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Comment & Response
July 17, 2019

Are Atherogenic Lipoprotein Phenotype and Inflammation Indicative of Plaque Phenotype and Clinical Stability in Coronary Artery Disease?—Reply

Author Affiliations
  • 1Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica Sacro Cuore, Rome, Italy
  • 2Cardiovascular Unit, Department of Internal Medicine and Specialties (DIMI), Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, Università di Genova, Genova, Italy
JAMA Cardiol. 2019;4(9):951-952. doi:10.1001/jamacardio.2019.2231

In Reply We appreciate the interest of Lechner and Halle in our study assessing the coronary atherosclerotic phenotype and plaque healing by optical coherence tomography (OCT) imaging in patients at the extremes of the coronary artery disease spectrum.1 We fully agree with their perspective about the need to identify patients with high-risk atherosclerotic disease using circulating biomarkers, such as atherogenic lipoproteins and markers of inflammation, as intracoronary imaging tools like OCT are not always available or feasible and are costly. Twenty-five years ago, our group found that high levels of circulating C-reactive protein (CRP), a prototypic marker of inflammation, portended a worse outcome in patients with acute coronary syndrome (ACS) and proposed that plaque inflammation might be associated with a high-risk plaque phenotype culminating into plaque fissure.2 More than 2 decades later, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial3 has convincingly proved the inflammatory hypothesis of ACS, showing that interleukin 1β inhibition by canakinumab in patients with a history of myocardial infarction and high-sensitivity CRP levels greater than 2 mg/L (to convert to nanomoles per liter, multiply by 9.524) resulted in a 15% reduction in the rate of the primary composite end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death compared with placebo. In our study, patients with recurrent ACS had higher systemic levels of high-sensitivity CRP and greater local macrophage infiltration at OCT imaging.1 Furthermore, another 2019 study from our group4 demonstrated that the combination of systemic inflammation (ie, high CRP levels) with OCT high-risk features (ie, plaque fissure, macrophage infiltration, and multifocal atherosclerosis) was highly predictive of ACS recurrence. We agree that atherogenic lipoprotein phenotype represents another key factor to be considered for risk stratification in ACS. An elegant study by Takata et al5 correlated the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio with the presence of vulnerable plaque features at OCT imaging in patients with diabetes and coronary artery disease receiving statin treatment. Interestingly, a high TG:HDL-C ratio was correlated with the lipid pool size and with the presence of cholesterol crystals, both hallmarks of high-risk plaques, and this association was independent of low-density lipoprotein cholesterol levels.5 We checked the TG:HDL-C ratio values for the patients included in our study,1 and we found a significant association of TG:HDL-C ratio with both plaque phenotype and clinical presentation. Of note, the median (interquartile range) TG:HDL-C ratio was significantly higher in patients with thin-cap fibroatheroma than in those without (3.85 [2.96-6.22] vs 2.31 [1.29-4.17]; P = .008) and nonsignificantly higher in patients with multiple recurrent ACS than in those with long-standing stable angina (3.34 [1.72-5.19] vs 2.20 [1.15-3.30]; P = .07). To further highlight the importance of these factors, mounting evidence suggests that dyslipidemia, in turn, aggravates the inflammatory response initiated in the bone marrow through activation of the transcription factor sterol regulatory element-binding protein 2,6 supporting the hypothesis that cholesterol metabolism may be a driver of inflammation in atherosclerosis.

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