George W. Vetrovec

Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA registry of the national heart, lung, and blood institute

The results of follow-up angiography in patients from 27 clinical centers enrolled in the PTCA Registry were analyzed to evaluate restenosis after PTCA. Of 665 patients with successful PTCA, 557 (84%) had follow-up angiography (median follow-up 188 days). Restenosis, defined as an increase of at least 30% from the immediate post-PTCA stenosis to the follow-up stenosis or a loss of at least 50% of the gain achieved at PTCA, was seen in 187 patients (33.6%). The incidence of restenosis in patients who underwent follow-up angiography was highest within the first 5 months after PTCA. Restenosis was found in 56% of patients with definite or probable angina after PTCA and in 14% of patients without angina after PTCA. Twenty-four percent of patients with restenosis did not have either definite or probable angina. Multivariate analysis selected 4 factors associated with increased rate of restenosis: male sex, PTCA of bypass graft stenosis, severity of angina before PTCA and no history of MI before PTCA.

Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction

Background— Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Methods and Results— Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [P<0.001] and 4.2±0.4% versus 1.1±0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities. Conclusions— Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.

Intracoronary thrombus in syndromes of unstable myocardial ischemia

The association of coronary thrombosis and transmural myocardial infarction is well documented. We have recently observed apparent intracoronary thrombi in patients with unstable myocardial ischemia without transmural infarction. To assess the frequency and angiographic characteristics of intracoronary defects consistent with thrombi, we reviewed the angiograms of all patients undergoing catheterization within 1 month of the onset of unstable angina or the intermediate coronary syndrome. Of 129 such patients, eight (6.2%) had nonoccluding, hazy, or nonopacified intracoronary filling defects consistent with thrombus in angiographically well-opacified vessels. All defects were just distal to a significant (80% to 99%) coronary stenosis. In each instance the thrombus-involved vessel supplied a myocardial segment referable to the electrocardiographically defined area of ischemia. Support for the theory that the intracoronary defects were thrombi includes three patients with enlargement of the filling defects, who underwent repeat angiography within 7 days, and two patients with embolization of defect fragments. Furthermore these defects were angiographically similar to poststenotic intraluminal defects seen transiently in some patients after partial intracoronary streptokinase recanalization. In conclusion, we have observed, angiographically, intracoronary filling defects consistent with thrombus in some patients with unstable myocardial ischemia.

Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients

OBJECTIVES This study sought to analyze the outcomes of revascularization procedures in the treatment of allograft coronary disease. BACKGROUND Allograft vasculopathy is the main factor limiting survival of heart transplant recipients. Because no medical therapy prevents allograft atherosclerosis, and retransplantation is associated with suboptimal allograft survival, palliative coronary revascularization has been attempted. METHODS Thirteen medical centers retrospectively analyzed their complete experience with percutaneous transluminal coronary angioplasty, directional coronary atherectomy and coronary bypass graft surgery in allograft coronary disease. RESULTS Sixty-six patients underwent coronary angioplasty. Angiographic success (< or = 50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 +/- 14 (mean +/- SD) months after angioplasty. The consequences of failed revascularization were severe. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 +/- 5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Eleven patients underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Two periprocedural deaths occurred. Nine patients are alive without transplantation at 7 +/- 4 months after atherectomy. Bypass graft surgery was performed in 12 patients. Four patients died perioperatively. Seven patients are alive without retransplantation at 9 +/- 7 months after operation. CONCLUSIONS Coronary revascularization may be an effective palliative therapy in suitable cardiac transplant recipients. Angioplasty has an acceptable survival in patients without angiographic distal arteriopathy. Because few patients underwent atherectomy and coronary bypass surgery, assessment of these procedures is limited. Angiographic distal arteriopathy is associated with decreased allograft survival in patients requiring revascularization.

Seven Direct Methods for Measuring HDL and LDL Cholesterol Compared with Ultracentrifugation Reference Measurement Procedures

BACKGROUND Methods from 7 manufacturers and 1 distributor for directly measuring HDL cholesterol (C) and LDL-C were evaluated for imprecision, trueness, total error, and specificity in nonfrozen serum samples. METHODS We performed each direct method according to the manufacturers instructions, using a Roche/Hitachi 917 analyzer, and compared the results with those obtained with reference measurement procedures for HDL-C and LDL-C. Imprecision was estimated for 35 runs performed with frozen pooled serum specimens and triplicate measurements on each individual sample. Sera from 37 individuals without disease and 138 with disease (primarily dyslipidemic and cardiovascular) were measured by each method. Trueness and total error were evaluated from the difference between the direct methods and reference measurement procedures. Specificity was evaluated from the dispersion in differences observed. RESULTS Imprecision data based on 4 frozen serum pools showed total CVs <3.7% for HDL-C and <4.4% for LDL-C. Bias for the nondiseased group ranged from -5.4% to 4.8% for HDL-C and from -6.8% to 1.1% for LDL-C, and for the diseased group from -8.6% to 8.8% for HDL-C and from -11.8% to 4.1% for LDL-C. Total error for the nondiseased group ranged from -13.4% to 13.6% for HDL-C and from -13.3% to 13.5% for LDL-C, and for the diseased group from -19.8% to 36.3% for HDL-C and from -26.6% to 31.9% for LDL-C. CONCLUSIONS Six of 8 HDL-C and 5 of 8 LDL-C direct methods met the National Cholesterol Education Program total error goals for nondiseased individuals. All the methods failed to meet these goals for diseased individuals, however, because of lack of specificity toward abnormal lipoproteins.

Intracoronary thrombolysis in syndromes of unstable ischemia: Angiographic and clinical results

For an assessment of association of intracoronary thrombus with prolonged unstable myocardial ischemia and of the possible efficacy of local thrombolysis, 12 patients with recent prolonged unstable angina underwent 13 intracoronary streptokinase infusions. All patients had prolonged rest angina within 5 days of coronary angiography. Abnormal resting ECGs were present in all patients, and 10 had ECG changes referable to the ischemic-related vessel. There were seven native coronary and six bypass graft infusions with a mean streptokinase dose of 187,00 +/- 22,000 IU (standard error of mean). Angiographic findings consistent with intracoronary thrombus were identified in 11 of 13 ischemia-related vessels. Evidence of partial or complete intracoronary thrombolysis was noted angiographically in 10 of 13 ischemia-related vessels (77%), although reestablishment of anterograde flow was seen in only two of six totally or subtotally occluded vessels. Nine patients experienced rest angina during the 48 hours prior to infusion, whereas only three experienced angina during the 48 hours following infusion. In conclusion, angiographic findings before and after thrombolysis in this preliminary study demonstrate a high frequency of intracoronary thrombus in preinfarction syndromes. Furthermore, these limited observations suggest a decrease in angina frequency following thrombolytic therapy.

Usefulness of Statin Pretreatment to Prevent Contrast-Induced Nephropathy and to Improve Long-Term Outcome in Patients Undergoing Percutaneous Coronary Intervention

Contrast-induced nephropathy (CIN) is an important cause of mortality and morbidity in patients undergoing angiography. This study investigated whether statins decrease incidence of CIN in the setting of percutaneous coronary intervention (PCI) and evaluated the influence of such potential benefit on long-term outcome. Four-hundred thirty-four patients undergoing PCI were prospectively enrolled and followed up to 4 years. Patients were stratified according to preprocedural statin therapy (260 statin treated, 174 statin naive). CIN was defined as a postprocedural increase in serum creatinine of >or=0.5 mg/dl or>25% from baseline. Follow-up assessment included 4-year occurrence of major adverse cardiac events. Statin-treated patients had a significantly lower incidence of CIN (3% vs 27%, p<0.0001; 90% risk decrease) and had better postprocedural creatinine clearance (80+/-20 vs 65+/-16 ml/min, p<0.0001). Benefit of statin before treatment was observed in all subgroups, except in patients with a pre-existing creatinine clearance<40 ml/min. During follow-up, CIN was a predictor of poorer outcome; 4-year survival free of major adverse cardiac events was highest in statin-treated patients without CIN (95%, p<or=0.015) and lowest in statin-naive patients with CIN (53%, p<or=0.018). In conclusion, patients receiving statins before PCI have a significant decrease of CIN; this early protective effect translates into better long-term event-free survival. These results may lend further support to utilization of statins as adjuvant pharmacologic therapy before PCI.

Coronary angioplasty of multiple vessels: short-term outcome and long-term results.

Experience with percutaneous transluminal coronary angioplasty (PTCA) of multiple vessels was reviewed to assess short-term outcome and long-term results. PTCA of multiple vessels was performed in 100 of the initial 500 patients (20%) who underwent PTCA at the Medical College of Virginia between July 1979 and August 1984. Eighty-nine percent had class 3 or 4 angina, and 66% had unstable angina. Two-thirds had severe stenosis of two vessels or major branches and one-third had three-vessel disease. One or more significant lesions were dilated in two vessels in 84 patients, in three vessels in 14 patients, and in four vessels in two patients. PTCA of 273 lesions (2.7/patient) was attempted (range two to eight per patient) with angiographic success in 250 lesions (91.6%). Primary success (angiographic and clinical improvement) was achieved in 95 of 100 patients (95%); 84% had success in multiple vessels, and 79% had success in all attempted lesions. Complications occurred in 11 patients (11%); four patients (4%) underwent urgent bypass surgery and four additional patients (4%) had myocardial infarction. Long-term results were assessed in 44 patients with primary success who had follow-up of more than 1 year (mean 26 months) after multiple-vessel PTCA. Twenty-eight patients (64%) remain event-free and improved and 48% are event-free and asymptomatic. Clinical recurrence developed in 15 patients (34%); four had sustained improvement with repeat PTCA, three remain improved with medical therapy, and eight (18%) have undergone bypass surgery during follow-up. One patient (2.3%) developed late myocardial infarction, and deaths have occurred in the follow-up cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Thromboxane A2 Blockade on Clinical Outcome and Restenosis After Successful Coronary Angioplasty Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART II)

BACKGROUND Antithromboxane therapy with aspirin reduces acute procedural complications of coronary angioplasty (PTCA) but has not been shown to prevent restenosis. The effect of chronic aspirin therapy on long-term clinical events after PTCA is unknown, and the utility of more specific antithromboxane agents is uncertain. The goal of this study was to assess the effects of aspirin (a nonselective inhibitor of thromboxane A2 synthesis) and sulotroban (a selective blocker of the thromboxane A2 receptor) on late clinical events and restenosis after PTCA. METHODS AND RESULTS Patients (n = 752) were randomly assigned to aspirin (325 mg daily), sulotroban (800 mg QID), or placebo, started within 6 hours before PTCA and continued for 6 months. The primary outcome was clinical failure at 6 months after successful PTCA, defined as (1) death, (2) myocardial infarction, or (3) restenosis associated with recurrent angina or need for repeat revascularization. Neither active treatment differed significantly from placebo in the rate of angiographic restenosis: 39% (73 of 188) in the aspirin-assigned group, 53% (100 of 189) in the sulotroban group, and 43% (85 of 196) in the placebo group. In contrast, aspirin therapy significantly improved clinical outcome in comparison to placebo (P = .046) and sulotroban (P = .006). Clinical failure occurred in 30% (49 of 162) of the aspirin group, 44% (73 of 166) of the sulotroban group, and 41% (71 of 175) of the placebo group. Myocardial infarction was significantly reduced by antithromboxane therapy: 1.2% in the aspirin group, 1.8% in the sulotroban group, and 5.7% in the placebo group (P = .030). CONCLUSIONS Thromboxane A2 blockade protects against late ischemic events after angioplasty even though angiographic restenosis is not significantly reduced. While both aspirin and sulotroban prevent the occurrence of myocardial infarction, overall clinical outcome appears superior for aspirin compared with sulotroban. Therefore, aspirin should be continued for at least 6 months after coronary angioplasty.