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Background Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. Design The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. Summary If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

Background Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. Methods APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitozone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. Result A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body 2 mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. Conclusions APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitozone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease. (Am Heart J 2008; 156:1074-9.)

A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Passive transcatheter coronary arterial perfusion, i.e., autoperfusion, has been introduced for clinical use to ameliorate short episodes of myocardial ischemia during percutaneous transluminal coronary angioplasty. The primary goal of this study was to evaluate the cardioprotective effect of autoperfusion after prolonged coronary artery occlusion. Accordingly, in 24 anesthetized dogs, either the left anterior descending or left circumflex coronary artery was occluded for 6 hours. The dogs were randomized to a control group subjected to coronary artery occlusion alone (n = 13) or to a group treated with transcatheter autoperfusion (n = 11). The hypoperfused zone, i.e., risk area and infarct size, were measured by autoradiography and triphenyltetrazolium chloride staining, respectively. The hypoperfused zone was 30 +/- 2% and 29 +/- 2% in the control and treated (NS) groups, respectively. When infarct size was expressed as a percent of the hypoperfused zone, it was 84 +/- 5% in the control group and 25 +/- 9% in the group treated with transcatheter autoperfusion (p less than 0.001), showing a reduction of 70%. In addition, an in vitro study showed pressure-dependent flow during autoperfusion as reflected by close linear relationship between perfusion pressure and flow (Flow = 0.54 X Pressure + 16.16, r = 0.99, n = 16). These data suggest that although passive coronary arterial perfusion for 6 hours after coronary occlusion does not prevent myocardial necrosis, it markedly reduces myocardial infarction in the canine model.

Patients undergoing coronary angioplasty who have had a prior transmural myocardial infarction in the distribution of a contralateral coronary artery are considered a high-risk group because of potentially severe left ventricular dysfunction if an ischemic complication occurs. The purpose of this study was to evaluate the safety and efficacy of coronary angioplasty in 28 patients with prior myocardial infarction remote from the artery undergoing dilatation. Prior myocardial infarction was defined by the presence of pathologic Q waves on ECG or segmental akinesis on ventriculography. Angioplasty was successful in 30 of 33 lesions (91%) and in 25 of 28 patients (89%). Mean stenosis diameter was reduced from 91% ± 7% to 28% ± 16%; mean translesional gradient after angioplasty was 6 ± 5 mm Hg. No patient developed severe hemodynamic deterioration from transient coronary occlusion during balloon inflation or from an acute ischemic complication. Three patients underwent coronary artery bypass surgery after unsuccessful angioplasty. There were no new Q wave infarctions or deaths. The results of coronary angioplasty in patients with prior infarction were compared with those of 203 patients without prior remote infarction. Primary success and occurrence of major complications were comparable in both groups. At a mean follow-up of 12 ± 6 months, 18 of the 25 patients (72%) who underwent initially successful dilatation have remained symptom free with angioplasty alone. Therefore, coronary angioplasty is a suitable therapeutic procedure in carefully selected patients with angina pectoris and prior myocardial infarction at a distance from the site of angioplasty.

The aim of the study was to determine whether regional beta-adrenergic blockade via the coronary sinus limited myocardial damage after coronary artery occlusion in the canine model. Accordingly, open-chest anesthetized dogs were randomly allocated to one of three groups: a control group and groups treated with propranolol (in doses of 0.02, 0.2, and 2.0 mg/kg) given either intravenously or via the coronary sinus. The hypoperfused zone (i.e., risk area) and the extent of myocardial damage were assessed by autoradiography and triphenyltetrazolium chloride staining, respectively. Myocardial damage expressed as a percent of the hypoperfused zone was 84 +/- 5% in the control group (n = 9) and 78 +/- 7% (0.02 mg/kg, n = 7, NS), 63 +/- 6% (0.2 mg/kg, n = 7, p less than 0.05), and 62 +/- 7% (2.0 mg/kg, n = 9, p less than 0.02) in the groups receiving intravenous propranolol and 73 +/- 6% (0.02 mg/kg, n = 7, NS), 58 +/- 7% (0.2 mg/kg, n = 7, p less than 0.01), and 44 +/- 9% (2.0 mg/kg, n = 9, p less than 0.001) in groups receiving propranolol via the cardiac veins. There was a significant enhancement of myocardial salvage with increasing doses of propranolol delivered via the cardiac veins (linear regression trend, p less than 0.05). In contrast, myocardial damage expressed as a percent of the hypoperfused zone remained comparable with propranolol doses of 0.2 and 2.0 mg/kg administered intravenously (linear regression trend, NS).(1) regional beta-adrenergic blockade via the cardiac veins afforded significant myocardial salvage and (2) the regional administration of propranolol resulted in significant reduction of myocardial damage in a dose-dependent fashion.

The effects of cytochrome C, an electron carrier in the process of oxidative phosphorylation, on infarct size and regional left ventricular function after a coronary artery occlusion were investigated. Thus, in 30 dogs, 1 minute after left anterior descending coronary artery occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for subsequent assessment of the hypoperfused zone, that is, the area at risk of infarction. Fifteen minutes after coronary artery occlusion, dogs were randomized into a control group (n = 15) and a cytochrome C-treated group (n = 15). The latter immediately received cytochrome C, 2.5 mg/kg intravenously. Six hours after coronary artery occlusion the dogs were sacrificed and their left ventricles were cut into 3 mm thick slices. Infarct size was determined by triphenyltetrazolium chloride staining and measured by planimetry. The same slices were then submitted to autoradiography and the hypoperfused zone was then measured by planimetry. The hypoperfused zone was 22 +/- 2% and 23 +/- 2% of the left ventricle in the control and treated groups, respectively (NS), indicating that the extent of myocardium at risk before treatment was similar. The extent of the hypoperfused zone which evolved to necrosis was 90 +/- 3% in the control group but only 50 +/- 7% in the treated group (p less than 0.001). Myocardial salvage in the treated group was paralleled by improvement in systolic wall thickness of the ischemic segment as measured by two-dimensional echocardiography. Thus, cytochrome C reduced the extent of myocardial necrosis by 44% and improved systolic function of the ischemic myocardium.

Effective therapy for patients with unstable angina or evolving myocardial infarction following coronary bypass surgery requires accurate delineation of the pathoanatomy and prompt intervention. We therefore performed cardiac catheterization in 10 consecutive patients: four with acute myocardial infarction and six with refractory unstable angina (NYHA class IV). All patients with acute myocardial infarction were found to have completely thrombosed vein grafts supplying totally occluded native coronary arteries. In three patients with evolving myocardial infarction occurring within 4 weeks of coronary bypass surgery, graft thrombosis was caused by venous valves in two patients and a suboptimal anastomosis in a third. The fourth patient sustained a myocardial infarction 7 years after coronary bypass surgery with atherosclerotic plaque rupture causing vein graft thrombosis. Therapy with intragraft streptokinase resulted in complete clearing of thrombus, pain relief, and control of injury current in all four patients. Rest angina with concomitant ST and T wave changes occurred in six patients. In two patients symptoms occurred early (within 6 months), whereas angina developed 4 to 10 years after coronary bypass graft surgery in four patients. In the two patients with early recurrence of symptoms suboptimal anastomosis was found in one, while the other patient had a venous valve in the vein graft in conjunction with a stenosis in the native coronary artery. In three of four patients with late recurrence of angina, symptoms developed as a result of atherosclerotic stenosis in their vein grafts; in the fourth patient an occluded graft was found to supply a stenosed native coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the efficacy of coronary angioplasty (PTCA) of the infarct-related artery in 54 patients with recurrent myocardial ischemia in the zone of prior infarction. Our patients had recurrent ischemia 10 ± 7 days after infarction, with 75% experiencing rest angina and 15% having evidence of reinfarction. Angiography of the infarct-related artery demonstrated a critical stenosis in 35 of 54, a subtotal occlusion in 5 of 54, and a total occlusion in 14 of 54. PTCA was successful in 94% of critical stenoses, 80% of subtotal occlusions, but in only 50% of total occlusions. Complications related to PTCA included a 3.7% rate of emergency surgery, but no deaths or infarctions. During the clinical follow-up period of 11 ± 7 months, there was one reinfarction and no deaths. Although 27% of our 44 patients with a successful initial PTCA required a second revascularization procedure for recurrent angina, 40 patients (91%) remained symptomatically improved with angioplasty alone (including successful repeat PTCA in eight patients). We conclude that PTCA of the infarct-related artery is beneficial for selected patients with recurrent ischemia in the zone of prior infarction.