Tim Crowe

Extent and Direction of Arterial Remodeling in Stable Versus Unstable Coronary Syndromes An Intravascular Ultrasound Study

BACKGROUND The morphological characteristics of coronary plaques in patients with stable versus unstable coronary syndromes have been described in vivo with intravascular ultrasound, but the relationship between arterial remodeling and clinical presentation is not well known. METHODS AND RESULTS We studied 85 patients with unstable and 46 patients with stable coronary syndromes using intravascular ultrasound before coronary intervention. The lesion site and a proximal reference site were analyzed. The remodeling ratio (RR) was defined as the ratio of the external elastic membrane (EEM) area at the lesion to that at the proximal reference site. Positive remodeling was defined as an RR >1.05 and negative remodeling as an RR <0.95. Plaque area (13.9+/-5.5 versus 11.1+/-4.8 mm(2); P=0.005), EEM area (16.1+/-6.2 versus 13.0+/-4.8 mm(2); P=0. 004), and the RR (1.06+/-0.2 versus 0.94+/-0.2; P=0.008) were significantly greater at target lesions in patients with unstable syndromes than in patients with stable syndromes. Positive remodeling was more frequent in unstable than in stable lesions (51. 8% versus 19.6%), whereas negative remodeling was more frequent in stable lesions (56.5% versus 31.8%) (P=0.001). CONCLUSIONS Positive remodeling and larger plaque areas were associated with unstable clinical presentation, whereas negative remodeling was more common in patients with stable clinical presentation. This association between the extent of remodeling and clinical presentation may reflect a greater tendency of plaques with positive remodeling to cause unstable coronary syndromes.

Determinants of arterial wall remodeling during lipid-lowering therapy : Serial intravascular ultrasound observations from the reversal of atherosclerosis with aggressive lipid lowering therapy (REVERSAL) trial

Background— Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. Methods and Results— Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9±25.7%) and a decrease in the RR (−3.0±11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area (P<0.0001), baseline RR (P<0.0001), baseline lesion lumen area (0.019), logarithmic value of the change in high-sensitivity C-reactive protein (P=0.027), and hypertension at baseline (P=0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery (P=0.006), percentage change in triglyceride levels (P=0.049), and age (P=0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. Conclusions— Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.

Development of Transplantation Vasculopathy and Progression of Donor-Transmitted Atherosclerosis Comparison by Serial Intravascular Ultrasound Imaging

BACKGROUND Transplant coronary artery disease is a combination of atherosclerosis transmitted from the donor and new lesions of allograft vasculopathy. We sought to determine the morphological characteristics of allograft vasculopathy and differentiate it from donor-transmitted atherosclerosis with serial intravascular ultrasound. METHODS AND RESULTS Intravascular ultrasound examination was performed in 93 patients at 27.2+/-15.0 and 369. 7+/-23.9 days after transplantation. The maximally and minimally diseased sites were selected in each segment as defined by Coronary Artery Surgery Study classification. For each matched site, maximal plaque thickness was measured. Lesions (maximum plaque thickness >/=0.5 mm) present at baseline examination were defined as donor lesions. On follow-up, lesions that developed at previously normal sites were defined as de novo lesions. The distribution and severity of donor and de novo lesions were similar in proximal, mid, and distal segments. The de novo lesions were less focal (43% vs 74%) and more circumferential (69% vs 45%) compared with the donor lesions, but there was significant morphological heterogeneity. Similar numbers of patients with and those without donor lesions developed de novo lesions. Moreover, progression of donor lesions was not associated with the presence or absence of de novo lesions. CONCLUSIONS Differentiation between early allograft vasculopathy from conventional atherosclerosis by distribution and morphology of lesions alone is difficult. Serial intravascular ultrasound imaging with early baseline examination is necessary to make this distinction. This distinction is important because the progression of donor lesions and the development of de novo lesions are independent of each other.

Coronary Plaque Morphology and Frequency of Ulceration Distant From Culprit Lesions in Patients With Unstable and Stable Presentation

Objective—Intravascular ultrasound studies describe ruptured coronary plaques at sites remote from the culprit lesion in patients with acute myocardial infarction (MI), suggesting multifocal plaque vulnerability. However, the role of intravascular ultrasound in the diagnosis of lesion vulnerability before rupture is unclear. Methods and Results—We compared morphology and frequency of ulceration of additional plaques proximal to the culprit lesion in 105 patients treated with emergent stenting during an evolving, acute MI in the CADILLAC study and 92 patients with stable/subacute presentation who underwent elective stenting. Additional plaques proximal to the culprit lesion were found in 52 (50%) and 54 (59%) patients in the acute MI and stable/subacute group, respectively. The prevalence of ulceration was significantly higher in the acute MI than in the stable/subacute group (19% versus 4%; P =0.014). However, there was no significant difference in other morphological lesion characteristics. Conclusions—Additional plaques are frequently found adjacent to the culprit lesions in patients undergoing percutaneous coronary intervention independent of clinical presentation. The increased prevalence of plaque ulceration but otherwise similar morphology of additional lesions in patients with acute MI versus stable/subacute presentation demonstrates the limitations of imaging in the assessment of plaque vulnerability.

β-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials

Context The mechanisms by which -blockers prevent recurrent myocardial infarction are not clear. Contribution This pooled analysis of individual patient data examines changes in coronary atheroma volume as measured by serial intravascular ultrasonography in 4 randomized trials. The trials followed 1515 patients with coronary artery disease for 18 to 24 months. Atheroma volume decreased in patients who were receiving -blockers but stayed the same in those not receiving -blockers. Cautions The trials tested other interventions (such as statins) that could have affected atheromas. We do not know whether changes in atheroma volume predict cardiovascular outcomes. Implication -Blockers probably slow progression of coronary atherosclerosis. The Editors Clinical trials conducted in the 1980s (16) showed that -adrenergic blockers effectively reduce recurrent myocardial infarction, sudden cardiac death, and total mortality in patients with myocardial infarction. Researchers have attributed these effects to many properties of -adrenergic blockers, including reduced myocardial oxygen consumption, sympathetic blockade, decreased blood pressure, and potential antiatherosclerotic effects. Although the first 3 of these actions are well established, antiatherosclerotic effects in human coronary arteries have not been shown. On the other hand, whether -blockers still provide benefit in the current era of aggressive reperfusion for myocardial infarction, in which the beneficial effects of these drugs on preserving ventricular function is seemingly less important, is not known. Intravascular ultrasonography (IVUS) is increasingly used to assess the possible coronary antiatherosclerotic effects of various classes of drugs. Four major trials used IVUS to assess this effect: REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) (7), CAMELOT IVUS (Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis Intravascular Ultrasound) substudy (8), ACTIVATE (Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation) (9), and ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden) (10). The REVERSAL study evaluated the effects of moderate versus intensive lipid-lowering therapy with statins, the CAMELOT IVUS substudy examined the effects of a calcium-channel blocker (amlodipine) and an angiotensin-converting enzyme (ACE) inhibitor (enalapril), ACTIVATE evaluated the effect of the acyl coenzyme A (CoA)cholesterol acyltransferase inhibitor pactimibe, and ASTEROID evaluated the effect of very-high-intensity lipid-lowering therapy with rosuvastatin on the progression rate of coronary atherosclerosis. However, no study has evaluated the potential coronary antiatherosclerotic effects of -blockers by using IVUS or any other technique that allows direct quantification of plaque volume. Thus, we aimed to determine the relationship between concomitant -blocker treatment and the progression rate of coronary atherosclerosis in the combined samples of REVERSAL, CAMELOT IVUS, ACTIVATE, and ASTEROID. Methods Study Samples The samples of the 4 trials included in our analysis are fully described elsewhere (711) (Table 1). The studies enrolled patients with a clinical indication for coronary angiography (stable or unstable angina or positive results on a stress test) who had luminal narrowing of more than 20% in at least 1 vessel on angiography. Table 1. Characteristics of the Included Trials* The 4 trials assessed vital signs, use of concomitant medications, and fasting plasma lipid and glucose levels every 3 months. Because of study protocols, all patients in REVERSAL and ASTEROID were considered to have continuously received statins. -Blocker use was defined as receipt of a -blocker at any time during the trial period. The Cleveland Clinic institutional review board approved the research by using the databases of these 4 trials. Intravascular Ultrasonography The same acquisition and measurement method was used in all 4 studies (711). The IVUS catheter was inserted into the target vessel, and the transducer was positioned distal to a side branch. A motor drive unit withdrew the transducer at a constant speed. External elastic membrane (EEM) and lumen area measurements were obtained every 1 mm starting at the distal branch site and ending at a proximal branch site, in accordance with the standards of the American College of Cardiology and the European Society of Cardiology (12, 13). At the end of the trial, a follow-up IVUS was performed in the same arterial segments. All IVUS interrogations were analyzed in the same core laboratory at the Cleveland Clinic. The reproducibility of IVUS measurements was excellent for both intraobserver and interobserver variability (correlation coefficient, 0.99 for EEM measurements and 0.98 for lumen area measurements) (7). Atheroma volume was calculated as (EEM arealumen area), corresponding to the sum of the atheroma areas in slices spaced 1 mm apart. Because volume calculations are dependent on the length of the imaged segment, normalized atheroma volume was calculated for each patient, which corresponded to: Statistical Analysis We report the quantitative data as mean (SD) and categorical data as number (percentage), unless stated otherwise. Average blood pressure, plasma lipid levels, and glucose levels during treatment were calculated by averaging all of the available data collected during follow-up visits that were performed every 3 months. The characteristics of patients who received and did not receive -blocker treatment were compared by using the chi-square test or the unpaired t test, except for the nonnormally distributed characteristics of average triglyceride levels during treatment and baseline atheroma volume, for which the MannWhitney test was used. The prespecified primary outcome measure was the comparison of changes in atheroma volume of patients who received and those who did not receive -blocker treatment, after controlling for histories of hypertension, angina, and myocardial infarction (the major indications for -blocker treatment). We constructed additional multivariable models to evaluate the effect of other possible confounders, including heart rate, plasma lipid levels, other concomitant medications, and the specific trials in which the patients were enrolled. We evaluated the outcome measures by using linear mixed-effects models and estimated annual changes in atheroma volume from these models (14). In addition, we developed a propensity score by using a logistic regression model to determine the predicted probability of -blocker use (15). Covariates that we entered into the logistic model included demographic characteristics (age, sex, race, and body mass index), medical history (hypertension, angina, myocardial infarction, heart failure, and diabetes), hemodynamic variables (baseline blood pressure and heart rate), and concomitant use of other medications (aspirin, ACE inhibitors, calcium-channel blockers, and nitrates). Concomitant use of other medications referred to any use of these medications during the trial period. We entered the predicted probability from this model as a covariate in the linear mixed-effects models to help reduce the bias of the baseline differences. We did not include patients with missing data in the multivariable analyses. We performed a sensitivity analysis by using multiple imputation methods to assign missing end point data for patients who did not complete the original trials and those with missing covariate information. We considered 2-sided P values less than 0.05 to be statistically significant. We performed analyses by using SPSS, version 11.5 for Windows (SPSS, Chicago, Illinois), and SAS software, version 8.2 (SAS Institute, Cary, North Carolina). Role of the Funding Sources The sponsors of the original trials, Pfizer (REVERSAL and CAMELOT IVUS), Sankyo (ACTIVATE), and AstraZeneca (ASTEROID), contributed to the data collection for our pooled analysis. The sponsors had no role in the study design, data interpretation, writing of the manuscript, or decision to submit the paper for publication. Results -Blocker Use A total of 2129 patients were randomly assigned in the 4 trials, and 1533 patients completed the trials. -Blocker use could not be determined in 18 patients, leaving 1515 patients for our analysis. Of these patients, 1154 (76%) received concomitant -blocker treatment during the trials (Table 2); 993 (86%) received treatment continuously and 161 (14%) received treatment intermittently. Patients who received any concomitant -blocker treatment received these drugs on average for 91% of the trial durations. The treatment groups in individual studies did not significantly differ in frequency of concomitant -blocker treatment (P= 0.82 for REVERSAL, P= 0.44 for CAMELOT IVUS, and P= 0.98 for ACTIVATE; ASTEROID had 1 group). Metoprolol was the most commonly used -blocker in all studies (46.2% in REVERSAL, 50.2% in CAMELOT IVUS, 53.4% in ACTIVATE, and 41.1% in ASTEROID), followed by atenolol (25.2%, 31.9%, 18.5%, and 26.7%, respectively). Table 2. -Blocker Use during the 4 Trials* Patient Characteristics Table 3 shows the characteristics of patients according to -blocker treatment. Patients who received -blocker treatment had lower average diastolic blood pressure (P= 0.063). They were also more likely to have histories of hypertension, angina, and myocardial infarction. Average high-density lipoprotein cholesterol levels during treatment were lower and triglyceride levels were higher in patients who received -blockers. Patients who received -blockers were also more likely to receive aspirin and nitrate therapy. The use of other medications was similar between patients who did and did not receive -blocker treatment. The consistency of treatment status throughout the study period (that is, no intermittent therapy) was high for all

Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study

OBJECTIVES We sought to determine the role of conventional atherosclerosis risk factors in the development and progression of transplant coronary artery disease (CAD) using serial intravascular ultrasound imaging. BACKGROUND Transplant artery disease is a combination of allograft vasculopathy and donor atherosclerosis. The clinical determinants for each of these disease processes are not well characterized. Intravascular ultrasound imaging is the most sensitive tool to serially study these processes. METHODS Baseline intravascular ultrasound imaging was performed 0.9 +/- 0.5 months after transplantation to identify donor atherosclerosis. Follow-up imaging was performed at 1.0 +/- 0.07 year to evaluate progression of donor atherosclerosis and development of transplant vasculopathy. Conventional risk factors for CAD included recipient age, gender, smoking history, diabetes mellitus, hypertension and hypercholesterolemia. RESULTS Donor-transmitted atherosclerosis was present in 36 patients (39%). At follow-up, progression of donor lesions was seen in 15 patients (42%) and 42 patients (45%) developed transplant vasculopathy, leaving 35 patients (38%) without any disease. There was no difference in any conventional risk factors in patients with and without allograft vasculopathy. However, the severity of allograft vasculopathy was associated with a larger increase in low density lipoprotein (LDL) cholesterol from baseline (p = 0.02). High one-year posttransplant serum triglyceride level and pretransplant body mass index were the only significant predictors (p = 0.03) for progression of donor atherosclerosis. CONCLUSIONS Conventional atherosclerosis risk factors do not predict development of allograft vasculopathy, but greater change in serum LDL cholesterol level during the first year after transplant is associated with more severe vasculopathy. Therefore, maintenance of LDL cholesterol as close to pretransplant values as possible may help to limit the rate of progression of acquired allograft vasculopathy.

Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome.

OBJECTIVES We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. METHODS One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. RESULTS Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 +/- 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 +/- 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01). CONCLUSIONS The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy.

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.

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

OBJECTIVES We investigated coronary atheroma progression in patients with low levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP). BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Does acute cellular rejection correlate with cardiac allograft vasculopathy

BACKGROUND Previous studies of the association between acute cellular rejection and cardiac allograft vasculopathy (CAV) have yielded conflicting conclusions. We explored a possible association between acute cellular rejection and the extent of CAV, and we found a potential confounding variable that may obscure such an association. METHODS We investigated 140 patients (mean age, 51 +/- 11 years) who underwent serial intravascular ultrasound examinations at baseline and at 1 year after heart transplantation to assess CAV as change in maximal intimal thickness (CMIT). Patients were classified according to the presence or absence of biopsy-proven myocardial fibrosis. We used a standard biopsy-scoring system and a novel biopsy-scoring system, developed in our institution, to assess acute cellular rejection. Using univariate analysis, we found that CMIT was not associated with acute cellular rejection in the overall patient population (n = 140). However, we observed a correlation between CMIT and acute cellular rejection (standard method, r = 0.30, p = 0.01; novel method, r = 0.51, p < 0.0001) in patients who had no evidence of ischemic injury or fibrosis in their biopsy specimens (n = 57). Step-wise multiple regression showed that the rejection score derived from our novel method was associated more closely with the CMIT than was that derived from the traditional method. CONCLUSIONS This data indicate that the presence of myocardial fibrosis masks an actuarial association between acute cellular rejection and the development of de novo allograft vasculopathy. As previously suspected, myocardial fibrosis is a marker for non-immune-mediated graft injury independently associated with an increased incidence of CAV.