Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure

Area of Science:

• Biochemistry
• Cardiovascular Physiology
• Metabolic Diseases

Background:

• Pharmacologic activation of branched-chain amino acid (BCAA) catabolism shows promise in heart failure (HF) models.
• The precise mechanism of this cardioprotection remains elusive, with a presumed block in cardiac BCAA oxidation.

Purpose of the Study:

• To investigate the role of cardiac BCAA oxidation in HF.
• To elucidate the mechanisms underlying BCAA catabolism-mediated cardioprotection in HF.

Main Methods:

• In vivo isotope infusions in HF models.
• Cardiac-specific and systemic BCAA oxidation activation studies.
• Plasma and cardiac BCAA level measurements.
• Blood pressure monitoring and vascular resistance assessment.
• Mendelian randomization studies in humans.

Main Results:

• Cardiac BCAA oxidation increases, not decreases, in HF.
• Cardiac-specific BCAA oxidation activation does not protect against HF.
• Systemic BCAA activation confers protection, linked to blood pressure reduction.
• BCAA catabolism activation lowers blood pressure independently of nitric oxide.
• Elevated plasma BCAAs correlate with higher blood pressure in humans.

Conclusions:

• Cardiac BCAA oxidation is not the primary protective mechanism in HF.
• BCAA catabolism lowers vascular resistance, contributing to cardioprotection in HF.
• Reduced blood pressure, mediated by vascular effects, may explain BCAA-related HF protection.