Baseline Intravascular Ultrasound Research Articles

Circulating progenitor cells are associated with plaque progression and long-term outcomes in heart transplant patients.

Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation. A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements [median 3.0, interquartile range (2.8-3.1) years] and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACEs) were defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke, and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression [odds ratio 0.58, 95% confidence interval (CI) (0.37-0.92), P = 0.01] and MACE [hazard ratio (HR) 0.79, 95% CI (0.66-0.99), P = 0.05] during a median (interquartile range) follow-up of 8.0 years (7.2-8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE [HR 1.26, 95% CI (1.03-1.57), P = 0.02]. Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long-term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression.

Abstract 15245: Cd34+ Progenitor Cells in the Progression of Cardiac Allograft Vasculopathy

Introduction: CD34+ progenitor cells play a role in vascular repair and plaque stability. However, their role in cardiac allograft vasculopathy (CAV), vessel remodeling, and changes in plaque morphology is incompletely understood. Hypothesis: We hypothesized that decreased levels of baseline CD34+ progenitor cells would be associated with Intravascular Ultrasound (IVUS)-defined vulnerable plaque characteristics and CAV progression. Methods: In heart transplant patients undergoing annual IVUS, CD34+ cells were counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcific). Positive remodeling was defined as expansion of external elastic membrane area on follow-up. Patients were divided into two groups by the median of the change (Δ) in necrotic core volume over the subsequent 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. Median time after transplant was 4.2 years at baseline. Average vessel area at baseline and three years were 15.8±4.6 and 15.3±5.4 mm, respectively (p=0.32). Twenty-four patients (44%) who showed positive remodeling at follow-up, compared to those who did not, had lower levels of baseline CD34+ progenitor cells (absolute count per 100,000 counts, 980 [690, 1460]) vs. 665 [438, 1015], p=0.02) (Fig. 1A). Patients with greater than median (>1.96 mm3) Δnecrotic core volume, as compared to those with below median Δ, also had lower baseline CD34+ cells (705 [483, 998] vs. 1180 [660, 1620] per 100,000 counts, p=0.04) (Fig. 1B). Conclusions: Lower levels of CD34+ progenitor cells are associated with long-term positive coronary vascular remodeling and increased plaque necrotic core volume in patients who underwent allograft heart transplant. This study supports the notion that circulating CD34+ progenitor cells play a role in CAV.

Abstract 15260: Higher Levels of Osteoblast-lineage Cells Are Associated With Cardiac Allograft Vasculopathy Progression

Introduction: Cardiac allograft vasculopathy (CAV) is a major determinant of long term graft survival. Endothelial progenitor cells (EPC) expressing osteocalcin (OC) have been linked to atherosclerosis. However, little is known regarding bone-forming osteoblast-lineage (OL) cells, and their role in atherosclerosis and CAV. Methods: Heart transplant patients undergoing serial Intravascular Ultrasound (IVUS) and progenitor cell studies were included in the study. OL cells, defined as cells positive for alkaline phosphatase (AP) and OC, were counted using flow cytometry on the day of baseline IVUS. A follow up IVUS was done 3 years later. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcified). Patients were divided into two groups by the median change (Δ) in necrotic core volume and plaque volume over 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. At baseline, median time after transplant was 4.2 years. Average vessel area at baseline and three years were 15.8 ±4.6 and 15.3 ±5.4 mm2, respectively (p=0.32). However, 24/55 patients (44%) had positive remodeling. The number of OL cells was positively correlated with Δvessel (r=0.36, p=0.01) and Δlumen areas. (r=0.30, p=0.02). Patients with greater Δplaque volume and Δnecrotic core volume had higher OL cell levels compared to those with below medians (Δplaque volume: 95 [30,348] vs. 30 [10, 90] OL per 100,000 counts, p=0.01; Δnecrotic core volume: 95 [22.5, 320] vs. 30 [10, 90] OL per 100,000 counts, p=0.03) (Fig. 1A and 1B). Conclusions: The number of OL cells in heart transplant patients correlates with positive vascular remodeling, accompanied by increased lumen area over 3 months. Furthermore, patients with unstable plaque features had higher OL cells, suggesting a possible role in pathologic plaque progression.

Initial Intravascular Ultrasound Without a Routine Early Baseline Study in the Evaluation of Cardiac Transplant Vasculopathy has Prognostic Valve.

Abnormal minimal intimal thickening (MIT) on intravascular ultrasound (IVUS) defined as difference of ≥0.5 mm between baseline and one-year post-transplantation has been shown to have prognostic value. The goal of this retrospective cohort study was to evaluate whether abnormal MIT found on routine IVUS studies in cardiac transplant patients after 6 months without an early baseline study (modified MIT or MMIT), has any prognostic value. Furthermore, we evaluated the prognostic effect of serial IVUS performed beyond one year. A cohort of 149 cardiac transplant patients who underwent IVUS examination > 6 months post-transplant were evaluated retrospectively. Of these 149 patients, 109 patients underwent a subsequent IVUS study approximately 1 year following the initial study. MMIT values of ≥0.5 mm without an early baseline study were correlated with major adverse cardiac event (MACE). The all-cause mortality was 4.7% (5/107) in patients with MMIT of <0.5 mm vs. 14.6% (6/41) in patients with MMIT of ≥0.5 mm [hazards ratio (HR): 3.2; 95% confidence interval (CI): 1.002-12.17; p = 0.039]. The overall MACE rate was 8.4% (9/107) in patients with MMIT of <0.5 mm vs. 24.4% (10/41) in patients with MMIT of ≥0.5 mm [HR: 6.7; 95% CI: 1.30-9.42; p = 0.009]. After adjusting for age, abnormal MMIT remained a significant independent predictor of MACE (HR: 3.93; CI 1.21-12.81; p = 0.023). The presence of abnormal MMIT noted on IVUS performed after 6 months post-transplantation without a routine baseline IVUS carries important prognostic value.

Uric acid is an independent predictor of cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation (HT). Uric acid (UA) may play a role in CAV due to its role in stimulating T-cell-mediated immunity. Sirolimus is associated with CAV attenuation through a number of mechanisms, including immune-mediated effects. We aimed to determine whether UA is an independent predictor of CAV and whether conversion to sirolimus as primary immunosuppression modulates UA levels. We retrospectively analyzed a cohort of 224 patients who underwent HT between 2004 and 2015 and had serial coronary intravascular ultrasound (IVUS) studies. Serum UA levels were measured at baseline and last follow-up IVUS in all participants. CAV progression was assessed by measuring the change in plaque volume (ΔPV) and plaque index (ratio of plaque volume to vessel volume [ΔPI]) between last follow-up and baseline IVUS after correction for time of follow-up. Patients with high (≥7 mg/dl) compared with low (<7 mg/dl) UA had increased median ΔPV (0.33 [interquartile range 0.08 to 0.93] vs 0.07 [-0.17 to 0.38] mm3/mm/year; p < 0.001) and ΔPI (2.0% [0.31% to 3.9%] vs 0.33% [-1.2% to 2.0%]; p < 0.001). Elevated UA levels were associated with a significantly increased risk of developing significant CAV progression (ΔPV >0.50 mm3/mm) (hazard ratio 2.2, 95% confidence interval 1.1 to 4.6; p = 0.037). Sirolimus resulted in decreased UA levels (5.8 ± 1.4 vs 5.2 ± 1.5; p = 0.002) and patients converted to sirolimus and had low UA levels had the least CAV progression (p < 0.001). After adjustment for potential confounders, change in UA level was also an independent predictor of CAV progression. UA is an independent predictor of CAV after HT. Sirolimus is associated with decreased UA levels and may explain one of the mechanisms by which sirolimus attenuates CAV progression.

Morphological changes and clinical impact of unstable plaques within untreated segments of acute myocardial infarction patients during a 3-year follow-up: an analysis from the HORIZONS-AMI trial.

Plaque ruptures and attenuated plaques are considered to be unstable and have been identified in both culprit and nonculprit lesions of patients with ST-segment elevation myocardial infarction (STEMI). However, there are limited data available on the natural evolution of these plaques and their long-term clinical outcome. We investigated the natural evolution and long-term impact of plaque ruptures and attenuated plaques in untreated segments of infarct-related arteries in patients with STEMI. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial, 389 patients with 429 lesions underwent intravascular ultrasound (IVUS) at baseline. Follow-up IVUS at 13 months was conducted in 245 patients. Three-year follow-up data were available for all patients. Segments not treated between baseline and follow-up were compared. Baseline IVUS identified 29 plaque ruptures in 27 patients (7%). Of 11 plaque ruptures with follow-up IVUS, four healed and seven persisted. Conversely, through follow-up IVUS, nine new plaque ruptures in nine patients (4%) were identified. Attenuated plaques were identified in 31 of 38 plaque ruptures (81.5%), of which 24 were in the same circumferential segment as the ruptured cavity and seven were within 5 mm proximal or distal to the plaque rupture. Morphologic changes during follow-up, including new plaque ruptures and changes in the attenuated plaque frequency and distribution, were not accompanied by either serious lumen compromise or clinical events. Serial IVUS analysis demonstrated that the morphology of unstable plaques within untreated segments in STEMI patients treated with optimal systemic therapies markedly changed during the 13-month follow-up period, without lumen compromise or clinical events at the 3-year follow-up.

Repeated episodes of thrombosis as a potential mechanism of plaque progression in cardiac allograft vasculopathy

The pathogenesis of cardiac allograft vasculopathy (CAV) remains complex and may involve multiple mechanisms. We tested the hypothesis that the multilayer (ML) appearance, an intravascular ultrasound (IVUS) finding suggestive of repetitive thrombosis, is associated with plaque progression in heart transplant (HTx) recipients. Our study population consisted of 132 HTx recipients undergoing at least two grayscale and virtual histology (VH)-IVUS examinations. A retrospective serial analysis was performed between the first (baseline) and the last (follow-up) IVUS data during a median follow-up of 3.0 years. The subjects were divided into two groups based on the presence of the ML appearance on the baseline IVUS. At baseline, subjects with ML appearance (n = 38) had a longer time elapsed since transplant, larger vessel volume, and larger plaque volume than those without (n = 94) (all P < 0.01). Intraluminal thrombi and plaque ruptures were identified only in subjects with ML appearance (P < 0.01 vs. those without). More subjects with ML appearance at baseline developed subsequent ML formation compared with those without [21 (55%) vs. 22 (23%), P < 0.01] during follow-up. There was an increase in plaque volume, necrotic core volume, and dense calcium volume in subjects with ML appearance (all P < 0.01 vs. those without). Multivariable linear regression analysis showed that ML appearance was a potential predictor of plaque progression (regression coefficient 0.28, 95% CI 0.10-0.45, P < 0.01). The current study demonstrates that a finding of ML appearance, indicative of repeated episodes of mural thrombosis, is not infrequent in asymptomatic HTx recipients and possibly contributes to progression of CAV.

Intravascular Ultrasound Findings of Early Stent Thrombosis After Primary Percutaneous Intervention in Acute Myocardial Infarction

Background— Small stent area and residual inflow/outflow disease have been reported as the strongest intravascular ultrasound (IVUS) predictors of early stent thrombosis (ST) in patients with stable angina. IVUS predictors of early ST in patients with acute myocardial infarction have not been studied. Methods and Results— In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, a formal substudy included poststent and 13-month follow-up IVUS at 36 centers. Twelve patients with baseline IVUS who had definite/probable early ST ≤30 days after enrollment were compared with 389 patients without early ST. Significant residual stenosis was a lumen area &lt;4.0 mm 2 with ≥70% plaque burden ≤10 mm from each stent edge. Significant edge dissection was more than medial dissection with lumen area &lt;4 mm 2 or dissection angle ≥60°. Randomization to bivalirudin ( P =0.29) or paclitaxel-eluting stent ( P =0.74) was not related to early ST. Minimum lumen area was smaller in patients with versus without early ST (4.4 mm 2 [3.6, 6.9] versus 6.7 mm 2 [5.3, 8.0], respectively, P =0.014). Minimum lumen area &lt;5 mm 2 , significant residual stenosis, significant stent edge dissection, and significant tissue (plaque/thrombus) protrusion (more than the median that narrowed the lumen to &lt;4 mm 2 ) were more prevalent in patients with early ST, but significant acute malapposition (more than the median) was not. Overall, 100% of patients with early ST had at least 1 of these significant features: minimum lumen area &lt;5 mm 2 , edge dissection, residual stenosis, or tissue protrusion versus 23% in patients without early ST ( P &lt;0.01). Conclusions— Smaller final lumen area and inflow/outflow disease (residual stenosis or dissection) but not acute malapposition were related to early ST after acute myocardial infarction intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00433966.

Late stent malapposition with marked positive vascular remodeling observed only at the site of drug-eluting stents after multivessel coronary stenting

A 74-year-old woman presented with effort-induced chest pain. Diagnostic coronary angiography revealed three-vessel disease. A successful angioplasty was performed with two sirolimus-eluting stents placed in the left anterior descending artery (LAD) and left circumflex artery (LCX). The right coronary artery (RCA) was treated with a bare-metal stent. Follow-up angiography and intravascular ultrasound (IVUS) assessment were performed 8 months later, which showed late stent malapposition (LSM) with marked positive vascular remodeling around the drug-eluting stents (DES) in both LAD and LCX lesions, but there was no evidence of ectatic area around the BMS in the RCA lesion. Compared with the baseline IVUS, a significant increase in external elastic membrane (EEM) cross-sectional area was found. Twenty-seven months later, we performed repeat follow-up angiography. Intravascular ultrasound still showed vessel malapposition. A previous report showed that aneurysmal dilatation of the stented segment with severe localized hypersensitivity reaction could be a potential cause of late thrombosis after DES implantation. If LSM is related to hypersensitivity of the DES, it may have a potential risk of adverse events. Although there is a paucity of data regarding malapposition as the cause of adverse events, careful long-term follow-up of patients with vessel enlargement after DES placement is recommended.

Effects of Reconstituted High-Density Lipoprotein Infusions on Coronary Atherosclerosis&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;

High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was -3.4% with CSL-111 and -1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was -5.3 mm3 with CSL-111 and -2.3 mm3 with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (-0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (-0.039 mm for CSL-111 and -0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted. clinicaltrials.gov Identifier: NCT00225719

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial

Conclusion: Very-high-intensity statin therapy with rosuvastatin can reduce coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). Summary: The authors performed a prospective, open-labeled, blinded end point trial to determine the effect of very-high-intensity statin therapy on coronary atherosclerosis as assessed by IVUS. The study was conducted in 53 community and tertiary medical centers in the United States, Canada, Europe, and Australia. Coronary atheromas were assessed at baseline and after 24 months of treatment. A total of 507 patients had a baseline IVUS examination and received at least one 40-mg dose of rosuvastatin a day. There was no placebo arm of the trial, with all patients receiving 40 mg/d of rosuvastatin. At 24 months, 349 patients had an evaluable IVUS examination. Primary efficacy parameters were a change in atheroma volume percentage measured by IVUS and change in atheroma volume in a 10-mm subsegment of artery with the greatest disease severity at baseline. A second efficacy variable was normalized atheroma volume for the entire artery. At baseline, the mean low-density lipoprotein cholesterol (LDL) was 130.4 ± 34.3 mg/dL. This declined to 60.8 ± 20.0 mg/dL with treatment with rosuvastatin, a mean reduction of 53.2% (P < .001). The mean high-density lipoprotein cholesterol (HDL) level at baseline was 43.1 ± 11.1 mg/dL. This increased to 49.0 ± 12.6 mg/dL with rosuvastatin treatment, an increase of 14.7% (P < .001). The mean change in the percentage of atheroma volume was –0.98% ± 3.15% with a median of –0.79% (97.5% confidence interval [CI], –1.21% to –0.53%), P < .001 compared with baseline. The mean change in atheroma volume in the most diseased 10-mm subsegment was –6.1 ± 10.1 mm3, with a median change of –5.6 mm3 (97.5% CI, –6.8 mm to –.40 mm3), P < .001 compared with baseline. Total atheroma volume showed a 6.8% median reduction, with a mean reduction of –14.7 ± 25.7 mm3 and a median reduction of –12.5 mm3 (95% CI, –15.5 to 10.5 mm3), P < .001 compared with baseline. Comment: This study demonstrates convincing regression of atherosclerosis in the coronary circulation with high-dose statin therapy. The study has some limitations in that there was no placebo control. Also, 22 patients were withdrawn because of ischemic events, and those patients may represent actual progression of atherosclerosis under the treatment protocol. Nevertheless, in the patients evaluated, coronary atherosclerosis was reduced with the high-dose statin therapy used in this study. There were minimal complications and intolerance associated with the drug. It seems clear that high-dose statin therapy is indicated for patients with significant coronary disease. There is no evidence to date, however, that such therapy will benefit patients with cerebrovascular or peripheral arterial disease. Those trials still need to be done.

Static and serial assessments of coronary arterial remodeling are discordant: An intravascular ultrasound analysis from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial

Arterial remodeling is a major determinant of the clinical manifestations of coronary artery disease. Assessment of arterial remodeling with intravascular ultrasound (IVUS) used to rely on comparing the external elastic membrane (EEM) areas of lesion and reference sites at a single time point (static assessment). Recently, performance of serial IVUS provided the opportunity for direct assessment of remodeling. Our aim was to study the concordance of the static and serial methods. We identified 210 focal coronary lesions on the baseline IVUS interrogations of the REVERSAL trial. A follow-up IVUS was performed at 18 months. Static assessment was performed by calculating the remodeling index (RI) (lesion EEM area / reference EEM area) and serial assessment by comparing the changes in atheroma and EEM areas at follow-up. Using the serial method, there was a 1.24 mm2 increase in EEM area for every 1 mm2 increase in atheroma area at the lesion site, which was indicative of expansive (overcompensatory) remodeling. By using the static method, the RI was paradoxically lower at follow-up (1.062 +/- 0.15 at baseline vs 1.027 +/- 0.14 at follow-up, P < .001), indicating a trend toward constrictive remodeling. The reason for decreased RI at follow-up was the relatively larger expansion of the EEM areas at the reference sites. Static and serial assessments of arterial remodeling are discordant. This is due to concomitant remodeling of the reference sites used in the static assessment. Intravascular ultrasound performed at a single point in time does not reflect the dynamic remodeling response.

Usefulness of Follow-Up Low-Density Lipoprotein Cholesterol Level as an Independent Predictor of Changes of Coronary Atherosclerotic Plaque Size as Determined by Intravascular Ultrasound Analysis After Statin ( Atorvastatin or Simvastatin) Therapy

Using serial intravascular ultrasound (IVUS), we identified independent predictors of changes in coronary plaque size in relation to serum lipid levels. One hundred three patients with nonstenotic coronary plaques underwent baseline and 12-month follow-up IVUS studies; 54 patients (52%) were treated with statins. Standard IVUS analyses were performed. Baseline IVUS study showed no statistical differences in mean external elastic membrane, lumen, and plaque/media (P&M) area between statin-treated and nonstatin-treated patients. Although there was an increase in mean P&M cross-sectional area in nonstatin-treated patients, mean P&M cross-sectional area decreased in statin-treated patients (0.11 +/- 0.24 vs -0.20 +/- 0.30 mm(2), p <0.001). There was a positive relation between changes in mean P&M area and follow-up low-density lipoprotein (LDL) cholesterol level (r = 0.430, p <0.001), follow-up total cholesterol level (r = 0.365, p <0.001), changes in LDL cholesterol level (r = 0.312, p = 0.002), and changes in total cholesterol level (r = 0.252, p = 0.012). In multivariate linear regression analysis, the only independent predictor of changes in mean P&M area was follow-up LDL cholesterol level (r = 0.469, p <0.001, 95% confidence interval 0.003 to 0.006). The cut-off value of follow-up LDL cholesterol for no change or a decrease in mean P&M area was <100 mg/dl at regression analysis. In conclusion, the present 12-month follow-up IVUS study showed that follow-up LDL cholesterol level was the only independent predictor of changes in coronary plaque size. When patients achieved a follow-up LDL cholesterol level <100 mg/dl, regression or no progression of coronary plaque was expected. Aggressive lipid-lowering treatments with statins to decrease the follow-up LDL cholesterol level to <100 mg/dl are recommended.

Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis

Prior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression. To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging. Prospective, open-label blinded end-points trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion. Between November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug. After 24 months, 349 patients had evaluable serial IVUS examinations. All patients received intensive statin therapy with rosuvastatin, 40 mg/d. Two primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified. The mean (SD) baseline low-density lipoprotein cholesterol (LDL-C) level of 130.4 (34.3) mg/dL declined to 60.8 (20.0) mg/dL, a mean reduction of 53.2% (P<.001). Mean (SD) high-density lipoprotein cholesterol (HDL-C) level at baseline was 43.1 (11.1) mg/dL, increasing to 49.0 (12.6) mg/dL, an increase of 14.7% (P<.001). The mean (SD) change in PAV for the entire vessel was -0.98% (3.15%), with a median of -0.79% (97.5% CI, -1.21% to -0.53%) (P<.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 (10.1) mm3, with a median of -5.6 mm3 (97.5% CI, -6.8 to -4.0 mm3) (P<.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of -14.7 (25.7) mm3, with a median of -12.5 mm3 (95% CI, -15.1 to -10.5 mm3) (P<.001 vs baseline). Adverse events were infrequent and similar to other statin trials. Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. Further studies are needed to determine the effect of the observed changes on clinical outcome. ClinicalTrials.gov Identifier: NCT00240318.

Compensatory enlargement of human coronary arteries during progression of atherosclerosis is unrelated to atheroma burden: serial intravascular ultrasound observations from the REVERSAL trial

On the basis of the evidence from autopsy studies, it is accepted that compensatory enlargement (remodelling) of coronary arteries during progression of atherosclerosis diminishes once atheroma burden (cross-sectional area stenosis) reaches approximately 40%. Our aim was to evaluate whether atheroma burden is a limiting factor for coronary arterial remodelling using in vivo serial intravascular ultrasound (IVUS). From the cohort of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, we identified 210 focal coronary lesions at baseline IVUS. Of these, 128 lesions that had an increase in atheroma area at the 18-month follow-up IVUS were included in the analysis. Lesions were matched at baseline and follow-up. The increase in external elastic membrane (EEM) area for each mm(2) increase in atheroma area was not significantly different in lesions with <40 and >or=40% atheroma burden at baseline (1.62 vs. 1.28 mm(2), P=0.30). There were no correlations between atheroma burden at baseline and change in EEM (r=0.02, P=0.86) or change in lumen (r=0.04, P=0.64) areas. Assessment of coronary arterial remodelling by serial IVUS revealed that compensatory remodelling is not limited by atheroma burden. Atheroma burden is not a determinant of arterial enlargement during the progression of atherosclerosis.

Paradoxical increase in lumen size during progression of coronary atherosclerosis: Observations from the REVERSAL trial

Relative changes in lumen size during progression and regression of coronary atherosclerosis remain largely unknown. We assessed these changes using serial intravascular ultrasound (IVUS). From the baseline IVUS interrogations of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, 210 focal coronary lesions with <50% angiographic stenosis were identified. Lesions were matched to the follow-up IVUS, performed after 18 months of treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day. Changes in external elastic membrane (EEM) and lumen areas of lesions demonstrating progression and regression (i.e. increased and decreased atheroma area) were examined. In progressors ( n = 128), there was 1.34 mm 2 increase in EEM area for every 1 mm 2 increase in atheroma area ( r = 0.72, p < 0.0001). This resulted in 0.34 mm 2 increase in lumen area for every 1 mm 2 increase in atheroma area ( r = 0.25, p = 0.004). In contrast, there was no significant change in lumen area with regression of disease ( n = 82, r = −0.06, p = 0.59). Progression of coronary atherosclerosis can be associated with a paradoxical increase in lumen cross-sectional area, whereas regression is not associated with any change in lumen area. Measurement of changes in lumen size may not be an accurate method to study progression and regression of atherosclerotic lesions with <50% stenosis.