High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels are inversely associated with adverse cardiovascular outcomes. Associations between these HDL-C–related measurements and coronary plaque progression have not been studied. We performed a retrospective analysis of 2,566 statin-treated patients with angiographic coronary artery disease who underwent serial evaluation of atheroma burden with intravascular ultrasound. Relations between achieved levels of HDL-related measurements with clinical characteristics and changes in plaque burden were determined. A strong correlation between HDL-C and apoA-I (r = 0.80, p <0.001) was observed. HDL-C, apoA-I, and the HDL-C:apoA-I ratio demonstrated negative correlations with the change in percent atheroma volume and total atheroma volume (all p ≤0.001). Increasing levels of achieved HDL-C:apoA-I (p = 0.04), but not HDL-C (p = 0.18) or apoA-I (p = 0.67), were associated with less progression of percent atheroma volume. Similar results were seen for change in total atheroma volume, with less progression seen with increased HDL-C:apoA-I (p = 0.002) but not with increases in HDL-C (p = 0.09) or apoA-I (p = 0.19). In conclusion, increasing levels of HDL-C:apoA-I associated with less progression of coronary atherosclerosis. This suggests that interventions increasing the cholesterol content of HDL particles may be of cardiovascular benefit.
We sought to characterize the relation between the presence of more highly cholesterol-rich high-density lipoprotein (HDL) particles and coronary plaque progression as determined by intravascular ultrasonography (IVUS). We used the ratio of HDL cholesterol (HDL-C) to apolipoprotein A-I (apoA-I), the main apolipoprotein associated with HDL, to serve as a surrogate for the size of an HDL particle, with a higher HDL-C:apoA-I ratio representing a larger and more cholesterol-rich particle. Specifically, we sought to determine if an increased HDL-C:apoA-I ratio was associated with changes in disease progression.
Methods
The current analysis included patients with angiographic coronary artery disease treated with a statin and with recorded HDL-C and apoA-I values in the following 6 IVUS trials: Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE; performed at 137 centers in North America and Europe from October 2003 to August 2004), Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE; performed at 52 sites in the United States from December 2002 to July 2005), A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Atheroma Burden (ASTEROID; performed at 53 sites in North America, Europe, and Australia from November 2002 to October 2005), Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation (PERISCOPE; performed at 97 sites in North and South America from August 2003 to March 2006), Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study (STRADIVARIUS; performed at 112 sites in North America, Europe, and Australia from December 2004 to December 2005), and Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN; performed at 208 centers in North America and Europe from January 2008 to June 2009).
The clinical trials evaluated serial changes in coronary atheroma burden using intravascular ultrasound in response to a cholesteryl ester transfer protein (CETP) inhibitor, an experimental inhibitor of acyl-coenzymeA:cholesterol acyltransferase, high-dose statins, antidiabetic drugs, or a cannabinoid receptor agonist. Any patient treated with experimental antiatherosclerotic agents was excluded from the current analysis to evaluate the association between HDL-related measurements and disease progression in patients treated with established therapies. In all trials, subjects were required to have coronary artery disease (≥20% luminal narrowing in a major coronary artery) on clinically indicated coronary angiography. For IVUS analysis, the target segment was required to have no >50% lumen narrowing for a length of at least 30 mm. The target vessel could not have undergone previous percutaneous coronary intervention. All participants provided written informed consent.
The technique of acquiring and analyzing IVUS images has been previously described in detail. After anticoagulation and administration of intracoronary nitroglycerin, a high-frequency (40 to 45 MHz) ultrasound transducer was placed as distally as possible within the target coronary artery. Images were acquired as the catheter continuously withdrew through the artery and back to the aorta at a constant rate of 0.5 mm/s through a motorized pullback. Images were digitized, and the analysis segments were selected using proximal and distal side branches as fiduciary points to allow for analysis of the same segment at follow-up. Images spaced 1 mm apart were selected for analysis. The leading edges of the lumen and external elastic membrane were traced by manual planimetry in accordance with IVUS guidelines from the American College of Cardiology and the European Society of Cardiology.
The primary end point of each of the trials, percent atheroma volume (PAV), was calculated as the percentage of vessel wall occupied by atherosclerotic plaque:
PAV = ( ( ∑ ( EEM area – lumen area ) ) / ( ∑ EEM area ) ) × 100 .
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