Citations

Background —The prognostic value of treadmill exercise testing (TMET) has been studied in selected populations. The generalizability of these data to different populations and to women is uncertain. Methods and Results —A retrospective, population-based cohort study of all persons (1452 men and 741 women) who underwent TMET in years 1987 to 1989 in Olmsted County, Minnesota, was undertaken. Individuals were followed up for all-cause mortality and cardiac events (cardiac deaths, nonfatal myocardial infarction, or congestive heart failure). Sex-specific analyses were performed to determine whether the predictors of outcome and the magnitude of the associations were similar in both sexes. In men, 77 deaths and 106 cardiac events occurred during 8956 person-years of observation; in women, 46 deaths and 54 cardiac events occurred during 4801 person-years of follow-up. Exercise-induced angina, ECG changes, and workload achieved on the TMET were strongly associated with all-cause mortality and cardiac events in both sexes, and the strength of the association was similar. After adjustment, workload was the only TMET variable associated with outcome. A higher workload was associated with a reduction in the risk of cardiac events and of all-cause mortality; the protective effect of exercise capacity was strong and was similar in both sexes. Conclusions —In this population-based cohort, exercise capacity was the TMET variable that exhibited the strongest association with all-cause mortality and cardiac events. This protective effect of exercise capacity was observed in both sexes.

Background—Opening of cardiac ATP-sensitive K+(KATP) channels has emerged as a promising but still controversial cardioprotective mechanism. Defining KATPchannel function at the level of recombinant channel proteins is a necessary step toward further evaluation of the cardioprotective significance of this ion conductance.Methods and Results—KATPchannel–deficient COS-7 cells were found to be vulnerable to chemical hypoxia-reoxygenation injury that induced significant cytosolic Ca2+loading (from 97±3 to 236±11 nmol/L). In these cells, the potassium channel opener pinacidil (10 μmol/L) did not prevent Ca2+loading (from 96±3 nmol/L before to 233±12 nmol/L after reoxygenation) or evoked membrane current. Cotransfection withKir6.2/SUR2Agenes, which encode cardiac KATPchannel subunits, resulted in a cellular phenotype that, in the presence of pinacidil (10 μmol/L), expressed K+current and gained resistance to hypoxia-reoxygenation (Ca2+concentration from 99±7 to 127±11 nmol/L;P>0.05). Both properties were abolished by the KATPchannel blocker glyburide (1 μmol/L). In COS-7 cells transfected with individual channel subunitsKir6.2orSUR2A, which alone do not form functional cardiac KATPchannels, pinacidil did not protect against hypoxia-reoxygenation.Conclusions—The fact that transfer of cardiac KATPchannel subunits protected natively KATPchannel–deficient cells provides direct evidence that the cardiac KATPchannel protein complex harbors intrinsic cytoprotective properties. These findings validate the concept that targeting cardiac KATPchannels should be considered a valuable approach to protect the myocardium against injury.

Background —Numerous studies have shown that women undergoing coronary revascularization procedures do so at a higher risk for an adverse outcome compared with men. However, the impact of advances in technology and improvements in techniques on in-hospital and long-term outcome after revascularization in women is unclear. Methods and Results —We evaluated 1829 patients with symptomatic multivessel coronary disease randomized to CABG or PTCA in the Bypass Angioplasty Revascularization Investigation (BARI), of whom 27% were women. As expected, women were older (64.0 versus 60.5 years), with more congestive heart failure (14% versus 7%), hypertension (68% versus 42%), treated diabetes mellitus (31% versus 15%), and unstable angina (67% versus 61%) than men but had similar preservation of left ventricular function and extent of multivessel disease. Women assigned to surgery received the same number of total grafts but fewer internal mammary artery grafts (72% versus 85%, P <0.01), and those assigned to angioplasty had more intended lesions (76% versus 71%, P <0.01) successfully dilated than men. At an average of 5.4 years’ follow-up, crude mortality rates were similar in women (12.8%) and men (12.0%). The Cox regression model adjusting for baseline differences revealed that women had a significantly lower risk of death (relative risk, 0.60; 95% CI, 0.43 to 0.84; P =0.003) but not a significantly lower risk of death plus myocardial infarction (relative risk, 0.84; 95% CI, 0.66 to 1.07; P =0.16) than men. Conclusions —Although the unadjusted mortality rate suggests that women and men undergoing CABG and PTCA have a similar 5-year mortality, women have higher risk profiles; consequently, contrary to previous reports, female sex is an independent predictor of improved 5-year survival after we control for multiple risk factors.

Background —The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. Methods and Results —The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (≥30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or ≥10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. Conclusions —Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

Background —Plaque disruption and exposure of subendothelial procoagulants such as tissue factor (TF) to circulating factor VII/VIIa (FVII/VIIa) lead to intravascular thrombosis. Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of TF-induced coagulation that binds to factor Xa and the TF-FVIIa catalytic complex in a two-step process. The aim of this study was to determine the expression of TFPI within human atherosclerotic plaque and its role in modulation of TF activity. Methods and Results —We measured the level of TFPI antigen in human carotid plaque and determined the relationship between TFPI and TF activity within plaque. Furthermore, we examined the biological activity and immunolocalization patterns of TFPI within carotid plaque. TFPI was detectable (TFPI+ group) in 22 of 34 specimens (mean±SEM, 404.4±91.8 pg/mg) and undetectable (TFPI− group) in 12 of 34 specimens. In the TFPI− group, normalized TF activity was significantly greater than that in the TFPI+ group (0.28±0.04 vs 0.14±0.02 U/pg, P =0.002). Furthermore, neutralization of TFPI activity using a polyclonal antibody resulted in an 8-fold increase in TF activity in the TFPI+ group ( P =0.001) but had no effect in the TFPI− group. Immunostaining for TFPI showed localization to endothelial cells, vascular smooth muscle cells within the fibrous cap region of the plaque, and macrophages within the shoulder region of the plaque. Conclusions —Taken together, these data suggest that biologically active TFPI is present within human atherosclerotic plaque and is associated with attenuated TF activity.

Background —As endothelin binds to ET A receptors, it stimulates vascular smooth muscle cell proliferation and may thus be pivotally involved in the pathogenesis of restenosis. This study assessed the ability of a potent and selective ET A antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model. Methods and Results —Fifty-five pigs were randomized to receive placebo or the oral ET A -selective antagonist ABT147627 twice daily for 28 days in one of three doses: 0.75 mg/kg (low), 3.75 mg/kg (mid), and 10.0 mg/kg (high). Each underwent oversized stent deployment in two randomly assigned major epicardial coronary arteries. Three animals (5.5%) died as a consequence of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until predetermined euthanasia at 28 days. In the placebo group, mean injury score was 1.73±0.80, with a mean neointimal response of 0.45±0.24 mm. By comparison, the low-dose group had a similar mean injury score of 1.79±0.75 with reduced neointimal response, 0.36±0.22 mm ( P <0.01). Mean injury score in the mid-dose animals was significantly greater than in the placebo group (1.94±0.92; P <0.05). The neointimal hyperplasia associated with this injury was less than with placebo, although the difference did not reach statistical significance (0.40±0.25 mm; P =0.05). In the high-dose pigs, mean injury score was also significantly greater than in the placebo arm (1.93±0.73; P <0.05). Despite this, neointimal response was also significantly less (0.37±0.37 mm; P <0.01). Conclusions —Oral, selective ET A receptor antagonism significantly reduced neointimal hyperplasia forming over porcine coronary stented injuries in the first 28 days. This strategy may have clinical potential for the limitation and treatment of coronary restenosis after percutaneous revascularization.

Background —Coronary endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors and coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine. Thus, the present double-blind, randomized study was designed to test the hypothesis that long-term, 6-month supplementation of l -arginine, the precursor of the endothelium-derived vasodilator NO, reverses coronary endothelial dysfunction to acetylcholine in humans with nonobstructive coronary artery disease. Methods and Results —Twenty-six patients without significant coronary artery disease on coronary angiography and intravascular ultrasound were blindly randomized to either oral l -arginine or placebo, 3 g TID. Endothelium-dependent coronary blood flow reserve to acetylcholine (10 −6 to 10 −4 mol/L) was assessed at baseline and after 6 months of therapy. There was no difference between the two study groups in clinical characteristics or in the coronary blood flow in the response to acetylcholine at baseline. After 6 months, the coronary blood flow in response to acetylcholine in the subjects who were taking l -arginine increased compared with the placebo group (149±20% versus 6±9%, P <0.05). This was associated with a decrease in plasma endothelin concentrations and an improvement in patients’ symptoms scores in the l -arginine treatment group compared with the placebo group. Conclusions —Long-term oral l -arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for l -arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.