The Cornucopia of “Pleiotropic” Actions of Statins
2009; Lippincott Williams & Wilkins; Volume: 104; Issue: 2 Linguagem: Inglês
10.1161/circresaha.108.192500
ISSN1524-4571
AutoresRoberto Bolli, Buddhadeb Dawn,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoHomeCirculation ResearchVol. 104, No. 2The Cornucopia of "Pleiotropic" Actions of Statins Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Cornucopia of "Pleiotropic" Actions of StatinsMyogenesis As a New Mechanism for Statin-Induced Benefits? Roberto Bolli and Buddhadeb Dawn Roberto BolliRoberto Bolli From the Institute of Molecular Cardiology, University of Louisville, Ky. and Buddhadeb DawnBuddhadeb Dawn From the Institute of Molecular Cardiology, University of Louisville, Ky. Originally published30 Jan 2009https://doi.org/10.1161/CIRCRESAHA.108.192500Circulation Research. 2009;104:144–146Initially 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 caused by reduced blood flow.1,2 In this precarious equilibrium, the myocardium can remain viable for sustained periods of time (although not indefinitely) and slowly resumes contractile activity on 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 disease1,2; 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 19924 and subsequently tested in various animal models5–8: 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 resulting from degenerative changes and apoptosis.2,8Because 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 revascularization10 and intramyocardial gene transfer of phVEGF16511 or fibroblast growth factor-57 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 (ie, 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 Circulation Research, Suzuki et al demonstrate that pravastatin can improve the contractile function of hibernating myocardium without any increase in perfusion.13 Pigs with established hibernating myocardium attributable to chronic coronary stenosis received a 5-week course of pravastatin, at the end of which regional myocardial function was found to be improved (global left ventricular 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 study13 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 left ventricular 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). Because 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 et al 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 present investigation provides a laudable example of the feasibility and value of such an approach.Conceptually, the observations of Suzuki et al13 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 5 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, because 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 present 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.17Because 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 thickening13 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 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, ie, they may be relatively resistant to hypoxia.21 Furthermore, as shown in murine hearts, younger myocytes may possess a more efficient electromechanical system and exhibit greater contractile performance.22Irrespective 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. Although 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 trial25) and in nonselected heart failure patients (GISSI-HF trial26), 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 present 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 hibernating myocardium, a syndrome 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 statins 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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingThis publication was supported in part by grants from the NIH.DisclosuresNone.FootnotesCorrespondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, 550 S Jackson St, ACB, 3rd Floor, Louisville, KY 40292. E-mail [email protected] References 1 Rahimtoola SH. The hibernating myocardium. Am Heart J. 1989; 117: 211–221.CrossrefMedlineGoogle Scholar2 Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005; 288: H984–H999.CrossrefMedlineGoogle Scholar3 Bax JJ, Visser FC, Poldermans D, Elhendy A, Cornel JH, Boersma E, van Lingen A, Fioretti PM, Visser CA. Time course of functional recovery of stunned and hibernating segments after surgical revascularization. Circulation. 2001; 104 (suppl I): I-314–I-318.LinkGoogle Scholar4 Bolli R. Myocardial 'stunning' in man. Circulation. 1992; 86: 1671–1691.CrossrefMedlineGoogle Scholar5 Bolli R, Zughaib M, Li XY, Tang XL, Sun JZ, Triana JF, McCay PB. Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning." J Clin Invest. 1995; 96: 1066–1084.CrossrefMedlineGoogle Scholar6 Kim SJ, Peppas A, Hong SK, Yang G, Huang Y, Diaz G, Sadoshima J, Vatner DE, Vatner SF. Persistent stunning induces myocardial hibernation and protection: flow/function and metabolic mechanisms. Circ Res. 2003; 92: 1233–1239.LinkGoogle Scholar7 Suzuki G, Lee TC, Fallavollita JA, Canty JM Jr. Adenoviral gene transfer of FGF-5 to hibernating myocardium improves function and stimulates myocytes to hypertrophy and reenter the cell cycle. Circ Res. 2005; 96: 767–775.LinkGoogle Scholar8 Canty JM Jr, Fallavollita JA. Chronic hibernation and chronic stunning: a continuum. J Nucl Cardiol. 2000; 7: 509–527.CrossrefMedlineGoogle Scholar9 Galli M, Marcassa C, Bolli R, Giannuzzi P, Temporelli PL, Imparato A, Silva Orrego PL, Giubbini R, Giordano A, Tavazzi L. Spontaneous delayed recovery of perfusion and contraction after the first 5 weeks after anterior infarction. Evidence for the presence of hibernating myocardium in the infarcted area. Circulation. 1994; 90: 1386–1397.CrossrefMedlineGoogle Scholar10 Hughes GC, Kypson AP, St Louis JD, Annex BH, Coleman RE, DeGrado TR, Donovan CL, Lowe JE, Landolfo KP. Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium. Ann Thorac Surg. 1999; 67: 1714–1720.CrossrefMedlineGoogle Scholar11 Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF, Isner JM. Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation. 2000; 102: 965–974.CrossrefMedlineGoogle Scholar12 Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, Emmrich F, Kluge R, Kendziorra K, Sabri O, Schuler G, Hambrecht R. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res. 2005; 97: 756–762.LinkGoogle Scholar13 Suzuki G, Iyer V, Cimato T, Canty JM Jr. Pravastatin improves function in hibernating myocardium by mobilizing CD133+ and cKit+ bone marrow progenitor cells and promoting myocytes to reenter the growth phase of the cardiac cell cycle. Circ Res. 2009; 104: 255–264.LinkGoogle Scholar14 Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002; 90: 737–744.LinkGoogle Scholar15 Satoh K, Ichihara K. Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs. J Cardiovasc Pharmacol. 2000; 35: 256–262.CrossrefMedlineGoogle Scholar16 Marz W, Siekmeier R, Muller HM, Wieland H, Gross W, Olbrich HG. Effects of lovastatin and pravastatin on the survival of hamsters with inherited cardiomyopathy. J Cardiovasc Pharmacol Ther. 2000; 5: 275–279.CrossrefMedlineGoogle Scholar17 Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001; 108: 391–397.CrossrefMedlineGoogle Scholar18 Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest. 2001; 108: 399–405.CrossrefMedlineGoogle Scholar19 Walter DH, Zeiher AM, Dimmeler S. Effects of statins on endothelium and their contribution to neovascularization by mobilization of endothelial progenitor cells. Coron Artery Dis. 2004; 15: 235–242.CrossrefMedlineGoogle Scholar20 Urbich C, Dimmeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors. Kidney Int. 2005; 67: 1672–1676.CrossrefMedlineGoogle Scholar21 Malhotra R, Brosius FC, III. Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem. 1999; 274: 12567–12575.CrossrefMedlineGoogle Scholar22 Rota M, Hosoda T, De Angelis A, Arcarese ML, Esposito G, Rizzi R, Tillmanns J, Tugal D, Musso E, Rimoldi O, Bearzi C, Urbanek K, Anversa P, Leri A, Kajstura J. The young mouse heart is composed of myocytes heterogeneous in age and function. Circ Res. 2007; 101: 387–399.LinkGoogle Scholar23 Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation. 2003; 108: 839–843.LinkGoogle Scholar24 Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol. 2004; 43: 642–648.CrossrefMedlineGoogle Scholar25 Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Janosi A, Kamensky G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007; 357: 2248–2261.CrossrefMedlineGoogle Scholar26 Gissi HFI, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372: 1231–1239.CrossrefMedlineGoogle Scholar27 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005; 45: 89–118.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Deligiorgi M, Panayiotidis M, Siasos G and Trafalis D Osteoporosis Entwined with Cardiovascular Disease: The Implication of Osteoprotegerin and the Example of Statins, Current Medicinal Chemistry, 10.2174/0929867327666200123151132, 28:7, (1443-1467) Yang C, Madonna R, Li Y, Zhang Q, Shen W, McNamara K, Yang Y and Geng Y (2014) Simvastatin-enhanced expression of promyogenic nuclear factors and cardiomyogenesis of murine embryonic stem cells, Vascular Pharmacology, 10.1016/j.vph.2013.10.004, 60:1, (8-16), Online publication date: 1-Jan-2014. Camara A and Stowe D (2014) Reactive Oxygen Species (ROS) and Cardiac Ischemia and Reperfusion Injury Systems Biology of Free Radicals and Antioxidants, 10.1007/978-3-642-30018-9_75, (889-949), . Malecki M, Sabo C, Putzer E, Stampe C, Foorohar A, Quach C, Beauchaine M, Tombokan X and Anderson M (2013) Recruitment and retention of human autologous CD34+ CD117+ CD133+ bone marrow stem cells to infarcted myocardium followed by directed vasculogenesis: Novel strategy for cardiac regeneration, Molecular and Cellular Therapies, 10.1186/2052-8426-1-4, 1:1, (4), . Li Q, Guo Y, Ou Q, Chen N, Wu W, Yuan F, O'Brien E, Wang T, Luo L, Hunt G, Zhu X and Bolli R (2011) Intracoronary administration of cardiac stem cells in mice: a new, improved technique for cell therapy in murine models, Basic Research in Cardiology, 10.1007/s00395-011-0180-1, 106:5, (849-864), Online publication date: 1-Sep-2011. Ghio S, Scelsi L, Latini R, Masson S, Eleuteri E, Palvarini M, Vriz O, Pasotti M, Gorini M, Marchioli R, Maggioni A and Tavazzi L (2014) Effects of n -3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial , European Journal of Heart Failure, 10.1093/eurjhf/hfq172, 12:12, (1345-1353), Online publication date: 1-Dec-2010. January 30, 2009Vol 104, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.108.192500PMID: 19179666 Originally publishedJanuary 30, 2009 Keywordsmyocardial hibernationcellular proliferationpravastatinangiogenesisPDF download Advertisement
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