Author + information
- Published online June 4, 2018.
- aDalio Institute of Cardiovascular Imaging, Weill Cornell Medical College and NewYork–Presbyterian Hospital, New York, New York
- bUniversity of Minnesota School of Medicine, and VA Medical Center, Minneapolis, Minnesota
- cIchan School of Medicine at Mount Sinai, New York, New York
- ↵∗Address for correspondence:
Dr. James K. Min, Dalio Institute of Cardiovascular Imaging, NewYork–Presbyterian Hospital and Weill Cornell Medicine, Radiology, 413 East 69th Street, Suite 108, New York, New York 10021.
Since the publication of the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial more than 10 years ago, high-intensity statin therapy has become an integral part of the therapeutic regimen for patients presenting with acute coronary syndromes (ACSs). In this study of 4,162 patients presenting with ACS randomized to high-dose (80 mg atorvastatin per day) versus standard-dose (40 mg pravastatin per day), patients receiving high-dose statin therapy experienced a 28% reduction in major adverse cardiac events (1). Within this study, the salutary effects of statins were proven beneficial in both the immediate-term (<30 days) as well as the long-term (>6 months) period following drug initiation (2). High-intensity statin use is associated with a rapid reduction in low-density lipoprotein cholesterol, with patients receiving high-dose atorvastatin in the PROVE IT-TIMI 22 trial achieving levels of 60 mg/dl within 30 days. Yet despite its proven clinical effectiveness, the mechanism of how statins influence atherosclerotic plaque substrate to exert such profound benefit—particularly in the immediate period surrounding the ACS event—has not been established.
An array of elegant pathology studies led to the concept of a “culprit” lesion or plaques prone to rupture—such plaques are thought to mediate ACS in a majority of such patients (3). These coronary atherosclerotic lesions share several common morphologic features. Ruptured plaques are often voluminous, occupying more than one-half of the cross-sectional area of the artery, and expanded outwardly to maintain coronary luminal integrity. However, although many plaques show such morphology, ACS events are more selective and identifying “plaques that could rupture” becomes an important preventive and therapeutic goal. An important observation was that rupture often happens at the shoulders of the fibrous cap separating the plaque necrotic core and the lumen. Plaques with thin fibrous caps seemed to better predict those prone to rupture; because these plaques often contained large lipid-rich intra-plaque cores, and were infiltrated by inflammatory cells such as macrophages, it appeared that a dynamic interplay between plaque thickness, amount of plaque inflammation, and size of the necrotic core explained some of the proclivity towards rupture and a clinical ACS event. The advent of imaging allows us to measure some of these adverse components and there has been much focus on altering or tempering each of these detrimental plaque morphologies. One of the most promising areas might be strategies to thicken the plaque fibrous cap.
For stable patients undergoing high-dose statin therapy, long-term serial analysis of coronary atherosclerosis by intravascular ultrasound have identified overall percent atheroma volume regression, with significant changes in morphologic plaque characteristics (4,5). In particular, fibro-fatty plaque volume decreases while dense calcified plaque volume increases. By optical coherence tomography (OCT), an invasive imaging method with very high spatial resolution capable of characterizing the fibrous cap thickness of a coronary atherosclerotic lesions, chronic statin pre-treatment is associated with a lower prevalence of thin cap fibroatheromas at the time of ACS (5,6).
There is some evidence that statins can thicken the fibrous cap. Yet the specific effect of de novo initiation of statins on plaque morphology has been scantily studied to date. In this issue of iJACC, Nishiguchi et al. (7) report the results of a single-center randomized controlled trial using serial OCT on patients presenting with ACS who were evaluated at baseline, 3 weeks, and 36 weeks after event. In their study, patients were randomized to receive moderate-intensity statins (pitavastatin 4 mg per day) immediately versus after 3 weeks from presentation. The intent of this study was to determine the morphologic effects of statins on nonculprit coronary plaques in the immediate term.
At the 3-week OCT evaluation, patients treated with statins from the time of event showed increasing fibrous cap thickness (140 μm to 160 μm), unlike those in whom statins were deferred for 3 weeks (fibrous cap thickness; 135 μm to 130 μm). Notably, at the 36-week evaluation, the fibrous cap thickness of the early (230 μm) versus late (200 μm) statin treatment groups did not differ. Further, in both groups, the maximum lipid arcs and lipid lengths decreased at 36 weeks, whereas these changes were not evident in either group at 3 weeks. Although simple, these findings significantly advance our understanding of the immediacy of effects of statin therapy at the time of ACS. Rather than regression of plaque, which has been posited as a mechanism of benefit in long-term treatment with statins, these current study findings are consistent with the ability of statins to exert near-term effects (8) that could cause early phenotypic changes in the morphologic features of coronary plaques.
Despite these novel study findings, numerous questions remain which may reduce generalizability. Although 70 patients were randomized into this trial, only 53 patients completed follow-up. Although baseline characteristics were similar between the early and late statin groups, it nevertheless renders this study susceptible to selection biases that may have skewed the trial results. Further, while it is described that OCT was performed on nonculprit lesions of intermediate stenosis severity, the lesion number and exact location within the coronary vascular bed remain unknown. Notably, at baseline, the minimum lumen area of interrogated coronary lesions was more 5.45 mm2, suggesting that these plaques displayed moderate stenosis severity rather than severe stenosis, which is often the target of revascularization. Also, the fibrous cap thickness, the most important determinant of plaque vulnerability, was not in the range that would render plaques into high-risk category.
As with all provocative studies, this trial engenders more questions than it answers. As an example, is this thickening of the fibrous cap of nonculprit coronary lesions a sign of “stabilization” or merely a universal effect of statins on all plaques? If this is a marker of stabilization, is regression of this plaque required to avoid future ACS events (9)? Long-term serial evaluation by OCT of post-ACS plaques, while admittedly difficult to perform, would be highly useful to examine the natural history of statin therapy on coronary atherosclerosis and whether these morphologic changes to fibrous cap thickness and lipid content are associated with improved event-free survival. Further, while the high spatial resolution of OCT allows it to excel at characterization of the fibrous cap and, to a lesser degree, lipid content and macrophage infiltration (the latter of which was not evaluated in this study), it nevertheless suffers from its inability to volumetrically quantify and clarify plaque type as calcified, fibrous, fibrolipoid, or necrotic core. Such findings would be undoubtedly an additive for helping to clarify the effects of statins on plaque. The information derived from improved plaque characterization would further enable physiologic characterization of shear stresses around different types of plaque—which are central to the pathogenesis of thin cap fibroatheromas—by fluid dynamics and fluid structure interactions (10). While this study did provide information on the timeline for fibrous cap thickening, statin therapy was withheld for 3 weeks in the late treatment arm for patients presenting with ACS; while consistent with their local practice this is not consonant with current U.S. and European practice guidelines. Yet, this study design offers unique insights into the immediate and intermediate-term effects of statins on atherosclerotic plaque features. Despite these limitations, the authors should be commended for their study, given how difficult it is to perform serial invasive imaging and execute a study in a randomized fashion. It clarifies the mechanistic underpinnings for the advantage of early statin use in terms of plaque stability and can encourage new therapeutic modalities guided by intravascular or noninvasive imaging of plaque components.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Harvey Hecht, MD, served as the Guest Editor for this paper.
- 2018 American College of Cardiology Foundation
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