

• Cardiovascular disease is a primary cause of death in chronic kidney disease (CKD) patients.
• Trimethylamine-N-oxide (TMAO), a metabolite elevated in CKD, is a suspected cardiovascular risk factor.
• The direct impact of TMAO on cardiac and smooth muscle function requires further investigation.

Purpose of the Study:

• To investigate the acute effects of pathological TMAO concentrations on cardiac and smooth muscle contractility.
• To determine if TMAO contributes to cardiac dysfunction in the context of CKD.
• To elucidate the cellular mechanisms underlying TMAO's effects on cardiac function.

Main Methods:

• Ex vivo assessment of human cardiac muscle biopsy contractility under varying TMAO levels.
• Evaluation of isolated mouse heart contractility using Langendorff apparatus perfusion with TMAO.
• Two-photon microscopy to measure intracellular calcium changes in paced mouse hearts treated with TMAO.
• Assessment of isolated aortic ring contractility following TMAO administration.

Main Results:

• High TMAO levels significantly increased contractility in human cardiac muscle biopsies and isolated mouse hearts.
• TMAO enhanced cardiac contractility via reverse perfusion through coronary arteries.
• TMAO significantly increased intracellular calcium fluorescence in mouse hearts.
• The precursor molecule trimethylamine (TMA) did not affect cardiac contractility.
• TMAO did not significantly alter isolated aortic ring contractility.

Conclusions:

• TMAO directly augments myocardial contractile force ex vivo, correlating with increased intracellular calcium.
• TMAO does not acutely affect vascular smooth muscle or endothelial function of the aorta.
• The long-term implications of TMAO's acute inotropic action on cardiac muscle in CKD remain to be determined.