Number 36, 2007
Improving prognosis in ischemic heart disease: time to maximize benefit

Pharmacologic prevention of coronary plaque rupture – the major cause of acute coronary syndromes

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Petri T. Kovanen, Markku O. Pentikäinen
Wihuri Research Institute, Helsinki, Finland
Correspondence: Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. Tel: +358 9 681 4131; fax: +358 9 637 476; e-mail: petri.kovanen@wri.fi

Introduction
Atherosclerosis of epicardial coronary arteries and their major branches is the underlying cause of ischemic coronary heart disease. Acute coronary syndrome usually results from an occluding thrombus of the culprit coronary artery and manifests clinically as unstable angina, acute myocardial infarction, or sudden cardiac death. The most common cause of acute coronary thrombosis is plaque rupture, notably the rupture of a thin-cap fibroatheroma [1]. Careful analysis of such ruptured culprit lesions has created the concept of “vulnerable plaques”. These plaques typically cause only minor stenosis of the coronary lumen and are morphologically characterized by a large lipid core and a thin cap, which contains few collagen-producing smooth muscle cells but numerous inflammatory cells, namely macrophages, T cells, and mast cells [2].
Ambrose and D’Agate recently discussed the systemic therapies that prevent acute myocardial infarction by potentially stabilizing vulnerable plaques [3]. Since then, new clinical studies, new imaging techniques, and direct analysis of excised atherosclerotic lesions after defined drug therapies have provided new insight into pharmacological plaque stabilization. Here, we briefly discuss some of these new findings and their implications for pharmacological stabilization of vulnerable coronary plaques. The findings are summarized in Table I.

Table I. Clinical and biological effects of drugs used to treat cardiometabolic diseases

High-density lipoprotein infusion therapy
High-density lipoprotein infusion therapy is a novel and emerging modality in the acute treatment of atherosclerosis. In this treatment, synthetic HDL particles containing complexes of phospholipids with either native apolipoprotein (apo) A-I or recombinant apolipoprotein (apo) A-I Milano, a variant form of native apoA-I, are repeatedly infused intravenously. Experiments with animal models have convincingly shown that induction of reverse cholesterol transport by infusion of phospholipid vesicles or either type of synthetic HDL leads to rapid mobilization of cholesterol from tissues, promotes fecal excretion of steroids, and reverses endothelial dysfunction induced by hypercholesterolemia [11]. Most importantly, after a single injection of a high dose of synthetic HDL containing apoA-I Milano, the size and macrophage content of established atherosclerotic lesions in apoE-deficient mice were significantly decreased within 48 h, reflecting regression and potential stabilization of atherosclerotic lesions [12]. Recently, two small clinical studies have evaluated the use of these compounds in patients with acute coronary syndromes. Nissen et al [13] reported that over a period of 5 weeks, weekly injections of synthetic HDL containing apoA-I Milano induced a 4.2% decrease in atheroma volume, as assessed by intravenous ultrasound. Using similar intravenous ultrasound examinations, Tardif et al [14] showed that four weekly injections of reconstituted HDL containing normal apoA-I decreased atheroma volume by 3.4%, with a concomitant change in plaque characteristics compatible with an increase in the content of dense fibrous tissue – that is, the treatment appeared to induce more stable plaque composition. Moreover, the treatment significantly decreased the mean reduction in coronary luminal diameter, as determined with quantitative coronary angiography. Overall, on the basis of experimental and clinical data, induction of reverse cholesterol transport with synthetic HDL appears a promising way to stabilize plaques. However, before this mode of treatment is ready for common use, larger studies are needed to verify the safety of these compounds and to demonstrate that the observed beneficial effect on atherosclerotic plaques will actually lead to a decrease in the incidence of adverse cardiovascular events.

Peroxisome proliferator activated nuclear receptor agonists
Peroxisome proliferator activated receptors α and γ are members of the superfamily of nuclear receptors that regulate both lipid and glucose homeostasis in response to fatty acids and their metabolites [15]. They are expressed by the major cell types of atherosclerotic lesions, where they have the potential for negative regulation of the transcription of proinflammatory genes. Thus their activators or agonists, notably the two classes of drugs, the fibrates and thiazolidinediones, could theoretically exert direct anti-inflammatory actions on vulnerable plaques.
Fibrates are ligands for PPARα and their major lipid-regulatory effects consist of a reduction in triglycerides and an increase in HDL cholesterol. Various fibrates have been shown to decrease the incidence of acute cardiovascular events, but to do so less consistently than statins [15]. Fibrates also decrease experimental atherogenesis and diminish the size of carotid plaques, with a concomitant decrease in the incidence of strokes in patients with essential hypertension [16]. Thus fibrates appear to have some plaque-stabilizing effects. It is obvious that these effects largely result from the ability of fibrates to regulate plasma lipids; the extent of their plaque-stabilizing potential attributed to direct effects on various cell types present in vulnerable plaques remains unknown.
Thiazolidinediones are ligands for PPARγ and they increase insulin sensitivity and have favorable effects on blood glucose concentrations and the serum lipid profile. Moreover, thiazolidinediones have anti-inflammatory effects on cultured vascular cells and slow down the development of atherogenesis in experimental animals. In the PROactive study, pioglitazone was found to decrease cardiovascular events in patients with type 2 diabetes [17]. Moreover, both pioglitazone [18] and rosiglitazone [19] decreased carotid atherosclerosis in diabetic patients and, interestingly, rosiglitazone has been shown to inhibit inflammation and to stabilize carotid plaques in non diabetic patients [20,21]. Unfortunately, however, a recent meta-analysis of the cardiovascular effects of rosiglitazone showed that its use was associated with a significant increase in the risk of myocardial infarction, which necessitates careful reconsideration of its use in patients with cardiovascular diseases [22].

Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists
By reducing blood pressure, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 antagonists also reduce the physical stress exerted on vulnerable plaques and hence tend to prevent their rupture. As ACE is abundantly expressed in atherosclerotic lesions, and angiotensin II has been shown to possess potent proinflammatory effects, these compounds may also have direct effects on plaque biology. Both ACE inhibitors and angiotensin receptor antagonists have been shown to decrease cardiovascular events in high-risk patients without heart failure [23–25]. Importantly, ultrasound imaging analysis of carotid arteries has shown that both ACE inhibitors [26] and angiotensin receptor antagonists [27] decrease the size of carotid artery atherosclerotic lesions, and treatment with irbesartan for 4 months was shown to decrease the degree of inflammation in human carotid plaques [28]. Overall, these finding suggest that inhibition of the renin–angiotensin system, both systemically and locally in lesions, helps to stabilize plaques.

Calcium channel blockers
Dihydropyridine calcium channel blockers have been shown to have direct plaque-stabilizing effects beyond the decreasing of blood pressure, and some of these actions appear to be dependent on, and some others independent of, calcium channel modulation [29]. Earlier studies with short-acting dihydropyridine calcium channel blockers failed to show any effect on plaque size or to reduce coronary events, but more recent studies with the long-acting third-generation dihydropyridine calcium channel blockers, amlodipine and lacidipine, have shown some clinical benefit. Thus, in patients with coronary heart disease and normal blood pressure, amlodipine decreased cardiovascular morbidity and slowed down the progression of coronary and carotid atherosclerosis [30,31]. Similarly, lacidipine has been shown to inhibit the progression of carotid atherosclerosis in patients with hypertension [32].

β-Blockers
β-Blockers are indicated and widely used to prevent adverse cardiovascular events after myocardial infarction. In addition, they are used in antihypertensive drug regimens. However, recent large clinical trials have challenged the use of β-blockers, especially atenolol, as first-line antihypertensive drugs [33]. β-Blockers are likely to have beneficial effects on plaque biology by regulating hemodynamic forces exerted on the plaques, and so prevent cardiovascular events triggered by heavy physical exertion or psychosocial stress [34]. There is also some evidence that β-blockers may have antiatherogenic effects that are not mediated by their effects on hemodynamics. Thus, in experimental animals, endothelial injury caused by adrenergic stimulation can be prevented with β-blockers [35], and β-blockers have also been shown to decrease diet-induced and stress-induced atherosclerosis [36,37]. In humans, β-blockers have been shown to retard the progression of carotid atherosclerosis in patients without [38] and with [39] statin medication. Overall, β-blockers are indicated in the primary and secondary prevention of cardiovascular diseases, and some of their beneficial effects may be derived from plaque-stabilizing effects.

Aspirin
Aspirin, when administered in a daily single low dose (100 mg or less), is an antiplatelet agent that completely blocks the synthesis of thromboxane A₂ in platelets and therefore effectively inhibits platelet-dependent formation of arterial thrombus. On the basis of this well characterized antiplatelet effect, it is easy to appreciate that low-dose aspirin is effective not only for secondary but also for primary prevention of atherothrombotic diseases [40]. Importantly, low-dose aspirin has also been demonstrated to reduce proinflammatory cytokines in patients with chronic stable angina [41]. Moreover, among apparently healthy men, aspirin was most effective in reducing the cardiovascular risk in the individuals with the most increased concentrations of C-reactive protein [42]. These findings have provided strong suggestive evidence that aspirin, besides its antiplatelet action, may have additional anti-inflammatory effects on atherosclerotic plaques. To date, this hypothesis has been tested in genetically hyperlipidemic mice, in which low-dose aspirin was found to suppress aortic inflammation and to increase the stability of already developed atherosclerotic plaques [43]. These experimental studies call for future human investigations to evaluate whether low-dose aspirin might retard the progression and evolution of human atherosclerotic plaques and prevent their conversion into vulnerable plaques.

Conclusion
It is of major importance to realize that none of the currently available systemically applied pharmacotherapies specifically targets vulnerable coronary plaques prone to rupture. The pharmaceutical industry is actively developing molecules with this ability, and searching for the “magic bullet”. At present, decreasing LDL concentrations to physiological values and induction of true regression of lesions with statins appears to be the treatment modality closest to this ideal. In our present enthusiasm about modern medications, we should not forget the emergence of the concept of plaque stabilization [44,45]. Indeed, the formulation of this concept was prompted by the amazing results attained with “old drugs”, such as niacin and colestipol. Thus, in the Familial Atherosclerosis Treatment Study (FATS) study, a combination of these two drugs induced a remarkable 80% reduction in cardiovascular events [46]. We are now witnessing the second coming of niacin along with the discovery of its receptor, and the replacement of bile acid binding resins by molecularly targeting the absorption of cholesterol from the gut with ezetimibe. We have good reason to believe that the reduction in plasma LDL cholesterol to extremely low concentrations, which is already possible today, will stabilize vulnerable plaques sufficiently to lead to a significant decrease in acute coronary events.

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