Barry Templin

A Prospective Natural-History Study of Coronary Atherosclerosis

BACKGROUND Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. METHODS In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. RESULTS The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). CONCLUSIONS In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.).

Plaque Composition and Clinical Outcomes in Acute Coronary Syndrome Patients With Metabolic Syndrome or Diabetes

OBJECTIVES The goal of this study was to characterize the extent and composition of coronary atherosclerosis in patients with diabetes mellitus or the metabolic syndrome (Met Syn) presenting with acute coronary syndromes (ACS). BACKGROUND Diabetes and Met Syn patients have increased rates of major adverse cardiac events (MACE), yet a systematic description of nonculprit lesions for these high-risk groups is incomplete. METHODS In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, ACS patients underwent 3-vessel quantitative coronary angiography, grayscale, and radiofrequency intravascular ultrasound after successful percutaneous coronary intervention (PCI). Subsequent MACE (cardiac death or arrest, myocardial infarction, or rehospitalization for unstable or progressive angina) were adjudicated to the originally treated culprit versus untreated nonculprit lesions in 3 patient groups: 1) diabetes; 2) Met Syn; and 3) neither. Median length of follow-up was 3.4 years. RESULTS Of 673 patients, 119 (17.7%) had diabetes and 239 (35.5%) had Met Syn. The cumulative 3-year MACE rate was 29.4% in patients with diabetes, 21.3% with Met Syn, and 17.4% with neither (p = 0.03). MACE adjudicated to untreated nonculprit lesions occurred in 18.7%, 11.7%, and 9.7% of patients, respectively (p = 0.06). Nonculprit lesions in diabetes and Met Syn patients were longer and had greater plaque burden, smaller lumen areas, with greater necrotic core and calcium content. Diabetes and Met Syn patients with future MACE had greater necrotic core and calcification compared with the normal cardiometabolic group. CONCLUSIONS In this PCI ACS population, patients with diabetes and Met Syn had higher 3-year MACE rates. Lesion length, plaque burden, necrotic core, and calcium content were significantly greater among nonculprit lesions of patients with diabetes and Met Syn, but only necrotic core and calcium were significantly greater in the nonculprit lesions of patients with a future MACE in this exploratory analysis.

Intravascular Ultrasound Classification of Plaque Distribution in Left Main Coronary Artery Bifurcations Where Is the Plaque Really Located

Background—Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. Methods and Results—We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with ≥40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis ≥50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. Conclusions—Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180466.

Intravascular Ultrasound Classification of Plaque Distribution in Left Main Coronary Artery Bifurcations

Background—Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. Methods and Results—We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with ≥40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis ≥50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. Conclusions—Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180466.

Coronary Plaque Composition, Morphology, and Outcomes in Patients With and Without Chronic Kidney Disease Presenting With Acute Coronary Syndromes

OBJECTIVES This study sought to evaluate the impact of chronic kidney disease (CKD) on coronary atherosclerotic plaque composition, morphology, and outcomes in patients with acute coronary syndromes (ACS). BACKGROUND CKD patients presenting with ACS are at increased risk for adverse events. Whether or not this increased risk reflects differences in coronary plaque composition remains unknown. METHODS In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, patients presenting with ACS in whom percutaneous coronary intervention was successful underwent 3-vessel grayscale and radiofrequency intravascular ultrasound imaging. Lesions were prospectively characterized, and patients were followed for a median of 3.4 years. We conducted a patient-level and lesion-level analysis of study participants by comparing intravascular ultrasound parameters of untreated nonculprit lesions in patients with and without CKD. RESULTS Patients with CKD (n = 73, 11.3%) were older, more often female and diabetic compared to those without CKD (n = 573). Nonculprit lesions in patients with (n = 280) versus without (n = 2,390) CKD were more likely to have plaque burden ≥ 70% (11.8% vs. 8.5%, p = 0.05) and minimal luminal area ≤ 4.0 mm(2) (25.9% vs. 19.2%, p = 0.005). The percentage of plaque comprised of necrotic core (15.0% vs. 13.0%, p = 0.0001) and dense calcium (8.2% vs. 6.4%, p < 0.0001) was higher while fibrous tissue (57.7% vs. 59.8%, p < 0.0001) was lower in CKD versus non-CKD lesions. The 3-year composite rate of cardiac death, cardiac arrest, or myocardial infarction (15.1% vs. 3.3%, p < 0.0001) was significantly higher in patients with than in those without CKD, although there were no differences in the rates of events adjudicated to nonculprit lesions. CONCLUSIONS Following percutaneous coronary intervention of all culprit lesions in ACS, patients with versus without CKD have more extensive and severe atherosclerosis remaining in their coronary tree with plaque composed of greater necrotic core and less fibrous tissue. These influences resulted in nonsignificantly different rates of non-culprit lesion-related adverse events, although cardiac death, arrest, or myocardial infarction were more common in patients with CKD.

Definitions and Methodology for the Grayscale and Radiofrequency Intravascular Ultrasound and Coronary Angiographic Analyses

OBJECTIVES In a prospective study of the natural history of coronary atherosclerosis using angiography and grayscale and radiofrequency intravascular ultrasound (IVUS)-virtual histology (VH), larger plaque burden, smaller luminal area, and plaque composition thin-cap fibroatheroma emerged as independent predictors of future adverse cardiovascular events. BACKGROUND The methodology for IVUS-VH classification for an in vivo natural history study and the prospective image mapping by angiography and grayscale and IVUS-VH have not been established. METHODS All culprit and nonculprit lesions (defined as ≥ 30% angiographic visual diameter stenoses) were analyzed. Three epicardial vessels as well as all ≥ 1.5-mm-diameter side branches were divided into 29 CASS (Coronary Artery Surgery Study) segments. Each CASS segment was then subdivided into 1.5-mm-long subsegments, and dimensions were analyzed. All grayscale and IVUS-VH slices from the proximal 6 to 8 cm of the 3 coronary arteries were analyzed, with lesions defined as having more than 3 consecutive slices with ≥ 40% plaque burden categorized as: 1) VH thin-cap fibroatheroma; 2) thick-cap fibroatheroma; 3) pathological intimal thickening; 4) fibrotic plaque; or 5) fibrocalcific plaque. The locations of angiographic and grayscale and IVUS-VH lesions were recorded in relation to the corresponding coronary artery ostium and nearby side branches. RESULTS The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. On multivariate analysis, nonculprit lesions associated with recurrent events were characterized by a plaque burden ≥ 70% (hazard ratio: 5.03; 95% confidence interval: 2.51 to 10.11; p < 0.0001), a minimal luminal area ≤ 4.0 mm(2) (hazard ratio: 3.21; 95% confidence interval: 1.61 to 6.42; p = 0.001), and IVUS-VH phenotype of a thin-cap fibroatheroma (hazard ratio: 3.35; 95% confidence interval: 1.77 to 6.36; p < 0.001). CONCLUSIONS Three-vessel multimodality coronary artery imaging was feasible and allowed the identification of lesion-level predictors for future events in this natural history study.

Longitudinal distribution of plaque burden and necrotic core-rich plaques in nonculprit lesions of patients presenting with acute coronary syndromes.

OBJECTIVES In this substudy of the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, we examined the longitudinal distribution of atherosclerotic plaque burden, virtual histology-intravascular ultrasound (VH-IVUS) characterized necrotic core (NC) content and VH-thin-cap fibroatheroma (TCFA) distribution in nonculprit lesions of patients presenting with acute coronary syndromes. BACKGROUND Previous analyses suggested that vulnerable plaques and acute myocardial infarction may occur more frequently in the proximal than the distal coronary tree. METHODS A total of 4,234 proximal, mid, and distal 30-mm-long segments of each epicardial coronary artery were compared with each other and to the left main coronary artery (LMCA). RESULTS Combining IVUS data from all 3 arteries, there was a gradient in plaque burden from the proximal (42.4%) to mid (37.6%) to distal (32.6%) 30-mm-long segments (p < 0.0001). Overall, 67.4% of proximal, 41.0% of mid, and 29.7% of distal 30-mm-long segments contained at least 1 lesion (plaque burden >40%). Proportion of NC, however, was similar in the proximal and mid 30-mm-long segments of all arteries (10.3% [interquartile range (IQR): 4.8% to 16.7%] vs. 10.6% [IQR: 5.0% to 18.1%], p = 0.25), but less in the distal 30-mm-long segment (9.1% [IQR: 3.7% to 17.8%], p = 0.03 compared with the proximal segment and p = 0.003 compared with the mid segment). Overall, 17.3% of proximal, 11.5% of mid, and 9.1% of distal 30-mm-long segments had at least 1 lesion that was classified as VH-TCFA (p < 0.0001). Comparing the LMCA with the combined cohort of proximal left anterior descending, left circumflex, and right coronary artery 30-mm-long segments: 1) plaque burden was less (35.4% [IQR: 28.8% to 43.5%] vs. 40.9% [IQR: 33.3% to 48.0%], p < 0.0001); 2) fewer LMCAs contained at least 1 lesion (17.5%, p < 0.0001); 3) there was less NC (6.5% [IQR: 2.9% to 12.2%] vs. 9.3% [IQR: 4.3% to 15.9%], p < 0.0001); and 4) LMCAs rarely contained a VH-TCFA (1.8%, p < 0.0001). CONCLUSIONS The current analysis appears to confirm that lesions that are responsible for acute coronary events (large, plaque burden-rich in NC) are somewhat more likely to be present in the proximal than the distal coronary tree, except for the LMCA.

Age- and gender-related changes in plaque composition in patients with acute coronary syndrome: The PROSPECT study

AIMS Atherosclerosis accelerates with increasing age; however, young women presenting with acute coronary syndromes (ACS) have adverse outcomes compared to men despite less obstructive coronary artery disease. We sought to evaluate the in vivo plaque characteristics and composition of untreated non-culprit lesions (NCL) at two ages (<65 years old and ≥65 years old) in patients with ACS and examine the effect of sex in both groups. METHODS AND RESULTS Untreated NCLs from 697 patients with ACS were imaged with greyscale and radiofrequency intravascular ultrasound. NCL plaque morphology, burden, composition, and major adverse cardiac events (MACE) were analysed in both age groups, and a posterior sex-based sub-analysis was performed. Plaques from patients ≥65 (n=974) vs. <65 (n=2,275) years old were longer (median 12.62 mm vs. 10.75 mm, p=0.008) and had greater plaque burden (48.2% vs. 47.5%, p=0.001), necrotic core (12.5% vs. 11.0%, p=0.001) and dense calcium (5.7% vs. 4.0%, p<0.0001). Men <65 years old also had a greater number of fibroatheromas (3.0 vs. 2.0, p=0.007) and NCLs per patient (5.0 vs. 4.0, p=0.004) with larger plaque volumes (47.7% vs. 46.8%, p=0.04), and fewer fibrotic plaques (2.2% vs. 4.4%, p=0.03) than women in the same age group. These sex differences were not observed in patients ≥65 years old. The incidence of MACE during median 3.4 year follow-up did not significantly differ according to age in this study. CONCLUSIONS The current study confirms in vivo that, with aging, plaque burden, necrotic core and calcium content increase significantly. Moreover, gender-specific differences in the extent and composition of coronary plaque are present in patients <65 years (but not ≥65 years) of age, which suggest differential sex-related effects on atherosclerosis development and progression.

Residual Plaque Burden in Patients With Acute Coronary Syndromes After Successful Percutaneous Coronary Intervention

OBJECTIVES The aim of this study was to characterize and evaluate the clinical impact of untreated atherosclerotic disease after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS). BACKGROUND Residual atherosclerotic disease after successful PCI may predispose future major adverse cardiovascular events (MACE). Compared with intravascular ultrasound (IVUS), angiography underestimates the presence and severity of coronary artery disease. METHODS Following successful PCI of all clinically significant lesions in 697 patients with ACS, 3-vessel grayscale and radiofrequency IVUS was performed. Lesions were prospectively characterized, and patients were followed for a median of 3.4 years. A total of 3,229 untreated lesions (4.89 ± 1.98 lesions/patient) were identified by IVUS, with mean plaque burden (PB) of 49.6 ± 4.2%. RESULTS By angiography these nonculprit lesions were mild, with mean diameter stenosis of 38.9 ± 15.3%. At least 1 lesion with a PB ≥70% (PB70 lesion) was found in 220 (33%) patients. By multivariable analysis, a history of prior PCI and angiographic 3-vessel disease were independent predictors of PB70 lesions. Patients with PB70 lesions had greater total percent plaque volume, normalized PB, fibroatheromas, thin-cap fibroatheromas, and normalized volumes of necrotic core and dense calcium. Patients with PB70 lesions had greater 3-year rates of MACE due to untreated nonculprit lesions (20.8% vs. 7.7%, p < 0.0001). Among imaged nonculprit lesions, the proportion of PB70 lesions causing MACE was significantly greater than non-PB70 lesions (8.7% vs. 1.0%, p < 0.0001). CONCLUSIONS After successful PCI of all angiographically significant lesions, overall untreated atherosclerotic burden remains high, and PB70 lesions are frequently present in the proximal and mid-coronary tree. Patients with PB70 lesions have greater atherosclerosis throughout the coronary tree, have more thin-cap fibroatheromas, and are at increased risk for future cardiovascular events. ( PROSPECT An Imaging Study in Patients With Unstable Atherosclerotic Lesions; NCT00180466).

Relation Between Angiographic Lesion Severity, Vulnerable Plaque Morphology and Future Adverse Cardiac Events (from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree Study)

Previous angiographic studies have suggested that the future risk for major adverse cardiovascular events (MACEs) is related to coronary stenosis severity. The aim of this study was to use the grayscale and virtual histology (VH)-intravascular ultrasound (IVUS) data from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study to identify underlying lesion morphologic characteristics that might explain these findings. In PROSPECT, patients presenting with acute coronary syndromes in whom percutaneous coronary intervention was successful underwent 3-vessel grayscale and VH-IVUS and were followed for a median of 3.4 years for the incidence of MACEs. Overall, 3,115 nonculprit lesions detected by IVUS were divided into quartiles according to baseline angiographic diameter stenosis. From the first to fourth quartiles, there were increases in the prevalence of lesions with IVUS minimum luminal areas ≤ 4 mm(2), IVUS plaque burden ≥ 70%, and VH-IVUS thin-cap fibroatheroma (13.4%, 22.0%, 24.2%, and 30.3%, respectively, p <0.001), along with an increased frequency of plaque ruptures and greater necrotic core volumes. The incidence of lesions with plaque burden ≥ 70%, minimum luminal area ≤ 4 mm(2), and VH thin-cap fibroatheroma was highest in the fourth quartile (0%, 0.4%, 0.4%, and 2.8% in the first through fourth quartiles, respectively, p <0.001). Three-year MACE rates were also highest in the fourth quartile (0.3%, 0.7%, 1.3%, and 5.1%, respectively, p <0.001). In conclusion, increasing angiographic diameter stenosis was associated with an increased frequency of grayscale and VH-IVUS lesion morphologic features that have been associated with adverse events and that may, in part, explain why future MACEs were related to baseline lesion severity.