YELLOW II: Improved Cholesterol Efflux Linked to Plaque Stabilization in Statin-Treated Patients

WASHINGTON, DC—A new study of patients treated with intensive statin therapy reveals changes in plaque morphology, specifically a thickening of the fibrous cap, that are associated with improved cholesterol transport.

The researchers say the results—improved cholesterol efflux capacity contributing to the stabilization of plaque—suggest a potential mechanism underlying the beneficial effects of statin therapy in treated patients.

“Many studies have shown that if you treat patients with high-dose statins, plaque morphology changes, especially the cholesterol content within the plaque, along with changes in blood chemistry, such as LDL cholesterol, HDL cholesterol, and other apolipoproteins,” lead investigator Annapoorna Kini, MD (Icahn School of Medicine at Mount Sinai, New York, NY) told TCTMD. “We wanted to take things a little bit further and see exactly how the plaque morphology changes. We wanted to see exactly how the lipid is removed from the plaque.”

Kini noted that previous studies have shown statin therapy significantly reduces atheroma volume when assessed by IVUS and alters plaque lipid content when measured by near infrared spectroscopy. In addition, statin therapy has been shown to reduce the necrotic core and increase fibrous cap thickness when assessed by virtual histology and optical coherence tomography (OCT), respectively.

The present study, however, is an attempt to provide a wider snapshot of how high-dose statin therapy exerts its influence, as well as to study underlying changes in gene expression that result from treatment, said Kini. 

Better Efflux, Thicker Caps

The study, known as YELLOW II, published today in the Journal of the American College of Cardiology and slated for presentation Monday at TCT 2016 in Washington, DC, included 85 patients with stable multivessel coronary artery disease who underwent PCI for a culprit lesion. Patients also underwent multimodality imaging of an obstructive nonculprit lesion with OCT, near-infrared spectroscopy, and IVUS. Cholesterol efflux capacity was assessed by measuring the outflow of cholesterol from macrophages to apolipoprotein B (apoB)-depleted serum.  

Patients were treated with rosuvastatin 40 mg for 8 to 12 weeks and then follow-up imaging was performed. During the study period, total cholesterol levels were reduced from 153.3 mg/dL to 115.0 mg/dL, while LDL cholesterol decreased from 87 mg/dL to 50.6 mg/dL. In addition, there was an improvement in the apolipoprotein profile, while C-reactive protein (CRP) levels also declined. There was no change in HDL cholesterol levels.

At baseline, the minimal thickness of the fibrous cap was 100.9 µm, which increased to 108.6 µm after treatment. The prevalence of thin-cap fibroatheroma (TCFA), a high-risk plaque vulnerable to rupture, decreased from 20.0% to 7.1% (P = 0.003). “When the cap thickens, you know the plaque is becoming stable and is unlikely to rupture and cause problems,” said Kini.

The researchers also observed significant improvements in cholesterol efflux capacity, which measures the ability of HDL to promote the removal of cholesterol from lipid-laden macrophages. This is one of the initial steps in reverse transport that takes cholesterol from the periphery to the liver. On multivariate analysis, the change in fibrous cap thickness was independently associated with the increase in cholesterol efflux capacity.  

“Anybody who had thick fibrous cap, meaning the fibrous cap was thin at baseline but came back and then the fibrous cap thickness improved, they also had better cholesterol efflux and lower CRP levels,” Kini told TCTMD. “They received a statin, efflux is better, CRP goes down, and the cap thickens. They all correlated, suggesting it could be a mechanism. The biggest criticism is that since we did not have a control arm, we can’t be 100% clear that this is the mechanism. We can only postulate.”

Gene Expression

As part of the study, the researchers also evaluated gene expression in isolated samples of peripheral blood mononuclear cells before and after high-dose statin therapy. They identified 117 differentially expressed genes at follow-up compared with baseline, six of which were involved in cholesterol synthesis (SQLE), regulation of fatty acid unsaturation (FADS1), cellular cholesterol uptake (LDLR), cholesterol efflux (ABCA1, ABCG1), and inflammation (DHCR24).

SQLE, which is involved in the oxygenation step of sterol biosynthesis, and the other genes were “found to be most strongly associated with favorable outcomes” in terms of fibrous cap thickness and cholesterol efflux capacity.    

To TCTMD, Kini said the transcriptomic research is an attempt to isolate specific genetic biomarkers that might one day be used to identify responders to statin therapy, such as those who have improvements in plaque morphology and cholesterol efflux capacity and not simply reductions in LDL cholesterol levels. As Kini explained, physicians frequently encounter individuals who continue to have adverse clinical events despite improvements in LDL cholesterol levels.  

“The main reason this is important is because we treat patients day in and day out, but there are still a group of patients who come to us and say they are doing everything right,” said Kini. “They are taking their medicine and blood chemistry looks right, but they are still developing blockages. We don’t have an answer for this.”

Michael O’Riordan is the Associate Managing Editor for TCTMD and a Senior Journalist. He completed his undergraduate degrees at Queen’s…

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  • Kini A, Vengrenyuk Y, Shameer K, et al. Intracoronary imaging, cholesterol efflux, and transcriptomes after intensive statin treatment: the YELLOW II study. J Am Coll Cardiol. 2016;Epub ahead of print.

  • The research was supported by the investigator-sponsored study program of AstraZeneca, Infraredx, and the Mount Sinai catheterization laboratory endowment funds allocated to Kini.