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INVITED REVIEW
3Donald W. Reynolds Cardiovascular Clinical Research Center and the Departments of 1Internal Medicine and 2Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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ABSTRACT |
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 TOP ABSTRACT A CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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congestive heart failure; eccentric hypertrophy; concentric hypertrophy; systolic dysfunction
Hypertension is the most important antecedent risk factor for development of heart failure (42). The prevailing paradigm of hypertensive heart disease is that it first leads to concentric ventricular hypertrophy, followed by the development of ventricular dilation and contractile impairment with systolic dysfunction and a reduced left ventricular (LV) ejection fraction (EF) (23). Supporting this paradigm are numerous epidemiological studies, starting with the Framingham Heart Study, that have demonstrated an association between ventricular hypertrophy and elevated risk of developing clinical heart failure. Additionally, patients with aortic stenosis (30) and some with familial hypertrophic cardiomyopathy (FHC) (71) progress through this transition from hypertrophy to failure. Finally, a wealth of data gathered from animal models demonstrates that the same stress-responsive pathways that induce ventricular growth often lead to systolic dysfunction, ventricular dilation, and a syndrome compatible with clinical heart failure.
The picture is clouded by the fact that conditions that predispose to hypertrophy (e.g., hypertension) also predispose to other forms of heart disease (e.g., coronary artery disease) that can in turn lead to heart failure. The relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. Despite the above evidence, we (18, 60) recently have begun to question whether concentric LV hypertrophy (LVH) is a common precursor to the development of systolic dysfunction.
In this article, we review the clinical literature and highlight pertinent basic research studies aimed at determining the role of hypertrophic transformation of the myocardium in the development of systolic dysfunction. Is LVH a pathogenic step in the development of systolic heart failure (Fig. 1A) ? Is LVH an associated, but causally unrelated, phenomenon that develops as a result of other factors, such as hypertension (Fig. 1B)? Does LVH play a protective role in the setting of other forces that cause heart failure (Fig. 1C)?
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A CLINICAL CASE |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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10 min. He was diagnosed with hypertension 20 years ago and was currently taking three antihypertensive medications. He had never smoked, consumed alcohol, or used recreational drugs. He was moderately active physically, working as a mail carrier. His father had a fatal myocardial infarction at age 57.
On examination, he was tachycardic, tachypneic, and hypertensive (blood pressure 156/100 mmHg). The neck veins were mildly distended at 12 cm, and rales were noted at both lung bases. Heart tones were normal except for a soft third heart sound. Trace peripheral edema was present.
An ECG revealed normal sinus rhythm, left axis deviation, voltage criteria for ventricular hypertrophy, and "strain pattern" ST-T wave abnormalities. Chest roentgenography revealed interstitial edema and Kerley B lines. Echocardiography revealed ventricular hypertrophy, ventricular dilation, and a moderately depressed EF. Coronary angiography revealed no evidence of significant epicardial coronary artery disease.
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THE CLINICAL PROBLEM |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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The scope of the problem is significant. LVH is common. Its prevalence in the predominantly white Framingham population was 16% in men and 19% in women (43). In African Americans, the prevalence of LVH is even higher (35). If LVH is mechanistically linked to the development of systolic dysfunction, it contributes to a major health issue that may warrant screening measures and further investigation of therapeutic strategies (21). Despite many years of clinical experience and a great deal of scientific investigation, we know surprisingly little about the relationship between hypertrophic transformation of the heart and often-associated systolic failure. Does ventricular hypertrophy progress to systolic heart failure?
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HYPERTROPHIC REMODELING OF THE MYOCARDIUM |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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Classically, hypertrophic growth of the heart has been divided into three morphological patterns (25): concentric remodeling (increase in relative wall thickness but with normal cardiac mass), concentric hypertrophy (increase in relative wall thickness and cardiac mass with little or no change in chamber volume), and eccentric hypertrophy (increase in cardiac mass with increased chamber volume; relative wall thickness may be normal, decreased, or increased.
Estimates of cardiac mass and morphology are dependent on the techniques used to measure them and may vary from study to study. In many clinical studies, LV mass has been measured with M-mode echocardiography. With this approach, LV mass is calculated based on a formula that takes into consideration the LV diameter at end diastole as well as the thickness of the LV walls (12). Therefore, increased LV diastolic diameter (ventricular dilation) will increase the estimate of mass even in the presence of wall thinning. MRI is a newer modality to assess ventricular mass, and recent data suggest that MRI-derived estimates of ventricular mass are lower—and more accurate—than those derived by echocardiography (4, 66).
The pathophysiological implications of a transition from normal to decreased systolic function are different depending on whether the ventricle was originally dilated or thickened. Whereas some studies have suggested that knowledge of ventricular geometry offers little additional information beyond measuring ventricular mass (38, 78), the importance of LV geometry specifically in relation to systolic heart failure was not addressed. Indeed, subtle systolic dysfunction has been reported in a significant number of patients with concentric remodeling (63, 77); however, patients with eccentric hypertrophy manifest more severe systolic dysfunction (11). Eccentric hypertrophy was also associated with worse systolic function in a subgroup of the Losartan Intervention for Endpoint (LIFE) study (80), findings consistent with epidemiological data linking LV dilation and development of heart failure (76). Increases in LV chamber diameter often precede heart failure in animal models of pressure overload (45). Thus we would argue that the extent to which LVH can be considered a risk factor for development of systolic dysfunction depends on whether it is concentric or eccentric, with eccentric LVH posing the greater risk.
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ADAPTIVE ROLE OF LVH: A HISTORICAL PERSPECTIVE |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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Working with animal models of pressure overload during the 1960s, Meerson provided evidence that biomechanical stress-induced cardiac hypertrophy plays a protective role, at least in the short term. After an initial, transient phase of load-induced heart failure, hypertrophy develops and systolic performance normalizes (48). Meerson (48) further argued that after a period of stable hypertrophy, progressive ventricular dilation and failure develop in association with cell death and fibrosis.
The concept of adaptive hypertrophic growth gained support in the 1970s and 1980s based on hemodynamic measurements in patients with valvular heart disease. Laplace's law dictates that afterload-induced increases in systolic wall stress are offset by increases in wall thickness (26). Gunther and Grossman (27) demonstrated correlation between increased wall stress and the presence of systolic dysfunction in patients with aortic stenosis and heart failure. These investigators concluded that when hypertrophy is "inadequate" it fails to normalize wall stress and systolic dysfunction develops (27). In a larger study, however, Huber et al. (33) found that the degree of hypertrophy was a stronger determinant of contractile dysfunction than wall stress. Even in patients with normal wall stress (i.e., "adequate hypertrophy"), higher LV mass was associated with worse LV systolic function (33, 37).
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HUMAN DATA |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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Despite the concordance of these findings, several caveats pertain. First, although EF is technically easy to measure, and hence frequently used as a surrogate for systolic function, it is not a true measure of intrinsic contractility because it varies with myocardial loading conditions. Additionally, EF overestimates contractility in the setting of hypertrophy due to changes in LV geometry during contraction (6, 70). To overcome these limitations, other sensitive, noninvasive measures of systolic performance have been developed, although their complexity has largely limited their use to research applications. One such method is midwall fractional shortening (MWFS) (10, 69, 70). This method detects subtle systolic dysfunction by evaluating movement of the midsection of the LV wall during systole (as opposed to tracking movement of the endocardium). With this more sophisticated measure of systolic function in hypertensive patients with LVH, subtle decreases in LV contractility can be detected even in the early stages of hypertrophy (10, 58, 80).
However, it is important to recognize that association of LVH with either depressed EF or abnormal MWFS does not necessarily imply a causal relation. From cross-sectional data such as these, it is entirely unclear whether increased LV mass leads to systolic dysfunction or whether increased LV mass develops as a result of systolic dysfunction. To address these questions, longitudinal studies are necessary.
Longitudinal cohort studies. The landmark Framingham Heart Study provided evidence for association between LVH and subsequent development of clinical heart failure. In 1987, Kannel and colleagues (34) reported that subjects with ECG-documented LVH and associated repolarization abnormalities were at two- to fivefold increased risk of developing heart failure. This association held in both genders and in all age groups. Subsequently, the Framingham Heart Study reported that echocardiographic LVH was a risk factor for the development of a composite end point of adverse cardiovascular events, viz., heart failure, atherosclerotic cardiovascular disease, transient ischemic attack, and stroke (41). In both studies, the diagnosis of heart failure was adjudicated on clinical grounds, e.g., based on the presence of a third heart sound or jugular venous distension (34).
Caution is warranted, however, in interpreting these and other studies that rely either on electrocardiographic measures of LVH or on clinical definitions of heart failure. First, ECG recordings do not distinguish between eccentric and concentric hypertrophy, and this difference is likely to be relevant (see above). Second, because heart failure was diagnosed on clinical grounds, it is not known whether it occurred in the setting of a normal or reduced LVEF. Because concentric LVH is associated with diastolic dysfunction, which itself is a common cause of heart failure (85), such studies do not clarify whether concentric hypertrophy is a common precursor to systolic dysfunction.
Recently, in an analysis of the Cardiovascular Health Study, we (M. H. Drazner) found that echocardiographically documented LVH was associated with development of depressed EF after 5 years of follow-up in subjects with a normal EF at baseline. However, in that cohort of predominantly elderly white individuals, eccentric hypertrophy—but not concentric hypertrophy—was shown to be a risk factor for development of a low EF (18). In a second report (60), we studied 159 predominantly African American subjects with concentric echocardiographic LVH (mean age 56 yr) and normal LVEF. After a mean follow-up of 4 years, only 18% progressed to a low EF. Furthermore, interval myocardial infarction and baseline coronary artery disease were powerful risk factors for the transition to a low EF, suggesting that concentric hypertrophy in the absence of coronary artery disease may not frequently lead to systolic dysfunction over this time frame.
Clinical trials. Additional data regarding whether LVH leads to systolic dysfunction come from trials that assessed the impact of LV mass regression on systolic function. Effective treatment of hypertension leads to regression of LVH, and a few studies have documented improvement in systolic function. For example, in separate studies of 152 and 508 hypertensive patients, decreases in LV mass index were associated with improvement in systolic function measured by MWFS (59, 84). Similar results were reported in a subgroup of LIFE: decreased LV mass in 679 hypertensive patients treated with an angiotensin II receptor blocker was associated with improved MWFS and increased stroke volume (79). Clinical outcomes were improved in those patients enrolled in LIFE whose LVH regressed on treatment, independent of blood pressure or type of antihypertensive therapy (14, 55). In the Heart Outcomes Prevention Evaluation (HOPE) study, treatment with ramipril was associated with a 22% reduction in absolute risk of developing heart failure (3).
Summary of data in humans. In aggregate, then, the available epidemiological data reveal an association between the presence of increased LV mass and/or LVH and systolic dysfunction (10, 11, 13, 58, 80). Clinical trial data document improvement in systolic function in concert with regression of LVH (3, 59, 79, 84). Both hypertension (42) and echocardiographic LVH are associated with development of clinical heart failure (34), and eccentric, but not concentric, hypertrophy on echocardiography is associated with a subsequent decrease in EF in elderly individuals (18). Most other cohort studies that have addressed echocardiographic LVH as a risk factor for heart failure did not evaluate systolic function when heart failure developed or did not distinguish eccentric vs. concentric hypertrophy at baseline. As a result, it remains unclear whether concentric hypertrophy is a common, intermediate phenotype before development of systolic dysfunction in humans. Indeed, limited, short-term follow-up data in patients with hypertension-related concentric hypertrophy and normal EF suggest that few develop a reduced EF, especially in the absence of coronary artery disease or interval myocardial infarction (60). Given the paucity of definitive evidence from patient-oriented research, it is relevant to review experimental findings from animal studies that address this question.
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ANIMAL MODELS OF PRESSURE STRESS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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One study in dogs suggested that lower LV mass before aortic constriction predicts development of systolic dysfunction, implying that LVH might be a protective adaptation (36). Studies using sophisticated hemodynamic techniques in dogs and mice subjected to aortic banding produced results similar to those described by Meerson: LV systolic function declines acutely after aortic banding, with recovery of function after development of hypertrophy, suggesting adaptive benefit of LVH (52, 73).
More recent animal studies, however, have called into question the notion that pressure-overload hypertrophy is adaptive and protective (recently reviewed in Ref. 21). During the past 10 years, enormous strides have been made in deciphering mechanisms that underlie pathological growth of the heart. As a result, it has become possible to interrupt signaling pathways at critical nodal points and, in many instances, abolish hypertrophic growth. Often, attenuation or elimination of hypertrophy in the face of pressure stress is surprisingly well tolerated; evidence of ventricular dilation or decompensation is not seen. These studies suggest that, under certain circumstances, pressure overload-induced hypertrophy is not required to maintain systolic function (21).
It is important to note, however, that acute increases in pressure stress induced by experimental aortic banding may not translate to chronic conditions such as hypertension in humans. In addition, criteria for diagnosing cardiac hypertrophy in animal research are not well established; the contributions to heart mass of myocyte hyperplasia, cellular infiltration, myocyte loss, tissue fibrosis, and edema are unclear in most studies.
Thus, under experimental conditions of acute pressure stress, ventricular hypertrophy develops and failure often ensues. Contrary to the notion that pressure-overload hypertrophy is compensatory, suppression of hypertrophic growth is often not detrimental—and may even be protective—in preventing progressive pathological remodeling of the heart.
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HYPERTROPHY AND FAILURE: COMMON MOLECULAR PATHWAYS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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Numerous intracellular signaling pathways have been implicated in the regulation of hypertrophic growth, a topic that has been reviewed recently (22). Importantly, recent studies have demonstrated commonality between signal transduction pathways that induce hypertrophy and failure. For example, dysregulation of Ca2+ handling is thought to be a critical early step in the induction of hypertrophy (7). Both the protein phosphatase calcineurin and the protein kinase Ca2+/calmodulin-dependent protein kinase (CaMK) are activated by an elevation in intracellular Ca2+ levels, and activation of either of these enzymes has been shown to contribute to hypertrophy. Transgenic animals with persistent activation of calcineurin in the heart initially develop hypertrophy that progresses to decompensation and failure (50). Calcineurin activity in the mouse heart increases in response to pressure overload or myocardial infarction (83). Calcineurin is activated in patients with aortic stenosis, ventricular hypertrophy, and normal systolic function (61), as well as in patients with heart failure (44, 75). Targeted inhibition of calcineurin blunts hypertrophy without deleterious consequences and improves survival after myocardial infarction (21). These findings suggest that calcineurin activation can lead to both hypertrophy and heart failure and that targeted inhibition of this molecular signal may be a viable therapeutic strategy (15, 29).
Experiments using transgenic mice have also demonstrated that signaling pathways activated by the release of neurohumoral factors can lead either to cardiac hypertrophy or to failure, depending on the extent of activation. An excellent case in point is the Gq/G11 class of heterotrimeric GTP-binding G proteins through which many membrane receptors signal. When phenylephrine, ET-1, or angiotensin II binds to its cognate receptor, G
q is released as a second messenger. In transgenic mice, cardiomyocyte overexpression of Gq induces cardiac hypertrophy or failure depending on the level of expression (8). Whereas twofold overexpression of Gq has no deleterious effect on function, a fourfold increase causes hypertrophy with decreased systolic function and an eightfold increase in expression induces heart failure (8). Furthermore, animals with either cardiac-specific deletion of Gq (82) or disruption of its function in heart (1) manifest a blunted hypertrophic response to pressure stress. These studies demonstrate that Gq signaling is a common molecular pathway in both hypertrophy and failure.
Thus a large body of evidence from animal studies demonstrates that hypertrophy, initiated either by pressure stress or by activation of key intracellular regulators, can progress directly to systolic dysfunction and failure. However, despite tantalizing clues pointing to the commonality of pathways leading to hypertrophy and failure, there is no clear understanding of the mechanisms underlying the transition from stable hypertrophy with preserved systolic function to a state of decompensated heart failure in humans. Hypertrophic change may not be required, for example, as forced expression in the myocardium of MEK5 induces LV dilation and heart failure with no intervening hypertrophic prelude (54).
An early hypothesis held that blood supply inadequate to meet the demands of the thickened myocardium results in ischemia (24), but this theory has not been confirmed. Other potential explanations include alteration of contractile proteins (53), remodeling of the extracellular matrix with consequent fibrosis (81), and changes in activation of the 
-adrenergic pathway (5, 62). It is possible that tissue ischemia in massively hypertrophied myocytes contributes to decompensation. However, as with the clinical case presented above, heart failure often occurs without associated atherosclerotic epicardial coronary artery disease or consequent myocardial infarction. We anticipate that studies focused on understanding events that trigger the transition from hypertrophy to decompensated failure will reveal new therapeutic targets.
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POTENTIAL THERAPEUTIC TARGETS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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Handling of intracellular Ca2+ is perturbed in hypertrophy and failure and, as such, has been the focus of mechanistic and therapeutic studies for many years. Intracellular movement of Ca2+ accomplishes three critical functions within the myocyte (Fig. 3): transsarcolemmal charge movement during the action potential plateau that contributes to membrane potential and, secondarily, activation of other ion channels; second messenger signaling to numerous Ca2+-responsive enzymes, many of which participate in the regulation of hypertrophic growth; and regulation of excitation-contraction coupling.
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Much of heart failure therapy has focused on therapeutic manipulation of intracellular Ca2+ dynamics by increasing intracellular cAMP levels, either by adrenergic stimulation or by phosphodiesterase inhibition. It has become apparent, however, that this approach is associated with unequivocal, long-term mortality detriment (5). As a result, more recent research has focused on transsarcoplasmic reticular Ca2+ handling and myocyte Ca2+ sensitivity (16). For instance, sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is responsible for Ca2+ reuptake into the sarcoplasmic reticulum during diastole. This replenishes intracellular Ca2+ stores for release during systole. In heart failure, SERCA expression declines and the inhibitory activity of phospholamban on SERCA is elevated (74), and both of these maladaptive changes can be antagonized by -adrenergic blockade therapy (39).
Deletion of phospholamban in mice not only enhances systolic function (47) but can prevent heart failure when these mice are bred with transgenic models of DCM (49). These data raised interest in the potential therapeutic benefit of neutralizing phospholamban activity in chronic heart failure (9). However, identification of a nonfunctional allele for phospholamban in two families with DCM has raised concern (28, 65) and highlights the dangers of manipulating molecular pathways contributing to heart failure with incomplete knowledge of their multifaceted impact.
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LIMITATIONS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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CONCLUSIONS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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In hypertensive patients, sensitive measures of systolic performance reveal contractile dysfunction in a significant number of individuals with increased LV mass. Recent trials of antihypertensive therapy suggest that regression of hypertrophy may be linked to improvements in systolic performance and decreased incidence of clinical heart failure. Further, recent evidence from rodent models of pressure overload suggests that, at least in the short term, hypertrophy may not always be required to preserve systolic function, raising the prospect of targeted antihypertrophic therapy. To bring such therapy to fruition, additional investigation is required to determine the role of concentric hypertrophy in the pathophysiology of systolic heart failure in humans.
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GRANTS |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTA CLINICAL CASETHE CLINICAL PROBLEMHYPERTROPHIC REMODELING OF THE...ADAPTIVE ROLE OF LVH:...HUMAN DATAANIMAL MODELS OF PRESSURE...HYPERTROPHY AND FAILURE: COMMON...POTENTIAL THERAPEUTIC TARGETSLIMITATIONSCONCLUSIONSGRANTSREFERENCES |
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q overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA 94: 8121–8126, 1997.-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation 104: 1012–1018, 2001.q/G11 in cardiomyocytes. Nat Med 7: 1236–1240, 2001.[CrossRef][Web of Science][Medline]
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