David Hasdai

Coronary Endothelial Dysfunction in Humans Is Associated With Myocardial Perfusion Defects

BACKGROUND Coronary endothelial dysfunction may occur in patients with minimally obstructive coronary artery disease and angina, and potentially may cause myocardial ischemia. METHODS AND RESULTS Coronary endothelium-dependent vasodilation was examined in patients with angina and <50% coronary artery diameter (CAD) stenosis by selectively infusing acetylcholine (10(-6) mol/L to 10(-4) mol/L) into the left anterior descending coronary artery (LAD). Percent change in CAD (%deltaCAD) was measured by quantitative coronary angiography, and percent change in coronary blood flow (%deltaCBF) was calculated using intracoronary flow Doppler. Coronary endothelium-independent vasodilation was examined using intracoronary adenosine and nitroglycerin. 99mTc sestamibi was injected intravenously just prior to the infusion of the highest dose of acetylcholine. Patients were divided blindly into three groups: Perfusion defects in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and perfusion defects in the LAD territory (group 3, n=7). All patients had intact endothelium-independent vasodilation. In group 1, perfusion defects outside the LAD territory reflected an increase in %deltaCAD and %deltaCBF by 24+/-5% and 241+/-46% in the LAD. In group 2, %deltaCAD decreased by 26+/-5%, but %deltaCBF increased by 54+/-17%. In group 3, perfusion defects were within the LAD territory, reflecting a decrease in %deltaCAD and %deltaCBF by 35+/-5% and 51+/-14%, respectively. CONCLUSIONS This study demonstrates that coronary endothelial dysfunction in humans may be temporally associated with myocardial perfusion defects and supports a role for the coronary epicardial and microcirculation endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in humans with impaired endothelium-dependent coronary flow reserve of the coronary epicardial and microcirculation.

Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization.

BACKGROUND Cigarette smoking is known to be deleterious to patients with coronary artery disease, but the effect of smoking on the clinical outcome of percutaneous coronary revascularization is unknown. METHODS Patients who had undergone successful percutaneous coronary revascularization at the Mayo Clinic between 1979 and 1995 were divided into nonsmokers (n=2009), former smokers (those who had stopped smoking before the procedure, n=2259), quitters (those who stopped smoking after the procedure, n=435), and persistent smokers (those who smoked before and after the procedure, n=734). RESULTS The maximal follow-up was 16 years (mean [+/-SD], 4.5+/-3.4). The nonsmokers and former smokers had similar base-line characteristics and outcomes. The quitters and persistent smokers were younger than the nonsmokers and former smokers and had more favorable clinical and angiographic characteristics. In analyses adjusted for confounding base-line characteristics, the persistent smokers had a greater relative risk of death (1.76 [95 percent confidence interval, 1.37 to 2.26]) and of Q-wave infarction (2.08 [95 percent confidence interval, 1.16 to 3.72]) than the nonsmokers. The quitters and persistent smokers were less likely than the nonsmokers to undergo additional percutaneous coronary procedures (relative risk, 0.80 [95 percent confidence interval, 0.64 to 0.98] and 0.67 [95 percent confidence interval, 0.56 to 0.81], respectively) or coronary bypass surgery (relative risk, 0.72 [95 percent confidence interval, 0.54 to 0.95] and 0.68 [95 percent confidence interval, 0.54 to 0.86], respectively). The persistent smokers were also at greater risk for death than the quitters (relative risk, 1.44 [95 percent confidence interval, 1.02 to 2.11]). CONCLUSIONS Patients who continued to smoke after successful percutaneous coronary revascularization were at greater risk for Q-wave infarction and death than nonsmokers. The cessation of smoking either before or after percutaneous revascularization was beneficial. Patients undergoing percutaneous revascularization should be encouraged to stop smoking.

Safety and Efficacy of Ticlopidine for Only 2 Weeks After Successful Intracoronary Stent Placement

BACKGROUND In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis. METHODS AND RESULTS We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64+/-11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3+/-0.5 mm. High-pressure inflations (>/=12 atm) were performed in all patients (mean, 17+/-4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%. CONCLUSIONS In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.

Apoptosis: Basic Concepts and Implications in Coronary Artery Disease

Apoptosis is an active form of cell death that is intricately regulated and distinct from necrosis. Data suggest that apoptosis may play a role in the pathophysiology of coronary atherosclerotic disease. Anatomic evidence of apoptosis has been observed in coronary atherosclerosis, restenosis, and transplant arteriopathy, accompanied by an increase in biochemical and genetic markers of apoptosis. Vasoactive substances such as nitric oxide and angiotensin II also regulate vascular smooth muscle cell apoptosis; vasodilating factors may induce apoptosis, whereas vasoconstricting factors may inhibit apoptosis. The aim of this article is to review key points regarding the detection of apoptosis, its regulation, and its possible role in the pathogenesis of coronary artery disease.

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

BACKGROUND Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. METHODS AND RESULTS Acetylcholine (10(-6) to 10(-4) mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: -41.6%+/-10.7%, group 2: -4.7%+/-11.9%, group 3: 11.4%+/-7.4%). CONCLUSIONS Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.

Mechanical Pressure and Stretch Release Endothelin-1 From Human Atherosclerotic Coronary Arteries In Vivo

BACKGROUND Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogenic properties. In vitro, vascular release of ET-1 is increased in response to mechanical stress. The goal of the present study was to examine whether ET-1 is released from human atherosclerotic coronary arteries in vivo in response to mechanical pressure and stretch and to characterize immunoreactivity for ET-1 and its precursor, big ET-1, within the atheromatous plaque. METHODS AND RESULTS Circulating ET-1 levels were measured in 20 patients before and after coronary angioplasty for stable angina at three sampling sites: the femoral artery and the coronary artery segments proximal and distal to the lesion dilated. In addition, atheromatous tissue obtained from 20 patients undergoing directional coronary atherectomy for stable angina were analyzed for immunoreactivity for ET-1 and big ET-1. In patients undergoing angioplasty, ET-1 levels in the distal coronary artery increased after balloon dilatation (8.4 +/- 0.9 to 16.4 +/- 2 pg/mL, P < .05); proximal coronary artery and systemic ET-1 levels were unchanged. The degree of mechanical stress applied (product of duration and pressure of balloon inflation) correlated with the change in distal coronary artery ET-1 levels (r = .71, P < .01). Immunoreactivity for big ET-1 and ET-1 was ubiquitous in the extracellular space and the intracellular compartment (macrophages, myointimal cells, myofibroblasts, and endothelial cells) of human coronary atheromatous tissue. CONCLUSIONS Big ET-1 and ET-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of coronary atherosclerotic tissue. ET-1 is released from these sites in response to mechanical stress. These findings support a role for endothelins in the evolution and progression of coronary atherosclerosis in humans.

Coronary angioplasty and intracoronary thrombolysis are of limited efficacy in resolving early intracoronary stent thrombosis

OBJECTIVES This study sought to evaluate treatment of early intracoronary stent thrombosis. BACKGROUND Although refinements in intracoronary stent implantation technique and pharmacologic treatment have reduced the frequency of early stent thrombosis, stent thrombosis remains a feared complication of this procedure. Optimal treatment for stent thrombosis is still undefined. METHODS Twenty-nine patients (44 stents) with early (< or = 30 days) coronary stent thrombosis over a 5-year period at our institution were identified. Treatment and outcome of stent thrombosis were analyzed. RESULTS Mean (+/- SD) time from implantation to stent thrombosis was 6.1 +/- 5 days. Twenty-three patients were treated with catheter-based therapies (angioplasty alone in 14, angioplasty and intracoronary urokinase in 7, intracoronary urokinase alone in 2). Flow was restored without residual thrombus in 11 (48%) of the catheter-treated patients (6 of 14 with angioplasty alone, 4 of 7 with angioplasty and urokinase, 1 with urokinase alone). Of the 23 patients, 2 died despite restoration of anterograde flow, and 9 were referred for emergent or urgent bypass surgery because of residual thrombus and refractory angina despite restoration of blood flow. Of the remaining six patients, five were treated medically and one with coronary bypass surgery; three died. Acute myocardial infarction evolved in 26 patients (90%), including 20 (87%) of the 23 catheter-treated patients. CONCLUSIONS Stent thrombosis is associated with severe adverse outcomes. Although catheter-based therapies are effective in restoring patency in a majority of patients, patients are referred frequently for coronary bypass surgery because of residual thrombus and refractory angina. These findings suggest that alternative or adjunctive therapies for stent thrombosis are needed.

The Role of Endothelin in Coronary Atherosclerosis

During the evolution of coronary atherosclerosis, growth factors, cytokines, and other molecules are involved in cell recruitment, migration, and proliferation. Endothelin is an endothelial-derived vasoconstrictor peptide that possesses mitogenic properties. In this review, current evidence is provided that suggests that endothelin fulfills proposed criteria to be considered an atherogenic peptide because of its mitogenic and proliferative properties, as well as its inter-actions with known atherogenic factors. In addition, a proposed role of endothelin in the evolution of atherosclerosis is outlined.

Insulin and Insulin-like Growth Factor-I Cause Coronary Vasorelaxation In Vitro

Insulin and insulin-like growth factor-I (IGF-I) may play a role in the modulation of coronary artery tone, yet there are few data regarding their vasoactive effects on the coronary vascular bed. We evaluated the vasorelaxation effects of insulin and IGF-I on porcine coronary epicardial vessels in vitro and elucidated possible mechanisms. Porcine epicardial arteries were contracted with 10(-7) mol/L endothelin-1 and relaxed with cumulative concentrations of either insulin or IGF-I (10(-12) to 10(-7) mol/L). The above experiments were repeated in vessels without endothelium. Vessels were also incubated with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10(-4) mol/L) with and without 10(-3.5) mol/L L-arginine, the potassium channel blocker tetraethylammonium (TEA; 10(-2) mol/L), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ; 10(-5.5) mol/L); vessels were then contracted with endothelin-1 and relaxed with insulin or IGF-I. Insulin and IGF-I were also added after contraction with 60 mmol/L KCl. Insulin and IGF-I caused a similar decrease in coronary epicardial tension after contraction with endothelin-1 (relaxation of 28+/-4% [n=7] and 25+/-3% [n=8] with insulin and IGF-I, respectively; P<0.0001 for both peptides). Removal of the endothelium did not affect these responses. Incubation with L-NMMA, but not ODQ, attenuated the vasorelaxation response to insulin and IGF in vessels without endothelium. L-Arginine did not reverse this effect of L-NMMA. KCl and TEA attenuated the vasorelaxation effect of both insulin and IGF-I. Thus, both insulin and IGF-I caused non-endothelium-dependent coronary vasorelaxation in vitro, probably through a mechanism involving the activation of potassium channels. These findings suggest that insulin and IGF-I participate in the regulation of coronary vasomotor tone.

Outcome ≥10 Years After Successful Percutaneous Transluminal Coronary Angioplasty

Patients (n = 611) after successful percutaneous transluminal coronary angioplasty were prospectively followed over 10 to 16 years for major adverse events. The effect of gender, extent of coronary artery disease, left ventricular dysfunction, and age on occurrence of adverse events were analyzed in detail. The incidence of death, Q-wave myocardial infarction, and coronary bypass surgery was 23.1%, 3.9%, and 32.7%, respectively. Men and women had similar mortality (p = 0.13) and Q-wave myocardial infarction (p = 0.57), but men had more coronary bypass surgery (p = 0.06). Patients with multivessel disease had higher mortality (p < 0.0001), and patients with 3-vessel disease had a higher incidence of Q-wave myocardial infarction (p = 0.04) and coronary bypass surgery (p < 0.001). Left ventricular dysfunction was associated with higher mortality (p < 0.0001) and coronary bypass surgery (p = 0.045), but not Q-wave myocardial infarction (p = 0.99). Mortality was higher in elderly patients (p < 0.0001), but the incidence of Q-wave myocardial infarction was similar (p = 0.64). Older patients underwent coronary bypass surgery less often (p = 0.004). By multivariate analysis, only the extent of coronary disease (relative risk [RR] 1.71, confidence interval [CI] 1.34 to 2.19; p = 0.0001), diabetes mellitus (RR 1.82, CI 1.28 to 2.59; p = 0.001), hypertension (RR 1.30, CI 1.08 to 1.96, p = 0.009), male gender (RR 1.30, CI 0.99 to 1.71, p = 0.058), and prior myocardial infarction (RR 1.44, CI 1.14 to 1.81, p = 0.002) independently influenced the incidence of major adverse events. We conclude that it is possible to identify patients with worse long-term prognosis after percutaneous transluminal coronary angioplasty based on clinical and angiographic parameters.