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Cardiovascular Research 2005 65(2):296-298; doi:10.1016/j.cardiores.2004.11.030
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Copyright © 2004, European Society of Cardiology

Statins–is there no end to their usefulness?

Cherry L. Wainwright*

School of Pharmacy, The Robert Gordon University, Aberdeen, Schoolhill, AB10 1FR, Scotland, UK

* Tel.: +44 1224 262450; fax: +44 1224 262555. Email address: c.wainwright{at}rgu.ac.uk

Received 22 November 2004; accepted 25 November 2004

See also article by Birnbaum et al. [15] (pages 345–355) in this issue.

Ever since the data from the West of Scotland Coronary Prevention (WOSCOP) Study demonstrated an unequivocal beneficial effect in patients at risk from coronary events [1], statins have become a standard addition to the therapeutic management of this group of the population. As inhibitors of HMG-CoA reductase, the primary pharmacodynamic effect of the statins is to inhibit the synthesis of cholesterol by the liver, thereby increasing hepatic cholesterol uptake and reducing circulating lipid levels–or is it? While lipid lowering is more than likely to underpin the clinical observations of a deceleration of atherosclerotic lesion formation and induction of regression and stabilisation of plaques, evidence is growing that the pleiotropic effects of statins (i.e. their effects beyond lipid lowering) may also contribute to their beneficial effects in this setting and may imply an earlier initiation of treatment. The pleiotropic effects of statins include an improvement in endothelial dysfunction and bioavailability of nitric oxide (NO), antioxidant potential, and anti-inflammatory properties. These properties immediately widen the scope for this increasingly versatile group of drugs. With respect to cardiovascular pathologies, statins have been shown to inhibit atrial myocardial remodelling [2,3], prevent atrial fibrillation [4], to conserve NO production in heart failure [5], to reduce the activity of small G-proteins in cardiac hypertrophy [6], and to contribute to post-ischaemic myocardial repair through mobilisation of endothelial progenitor cells [7]. A further potential use for statins is their ability to protect the myocardium from ischaemia/reperfusion injury.

The infarct-limiting effects of statins have been observed with a number of different statins, including simvastatin, [8,9], pravastatin [10,11], and cerivastatin [12], in a range of experimental models. As the mechanisms underlying these protective effects are slowly emerging, the PI 3-kinase/Akt/eNOS pathway has been a focus for several studies, since cardioprotection can be prevented by NO synthase inhibition [9,10,12] and the PI 3-kinase inhibitor wortmannin [9]. Subsequent activation of KATP channels by NO, resulting in an improved myocardial metabolism, may represent the subsequent step in statin-induced cardioprotection, since glibenclamide reverses the cardioprotective effects of pravastatin [11]. However, in the clinical setting, the mechanism of protection may well be different, since the reduction in ST-segment shifts in pravastatin-treated patients undergoing angioplasty [13] has been proposed to be due to release of endogenous adenosine (theophylline abrogates its effects). Experimental evidence from rabbits supports this hypothesis, where the reversal by pravastatin of the blunting effect of hypercholesterolaemia on ischaemic preconditioning was associated with an increase in the activity of the adenosine-forming enzyme ecto-5'-nucleotidase [14].

The article by Birnbaum et al. [15], in the current issue of Cardiovascular Research, advances our understanding of the mechanism of statin-induced cardioprotection. In a well-established model of coronary artery occlusion and reperfusion in rats, the group has shown that atorvastatin reduces myocardial infarct size through a prostanoid-mediated mechanism. In a series of detailed studies to determine the mechanism of this protection, atorvastatin was shown to increase the levels of both 6-keto-PGF1{alpha} (the stable metabolite of prostacyclin) and PGE2. Enzyme activity studies demonstrated that this was achieved through an increase in the activity of cPLA2, COX-2, and PGI2 synthase. Furthermore, the demonstration that the protective effects could be attenuated by the selective COX-2 inhibitor valdecoxib supports the conclusion that prostanoids act as mediators in the infarct-limiting effects of statins. However, the failure of valdecoxib to completely abrogate the statin-induced infarct size reduction implies that this is not the only mechanism involved in the cardioprotection. Interestingly, atorvastatin also increased the tissue content of both iNOS and phosphorylated eNOS without affecting absolute eNOS concentration. This finding builds on previous studies in which acute administration of statins to cellular preparations causes a transient increase in the activity of eNOS through eNOS phosphorylation [16], demonstrating that there is a more prolonged effect on eNOS phosphorylation following in vivo sub-acute oral administration. Valdecoxib did not abrogate these changes in eNOS and iNOS, which led the authors to conclude that changes in iNOS expression and eNOS phosphorylation are upstream of the statin-induced activation of the prostaglandin pathway. Since iNOS has been identified as a mediator of delayed ischaemic preconditioning, this might imply that statins can induce a preconditioning-like state. An earlier study demonstrated that simvastatin fails to reduce myocardial infarct size in iNOS knockout mice, which supports the notion of statins activating an iNOS–PLA2–prostanoid sequence of events in inducing cardioprotection.

While all the studies of the cardioprotective effects of statins differ hugely with respect to the models employed (ranging from isolated cardiomyocytes to whole animal studies), the end point measured, and the dose and route of administration of the statin used, they have one major aspect in common: they all demonstrate an acute effect of statins without any effect on circulating lipids. This is likely due to the short duration of administration (ranging from hours to a few days). In the Birnbaum study [15], atorvastatin was administered orally for 3 days to normocholesterolaemic rats–too short a time for any effects on circulating lipids to develop, although one might not expect any changes in normocholesterolaemic conditions in any event. Other studies have shown intravenous statin administration in vivo, or acute in vitro exposure to statins, to similarly exert a pharmacological effect that is entirely independent of systemic lipid lowering. This raises the question, therefore, as to what the underlying mechanisms of the pleiotropic effects are. Are they due to an action through HMG-CoA reductase inhibition in cardiovascular tissues, or are they through mechanisms completely dissociated from this? Certainly, there is evidence that at the cellular level, statins exert effects on membrane cholesterol that could explain their effects on, for example, endothelial dysfunction (reviewed in Ref. [17]). Under normal conditions, eNOS is associated with caveolae that are enriched with cholesterol, a system that functions to closely regulate eNOS activity [18]. Hyperlipidaemia disrupts this process, leading to loss of control of eNOS activity. Statins have been shown to stimulate endothelial NO production via a marked reduction in the levels of caveolin in the plasma membrane, predominantly through interruption of cholesterol supply to the plasma membrane [19]. Furthermore, statins may increase the supply of the NO substrate L-arginine, again through restoring membrane events that are suppressed by high cholesterol [20]. But could these effects explain findings that statins are cardioprotective in animals that are normocholesterolaemic? Do statins, as a class of drug, interfere with other systems that could mediate their response? These are clearly points that deserve investigation if we are to exploit the potentially useful facet of statin therapy. What is interesting about the majority of studies addressing the cardioprotective effects of statins is that the search for potential mechanisms focuses almost completely on the myocyte. Considering that statins are well documented to interfere with processes that are also implicated in the process of cardiomyocyte injury and death following reperfusion (e.g. inflammation), one prospect for future study may be to investigate whether a favourable effect on inflammatory processes contributes to cardioprotection in vivo.

What does the future hold for statin therapy? Researchers are already dabbling with combining statins with other forms of therapeutic intervention to enhance their therapeutic effects. Seeger et al. [21] have shown that a combination of fluvastatin with β-oestradiol has a greater inhibitory effect on the synthesis of plasminogen activator inhibitor-1 (used as a marker of cardiovascular risk) in human endothelial cells than either agent alone. Furthermore, novel NO-releasing statin derivatives have been developed that show a superior anti-inflammatory and antiproliferative profile compared to the native statin alone [22]. Whether or not these combinations would enhance the cardioprotective effects of statins remains to be seen.

Finally, some comment on the clinical value of the ability of statins to reduce myocardial injury seems justified. With the increasing use of chronic statin therapy for the cardiovascular management of an increasingly large proportion of the population, it would appear from the aforementioned studies on cardioprotection that not only can statins reduce the risk of an acute coronary event, but that their value may also extend to protecting the heart should an AMI occur. Moreover, the observations that acute exposure to statins can also confer cardioprotection imply their potential use in situations of controlled, deliberate myocardial ischaemia and reperfusion, such as coronary angioplasty, coronary artery by-pass grafting, and cardiac transplantation. What should also not be overlooked is the final and cautionary comment of Birnbaum and his colleagues, who suggest that if the statin-induced cardioprotection is indeed mediated by prostanoids, there is the potential for selective COX-2 inhibitors to compromise these beneficial effects. As usual, nothing is ever simple!


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 References
 

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U. Laufs and M. Bohm
Cardiac effects of statins-advancements and open questions
Cardiovasc Res, June 1, 2005; 66(3): 427 - 429.
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