Abstract Body (Do not enter title and authors here): Background: Heart failure with preserved ejection fraction (HFpEF) represents a major unmet need in cardiovascular medicine, yet understanding of its causative mechanisms is limited. Recent metabolomic studies using a two-hit murine HFpEF model (high fat diet: HFD + NOS inhibition via L-NAME) revealed reduced myocardial levels of histidyl dipeptides, such as carnosine (β-alanyl-L-histidine). Carnosine is present at 0.1-1 mM in cardiac tissues and is known to sequester lipid peroxidation products from oxidative stress, such as acrolein. Based on these findings, we investigated whether enhancing myocardial carnosine by β-alanine feeding, the precursor amino-acid for carnosine, could modify HFpEF pathophysiology.
Hypothesis: Augmenting myocardial carnosine levels by β-alanine supplementation will improve cardiac function in HFpEF.
Methods: Eight-week-old wild type C57BL/6J male mice were assigned to three groups; normal chow (NC), HFD (60% kcal from fat) + drinking water with 0.5 g/L L-NAME (HFD/L), and HFD/L plus 20 g/L β-alanine in drinking water (β-ala). After 10 weeks, assessments included body composition by DEXA scan, diastolic function by echo, and glucose and insulin sensitivity by glucose and insulin tolerance tests (GTT and ITT). Histidyl dipeptide levels were measured using LC-MS/MS.
Results: HFD+L-NAME feeding increased body weight (NC:33±0.5 vs HFD/L:45±2 g, p<0.05), fat mass (NC:4±0.2 vs HFD/L:16±1 gm, p<0.05), decreased grip strength (NC:2.3±0.2 vs HFD/L:1.2±0.1 N, p<0.05), and induced diastolic dysfunction as evidenced by increased IVRT (NC:10.4±1.1 vs HFD/L:19±2 ms, p<0.05), E/A (NC:1.4±0.1 vs HFD/L:1.5±0.1, p<0.05) and E/e’ (NC:33±9 vs HFD/L:70±7, p<0.05). β-alanine supplementation improved body weight (β-ala:39±2 g, p<0.05), fat mass (12±2 g, p<0.05), and diastolic parameters: IVRT (14±2 g, p<0.05), E/A (1.5±0.2, p<0.05), and E/e’ (33±12, p<0.05). Cardiac carnosine levels were decreased in HFD/L (NC:466.4±40.3 vs HFD/L: 311.9±45.7 pmol/mg, p<0.05) but were increased ~10 fold with β-alanine feeding (4316.3±568.7 pmol/mg, p<0.05). β-alanine hearts also showed increased removal of acrolein via carnosine conjugates (HFD/L: 5.1±0.5 vs β-ala: 54±8 pmol/g, p<0.05).
Conclusion: β-alanine supplementation improves diastolic function in a two-hit mouse model of HFpEF, likely through increased myocardial carnosine and its ability to sequester toxic aldehydes. These findings suggest carnosine may be a safe and effective therapeutic intervention in HFpEF.