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Mechanisms of benefit of lipid lowering in patients with coronary heart disease

Robert S Rosenson, MD


UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on March 28, 2006. The next version of UpToDate (14.3) will be released in October 2006.

INTRODUCTION — Lipid-lowering therapy in patients with hypercholesterolemia has a proven survival benefit for both primary prevention (ie, in patients without clinical evidence of coronary disease) and secondary prevention (ie, in patients with established coronary disease), even when serum cholesterol concentrations are "normal" for the population or borderline high. (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and see "Clinical trials of cholesterol lowering in patients with coronary heart disease").

TIMING AND MECHANISMS OF BENEFIT — The mechanisms by which lipid-lowering therapy (particularly with statins) is beneficial are incompletely explained by the serum low density lipoprotein (LDL) concentration at baseline or after treatment [1-6]. Although statins probably cause regression of atherosclerosis, an improvement in outcome can be demonstrated as early as six months (show figure 1) [7,8], a time considered too early for significant regression. In addition, the amount of lesion regression is small compared with the magnitude of the observed clinical benefit.

A case-control study of adults with a first clinical presentation of coronary heart disease found that use of statins was associated with a decreased likelihood of that presentation being an acute myocardial infarction (odds ratio 0.45) and thus an increased likelihood of presenting with stable angina [9]. These observations suggest a mechanism of benefit with statins that might involve unstable coronary lesions.

Among the nonlipid mechanisms that may be involved are plaque stabilization, reduced inflammation, reversal of endothelial dysfunction, and decreased thrombogenicity [10,11].

Regression of atherosclerosis — Regression of the atherosclerotic lesions can occur after lipid lowering, without change in vessel wall thickness or vessel wall area, and may be clinically important [12]. One limitation to arteriographic studies is the relative lack of sensitivity to morphologic changes in atheroma, which can be better characterized by intracoronary ultrasonography (ICUS) [13], or to small changes, which might be detectable by other techniques such as B-mode ultrasonography for measurement of carotid intima thickness [14], electron beam or multidetector row computed tomography to detect coronary artery calcification [15], or high-resolution magnetic resonance imaging MRI [12]. (See "Diagnostic and prognostic implications of coronary artery calcification detected by computed tomography" and see "Clinical utility of cardiovascular magnetic resonance imaging").

The benefit of lipid lowering can be illustrated by the following observations:

In different studies, coronary angiography has shown increases in lumen diameter at two and four years or a lesser degree of progression of stenosis at three years after the onset of statin therapy [16,17].
A net reduction in the calcium-volume score has been demonstrated by EBCT after a minimum of 12 months of statin therapy [15]. This effect was only seen when the final serum LDL-cholesterol concentration was less than 120 mg/dL (3.1 mmol/L). In contrast, the calcium-volume score increased in both untreated patients and, to a lesser degree, in treated patients whose LDL-cholesterol was 120 mg/dL (3.1 mmol/L) (show figure 2).
There are limited data on the exact timing of regression of atherosclerosis, particularly coronary atherosclerosis, after statin therapy. This issue was addressed using high-resolution MRI to assess aortic and carotid artery plaques. No changes were seen at six months [12], but progressive regression was noted at 12 and 24 months [18]. The earliest change, seen at 12 months, was a reduction in plaque size followed by an increase in luminal area due to arterial remodeling [18].

Plaque stabilization — Coronary artery plaque rupture is a central component in most patients with an acute coronary syndrome. Furthermore, there is increasing evidence that many of these patients have multiple unstable plaques in different coronary arteries, suggesting widespread inflammation in the coronary circulation. Thus, intervention aimed only at the culprit lesion is not likely to be optimal and the ability of statins to induce plaque stabilization may be an important mechanism of benefit. (See "The role of plaque rupture in acute coronary syndromes").

Animal models and human studies have shown that statin therapy can reduce the rate of progression of plaque development and stabilize atherosclerotic plaques that have ruptured as well as those that are vulnerable to rupture [13,19-21]. One report of 131 patients evaluated the effect of 12 months of atorvastatin therapy using ICUS [13]. Compared to placebo, atorvastatin reduced the progression of mean plaque volume or thickness (1.2 versus 9.6 mm3 for placebo) and increased the hyperechogenicity of the plaque, indicating a change in plaque composition (from lipid-rich to fibrotic and calcified) that corresponds to increased plaque stability and a reduced tendency for rupture.

A variety of factors may contribute to the pathogenesis of plaque rupture and the induction of acute coronary syndromes [22,23]. (See "Pathogenesis of plaque rupture in acute coronary syndromes"). One important effect of statin therapy may be maintenance of integrity of the fibrous cap of the plaque, thereby protecting against plaque rupture. This effect appears to be mediated by inhibition of macrophage proliferation, reduced expression of matrix metalloproteinases (MMPs) and tissue factor (which promotes thrombus formation) by macrophages, and an increase in tissue inhibitor of metalloproteinase-1 [20,24,25]:

The inhibitory effect on MMPs may be mediated in part by statin-induced inhibition of prostaglandin synthesis [26]. In cell cultures of mouse and human macrophages, lipophilic statins (fluvastatin, simvastatin) inhibit MMP-9 activity by 20 to 40 percent in a dose-dependent manner [25]. This effect was fully reversed by mevalonate.
In animal models, statins induce smooth muscle cell apoptosis. This may diminish collagen biosynthesis and thus the formation of the protective fibrous cap [27]. There are differences among the statins in their effects on smooth muscle cell apoptosis and collagen biosynthesis [28,29].
The clinical relevance of the differential tissue effects of statins is uncertain; a comparison study of statins in a high risk population at equivalent LDL-C-lowering doses would be required to sort this out. It is likely that these effects are in part due to lipid lowering. In animal models, reductions in macrophage content, MMP, and tissue factor expression can be induced by dietary modification [30,31]. Additional support for the importance of lipid lowering comes from examination of the coronary arteries and plaque morphology of 113 men who died suddenly [32]. By multivariate analysis, the serum concentrations of total cholesterol, HDL-cholesterol, and the ratio of total cholesterol to HDL-cholesterol were independently associated with plaque rupture.

Reduced inflammation — Inflammation appears to be another important contributor to atherosclerosis and plaque rupture. (See "Pathogenesis of plaque rupture in acute coronary syndromes"). Elevated serum markers of inflammation, particularly C-reactive protein (CRP), are associated with progression of atherosclerosis, predict the risk of a first myocardial infarction among apparently healthy men, and are associated with a worse prognosis among patients with stable and unstable angina and those who undergo coronary stenting. (See "Screening for cardiovascular risk with C-reactive protein" and see "C-reactive protein in cardiovascular disease").

Statin therapy, given as primary or secondary prevention, reduces the serum CRP concentration, an effect that is mostly unrelated to lipid levels at baseline or during therapy [33-36]. The fall in serum CRP begins within 14 days [36].

Additional evidence that statins may have an anti-inflammatory effect is provided by a randomized trial that found that patients with Rheumatoid Arthritis experienced modest clinical improvement with atorvastatin; atorvastatin also reduced CRP levels and the erythrocyte sedimentation rate compared with placebo [37]. (See "Novel and investigational therapies in Rheumatoid Arthritis other than anticytokine therapy").

Such an antiinflammatory effect could contribute to the benefit from the early institution of statin therapy in patients with an acute coronary syndrome [38]. (See "Cholesterol lowering after an acute coronary syndrome"). Results from PROVE IT, MIRACL, and Phase Z of the A to Z trial raise the possibility that the antiinflammatory effects of statins may differ among statins [39]. (See "Clinical trials of cholesterol lowering in patients with coronary heart disease"). The first two trials showed early benefit with atorvastatin [40,41], while in the last trial, despite achieving an LDL-C concentration of 68 mg/dL (1.76 mmol/L) after one month of simvastatin 40 mg daily, there was no evidence of clinical benefit and no reduction in CRP [42].

Baseline inflammatory markers — In clinical trials, statins appear to have greater effects in patients with evidence of inflammation at baseline.

The potential importance of statin-induced reduction in serum markers of inflammation was illustrated by an analysis from the secondary prevention CARE trial [43]. Patients with baseline serum concentrations of CRP and serum amyloid A in the highest quintile had a relative risk for a recurrent event 75 percent higher than those with levels in the lowest quintile (show figure 3). However, in patients who were treated with pravastatin, the association between inflammation and risk was attenuated and was no longer statistically significant (show figure 4).

Similar findings were noted in a prospective study of patients with angiographically severe coronary disease; the improvement in survival with statin therapy occurred primarily in those with elevated serum CRP [44]. In addition, in a prospective observational study of patients undergoing percutaneous coronary interventions, pretreatment with statins was associated with a marked improvement in survival in those patients in the highest quartile of CRP levels [45].

An analysis from the AFCAPS/TexCAPS trial of primary prevention enhanced our understanding of the interactions among statin therapy, serum lipids, serum CRP, and patient outcomes [46]. Lovastatin reduced serum CRP by almost 15 percent. The following results were noted:

Among patients with a total cholesterol-to-HDL cholesterol ratio above the median, the beneficial effect of lovastatin on coronary events was independent of serum CRP; the number of subjects needed to treat for five years to prevent one event was 47.
Lovastatin was also effective in those with a ratio that was lower than the median in whom the serum CRP level was above the median; the number of subjects needed to treat for five years to prevent one event was 43.
Lovastatin was ineffective in patients with a low ratio and a CRP level below the median.
An effect of statins unrelated to lipid lowering has also been shown in a prospective study including patients with antibodies to cytomegalovirus (CMV). Statin usage, CMV seropositivity, and serum CRP level were measured in 2315 patients with angiographically significant coronary disease [47]. After 2.4 years, patients who were CMV positive and had high serum CRP levels had a lower mortality rate with statin use (6 versus 17 percent without statins). Those who had both a low serum CRP and a negative CMV titer had no improvement in mortality rate with statins (5 versus 4 percent). (See "Pathogenesis of atherosclerosis", section on Infection).

Reduction in CRP — Analyses from randomized trials that compared intensity of statin therapy suggest that beyond reduction in LDL-C, the differential effects of statins are explained, at least in part, by reduction in CRP:

In the PROVE IT-TIMI 22 trial, the residual differential effects of atorvastatin and pravastatin (after considering reductions in LDL-C) appeared to be largely explained by effects on CRP [48]. While there was only a weak correlation between reduction in CRP and reduction in LDL-C, adjusting for both the CRP achieved and the LDL achieved appeared to explain the benefits of atorvastatin compared with pravastatin with regard to the outcome of recurrent myocardial infarction or death from coronary causes past 30 days (hazard ratio 1.00, 95% CI 0.75-1.34). (See "C-reactive protein in cardiovascular disease" and see "Clinical trials of cholesterol lowering in patients with coronary heart disease", section on PROVE IT trial).
In the REVERSAL trial, while there was only a weak correlation between reduction in LDL-C and reduction in CRP, adjusting for CRP partially explained the slower rate of progression in atherosclerosis seen with atorvastatin at a given level of LDL-C [49]. (See "C-reactive protein in cardiovascular disease" and see "Clinical trials of cholesterol lowering in patients with coronary heart disease", section on REVERSAL trial).
The possible clinical implications of these observations are discussed separately. (See "Risk factor reduction (secondary prevention) of cardiovascular disease").

These results, and those from other studies [50], suggest that high-dose atorvastatin and rosuvastatin produce greater lowering of CRP levels than other statins.

Mechanism — How statins might interfere with the inflammatory response is not well understood. One possible mechanism is impairment of inflammatory cell adhesion by inhibition of the main beta-2 integrin, LFA-1 [51,52]. However, pravastatin has antiinflammatory activity but does not interfere with this integrin [51]. Other contributing factors may include reduced lipidation of intracellular proteins and reduced expression of major histocompatibility complex class II molecules on antigen-presenting cells in response to interferon, decreasing subsequent T-lymphocyte activation [52,53]. (See "Transplantation immunobiology").

These effects could also contribute to the reduction in transplant vasculopathy and the improved outcome in heart transplant recipients treated with pravastatin. (See "Prevention and treatment of cardiac transplant vasculopathy").

The fall in CRP induced by statins may be mediated in part by reduced monocyte expression of proinflammatory cytokines that stimulate the release of acute phase proteins [54]. (See "Acute phase proteins").

Decreased thrombogenicity — Thrombus formation at the site of plaque rupture appears to account for most acute coronary syndromes. (See "The role of plaque rupture in acute coronary syndromes"). Lipid lowering, particularly with statin therapy, has a variety of effects that may reduce thrombus formation [55]. These include:

Reduced expression of tissue factor in endothelial cells and by macrophages in the atherosclerotic plaque [24,31,56]
Decreased prothrombin activation and thrombin generation [57,58]
Improved fibrinolytic profile [59]
These changes are either independent of [57] or only partially explained by cholesterol lowering [59]. Statins also reverse the hypercholesterolemia-induced increases in platelet reactivity, platelet-vessel wall interactions, and platelet thrombus formation [60,61].

The molecular mechanisms by which these events occur are becoming clearer. Both membrane bound and soluble CD40 ligand (sCD40L) interact with CD40 expressed on vascular cells, resulting in inflammatory and prothrombotic responses [62,63]. Elevated levels of sCD40L have been implicated in acute coronary syndromes and predict an increased risk of future cardiovascular events in healthy subjects [64,65].

A study of 80 patients with hypercholesterolemia found that compared with matched controls, hypercholesterolemic patients had higher levels of sCD40L, factor VIIa, and prothrombin fragment [66]. The level of sCD40L correlated with serum total and LDL-cholesterol, and it was positively associated with both in vivo platelet activation and with a procoagulant state. Inhibition of cholesterol biosynthesis with either pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, factor VIIa, and prothrombin fragment. Atorvastatin has also been found to inhibit platelet CD40L and CD40L-mediated thrombin generation [67].

Reversal of endothelial dysfunction — Endothelial dysfunction is a frequent finding in atherosclerotic coronary arteries, one characteristic of which is the induction of vasoconstriction by acetylcholine rather than the expected, nitric oxide-mediated vasodilation [68-70]. (See "Endothelial dysfunction").

Most [68-71], but not all [72], studies have shown that vasoconstriction can be attenuated or abolished with statin therapy, an effect that can improve overall vasodilator capacity and myocardial blood flow reserve [73,74]. The improvement in endothelial function can be seen within six weeks [75]. It results in part from an increase in endothelial nitric oxide activity by activation of nitric oxide release and concurrent inactivation of superoxide [76,77]. A reduction in serum oxidized LDL may contribute, as oxidized LDL but not native LDL downregulates endothelial nitric oxide synthase activity [78].

In addition, statins:

Increase nitric oxide synthase activity independent of lipid lowering [79,80]. Nitric oxide is generated in endothelial cells by endothelial nitric oxide synthase (eNOS). Oxidized LDL and cytokines downregulate eNOS by destabilizing eNOS mRNA. Rho is a small molecular weight GTP-binding protein that regulates eNOS mRNA stability by posttranslational mechanisms that involve attachment of the isoprenoid geranylgeraniol. Activation of Rho by geranylgeraniol attachment is necessary for the translocation of Rho from the cytosol to the membrane. Statins inhibit isoprenoid biosynthesis, and reduce activation of Rho. This inhibition of Rho GTPase (Rho kinase) improves the stability of eNOS and mRNA [81].
Improve endothelial integrity, reducing endothelial permeability to LDL cholesterol [82].
Directly decrease endothelin synthesis [78]. Rho is required for basal expression of preproendothelin-1 in vascular endothelial cells [83]. Preproendothelin-1 is a precursor of endothelin-1, a potent vasoconstrictor that modulates vascular tone and a mitogen involved in remodeling. Rho activation involves the attachment of geranylgeraniol which is an isoprenoid intermediary in the cholesterol biosynthetic pathway [84]. Through inhibition of cholesterol biosynthesis, statins reduce endothelin through a transcriptional mechanism.
A four-week randomized trial in 20 patients with heart failure found that simvastatin 10 mg daily and ezetimibe 10 mg daily produced similar reductions in LDL-C (15.6 versus 15.4 percent) [85]. However, flow-dependent dilation of the radial artery was significantly improved with simvastatin but not with ezetimibe. The improvement in endothelial function with statin therapy may have clinical benefit. It may contribute to a reduction in transient ischemic events and exercise induced ischemia in patients with stable angina pectoris [86-88] and to stabilization of or increase in myocardial perfusion [89-91].

Different mechanisms may be involved in the improvement in endothelial function with fibrate therapy in patients with type 2 diabetes [92]. This effect may be mediated by an elevation in serum HDL and an attenuation of postprandial lipemia and the associated oxidative stress.

Reduction in ventricular arrhythmias — The major cause of cardiac mortality in patients with CHD is sudden death, which is primarily due to a life-threatening ventricular tachyarrhythmia. (See "Epidemiology and prognosis of coronary heart disease"). Lipid lowering in patients with CHD reduces the incidence of cardiac death and, among those with an implantable cardioverter-defibrillator, may reduce the rate of life-threatening ventricular arrhythmia (unstable ventricular tachycardia or ventricular fibrillation) [93,94]. (See "Pharmacologic therapy in survivors of sudden cardiac death", section on Lipid-lowering).

Other — Statin therapy has a variety of other effects that may contribute to improved outcomes in patients with CHD.

Reduced monocyte adhesion to the endothelium [95]. Monocyte recruitment into the vascular wall is important for the initiation and progression of an atherosclerotic lesion.
Reduced oxidative modification of LDL, which is thought to play an important role in the pathogenesis of atherosclerosis [96,97].
Increased mobilization and differentiation of endothelial progenitor cells, suggesting a possible role in new vessel formation [98,99].
There is some variability among the statins and fibrates on plasma fibrinogen and viscosity, which may be risk factors for coronary disease. Several small uncontrolled studies found that plasma fibrinogen levels rise with atorvastatin and lovastatin, may rise or fall with pravastatin, and are generally unchanged with simvastatin or fluvastatin [59,100,101]. Similar variability occurs with fibrates. Plasma fibrinogen tends to rise with gemfibrozil and fall with bezafibrate and fenofibrate [102].


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