Cardiac remodelling: concentric versus eccentric hypertrophy in strength and endurance athletes

Cardiac remodelling is commonly defined as a physiological or pathological state that may occur after conditions such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload. When training excessively, the heart develops several myocardial adaptations causing a physiological state of cardiac remodelling. These morphological changes depend on the kind of training and are clinically characterised by modifications in cardiac size and shape due to increased load. Several studies have investigated morphological differences in the athlete’s heart between athletes performing strength training and athletes performing endurance training. Endurance training is associated with an increased cardiac output and volume load on the left and right ventricles, causing the endurance-trained heart to generate a mild to moderate dilatation of the left ventricle combined with a mild to moderate increase in left ventricular wall thickness. Strength training is characterised by an elevation of both systolic and diastolic blood pressure. This pressure overload causes an increase in left ventricular wall thickness. This may or may not be accompanied by a slight raise in the left ventricular volume. However, the development of an endurancetrained heart and a strength-trained heart should not be considered an absolute concept. Both forms of training cause specific morphological changes in the heart, dependent on the type of sport. (Neth Heart J 2008;16:129-33.)     

Does load-induced ventricular hypertrophy progress to systolic heart failure?

Ventricular hypertrophy develops in response to numerous forms of cardiac stress, including pressure or volume overload, loss of contractile mass from prior infarction, neuroendocrine activation, and mutations in genes encoding sarcomeric proteins. Hypertrophic growth is believed to have a compensatory role that diminishes wall stress and oxygen consumption, but Framingham and other studies established ventricular hypertrophy as a marker for increased risk of developing chronic heart failure, suggesting that hypertrophy may have maladaptive features. However, the relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. For instance, coronary artery disease is induced by many of the same risk factors that cause hypertrophy and can itself lead to systolic dysfunction. It is uncertain, therefore, whether ventricular hypertrophy commonly progresses to systolic dysfunction without the contribution of intervening ischemia or infarction. In this review, we summarize findings from epidemiologic studies, preclinical experiments in animals, and clinical trials to lay out what is known-and not known-about this important question.     

Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy

Although it has been shown that Epac1 mRNA is expressed ubiquitously and Epac2 mRNA predominantly in the brain and endocrine tissues, developmental and pathophysiological changes of these molecules have not been characterized. Developmental changes were analyzed in murine heart, brain, kidneys, and lungs by RT-PCR analysis, which revealed more drastic developmental changes of Epac2 mRNA than Epac1. Only the Epac2 mRNA in kidney showed a transient expression pattern with dramatic decline into adulthood. In addition to developmental changes, we found that Epac gene expression was upregulated in myocardial hypertrophy induced by chronic isoproterenol infusion or pressure overload by transverse aortic banding. Both Epac1 and Epac2 mRNA were upregulated in isoproterenol-induced left ventricular hypertrophy, whereas only Epac1 was increased in pressure overload-induced hypertrophy. Stimulation of H9c2, cardiac myoblast cells, with fetal calf serum, which can induce myocyte hypertrophy, upregulated Epac1 protein expression. We also demonstrated that Epac was the limiting moiety, relative to Rap, in the Epac-Rap signaling pathway in terms of stoichiometry and that Epac stimulation led to the activation of ERK1/2. Our data suggest the functional involvement of Epac in organogenesis and also in physiological as well as pathophysiological processes, such as cardiac hypertrophy. Furthermore, our results suggest the importance of the stoichiometry of Epac over that of Rap in cellular biological effects.     

Changes in heart genome expression in hypertensive diseases]

Chronic increases in haemodynamic load modify the expression of cardiac genes, leading to cardiac hypertrophy and a new phenotype. As an example, changes in the expression of the genes encoding the main contractile proteins, the isomyosin heavy chains, have been associated with modifications of the physiological properties of cardiac muscle. The cellular and molecular mechanisms which either do or do not initiate and maintain these changes in cardiac genomic expression remain to be elucidated. Using in situ hybridization we show that mRNAs encoding a cellular form of fibronectin (c-FN), a protein of the basal membrane which is not or poorly expressed in adult rat heart, are reexpressed as a result of severe hypertension with a similar time course than the beta-heavy chain of myosin (beta-MHC), also mostly expressed in fetal heart. The accumulation of the c-FN mRNAs was found in the wall of coronary arteries whilst that of the beta-MHC mRNAs occurred in the myocytes at the border zone of these arteries. Thus a high pressure in the arteries could be the trigger inducing the synthesis of factors which could, through a gradient, modulate the phenotype of both the smooth muscle cells of the media and the cardiocytes. Besides, using a model of cultured adult rat cardiocytes, we show that the differential expression of the MHC isoforms is dependent on the beta-adrenergic stimulation but that the regulation depends on the stage of development of the cells and differs for the alpha and beta MHC. These 2 complementary approaches for identifying the molecular mechanisms that control cardiac muscle growth should help for understanding cardiac adaptation triggered by haemodynamic overload, such as arterial hypertension as well as cardiac failure.     

Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules

Cardiac hypertrophy is enlargement of the heart in response to physiological or pathological stimuli, chiefly involving growth of myocytes in size rather than in number. Previous studies have shown that the expression pattern of a group of genes in hypertrophied heart induced by pressure overload resembles that at the embryonic stage of heart development, a phenomenon known as activation of the "fetal gene program". Here, using a genome-wide approach we systematically defined genes and pathways regulated in short- and long-term cardiac hypertrophy conditions using mice with transverse aortic constriction (TAC), and compared them with those regulated at different stages of embryonic and postnatal development. In addition, exon-level analysis revealed widespread mRNA isoform changes during cardiac hypertrophy resulting from alternative usage of terminal or internal exons, some of which are also developmentally regulated and may be attributable to decreased expression of Fox-1 protein in cardiac hypertrophy. Genes with functions in certain pathways, such as cell adhesion and cell morphology, are more likely to be regulated by alternative splicing. Moreover, we found 3'UTRs of mRNAs were generally shortened through alternative cleavage and polyadenylation in hypertrophy, and microRNA target genes were generally de-repressed, suggesting coordinated mechanisms to increase mRNA stability and protein production during hypertrophy. Taken together, our results comprehensively delineated gene and mRNA isoform regulation events in cardiac hypertrophy and revealed their relations to those in development, and suggested that modulation of mRNA isoform expression plays an importance role in heart remodeling under pressure overload.     

Bariatric surgery to unload the stressed heart: a metabolic hypothesis

Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.     

Pressure overload and neurohumoral activation differentially affect the myocardial proteome

Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.     

HSP75 protects against cardiac hypertrophy and fibrosis

Cardiac hypertrophy, a major determinant of heart failure, is associated with heat shock proteins (HSPs). HSP75 has been reported to protect against environmental stresses; however, its roles in cardiac hypertrophy remain unclear. Here, we generated cardiac-specific inducible HSP75 transgenic mice (TG) and cardiac hypertrophy was developed at 4 weeks after aortic banding in TG mice and wild-type littermates. The results revealed that overexpression of HSP75 prevented cardiac hypertrophy and fibrosis as assessed by heart weight/body weight ratio, heart weight/tibia length ratio, echocardiographic and hemodynamic parameters, cardiomyocyte width, left ventricular collagen volume, and gene expression of hypertrophic markers. Further studies showed that overexpression of HSP75 inhibited the activation of TAK/P38, JNK, and AKT signaling pathways. Thus, HSP75 likely reduces the hypertrophy and fibrosis induced by pressure overload through blocking TAK/P38, JNK, and AKT signaling pathways.     

Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy

Alterations in cardiac G protein-mediated signaling, most prominently G(q/11) signaling, are centrally involved in hypertrophy and heart failure development. Several RGS proteins that can act as negative regulators of G protein signaling are expressed in the heart, but their functional roles are still poorly understood. RGS expression changes have been described in hypertrophic and failing hearts. In this study, we report a marked decrease in RGS2 (but not other major cardiac RGS proteins (RGS3-RGS5)) that occurs prior to hypertrophy development in different models with enhanced G(q/11) signaling (transgenic expression of activated Galpha(q)(*) and pressure overload due to aortic constriction). To assess functional consequences of selective down-regulation of endogenous RGS2, we identified targeting sequences for effective RGS2 RNA interference and used lipid-based transfection to achieve uptake of fluorescently labeled RGS2 small interfering RNA in >90% of neonatal and adult ventricular myocytes. Endogenous RGS2 expression was dose-dependently suppressed (up to 90%) with no major change in RGS3-RGS5. RGS2 knockdown increased phenylephrine- and endothelin-1-induced phospholipase Cbeta stimulation in both cell types and exacerbated the hypertrophic effect (increase in cell size and radiolabeled protein) in neonatal myocytes, with no major change in G(q/11)-mediated ERK1/2, p38, or JNK activation. Taken together, this study demonstrates that endogenous RGS2 exerts functionally important inhibitory restraint on G(q/11)-mediated phospholipase Cbeta activation and hypertrophy in ventricular myocytes. Our findings point toward a potential pathophysiological role of loss of fine tuning due to selective RGS2 down-regulation in G(q/11)-mediated remodeling. Furthermore, this study shows the feasibility of effective RNA interference in cardiomyocytes using lipid-based small interfering RNA transfection.     

Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy

Gender differences in the prevalence of cardiovascular disease have been observed both clinically and experimentally. These cardioprotective effects have frequently been attributed to female hormones, however, the underlying mechanisms responsible for this cardioprotection are still poorly understood. Accordingly, this study sought to determine the contribution of ovarian hormones to the prevention of adverse ventricular remodeling and congestive heart failure in chronic volume overload (i.e. aortocaval fistula in intact or ovariectomized female rats). Ovariectomized rats developed more extensive cardiac remodeling than intact females at 21 weeks post-fistula, characterized by significantly greater left ventricular (LV) hypertrophy (167 vs. 86%, respectively, p < 0.05) and a substantial increase in LV dilatation (71%, p < 0.05) relative to control. In contrast to the eccentric hypertrophy in ovariectomized females post-fistula, the hypertrophic response in the intact female hearts was essentially concentric. While neither fistula group suffered significant mortality, there was a marked increase in the lung weight of ovariectomized rats (87%, p < 0.05) consistent with the development of pulmonary edema. Overall, the extent of myocardial remodeling and decrease in LV function in the ovariectomized females was comparable to those changes reported for males with symptomatic heart failure, while intact females maintained chronic compensated ventricular function similar to that of controls. The marked ventricular dilatation and symptoms of congestive heart failure seen at 21 weeks post-fistula in the ovariectomized females clearly demonstrate the influence of circulating ovarian hormones on the pattern of myocardial remodeling resulting from a chronic volume overload.     

Epigenetics in cardiac development,function, and disease

Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine.     

MicroRNAs in a hypertrophic heart: from foetal life to adulthood

The heart is the first organ to form and undergoes adaptive remodelling with age. Ventricular hypertrophy is one such adaptation, which allows the heart to cope with an increase in cardiac demand. This adaptation is necessary as part of natural growth from foetal life to adulthood. It may also occur in response to resistance in blood flow due to various insults on the heart and vessels that accumulate with age. The heart can only compensate to this increase in workload to a certain extent without losing its functional architecture, ultimately resulting in heart failure. Many genes have been implicated in cardiac hypertrophy, however none have been shown conclusively to be responsible for pathological cardiac hypertrophy. MicroRNAs offer an alternative mechanism for cellular regulation by altering gene expression. Since 1993 when the function of a non‐coding DNA sequence was first discovered in the model organism Caenorhabditis elegans, many microRNAs have been implicated in having a central role in numerous physiological and pathological cellular processes. The level of control these antisense oligonucleotides offer can often be exploited to manipulate the expression of target genes. Moreover, altered levels of microRNAs can serve as diagnostic biomarkers, with the prospect of diagnosing a disease process as early as during foetal life. Therefore, it is vital to ascertain and investigate the function of microRNAs that are involved in heart development and subsequent ventricular remodelling. Here we present an overview of the complicated network of microRNAs and their target genes that have previously been implicated in cardiogenesis and hypertrophy. It is interesting to note that microRNAs in both of these growth processes can be of possible remedial value to counter a similar disease pathophysiology.     

Renin-angiotensin system and sympathetic nervous system in cardiac pressure-overload hypertrophy

Angiotensin II and norepinephrine (NE) have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. The purpose of this study was to determine the temporal sequence for activation of the renin-angiotensin and sympathetic nervous systems in the rat after 3-60 days of pressure overload induced by aortic constriction. Initially on pressure overload, there was transient activation of the systemic renin-angiotensin system coinciding with the appearance of left ventricular hypertrophy (day 3). At day 10, there was a marked increase in AT(1) receptor density in the left ventricle, increased plasma NE concentration, and elevated cardiac epinephrine content. Moreover, the inotropic response to isoproterenol was reduced in the isolated, perfused heart at 10 days of pressure overload. The affinity of the beta(2)-adrenergic receptor in the left ventricle was decreased at 60 days. Despite these alterations, there was no decline in resting left ventricular function, beta-adrenergic receptor density, or the relative distribution of beta(1)- and beta(2)-receptor sites in the left ventricle over 60 days of pressure overload. Thus activation of the renin-angiotensin system is an early response to pressure overload and may contribute to the initial development of cardiac hypertrophy and sympathetic activation in the compensated heart.     

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

Inflammation plays a key role in pressure overload‐induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High‐mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload‐induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild‐type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin‐embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC‐induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up‐regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload‐induced cardiac hypertrophy and cardiac dysfunction.     

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease.     

Involvement of transient receptor potential proteins in cardiac hypertrophy

Cardiac hypertrophy is an adaptive process that occurs in response to increased physical stress on the heart. Hypertrophy, which may be induced by hypertension among other factors, is characterized by an increase in left ventricular mass and an associated increase in force production capacity. However, as sustained cardiac hypertrophy may lead to heart failure and sudden death, an understanding of the molecular processes involved in both the onset and consequences of hypertrophy is of significant importance. Calcium is a key player in the process underlying the development of cardiac hypertrophy. Recently, several Transient Receptor Potential proteins (TRPs), including calcium-permeable and calcium-regulated ion channels, have been shown to be related to various aspects of cardiac hypertrophy. TRPs are implicated in the development of cardiac hypertrophy (TRPC1, TRPC3, TRPC6), the electrophysiological perturbations associated with hypertrophy (TRPM4) and the progression to heart failure (TRPC7). This review describes the major characteristics of cardiac hypertrophy and focuses on the roles of TRPs in the physiological processes underlying hypertrophy.