1In general, cardiac hypertrophy (an increase in heart mass) is a poor prognostic sign. Cardiac enlargement is a characteristic of most forms of heart failure. Cardiac hypertrophy that occurs in athletes (physiological hypertrophy) is a notable exception.
2Physiological cardiac hypertrophy in response to exercise training differs in its structural and molecular profile to pathological hypertrophy associated with pressure or volume overload in disease. Physiological hypertrophy is characterized by normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and increased mortality.
3It is now clear that several signalling molecules play unique roles in the regulation of pathological and physiological cardiac hypertrophy.
4The present review discusses the possibility of targeting cardioprotective signalling pathways and genes activated in the athlete's heart to treat or prevent heart failure.
Cardiac hypertrophy (an increase in heart mass) is usually considered a poor prognostic sign and is associated with nearly all forms of heart failure.1 Heart failure is a debilitating disease, with increasing mortality rates, hospitalizations and prevalence rates.2,3 A striking exception to the association between cardiac enlargement and the incidence of heart failure is the athlete's heart.4,5 Chronic exercise training also induces a hypertrophic response, but this is associated with preserved or enhanced cardiac function.4,5
The heart is composed of cardiac myocytes, non-myocytes (e.g. fibroblasts, endothelial cells, mast cells, vascular smooth muscle cells) and surrounding extracellular matrix.6 Cardiac myocytes are specialized muscle cells composed of bundles of myofibrils. The myofibrils have repeating micro-anatomical units called sarcomeres (the basic contractile unit of the heart).7 In mammals, at birth or soon after, it is generally believed that most cardiac myocytes lose their ability to proliferate and growth occurs primarily as a result of an increase in myocyte size.8 Even though ventricular cardiac myocytes make up only one-third of the total cell number, they account for 70–80% of the heart's mass.6 In the adult, the growth of the heart is usually closely matched to its functional load and, under normal circumstances, is mainly constitutive in nature. In response to changes in functional load, the heart triggers a hypertrophic response to counterbalance the increase in wall stress.6 This hypertrophic response can broadly be classified as either physiological or pathological. The following review describes: (i) the distinct characteristics of pathological and physiological cardiac hypertrophy; (ii) signalling cascades that play distinct roles in inducing pathological and physiological cardiac hypertrophy; and (iii) the possibility of targeting genes activated in the athlete's heart (physiological hypertrophy) in a setting of heart failure.
DISTINCT CHARACTERISTICS OF PATHOLOGICAL AND PHYSIOLOGICAL CARDIAC HYPERTROPHY
Pathological and physiological cardiac hypertrophies are caused by different stimuli, functionally distinguishable, and are associated with distinct structural and molecular phenotypes (Table 1; Fig. 1).
Table 1. Characteristics of pathological and physiological cardiac hypertrophy
Pathological cardiac hypertrophy
Physiological cardiac hypertrophy
Biological significance not clear.
Pressure load in a disease setting (e.g. hypertension, aortic coarction) or volume load (e.g. valvular disease)
Regular physical activity or chronic exercise training
Association with heart failure and increased mortality
Pathological cardiac hypertrophy occurs in response to diverse stimuli, including hypertension, valve disease, myocardial infarction and genetic mutations.6,9–11 In contrast, physiological hypertrophy occurs in response to regular physical activity or chronic exercise training.5,6 More active animals of the same or related species have larger hearts (e.g. wild hare compared with domestic rabbit).6 Physiological growth also includes the embryonic and fetal stages of development, the rapidly growing phase during postnatal development and pregnancy.6,12 However, in this review, we have largely focused on physiological cardiac growth in the normal adult (i.e. induced by exercise).
Concentric and eccentric cardiac hypertrophy
Pathological and physiological hypertrophy can be subclassified as concentric or eccentric based on changes in shape that are dependent on the initiating stimulus.4,13
A pathological stimulus causing pressure overload (e.g. hypertension, aortic stenosis) produces an increase in systolic wall stress that results in concentric hypertrophy (hearts with thick walls and relatively small cavities).13 In contrast, a pathological stimulus causing volume overload (e.g. aortic regurgitation, arteriovenous fistulas) produces an increase in diastolic wall stress and results in eccentric hypertrophy (hearts with large dilated cavities and relatively thin walls).4,13
Isotonic exercise, such as running, walking, cycling and swimming, involves movement of large muscle groups. The profound vasodilatation of the skeletal muscle vasculature that is involved produces eccentric hypertrophy by increasing venous return to the heart and volume overload.4,6 This hypertrophy is characterized by chamber enlargement and a proportional change in wall thickness. In contrast, isometric or static exercise, such as weight lifting, involves developing muscular tension against resistance with little movement. Reflex and mechanical changes cause a pressure load on the heart rather than volume load resulting in concentric hypertrophy.4,6
In pathological hypertrophy, the enlargement of cardiac myocytes and the formation of new sarcomeres initially serves to normalize wall stress and permit normal cardiovascular function at rest (i.e. compensated growth). However, function in the hypertrophied heart may eventually decompensate, leading to left ventricle dilation and heart failure.6 In contrast, physiological hypertrophy does not decompensate into dilated cardiomyopathy or heart failure.4,5
Structural and molecular differences
List of Abbreviations:
Atrial natriuretic peptide
Mitogen-activated protein kinase
B-Type natriuretic peptide
Myosin heavy chain
Extracellular signal-regulated kinase
Nuclear factor of activated T cells
Protein kinase C
Insulin-like growth factor 1
Ribosomal S6 kinases
Animal studies have demonstrated that physiological and pathological hypertrophy have distinct structural and molecular bases.14–16 In mice, a surgical model of pathological hypertrophy that caused left ventricular hypertension (pressure overload induced by aortic banding) and a physiological model induced by chronic swim training resulted in a similar increase in heart mass (Fig. 1a). However, these models were associated with distinct histological and molecular characteristics. A fine network of collagen fibres surrounds cardiac myocytes under normal conditions to provide a supporting framework. In response to a pathological insult, cardiac fibroblasts and extracellular matrix proteins accumulate disproportionately and excessively. This leads to mechanical stiffness, which contributes to diastolic dysfunction and can progress to systolic dysfunction.17 Aortic banding was associated with increased interstitial fibrosis, whereas the exercise model was not (Fig. 1b). Models of pathological cardiac hypertrophy are often associated with upregulation of fetal genes, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and genes for fetal isoforms of contractile proteins, such as skeletal α-actin and β-myosin heavy chain (MHC; Fig. 1c). This can be accompanied by downregulation of genes normally expressed at higher levels in the adult than in the embryonic ventricle, such as α-MHC and sarcoplasmic reticulum Ca2+-ATPase.18 In contrast, re-expression of the fetal gene programme does not usually occur in models of physiological hypertrophy induced by exercise training (Fig. 1c).16
SIGNALLING PATHWAYS IMPLICATED IN THE DEVELOPMENT OF PHYSIOLOGICAL AND PATHOLOGICAL CARDIAC HYPERTROPHY
Despite physiological and pathological cardiac hypertrophy having distinct characteristics, until relatively recently it was unclear whether these two forms of hypertrophy were induced by distinct biochemical pathways. Transgenic and knockout technology in combination with surgical and exercise models has proven very powerful in delineating signalling cascades that play a role in regulating physiological and pathological growth.
To date, the best characterized examples of pathways that play distinct roles for inducing pathological and physiological hypertrophy are Gαq and insulin-like growth factor (IGF) 1–phosphoinositide-3 kinase (PI3-K; p110α), respectively. Gαq, one of the three subunits (α, β and γ) of heterotrimeric G-proteins of the Gq family, couple to cell surface receptors known as G-protein-coupled receptors (GPCR).19 In contrast, the p110α isoform of PI3-K is coupled to cell surface receptor tyrosine kinases (e.g. IGF1 receptors).20
The Gαq pathway regulates pathological hypertrophy
The formation of cardiac paracrine and/or autocrine factors, including angiotensin (Ang) II, endothelin (ET)-1 and noradrenaline, in response to a pathological stimulus plays an important role in the development of pathological cardiac hypertrophy (Fig. 2). These ligands activate GPCR, which leads to the dissociation of Gαq and activation of downstream signalling molecules. Cardiac-specific overexpression of the AngII AT1 receptor and Gαq in transgenic mice induced cardiac hypertrophy that was associated with altered cardiac gene expression and/or cardiac dysfunction and premature death.21–23 In contrast, mice lacking G-proteins (Gαq and Gα11) in cardiac myocytes and cardiac-specific transgenic mice expressing a peptide specific for inhibiting Gq-coupled receptor signalling did not develop cardiac hypertrophy in response to pressure overload, suggesting the Gq/11 pathway is important for the induction of pathological hypertrophy.24,25 Consistent with the idea that activation of GPCR induces hypertrophy in response to pathological stimuli, pressure overload-induced hypertrophy, but not exercise-induced hypertrophy, was inhibited by AngII receptor blockade.26,27
The IGF1–PI3-K pathway regulates physiological hypertrophy
Insulin-like growth factor 1 has been implicated in the regulation of body and organ size during postnatal development and is released in response to exercise training.28,29 Cardiac formation of IGF1, but not ET-1 or AngII, was higher in professional athletes than in control subjects29 and serum levels of IGF1 were elevated in humans and animals in response to chronic exercise training.30,31 Insulin-like growth factor 1 acts via the IGF1 receptor (IGF1R), a receptor tyrosine kinase, that activates PI3-K (p110α; class IA). Phosphoinositide-3 kinase is a lipid kinase that releases inositol lipid products from the plasma membrane that mediate intracellular signalling. Phosphoinositide-3 kinases regulate a number of physiological functions, including cell growth and survival.32
Transgenic mice with enhanced cardiac IGF1/PI3-K (p110α) signalling developed cardiac hypertrophy, but life span was normal and cardiac function was normal or enhanced.33–35 Conversely, mice with reduced cardiac IGF1/PI3-K (p110α) signalling had significantly smaller hearts.35,36 These data suggest that the IGF1–PI3-K (p110α) pathway is important for physiological developmental growth of the heart. To examine the role of PI3-K (p110α) in the induction of physiological hypertrophy induced by exercise training, studies were performed in which control mice (non-transgenic) and mice with reduced PI3-K activity (dominant negative PI3-K transgenics or knockout mice lacking p85α and p85β (regulatory subunits of class IA PI3-K)) were subjected to chronic swim training for 4 weeks.16,36 Mice with reduced cardiac PI3-K activity displayed a blunted hypertrophic response to swim training but not pressure overload, suggesting this pathway plays a critical role in regulating physiological hypertrophy induced by exercise training.
DOWNSTREAM EFFECTORS INDUCING PATHOLOGICAL AND PHYSIOLOGICAL CARDIAC HYPERTROPHY
Distal of transmembrane events, the identification of signalling molecules that play distinct roles in the development of pathological and physiological hypertrophy has proven more difficult. This is possibly not surprising considering the complex array of events, cross-talk and parallel signalling pathways that are able to compensate for the loss of some signalling molecules.
Effectors downstream of Gq
Downstream of Gq, mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase (ERK1/2), p38, c-Jun amino-terminal kinase) and some protein kinase (PK) C isoforms have been implicated in mediating pathological cardiac hypertrophy.18,37,38 However, later studies using transgenic and knockout mice have questioned some of these findings.39–42 For instance, cardiac-specific transgenic expression of constitutively active MAPK/ERK kinase (MEK) 1 increased ERK1/2 activation, but resulted in a physiological phenotype (i.e. augmented cardiac function and partial resistance to apoptosis).39 Protein kinase Cɛ transgenics also displayed cardiac hypertrophy that was physiological in nature (normal cardiac function and histology).40 Of note, some of the signalling molecules in this cascade may participate in the pathological phenotype without directly regulating myocyte size. Reduced activation of p38 in transgenic mice inhibited fibrosis in response to pressure overload, but had no effect on the hypertrophic response.42
The calcium-dependent signalling molecule calcineurin (also downstream of Gq) appears to largely mediate pathological hypertrophy in conjunction with the family of transcription factors known as nuclear factor of activated T cells (NFAT). Cardiac-specific transgenic mice expressing activated forms of calcineurin or NFAT3 developed cardiac hypertrophy and heart failure.43 In contrast, calcineurin Aβ-deficient mice displayed an impaired hypertrophic response to pathological hypertrophic models (pressure overload, AngII infusion or isoproterenol infusion).44 Furthermore, when NFAT–luciferase reporter mice were subjected to both physiological stimuli (exercise training, growth hormone–IGF1 infusion) and pathological stimuli (pressure overload, myocardial infarction), NFAT–luciferase reporter activity was upregulated in both pathological models, but not in the physiological models.45 In another study, calcineurin signalling was implicated in the induction of both physiological and pathological cardiac hypertrophy. Cardiac-specific transgenic overexpression of the calcineurin inhibitory protein myocyte-enriched calcineurin-interacting protein (MCIP) 1 inhibited the hypertrophic response induced by exercise training and pathological stimuli (calcineurin transgenic expression or β-adrenoceptor stimulation).46 However, more recently it was reported that MCIPs can serve either a permissive or facilitative function for calcineurin signalling.47
Nerve growth factor (NGF) 1A-binding protein, a member of a recently described family of corepressors for early growth response transcription factors, was reported to regulate pathological cardiac hypertrophy.48 Transgenic mice with cardiac overexpression of NGF1A-binding protein displayed an attenuated hypertrophic response to pathological stimuli (pressure overload or adrenoceptor induced) but not physiological stimuli (development or exercise training).
Effectors downstream of IGF1–PI3-K
Similar complexities have arisen in the study of molecules downstream of the IGF1–PI3-K pathway. Akt, a serine threonine kinase (also known as PKB), is a well-characterized target of PI3-K. Transgenic mice with activation of Akt in the heart have demonstrated phenotypes ranging from absence of hypertrophy associated with protection from ischaemia–reperfusion injury to substantial hypertrophy associated with a pathological phenotype and death.49–52 The range of phenotypes may be related, at least in part, to the degree of Akt expression and subcellular localization. However, more recently, convincing evidence suggests Akt1 is required for physiological rather than pathological heart growth.53 Akt1-knockout mice showed a blunted hypertrophic response to swim training but not to pressure overload.53
Ribosomal S6 kinases (S6Ks; S6K1 and S6K2) are considered to play a critical role in the regulation of protein synthesis downstream of PI3-K and Akt. The activity of S6K1 was elevated in transgenic models of physiological hypertrophy (mice with increased activation of the IGF1–PI3-K pathway: IGF1R and constitutively active PI3-K transgenics).34,35 The role of S6Ks in the heart was examined by subjecting global S6K-knockout mice to swim training or genetically crossing them with constitutively active PI3-K or IGF1R transgenics. Surprisingly, deletion of S6Ks did not attenuate cardiac hypertrophy induced by exercise training or transgenic expression of IGF1R or constitutively active PI3-K.54
Of note, S6Ks are considered important regulators of translational control and are also considered to play a role in the induction of pathological hypertrophy. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), is considered a proximal effector of S6Ks. Rapamycin attenuated and regressed pathological hypertrophy induced by pressure overload and this was considered to be mediated by inhibition of S6Ks.55,56 However, unexpectedly, the hypertrophic response of S6K-knockout mice to pressure overload was similar to that observed in control animals.54 Together, these data suggest that S6Ks may not be critical for the induction of physiological or pathological cardiac hypertrophy. However, it is impossible to completely rule out the possibility that a compensatory pathway in S6K-knockout mice may have masked the role of S6Ks under normal conditions.
ONGOING ISSUES SURROUNDING PATHOLOGICAL AND PHYSIOLOGICAL HYPERTROPHY
Type of stimulus
The most commonly used mouse models of pathological hypertrophy (e.g. aortic banding, hypertension) represent a chronic pressure load that results in concentric hypertrophy. In contrast, models of physiological hypertrophy (e.g. treadmill, swimming) represent an intermittent volume load that results in eccentric hypertrophy. This raises the issue of whether differences in signalling observed in models of pathological and physiological hypertrophy can be explained by the duration of the insult (constant vs intermittent) or type of load (volume vs pressure). Transgenic models with chronic activation of the IGF1–PI3-K pathway, at least to some degree, argue that the duration of the stimulus alone is unlikely to account for the differences.34,35 In both models, the physiological phenotype was not reported to progress to a pathological phenotype. Furthermore, it was recently reported that mouse hearts subjected to intermittent pressure overload displayed pathological features, including diastolic dysfunction, altered β-adrenoceptor function and chronic activation of signalling pathways, associated with histological and cellular abnormalities.57 Together, these data suggest that it is not whether a stimulus is chronic or intermittent that determines whether the resultant cardiac hypertrophy is pathological or physiological.
There is also some evidence to suggest that differences cannot be explained by stimuli causing eccentric or concentric hypertrophy. Transgenic mice with enhanced ERK5 activation developed eccentric hypertrophy that progressed to dilated cardiomyopathy.58 Furthermore, in the rat, a pathological model of eccentric hypertrophy (myocardial infarction) and a physiological model of eccentric hypertrophy (voluntary exercise wheel) were associated with differential regulation of signalling molecules. Extracellular signal-regulated kinase 1/2 was activated in the non-infarcted left ventricle, but not in the ventricle of rats that underwent exercise. Akt was activated in both models.59
Signalling pathways responsible for the induction of cardiac hypertrophy are considerably more complex than those illustrated in Fig. 2 and cannot explain all current observations. For instance, the signalling mechanisms responsible for cardiac hypertrophy induced by pressure overload or cardiac-specific overexpression of Gαq do not appear to be identical. Mice deficient in MEK kinase-1 displayed an attenuated response to Gαq overexpression,60 but not to pressure overload.61 Furthermore, although the IGF1–PI3-K pathway appears to play a critical role in the induction of physiological hypertrophy, it may also be activated in some pathological models as a protective mechanism.
Transcriptional changes observed in pathological and physiological cardiac hypertrophy
The significance of changes in the fetal genes with regard to their direct effects on cardiac growth and phenotype (e.g. fibrosis) are not completely understood. Although fetal genes are often upregulated in models of pathological hypertrophy, some studies have demonstrated that the fetal gene programme can be upregulated in mice without cardiac hypertrophy.35,62 Furthermore, upregulation of some fetal genes may be beneficial. Evidence suggests that ANP/BNP signalling has antihypertrophic actions within cardiac myocytes.63
It is also of note that some transgenic models of physiological hypertrophy have been associated with a modest upregulation of fetal genes (e.g. IGF1R34 and transgenics with increased ERK1/2 activation39). Both models were associated with enhanced cardiac function and expression of IGF1R was protective against the induction of interstitial fibrosis in a pressure overload model.34 In addition, the recently described model of intermittent pressure overload was associated with a pathological phenotype, but not upregulation of the fetal gene programme.57 Thus, until we have a better understanding of the biological significance of changes in the fetal gene programme, it would appear more accurate to categorize models of hypertrophy based on functional and structural parameters.
THERAPEUTIC APPLICATIONS: TARGETING GENES IMPORTANT FOR THE INDUCTION OF PHYSIOLOGICAL HYPERTROPHY TO TREAT/PREVENT HEART FAILURE
Prior to the late 1980s, patients with heart failure were advised to avoid physical exercise.64 We now know that regular physical activity protects against cardiovascular disease, exercise training in selected heart failure patient groups is safe and beneficial, and exercise can reverse molecular and functional abnormalities in patients and animal models of cardiac disease.64–71 Furthermore, transgenic models of physiological cardiac hypertrophy (activation of the IGF1–PI3-K pathway) have been reported to play a critical role in maintaining or improving cardiac function and reducing interstitial fibrosis in a setting of heart failure.34,72,73 Together, these data suggest that it may be beneficial to target genes activated in the athlete's heart (physiological hypertrophy) in a setting of heart disease.
Recently, we and our colleagues examined whether progressive exercise training and PI3-K activity had an impact on survival in a mouse model of dilated cardiomyopathy.74,75 It has been difficult to accurately assess the effects of exercise on survival in patients with dilated cardiomyopathy, possibly due to confounding factors including medications, diet, smoking and exercise compliance. We found that exercise and enhanced cardiac PI3-K activity improved survival by 15–20% in the model of dilated cardiomyopathy, whereas depressed PI3-K activity shortened life span by almost 50%.74 We have also demonstrated that supranormal cardiac PI3-K activity resulted in functional improvement in mice subjected to pressure overload (aortic banding), whereas reduced cardiac PI3-K activity markedly accelerated the progression of heart failure in the same model.16,74
Data from us and others suggest that IGF1–PI3-K–Akt signalling may have a beneficial effect, at least in part, by inhibiting pathological growth and signalling molecules downstream of GPCR.53,74 We recently reported that PI3-K (p110α) signalling negatively regulated GPCR-stimulated ERK activation in isolated cardiac myocytes.74
The PI3-K pathway has numerous actions in different cell types. Thus, a challenge in targeting the PI3-K family with drugs is to understand how individual PI3-K isoforms control normal physiology in different cell types. Recent articles describing the possible use of isoform-specific inhibitors of PI3-K have generated great interest in the cancer field.76,77 Uncontrolled activation of Akt through PI3-K (p110α) allows cancer cells to bypass normal growth-limiting controls. However, because PI3-K also regulates insulin, diabetes is a potential side-effect of such agents. Although later findings suggested that such inhibitors may not lead to unmanageable metabolic disturbances,77 our recent observations raise concerns for patients who have heart disease or are at risk. Even though mice with reduced cardiac PI3-K (p110α) activity had normal cardiac function under basal conditions,35 they displayed accelerated heart failure in a setting of dilated cardiomyopathy or pressure overload.74 Together, these data suggest that targeting PI3-K isoforms as therapeutic agents may still require drug delivery systems that specifically target particular cell types or organs. The diverse actions of the IGF1–PI3-K pathway on numerous cell types may also explain some of the adverse effects obtained when administering growth hormone or IGF1 to patients with heart failure.78
Although both pathological and physiological cardiac hypertrophy are associated with an increase in heart mass, pathological hypertrophy is associated with a complex array of events, including upregulation of fetal genes, histopathology and cardiac dysfunction. In contrast, physiological hypertrophy is associated with normal cardiac structure and normal or enhanced cardiac function. It is now clear that pathological and physiological hypertrophy are mediated by distinct signalling molecules. Heart failure research and therapy has generally focused on identifying and inhibiting pathological processes. Pro-active therapeutic interventions based on stimuli and genes leading to physiological growth may provide an additional strategy to treat or reverse heart failure.
The authors acknowledge funding support from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia.