Is Atherosclerosis Regression a Realistic Goal of Statin Therapy and What Does That Mean?
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- Singh, M. & Bedi, U.S. Curr Atheroscler Rep (2013) 15: 294. doi:10.1007/s11883-012-0294-4
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Atherosclerosis is a complex disease associated with aberrant lipoprotein metabolism and leukocyte infiltration into arterial tissue that leads to cardiovascular diseases. Statins have emerged as among the most effective means of reducing the risk of cardiovascular disease in both primary and secondary prevention settings. Statins are the only pharmacological agents that have been consistently shown to have antiatherosclerotic effects. Statins slow atherosclerosis progression and can even induce atherosclerosis regression. Technological advances in imaging modalities to assess atherosclerosis have made possible direct visualization of atherosclerotic plaques and estimation of plaque burden and permit the evaluation of the impact of medical therapies on the natural history of plaque progression. However, owing to several limiting factors as discussed in this review, presently atherosclerotic plaque progression cannot be used as a therapeutic goal for reduction of the risk of cardiovascular disease. In this review we discuss the evidence for the use of imaging modalities in the detection of atherosclerotic plaque regression, the effects of statins on the atherosclerotic process, and the clinical relevance of atherosclerosis regression.
KeywordsStatinAtherosclerosis regressionVascular imaging
Atherosclerosis is a complex disease associated with aberrant lipoprotein metabolism and leukocyte infiltration into arterial tissue  that leads to cardiovascular diseases (CVD). Atherosclerotic CVD is the leading cause of morbidity and mortality in the Western world  and has been the leading cause of death for the past 50 years . Statins have emerged as among the most effective means of reducing the risk of CVD in both primary and secondary prevention settings [4–8]. Subclinical atherosclerosis develops and progresses slowly over many decades, before suddenly causing clinical manifestations . Research has been focused on finding markers for early detection of atherosclerosis, and various imaging modalities, including ultrasonography for assessment of carotid intima–media thickness, computed tomography (CT) for assessment of coronary calcium content, and intravascular ultrasonography (IVUS) for assessment of coronary atheroma volume, have been promising. Emerging approaches are evaluating endothelial function, plaque composition, and imaging with novel, noninvasive modalities, including CT and MRI. In this review we discuss the evidence for the use of imaging modalities in the detection of atherosclerotic plaque regression, the effects of statins on atherosclerotic process, and the clinical relevance of atherosclerosis regression.
Pathogenesis of Atherosclerosis
Atherosclerosis is a dynamic process, with continuous molecular and cellular activity within the atherosclerotic plaques . Initiation of atherosclerosis involves a complex interplay between oxidative stress, inflammatory stimuli with chemokines, proinflammatory cytokines such as tumor necrosis factor α and interleukin-1, and the infiltration of oxidized low-density lipoproteins (LDLs) that cause endothelial dysfunction . Various risk factors, such as elevated LDL cholesterol (LDL-C) levels, smoking, and hypertension, cause stress on the arterial wall, resulting in endothelial dysfunction and the onset of atherosclerosis [12, 13]. The first stage in atherosclerotic lesion formation is a thickening of the intima that results from proliferation of smooth muscle cells. Atherosclerosis progresses with the accumulation of lipids, carbohydrates, blood products, fibrous tissue, and calcium deposits within the lesions, resulting in hard, calcified plaques [13, 14]. The development of a lipid-rich plaque initiates inflammatory processes that include recruitment of circulating macrophages and subsequent phagocytosis of oxidized LDL-C particles by these inflammatory cells . Initially, the atherosclerotic lesion grows into the vessel wall, maintaining the diameter of the vessel lumen and thereby having little effect on blood flow . However, further lesion progression may result in plaques protruding into the lumen of the artery, narrowing the vessel and ultimately leading to occlusion . Animal and human studies indicate that atherosclerosis, to some extent, is a reversible process. It has been shown, in humans, that plaque stabilization using lipid-lowering agents leads to a reduced incidence of serious cardiovascular events . Strategies that stabilize atheromatous plaques could also promote plaque regression . Atherosclerosis regression has been defined differently with different modalities.
Statins and Atherosclerosis
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are the only pharmacological agents that have been consistently shown to have antiatherosclerotic effects. Statins slow atherosclerosis progression and can even induce atherosclerosis regression. Antiatherosclerotic effects of statins have been postulated to be LDL-related and non-LDL-related or pleiotropic effects. Cholesterol, in particular lipoproteins containing apolipoprotein B, is intimately involved in the initiation, progressive growth, and ultimately local disruption of plaques. Several studies using statins have shown that lowering of lipid levels with statins leads to plaque stabilization. Statins affect the plaque lipid pool composition and reduce inflammation , thus leading to plaque stabilization and, potentially, regression. The pleiotropic effects of statins include anti-inflammatory and antiplatelet activity, and enhanced nitric oxide production. These effects play an important role in plaque stabilization and the clinical benefits observed with the use of these agents .
Imaging of Atherosclerosis
Technological advances in imaging modalities to assess atherosclerosis have made possible direct visualization of atherosclerotic plaques and estimation of plaque burden and permit the evaluation of the impact of medical therapies on the natural history of plaque progression. These techniques differ according to their ability to visualize the vessel wall and/or the lumen, their resolution, invasiveness, exposure to radiation, and robustness in terms of established links with clinical outcomes [22••]. These tests measure a wide variety of characteristics of vascular anatomy and physiology, which all reflect the atherosclerotic disease process, progression/regression, and plaque stability. Most current evidence is based on measurement of luminal stenosis and plaque burden with these techniques.
Statins and Carotid Intima–Media Thickness
B-mode ultrasonography of the carotid arteries quantifies carotid intima–media thickness (CIMT) as a marker of atherosclerotic burden. B-mode ultrasonography allows early atherosclerotic changes in the walls of the carotid arteries to be seen (these have been shown to correlate with CIMT) and has been standardized for measurement of CIMT . An association between increased CIMT and CVD has been demonstrated in a number of studies in different populations including both symptomatic and asymptomatic patients [24–30]. The advantage of B-mode ultrasonography for the assessment of CIMT is its noninvasiveness, which allows data collection in lower-risk populations. However, the data are collected in the carotid arteries and not directly in the coronary arteries. Amarenco et al.  in their meta-analysis of nine randomized controlled trials of stroke patients found a strong relationship between reduction in LDL-C levels with statin therapy and reduction in CIMT, implying regression of atherosclerosis with statin therapy. Similarly, we found direct correlation between reduction of LDL-C levels with statin therapy and CIMT reduction . With serial CIMT measurements, three trials [33–35] showed slowing of progression of carotid atherosclerosis, whereas seven [36–42] revealed regression of carotid atherosclerosis. In the LIPID trial , progressive benefit with prolonged statin therapy was seen. The carotid wall thickness was unchanged at 2 years of therapy, decreased at 4 years after starting the treatment, but continued to increase in the placebo group. The difference between the treatment and placebo groups was statistically significant at both 2 years (P = 0.03) and 4 years (P < 0.001). This implies that early benefit from statin therapy may be due to plaque stabilization, whereas in the long term, statins cause measurable regression of atherosclerotic plaques. Mercuri et al.  performed serial CIMT measurements every 6 months for up to 3 years in asymptomatic hypercholesterolemic patients randomly assigned to pravastatin or placebo and demonstrated that statins significantly slowed progression of atherosclerosis as measured by CIMT (−0.0043 mm/year in the statin group vs. +0.009 mm/year in the placebo group, p < 0.0007). This implies a persistent and progressive benefit seen with statin therapy with regard to the atherosclerotic process.
Statins and IVUS
IVUS is an accurate and reproducible method to measure atheroma burden and can be used to evaluate progression of coronary atherosclerosis. IVUS is a particularly good method for assessing atherosclerosis because it allows measurement of atheroma burden, not just luminal narrowing . IVUS allows the earlier stage of eccentric growth and intramural atheroma formation to be quantified and followed . IVUS is currently the most used imaging technique for arterial wall imaging  as it allows good axial resolution (80 μm for a 20–40-MHz IVUS transducer)  and three-dimensional measurement of soft tissue. IVUS has also been shown to provide a close correlation with the histological features of the plaque and thus constitutes a reliable method for the assessment of plaque morphology and atherosclerotic burden determination. With IVUS, the percent atheroma volume is a commonly used measure of atheroma burden and is derived from the external elastic membrane and luminal elastic membrane [19•]. Despite its usefulness, IVUS is limited by its invasive nature, exposure to radiation, and the fact that not all coronary lesions can be interrogated with this technique .
The recent application of IVUS in progression–regression trials permitted systematic assessment of the effects of various therapies including satins on various components of the vessel, including the atheroma itself [49–52]. Nicholls et al.  pooled data from four prospective randomized trials, in which 1,455 patients with angiographic evidence of coronary artery disease (CAD) underwent serial measurements using IVUS while receiving statins for 18 or 24 months. The rate of change in plaque volume was independently associated with the LDL-C level achieved during treatment and the change from the baseline in high-density lipoprotein cholesterol (HDL-C) level. Substantial plaque regression, defined as a 5 % or greater reduction in plaque volume, was observed in patients who achieved LDL-C levels below the mean of 87.5 mg/dl and HDL-C level increases above the mean of 7.5 %. These findings suggest that the benefits of statin therapy on atherosclerosis may be derived from both decreases in the level of LDL-C and increases in the level of HDL-C [54••]. In a meta-analysis of eight randomized trials using serial IVUS measurements, we found that treatment with statins in high-risk patients with diabetes mellitus or coronary heart diseases not only slowed the progression, but also led to regression of coronary atherosclerosis . In the trials showing plaque regression [51, 56], there was an average 8.7 % reduction in plaque volume after treatment with statins (mean treatment duration of 14 months). The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL)  and GAIN  trials showed a slower rate of atherosclerosis progression in the aggressively treated groups than in the placebo groups (the increase in plaque volume in the aggressively treated group was 3.3 % vs. 8.6 % in the placebo group). In the REVERSAL trial , the rate of atherosclerosis progression measured by IVUS during an 18-month follow-up of 502 CAD patients treated with either moderate statin therapy (pravastatin 40 mg/day) or intensive statin therapy (atorvastatin 80 mg/day) was correlated with changes in the levels of both LDL-C and C-reactive protein (CRP), a biomarker of systemic inflammation. Patients who achieved greater-than-median reductions in the levels of both LDL-C and CRP had significantly less atherosclerosis progression than those with less-than-median reductions in the levels of these markers (p = 0.001). These findings provide further evidence of the long-term benefits of statin therapy in slowing or reversing the atherosclerotic process.
Statins and Coronary Artery Calcium Score
CT without administration of contrast material allows the quantification of coronary calcification, which is a surrogate marker for atherosclerosis in coronary vasculature. Total calcium load in the coronary tree can be quantified using various algorithms to generate a calcium score [59–61] that correlates well with conventional risk factors for CAD . The predictive value of the overall calcium score for future coronary events is well established, and an incremental value of calcium scores over clinical risk assessment in selected patient groups with intermediate risk has been shown [63–66, 67•]. A recently published study [67•] comparing the coronary artery calcium (CAC) score with the ankle brachial index, the level of high-sensitivity CRP, and family history in intermediate-risk individuals concluded that the CAC score was an independent predictor of incident CHD/CVD in intermediate-risk individuals. Moreover, the CAC score provided superior discrimination and risk reclassification compared with other risk markers. Using electron-beam CT, Callister et al.  showed a reduction in the coronary calcium volume score after aggressive lowering of the LDL-C level with statins. Although the calcium score predicts risk, it does not localize the site of plaques prone to rupture. High-grade stenotic lesions causing chronic, stable angina pectoris often demonstrate dense calcifications. In contrast, high-risk culprit lesions causing acute coronary events are frequently not calcified or are minimally calcified and may not be reflected by calcium scoring . It is also not well understood how plaque stabilization affects individual lesion calcification during progression/regression, and results of CT studies examining dynamic changes in the calcium volume score during pharmacological therapy have been inconclusive [68, 70–72]. CT calcium scoring is an established tool for initial risk assessment, but has currently limited value as an end point in serial progression/regression trials. CT coronary angiography allows identification and quantification of calcified and noncalcified coronary plaques [73–76]. Precise quantification is limited and it is unclear whether the CT assessment of the coronary plaque burden is accurate in stratifying cardiac risk and whether it adds to the calcium score [77, 78].
Statins and MRI
Cardiac MRI is another noninvasive tool that allows imaging of the vessel wall and can not only provide useful information regarding the plaque volume change, but also has been shown to provide adequate identification of plaque composition and activity, although its low resolution (0.6–0.8 mm) compared with IVUS is a disadvantage . Recently, cardiac MRI has been shown to be useful for the assessment of inflammatory activity within plaques [80••], which may enhance the utility of this imaging technique. Several studies have examined the effect of statin therapy on atherosclerotic plaque size in noncoronary vessels such as the carotid arteries [81–83] and the aorta [83–85]. Most of these studies were limited by small sample size, but the results have been promising as these showed evidence of plaque regression and two studies revealed stabilization of the plaque by reduction of the level of the lipid component, enhanced fibrosis, and reduced inflammation [81, 83] with statin therapy.
Atherosclerosis Regression as a Therapeutic Goal
Atherosclerosis regression as a therapeutic goal
Current data indicate that atherosclerosis is reversible at least partially
A relationship between atherosclerotic regression seen on imaging and clinical outcomes has not yet been unequivocally established
Technology is available to measure atherosclerotic surrogates
Standardization and interpretation of imaging techniques for wide application is lacking
Technology is available to measure atherosclerotic plaques directly
A standard definition of atherosclerosis regression is lacking
Medications are available that have been shown to slow and reverse the atherosclerotic process, making it an objective evaluation
The long time course of the atherosclerotic process and serial imaging of atherosclerotic plaques is expensive
Advanced imaging techniques such as measurement of CIMT and CT-based assessment of CAC offer the potential to identify subclinical atherosclerotic plaque burden. On the basis of current evidence, these imaging technologies are best used in asymptomatic individuals considered to be at risk, where test results can improve risk stratification and affect the intensity of the therapeutic intervention. Current evidence indicates that intensive statin therapy not only slows the progression of atherosclerosis but may even cause atherosclerosis regression. However, owing to several limiting factors as stated herein, presently atherosclerotic plaque progression cannot be used as a therapeutic goal for CVD risk reduction.
No potential conflicts of interest relevant to this article were reported.
Sources of Funding
There were no external funding sources for this study.