Charles J. McKenna

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.

Fibrin-film stenting in a porcine coronary injury model: efficacy and safety compared with uncoated stents

OBJECTIVES This study was designed to test the efficacy and safety of a fibrin-film-covered stent compared with that of a bare metal stent in the porcine coronary injury model. BACKGROUND Biodegradable stents are a potential method of achieving total lesion coverage and delivering local, lesion-specific drug therapy. METHODS Two coronary arteries in each pig were randomly assigned to deployment of either a fibrin-film or a bare tantalum wire-coil stent. An oversized balloon injury, 1.15 to 1.30 times the reference vessel diameter, was induced in each coronary segment before stenting to simulate angioplasty injury. Thirty pigs were studied: group 1 for 28 days (15 pigs); group 2 for 90 days (5 pigs); group 3 for 6 months (5 pigs); group 4 for 1 year (5 pigs). RESULTS Two pigs died of occlusion of the bare stent and one of occlusion of the fibrin stent (p > 0.99). There were no significant differences between the fibrin-stented and bare-stented coronary segments with regard to arterial injury. In group 1 (28 days, 14 pigs), the mean neointimal thicknesses in the fibrin-stented and bare-stented groups were 0.57+/-0.31 and 0.57+/-0.27 mm, respectively (p=0.89). In groups 2 to 4 (90 days, four pigs; 6 months, four pigs; 1 year, five pigs), the mean neointimal thicknesses for fibrin- and bare-stented coronary segments at the times studied were 0.48+/-0.26 versus 0.50+/-0.22 mm at 90 days; 035+/-0.04 versus 0.35+/-0.16 mm at 6 months; and 0.33+/-0.14 versus 0.30+/-0.14 mm at 1 year (p=0.98). CONCLUSIONS Fibrin-film stents appear to be an excellent candidate for local drug delivery because they can completely and safely cover the stented coronary segment while degrading slowly over 1 to 3 months. This result is important when compared with the poor results of previous studies of synthetic polymer stents.

Neointimal response following rotational atherectomy compared to balloon angioplasty in a porcine model of coronary in-stent restenosis.

In-stent restenosis remains a clinical therapeutic challenge. Rotational atherectomy (RA) is an attractive treatment option as it may cause less vascular injury than balloon angioplasty (BA) and, therefore, limit further neointimal response. In an animal model of coronary in-stent restenosis, thermal injury and stenting created neointima (old NI). The treatment of in-stent restenosis with either BA (n = 9) or RA (n = 11) also generated neointima (new NI). The average areas (mm2) of old NI in the BA and RA groups were similar (3.77 +/- 0.40 vs. 3.67 +/- 0.53; P = 0.32). However, new NI formed after treatment of in-stent restenosis was significantly less in the RA as compared to the BA group (0.33 +/- 0.12 vs. 0.73 +/- 36, P < 0.01). In this porcine coronary artery model of in-stent restenosis, treatment with rotational atherectomy resulted in significantly less recurrent neointimal hyperplasia than balloon angioplasty. This animal study, thus, provides a rationale for the clinical use of rotablation in the treatment of in-stent restenosis.

Transmyocardial and Percutaneous Myocardial Revascularization: Current and Future Role in the Treatment of Coronary Artery Disease

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.

Histopathologic changes in asymptomatic relatives of patients with idiopathic dilated cardiomyopathy

Echocardiographic screening of asymptomatic relatives of patients with idiopathic dilated cardiomyopathy identifies a subset with left ventricular enlargement who are assumed to have early familial idiopathic dilated cardiomyopathy. This study shows for the first time that the myocardium in such relatives demonstrates abnormal cellularity.

Novel Stents for the Prevention of Restenosis

Since the introduction of Interventional Cardiology in 1976, there has been rapid expansion both in its clinical application and the tools of the trade. This growth was accelerated with the introduction of the intra-coronary stent in 1987. The demonstration that stents may reduce the incidence of restenosis after percutaneous coronary revascularization has further stimulated the search for the perfect endovascular prosthesis. By creating a hybrid stent, incorporating natural coatings and local drug delivery in the design, it is hoped that the complications associated with stent thrombosis and restenosis can be eradicated. (Trends Cardiovasc Med 1997;7:245-249).

Abnormal cellularity in asymptomatic relatives of patients with idiopathic dilated cardiomyopathy.

I read with great interest the study by Mahon et al. [(1)][1]demonstrating abnormal myocardial pathology in apparently asymptomatic relatives of patients with idiopathic dilated cardiomyopathy (DCM). This finding, of course, has great clinical import. The investigators state that their study “