Hypoxia-driven glycolytic and fructolytic metabolic programs: Pivotal to hypertrophic heart disease

Pathologic cardiac growth is an adaptive response of the myocardium to various forms of systemic (e.g. pressure overload) or genetically-based (e. g. mutations in genes encoding sarcomeric proteins) stress. It represents a key aspect of different types of heart disease including aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM). While many of the pathophysiological and hemodynamical aspects of pathologic cardiac hypertrophy have been uncovered during the last decades, its underlying metabolic determinants are only beginning to come into focus. Here, we review the epidemiological evidence and pathological features of hypertrophic heart disease in AS and HCM and consider in this context the development of microenvironmental tissue hypoxia as a key component of the heart's growth response to pathologic stress. We particularly reflect on recent evidence illustrating how activation of hypoxia-inducible factor (HIF) drives glycolytic and fructolytic metabolic programs to maintain ATP generation and support anabolic growth of the pathologically-stressed heart. Finally we discuss how this metabolic programs, when protracted, deprive the heart of energy leading ultimately to heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.