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Waters DD, Alderman EL, Hsia J, et al. JAMA 2002;288:2432-2440. CONTEXT: Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, [...]

Background: Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus., Methods and Results: We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly (P=5.5 × 10(-6)) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post-myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P=3.7 × 10(-2)) and myocardial jeopardy index (P=8.7 × 10(-4)). In general linear regression modeling, TLL1rs1503298 explained more variance of extent of CAD than the previously determined clinical factors., Conclusions: We identified a variant in a single PPAR pathway gene, TLL1, that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Patients sustaining acute myocardial infarction (AMI) often require urgent percutaneous revascularization within the first 24 h from onset of the infarction due to continuous ischemia and hemodynamic instability. Upon arrival to the cardiac catheterization, the electrocardiogram of AMI patients may exhibit acute ST-elevation (STEMI) with or without accompanying Q-wave or depression of the ST segment (non-STEMI or non-Q-wave infarction). Data comparing acute outcome of device application in patients presenting for urgent revascularization with established Q-wave myocardial infarction (QWMI) versus those with non-STEMI (NQMI) are sparse. Excimer laser is a revascularization modality applied for debulking of atherosclerotic plaque and vaporization of associated thrombus in the setting of AMI. One hundred fifty-one AMI patients with continuous chest pain and ischemia who enrolled into a multicenter study and underwent urgent revascularization were divided for the purpose of a retrospective analysis into two groups. One group presented with established electrocardiographic Q-wave, whereas the other had ST-depression (NQMI). In comparison with the NQMI group, the QWMI patients had a higher incidence of failed thrombolytic therapy (17% vs 3, p = 0.006), cardiogenic shock (20 vs 6%, p = 0.01), left anterior descending as a culprit infarct-related vessel (46 vs 14%, p < 0.0001), a higher incidence of TIMI 0 flow (48 vs 24%, p = 0.04), a heavier thrombus burden (grade 4 TIMI thrombus, 58 vs 23%; p = 0.0001), and higher CPK (1272 +/- 2180 vs 404 +/- 577, p = 0.001) and troponin levels (62 +/- 95 vs 14 +/- 48, p = 0.0003). Both groups underwent laser angioplasty and stenting for relief of continuous chest pain and ischemia within 24 h of infarction onset. Quantitative coronary arteriography in an independent core laboratory measured similar improvement in baseline minimal luminal diameter and percent diameter stenosis by application of laser energy in both groups. Among the QWMI patients, a significantly higher acute gain was recorded with the laser treatment in lesions containing a large/extensive thrombus burden as compared with lesions containing only a small clot burden (1.2 +/- 0.7 vs 0.8 +/- 0.5, p = 0.01). Such a phenomenon was not detected among the NQMI patients (1.0 +/- 0.5 vs 0.8 +/- 0.6, p=ns). Baseline TIMI flow grade (0.9 +/- 1.0 for QWMI vs 1.5 +/- 1.2 for NQMI, p = 0.0001) increased with laser emission to 2.8 +/- 0.5 and subsequently reached a final level of TIMI 3 in both groups. In comparison with the QWMI patients, there was a trend toward a reduced rate of major adverse coronary events among the NQMI patients (12% QWMI vs 4% NQMI, p = 0.09). Significant differences in baseline clinical characteristics, extent of myocardial damage, location of infarct related vessel, thrombus burden, and TIMI flow exist between QWMI and NQMI patients who require urgent intervention. However, application of excimer laser results in similar high procedural success and low complication rates in both groups. Maximal acute laser gain is achieved among QWMI patients whose lesions are laden with a heavy thrombus burden.

Background: The PAS-Port device (Cardica, Redwood City, CA) allows the rapid deployment of a clampless proximal anastomosis between a vein graft and the aorta., Methods: Fifty-four patients awaiting elective coronary artery bypass graft surgery were enrolled. Outcome variables were intraoperative device performance, early and 6- month angiographic graft patency, and 12-month clinical follow-up., Results: Sixty-three PAS-Port devices were deployed in 54 patients. Two deployments were unsuccessful. There were no reoperations for bleeding. Two patients died of causes unrelated to the device. Patency evaluation at discharge was performed by angiogram on 49 implants and computed tomography in 2 implants (86% follow-up). At discharge, all evaluated grafts were patent (100%) and rated Fitzgibbon A. At 6-month follow-up, there was no additional mortality; 47 implants (88% follow-up) were evaluated by angiography (Fitzgibbon O [n = 1], Fitzgibbon B [n = 1], and Fitzgibbon A [n = 45]) and 5 by computed tomography. All grafts but 1 were patent (98.1%). At 12 months, 2 additional patients died of causes unrelated to the PAS-Port implant. Forty-six of 50 alive patients (95.8%) were followed up without any reports of device-related major adverse cardiac events., Conclusions: Discharge (100%) and 6-month patency (98%) are excellent; patency and 12 months' clinical follow-up compares favorably with data from historical hand-sewn controls. The PAS-Port system safely allows the clampless creation of a proximal anastomosis.

Objectives: The C-Port System (Cardica, Inc, Redwood City, Calif) integrates in one tool all functions necessary to enable rapid automated distal coronary anastomoses. The goal of this prospective, nonrandomized, and multicenter study is to determine the safety and efficacy of this novel anastomotic system., Methods: Five centers enrolled 133 patients awaiting elective coronary artery bypass grafting surgery. Outcome variables were intraoperative device performance, incidence of device-related adverse events, predischarge and 6-month angiographic graft patency, and 12-month clinical outcome. Independent core laboratories performed qualitative and quantitative angiographic and computed tomographic assessments., Results: The C-Port was used to perform a vein-to-coronary anastomosis in 130 patients. Intraoperative conversion to a hand-sewn anastomosis was necessary in 11 patients because of inadequate target site preparation, inappropriate target vessel selection, or both. Inadequate blood flow related to poor runoff required conversion in 3 additional patients. Three patients died before discharge of causes unrelated to the device. At discharge, 113 patients had a C-Port implant in place, and 104 C-Port anastomoses were studied by means of angiography, resulting in 100 FitzGibbon A, 3 FitzGibbon B, and 1 FitzGibbon 0 classifications. At 6 months, one additional patient died of a device-unrelated cause, and 98 patients were evaluated by means of angiography (n = 89). Overall patency (FitzGibbon A) was 92.1%. Three C-Port anastomoses were rated FitzGibbon B, and 4 were rated FitzGibbon 0. At 12 months, 107 (98.2%) of 109 alive patients were followed up, without any reports of device-related major adverse cardiac events., Conclusions: The C-Port System allows for a rapid, reliable, and compliant distal anastomosis and yields favorable 6-month angiographic and 12-month clinical results when compared with published studies.

Objectives: Coronary angiograms obtained five years following revascularization were examined to assess the extent of compromise in myocardial perfusion due to failure of revascularization versus progression of native disease., Background: The Bypass Angioplasty Revascularization Investigation (BARI) randomized revascularization candidates between bypass surgery and angioplasty. Entry and five-year angiograms from 407 of 519 (78%) patients at four centers were analyzed., Methods: Analysis of the distribution of coronary vessels and stenoses provided a measure of myocardial jeopardy that correlates with presence of angina. The extent to which initial benefits of revascularization were undone by failed revascularization versus native disease progression was assessed., Results: Myocardial jeopardy fell following initial revascularization, from 60% to 17% for percutaneous coronary intervention (PCI)-treated patients compared with 60% to 7% for coronary artery bypass graft (CABG) surgery patients (p < 0.001), rebounding at five years to 25% for PCI and 20% for surgery patients (p = 0.01). Correspondingly, angina prevalence was higher at five years in PCI-treated patients than in surgery-treated patients (28% vs. 18%; p = 0.03). However, myocardial jeopardy at five years, and not initial treatment (PCI vs. surgery), was independently associated with late angina. Increased myocardial jeopardy from entry to five-year angiogram occurred in 42% of PCI-treated patients and 51% of CABG-treated patients (p = 0.06). Among the increases in myocardial jeopardy, two-thirds occurred in previously untreated arteries., Conclusions: Native coronary disease progression occurred more often than failed revascularization in both PCI- and CABG-treated patients as a cause of jeopardized myocardium and angina recurrence. These results support intensive postrevascularization risk-factor modification.

Objectives: To evaluate the safety and effectiveness of a self-closing surgical clip with an interrupted technique in left internal thoracic artery to left anterior descending artery bypass grafting., Methods: Eighty-two patients were enrolled and treated (February 2000 through August 2001) in a prospective, nonrandomized, multicenter trial. Left internal thoracic artery to left anterior descending artery anastomoses were performed in 60 off-pump coronary artery bypasses (73%), 12 conventional coronary artery bypass grafting (15%), and 10 minimally invasive direct coronary artery bypass (12%) procedures. Angiograms (64 to 383 days, mean 200 days) were obtained on 63 patients (77%). Qualitative and quantitative angiographic assessment was performed by an independent core laboratory., Results: The self-closing surgical clip was used for 82 left internal thoracic artery to left anterior descending artery interrupted anastomoses without the requirement for knot tying or primary suture management. Minimum left internal thoracic artery to left anterior descending artery anastomosis time was 3 minutes. There was one perioperative and one late death (both not heart related) and one reexploration for bleeding unrelated to the anastomotic site. FitzGibbon grades were as follows: A (n = 60, 95.2%), B (n = 3, 4.8%) including one kinked left internal thoracic artery, and O (n = 0, 0%). Quantitative analysis (n = 57) showed mean lumen diameters of left internal thoracic artery proximal to the anastomosis of 2.1 mm, at anastomosis of 2.0 mm, and in the left anterior descending artery distal to the anastomosis of 1.9 mm. The average ratio of the anastomosis to the left anterior descending artery diameter was 1.14 (0.45 to 1.93). Anastomotic stenosis as a percentage of average left internal thoracic artery to left anterior descending artery diameter was -2.3%, comparing favorably with results (23% to 24%) reported from the Patency, Outcomes, Economics, Minimally invasive direct coronary artery (POEM) bypass study., Conclusions: The interrupted technique, facilitated by a self-closing anastomotic clip, yields favorable 6-month angiographic results when compared with other published studies.

Objective: LDLs include particle subclasses that have different mobilities on polyacrylamide gradient gels: LDL-I (27.2 to 28.5 nm), LDL-IIa (26.5 to 27.2 nm), LDL-IIb (25.6 to 26.5 nm), LDL-IIIa (24.7 to 25.6 nm), LDL-IIIb (24.2 to 24.7 nm), LDL-IVa (23.3 to 24.2 nm), and LDL-IVb (22.0 to 23.3 nm in diameter). We hypothesized that the association between smaller LDL particles and coronary artery disease (CAD) risk might involve specific LDL subclasses., Methods and Results: Average 4-year onstudy lipoprotein measurements were compared with annualized rates of stenosis change from baseline to 4 years in 117 men with CAD. The percentages of total LDL and HDL occurring within individual subclasses were measured by gradient gel electrophoresis. Annual rate of stenosis change was related concordantly to onstudy averages of total cholesterol (P=0.04), triglycerides (P=0.05), VLDL mass (P=0.03), total/HDL cholesterol ratio (P=0.04), LDL-IVb (P=0.01), and HDL(3a) (P=0.02) and inversely to HDL(2)-mass (P=0.02) and HDL(2b) (P=0.03). The average annual rate in stenosis change was 6-fold more rapid in the fourth quartile of LDL-IVb (>or=5.2%) than in the first quartile (<2.5%, P=0.03). Stepwise multiple regression analysis showed that LDL-IVb was the single best predictor of stenosis change., Conclusions: LDL-IVb was the single best lipoprotein predictor of increased stenosis, an unexpected result, given that LDL-IVb represents only a minor fraction of total LDL.

The Women's Angiographic Vitamin and Estrogen trial was a randomized, double-blind, placebo-controlled study designed to test the efficacy of estrogen replacement and antioxidant vitamins for preventing angiographic progression of coronary artery disease. Postmenopausal women with one or more angiographically documented coronary stenoses of 15-75% at baseline were assigned in a 2 x 2 factorial randomization to active hormone replacement therapy (conjugated estrogens for women who had had a hysterectomy or conjugated estrogens with medroxyprogesterone for women with intact uteri) or placebo and to active vitamins E and C or their placebos. Seven clinical centers, five in the United States and two in Canada, randomized 423 women between July 1997 and July 1999. Quantitative coronary angiography was performed at baseline and repeated after projected mean follow-up of 3 years.

Context: Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use., Objective: To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography., Design, Setting, and Patients: The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada., Interventions: Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo., Main Outcome Measure: Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome., Results: The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P =.17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P =.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P =.045), and suggested an increased risk in the active vitamin group (P =.09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions., Conclusion: In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.

Background: Few studies have compared long-term status of bypass grafts between patients with and without diabetes, and uncertainty exists as to whether diabetes independently predicts poor clinical outcome after CABG., Methods and Results: Among 1526 patients in BARI who underwent CABG as initial revascularization, 99 of 292 (34%) with treated diabetes mellitus (TDM) (those on insulin or oral hypoglycemic agents) and 469 of 1234 (38%) without TDM had follow-up angiography. Angiograms with the longest interval from initial surgery and before any percutaneous graft intervention (mean 3.9 years) were reviewed. An average of 3.0 grafts were placed at initial CABG for patients with TDM (n=297; internal mammary artery [IMA], 33%) and 2.9 grafts for patients without TDM (n=1347; IMA, 34%). Patients with TDM were more likely than those without to have small (<1.5 mm) grafted distal vessels (29% versus 22%) and vessels of poor quality (9% versus 6%). On follow-up angiography, 89% of IMA grafts were free of stenoses > or =50% among patients with TDM versus 85% among patients without TDM (P=0.23). For vein grafts, the corresponding percentages were 71% versus 75% (P=0.40). After statistical adjustment, TDM was unrelated to having a graft stenosis > or =50% (adjusted odds ratio, 0.87; 95% CI, 0.58 to 1.32)., Conclusions: Despite diabetic patients' having smaller distal vessels and vessels judged to be of poorer quality, diabetes does not appear to adversely affect patency of IMA or vein grafts over an average of 4-year follow-up. Previously observed differences in survival between CABG-treated patients with and without diabetes may be largely a result of differential risk of mortality from noncardiac causes.

Background: Data are absent that compare midterm angiographic outcome between patients with and without diabetes after initial percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). Importantly, diabetes mellitus may differentially influence long-term survival after PTCA or CABG., Methods and Results: Patients with multivessel coronary disease who were previously enrolled in the Bypass Angiopathy Revascularization Investigation to compare initial PTCA versus CABG (n=1829) and who had a reduction in jeopardized myocardium after initial revascularization and at least 1 angiogram during 5-year follow-up were analyzed (n=897). This included 369 CABG-treated patients (16% with diabetes) and 528 PTCA-treated patients (18% with diabetes). The influence of diabetes on angiographic increase in percentage of jeopardized myocardium after initial revascularization with either PTCA or CABG was investigated. Among PTCA patients, the mean percentage increase in total jeopardized myocardium was significantly greater in those with diabetes than in those without at 1-year protocol-directed angiography (42% versus 24%, P=0.05) and on the first clinically performed (unscheduled) angiogram within 30 months (63% versus 50%, P=0.01) but not at 5-year protocol-directed angiography (34% versus 26%, P=0.33). This excess midterm risk associated with diabetes persisted after statistical adjustment. In contrast, among CABG patients, diabetes was not associated with percentage increase in jeopardized myocardium at any angiographic follow-up interval., Conclusions: Presence of diabetes differentially influences worsening of jeopardized myocardium after initial PTCA compared with CABG. This differential effect occurs irrespective of whether follow-up angiography is undertaken for clinical or nonclinical purposes.

Background: Interrupted suture technique avoids the "purse string" and puckering effects frequently seen with continuous suture techniques and should represent the standard of care in the creation of high-quality vascular anastomoses. This clinical study evaluated the safety and effectiveness of a self-closing surgical clip (Coalescent Surgical U-CLIP Anastomotic Device [U-CLIP]) designed to facilitate this interrupted technique. Left internal mammary artery (LIMA) to left anterior descending (LAD) coronary bypass grafting was studied., Methods: Eighteen patients meeting inclusion criteria were enrolled (October 2000 through September 2001) into this prospective study. Anastomoses were performed using a beating-heart median sternotomy procedure (off-pump coronary artery bypass) in 17 cases (94%) and a minimally invasive beating-heart procedure (minimally invasive direct coronary artery bypass [MIDCAB]) in one case (6%). Six-month follow-up was completed on 18 patients (100%), with angiograms performed on 17 patients (94%) at a mean of 179 days (range, 168-191 days). Qualitative and quantitative angiographic assessment was performed by an independent core laboratory., Results: The U-CLIP was used for 18 LIMA-to-LAD interrupted anastomoses without the requirement for knot tying or suture management and with no device-related morbidity or mortality. Mean LIMA-to-LAD anastomosis time was 8.6 minutes (range, 5-14 minutes). All anastomoses were FitzGibbon grade A at 6 months postprocedure. Quantitative analysis showed mean luminal diameters proximal to the anastomosis of 2.32 mm, at the anastomosis of 2.25 mm, and immediately distal to anastomosis of 1.99 mm. The average ratio of anastomosis to LAD diameter was 1.17 (range, 0.93- 1.93). Anastomotic stenosis as a percentage of average LIMA/LAD diameter was a negative 4.2%, comparing favorably with the 23% to 24% reported in the POEM (Patency, Outcomes, Economics of MIDCAB) study., Conclusions: The interrupted technique, facilitated by a self-closing anastomotic clip, yielded 6-month follow-up and angiographic results that compared favorably with results of other published studies.

Background: Uncertainty exists regarding the frequency of early occlusion when the left internal mammary artery (LIMA) is anastomosed to the left anterior descending artery (LAD) through a sternotomy with conventional coronary artery bypass grafting (CABG). The issue has gained importance for comparison with less invasive surgical approaches in which operative exposure may be limited and graft anastomosis more difficult., Methods and Results: Data were analyzed from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial in which 617 patients underwent conventional CABG of the LAD with a LIMA between April 1993 and May 1995. Coronary angiography was performed a mean of 10.8 days postoperatively. Patients were randomized to receive intraoperative aprotinin, an inhibitor of several serine proteinases, or placebo. Because no differences existed in patency rates of LIMA grafts between patients who received aprotinin and placebo, both groups were analyzed collectively. On coronary angiography, the LIMA was widely patent (<50% stenosis) in 561 patients (91%), had > or = 50% and <99% stenosis in 48 patients (7.8%), and was occluded in 8 patients (1.3%). Therefore, the LIMA was patent in 609 patients (98.7%). Conclusions-In the IMAGE trial, the largest and most contemporary early angiographic analysis of CABG available, early patency of the LIMA was >98% when anastomosed to the LAD. These data provide an important benchmark for less invasive surgical approaches in which the LIMA is anastomosed to the LAD.

Objectives: To determine the relative degree of revascularization obtained with bypass surgery versus angioplasty in a randomized trial of patients with multivessel disease requiring revascularization (Bypass Angioplasty Revascularization Investigation [BARI]), one-year catheterization was performed in 15% of patients., Background: Complete revascularization has been correlated with improved outcome after coronary artery bypass grafting (CABG) but not with percutaneous transluminal coronary angioplasty (PTCA). Relative degrees of revascularization after PTCA and surgery have not been previously compared and correlated with symptoms., Methods: Consecutive patients at four BARI centers consented to recatheterization one year after revascularization. Myocardial jeopardy index (MJI), the percentage of myocardium jeopardized by > or =50% stenoses, was compared and correlated with angina status., Results: Angiography was completed in 270 of 362 consecutive patients (75%) after initial CABG (n = 135) or PTCA (n = 135). Coronary artery bypass grafting patients had 3+/-0.9 distal anastomoses and PTCA patients had 2.4+/-1.1 lesions attempted at initial revascularization. At one year, 20.5% of CABG patients had > or =1 totally occluded graft and 86.9% of vein graft, and 91.6% of internal mammary artery distal anastomotic sites had <50% stenosis. One year jeopardy index in surgery patients was 14.1+/-11%, 46.6+/-20.3% improved from baseline. Initial PTCA was successful in 86.9% of lesions and repeat revascularization was performed in 48.4% of PTCA patients by one year. Myocardial jeopardy index one year after PTCA was 25.5+/-22.8%, an improvement of 33.8+/-26.1% (p<0.01 for greater improvement with CABG than PTCA). At one year, 29.6% of PTCA patients had angina versus 11.9% of surgery patients, p = 0.004. One-year myocardial jeopardy was predictive of angina (odds ratio 1.28 for the presence of angina per every 10% increment in myocardial jeopardy, p = 0.002). Randomization to PTCA rather than CABG also predicted angina (odds ratio 2.19, p = 0.03)., Conclusions: In this one-year angiographic substudy of BARI, CABG provided more complete revascularization than PTCA, and CABG likewise improved angina to a greater extent than PTCA.

Background: In PTCA patients with multivessel coronary artery disease, incomplete revascularization (IR) is the result of both pre-PTCA strategy and initial lesion outcome. The unique contribution of these components on long-term patient outcome is uncertain., Methods and Results: From the Bypass Angioplasty Revascularization Investigation (BARI), 2047 patients who underwent first-time PTCA were evaluated. Before enrollment, all significant lesions were assessed by the PTCA operator for clinical importance and intention to dilate. Complete revascularization (CR) was defined as successful dilatation of all clinically relevant lesions. Planned CR was indicated in 65% of all patients. More lesions were intended for PTCA in these patients compared with those with planned IR (2.8 versus 2.1). Successful dilatation of all intended lesions occurred in 45% of patients with planned CR versus 56% with planned IR (P<0. 001). In multivariable analysis, planned IR (versus planned CR), initial lesions attempted (not all versus all intended lesions attempted), and initial lesion outcome (not all versus all attempted lesions successful) were unrelated to 5-year risk of cardiac death or death/myocardial infarction but were all independently related to risk of CABG., Conclusions: Overall, a pre-PTCA strategy of IR in BARI-like patients appears comparable to a strategy of CR except for a higher need for CABG. Whether the use of new devices may attenuate the elevated risk of CABG in patients with multivessel disease and planned IR remains to be determined.

Objectives: Our objective was to determine whether a strategy of intended incomplete percutaneous transluminal coronary angioplasty revascularization (IR) compromises long-term patient outcome., Background: Complete angioplasty revascularization (CR) is often not planned nor attempted in patients with multivessel coronary disease, and the extent to which this influences outcome is unclear., Methods: Before randomization, in the Bypass Angioplasty Revascularization Investigation, all angiograms were assessed for intended CR or IR via angioplasty. Outcomes were compared among patients with IR intended if assigned to angioplasty, randomized to coronary artery bypass graft surgery (CABG) versus angioplasty; and within angioplasty patients only, among patients with IR versus CR intended., Results: At 5 years, there was a trend for higher overall (88.6% vs. 84.0%) and cardiac survival (94.5% vs. 92.1%) in CABG versus angioplasty patients with IR intended. The excess mortality in angioplasty patients occurred solely in diabetic subjects; overall and cardiac survival were similar among nondiabetic CABG and angioplasty patients. Freedom from myocardial infarction (MI) at 5 years was higher in nondiabetic CABG versus angioplasty patients (92.4% vs. 85.2%, p = 0.02), vet was similar to the rate observed (85%) in nondiabetic CABG and angioplasty patients with CR intended. Five-year rates of death, cardiac death, repeat revascularization and angina were similar in all angioplasty patients with IR versus CR intended. However, a trend for greater freedom from subsequent CABG was seen in CR patients (70.3% vs. 64.0%, p = 0.08)., Conclusions: Intended incomplete angioplasty revascularization in nondiabetic patients with multivessel disease who are candidates for both angioplasty and CABG does not compromise long-term survival; however, subsequent need for CABG may be increased with this strategy. Whether the risk of long-term MI is also increased remains uncertain.

Palmaz-Schatz stents were implanted in 79 lesions in 76 patients, and serially expanded at 12, 15, and 18 atm of pressure using noncompliant balloons. By core lab analysis, intravascular ultrasound demonstrated marked stent expansion as pressure was raised, which was not apparent by angiography.

Objective: We examined the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass., Methods: Patients from 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated., Results: In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% (P < .0001) and requirement for red blood cell administration by 49% (P < .0001). Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo (P = .03). After we had adjusted for risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of prior aspirin therapy, small and poor distal vessel quality, and possibly use of aprotinin-treated blood as excised vein perfusate. At United States sites, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P = .72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients (P = .01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin: 1.4%; placebo: 1.6%)., Conclusions: In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.

Background: The validity of quantitative coronary angiography (QCA) after stent placement has been questioned because the optical density of a metallic stent, added to the density of a contrast-filled lumen, could affect border definition., Methods and Results: We deployed 3.0- and 4.0-mm Palmaz-Schatz, Wiktor, Multilink, NIR, and InStent stents in precision-cast phantoms. Central lumens of 2.0 mm were created. There was no difference between the "true" diameters of any stented lumen by both QCA and quantitative ultrasonic (QCU) measurement poststenting. QCA systematic error (SE) varied from 0.01 for the Wiktor stents to 0.14 mm for the Palmaz-Schatz stents; the random error (RE) was 0.03 to 0.14 mm. QCU SE varied from 0.05 to 0.11 mm, and RE ranged from 0.01 to 0.07 mm. At the next stage, 4.0-mm Wiktor and Palmaz-Schatz stents were deployed into the phantom lumens; 1.5-, 2.0-, 2.5- and 3.0-mm lumens were created inside the stents. QCA and QCU measurements of 1.5- to 2.5-mm residual lumens were overestimated by 0.1 to 0.3 mm. In the 3. 0-mm residual lumen within the Wiktor stent, QCA underestimated the luminal size by -0.1 mm. There was no QCA inaccuracy for a 3.0-mm lumen within the Palmaz-Schatz stent. In patients, in 25 stented segments in both the Palmaz-Schatz and Wiktor groups, there was no difference between QCA and QCU diameters., Conclusions: QCU is sufficiently precise for the assessment of the coronary lumen after stenting. QCA can be used as an accurate method of poststent assessment, except when a very mild recurrence within a highly opaque stent is measured. In that instance, QCA may underestimate the luminal diameter.

Assumed oxygen consumption (VO2) is increasingly used as a convenient surrogate for measured VO2 for calculation of cardiac output. This substitution is often based on empirical formulae, previously validated only in relatively young patients. To assess the inaccuracy introduced by extrapolating these formulae to older patients, we compared measured VO2 with assumed VO2 in 57 patients. VO2 was measured using an open circuit analyzer. Assumed VO2 was calculated according to the LaFarge or Bergstra formulae. Agreement between both methods was assessed according to the method of Bland and Altman. The mean difference of measured VO2 minus assumed VO2 was 7.9 ml/min/m2 (P < 0.02) using the LaFarge formula, and -15.6 ml/min/m2 (P < 0.0002) using the Bergstra formula across a range of measured VO2 from 70 to 176 ml/min/m2. A systematic error was introduced by assumed VO2 from both formulae of underestimating higher and overestimating lower values of VO2, resulting in poor overall agreement with measured VO2. The same error and poor agreement was found when analyzing subgroups of patients > or =60 or <70 years of age. In summary, use of assumed VO2 introduces large, unpredictable errors in adult patients, suggesting requirement for measurement of VO2 when calculating cardiac output.

Objectives: This study assessed the influence of donor age and preexisting donor coronary disease on the later development of allograft coronary artery disease, ischemic events and overall survival., Background: The increasing demand for heart donors has led to a tendency to liberalize age criteria for donor acceptability., Methods: A total of 233 consecutive heart transplant recipients who had baseline, early postoperative and follow-up coronary angiograms, as well as a subset of 47 patients with baseline intracoronary ultrasound imaging recordings, were analyzed (mean 3.8 years of follow-up). Patients were subclassified according to the presence of donor coronary artery disease on the baseline angiogram and stratified at age 40 years., Results: patients without evidence of preexisting coronary artery disease on a baseline angiogram (n = 219) were significantly less likely to develop new disease than the 14 patients with preexisting coronary artery disease (p = 0.002). Although older donors exhibited earlier coronary artery disease than younger donors at 3 years of follow-up, there was no difference by 5 years (p = 0.25). There was no difference in survival or probability of developing ischemic events between the groups. Baseline ultrasound imaging revealed substantial disease in 7 of 9 older donated hearts, and in only 7 of 38 younger donated hearts (p = 0.002). Preexisting coronary artery disease, nonuse of calcium channel blocking agents, older donor age, posttransplantation cytomegalovirus infection, elevated very low density lipoprotein levels and previous ischemic heart disease in the recipient were significant predictors of allograft coronary artery disease., Conclusions: Heart donors with angiographic evidence of preexisting coronary artery disease and older donors are more likely to develop new allograft coronary artery disease by 3 years. However, there is no difference in survival or freedom from ischemic events between younger and older donors at a mean follow-up of 3.8 years.

Retained graft patency after revascularization lowers risk of subsequent myocardial infarction or death. Patients who have surgical rather than medical therapy are far less likely to die of a subsequent nonperioperative infarction. Both myocardial infarction size and lethality are modified by prior coronary artery bypass grafting. The procedure risk for either death or nonfatal infarction remains higher in coronary artery bypass grafting than in angioplasty, but among patients who survive for 30 days, subsequent risk is only two-thirds that of patients who had angioplasty. Better graft patency rates are associated with the use of an internal thoracic artery rather than a saphenous vein, larger size of the recipient coronary artery, and better blood flow through the grafts. Aspirin therapy clearly decreases the occlusion rate per distal anastomosis, but aprotinin therapy appears to have little or no effect on graft patency. Numerous other factors can influence graft patency. Prominent among the factors increasing risk for requirement of a reoperation are nonuse of an internal thoracic artery, incomplete revascularization, and continued cigarette smoking.

Background: LDL particles differ in size and density. Individuals with LDL profiles that peak in relatively small, dense particles have been reported to be at increased risk of coronary artery disease. We hypothesized that response to coronary disease therapy in such individuals might differ from response in individuals whose profiles peak in larger, more buoyant LDL. We examined this hypothesis in the Stanford Coronary Risk Intervention Project, an angiographic trial that compared multifactorial risk-reduction intervention with the usual care of physicians., Methods and Results: For 213 men, a bimodal frequency distribution of peak LDL density (g/mL) determined by analytical ultracentrifugation was used to classify baseline LDL profiles as "buoyant mode" (density < or = 1.0378) or "dense mode" (density > 1.0378). Coronary disease progression after 4 years was assessed by rates of change (mm/y, negative when arteries narrow) of minimum artery diameter. Rates for buoyant-mode subjects were -0.038 +/- 0.007 (mean +/- SEM) in usual care (n = 65) and -0.039 +/- 0.010 in intervention (n = 56; P = .6). Rates for dense-mode subjects were -0.054 +/- 0.012 in usual care (n = 51) and -0.008 +/- 0.009 in intervention (n = 41, P = .007). Lipid changes did not account for this difference in angiographic response., Conclusions: Different types of LDL profile may predict different-responses to specific therapies, perhaps because metabolic processes determine both LDL profiles and responses to therapies.

Background: Intracoronary ultrasonography has proven to be a more sensitive test than angiography for the detection of intimal thickening in transplant recipients. However, the prognostic significance of the intimal thickening detected by intracoronary ultrasonography has not been proven., Method: During a 1-year period, 70 transplant recipients without angiographically apparent coronary artery disease underwent intracoronary ultrasonography examination. For each intracoronary ultrasonography study an intimal index, defined as the ratio of the plaque area to the area within the media, was measured for the most diseased segment imaged. The subsequent annual follow-up angiograms of these 70 patients were reviewed for the development of visually apparent coronary artery disease. The time since transplantation for the 70 patients without angiographically apparent coronary artery disease ranged from 1 to 15 years, with a mean of 4.2 years an median of 3.9 years. Mean duration of angiographic follow-up was 2.0 years (range 1 to 3 years)., Results: Angiographically apparent coronary artery disease developed on follow-up angiograms in 13 of the 70 patients, with a mean time to development of 1.5 years. Four of 46 patients (9%) with an intimal index < 0.3 subsequently had angiographically apparent coronary artery disease, whereas of 25 patients (36%) with an intimal index > or = 0.3 subsequently had angiographically apparent coronary artery disease. Odds ratio for future angiographically apparent coronary artery disease between patients with an intimal index > or = and intimal index < 0.3 was 5.9 (p < 0.01 by Fisher's Exact test). In a subgroup of 22 patients more than 5 years after transplantation at the time of intracoronary ultrasonography, 12 had an intimal index < 0.3 and 10 had an intimal index > or = 0.3. In this subgroup none of the 12 patients with an intimal index < 0.3 had angiographically apparent coronary artery disease and only 1 of the 10 with an intimal index > or = 0.3 had angiographically apparent coronary artery disease (difference not significant)., Conclusions: The presence of moderate to severe intimal thickening by intracoronary ultrasonography is predictive of the future development of angiographically apparent coronary artery disease among patients more than 1 year and less than 5 years after transplantation. This same degree of intimal thickening may not carry the same prognostic significance among patients greater than 5 years after transplantation without the development of angiographically apparent coronary artery disease.

Objectives: This study assessed the time of first appearance of angiographic graft coronary artery disease in relation to clinical and laboratory variables and clinical events in heart transplant recipients., Background: Graft coronary artery disease is the main factor limiting long-term survival after heart transplantation, and it is important to understand its natural history., Methods: One hundred thirty-nine consecutive patients who developed angiographic coronary artery disease after heart transplantation were classified according to early (< or = 2 years) versus late (> 2 years) posttransplantation initial detection of coronary artery disease. These subgroups were analyzed for differences in clinical and laboratory demographics, incidence of progression to ischemic events and incidence of antecedent cytomegalovirus infection., Results: The early-onset group (64 patients) had more rapid progression to ischemic events than the late-onset group (75 patients), with 59% of the late group and only 35% of the early group free from ischemic events by 5 years after initial detection (p = 0.02), but there were no significantly correlated clinical or laboratory predictors of ischemic events. The early group had a significantly higher incidence of antecedent cytomegalovirus infection., Conclusions: We conclude that 1) accelerated graft coronary artery disease develops at variable times after heart transplantation; 2) the early appearance of graft coronary artery disease may be a marker of intrinsically more aggressive disease; 3) cytomegalovirus infection is associated with earlier onset of graft coronary artery disease. Patients with early development of graft coronary artery disease should potentially be given priority for interventional strategies as they are developed.

The Bypass Angioplasty Revascularization Investigation (BARI) randomized 1,829 patients to percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). Clinical site angiographers categorized lesions of > or = 50% diameter stenosis (n = 4,977) as clinically significant (86.4%) or nonsignificant (13.6%), and as favorable or nonfavorable for PTCA or CABG. More lesions were considered favorable for revascularization by CABG than by PTCA (91.5% vs 78.4%; p <0.001), particularly in the subgroup of 99% to 100% lesions (77.6% for CABG vs 21.9% for PTCA, p <0.001). Lesion features, characterized by the BARI core laboratory, were correlated with clinical site angiographers' assessment of clinical importance and suitability for PTCA or CABG. By multivariate analysis, positive predictors of clinical importance for 50% to 95% stenoses were greater stenosis severity, more jeopardized myocardium, larger reference diameter, and proximal vessel location. For 99% to 100% occlusions, predictors were shorter duration of occlusion and more jeopardized myocardium. PTCA suitability for 50% to 95% stenoses was inversely related to lesion length, ostial location, location on a bend, difficult access, and age, and was directly associated with greater Thrombolysis in Myocardial Infarction (TIMI) trial flow rate and more jeopardized myocardium. Predictors of PTCA suitability for 99% to 100% lesions were a lower American College of Cardiology/American Heart Association class and higher TIMI grade. Predictors for 50% to 95% stenoses were more jeopardized myocardium, larger reference diameter, and more proximal vessel location, and for 99% to 100% occlusions, more jeopardized myocardium and shorter duration of occlusion. Suitability for PTCA depended on lesion potency (<99%) and multiple morphologic characteristics that contrasted with the few angiographic features that adversely affect CABG suitability.

This study examined the hypothesis that immunologic factors are the major correlates of coronary artery intimal thickening and luminal stenosis. The study population included 116 adult heart transplant recipients with a mean age of 44.7 +/- 12.0 years (89 men and 27 women) undergoing annual coronary angiography and intracoronary ultrasound 3.4 +/- 2.7 (range, 1.0-14.6) years after transplantation. Mean intimal thickness was obtained from several distinct sites along the left anterior descending and/or left circumflex coronary artery by intracoronary ultrasound. Coronary artery stenosis defined by angiography was classified as mild (< 30% luminal stenosis), moderate (> or = 30-70% luminal stenosis), or severe (> 70% luminal stenosis or diffuse pruning of distal vessels). Prevalence of any transplant coronary artery disease (TxCAD) was 85% by intracoronary ultrasound and 15% by angiography. By multiple regression analysis, only average fasting plasma triglyceride level (P < 0.006) and average weight (P < 0.007) were significantly correlated with severity of intimal thickening (R = 0.54, P < 0.0001). Donor age (P < 0.006) and average fasting plasma triglyceride level (P < 0.009) were significantly correlated with stenosis by angiography. Correlation of multiple immunologic and metabolic factors with intimal thickness by univariate analysis suggests a multifactorial etiology for TxCAD. Among the multiple univariate correlates of TxCAD, higher fasting plasma triglyceride levels and body weight are the only independent correlates of TxCAD. The absence of acute rejection as an independent predictor of intimal thickening suggests that mechanisms beyond those mediating typical cellular rejection should be targeted for advancing our understanding of Tx-CAD.

Background: Although intracoronary ultrasound (ICUS) has been validated for the early detection of transplant coronary artery disease (TxCAD), the prognostic importance of findings detected by this new imaging technique is unknown., Methods and Results: This study examined the relation of clinical outcome in 145 heart transplant recipients (mean age, 45.1 +/- 11.1 years) with the amount of intimal thickness measured by ICUS during routine annual coronary angiography 1 to 10 years (mean, 3.1 +/- 2.2 years) after transplantation. From published autopsy data, a mean intimal thickness of > 0.3 mm was considered significant. During a mean follow-up time of 48.2 +/- 10.2 months, 23 deaths (12 cardiac) occurred, and 6 patients required retransplantation. Angiographic TxCAD developed in 22 of 125 patients (17.6%) in the subgroup with normal angiograms at the time of ICUS and a follow-up annual angiographic study. In the total population and the subgroup, mean intimal thicknesses of > 0.3 and < or = 0.3 mm, respectively, were associated with significantly inferior 4-year actuarial overall survival (73% versus 96%, P = .005; 72% versus 92%, P = .05), cardiac survival (79% versus 96%, P = .005; 80% versus 98%, P = .04), and freedom from cardiac death and retransplantation (74% versus 98%, P < .0001; 70% versus 96%, P = .001). In addition, ICUS predicted freedom from development of subsequent angiographic TxCAD in the subgroup that was initially normal (26% versus 72%, P = .02). A mean intimal thickness by ICUS of > 0.3 mm was associated with inferior clinical outcome regardless of the presence of angiographic TxCAD and predicted the development of subsequent angiographic TxCAD. Despite significantly longer duration after transplantation, higher rejection incidence, and lower average daily cyclosporine dose, none of these covariates were independent risk factors for outcome., Conclusions: These findings confirm the prognostic importance of mean intimal thickening of > 0.3 mm in heart transplant recipients and suggest that these patients should be candidates for early interventional strategies.

Background: Transplant vasculopathy (TxCAD) limits longterm survival of allograft recipients. The possibility that preexistent donor coronary disease (PEDD) might accelerate this process is of concern. The serial progression of sites with and without PEDD as assessed by intravascular ultrasonic imaging is explored in this study., Methods and Results: Thirty patients with baseline intravascular imaging within 3 weeks of cardiac transplantation who had at least one annual follow-up study were included in this study. Vessel luminal area (LA), total area (TA), intimal index (II = TA - LA/TA), mean intimal thickness (MIT), and Stanford classification were expressed for each image site and for each patient at each study. Progression of sites and of patients with and without PEDD on the baseline study was compared. Patients with PEDD (n = 9) still had significantly more intimal disease than those without PEDD (n = 21) at the first follow-up study (MIT = 0.35 +/- 0.13 versus 0.13 +/- 0.11 mm; II = 0.29 +/- 0.11 versus 0.11 +/- 0.1; class = 3.7 +/- 0.5 versus 2.2 +/- 0.94; P < .001 for all comparisons). However, the increase in intimal thickness during the 1- year interval was not significantly different between the two groups. In 4 patients in whom both types of sites were present, no difference in progression was found. Data were similar for patients and sites studied over > 1 year., Conclusions: PEDD does not accelerate the progression of TxCAD within the first few years after cardiac transplantation. The pathophysiology of TxCAD is most likely immune mediated and does not seem to be accelerated by native coronary artery disease.

The mechanisms responsible for transplant coronary artery disease (CAD) and its predisposing factors remain incompletely understood. The influence of donor characteristics as predisposing factors has not been studied systematically. We examined the correlation of donor demographic, clinical, and immunologic parameters with transplant CAD assessed by both intracoronary ultrasound (ICUS) and coronary angiography in 116 heart transplant recipients (age 44.7 +/- 12.0 years) studied 3.4 years (range 1.0 to 14.6) after transplantation. Quantitative ultrasound data were obtained by calculating mean intimal thickness from several distinct coronary sites. Coronary angiograms were categorized visually as normal or showing any transplant CAD. By multivariate regression analysis, donor undersize of > 20% of recipient weight (p < 0.02) and duration after transplantation (p < 0.005) were independently correlated with the amount of ICUS intimal thickness (r = 0.36, p = 0.0007), and older donor age with angiographic evidence for the disease (r = 0.34, p < 0.006). In a subgroup analysis of the 39 patients studied 1 year after transplantation, white donor race (p < 0.05), fewer human leukocyte antigen-DR mismatches (p < 0.002), shorter ischemic time (p < 0.04), and donor smoking history (p < 0.02) were independent predictors for severity of ICUS intimal thickening (r = 0.92, p = 0.0009); higher donor age (p < 0.006) and higher arterial partial pressure of oxygen (p < 0.003) were independent predictors for angiographic disease (r = 0.67, p < 0.002). In conclusion, donor characteristics may contribute to the probably multifactorial pathogenesis of transplant CAD.

This report presents baseline clinical and angiographic data from the Bypass Angioplasty Revascularization Investigation (BARI), a multicenter international trial assessing the relative efficacy of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG) in selected patients with multivessel coronary artery disease. PTCA is commonly performed in patients with multivessel coronary artery disease, yet its long-term efficacy in comparison to CABG is unknown. From August 1988 through August 1991, 1,829 qualifying patients with multivessel disease suitable for either procedure were randomized to PTCA or CABG; sample size estimates were based on anticipated 5-year mortality. Two registry populations were also defined for follow-up: (1) 2,013 patients eligible for randomization but not randomized; and (2) 422 patients considered by angiography as unsuitable for randomization. Patients randomized in BARI were at relatively high risk for subsequent cardiac events: 39% were > or = 65 years old, 55% had prior myocardial infarction, 69% presented with unstable angina or non-Q wave myocardial infarction, and 43% had 3-vessel coronary artery disease. Patients randomized to PTCA and CABG were equally matched in all the important baseline variables. The randomized and the eligible but not randomized groups were similar in most respects. However, the nonrandomized group had a higher proportion with college education; fewer with a history of myocardial infarction, heart failure, diabetes, and smoking; and a somewhat better average ejection fraction. At the 3-month follow-up, PTCA had been performed more commonly in the nonrandomized eligible patients, especially those with 2-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: The aim of this study was to evaluate, using quantitative arteriography, whether the diameter of visually normal coronary segments might be influenced by the relative proximity of visually apparent disease., Background: Severity of coronary artery lesions is commonly referenced against a presumed normal nearby coronary segment with the presumption that visually smooth segments are relatively free of atherosclerotic disease., Methods: Angiograms from 136 male patients with focal coronary disease were examined, and visually normal segments in the proximal portions of the major vessels were identified for measurement of mean segment diameters. Normal segments with immediately adjacent disease were compared with normal segments with distal disease in the same vessel and compared with normal segments in vessels for which the only other visible disease was in distant vessels. Angiograms with entirely normal findings from 26 age-matched men with atypical chest pain were used as controls. Segments were measured after nitroglycerin administration by means of computer-assisted quantitation., Results: Mean diameters of visually normal segments with distant disease were smaller than those of control segments (p < 0.05). Normal left main and proximal left anterior descending coronary artery segments in patients with disease within the same vessel were significantly smaller than normal segments in patients with distant disease (p < 0.05). Normal segments with immediately adjacent disease had smaller mean diameters than normal segments with distal disease in the same vessel (p < 0.05)., Conclusions: Visually normal coronary segments have progressively smaller lumen diameters, depending on the relative proximity of visible disease. Measurement of percent stenosis on the basis of the diameter of apparently normal adjacent reference segments can result in underestimation of coronary lesion severity.

The longitudinal distribution and circumferential pattern of coronary intimal proliferation were studied with intravascular ultrasonography in 135 patients after heart transplantation. Eighty-seven (64%) of 135 patients had significant intimal thickening, with most lesions (63%) concentric and free of fibrosis or calcification. Both diffuse and nonuniform longitudinal patterns of intimal thickening were found.

Objectives: The purpose of this study was to quantify the severity of transplant coronary artery disease and to assess lesion characteristics early and up to 15 years after heart transplantation by using intracoronary ultrasound., Background: Intravascular ultrasound has the ability to measure the components of the arterial wall and has been shown to be a sensitive method for detection of transplant coronary artery disease., Methods: A total of 304 intracoronary ultrasound studies were performed in 174 heart transplant recipients at baseline and up to 15 (mean 3.3 +/- 0.2) years after transplantation. Mean intimal thickness and an intimal index were calculated, and lesion characteristics (eccentricity, calcification) were assessed for all coronary sites imaged (mean 3.0 +/- 0.1 sites/study). The Stanford classification was used to grade lesion severity., Results: Compared with findings in patients studied at baseline (< 2 months after transplantation, n = 50), mean intimal thickness (0.09 +/- 0.02 vs. 0.16 +/- 0.02 mm, p < 0.01), intimal index (0.07 +/- 0.01 vs. 0.14 +/- 0.02, p < 0.01) and mean severity class (1.5 +/- 0.2 vs. 2.3 +/- 0.2, p < 0.01) were significantly higher at year 1 (n = 52) after transplantation. Thereafter, all three variables further increased over time and reached highest values between years 5 and 15. Calcification of lesions was detected in 2% to 12% of studies up to 5 years after transplantation, with a significant increase to 24% at years 6 to 10 (p < 0.05)., Conclusions: Severity of transplant coronary artery disease appeared to progress with time after transplantation in this cross-sectional study. This characteristic was most prominent during the 1st 2 years after transplantation, whereas calcification of plaques occurred to a significant extent only later in the process. These data may serve as a reference for comparison of intravascular ultrasound findings in other studies of patients with transplant coronary artery disease.

Background: Serial quantitative coronary angiography is used to assess progression of coronary disease; however, pathology studies have demonstrated angiographic insensitivity for determining atheroma. Intracoronary ultrasound (ICUS) can define and measure the components of the arterial wall and offers the potential for precise quantitative assessment of disease progression on serial examinations. The present study was done to test the feasibility of serially assessing intimal proliferation at the same coronary site with ICUS imaging in cardiac transplant recipients., Methods and Results: ICUS imaging was done with a 30-MHz, 5F or 4.3F ultrasound imaging catheter at the time of angiography in 70 cardiac allografts (3.8 sites per patient) initially and 1 year later. Mean intimal thickness (IT), luminal area (LA), and total area (TA) of lumen plus intima and an index of intimal thickness (II = TA - LA/TA) were measured at each site. Additionally, vessels were graded using a scale incorporating criteria of intimal thickness and circumferential involvement. Side-by-side comparisons of paired angiograms were performed both to verify the similarity of ICUS imaging site and to detect new angiographic abnormalities. At least one site could be assessed serially by ICUS in 100% of patients, but only 189 of the original 263 coronary sites (72%) (2.7 sites per patient) could be matched satisfactorily on the second study. Thirty-nine patients (56%) had mild IT and 31 patients (44%) had moderate or severe IT on the initial study. Both groups showed the same IT progression the following year (delta = 0.05 +/- 0.13 versus 0.07 +/- 0.15 mm; P = NS). Twenty-seven of the 70 patients (39%) showed progression by ICUS. The 23 patients with ICUS progression and angiographically normal vessels had the same progression in intimal thickening as the 4 patients with ICUS progression but showing angiographic disease (delta = 0.17 +/- 0.13 versus 0.22 +/- 0.10 mm; P = NS)., Conclusions: Replication of the intracoronary imaging site by judgment of two observers at an initial study and at a second study 1 year later was possible in at least one vessel site in 100% of the 70 patients and in 72% (189 of 263) of the original imaging sites (2.7 sites per patient). Serial ICUS demonstrates progression of intimal thickening at specific sites in only some cardiac transplant patients. Progression of intimal proliferation can occur in individuals in the presence or absence of initially increased intimal thickening or of angiographic disease at the time of the initial studies. Angiography is insensitive for recognizing early intimal thickening of the coronary vessels.

Objectives: This study attempted to determine whether an intensive multifactor risk reduction program conducted over 4 years would reduce the rate of development of new coronary artery lesions., Background: Recent angiographic trials have generally demonstrated that normalization of plasma lipoprotein profiles reduces the rate of progression of established coronary lesions, but limited data exist on how these treatments influence the development of new lesions., Methods: Three hundred men and women with coronary artery disease were randomized to multifactor risk reduction or usual care. Highly significant improvements in risk factors were achieved by the risk reduction group compared with minimal changes by the usual care group. Quantitative coronary angiography was performed on entry and after 4 years under identical conditions. A decrement in the minimal diameter of visually normal segments > 0.2 mm was considered to indicate new lesion formation., Results: A total of 1,605 segments, representing 257 patients, were considered normal at baseline, with 804 and 801 disease-free segments in the usual care and risk reduction groups, respectively. Ninety-nine segments (6.1%) were identified by follow-up quantitative angiography and two angiographic observers as having new lesion formation (usual care 7.6%, risk reduction 4.7%, p = 0.05). New lesion formation was observed in 41 (31%) of 131 patients in the usual care group and in 29 (23%) of 126 patients in the risk reduction group (p = 0.16), with a mean number of new lesions/patient of 0.47 in the usual care group and 0.30 in the risk reduction group (p = 0.06). Multiple regression analysis identified on-study dietary fat intake as the best correlate with new lesion formation., Conclusions: These data indicate that intensive multifactor risk reduction tends to diminish the frequency of new coronary lesion formation.

Background: Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis., Methods and Results: Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002)., Conclusions: The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.

Background: Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis, but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications. This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects randomly assigned to the usual care of their physician., Methods and Results: Three hundred men (n = 259) and women (n = 41) (mean age, 56 +/- 7.4 years) with angiographically defined coronary atherosclerosis were randomly assigned to usual care (n = 155) or multifactor risk reduction (n = 145). Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet, exercise, weight loss, smoking cessation, and medications to favorably alter lipoprotein profiles. Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years. The main angiographic outcome was the rate of change in the minimal diameter of diseased segments. All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years, and reasons for all hospitalizations and deaths were documented. Of the 300 subjects randomized, 274 (91.3%) completed a follow-up arteriogram, and 246 (82%) had comparative measurements of segments with visible disease at baseline and follow-up. Intensive risk reduction resulted in highly significant improvements in various risk factors, including low-density lipoprotein cholesterol and apolipoprotein B (both, 22%), high-density lipoprotein cholesterol (+12%), plasma triglycerides (-20%), body weight (-4%), exercise capacity (+20%), and intake of dietary fat (-24%) and cholesterol (-40%) compared with relatively small changes in the usual-care group. No change was observed in lipoprotein(a) in either group. The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47% less than that for subjects in the usual-care group (change in minimal diameter, -0.024 +/- 0.066 mm/y versus -0.045 +/- 0.073 mm/y; P < .02, two-tailed). Three deaths occurred in each group. There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group (rate ratio, 0.61; P = .05; 95% confidence interval, 0.4 to 0.9)., Conclusions: Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events.

Background: To identify predictors of long-term outcome after balloon aortic valvuloplasty, we analyzed data on 674 adults (mean age, 78 +/- 9 years; 56% were women) undergoing this procedure at 24 clinical centers who had a mean initial increase in aortic valve area of 0.3 cm2., Methods and Results: Baseline data included clinical, echocardiographic, and catheterization variables. Follow-up data included mortality, cause of death, rehospitalization, 6-month echocardiography, and functional status. Kaplan-Meier curves and log-rank tests were used to evaluate survival in subgroups. Multivariate Cox regression models were used to identify independent predictors of survival. Overall survival was 55% at 1 year, 35% at 2 years, and 23% at 3 years, with the majority of deaths (70%) classified as cardiac by an independent review committee. Rehospitalization was common (64%), although 61% of survivors at 2 years reported improved symptoms. Echocardiography at 6 months (n = 115) showed restenosis from the postprocedural valve area of 0.78 +/- 0.31 cm2 to 0.65 +/- 0.25 cm2 (P < .0001). With stepwise multivariate analysis, sequentially adding clinical, echocardiographic, and catheterization variables, the overall model identified independent predictors of survival as baseline functional status, baseline cardiac output, renal function, cachexia, female gender, left ventricular systolic function, and mitral regurgitation. Baseline and postprocedural variables were examined to identify which subgroup of patients has the best outcome after aortic valvuloplasty. A "lower-risk" subgroup (28% of the study population), defined by normal left ventricular systolic function and mild clinical functional limitation, had a 3-year survival of 36% compared with 17% in the remainder of the study group., Conclusions: Long-term survival after balloon aortic valvuloplasty is poor with 1- and 3-year survival rates of 55% and 23%, respectively. Although survivors report fewer symptoms, early restenosis and recurrent hospitalization are common.

Background: Intracoronary ultrasound (ICUS) has the ability to quantitatively evaluate vessel wall morphology and is well suited for serial studies of coronary artery disease regression and progression. However, the potential risk for catheter-induced endothelial damage and accelerated atherosclerosis in instrumented vessels is a concern. The acute effects as well as the 1-year safety of ICUS regarding its impact on the atherosclerotic process were assessed., Methods and Results: The acute studies include 240 intracoronary studies performed in 170 cardiac transplant recipients. Patients were systematically heparinized. Only vessels > or = 2 mm in diameter were visualized. Coronary arteries of 38 patients were measured by quantitative coronary angiography in matched angiograms at an interval of 1 year after the initial ICUS examination was performed to assess long-term effects. The angiographic measurements in the previously instrumented and noninstrumented vessels were compared. Forty-nine vessels that had been imaged (IM) in these 38 patients with a 5F ICUS catheter were compared with 61 vessels not previously imaged (NIM) in the same patients. Absolute and percentage change in angiographically measured mean vessel diameters in the ICUS imaged and nonimaged segments were compared. Despite pretreatment with nitroglycerin, 20 patients (8.3%) had angiographically evident coronary spasm. In all cases, this was reversed by giving nitroglycerin. One year after the original imaging study, no difference was noted between imaged and nonimaged vessels in change in absolute vessel diameter (IM, -0.11 +/- 0.28 mm vs NIM, -0.07 +/- 0.22 mm; P = .49) or in percentage change in diameter (IM, -5 +/- 11% vs NIM, -3 +/- 7%; P = .32)., Conclusions: Intracoronary ultrasound in cardiac transplant recipients was associated with no clinical morbidity and a low incidence of vessel spasm in large and medium-size coronary arteries. It does not accelerate progression of angiographically quantifiable coronary artery disease. This study suggests that ICUS can be safely used even in coronary arteries not undergoing interventions.

Objectives: The Coronary Artery Surgery Study (CASS) required participants to undergo follow-up angiography at 5 years to identify clinical and angiographic features associated with progression of coronary artery disease., Background: The CASS randomized 780 patients at 11 participating clinical centers between an initial strategy of medical therapy versus bypass surgery. Five clinical sites accomplished follow-up angiography in > 50% of their randomized subjects within a 42- to 66-month period after the entry arteriogram (n = 314)., Methods: Qualified clinical site angiographers, using side by side film review, evaluated an average of 13 segments/patient on both arteriograms for initial stenosis severity, morphologic features, lesion location and occurrence of disease progression or occlusion. Progression was defined as further definite narrowing by > or = 15% and occlusion as lesion progression to > or = 98%. Lesions were subcategorized as to whether they were univariate and had or had not been treated with bypass surgery. Multivariate logistic regression analyses were performed., Results: For nonbypassed segments, right coronary artery and left anterior descending artery proximal and midlocations were associated with disease progression. For stenosis-containing segments, the initial severity, a non-left anterior descending artery location and increased treadmill duration predicted progression. Segment occlusion was associated with initial lesion severity, right coronary artery location and subsequent interval myocardial infarction. There were few predictors of progression or occlusion in bypassed arteries, other than initial lesion severity., Conclusions: Univariate and multivariate associations with lesion progression and occlusion included diabetes, lesion location, elevated cholesterol level, interval infarction and lesion morphology. These angiographic results, collected in a prospective trial, are consistent with known risk factors.

Background: Increases in coronary artery size and dilating capacity have been observed in some animals after endurance training, and at autopsy, active men appear to have enlarged epicardial coronary arteries. This cross-sectional study was designed to test the hypothesis that highly trained endurance runners have larger epicardial coronary arteries and greater dilating capacity than inactive men., Methods and Results: The subjects, ages 39-66 years, included 11 male volunteers who had participated in ultradistance running during the past 2 years and 11 physically inactive men who had been referred for arteriography but had no visible coronary artery disease. The internal diameter of the proximal segments of each major epicardial coronary artery was measured before and after nitroglycerin administration using a computer-based quantitative arteriographic analysis system. Measurements also included maximal oxygen uptake, plasma lipoprotein concentrations, body composition, and cardiac mass by echocardiography. Before nitroglycerin, the sum of the cross-sectional areas for the proximal right, left anterior descending, and circumflex arteries was not different for the runners and the inactive men: 22.7 +/- 4.79 versus 21.0 +/- 7.97 mm2 (p = 0.57), respectively. However, the increase in the sum of the cross-sectional area for the proximal right, left anterior descending, and circumflex arteries in response to nitroglycerin was greater for the runners (13.20 +/- 4.76 versus 6.00 +/- 3.02 mm2; p = 0.002). Left ventricular mass index (152 +/- 21 versus 116 +/- 41 g/m2; p < 0.05) but not left ventricular mass (284 +/- 40 versus 246 +/- 91 g; p = 0.22) was significantly greater for the runners. Among the runners, dilating capacity was positively correlated with aerobic capacity and negatively related to adiposity, resting heart rate, and plasma lipoprotein concentrations., Conclusions: Highly trained, middle-aged endurance runners demonstrated a significantly greater dilating capacity of their epicardial coronary arteries in response to nitroglycerin compared with inactive men. The causes of this greater dilating capacity and its clinical significance need to be determined.