Inhibition of Hypertrophy, Per Se, May Not Be a Good Therapeutic Strategy in Ventricular Pressure Overload: Other Approaches Could Be More Beneficial
2015; Lippincott Williams & Wilkins; Volume: 131; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.114.013895
ISSN1524-4539
AutoresBertrand Crozatier, Renée Ventura‐Clapier,
Tópico(s)Renin-Angiotensin System Studies
ResumoHomeCirculationVol. 131, No. 16Inhibition of Hypertrophy, Per Se, May Not Be a Good Therapeutic Strategy in Ventricular Pressure Overload: Other Approaches Could Be More Beneficial Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBInhibition of Hypertrophy, Per Se, May Not Be a Good Therapeutic Strategy in Ventricular Pressure Overload: Other Approaches Could Be More Beneficial Bertrand Crozatier, MD, PhD and Renée Ventura-Clapier, PhD Bertrand CrozatierBertrand Crozatier From Université Paris-Sud 11, and Institut National de la Santé et de la Recherche Médicale, Unit 1180, Châtenay-Malabry, France. and Renée Ventura-ClapierRenée Ventura-Clapier From Université Paris-Sud 11, and Institut National de la Santé et de la Recherche Médicale, Unit 1180, Châtenay-Malabry, France. Originally published21 Apr 2015https://doi.org/10.1161/CIRCULATIONAHA.114.013895Circulation. 2015;131:1448–1457Cardiac hypertrophy was initially defined by a directly observed increase in cardiac mass that was then assumed to be mainly linked to an increase in cardiomyocyte mass. When submitted to a physiological or pathological stress, the heart undergoes a process of remodeling that involves cardiomyocyte growth but also changes in other cell types: changes in intracellular and extracellular structure, protein expression, signaling pathways, energy metabolism, vascularization, and so forth. Although hypertrophy is only one manifestation of the multiparameter remodeling of the myocardium, progressively, this term has, by oversimplification, included all others aspects of the cardiac response to stress. Classically, hypertrophy induced by pressure overload was considered as adaptive via a decreased stress allowed by a thicker myocardium. The currently accepted concept is that of pathological hypertrophy with depressed ventricular function that leads to heart failure, as opposed to physiological hypertrophy induced by exercise, for example. In this view, hypertrophy development should be prevented during pressure overload. This was proposed 10 years ago in an editorial in Circulation.1 A large number of experimental studies have been published since then, and it appears that an evaluation of the results is necessary.Response by Schiattarella and Hill on p 1457Many studies showed a beneficial effect of hypertrophy blockade. However, some studies showed the opposite. Before reviewing them in detail, we rapidly present the evolution over time of the concept of adaptive hypertrophy that varied during the last 30 years. This reminds us of some important elements of the previous facts and interpretations that were forgotten as new ones appeared. This also allows understanding of why inhibition of hypertrophy, per se, may not be the best therapeutic strategy in the management of pressure overload–induced hypertrophy.Evolution of the Concept of Physiological Versus Pathological HypertrophyOne of the first complete reports of the initiation and evolution of the hypertrophic process toward heart failure was that of Meerson2 in 1969. In this long-lasting view, a defect in the left ventricle (LV) is immediately followed by a phase he called hyperfunction, during which hypertrophy develops, that lasts from a few days to some weeks. A stable hypertrophy phase follows. It is designated as the compensatory phase, because no sign of hemodynamic failure is usually observed. This can be followed by a decompensation phase leading to heart failure.In line with this scheme, the adaptation of the whole ventricle to an increased afterload was described as a normalization of wall stress through an increased wall thickness induced by hypertrophy3 (Figure 1). In parallel to this interpretation, biochemical modifications appearing in the hypertrophied LV were considered as beneficial through an economy of energy4 via a myosin isozyme shift leading to a decreased ATPase activity that had been described a few years before.5 This was the first description of the more general picture of ventricular adaptation to cardiac overload through a re-expression of the fetal phenotype (see a more recent review by Swynghedauw6). The question that arose was: what is (are) the mechanism(s) that trigger(s) the transition to heart failure? The proteins involved in the excitation-contraction process seemed to be good candidates.7,8 Because ATP is absolutely required to fuel normal contractile function, an energy starvation has been suspected as the cause of heart failure.97,8 Other factors have been shown to play a role in the transition to heart failure, such as proteins of the cytoskeleton,10 but no definite answer has emerged.Download figureDownload PowerPointFigure 1. Basis of the stress hypothesis of ventricular adaptation to pressure overload. The general shape of the pressure-volume and stress-strain lines was freely drawn using the calculated loops that we generated in dogs,45 with the mean values of diameter, pressure, and stress given in the references quoted below. A, Schematic representation of the pressure-diameter relations obtained in vivo in chronically instrumented closed-chest dogs.3 Pressure-diameter loops were performed by inflating an aortic cuff. An acute aortic stenosis was produced (dark solid lines). The end-systolic pressure-diameter (ESPD) relation was described. Two weeks after constriction, its release allowed the description of a new ESPD relation (light solid lines). There was a ventricular hyperfunction as shown by a leftward shift of the ESPD relation produced by an increased diameter shortening for the same systolic pressure as in the immediate pressure increase. B, Calculated end-systolic stress-strain relations of the above ESPD relations. The increase in wall thickness obtained by left ventricle (LV) hypertrophy allowed a normalization of the end-systolic stress for an increased end-systolic pressure. Lines obtained immediately after aortic stenosis and those obtained 14 days later were superimposed, showing the absence of an increased inotropic state. Thus, the increased wall thickness induced by hypertrophy allows for obtaining a normal ejection without an increase in inotropic state through a normalized wall stress. C, In contrast, when these relations were studied early (24 hours) after cuff inflation,45 an increased inotropic state was demonstrated, because normal shortening was obtained for a larger wall stress. This produced a leftward shift of the end-systolic stress-strain relation compared with the immediate cuff inflation.A major turn in the interpretation of the concept of hypertrophy as an adaptive mechanism appeared with the publication of the article by Levy et al11 in 1990. Based on a population analysis of the Framingham Heart Study, it was demonstrated that an increase in LV mass predicted a higher incidence of clinical events, including death, attributable to cardiovascular disease. LV mass appeared as prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors.11 In line with this concept, pharmacological interventions or studies in transgenic animals12,13 challenged the concept of hypertrophy as an adaptive mechanism. It was put forward that not only was ventricular hypertrophy not necessary for adaptation to ventricular overload, but even more it was identified as a pathological process associated with an increased cardiovascular risk. However, it was also recognized that some ventricular hypertrophies, such as those observed during pregnancy or exercise training, were not pathological, because they did not lead to heart failure. These hypertrophies were called physiological hypertrophy, as opposed to pathological hypertrophy14 induced by pressure or volume overload of the LV.14 The opposition between pathological and physiological hypertrophy was also based on gross and microscopic anatomy. In concentric LV hypertrophy, mostly induced by pressure overloads, cardiomyocytes only grow in a transverse direction while keeping cell length constant (asymmetrical hypertrophy).15 In contrast, in response to exercise, for instance, cardiomyocytes grow proportionally in both longitudinal and transverse directions (symmetrical hypertrophy).Pathological hypertrophy is considered to be associated with a depressed cardiac function and with an absence of reversal of cardiac remodeling when the overload is treated. The development of left ventricular assist devices that are used in the final phase of heart failure show that, even at that stage, a myocardial recovery may be observed when ventricular stress is decreased. It is called reverse remodeling, supporting the notion that, in contrast with the present opinion, the regression of pathological hypertrophy is possible in humans.16The involvement of a number of receptors and pathways has been described. As reviewed recently,17 they include mechanical stretch, adrenergic receptors, growth factors, angiotensin receptors, cytokines, and all of the intracellular pathways among them, including protein kinase A, protein kinase C, calcineurin, phosphoinositide kinase 3-Akt, and transcription factors. Two of them have been described as differently activated in physiological and pathological hypertrophies: phosphoinositide kinase-3 and calcineurin. Studies of the phosphoinositide kinase-3 pathway are in favor of a protective role of phosphoinositide kinase-3 during the development of hypertrophy,18,19 whereas calcineurin is shown to have deleterious effects during the hypertrophy process and to be associated with its pathological form, particularly in response to pressure overload.14,20The concept of pathological hypertrophy triggered the hypothesis that hypertrophy blockade could be associated with a preservation of ventricular function and that blocking hypertrophy could be a good therapeutic strategy.1 A number of articles indeed showed a beneficial effect of hypertrophy development blockade, but some articles showed the opposite. The goal of the present review is to critically review these articles and to examine whether other approaches in the management of hypertrophy development would be more appropriate.Is the Prevention of Hypertrophy Induced by Pressure Overload Beneficial?The pioneer studies by Akhter et al12 and Sussman et al13 showed that hypertrophy blockade could prevent ventricular dilatation and histological signs of the diseases, but ventricular function and survival were not evaluated. Ventricular function was measured in all of the ensuing studies listed in Table 1. Calcineurin was the target in many studies,13,21–24 but inhibition of other receptors or pathways was shown to be able to block hypertrophy without affecting ventricular function or even improving it. This was the case for many pathways involved in the hypertrophy process, such as the inhibition of stress-activated-protein kinase,25 angiotensin receptor type 2,26 gp130 (a common receptor for the interleukin 6 family),20 Gq protein,12,27 and histone deacetylase,28 as well as overexpression of c-flip (a modulator of Fas),29 activation of p21-activated kinase 1 (a natural inhibitor of small GTPases),30 inhibition of mTORC1,31 and recently inhibition32,33 or activation34 of different microRNAs (Table 1). It was also proposed that nuclear-targeted Akt or Pim-1 overexpression can be antihypertrophic and adaptive at the same time by promoting a hypercellular phenotype in mice.35Table 1. Inhibition of Hypertrophy Without Detrimental EffectsModelInterventionHypertrophyCardiac FunctionSurvivalAuthorsAbdominal AS in mice (3 wk), GMDN gp13040% in WT15% in TGFS unchanged in WT and TGNDUozumi et al20Abdominal AS in mice (10 wk), GMAT2 deletion≈60% in WTBlunted in GMSmall decrease (NS) in WTUnchanged in GMNDSenbonmatsu et al26TAC in mice (5 wk)Csa45% in NTBlunted in treatedNot significantly decreased in both groupsSimilar mortality in both groupsHill et al23TAC in TG mice (3 mo) GMDN MCIP170% in NT40% in DNFS maintained in GM and NTNot different in both groupsHill et al24TAC in mice(4 and 8 wk), GMTgGqIDbh–/–Decreased hypertrophy in both GM mice strainsWT: 40% decreased FS and dilatationTG: maintained function without dilatationNot different postoperativelyNo LT survival studiedEsposito et al27TAC in TG mice (2 wk)c-flip overexpress(modul of Fas)35% in WTBlunted in TGFS NS before and after TAC in both groupsNDGianpietri et al29TAC in mice(3 and 9 wk)Pharmacological HDAC inhibitionHypertrophy partially inhibited in treated (values only in figures)No statistical change in FS in both groups but decreased ESPVR in NT not in treatedshift V1 V3 preventedSurvival identical in both groupsKong et al28TAC in mice (5 wk), GMPak 1 (p21-activated kinase1)KO increases hypertrophyActivation inhibits hypertrophyNo change in FS in WT after 5-wk TAC and with Pak-1 activationDecreased function in KO with fibrosisNDLiuet al30TAC in mice with specific antagomir(3 and 6 wk)miRNA-199bInhibition and reversion of hypertrophy and fibrosisFS decreased in NTFS restored with antagomirNDMartins et al32TAC in mice (3 wk), GMmiRNA 212-132Partial inhibition of hypertrophyFS decreased in NTFS restored with antagomirNDUcar et al33Gene delivery in ascendic AS mice (9 wk)miRNA-1 gene deliveryDecreased hypertrophy7 wk after gene transferFS decreased in NTFS not different from sham in treated miceNDKarakikes et al34Gene transfer in TAC mice (4 wk)PRAS40 gene deliveryPartial inhibition of hypertrophy in treated miceEF decreased in shamEF preserved in treatedNDVölkers et al31The abbreviation of specific genes is given in the text. AS indicates aortic stenosis; Csa, cyclosporine; DN, dominant negative; EF, ejection fraction; ESPVR, end-systolic pressure-volume relation; FS, fractional shortening; GM, genetically modified; HF, heart failure; ND, not determined; TAC, transverse aortic constriction; TG, transgenic; and WT, wild-type.Some articles conversely showed that hypertrophy blockade may be detrimental (Table 2). Some studies used calcineurin blockade. In contrast with the studies presented in Table 1, a detrimental effect of calcineurin inhibition during hypertrophy development was demonstrated.36–38 Other gene inhibitions or deletions have also been shown to be deleterious.39,40 Although their numbers are much smaller than those presented in Table 1, they open a number a questions that need to be answered before reaching the conclusion that hypertrophy blockade could be beneficial in patients. We examine first the possible limitations of these studies.Table 2. Inhibition of Hypertrophy With Detrimental EffectsModelInhibitionHypertrophyFunctionSurvivalAuthorTAC in TG mice, 7 dRGS4 overexpressionReducedNo fetal gene program induction in TGAggravated and rapid decompensation in TGIncreased postoperative mortality in TG with tight TACRogers et al40TAC in WT mice, 3 wkCsaBluntedDecreased ventricular function and increased HF in treated miceIncreased mortality in treated miceMeguro et al38TAC in WT mice, graded response 21 dCsa or MCIP1ReducedNDIncreased mortality for severe stenosis with CsaRothermel et al37TAC in mice, 4 wk, GMMelusin gene deletionHypertrophy post TAC in WTReduced in KONormal FS in WTDecreased FS and dilatation and HF in KOIncreased mortalityBrancaccio et al39TAC in rats, 20 wkSex differenceMore hypertrophy in femalesDecreased function in maleNDDouglas et al48TAC in rats, 20 wkSex differenceMore hypertrophy in femalesDecreased function in maleNDLoyer et al49TACCalcineurinBluntedDiastolic abnormalitiesNDGelpi et al36The abbreviation of specific genes is given in the text. Csa indicates cyclosporine; FS, fractional shortening; GM, genetically modified; HF, heart failure; MI, myocardial infarction; ND, not determined; TAC, transverse aortic constriction; TG, transgenic; and WT, wild-type.Limitations of These StudiesModelThe first remark applies to the experimental models. Most studies use abrupt transverse aortic stenosis (TAC) for a few weeks in mice. Whether TAC accurately reflects human pathology is open to doubt. Moreover, very tight TAC can induce subendocardial ischemia, which can lead to cell death and failure from that mechanism. This also occurs in the clinical setting during the transition to heart failure, but, at that phase, the myocardium is already hypertrophied so that studies of the effect of hypertrophy blockade in the initial phase of its development may not apply to clinical situations. The specific role of TAC is shown by the study of melusin-null mice. In this model, hypertrophy was blocked after TAC and this was detrimental.39 In contrast, the hypertrophic response was identical in wild-type and melusin-null mice after chronic administration of angiotensin II or phenylephrine.There are other examples showing that a positive result in a model of hypertrophy may not be applicable to others. In a first series of articles, Senbonmatsu et al26 and Ichihara et al41 showed a beneficial role for angiotensin receptor type 2 receptor blockade that inhibited hypertrophy after pressure overload or chronic angiotensin infusion with a negligible amount of fibrosis and a preserved ventricular function (Table 1). However, in a further study, the same group42 presented data showing, in another model of overload (myocardial infarction), that targeted deletion of angiotensin receptor type 2 caused cardiac rupture. This indicates that, although fibrosis is a detrimental factor, some amount of fibrotic tissue may be necessary to protect a LV submitted to a large overload when myocardial ischemia is present.The role of the intensity of the overload is illustrated in different studies. Fibroblast specific deletion of a transcription factor (Kfl5) was shown to produce 2 opposite effects (beneficial or detrimental) depending on the intensity of the stimulus of hypertrophy.43 Similarly, hypertrophy development blockade by calcineurin inhibition was described as having a beneficial effect after TAC23 (Table 1), but 2 other studies in the same models showed that it was detrimental. It is likely that a higher degree of overload was responsible for the higher mortality rate during cyclosporin A treatment.37 It could be an explanation for the finding of a detrimental effect of calcineurin blockade during the development of hypertrophy37 published by Meguro et al38 in contrast with the beneficial effect presented by Hill et al.23Although this model does not reflect the clinical setting, no model can be proposed to completely mimic human pathology, which includes many types of etiologies with many associated disorders (hypertension, senescence, diabetes mellitus, etc). However, each model can answer a specific question. For instance, intermittent TAC,44 which induces a mild hypertrophy in contrast with permanent TAC, has been used to show the importance of the growth signaling and not hypertrophy development as the trigger of cardiac dysfunction. Problems may appear when the conclusions obtained with a specific model are generalized.Long-Term SurvivalAnother important limitation of the studies presented in the tables is the absence of systematic evaluation of survival that must be addressed in clinical trials. Survival was evaluated in only 4 of the studies presented in Table 1.23,24,27,28 In general, the duration of the study was short except in one28 lasting 9 weeks that the authors considered to be equivalent to 10 years in humans.28 In all of the studies, however, the number of animals was small and the survival rate was high in the control group (>70%), with most deaths appearing in the early postoperative period without progressive mortality during the evolution of the disease. Survival was not evaluated in cohorts with a high mortality rate in the control arm to determine whether hypertrophy blockade is beneficial or detrimental in this condition, which is closer to heart failure observed clinically. In contrast, some studies (Table 2) showed an increased mortality when the hypertrophy process was inhibited. A possible mechanism for this increased mortality is the role of inotropic stimulation necessary to maintain cardiac function when the myocardium is submitted to an increase in afterload and is not allowed to hypertrophy.Inotropic StateBasic principles of cardiac mechanics indicate that an increased inotropic state is necessary to maintain ventricular function when wall stress is increased without compensatory hypertrophy (Figure 1). This was shown in the study by Esposito et al27 in which, 7 days after TAC, a clear increase in inotropic state was demonstrated by a precise measurement of the stress-strain relations when hypertrophy development was blocked. This response is similar to the transient (24 hours after stenosis) increase in inotropic state we showed in dogs with pressure overload45 (Figure 1). In the study by Esposito et al,27 LV function was shown to be maintained 8 weeks after TAC in mice without hypertrophy, in contrast with wild-type mice that exhibited ventricular dilatation and decreased function. An increase in inotropic state may have protected mice with a very severe TAC that otherwise would have presented a vicious cycle of decreased ventricular function, in turn decreasing ventricular perfusion. However, a generalized beneficial effect of increased inotropic state can be questioned. As noted previously, this study was performed in the model of TAC in which a severe stenosis induces subendocardial ischemia. Long-term survival studies have not been performed in less abrupt overloads. It is well known that randomized clinical trials in patients with heart failure demonstrated that, although positive inotropic agents had beneficial effects on the hemodynamic status of patients with acute heart failure, a detrimental effect of chronic inotropic stimulation on survival appeared using positive β-adrenergic agents or inhibitors of phosphodiesterases.46,47 This is the reason why these agents are no longer used for treating chronic heart failure. LV function preservation during the blockade of hypertrophy is associated with a natural increase in inotropic state that resembles treatments with inotropic agents. It remains to be established whether, in other models with a less abrupt initiation of pressure overload, longer durations of surveys, such as those performed in large clinical trials, would demonstrate a beneficial effect of hypertrophy blockade.SexAs shown in Table 2, in response to TAC the degree of hypertrophy is larger in females than in males, with a smaller decrease in ventricular function in females.48,49 Thus, in female rats submitted to TAC, hypertrophy development is associated with a better ventricular function. However, it is impossible to date to determine whether hypertrophy is beneficial or not in female patients. In, human heart failure the role of sex differences is complex because the risk factors and the etiologies of heart failure are different (more hypertension and diabetes mellitus in women and more coronary artery disease in men).50 Although there are conflicting results, it is generally considered that ventricular function is less decreased in women because they develop heart failure with preserved ejection fraction.51 In that respect, it is interesting to note that no study was directed toward heart failure with preserved ejection fraction, which is a more recently identified entity. No experimental model exists thus far. It is possible that, in the future, more cases of evolution of pure aortic stenosis toward heart failure with preserved systolic function will be recognized, and the conclusions about the possible advantages of treating hypertrophy versus not treating hypertrophy might change.Thus, although many studies underline a beneficial effect of hypertrophy blockade on ventricular function in pressure overload hypertrophy, a number of issues need to be examined before it can be concluded that it is a good therapeutic strategy, particularly the major end point, survival, remains to be evaluated in large trials as in a clinical situation with different etiologies and different associated pathologies. In that respect, it can be noted that all of the experimental studies were performed in permanently resting animals. The adaptation to a normal life with exercise of animals for which hypertrophy has been blocked is completely unknown.In spite of these limitations, it remains established that hypertrophy is a cardiovascular risk factor. Blocking its development may thus appear as an obvious strategy by the search for deleterious intracellular signal transduction pathways. However, ventricles are not constituted only of cardiomyocytes. The next section examines other possible factors that could be involved in the deleterious effects of hypertrophy. This could open new therapeutic options in the management of hypertrophy development.Hypertrophy as a Cardiovascular Risk Factor: Possibly Involved FactorsMalignant ventricular arrhythmias are considered responsible for the high incidence of sudden death in patients with aortic stenosis52 and thus contribute to make ventricular hypertrophy a cardiovascular risk factor. It is beyond the scope of this review to discuss in detail the mechanisms of ventricular arrhythmias in pressure overload. The review will evaluate the possible roles of 3 factors.Myocardial PerfusionWhen myocardial energetic demand of dogs with LV hypertrophy is increased by pacing, a subendocardial coronary perfusion deficit appears.53 The same abnormality was described during exercise54,55 in a pressure overload model produced by aortic banding in puppies. This was attributed to a reduced subendocardial coronary reserve related in part to the larger compressive forces in the subendocardium where stress is larger. A vicious cycle can thus be initiated, in which an increased subendocardial stress present in severe hypertrophies produces a subendocardial exhaustion of blood flow reserve leading to subendocardial ischemia and increased fibrosis, aggravating heart failure.56Other than these effects of compressive forces on the intramyocardial coronary vessels, vascular growth may be abnormal during myocardial growth. As reviewed long ago by Anversa et al,57 structural factors that are modified during cardiac hypertrophy include capillary luminal volume density, capillary luminal surface density, and the average diffusion distance for oxygen. During maturation, a well-balanced growth was observed, because capillary microvasculature and myocytes grow in proportion to the increase in cardiac mass. In contrast, when pressure- or volume-overloaded hearts were examined, all 3 of the aforementioned parameters were altered, showing an inadequate growth adaptation of the component structures responsible for tissue oxygenation. It was thus concluded that this myocardial enlargement might increase its vulnerability to ischemia.57In patients, the presence of signs suggestive of myocardial ischemia despite normal coronary angiograms is a relatively frequent finding that has been called coronary microvascular dysfunction.58 It may be explained by the same abnormalities as those described in experimental animals: inadequate vascular growth during hypertrophy and compressive forces.The role of a nonparallel growth of myocytes and vasculature has been shown in a model of conditional transgenic mice with a sequential development of hypertrophy.59 Both heart size and cardiac function were shown to be angiogenesis dependent, and disruption of coordinated cardiac hypertrophy and angiogenesis appeared as contributing to the transition to heart failure. This finding is a major example of possible therapeutic strategies that could be directed toward a recoordination of tissue growth and angiogenesis during some sequences of the development of hypertrophy rather than trying to block hypertrophy, per se. Any other approach aimed at improving cardiomyocyte homeostasis will improve function and decrease hypertrophy (see, eg, dietary copper supplementation60 or genetic conditional ablation of fibronectin.)61FibrosisOther than cardiomyocytes, the myocardium is composed of arteries, fibroblasts, and extracellular matrix. Fibrosis increases with hypertrophy. It is no longer proportional to ventricular mass when hypertrophy is large, reaching ≈30% of the ventricular weight.62The development of fibrosis may be a cause of ventricular dysadaptation. Collagen deposition increases during the development of pressure overload and correlates with diastolic and systolic abnormalities in mice with pressure overload.63 The absence of a complete recovery of ventricular function after aortic valve replacement in patients correlates with the degree of fibrosis in aortic stenosis.64,65 However, the presence of fibrosis was not found only in pathological hypertrophy but also in strenuous prolonged exercise training, particularly in older athletes.66 Fibrosis is thus a detrimental factor both in pathological and physiological hypertrophies, with inadequate coronary perfusion playing a role in its development54 and suggesting that the intensity and the duration of the overload more than its type are responsible for the appearance of fibrosis.Nevertheless, fibrosis is not purely detrimental. As discussed above, fibrosis is sometimes necessary for survival after acute myocardial infarction,42 and a cross-talk between fibroblasts and cardiomyocytes can modulate cardiac remodeling.43 This suggests a possible therapeutic approach directed toward modulation of fibroblast function and interaction with cardiomyocytes.Cellular Architecture and EnergeticsAdult cardiomyocytes exhibit a sophisticated subcellular architecture in which large mitochondria are strictly ordered between rows of contractile proteins and are specifically arranged with the sar
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