Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure

TLDR

Sustained external load eventually leads to heart failure, though the mechanisms remain poorly understood. The study introduces a conditional Akt1 transgenic mouse model to observe the transition from adaptive hypertrophy to dilated cardiomyopathy. In this model, acute hypertrophy is accompanied by mTOR‑dependent upregulation of myocardial VEGF and angiopoietin‑2, driving angiogenesis, while chronic activation leads to pathological remodeling. Enhanced angiogenesis supports adaptive growth, whereas its inhibition reduces capillary density, impairs contractility, and ultimately promotes heart failure, demonstrating that coordinated angiogenesis is essential for maintaining cardiac function.

Abstract

Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin–dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.