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Published on: February 13, 2019
Hypoxia-driven glycolytic and fructolytic metabolic programs: Pivotal to hypertrophic heart disease
Peter Mirtschink1, Wilhelm Krek1
1Institute of Molecular Health Sciences, ETH Zurich, 8093 Zürich, Switzerland.
Insights
Pathologic cardiac hypertrophy, seen in aortic stenosis and hypertrophic cardiomyopathy, involves tissue hypoxia. Hypoxia-inducible factor (HIF) activation drives metabolic changes that support heart growth but can lead to heart failure when prolonged.
Area of Science:
- Cardiology
- Molecular Biology
- Metabolic Research
Background:
- Pathologic cardiac growth is a response to stress in conditions like aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM).
- While pathophysiology is known, metabolic drivers of cardiac hypertrophy are emerging areas of study.
- Microenvironmental tissue hypoxia is a key feature of the stressed heart.
Purpose of the Study:
- To review epidemiological and pathological aspects of hypertrophic heart disease in AS and HCM.
- To explore the role of tissue hypoxia in cardiac hypertrophy.
- To discuss the metabolic adaptations, particularly hypoxia-inducible factor (HIF) activation, in supporting cardiac growth and their link to heart failure.
Main Methods:
- Review of epidemiological evidence and pathological features of AS and HCM.
- Analysis of recent research on hypoxia-inducible factor (HIF) signaling in cardiac hypertrophy.
- Discussion of metabolic pathways, including glycolysis and fructolysis, in stressed cardiomyocytes.
Main Results:
- Hypoxia-inducible factor (HIF) activation promotes glycolytic and fructolytic pathways to maintain ATP production for cardiac growth.
- These metabolic adaptations are crucial for supporting the anabolic demands of the pathologically stressed heart.
- Prolonged activation of these pathways can lead to energy depletion and eventual heart failure.
Conclusions:
- Metabolic reprogramming, driven by HIF and characterized by increased glycolysis and fructolysis, is central to cardiac hypertrophy.
- While adaptive in the short term, these metabolic changes contribute to the progression of heart disease and heart failure.
- Understanding these metabolic determinants is crucial for developing targeted therapies for hypertrophic heart disease.
Abstract:
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.
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