Review article
Physiological and pathological cardiac hypertrophy

https://doi.org/10.1016/j.yjmcc.2016.06.001Get rights and content

Highlights

  • Pathological and physiological hypertrophy differs in the signaling pathways that drive these processes.

  • Pathological hypertrophy develops myocytes death and fibrotic remodeling, and this promotes cardiac dysfunction.

  • Interaction between cardiomyocytes and non-cardiomyocytes modulates cardiomyocyte hypertrophy.

Abstract

The heart must continuously pump blood to supply the body with oxygen and nutrients. To maintain the high energy consumption required by this role, the heart is equipped with multiple complex biological systems that allow adaptation to changes of systemic demand. The processes of growth (hypertrophy), angiogenesis, and metabolic plasticity are critically involved in maintenance of cardiac homeostasis. Cardiac hypertrophy is classified as physiological when it is associated with normal cardiac function or as pathological when associated with cardiac dysfunction. Physiological hypertrophy of the heart occurs in response to normal growth of children or during pregnancy, as well as in athletes. In contrast, pathological hypertrophy is induced by factors such as prolonged and abnormal hemodynamic stress, due to hypertension, myocardial infarction etc. Pathological hypertrophy is associated with fibrosis, capillary rarefaction, increased production of pro-inflammatory cytokines, and cellular dysfunction (impairment of signaling, suppression of autophagy, and abnormal cardiomyocyte/non-cardiomyocyte interactions), as well as undesirable epigenetic changes, with these complex responses leading to maladaptive cardiac remodeling and heart failure. This review describes the key molecules and cellular responses involved in physiological/pathological cardiac hypertrophy.

Introduction

Mammalian cardiomyocytes generally exit the cell cycle soon after birth, so most cardiomyocytes are terminally differentiated in adults and do not proliferate under physiological conditions. However, cardiac tissue exhibits plasticity that enables the heart to respond to environmental demands, and cells can grow, shrink, or die in reaction to various physiological or pathological stresses. Cardiac hypertrophy is classified as physiological when associated with normal cardiac function or as pathological when associated with cardiac dysfunction.

Normal physiological enlargement of the heart chiefly occurs through hypertrophy of cardiomyocytes in response to growth of the body or exercise, and the enlarged cardiomyocytes receive adequate nourishment due to corresponding expansion of the capillary network. Structural or functional cardiac abnormalities do not occur in this setting, and physiological hypertrophy is generally not considered to be a risk factor for heart failure. In contrast, pathological hypertrophy is associated with production of high levels of neurohumoral mediators, hemodynamic overload, injury and loss of cardiomyocytes. In the pathological setting, cardiomyocyte growth exceeds the capacity of the capillaries to adequately supply nutrients and oxygen, leading to cardiac hypoxia and remodeling in rodents [1], [2]. Because cardiac hypertrophy plays a central role in cardiac remodeling and is an independent risk factor for cardiac events, understanding this process is critically important.

Cardiac dysfunction is associated with a complex spectrum of pathophysiological changes, including capillary rarefaction, metabolic derangement, sarcomere disorganization, altered calcium handling, inflammation, cellular senescence, cell death and fibrosis. Due to such complexity, no simple therapeutic approach is adequate for the management of this condition. There is some overlap between the mechanisms of physiological and pathological cardiac hypertrophy, since there is evidence for a central role of Akt signaling or mechanotransduction in physiological hypertrophy, while neurohormonal factors or continuously overloaded biomechanical stress induce multiple signaling pathways, including Akt, in pathological hypertrophy.

Section snippets

Classification of heart failure

There are two broad types of heart failure, heart failure with reduced (HFrEF) and heart failure with preserved (HFpEF) ejection fraction. HFrEF develops through the accumulation of myocardial damage and progressive loss of cardiomyocytes, and is commonly caused by myocardial infarction, hypertensive heart disease, or cardiomyopathy. Oxidative stress present within the cardiomyocytes induces cardiomyocytes death and replacement fibrosis [3]. Cardiomyocyte loss promotes alterations within the

Various types of cardiac hypertrophy

Heart responses to environmental conditions and able to grow or shrink. Heart increases in size and depending on the types, strength and duration of stimuli, it results in physiological or pathological cardiac hypertrophy. Physiological hypertrophy is characterized with normal or enhanced contractile function coupled with normal architecture and organization of cardiac structure [10]. Pathological hypertrophy associates with increased cardiomyocytes death and fibrotic remodeling, and it is

Mechanism of physiological cardiac hypertrophy

Enlargement of the heart in response to growth, exercise, and pregnancy is associated with maintenance of normal cardiac function and is described as “physiological” hypertrophy. There is a linear relationship between the increase of body weight and cardiac weight. The increase of

cardiac weight during growth is largely attributable to enlargement of cardiomyocytes, and there is an almost 3-fold increase of cardiomyocyte diameter in humans during development from infants to adults. Physiological

Mechanisms of pathological cardiac hypertrophy

Enlargement of the heart in response to hypertensive stress, myocardial injury, or excessive neurohumoral activation is associated with cardiac dysfunction and is described as “pathological hypertrophy” [88]. Cardiac function is initially maintained in pressure overload-induced cardiac hypertrophy, and this is described as the adaptive phase. However, sustained pressure overload promotes the transition from the adaptive to maladaptive phase, which is characterized by a reduced ejection fraction

Autophagy

Autophagy is an evolutionary conserved catabolic system involved in degradation of unnecessary or dysfunctional cellular components through lysosomal machinery, thus recycling amino acids for the synthesis of proteins that are essential for cell survival. Autophagy is activated by various stresses, including starvation, ischemia-reperfusion, infection, ROS, and hypoxia [151]. A basal level of autophagy is essential for removal and renewal of dysfunctional mitochondria and for maintaining

Angiogenic response in physiological versus pathological cardiac hypertrophy

Coordination of cardiac growth and angiogenesis appears to be critically important in separating physiological or adaptive hypertrophy from pathological cardiac hypertrophy. It has long been observed that capillary rarefaction occurs in cardiac dysfunction, whereas the number of capillaries is maintained or increased in hearts with physiological hypertrophy [258], [259], [260]. Vascular endothelial growth factor (VEGF) is a major angiogenic molecule with a pivotal role in vessel formation,

Conclusions

Heart failure develops as the result of multiple factors affecting cardiac function in a complex manner, and this challenging condition does not respond to simple one-dimensional treatment. Cardiac hypertrophy is one of the most critical components of cardiac remodeling. Over the last decade, our understanding of cardiac hypertrophy has made significant progress and several important signaling molecules and modifiers involved in hypertrophy have been identified. Continuing investigation of this

Disclosure

I.S. and T.M. disclose no conflict of interests.

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research, a Grant-in-Aid for Scientific Research on Innovative Areas (Stem Cell Aging and Disease), and a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and grants from the Ono Medical Research Foundation, the Japan Diabetes Foundation, the Takeda Science Foundation, the Takeda Medical Research Foundation, and the Terumo Foundation (to T.M.) as well as by a

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