Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence
Introduction
Atherosclerosis is a progressive and systemic vascular disorder that is clinically manifested as coronary artery disease (CAD). The initial molecular and cellular events in atherogenesis are triggered by endothelial dysfunction, resulting in decreased nitric oxide production, increased cyclooxygenase activity and inflammation [1], [2]. The early inflammatory response to atherosclerosis is designed to be beneficial, yet often progresses with adverse consequences. Proinflammatory factors, such as oxidized low-density lipoprotein (LDL) and infectious agents, stimulate the release of cytokines from the diseased vessel and other peripheral sites. This process leads to the accumulation of mononuclear cells, migration and proliferation of smooth muscle cells, and formation of fibrous tissue that eventually results in the formation of the mature atherosclerotic plaque. As a number of these cellular and inflammatory processes are mediated by disruption in calcium homeostasis, there has been interest in the potential role of CCBs as antiatherogenic agents [3]. This hypothesis has been extensively tested in a variety of cellular and animal models of atherosclerosis.
The course of CAD involves not only plaque development, but plaque rupture, vasoconstriction and local thrombosis, resulting in arterial obstruction. It has been determined that plaque rupture is not necessarily related to size or the degree of stenosis—in most cases, myocardial infarction occurs as a result of thinning of the fibrous cap, often at the shoulder region of the cap where macrophages enter and accumulate and excessive apoptosis occurs [4], [5]. Cytokines are elevated in the vulnerable plaque where they recruit and activate macrophages [6], [7], [8]. Activated macrophages secrete proteolytic enzymes that erode the protein-rich cap, exposing an underlying, highly thrombogenic core, leading to acute coronary syndromes [1], [2]. A number of studies indicate that non-stenotic or minimal lesions often contribute to the development of thrombosis [4], [9]. Thus, agents that promote plaque stability can often improve the course of CAD without necessarily affecting plaque size [10]. These observations support the hypothesis that the arterial wall is a dynamic structure that undergoes remodeling as it accommodates the expanding plaque, without altering the dimensions of the lumen [11], [12]. As endothelial dysfunction has a central role in plaque development, it is important to identify and aggressively treat the risk factors that contribute directly to such cellular changes, especially hypertension, dyslipidemia and diabetes mellitus.
Episodes of clinical ischemia often result from an increase in vascular tone or from a loss of reactivity to normal physiologic stresses. Excessive vasoconstriction and vasospasm can lead directly to plaque rupture and vessel occlusion in patients with CAD. To counter these effects on vessel wall dynamics, vascular endothelial cells play a central role in the control of vasodilation by specifically mediating the release of locally synthesized NO from the cytosolic enzyme, NO synthase. Release of NO from the endothelium is stimulated by various factors, including shear stress associated with flowing blood. This basic mechanism for increasing flow capacity in the setting of increased flow demand is impaired in certain atherogenic states. Other agents that stimulate the release of NO from the endothelium, such as acetylcholine and serotonin, are often used to study the degree of pathologic impairment of the system.
There are a number of agents that promote vasodilation in the diseased vessel by attenuating these physiologic stressors, including CCBs. Beta-adrenergic agonists along with pharmacologic agents, especially nitroprusside (an NO donor), nitroglycerin (a modulator of guanylate cyclase), alpha-adrenergic antagonists and angiotensin-converting-enzyme (ACE) inhibitors also promote vasodilation through their direct or receptor-mediated actions on excitation-contraction mechanisms for smooth muscle cells in the arterial media. Conversely, excessive calcium, angiotensin II (AII) and neurohormonal alpha-adrenergic stimulation promote vasoconstriction, as do a number of vasoconstictor agents, such as norepinephrine and dopamine. Generally, diseased arteries appear to be more responsive to vasoconstictor agents and less responsive to NO-mediated vasodilation. Abnormal vasoconstriction can directly lead to plaque rupture by destabilizing the thinning fibrous cap enriched with inflammatory cells, resulting in thrombus formation. Thus, agents that attenuate vasoconstriction and vasospasm may have an important role in reducing episodes of ischemia, including CCBs.
Along with other risk factors, such as diabetes mellitus and dyslipidemia, hypertension contributes to atherogenesis in an apparent synergistic manner by common cellular pathways, including endothelial dysfunction. Hypertension and associated metabolic disorders, especially diabetes mellitus, increase endothelial cell synthesis of collagen IV and fibronectin while reducing nitric oxide-dependent renal and cardiovascular relaxation [13]. Elevated glucose also delays replication and promotes apoptotic cell death, in part by enhancing glycooxidation of key lipid and protein cell constituents. Vascular vessels isolated from diabetic animal models show a marked reduction in vascular reactivity and impaired nitric oxide synthesis, an effect that can be reproduced by exposing normal vessels to high glucose media [14]. Elevations in oxidized LDL associated with hypercholesterolemia also stimulate endothelial dysfunction and trigger inflammatory processes, such as foam cell formation and increased cytokine production. These observations justify the need for global risk assessment and an integrated therapeutic approach to the treatment of this complex disease process. Prospective clinical trials are evaluating the potential synergistic benefit of managing multiple risk factors, such as dyslipidemia and hypertension, with single drug delivery formulations.
Section snippets
A role for pharmacologic modulation of calcium in atherosclerosis
As there are marked cellular changes associated with loss of normal calcium transport in atherosclerotic vessels, it has been proposed that CCBs may be effective in slowing the progression of CAD, beyond their favorable effects on hemodynamics [3], [15], [16] (Table 1). Previous angiographic trials have shown that CCBs can significantly reduce new lesion formation among patients with documented disease [17], [18], [19], consistent with the results of animal studies [20]. The agents used in
Antiatherosclerotic mechanisms of action for a third-generation CCB amlodipine
A review of the scientific literature provides support for several antiatherosclerotic mechanisms that may contribute to the benefit of the third-generation CCB amlodipine in CAD, as reviewed in Table 5 [26], [31], [32], [33], [34], [35]. These cellular actions would lead to plaque stabilization and vascular remodeling among patients with CAD, resulting in reduced cardiovascular events and procedures as shown in the PREVENT study. Many of these distinct effects for amlodipine are attributed to
Analysis of CCB use and cardiovascular risk in diabetes
There has been special consideration for CCB use among individuals with diabetes, a group with greater risk for development of CAD [57]. Epidemiologic and observational studies demonstrate that cardiovascular and renal disease among patients with diabetes is strongly associated with hypertension, and not just high glucose levels [58], [59]. CCBs may have an important role, then, in gaining full control of hypertension among these patients along with angiotensin-converting enzyme
Conclusion
As changes in the calcium transport mechanisms contribute to cellular changes in atherogenesis, it has been proposed that CCBs may be effective in slowing the progression of CAD. A recent study showed significant clinical benefits with the long-acting CCB amlodipine as compared with placebo, including a marked reduction in cardiovascular morbidity. Amlodipine therapy was also associated with a significant slowing in the progression of carotid atherosclerosis, a strong surrogate marker for CAD,
Acknowledgements
The author acknowledges research support from NIH and the American Heart Association. Additional research support from Astra-Zeneca, Bayer, Pfizer and Yamanouchi Pharmaceuticals is also acknowledged.
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