Journal of the American College of Cardiology © 2007 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 49, No. 2, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2006.10.039


Atherosclerosis Regression, Vascular Remodeling, and Plaque Stabilization*
Lloyd W. Klein, MD, FACC Chicago and Melrose Park, Illinois

administered in 5 weekly infusions showed a 4.1% decrease in total atheroma volume (p Ͻ 0.001). Whether or not the small magnitude of plaque reduction that is observed leads directly to the improved outcomes in similarly designed clinical studies (4 – 6) is a provocative question. One possibility is that although the absolute amount of regression achieved is small, it may be sufficient to produce clinical benefit (7). However, the reduction in clinical events over the subsequent 1 to 2 years seems disproportionate to simply diminishing atheroma volume by Ͻ10% (8).
Which Components of the Plaque Are Most Likely to be Targets of Pharmacotherapy?

Improved characterization of the composition of plaque, advances in understanding the vascular biology of atherosclerosis progression, and the development of accurate imaging techniques that allow serial determinations of plaque morphology have created the opportunity for serious consideration of pharmacotherapeutic strategies to reverse atherosclerosis. Recent studies by Nissen et al. (1–3) show
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that atherosclerosis regression may be a realistic goal in some patients. Although the actual amount of plaque regression and compositional change is small, there may be substantial clinical benefit. Yet, the question arises: what is the therapeutic mechanism? Is it the reduced dimension of the plaque, the decreased atheroma burden, or the consequent compositional changes that confer the clinical improvement?
What Degree of Plaque Regression Has Been Achieved by Pharmacotherapy?

The lipid pool is a highly accessible target for statin therapy (8,9). Cholesterol esters can be mobilized if macrophage reverse cholesterol transport is activated (9,10). By increasing cholesterol efflux, either via the reverse cholesterol transport pathway (9) or by conversion to high-density lipoprotein esters via the cholesterol ester transfer protein pathway (11,12), an imbalance between the deposition and removal of vascular cholesterol after endothelial injury may be corrected. Fibrous tissue and ground substance would seem to be irreversible despite metabolic manipulation. However, statins have been shown to diminish smooth muscle cell accumulation and collagen deposition (13). Calcification also seems to be a nonreversible change, but this has not been formally evaluated. Conversely, inflammatory reaction in the forms of cellular migration, humoral substance release, and edema are obviously potential targets. Statins decrease inflammation, an effect correlated with clinical benefit (14 –16).
Regression and Stabilization: Is There a Relationship?

In the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial (1), median atheroma volume decreased (regressed) 0.4% in the high-dose statin group versus progressed 2.7% in the moderate-dose group over an 18-month period. In the ASTEROID (A Study to Evaluate the Effect of ROsuvastatin on Intravascular Ultrasound Derived Coronary Atheroma Burden) study (2), 63.6% of patients experienced regression and mean total atheroma volume decreased 7%, with a 1% decrease in percent atheroma volume, after 24 months of treatment. Intravenous recombinant apolipoprotein A1 Milano (3)

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Rush Medical College, Chicago, Illinois; and Gottlieb Memorial Hospital, Melrose Park, Illinois. Dr. Klein is on the Speakers’ Bureau for Pfizer, King, and Merck.

Decreasing endothelial injury, diminishing lipid content, and altering the cellular elements and inflammatory milieu in the subendothelial layer may ameliorate the susceptibility to plaque rupture. The targets of regression seem to be the same as those invoked in vulnerable plaque passivation. It is probably not coincidental that the smaller, lipid-rich plaques that are prone to rupture are also the ones most likely to regress (13), nor is it accidental that clinical trials evaluating the long-term effects of intensive pharmacotherapy identify study candidates as those with acute coronary syndromes (ACS) (3–7), or include them in large numbers (1,2). An important consideration is that vulnerable plaque is associated with positive remodeling, whereas nonvulnerable plaque undergoes negative remodeling. Plaques that show positive remodeling contain “soft” noncalcified plaque with large lipid cores and an active inflammatory process (17). Outward (or positive) remodeling is strongly associated with ACS and plaque rupture, whereas constrictive (or negative)

or whether atheroma volume decreased because of compression or actual decreases in atheroma tissue. 2. However. suggesting a complex relationship among these factors. Then. negative remodeling. The work of Nissen et al. calcification. In the investigators’ defense. but the data analysis implies that these are inseparable processes. male gender.18). Progression can be associated with a paradoxical increase in lumen cross-sectional area. lipoid. sets the stage for the development of a pharmacologic approach to producing regression of coronary atherosclerosis.03). Also. (27) in this issue of the Journal are extraordinarily relevant to understanding the vascular response to statin and antihypertensive therapy. It will also be important to correlate traditional risk factors with mechanisms of disease and potential response to therapy. and determined that the more calcified atheromas were resistant to change. IVUS is not the best imaging technique for reconciling these relationships. and age Ͼ80 years. and complicated lesions) results in transformation to types VII to VIII (calcific and fibrotic lesions). then improved imaging techniques that reliably identify it are required. patients could be treated acutely with intravenous infusions of various agents to induce stabilization and regression. fibroatheromas. and a history of prior revascularization are independent predictors of atherosclerotic burden (25). It is intuitive that remodeling is probably one aspect of regression. Schartl et al. because current studies exclude lesions with Ͼ50% luminal narrowing. No. whereas decreasing lipid content in lesion types IV to VI (atheromas. In the ESTABLISH (Early Statin Treatment in Patients With Acute Coronary Syndrome) trial (23). whereas regressors show negative remodeling (20). The development of therapeutic programs of the future depend on understanding the mechanisms of disease . These data further suggest an overlap between the concepts of passivation and regression. the natural history of these plaques must be definitively established for therapeutic judgments to be made once they are found (Table 1). and have been shown to have the potential for the greatest degree of regression (24. Progressors show positive remodeling. They did not describe whether the luminal dimension increased. New Findings Do vulnerable plaques manifest in a focal or diffuse manner within an atherosclerotic coronary segment? How frequently do they occur compared to stable or hard plaques? How far in advance of clinical events do they appear? Do they herald plaque rupture or progression routinely or just occasionally? What is the probability of a vulnerable plaque becoming active in the future? Over what time frame? Can they heal spontaneously without clinical significance or events? ● ● ● ● An important drawback of the study is that the investigators did not analyze whether constrictive remodeling is ascribable to diminished volume of hypolucent plaque on the IVUS. early statin treatment in patients with ACS resulted in regression of atherosclerotic lesions 6 months later. suggesting that the elderly may be less responsive to medical therapy (29). For example. Plaque volume was reduced 13% from baseline in the atorvastatin-treated group. 2007:271–3 remodeling is more common in patients with stable angina (17. whether or not high-grade lesions are less responsive to medical therapy cannot be addressed directly (8). either progression or regression. (22) found that the hyperechogenicity index (composed of dense fibrous or elastic tissue) increased in atorvastatin-treated patients.272 Klein Editorial Comment Questions of Soft and/or Regarding Vulnerable Location Plaques Questions Regarding Location Table 1 of Soft and/or Vulnerable Plaques ● JACC Vol. Conversely. the findings of Nicholls et al. Treatment with statins is associated with constrictive remodeling (21). the relationship between atherosclerosis regression and constrictive remodeling is ambiguous. and then placed on long-term oral therapy for further improvement and maintenance. A secondary conclusion is that imaging techniques that assess clinical response to therapy on the basis of changes in the degree of calcification may be theoretically flawed.25). Diminished lipid core. In the Stary classification (26). either progression or regression. If potentially vulnerable plaque is the form of atherosclerosis most amenable to regression. The findings suggest that the various components of atheroma respond differently to treatment with medical therapies. regression of types I to III (early and preatheroma) to normal is possible. and small changes in plaque size are observed in response to intensive lipid lowering (19). obstructive stenoses do remain capable of compensatory remodeling. A better comprehension of where soft and vulnerable plaques are located within a field of atherosclerosis is necessary to develop imaging techniques most apt to reliably find them. whereas calcification and hypoechogenic plaque (loose fibrous. There is also an association between negative remodeling. Because the remodeling index is calculated at the worst single site but atheroma volume is summated in multiple slices. whereas regression is not associated with any change in lumen area. and can be used to target plaques that are likely to respond. and necrotic tissue) remained constant. The qualities shared by drug-induced quiescence of the potentially vulnerable plaque and regression of soft plaque suggests that stable atheromas would be more resistant to regression. but increased 9% in the control group (p Ͻ 0. and it is not the most accurate method for quantifying calcification. 2007 January 16. In the future. less calcification was a sign of potential for significant changes over time. The investigators re-examined the intravascular ultrasound (IVUS) findings in the REVERSAL and NORMALIZE studies (28). diabetes. How May These Observations Alter the Diagnostic and Therapeutic Approach to Patients? In this context. 49.

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