Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events.

OBJECTIVES: The aim of this study was to evaluate the progression of atherosclerosis within the left main coronary artery (LMCA) in association with risk factor modifying therapies. BACKGROUND: Despite studies demonstrating slowing of disease progression within epicardial coronaries with risk factor modification, little is known about the natural history and clinical sequelae of atherosclerosis progression within the LMCA. METHODS: In 340 patients with angiographic coronary artery disease who underwent serial intravascular ultrasound imaging to evaluate the effects of anti atherosclerotic therapies across 7 clinical trials, LMCA and epicardial disease progression was characterized. Relationships between changes in plaque burden with remodeling parameters and the incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, hospital stay for unstable angina, and coronary revascularization) were investigated. RESULTS: Plaque regression was observed in the LMCA segment, and progression was observed in adjacent epicardial segments (percent atheroma volume [PAV] -0.39 ± 0.1% vs. +0.37 ± 0.1%, p < 0.001). Changes in LMCA lumen volume correlated strongly with changes in external elastic membrane (beta coefficient 0.91, p < 0.001) and negatively with the change in PAV (beta coefficient -0.55, p < 0.001). Patients who experienced a MACE had smaller baseline LMCA minimum lumen area (11.6 vs. 12.2 mm(2), p = 0.05) and greater progression of PAV in the LMCA (+0.51 ± 0.3% vs. -0.35 ± 0.2%, p = 0.02) compared with those who were MACE-free. Significant reductions from baseline in both external elastic membrane (-4.7 ± 1.7 mm(3), p < 0.01) and lumen volumes (-4.0 ± 1 mm(3), p < 0.01) were also observed in those having an event. CONCLUSIONS: Left main coronary atherosclerosis responds to systemic risk factor modification. Patients experiencing a MACE were more likely to demonstrate progressive disease and constrictive arterial remodeling within the LMCA segment.

Attenuated plaque at nonculprit lesions in patients enrolled in intravascular ultrasound atherosclerosis progression trials.

OBJECTIVES: We investigated attenuated plaque (hypoechoic plaque with deep ultrasonic attenuation despite absence of bright calcium) in nonculprit lesions. BACKGROUND: Recent intravascular ultrasound (IVUS) studies describe acoustic shadowing behind large, echolucent, acute culprit lesion sites in the absence of bright calcium. Such "attenuated plaque" is considered a characteristic of high-risk lesions, but its prevalence in stable nonculprit lesions is incompletely known. METHODS: We reviewed IVUS pullback data from nonculprit vessels in 159 patients from the ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial. We identified attenuated plaque and compared volumetric IVUS data in the segments with and without attenuation. In addition, we described plaque morphology in segments with attenuation at baseline and follow-up. RESULTS: Attenuated plaque was found in 17 of 159 patients (10.7%, 95% confidence interval: 6% to 17%). At baseline, there were no significant differences in clinical presentation and cardiovascular risk factors between patients with and without attenuation. Other than a greater plaque eccentricity index (p = 0.008), there were no significant differences between segments with and without attenuation. In segments with attenuated plaque, expansive remodeling was observed in 53%, and calcified plaque adjacent to the attenuation site in 70% of patients. During follow-up, attenuation remained stable, and no events occurred in the patients with attenuation. CONCLUSIONS: Attenuated plaque is present in a significant number of nonculprit segments in patients enrolled in IVUS progression trials and remains stable during follow-up. There is a relationship with mixed calcified lesions. These findings challenge the prior assumption that attenuated plaque is a finding limited to culprit lesions associated with acute clinical presentation.

Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials.

BACKGROUND: In patients with myocardial infarction, beta-adrenergic blockers reduce recurrent myocardial infarction and total mortality rates. However, whether a direct influence of beta-blockers on coronary atherosclerosis contributes to reduced recurrent myocardial infarction and total mortality rates is not known. OBJECTIVE: To assess whether beta-blocker therapy is associated with reduced atheroma progression in adults with known coronary artery disease. DESIGN: Post hoc, pooled analysis of individual patient data from 4 intravascular ultrasonography (IVUS) trials. SETTING: Four IVUS trials conducted in the United States, Europe, and Australia. PATIENTS: 1515 patients with coronary artery disease. INTERVENTION: The original trials used 3 different statins, a calcium-channel blocker, an angiotensin-converting enzyme inhibitor, or an acyl coenzyme A-cholesterol acyltransferase inhibitor. MEASUREMENTS: Changes in atheroma volume, as determined by IVUS after adjustment for possible confounders by using linear mixed-effects models, were compared in patients who did and did not receive concomitant beta-blocker treatment. RESULTS: Patients who received beta-blockers (n = 1154) were more likely to have histories of myocardial infarction, angina, and hypertension than were patients who did not receive beta-blockers (n = 361). The estimated annual change in atheroma volume was statistically significantly less in patients who received beta-blockers. This was true for univariate and multivariable analyses that controlled for history of myocardial infarction, angina, and hypertension (mean [+/-SE] atheroma volume, -2.4 +/- 0.5 mm3/y in treated patients vs. -0.4 +/- 0.8 mm3/y in untreated patients; P = 0.034). Accordingly, atheroma volume statistically significantly decreased at follow-up IVUS in patients who received beta-blockers (P < 0.001) and did not change in patients who did not receive beta-blockers (P = 0.86). Additional adjustments for low-density lipoprotein cholesterol level, concomitant medications, and clinical trial did not change the results. LIMITATIONS: Patients were not randomly assigned to beta-blocker therapy, and interventions other than beta-blocker therapy could have influenced the changes in atheroma volume. Whether progression rate of atherosclerosis as detected by IVUS predicts cardiovascular outcomes is unknown. CONCLUSIONS: The analysis demonstrates that beta-blockers can slow progression of coronary atherosclerosis. The findings provide additional support for the current clinical guidelines advocating long-term use of beta-blockers to treat most forms of coronary artery disease.

Coronary angiography for follow-up of heart transplant recipients: insights from TIMI frame count and TIMI myocardial perfusion grade.

BACKGROUND: The aim of this study was to evaluate the course of Thrombolysis in Myocardial Infarction (TIMI) frame count (TIMI FC) and myocardial perfusion grade (TIMI MPG) in heart transplant recipients and whether these parameters could predict mortality. METHODS: Sixty-two heart transplant recipients were enrolled in this study. All patients had coronary angiography at baseline and at 1 year, which were evaluated for TIMI FC and TIMI MPG. Also, 50 vessels in 35 patients were analyzed with volumetric intravascular ultrasound (IVUS) at baseline and at 1 year. Rejection episodes and mortality were recorded during the follow-up period. RESULTS: The mean follow-up interval was 51.5 +/- 17.2 months (range 12.2 to 78.4 months). TIMI FCs of all three coronary arteries and global TIMI FC (gTIMI FC) significantly increased from baseline during the first year (p < 0.0001). TIMI MPG deteriorated significantly (p < 0.0001 for left anterior descending and circumflex coronary arteries, p = 0.002 for right coronary artery). There was no correlation between changes in TIMI FC and progression of transplant vasculopathy as assessed by IVUS. Episodes of Grade > or = 3A rejection were significantly more frequent in the stable gTIMI FC group (p = 0.03). Mortality rate was significantly higher in the group with increasing gTFC (p = 0.02). CONCLUSIONS: gTIMI FCs and TIMI FCs of coronary arteries increase, and TIMI MPG gradually deteriorates during the first year after transplantation. Mortality rate is significantly higher in patients whose gTIMI FC increases from baseline. Change in gTIMI FC is a simple quantitative predictor of long-term mortality in heart transplant recipients.

Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis.

OBJECTIVES: The purpose of this study was to evaluate the effects of normal blood pressure (BP), pre-hypertension, and hypertension on progression of coronary atherosclerosis. BACKGROUND: The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) classifies BP as normal, pre-hypertension, and hypertension. The effects of these categories on progression of coronary atherosclerosis are unknown. METHODS: The 274 patients who completed the intravascular ultrasound (IVUS) substudy of the CAMELOT (Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis) trial were included. The entry criteria were > or =1 angiographic coronary stenosis >20% and diastolic BP <100 mm Hg. Patients underwent a baseline coronary IVUS, which was repeated after 2 years of amlodipine, enalapril, or placebo therapy. The BP was evaluated periodically, and the averages of the measurements were used in the analyses. RESULTS: Mean BP throughout the study was 127.0 +/- 12.0/75.5 +/- 6.8 mm Hg. In multivariable analysis, significant determinants of progression included systolic BP (r = 0.16; p = 0.006) and pulse pressure (r = 0.14; p = 0.02). Patients with "hypertensive" average BP had a 12.0 +/- 3.6 mm3 (least-square mean +/- SE) increase in atheroma volume, those with "pre-hypertensive" BP had no major change (0.9 +/- 1.8 mm3), and those with "normal" BP had a decrease of 4.6 +/- 2.6 mm(3) (p < 0.001 by analysis of covariance; p < 0.05 for comparison of all pairs). CONCLUSIONS: The most favorable rate of progression of coronary atherosclerosis is observed in patients whose BP falls within the "normal" JNC-7 category (i.e., systolic BP <120 mm Hg and diastolic BP <80 mm Hg). This study suggests that in patients with coronary artery disease, the optimal BP goal may be substantially lower than the <140/90 mm Hg level.

Donor or recipient hepatitis B seropositivity is associated with allograft vasculopathy.

BACKGROUND: Increasing interest has focused on possible viral triggers of cardiac allograft vasculopathy. Although much interest has centered on cytomegalovirus, it has recently been noted that donor hepatitis C seropositivity is associated with risk for accelerated vasculopathy. The current study hypothesized that hepatitis B (HBV) might be associated with accelerated vasculopathy. METHODS: Sixty-six patients who received heart transplants between September 1998 and July 2000 were analyzed by intravascular ultrasound within 6 weeks and again at 12 months after transplantation. These patients were divided into 2 groups: the HBV Group (n = 13) in which either the donor or recipient was seropositive for hepatitis B core antibody (HBcAb), and a Control Group (n = 53) in which neither donor nor recipient was positive for HBcAb. RESULTS: Baseline characteristics of the 2 groups were similar. The HBV Group had significant increase in the change in average intimal area (1.59 +/- 1.4 vs 0.46 +/- 0.4 mm2, p = 0.01) per mm length of the vessel compared with controls. Allograft vasculopathy at 1 year (defined as largest maximal intimal thickness increase of > or =0.50 mm) occurred in 46% of the HBV group compared with 24% of the control group (p = 0.05). When measured as an average maximal intimal thickness increase of >0.30 mm, allograft vasculopathy at 1 year occurred in 31% of the HBV Group compared with 5% of Controls (p = 0.01). CONCLUSIONS: These preliminary results suggest that HBV seropositivity in donor or recipient may be associated with an increased risk for cardiac allograft vasculopathy.

Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation.

OBJECTIVES: The aim of this study was to determine whether angiographically silent early coronary intimal thickening could predict long-term morbidity and mortality. BACKGROUND: Although intravascular ultrasound (IVUS) is widely used to detect early transplant coronary disease, its prognostic significance has not been well defined. METHODS: The study cohort consisted of 143 patients who underwent early multivessel (2.1 +/- 0.7 arteries/patient) IVUS examination 1.0 +/- 0.5 month and 12.0 +/- 1.0 month after transplantation. The change in intimal thickness was evaluated using paired analysis of 1,069 matched sites. Rapidly progressive vasculopathy was defined as the change in intimal thickness >/=0.5 mm. Patients were followed for a primary end point of all-cause mortality and a secondary composite end point of mortality and nonfatal myocardial infarction (MI). Angiographic disease, defined as any >/=50% diameter stenosis, was assessed in 126 patients. RESULTS: Intravascular ultrasound at one year demonstrated rapid progression in 54 (37%) of 143 patients and new lesions in 67 (47%) of 143 of patients. At a mean clinical follow-up of 5.9 years, more patients with rapidly progressive vasculopathy died, as compared with those without (26% vs. 11%, p = 0.03). Death and MI also occurred more frequently among those with rapid progression than in those without it (51% vs. 16%, p < 0.0001). There was no significant difference in outcome in patients with and without donor-transmitted lesions. Angiographic disease was found in 11 (22%) of 50 patients with and in 2 (2.1%) of 76 patients without (p = 0.003) rapidly progressive vasculopathy. The IVUS-defined rapid progression correlated highly with future development of angiographic disease (p = 0.0005). CONCLUSIONS: Rapidly progressive vasculopathy by IVUS, defined as an increase of >/=0.5 mm in intimal thickness within the first year after transplantation, is a powerful predictor of all-cause mortality, MI, and angiographic abnormalities. Accordingly, such patients may be candidates for more aggressive anti-atherosclerotic and/or immunosuppressive therapy.

Early constriction or expansion of the external elastic membrane area determines the late remodeling response and cumulative lumen loss in transplant vasculopathy: an intravascular ultrasound study with 4-year follow-up.

BACKGROUND: Early constriction of the external elastic membrane (EEM) area has been observed after cardiac transplantation. The aim of this study was to compare the late disease process of transplant vasculopathy between coronary segments with early constrictive and expansive remodeling. METHODS: Serial intravascular ultrasound data obtained annually for 4 years after transplantation in 38 transplant recipients was available. In 135 matched segments from 59 coronary arteries ultrasound images were digitized at 1-mm intervals. Mean values of the external elastic membrane (EEM), lumen and intimal areas were calculated. On the basis of a decrease or increase in EEM area within the first year after transplantation, we defined segments with early constrictive remodeling (CR, n = 71) or early expansive remodeling (ER, n = 64). RESULTS: Annual changes in intimal area were similar between segments with early CR and ER throughout the follow-up period. However, during the second and third year, annual increases in EEM area were greater in segments with early CR than in segments with early ER (second year: 1.5 +/- 2.7 vs 0.6 +/- 2.8 mm(2), p = 0.052; third year: 1.3 +/- 2.5 vs -0.03 +/- 2.6 mm(2), p = 0.003). Despite this late expansion, segments with early CR showed a cumulative decrease in the EEM area and a greater lumen loss than segments with early ER (-2.5 +/- 3.4 vs -0.6 +/- 2.6 mm(2), p < 0.001). CONCLUSIONS: In transplant vasculopathy, the late remodeling response was different between segments with early constrictive and expansive remodeling, despite similar intimal thickening. Early constriction caused an overall decrease in EEM area and greater loss of lumen during follow-up.

Influence of coronary pulsation on volumetric intravascular ultrasound measurements performed without ECG-gating. Validation in vessel segments with minimal disease.

Volumetric analysis of coronary arteries can be performed using intravascular ultrasound (IVUS) images selected at 1 mm intervals without ECG gating. However, there are few data regarding the influence of coronary pulsation on this volumetric analysis. We developed two models of consecutive area measurements consisting of duplicated area measurements from short coronary segments and virtual measurements based on a sine function. These models allowed the re-calculation of volumes using different sets of frames from the same simulated segments. The variability of the volume determinations was evaluated by its percent standard deviation [%SD = (SD/the mean value) x 100]. The relation of the variability to the extent of external elastic membrane (EEM) area change during the cardiac cycle (amplitude) and heart rates (frequency) were examined. In 58 short coronary segments of 15 patients, consecutive IVUS images were measured [%EEM area change: 12.3 +/- 7.7%, heart rate 78 +/- 21 beats/min (bpm)]. In both models, %SD of the volume calculations was directly proportional to the %EEM area change and showed two peaks at heart rates of 60 +/- 2 and 90 +/- 2 bpm. In the model based on actual coronary measurements, the %SD of volume calculations of a segment with 10% EEM area change was 0.7% except for heart rates of 60 +/- 2 and 90 +/- 2 bpm. The variability of a volumetric analysis based upon measuring IVUS images at constant intervals without ECG gating is affected by coronary pulsation, extent of cross-sectional area changes, and heart rate. Despite these limitations, this method is feasible and provides reproducible volume measurements.

Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary atherectomy to intravascular ultrasound observations on coronary remodeling.

We investigated the relation between the presence of matrix-metalloproteinases (MMPs) and direction of remodeling in the coronary lesions of 35 patients. Positive arterial remodeling describes a compensatory expansion of the external elastic membrane (EEM) area of atherosclerotic lesions. An association between positive remodeling and unstable clinical presentation has been previously described. However, the pathophysiology of the remodeling process is not completely understood. Preinterventional intravascular ultrasound images and directional atherectomy (DCA) samples were analyzed. The remodeling ratio was calculated as the EEM area at the lesion site divided by the EEM area at the proximal reference. Positive, intermediate, and negative remodeling were defined as ratios of >1.05, 0.95 to 1.05, and <0.95, respectively. The histologic samples were immunostained for MMP-1, -2, -3, and -9. Positive, intermediate, and negative remodeling was present in 15, 7, and 13 lesions, respectively. Mild and intense cell-associated staining for MMP-1 was found in 21 (68%) and 10 (32%) patients, respectively. Staining for MMP-3 was mild in 20 patients (67%) and intense in 10 patients (33%). Immunostaining for MMP-2 and -9 was mild in all samples. Intense staining for MMP-3 was significantly more common in lesions with positive than negative and/or intermediate remodeling (58% vs 17%; p = 0.04; p = 0.053 after adjustment for gender). Thus, in this in vivo intravascular ultrasound and histologic study, increased cell-associated MMP-3 staining was associated with positive arterial remodeling.