Biomedical subjects
Publications and source records attributed to D R Holmes.
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AIMS: Reteplase has been reported to achieve better patency of the infarct artery than alteplase. As infarct artery patency is strongly associated with survival among patients with cardiogenic shock, we postulated that treatment with reteplase would improve outcomes among shock patients. METHODS: We compared 30-day mortality rates among patients in GUSTO-III who either presented with shock or developed shock after enrollment; all patients received either front-loaded alteplase or reteplase (two bolus doses of 10 MU, 30 min apart). RESULTS: Shock occurred in 260 (5.3%) of 4921 patients randomized to alteplase and 560 (5.5%) of 10,138 patients randomized to reteplase. Of these patients, 28 (10.8%) and 55 (9.8%) randomized to alteplase and reteplase, respectively, presented with shock. In-hospital, 35% and 37% of shock patients assigned to alteplase or reteplase, respectively, underwent coronary angiography, with similar rates of percutaneous (approximately 11-13%) or surgical (approximately 2-3%) revascularization procedures subsequently performed. Death within 30 days occurred in 169 (65%) and 353 (63%) shock patients randomized to alteplase and reteplase, respectively (P = 0.59). Of patients presenting with shock, 64% and 58% of patients randomized to alteplase or reteplase died within 30 days (P = 0.59). CONCLUSION: Compared with alteplase, reteplase did not improve outcome among patients who presented with shock or developed shock after receiving thrombolytics. The newer-generation thrombolytic agents remain of limited efficacy in the treatment and prevention of shock.
BACKGROUND: Certain characteristics of unstable angina have been associated with worse clinical outcomes after percutaneous revascularization procedures. METHODS AND RESULTS: We compared outcomes of patients with (n = 690) and those without (n = 320) unstable angina in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) by unstable angina subgroup: rest chest pain, postinfarction chest pain, chest pain with ischemic electrocardiographic changes, chest pain with recent acceleration, and no chest pain. Regression models were constructed to predict in-hospital and 6-month composite end point death, infarction, bypass surgery, percutaneous revascularization, and abrupt closure (in-hospital) or restenosis (6 months) for each subgroup. Only chest pain with electrocardiographic changes predicted the composite in-hospital outcome (24% vs 17% with no chest pain, P =.0374.) This subgroup also had a greater acute gain, more late loss, and more restenosis than patients in the other subgroups. Rest chest pain carried a higher incidence of the composite 6-month outcome (39.9% vs 29% with no chest pain, P =.0472). For all unstable angina categories, atherectomy was associated with worse overall outcomes than angioplasty. CONCLUSIONS: Patients with unstable angina have more complications of percutaneous revascularization than patients without unstable angina, but event rates vary by anginal subgroup. The clinical presentation may help to identify unstable angina patients at particularly high risk for adverse outcomes.
Cardiac catheterization for diagnostic angiography and revascularization, if indicated, plays an increasing role in the management of acute coronary syndromes in the absence of ST elevation. The disagreement between those who favor a conservative approach to intervention and those who favor an aggressive approach centers on whether interventions should be routinely performed in all patients. New pharmacotherapies have emerged that reduce the incidence of death and myocardial infarction in this group of patients. At the same time, the success rate of percutaneous revascularizations has been improved by the widespread use of stenting, and a reduction in complications has been achieved with new pharmacologic agents. As therapies are rapidly evolving, it is difficult to extrapolate the results of earlier clinical trials to the most current practices. Until evidence is available comparing optimal medical management with the most successful interventional techniques, the best approach to intervention is likely to remain the subject of discussion.
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.
Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (n=7); group 2, RO-48-5695, a combined endothelin receptor antagonist, and an HC diet (n=8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (n=8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10(-11) to 10(-6) mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NO(x)) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NO(x) decreased after 12 weeks in group 1 (-74.8+/-5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, -28.2+/-15.0%; group 3, -38.9+/-20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.
Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10(-12) to 10(-7) mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10(-4) mol/L N(G)-monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10(-2) mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5+/-1.0 versus 1.9+/-0.08 mmol/L; P<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80) or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79+/-6% versus 42+/-8%; P=0.01) but not insulin (43+/-6% versus 53+/-7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.
Transmyocardial revascularization (TMR) is a new treatment modality under evaluation in patients with severely symptomatic, diffuse coronary artery disease, in whom the potential for medical or interventional management has been exhausted. Preliminary clinical trials show improved ischemic symptoms within the first 3 months in about 70% of TMR-treated patients. The original proposed mechanism of surgical or catheter-based TMR (percutaneous myocardial revascularization [PMR]) was that channels mediate direct blood flow between the left ventricular cavity and ischemic myocardium. However, several alternative explanations for the clinical success of TMR have recently been suggested, including improved perfusion by angiogenesis, an anesthetic effect by nerve destruction, and a potential placebo effect. This article reviews the clinical role of TMR/PMR, its possible pathophysiologic mechanisms, and its controversies. It provides an overview of the actual scientific and clinical status of TMR and details future directions.
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We describe a technique useful in complex coronary interventions wherein timed bilateral contrast injections are given in both coronary arteries. This technique is useful in chronic total occlusions in which the distal coronary vessel is not visualized except by collateral filling via the contralateral artery. This technique was applied in 12 patients; 11 with native coronary occlusion and one in whom the target site was visualized by contrast injections into a vein graft supplying competitive flow to an otherwise patent native vessel. With this technique, the distal coronary artery segment can be better visualized, which helps to aim and track the guide wire across the occluded segment.
The clinical and angiographic outcomes of 10 patients who received abciximab as part of their therapy for early stent thrombosis was compared with 25 patients (using historical controls) who received conventional therapy. Although the angiographic outcome and the incidence of myocardial infarction in both groups was similar, there were no deaths or referral for emergency coronary bypass surgery in the abciximab-treated group versus 3 deaths and 10 referrals for emergency bypass surgery in the conventionally treated group.
Strategies to noninvasively evaluate patients after coronary stenting have not been evaluated. To determine the accuracy of single-photon emission computed tomography (SPECT) myocardial perfusion imaging in patients after coronary stenting, 209 patients who had undergone stenting followed by late stress SPECT myocardial perfusion imaging were evaluated. Quantitative coronary angiography was performed in 33 patients following SPECT imaging. SPECT restenosis was defined as a reversible or fixed defect within the stented vascular territory. Angiographic restenosis was examined using 2 definitions: total area narrowing > or =50% or > or =70% of the stent site or stented artery. The SPECT and angiographic findings were concordant in 22 of 33 stented vascular territories using the 50% definition of restenosis and in 29 of 33 stented territories using the 70% definition. Use of the 70% definition of restenosis resulted in improved accuracy of SPECT to detect a significant stenosis in the stented artery. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of SPECT were 95%, 73%, 88%, 89%, and 88% respectively. In patients with positive SPECT scans, the most significant stenosis in the stented artery was outside the stent site in 50% of cases. SPECT imaging appears to be accurate to predict significant stenosis in the stented artery, although the most severe stenosis is frequently distant from the stent site.
Although adjunctive abciximab therapy improves outcome after angioplasty or atherectomy, there are few data demonstrating its benefit for intracoronary stent implantation. We characterized patients receiving abciximab for stent placement in our practice and determined the impact of abciximab on outcome. Abciximab was introduced to our practice in April 1995 for percutaneous revascularization. Demographic, clinical, and angiographic variables that were independently associated with the use of abciximab for stent placement through 1996 (abciximab era) were examined. We then examined among all patients receiving stents from 1992 through 1996 (preabciximab and abciximab eras) whether the use of abciximab was independently associated with improved outcome (death, nonfatal Q-wave myocardial infarction, coronary bypass surgery, or target vessel percutaneous revascularization) in the hospital and at 30 days. The 30-day event rate was 7% for those who did or did not receive abciximab. The following characteristics were independently associated with the use of abciximab for stent placement in the abciximab era: thrombus before stent placement (chi-square 50.5), > or =2 stents implanted (chi-square 10.8), stent in venous graft (chi-square 7.4), calcific lesion (chi-square 5.8), and hypertension (chi-square 5.5). Among all patients receiving stents in the preabciximab and abciximab eras (n=1,859), the presence of these characteristics was independently associated with worse outcome. Abciximab, however, did not improve outcome in the hospital (odds ratio [95% confidence interval]=0.96 [0.58 to 1.58]) or at 30 days (0.87 [0.53 to 1.41]), even after adjusting for these characteristics. Abciximab for stent placement was used in high-risk patients in our practice but was not associated with improved outcome.
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.
Bifurcation lesions of the coronary circulation are difficult to treat with standard balloon technology and are associated with relatively low procedural success rates and high complication rates. We hypothesized that effective debulking of bifurcation lesions with rotational atherectomy would improve observed results. Fifteen patients underwent rotational atherectomy of such lesions. Both limbs of the bifurcation were rotablated in seven patients and one limb in eight; seven patients also underwent stent deployment. Successful angiographic results were obtained in all limbs (<30% residual stenoses). One patient had a non-Q-wave myocardial infarction. No other significant complications occurred. We conclude that rotablation of bifurcation coronary stenoses is feasible, safe, and associated with a high likelihood of angiographic success.
We examined the short- and long-term outcome of 327 patients at Mayo Clinic who had undergone coronary angioplasty of saphenous vein graft stenoses to determine whether the traditional 6-month assessment of clinical end points after coronary angioplasty is as useful as it is for patients who have had angioplasty of native vessel disease. Follow-up over 3.3+/-2.7 years was performed. At 6 months, 96+/-1% of the patients were alive, whereas at the 1- and 5-year end points, survival had deteriorated to 92+/-2 and 67+/-3%, respectively. Only 80+/-2% were free of severe angina at 6 months and 62+/-3 and 36+/-3% after 1 and 5 years. Combined event-free rate for death, Q-wave myocardial infarction or repeat coronary artery bypass surgery was 86+/-2% at 6 months, 78+/-2% at 1 year, and 45+/-4% at 5 years. Independent predictors of mortality included advancing age, diabetes mellitus, target vein grafts >5 years old and left ventricular ejection fraction <40%. In conclusion, despite reasonable 6- to 12-month outcomes following vein graft angioplasty, significant attrition in survival and event-free survival was observed. These observations have important implications for the interpretation of results of trials comparing conventional angioplasty and coronary bypass surgery with newer interventional devices if only the traditional 6-month follow-up interval is used.
Vascular remodeling has been demonstrated in advanced and early coronary artery disease. Whereas the endothelium may play a role in the adaptive process of vascular remodeling, it is not known if this process occurs in association with changes in coronary blood flow reserve. Early coronary atherosclerosis is characterized by endothelial dysfunction which is manifested by an abnormal coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine. This study was designed to test the hypothesis that coronary vascular remodeling occurs in association with coronary endothelial dysfunction early in the development of coronary atherosclerosis. Thirty-six patients found to have normal coronary angiograms or mild coronary artery disease were studied. Acetylcholine was infused into the left anterior descending artery. Patients were divided into 2 groups based on their coronary blood flow response to acetylcholine. Intravascular ultrasound measurements of the proximal left anterior descending diameter and area were obtained. Vessel diameter and area were measured at the external elastic membrane and indexed to body surface area. Vessel diameter and area were greater in patients with abnormal than normal responses to acetylcholine (5.2 +/- 0.3 mm and 19.5 +/- 0.9 mm2 vs 3.9 +/- 0.3 mm and 12.3 +/- 1.0 mm2; p <0.02, respectively). This difference persisted when measurements were indexed to body surface area. The current study suggests in vivo in humans that coronary vascular remodeling characterized by enlargement of the proximal coronary arteries occurs in association with endothelial dysfunction early in the course of coronary artery disease.