Progression Of Percent Atheroma Volume Research Articles

The natural history and prediction of 10-year plaque progression on serial coronary CT angiography

Abstract Background Several studies have shown that plaque subcomponents such as low-attenuation or non-calcified plaque volume from coronary CT angiography (CCTA) are associated with the occurrence of major adverse cardiovascular events. However, it remains unknown how plaque morphology progresses over the long-term. Furthermore, it is unknown which plaque characteristics put patients at increased risk of plaque progression which would require more intensive image-guided follow-up. This study investigated the natural history and predictors of long-term coronary plaque progression in a serial CCTA cohort of patients with suspected coronary artery disease (CAD). Methods In this follow-up study, 539 patients from an earlier published CCTA cohort (Diemen, 2021) were invited for repeat CCTA imaging per-protocol, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [8.7-11.2] years. Patients who underwent coronary artery bypass grafting (CABG) between baseline and follow-up imaging were excluded. All scans were analyzed using artificial intelligence-guided quantitative CCTA (AI-QCT). Revascularized vessels were excluded. Quantitative plaque volumes (total, low-density, non-calcified and calcified plaque) depicted by AI-QCT were divided by the total vessel volume to represent percent atheroma volume (PAV). PAV progression was calculated subtracting baseline PAV from follow-up PAV. The association of the plaque components with PAV progression was evaluated in a multivariate linear regression model adjusted for clinical risk characteristics (age, sex, hypertension, hypercholesterolemia, diabetes, BMI, smoking, family history of CAD and statin use). Results In total, 274 patients without CABG were used for the serial analysis, mean age was 57 years, 42% were women. At baseline, median PAV was 2.5% [IQR 0.7-8.1], which increased to 6.1% [IQR 1.2-12.9] at follow-up (Figure). The mean PAV progression was 0.4±0.5% per year. Adjusted for clinical risk characteristics and other plaque volumes, baseline percent non-calcified plaque volume (NCP) was the only plaque volume associated with PAV progression (0.5% PAV progression increase per % increase in baseline non-calcified plaque volume). Conclusion Using an unique long-term serial CCTA cohort undergoing per-protocol repeat imaging with a 10-year scan interval, we found that coronary plaque burden more than doubled. Interestingly, the amount of non-calcified plaque volume at baseline was the only predictor for disease progression.Figure

Plaque Progression Differences Between Apixaban and Rivaroxaban in Patients With Atrial Fibrillation Measured With Cardiac Computed Tomography and Plaque Quantification.

Direct oral anticoagulants (DOACs) have been associated with less calcification and coronary plaque progression than warfarin. Whether different DOACs have different effects on coronary plaque burden and progression is not known. We compared the 12-month effects of apixaban and rivaroxaban on plaque characteristics and vascular morphology in patients with atrial fibrillation through quantitative cardiac computed tomographic angiography. In patients with nonvalvular atrial fibrillation using apixaban or rivaroxaban, are there differences in plaque quantification and progression measured with cardiac computed tomography? This is a post hoc analysis of 2 paired prospective, single-centered, randomized, open-label trials with blinded adjudication of results. In total, 74 patients were prospectively randomized in parallel trials: 29 to apixaban (2.5-5 mg BID) and 45 to rivaroxaban (20 mg QD). Serial cardiac computed tomographic angiography was performed at baseline and 52 weeks. Comprehensive whole-heart analysis was performed for differences in the progression of percent atheroma volume (PAV), calcified plaque (CP) PAV, noncalcified plaque (NCP) PAV, positive arterial remodeling (PR) ≥1.10, and high-risk plaque (Cleerly Labs, New York, NY). Both groups had progression of all 3 plaque types (apixaban: CP 8.7 mm 3 , NCP 69.7 mm 3 , and LD-NCP 27.2 mm 3 ; rivaroxaban: CP 22.9 mm 3 , NCP 66.3 mm 3 , and LD-NCP 11.0 mm 3 ) and a total annual plaque PAV change (apixaban: PAV 1.5%, PAV-CP 0.12%, and PAV-NCP 0.92%; rivaroxaban: PAV 2.1%, PAV-CP 0.46%, and PAV-NCP 1.40%). There was significantly lower PAV-CP progression in the apixaban group compared with the rivaroxaban group (0.12% vs. 0.46% P = 0.02). High-risk plaque characteristics showed a significant change in PR of apixaban versus rivaroxaban ( P = 0.01). When the propensity score weighting model is applied, only PR changes are statistically significant ( P = 0.04). In both groups, there is progression of all types of plaque. There was a significant difference between apixaban and rivaroxaban on coronary calcification, with significantly lower calcific plaque progression in the apixaban group, and change in positive remodeling. With weighted modeling, only PR changes are statistically significant between the 2 DOACs.

Relationship between arterial remodelling and serial changes in coronary atherosclerosis by intravascular ultrasound: an analysis of the IBIS-4 study.

Arterial remodelling is an important determinant of coronary atherosclerosis. Assessment of the remodelling index, comparing a lesion to a local reference site, is a suboptimal correlate of serial vascular changes. We assessed a novel approach which, unlike the local-reference approach, uses the entire artery's global remodelling as reference. Serial (baseline and 13 months) intravascular ultrasound was performed in 146 non-infarct-related arteries of 82 patients treated with high-intensity statin. Arteries were divided into 3-mm segments (n = 1479), and focal remodelling was characterized in individual segments at both timepoints applying the global arterial reference approach. First, we compared preceding vascular changes in relation to follow-up remodelling. Second, we examined whether baseline remodelling predicts subsequent plaque progression/regression. At follow-up, segments with constrictive vs. compensatory or expansive remodelling had greater preceding reduction of vessel area (-0.67 vs. -0.38 vs. -0.002mm2; P < 0.001) and lumen area (-0.82 vs. -0.09 vs. 0.40mm2; P < 0.001). Overall, we found significant regression in percent atheroma volume (PAV) [-0.80% (-1.41 to -0.19)]. Segments with constrictive remodelling at baseline had greater subsequent PAV regression vs. modest regression in the compensatory, and PAV progression in the expansive remodelling group (-6.14% vs. -0.71% vs. 2.26%; P < 0.001). Lesion-level analyses (n = 118) showed no differences when remodelling was defined by the local reference approach at baseline or follow-up. Remodelling assessment using a global arterial reference approach, but not the commonly used, local reference site approach, correlated reasonably well with serial changes in arterial dimensions and identified arterial segments with subsequent PAV progression despite intensive statin treatment and overall atheroma regression.

Quantitative assessment of coronary plaque volume change related to triglyceride glucose index: The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry

BackgroundThe association between triglyceride glucose (TyG) index and coronary atherosclerotic change remains unclear. We aimed to evaluate the association between TyG index and coronary plaque progression (PP) using serial coronary computed tomography angiography (CCTA).MethodsA total of 1143 subjects (aged 60.7 ± 9.3 years, 54.6% male) who underwent serial CCTA with available data on TyG index and diabetic status were analyzed from The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. PP was defined as plaque volume (PV) (mm3) at follow-up minus PV at index > 0. Annual change of PV (mm3/year) was defined as PV change divided by inter-scan period. Rapid PP was defined as the progression of percent atheroma volume (PV divided by vessel volume multiplied by 100) ≥ 1.0%/year.ResultsThe median inter-scan period was 3.2 (range 2.6–4.4) years. All participants were stratified into three groups based on TyG index tertiles. The overall incidence of PP was 77.3%. Baseline total PV (group I [lowest]: 30.8 (0.0–117.7), group II: 47.2 (6.2–160.4), and group III [highest]: 57.5 (8.4–154.3); P < 0.001) and the annual change of total PV (group I: 5.7 (0.0–20.2), group II: 7.6 (0.5–23.5), and group III: 9.4 (1.4–27.7); P = 0.010) were different among all groups. The risk of PP (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.167–2.327; P = 0.005) and rapid PP (OR 1.777; 95% CI 1.288–2.451; P < 0.001) was increased in group III compared to that in group I. TyG index had a positive and significant association with an increased risk of PP and rapid PP after adjusting for confounding factors.ConclusionTyG index is an independent predictive marker for the progression of coronary atherosclerosis.Clinical registration ClinicalTrials.gov NCT02803411

Effects of Statins on Coronary Atherosclerotic Plaques: The PARADIGM Study

ObjectivesThis study sought to describe the impact of statins on individual coronary atherosclerotic plaques. BackgroundAlthough statins reduce the risk of major adverse cardiovascular events, their long-term effects on coronary atherosclerosis remain unclear. MethodsWe performed a prospective, multinational study consisting of a registry of consecutive patients without history of coronary artery disease who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. Atherosclerotic plaques were quantitatively analyzed for percent diameter stenosis (%DS), percent atheroma volume (PAV), plaque composition, and presence of high-risk plaque (HRP), defined by the presence of ≥2 features of low-attenuation plaque, positive arterial remodeling, or spotty calcifications. ResultsAmong 1,255 patients (60 ± 9 years of age; 57% men), 1,079 coronary artery lesions were evaluated in statin-naive patients (n = 474), and 2,496 coronary artery lesions were evaluated in statin-taking patients (n = 781). Compared with lesions in statin-naive patients, those in statin-taking patients displayed a slower rate of overall PAV progression (1.76 ± 2.40% per year vs. 2.04 ± 2.37% per year, respectively; p = 0.002) but more rapid progression of calcified PAV (1.27 ± 1.54% per year vs. 0.98 ± 1.27% per year, respectively; p < 0.001). Progression of noncalcified PAV and annual incidence of new HRP features were lower in lesions in statin-taking patients (0.49 ± 2.39% per year vs. 1.06 ± 2.42% per year and 0.9% per year vs. 1.6% per year, respectively; all p < 0.001). The rates of progression to >50% DS were not different (1.0% vs. 1.4%, respectively; p > 0.05). Statins were associated with a 21% reduction in annualized total PAV progression above the median and 35% reduction in HRP development. ConclusionsStatins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features. Statins did not affect the progression of percentage of stenosis severity of coronary artery lesions but induced phenotypic plaque transformation. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)

Atrial fibrillation, progression of coronary atherosclerosis and myocardial infarction.

Background Despite atrial fibrillation representing an established risk factor for stroke, the association between atrial fibrillation and both progression of coronary atherosclerosis and major adverse cardiovascular events is not well characterized. We assessed the serial measures of coronary atheroma burden and cardiovascular outcomes in patients with and without atrial fibrillation. Methods Data were analyzed from nine clinical trials involving 4966 patients with coronary artery disease undergoing serial intravascular ultrasonography at 18-24 month intervals to assess changes in percent atheroma volume (PAV). Using a propensity weighted analysis, and following adjustment for baseline variables, patients with ( n = 190) or without ( n = 4776) atrial fibrillation were compared with regard to coronary plaque volume and major adverse cardiovascular events (death, myocardial infarction, and stroke). Results Atrial fibrillation patients demonstrated lower baseline PAV (36.0 ± 8.9 vs. 38.1 ± 8.9%, p = 0.002) and less PAV progression (-0.07 ± 0.34 vs. + 0.23 ± 0.34%, p = 0.001) compared with the non-atrial fibrillation group. Multivariable analysis revealed atrial fibrillation to independently predict both myocardial infarction [HR, 2.41 (1.74,3.35), p<0.001] 2.41 (1.74, 3.35), p < 0.00) and major adverse cardiovascular events [HR, 2.2, (1.66, 2.92), p<0.001] 2.20 (1.66, 2.92), p < 0.001]. Kaplan-Meier analysis showed that atrial fibrillation compared with non-atrial fibrillation patients had a significantly higher two-year cumulative incidence of overall major adverse cardiovascular events (4.4 vs. 2.0%, log-rank p = 0.02) and myocardial infarction (3.3 vs. 1.5%, log-rank p = 0.05). Conclusions The presence of atrial fibrillation independently associates with a heightened risk of myocardial infarction despite a lower baseline burden and progression rate of coronary atheroma. Further studies are necessary to define the pathogenesis of myocardial infarction in the setting of atrial fibrillation.

Impact of Statins on Serial Coronary Calcification During Atheroma Progression and Regression

BackgroundStatins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can modulate coronary atheroma calcification in vivo. ObjectivesThis study compared changes in coronary atheroma volume and calcium indices (CaI) in patients receiving high-intensity statin therapy (HIST), low-intensity statin therapy (LIST), and no-statin therapy. MethodsIn a post-hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume (PAV) and CaI were measured across matched coronary segments in patients with coronary artery disease. ResultsFollowing propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline (−0.6 ± 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 ± 0.1% and +1.0 ± 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median [interquartile range] HIST, +0.044 [0.0–0.12]; LIST, +0.038 [0.0–0.11]; no-statin, +0.020 [0.0–0.10]; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no-statin group. ConclusionsIndependent of their plaque-regressive effects, statins promote coronary atheroma calcification. These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression.

Atheroma progression in hyporesponders to statin therapy.

Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5 ± 6.1 versus 30.3 ± 5.9 kg/m(2); P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127 ± 15 versus 132 ± 17 mm Hg; P=0.01) and LDL-C (2.5 ± 0.6 versus 3.4 ± 0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9 ± 9.8% versus 38.3 ± 9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19 ± 0.48% versus 0.09 ± 0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83 ± 0.58% versus -0.21 ± 0.52%; P=0.006). A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy.

Relation of High-Density Lipoprotein Cholesterol:Apolipoprotein A-I Ratio to Progression of Coronary Atherosclerosis in Statin-Treated Patients

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.

Myeloperoxidase levels predict accelerated progression of coronary atherosclerosis in diabetic patients: Insights from intravascular ultrasound

ObjectiveWhile inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied. MethodsWe investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated. ResultsMPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline. ConclusionsIncreasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease.

Abstract 9358: Accelerated Progression of Coronary Atherosclerosis in Patients With Ultrasonic Features of Plaque Vulnerability

Backgrounds: Vulnerable plaques typically contain large lipid cores accompanied by expansive vascular remodeling and spotty calcification. While non-occlusive plaque rupture has been proposed as a mechanism for sudden disease progression, the natural history of atheroma progression in patients with vulnerable plaques have not been well characterized. Methods: 3460 patients with angiographic coronary artery disease underwent serial intravascular ultrasound imaging to monitor atheroma progression in 7 clinical trials of anti-atherosclerotic therapies. Patients with (n=1063) and without (n=2397) focal vulnerable plaques, defined as the combination of percent atheroma volume (PAV) &gt;40%, expansive vascular remodeling and spotty calcification, were compared with regard to clinical characteristics and the rate of atheroma progression. Results: Patients with vulnerable plaques were less likely to be female (24 v. 31%, p&lt;0.001) and more likely to have hypertension (82 v. 78%, p=0.01) and diabetes (38 v. 30%, p&lt;0.001). Vulnerable plaque patients harbored more extensive atherosclerotic disease at baseline, with a greater PAV (42.5±7.4 v. 36.9±9.2%, p&lt;0.001) and total atheroma volume (TAV, 207.6±82.7 v. 184.6±82.7 mm3, p&lt;0.001). On serial evaluation, less progression of PAV (0.25±0.28 v. 0.46±0.27%, p=0.08) and TAV (-4.6±2.2 v. -3.0±2.2mm3, p=0.03) was observed in vulnerable plaque patients. Use of statins and optimal control of risk factors including LDL-C and HDL-C levels were associated with the slowest disease progression in patients with vulnerable plaques (Figure). Conclusions: While focal vulnerable plaques are associated with more extensive atherosclerotic burden, these patients demonstrate the greatest benefit of risk factor interventions. These findings suggest that while vulnerable lesions have the propensity to promote ischemic syndromes, they present a modifiable substrate that is sensitive to intensive use of medical therapies.

Spotty Calcification as a Marker of Accelerated Progression of Coronary Atherosclerosis: Insights From Serial Intravascular Ultrasound

The purpose of this study was to determine atheroma progression in patients with spotty calcification. Although extensively calcified atherosclerotic lesions have been proposed to be clinically quiescent, the presence of spotty calcification within plaque has been reported to be associated with an increased incidence of ischemic cardiovascular events. The relationship between spotty calcification and disease progression has not been investigated. A total of 1,347 stable patients with angiographic coronary artery disease underwent serial evaluation of atheroma burden with intravascular ultrasound imaging. Patients with spotty calcification were identified based on the presence of lesions (1 to 4 mm in length) containing an arc of calcification of <90°. Clinical characteristics and disease progression were compared between patients with spotty calcification (n = 922) and those with no calcification (n = 425). Patients with spotty calcification were older (age 56 years vs. 54 years; p = 0.001), more likely to be male (68% vs. 54%; p = 0.01), and have a history of diabetes mellitus (30% vs. 24%; p = 0.01) and myocardial infarction (28% vs. 20%; p = 0.004), and have lower on-treatment high-density lipoprotein cholesterol levels (48 ± 16 mg/dl vs. 51 ± 17 mg/dl; p = 0.001). Patients with spotty calcification demonstrated a greater percent atheroma volume (PAV) (36.0 ± 7.6% vs. 29.0 ± 8.5%; p < 0.001) and total atheroma volume (174.6 ± 71.9 mm(3) vs. 133.9 ± 64.9 mm(3); p < 0.001). On serial evaluation, spotty calcification was associated with greater progression of PAV (+0.43 ± 0.07% vs. +0.02 ± 0.11%; p = 0.002). Although intensive low-density lipoprotein cholesterol and blood pressure lowering therapy slowed disease progression, these efficacies were attenuated in patients with spotty calcification. The presence of spotty calcification is associated with more extensive and diffuse coronary atherosclerosis and accelerated disease progression despite use of medical therapies.

Peripheral Arterial Disease and Progression of Coronary Atherosclerosis

The purpose of this analysis was to characterize the progression of coronary atherosclerosis in patients with concomitant peripheral arterial disease (PAD). Peripheral arterial disease is associated with adverse cardiovascular outcomes. The impact of concomitant PAD on coronary atherosclerosis progression in patients with coronary artery disease has not been well established. The burden and progression of coronary atherosclerosis was investigated in 3,479 patients with coronary artery disease with (n = 216) and without (n = 3,263) concomitant PAD who participated in 7 clinical trials that employed serial intravascular ultrasound imaging. Patients with PAD had a greater percent atheroma volume (40.4 ± 9.2% vs. 38.5 ± 9.1%, p = 0.002) and percentage of images containing calcium (35.1 ± 26.2% vs. 29.6 ± 24.2%, p = 0.002), in association with smaller lumen volume (275.7 ± 101.6 mm(3) vs. 301.4 ± 110.3 mm(3), p < 0.001) and vessel wall volume (467.7 ± 166.8 mm(3) vs. 492.9 ± 169.8 mm(3), p = 0.01). On serial evaluation, patients with PAD demonstrated greater progression of percent atheroma volume (+0.58 ± 0.38 vs. +0.23 ± 0.3%, p = 0.009) and total atheroma volume (-0.17 ± 2.69 mm(3) vs. -2.05 ± 2.15 mm(3), p = 0.03) and experienced more cardiovascular events (26.3% vs. 19.8%, p = 0.03). In patients with PAD and without PAD, respectively, achieving levels of low-density lipoprotein cholesterol <70 mg/dl was associated with less progression of percent atheroma volume (+0.16 ± 0.27% vs. +0.76 ± 0.20%, p = 0.04; and +0.05 ± 0.14% vs. +0.29 ± 0.13%, p < 0.001) and total atheroma volume (-3.0 ± 1.9 mm(3) vs. +1.0 ± 1.4 mm(3), p = 0.04; and -3.3 ± 1.1 mm(3) vs. -1.6 ± 1.0 mm(3), p < 0.001). Patients with concomitant PAD harbor more extensive and calcified coronary atherosclerosis, constrictive arterial remodeling, and greater disease progression. These changes are likely to contribute to adverse cardiovascular outcomes. The benefit for all patients achieving low levels of low-density lipoprotein cholesterol supports the need for intensive lipid lowering in patients with PAD.

Comparison of Rates of Progression of Coronary Atherosclerosis in Patients With Diabetes Mellitus Versus Those With the Metabolic Syndrome

Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 +/- 9.0%, 37.6 +/- 8.9%, and 38.1 +/- 9.1%, p <0.001) and total atheroma volume (198.3 +/- 85.9, 190.7 +/- 85.0, and 186.3 +/- 79.1 mm(3), p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 +/- 174.3 vs 484.4 +/- 160.7 mm(3), p = 0.02), whereas DM was associated with lumen constriction (290.6 +/- 111.7 vs 298.1 +/- 105.5 mm(3), p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 +/- 0.3, +0.3 +/- 0.2, and +0.1 +/- 0.2%, p <0.0001) and total atheroma volume (-1.0 +/- 1.8, -3.3 +/- 1.8, and -4.0 +/- 1.8 mm(3), p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.

Low Levels of Low-Density Lipoprotein Cholesterol and Blood Pressure and Progression of Coronary Atherosclerosis

We investigated coronary atheroma progression in patients with low levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP). Low LDL-C and SBP beneficially impact coronary atherosclerosis. However, the association between intensive control of both risk factors and coronary plaque progression remains unclear. Changes in atheroma burden monitored by intravascular ultrasound were studied in 3,437 patients with coronary artery disease (CAD) who were stratified according to on-treatment LDL-C and SBP. Patients with very low LDL-C (< or =70 mg/dl) and normal SBP (< or =120 mm Hg) had less progression in percent atheroma volume (PAV) (p < 0.001) and total atheroma volume (TAV) (p < 0.001), more frequent plaque regression (p = 0.01), and less frequent plaque progression (p < 0.001). In patients with SBP >120 mm Hg, very low LDL-C was associated with less progression of PAV (+0.30%, 95% confidence interval [CI]: -0.17% to 0.77% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.01) and TAV (-3.9 mm3, 95% CI: -7.24 to -0.63 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.001). In patients with LDL-C >70 mg/dl, normal SBP was not associated with less progression of PAV (+0.51%, 95% CI: 0.04% to 0.99% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.159) or TAV (-2.3 mm3, 95% CI: -5.59 to 1.05 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.617). Very low LDL-C and normal SBP are associated with the slowest progression of coronary atherosclerosis. Although a greater beneficial association is observed in patients with very low LDL-C, these findings suggest the need for intensive control of global risk in patients with CAD.

Effect of Diabetes on Progression of Coronary Atherosclerosis and Arterial Remodeling: A Pooled Analysis of 5 Intravascular Ultrasound Trials

Our goal was to characterize coronary atherosclerosis progression and arterial remodeling in diabetic patients. The mechanisms that underlie adverse cardiovascular outcomes in diabetic patients have not been well characterized. A systematic analysis was performed in 2,237 subjects in randomized controlled studies of atherosclerosis progression. The pattern of arterial remodeling, extent of coronary atherosclerosis, and disease progression was compared in subjects with and without diabetes. In association with more risk factors, diabetic patients demonstrated a greater percent atheroma volume (PAV) (40.2 +/- 0.9% vs. 37.5 +/- 0.8%, p < 0.0001) and total atheroma volume (TAV) (199.4 +/- 7.9 mm(3) vs. 189.4 +/- 7.1 mm(3), p = 0.03) on multivariate analysis. A stronger correlation was observed between PAV and glycated hemoglobin (r = 0.22, p = 0.0003) than fasting glucose (r = 0.09, p < 0.0001), although the difference just failed to meet statistical significance after controlling for study. Diabetic patients exhibited a smaller lumen (291.1 +/- 104.8 mm(3) vs. 306.5 +/- 108.2 mm(3), p = 0.005) but no difference in external elastic membrane (494.9 +/- 166.9 mm(3) vs. 498.8 +/- 167.2 mm(3), p = 0.61) volumes. More rapid progression of PAV (0.6 +/- 0.4% vs. 0.05 +/- 0.3%, p = 0.0001) and TAV (-0.6 +/- 2.5 mm(3) vs. -2.7 +/- 2.4 mm(3), p = 0.03) was observed in diabetic patients on multivariate analysis. Smaller external elastic membrane (482.5 +/- 160.7 mm(3) vs. 519.9 +/- 166.9 mm(3), p = 0.03) and lumen (276.0 +/- 100.3 mm(3) vs. 310.1 +/- 105.6 mm(3), p = 0.001) volumes were observed in diabetic patients treated with insulin despite the presence of a similar TAV (206.5 +/- 88.6 mm(3) vs. 209.9 +/- 90.2 mm(3), p = 0.84). Intensive low-density lipoprotein cholesterol lowering in patients improved the rate of plaque progression, but only to the level observed in nondiabetic patients with suboptimal lipid control. Diabetes is accompanied by more extensive atherosclerosis and inadequate compensatory remodeling. Accelerated plaque progression, despite use of medical therapies, supports the need to develop new antiatherosclerotic strategies in diabetic patients.

Abstract 684: Changes in Levels of High Density Lipoprotein Cholesterol Predict the Impact of Torcetrapib on Progression of Coronary Atherosclerosis: Insights from ILLUSTRATE

Background: Administration of the CETP inhibitor torcetrapib does not slow the rate of progression of coronary atherosclerosis. The reason for the lack of therapeutic efficacy remains unknown. This analysis investigated the relationship between changes in HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) and atheroma volume in patients treated with torcetrapib. Methods: 910 patients with angiographic coronary artery disease underwent IVUS imaging within a single coronary artery before and during 24 months of treatment with torcetrapib (n = 464) or placebo (n = 446) on a background of atorvastatin therapy. The relationship between changes in levels of HDL-C and LDL-C and both percent atheroma volume (PAV) and total atheroma volume (TAV) was evaluated in patients treated with torcetrapib. Results: Administration of torcetrapib raised HDL-C by 61% and lowered LDL-C by 20% when compared to atorvastatin alone. An inverse relationship was observed between changes in HDL-C and both PAV (r = −0.17, p &lt; 0.001) and TAV (r = −0.17, p &lt; 0.001). Patients with the highest level of HDL-C (&gt; 87 mg/dL) had the lowest rate of progression of PAV (−0.7 v +0.7%, p = 0.0003) and TAV (−9.2 v −4.6 mm 3 , p = 0.09). The greatest elevation in level of HDL-C (&gt; 80%) was associated with the lowest progression of PAV (−0.3 v +0.9%, p = 0.002) and TAV (−12.6 v −3.4 mm 3 , p = 0.0006). Patients undergoing regression (any reduction in PAV) had greater absolute levels (73 v 66 mg/dL, p = 0.02) and changes (59.5 v 48.3%, p = 0.02) of HDL-C. No difference in the impact of torcetrapib on changes in PAV (+0.3 v +0.1%, p = 0.34) and TAV (−9.1 v −9.3 mm 3 , p = 0.95) was observed in patients with baseline levels below or above 40 mg/dL. No relationship was observed between changes in LDL-C and either PAV (r = 0.06, p = 0.20) or TAV (r = 0.07, p = 0.12) in torcetrapib treated patients. On multivariate analysis, changes in levels of HDL-C independently predicted the impact of torcetrapib on progression of PAV (p = 0.007) and TAV (p = 0.004). Conclusion: Increasing levels of HDL-C from torcetrapib treatment were associated with a beneficial impact of torcetrapib on plaque progression. This is consistent with the generation of functional HDL particles and suggests other effects to be responsible for the lack of benefit of torcetrapib.

Abstract 1391: Atherogenic Dyslipidemia Predicts Accelerated Progression of Atherosclerosis in Patients with Coronary Artery Disease

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy. Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C &lt; 45 mg/dL for men and &lt; 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C &lt; 160mg/dL) Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p&lt;0.001) and were more likely to fit the definition of the metabolic syndrome (93 v 30.3%, p&lt;0.001). Accelerated progression of percent atheroma volume (PAV, +0.76 v +0.01%, p=0.001) and total atheroma volume (TAV, −4.75 v −7.18 mm3, p=0.022) was observed in patients with AD. Patients with AD were less likely to undergo substantial regression (reduction in PAV &gt;5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV &gt;5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045). Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.