Abstract
Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.
Key points
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The heart initially undergoes hypertrophy in response to haemodynamic overload to increase contractility and reduce ventricular wall stress, but this adaptive hypertrophy transitions to heart failure through pathological remodelling.
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There are two types of hypertrophy, physiological and pathological, which differ in their underlying molecular mechanisms, cardiac phenotype, and prognosis.
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The type of hypertrophic stimuli and the nature of the downstream signalling mechanisms largely determine the fate of cardiac hypertrophy, which is either physiological or pathological.
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Prioritizing the regulators of pathological hypertrophy on the basis of their clinical relevance for therapeutic targeting is important to improve the outcomes in patients with pathological hypertrophy and heart failure.
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Acknowledgements
The authors thank D. Zablocki (Rutgers New Jersey Medical School, Newark, NJ, USA) for the critical reading of the manuscript. M.N. is funded by an AHA Scientist Development Grant (17SDG33660358). J.S. is funded by the Leducq Foundation Transatlantic Network of Excellence and the US Public Health Service grants.
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Nature Reviews Cardiology thanks S. Lavandero, K. Walsh, M. A. Sussman, and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Laplace’s law
-
A physical law stating that the wall stress (WS) of a sphere (ventricle) is proportional to the intracavity (ventricular) pressure (P) and the chamber radius (R), and inversely proportional to the ventricular wall thickness (T), given by the formula WS = P*R/2T.
- Cardiac remodelling
-
Process of structural and functional changes in the heart in response to mechanical stress, neurohormonal activation, and myocardial injury that lead to progressively dilated hearts and impaired contractile function.
- Coronary flow reserve
-
The ratio between maximal and resting coronary flow, which is thought to reflect the capacity of the coronary arteries to dilate and increase coronary flow in response to metabolic demand.
- Store-operated Ca2+ entry
-
Ca2+ influx through the Ca2+ channels in the plasma membrane that is triggered when intracellular Ca2+ stores are depleted.
- Athlete’s heart
-
Dilated and hypertrophied heart observed in athletes, particularly those engaged in endurance training, that is mostly adaptive and benign.
- Glycolysis
-
Metabolic process in which glucose is converted into pyruvate in the cytosol, generating two molecules of ATP.
- Fatty acid oxidation
-
Catabolic processes in which fatty acyl-CoA is sequentially oxidized to generate acetyl-CoA, which is then used in the tricarboxylic acid cycle.
- Anaplerosis
-
Chemical reactions that replenish the tricarboxylic acid cycle intermediates that were extracted for biosynthesis (cataplerosis).
- Mechanical unloading
-
Clinical interventions to reduce ventricular pressure and/or volume with the help of circulatory assist devices in patients with heart failure.
- Biased ligands
-
Ligands that selectively affect some, but not all, of the many signalling pathways of a given receptor.
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Nakamura, M., Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15, 387–407 (2018). https://doi.org/10.1038/s41569-018-0007-y
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DOI: https://doi.org/10.1038/s41569-018-0007-y
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