We read with interest the study by Nozue et al, who investigated clinical and lesion-related factors associated with coronary plaque progression versus regression in statin-treated patients. The investigators reported that arteries showed increase in external elastic membrane (EEM) volume from baseline to follow-up (i.e., positive arterial remodeling) during plaque progression, as opposed to decrease in EEM volume (i.e., negative remodeling) during plaque regression. The study adds new insights to an important clinical issue, but it also raises a critical question: could the assessment of arterial remodeling be used to predict which statin-treated patients will subsequently develop plaque progression versus regression?
Systemic proatherogenic factors and antiatherosclerotic drugs (e.g., statins) critically affect the development and progression of coronary atheroma. However, in patients exposed to similar systemic risk factors or antiatherosclerotic mediations, plaques progress, remain quiescent, or regress in an independent manner, largely because of the concomitant effect of locally acting factors. These local factors include arterial remodeling and hemodynamic factors, particularly endothelial shear stress (ESS). Positive (expansive) remodeling is associated not only with high-risk plaque morphology and unstable clinical presentation but also, prospectively, with more pronounced additional plaque growth compared to lesions with negative (constrictive) remodeling. Lesions with positive remodeling generally have larger luminal dimensions and hence low local ESS, which promotes plaque growth, whereas plaques with constrictive remodeling have smaller lumens and hence higher (i.e., atheroprotective) ESS.
Nozue et al correctly assessed arterial remodeling serially by comparing the change of EEM volume from baseline to follow-up. Arterial remodeling, however, can also be assessed at a single time point by comparing the EEM and luminal dimensions of an atherosclerotic segment to a nondiseased reference segment or to the global remodeling of the entire artery. Assessment of remodeling at baseline in the study by Nozue et al might have provided additional prognostic information to identify plaques that subsequently progressed or regressed. Indeed, patients whose plaques eventually increased (so-called progressors) had slightly larger EEM, substantially larger lumens, and smaller plaque volume at baseline compared to regressors. These data likely suggest that progressors harbored smaller lesions with presumably positive remodeling and with a lesser extent of luminal stenosis and hence with lower (i.e., athero-prone ) local ESS at baseline. These baseline plaque characteristics might have contributed to the observed plaque growth among progressors, despite the similar statin doses, and despite the lower low-density lipoprotein and greater low-density lipoprotein reduction compared to regressors.
The systemic atheroprotective effects of statins and the local proatherogenic effects of lesion-specific hemodynamics are likely interrelated. In experimental models, statins attenuate the proatherogenic effect of low ESS and exert a vasculoprotective effect that is modulated by the local ESS. Consistently, varying local hemodynamic conditions might differentially affect the atheroprotective impact of statins in man and might thus account in part for the highly discordant plaque behavior in patients treated with equivalent statin regimens.
Given the additive role of systemic and local factors in the regulation of coronary artery disease, combined assessment of systemic risk factors, drug effects, and lesion-specific characteristics (e.g., arterial remodeling and local hemodynamics) might enhance the early identification of patients at highest risk to develop advanced coronary plaques. Consequently, intensifying the control of systemic proatherogenic factors (e.g., by using higher statin doses) in patients with plaque-prone local arterial characteristics might be a reasonable, risk-tailored approach to halting coronary plaque progression and averting adverse clinical events in the current era of optimal medical therapy.