The complex link of the folate-homocysteine axis to myocardial hypertrophy and heart failure: from mechanistic exploration to clinical vision

BACKGROUND: Globally, the pathogenesis and progression of many human diseases are intimately associated with folate metabolism disorder. Emerging evidence from recent investigations has underscored the pivotal role of folate metabolism in cardiovascular homeostasis, particularly in the context of myocardial hypertrophy and heart failure (HF). Despite a wealth of pre-existing research, the underlying pathophysiological mechanisms remain not fully elucidated. AIM OF REVIEW: To deeply explore the complex interrelationships among folate metabolism, myocardial hypertrophy, and heart failure, this review systematically elucidates the impact of the folate-homocysteine (Hcy) axis on myocardial hypertrophy and HF progression, integrating both experimental evidence and clinical observations. This review also investigates how genetic variations, and environmental factors modulate folate metabolism, and their mechanistic links to the development of myocardial hypertrophy and heart failure. Additionally, the review explores epigenetic modifications and their intricate crosstalk with the folate-homocysteine-heart disease axis, providing a comprehensive framework of the underlying pathophysiology. Finally, it proposes potential therapeutic strategies targeting the folate-homocysteine axis for myocardial hypertrophy and HF. KEY SCIENTIFIC CONCEPTS OF REVIEW: Folate deficiency can lead to homocysteine accumulation, resulting in hyperhomocysteinemia (HHcy), which contributes to the development of myocardial hypertrophy and HF. Correcting the imbalance of the folate-homocysteine axis may interrupt this pathological cascade, positioning the folate-homocysteine axis as a potential target for the treatment of myocardial hypertrophy and HF.