The Cornucopia of “Pleiotropic” Actions of Statins: Myogenesis As a New Mechanism for Statin-Induced Benefits?

Initially described in patients with coronary artery disease undergoing coronary artery bypass graft (CABG) surgery, myocardial “hibernation” denotes a state of adaptive reduction in myocardial contractile function in response to limited energy supply due to reduced blood flow [1,2]. In this precarious equilibrium, the myocardium can remain viable for sustained periods of time (though not indefinitely), and slowly resumes contractile activity upon restoration of perfusion [2,3]. Hibernating myocardium resulting from a flow-limiting coronary artery stenosis is a common clinical entity that contributes to myocardial dysfunction in many patients with ischemic heart disease [1,2]; its clinical importance stems from the fact that is it is potentially reversible. The pathophysiological basis of this syndrome was proposed as a conceptual framework in 1992 [4] and subsequently tested in various animal models [5-8]: it is likely to involve recurrent brief episodes of ischemia, which initially result in repetitive “stunning” with normal resting flow and eventually cause a persistent decrease in resting function and flow [2,4-6,8]. Over time, these changes lead to myocyte loss due to degenerative changes and apoptosis [2,8].

Because mechanical dysfunction is caused by a restriction in blood flow, revascularization has traditionally been the cornerstone of therapy for myocardial hibernation. Indeed, restoration of blood flow via CABG or percutaneous coronary interventions often improves the mechanical performance of hibernating myocardium [1-3,8,9]. In those cases in which these procedures are not feasible, however, there is a need for alternative approaches. Direct transmyocardial laser revascularization [10] and intramyocardial gene transfer of phVEGF₁₆₅ [11] or fibroblast growth factor-5 (FGF-5) [7] have been reported to enhance perfusion and contractile reserve and improve regional function in experimental models of hibernation. Transplantation of circulating progenitor cells following revascularization has also been reported to attenuate hibernation (i.e., to increase coronary flow reserve and regional function) in patients with chronic coronary occlusion [12]. Whether the functional benefits of the above therapies result primarily from improved perfusion, however, remains controversial [7,11]. Hypertrophy and proliferation of myocytes have been suggested as alternative mechanisms whereby function of hibernating regions can be boosted [7], but unequivocal evidence that the contractile performance of hibernating regions can improve without any change in flow has heretofore been lacking.

In this issue of the journal, Suzuki and colleagues demonstrate that pravastatin can improve the contractile function of hibernating myocardium without any increase in perfusion [13]. Pigs with established hibernating myocardium due to chronic coronary stenosis received a five-week course of pravastatin, at the end of which regional myocardial function was found to be improved (global LV function remained unchanged, presumably because it was not impaired in this model) [13]. Pravastatin had no appreciable effect on either resting or maximal (during adenosine) myocardial perfusion but increased the number of progenitor cells (CD133+ and c-kit+) in the bone marrow, in the peripheral blood, and in the myocardium, suggesting mobilization of these cells from the marrow to the heart. Importantly, following pravastatin administration, the number of Ki67+ and phosphohistone H3+ myocyte nuclei increased in diseased hearts, suggesting increased myocyte cell cycle entry and proliferation, whereas in sham-operated hearts there was no increase in these markers of proliferation despite the fact that infiltration by CD133+ and c-kit+ cells was similar [13]. The authors conclude that pravastatin improved the contractile function of hibernating tissue by increasing the infiltration of bone marrow progenitor cells (BMPCs) into the myocardium and by promoting formation of new myocytes within the dysfunctional regions, with no increase in blood flow per unit of tissue.

This study [13] has many strengths that are noteworthy. First, the observations were made in an elegant, clinically relevant, and well-established swine model of chronic hibernation. Second, this study enables one to dissect the influence of statins on hibernating myocardium from the influence on heart failure because the model used does not involve global LV dysfunction and the associated neurohormonal perturbations. Third, unlike many previous experimental studies of statins that used enormous doses, the effects of pravastatin were achieved with a clinically relevant dose (160 mg/d). Since high concentrations of statins are known to inhibit angiogenesis [14], the use of this relatively low dose obviates potential untoward effects on myocardial vascularity. Fourth, Suzuki and colleagues used a large animal model and state-of-the-art methods for assessing myocardial perfusion, features that are particularly precious in this day and age when almost every experimental in vivo investigation uses rodent models of unclear relevance to human disease. The efficacy of pravastatin in a large animal preparation increases the likelihood of efficacy in humans. As we strive to translate stem/progenitor cell work into clinical strategies, it is absolutely critical that we resist the temptation to rely exclusively on the cheaper and technically easier rodent models for exploring the therapeutic utility of cell therapy in the cardiovascular system. A rational strategy for clinical translation dictates that studies in rodents be complemented by the use of large preclinical animal models that are closer to the human situation and more likely to mimic it. The current investigation provides a laudable example of the feasibility and value of such an approach.

Conceptually, the observations of Suzuki and coworkers are important because they reveal a novel, heretofore unrecognized, potential action of statins that could illuminate the effects of these drugs on the cardiovascular system. If confirmed, the fact that statins promote myogenesis would be yet another useful property of these seemingly miraculous agents that could be exploited in various settings besides hibernation. Indeed, this would constitute a major advance in our understanding of the therapeutic effects of statins.

As in all studies, there are also areas of uncertainty that will necessitate additional work. First, the association between the increased proliferative activity in the hibernating region and the improvement in function does not necessarily indicate a cause-and-effect relationship. It remains possible that function improved for reason unrelated to the increased cellularity or even to the infiltration of the myocardium by BMPCs. Second, given the remarkable functional improvement observed after only five weeks of therapy, one cannot help but wonder what the effects of pravastatin would be in the long term (such as would be the case in the clinical scenario). The answer to this question will require very complex and costly investigations. Third, as is the case in all studies of stem/progenitor cells, caution is warranted in defining a cell a “myocyte” on the basis of one or few markers of cardiac specification. Finally, the molecular/cellular mechanisms underlying the findings of Suzuki et al. remain unclear (it is obvious, however, that they could not have been elucidated in this investigation). As the authors postulate based on GATA-4 expression in CD133+ and c-kit+ cells, the cycling myocytes may be derived at least in part from BMPCs homed in the hibernating myocardium, but definitive proof of this hypothesis can only come from a chimeric model with labeled BMPCs. The activation of resident cardiac progenitor cells either by pravastatin or by homed BMPCs constitutes another possible mechanism. In either scenario, since proliferation was not observed in sham-operated hearts despite homing of CD133+ and c-kit+ cells, a chemical or mechanical signal intrinsic to the hibernating myocardium seems to be critical in triggering proliferation. Future proteomic or microarray studies should attempt to identify the molecule(s) that is responsible for driving cellular proliferation and/or differentiation.

Whether the observations of Suzuki et al. can be generalized to all statins remains to be determined. Previous studies have suggested that the effects of statins in heart failure may not entirely be a “class effect”. For example, it has been reported that lipophilic statins worsen myocardial stunning and survival in models of cardiomyopathy whereas pravastatin (a hydrophilic molecule) exerts beneficial or neutral effects [15,16]. It is also unknown whether all statins are able to mobilize endothelial or bone marrow progenitors to the same extent. In this regard, the current data demonstrate a remarkable efficacy of pravastatin in mobilizing CD133+ and c-kit+ cells from the bone marrow and increasing their homing to the myocardium. This effect is important because the statin-induced increase in the number of endothelial progenitor cells (EPCs) in the bone marrow [17] as well as in the peripheral blood [18], and the consequent augmentation of vascularity of ischemic tissues, have been proposed to be the underlying mechanism of statin-induced functional benefits [19,20]. The increase in CD133+ and c-kit+ cells in the bone marrow is consistent with prior similar observations with regard to EPCs [17].

Because myocardial hibernation is caused by limited blood supply, the lack of change in blood flow in hibernating tissue in the face of a striking improvement in wall thickening [13] is intriguing, and represents one of the most thought-provoking observations in the present report. It impels a reassessment of current paradigms regarding the pathophysiology and therapy of hibernation. Although it is commonly assumed that in this syndrome perfusion is downregulated to “match” the lower level of function, the finding that function can increase with no increase in flow clearly demonstrates that this is not the case. Thus, one need not revascularize hibernating regions in order to improve their performance – a concept that has considerable novelty and implications. A possible explanation for the observations of Suzuki et al. is that the newly formed myocytes may exhibit a physiological behavior akin to neonatal myocytes, i.e., they may be relatively resistant to hypoxia [21]. Furthermore, as shown in murine hearts, younger myocytes may possess more efficient electromechanical system and exhibit greater contractile performance [22].

Irrespective of the cellular/molecular mechanisms, these findings have important clinical implications. There is still controversy with regard to the effect of statins in heart failure. While several earlier clinical trials indicated that statin therapy improves cardiac function and survival in patients with ischemic as well as nonischemic cardiomyopathy [23,24], two recent large, randomized, controlled trials have failed to confirm the survival benefit observed in earlier subgroup analyses or cohort studies: in these trials, rosuvastatin did not improve survival in elderly patients with ischemic systolic heart failure (CORONA trial [25]), and in nonselective heart failure patients (GISSI-HF trial [26]), dampening enthusiasm for statin use in heart failure. Although data regarding the effect of rosuvastatin on LVEF in CORONA and GISSI-HF are not yet available, the controversy over the effects of statins in heart failure increases the significance of the current study. In most clinical trials performed to date it was not possible to discern the specific effects of statins on hibernating myocardial regions as opposed to scarred, acutely ischemic, or stunned regions. The present results, which suggest that statins are useful in settings in which hibernation is a major cause of cardiac dysfunction, could help to unravel this issue.

Last but not least, the observations of Suzuki et al. have obvious therapeutic reverberations for a syndrome – hibernating myocardium – that is common among patients with ischemic heart disease. The concept that a widely used drug, known to have an excellent safety profile, is effective in improving myocardial function in this condition even in the absence of revascularization provides a new therapeutic strategy for those patients who are not candidates for CABG or percutaneous interventions. The present results provide a rationale for evaluating the effect of statin therapy in patients with cardiomyopathy underlain by myocardial hibernation and, possibly, by other forms of cardiac dysfunction in which myogenesis could be desirable (in principle, even nonischemic cardiomyopathy). Furthermore, the presence and duration of statin therapy need to be considered carefully, as they may affect the outcome of clinical trials. It would also seem important to determine whether the addition of statins to specific cell therapies yields additive beneficial effects.

Although lowering cholesterol has been the primary goal of statin therapy, studies over the past decade have identified numerous “pleiotropic” actions of statin therapy in patients with coronary artery disease and cardiovascular risk factors [27]. The present results add considerably to the growing body of evidence supporting a multifaceted beneficial profile of these wondrous drugs in the cardiovascular system. As in the mythological horn of Amalthea, statins appear to be a veritable cornucopia that keeps showering us with good things.