Copyright © 2005, European Society of Cardiology
Cardiac effects of statins–advancements and open questions
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany
* Corresponding author. Tel.: +49 6841 16 3000. Email address: ulrich{at}laufs.com
Received 11 March 2005; accepted 29 March 2005
See also article by Di Napoli et al.[8] (pages 462-471) in this issue.
The beneficial vascular effects of statins are important for the primary and secondary prevention of coronary heart disease and stroke; however, their cardiac effects are less clear. In addition to their lipid-lowering properties, statins have been shown to exert extrahepatic, cholesterol-independent effects in animal studies that have been called "pleiotropic" effects. There is indirect evidence from human studies suggesting that pleiotropic action may contribute to the reduction of clinical endpoints by statin treatment (for review see [1]). These data are important because in addition to the advancement of our understanding of cardiovascular pathophysiology, they imply that patients at risk for adverse cardiovascular events may benefit from statins irrespective of their cholesterol levels [2].
In experimental models of ischemia and reperfusion, statins have been shown to limit the size of myocardial infarction, an effect that seems to be shared by all members of the statin family (for review see [3]). Mechanistically, upregulation of endothelial nitric oxide synthase (eNOS) by statin treatment is important for protection during ischemia–reperfusion [1,4]. Wolfrum et al. showed that activated simvastatin given intravenously only 3 min before reperfusion after temporary coronary artery occlusion increased myocardial PI 3-kinase activity, AktSer473 and eNOSSer1177 phosphorylation, and reduced infarct size by 42% in rats [5]. Lefer et al. demonstrated that reduction of neutrophil adherence to the vascular endothelium and subsequent infiltration into the post-ischemic myocardium represents an important consequence of statin-induced eNOS regulation [4,6], and Birnbaum et al. recently showed that prostaglandins are essential for mediating the myocardial protective effects of statins and that their production is downstream of eNOS phosphorylation [7].
In an elegant paper published in this issue of Cardiovascular Research, Di Napoli et al. confirm the protective effect of statin treatment on ischemia–reperfusion injury [8]. Importantly, and in addition to previous experimental models, they have studied an isolated working heart model and applied chronic in vivo treatment of rats with rosuvastatin for 3 weeks. This long-term statin treatment was used to more closely reproduce the conditions in humans than acute addition of the drug to the cardiac perfusate. The authors convincingly demonstrate that rosuvastatin upregulates eNOS mRNA and protein in the heart, whereas iNOS is downregulated. Concomitantly, statin treatment reduces ischemia-induced myocardial and vascular damage. Treatment with a NOS inhibitor reversed the protective effects of rosuvastatin, demonstrating a significant contribution of eNOS to the protection conferred by statins. Notably, the experimental setup of the isolated working heart revealed protective statin effects in the complete absence of circulating cells or systemic mediators. The effects are therefore clearly extrahepatic. Furthermore, this finding is of interest since invading inflammatory cells, and, more recently, circulating progenitor cells have been implicated in statin-mediated cardiac protection [6,9]. In this model, however, only the direct effects of rosuvastatin on vascular and/or myocardial cardiac cells were responsible for the observed protection.
What may be the molecular mechanism of these cardiac effects of statins? By inhibiting L-mevalonic acid synthesis, statins also prevent the synthesis of other isoprenoid intermediates of the cholesterol biosynthetic pathway such as geranylgeranylpyrophosphate (GGPP). These intermediates serve as important lipid attachments for the post-translational modification of variety of proteins, including small GTP-binding proteins. Because Rho proteins are major target of geranylgeranylation, their inhibition is a likely mechanism mediating some of the pleiotropic effects of statins [1]. Rho family members play an important role in the organization of the actin cytoskeleton and cell signaling. In endothelial cells, inhibition of RhoA leads to upregulation of eNOS via prolongation of its mRNA stability [1]. In vascular smooth muscle cells as well as in cardiac myocytes, statin treatment inhibits the activity of Rho family member Rac1 GTPase. An important function of Rac1 is the regulation of the NADPH oxidase, the major source of reactive oxygen species (ROS) production both in the vessel wall and in the myocardium [10]. ROS not only participate in ischemia–reperfusion induced injury but may be important mediators of cardiac hypertrophy and the development of contractile dysfunction. Indeed, in patients with chronic heart failure, increased oxidative stress is associated with reduced left ventricular function and correlates with the severity of the disease. Inhibition of Rac1 by statins has been shown to decrease NADPH oxidase-related ROS production in vascular smooth muscle cells and cardiac myocytes [1,11,12]. NADPH-oxidase mediated ROS are increased in left ventricular myocardium from patients with heart failure and correlate with an increased activity of Rac1 GTPase, and oral statin treatment is able to decrease Rac1 function in the human heart [12]. In summary, inhibition of Rho family members by chronic treatment with rosuvastatin may explain the cardiac effects reported by Di Napoli et al. [8].
Are these findings important for the clinical cardiologist? Chronic heart failure, a consequence of both myocardial infarction and hypertrophy, remains a major cause of death and morbidity. Several lines of evidence indeed suggest that statins may emerge as a novel treatment option for patients with congestive heart failure [1,13]: Retrospective analysis of the large statin trials, such as the 4S, suggests that statins reduce the incidence and morbidity of heart failure. Secondly, patients with heart failure are characterized by increased vascular tone and endothelial dysfunction, which may be improved upon by statin therapy, irrespective of serum cholesterol levels. Thirdly, statins have proven to preserve cardiac function in a variety of animal models of heart failure. In agreement with the animal data, two small recent clinical trials showed beneficial effects of statin treatment in patients with heart failure due to dilated cardiomyopathy–irrespective of serum cholesterol levels and in the absence of atherosclerotic disease [14,15].
However, important open questions remain on cardiac effects of statins:
- (1) Do patients with heart failure significantly benefit from statin treatment? Heart failure patients have been excluded or under-represented in past large statin trials; therefore, the results of the secondary prevention trials of patients with coronary disease cannot necessarily be extrapolated to individuals with heart failure [13]. There has been some concern about lowering of coenzyme Q. Its production is affected by any statin treatment. Another concern in heart failure remains that lowering plasma lipoproteins and cholesterol too much maybe detrimental. We therefore need a prospective, large-scale trial to evaluate statin administration in patients with heart failure. The ongoing "controlled rosuvastatin multinational trial in heart failure" (CORONA) aims to recruit > 4900 patients with ischemic heart failure who will be randomized to 10 mg rosuvastatin or placebo. Patients will be followed up for 3 years, with cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke being the primary end points. Similarly, the GISSI-HF trial (Gruppo Italiano per lo studio della sopravvivenza nell'insufficienza cardiaca) investigates the effects of n-3 polyunsaturatedfatty acids (PUFA) and rosuvastatin in patients with chronic heart failure. Patients will be randomized to 1 g n-3 PUFA or placebo, and, in a second step, to rosuvastatin(10 mg once daily) or placebo.
- (2) In this issue of Cardiovascular Research, Di Napoli et al. have provided another example of a pleiotropic statin effect [8]. However, from the perspective of clinical patient care, the question of future research is no longer whether extrahepatic effects exist in animal and cell culture models, but the quantitative extent of clinical benefit related to pleiotropic effects on top of the proven effects of lipid lowering. This issue is difficult to determine in a prospective clinical trial because statins effectively reduce cholesterol levels even in individuals with low baseline cholesterol levels. New lipid-lowering drugs may help to address the question of quantitative benefit of pleiotropic effects in addition to lipid lowering in humans. For example, treatment with the inhibitor of cholesterol absorption, ezetimibe, leads to an upregulation of the activity of HMG CoA reductase in the liver and, thereby, potentially to increased isoprenoid synthesis. Ongoing studies comparing statins with ezetimibe may therefore help to assess the quantitative benefit of inhibition of isoprenoid synthesis in humans.
- (3) The question of the optimal statin dose is important for daily patient care and is related to the issue of the quantitative clinical contribution of statin pleiotropy, especially for patients with heart failure. Should we treat to a lipid target or use a fixed dose–as tested in the CORONA and GISSI-HF trials? Do patients with acute cardiac ischemia benefit from rapid statin treatment, e.g. is there the need for an i.v. preparation of statin drugs?
- (4) And finally, what role do other lipoproteins, especially the high density lipoproteins and triglycerides, play in the pathogenesis of cardiac injury and does their modification confer clinical benefit?
- (2) In this issue of Cardiovascular Research, Di Napoli et al. have provided another example of a pleiotropic statin effect [8]. However, from the perspective of clinical patient care, the question of future research is no longer whether extrahepatic effects exist in animal and cell culture models, but the quantitative extent of clinical benefit related to pleiotropic effects on top of the proven effects of lipid lowering. This issue is difficult to determine in a prospective clinical trial because statins effectively reduce cholesterol levels even in individuals with low baseline cholesterol levels. New lipid-lowering drugs may help to address the question of quantitative benefit of pleiotropic effects in addition to lipid lowering in humans. For example, treatment with the inhibitor of cholesterol absorption, ezetimibe, leads to an upregulation of the activity of HMG CoA reductase in the liver and, thereby, potentially to increased isoprenoid synthesis. Ongoing studies comparing statins with ezetimibe may therefore help to assess the quantitative benefit of inhibition of isoprenoid synthesis in humans.
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