Tradeoff between bleeding and stent thrombosis in different dual antiplatelet therapy regimes: Importance of case fatality rates and effective treatment durations.

BACKGROUND: The tradeoff between stent thrombosis (ST) and major bleeding (MB) of 12- versus 6-month dual antiplatelet therapy (DAPT) after coronary stent implantation has not been clearly defined. METHODS: Definite/probable ST and MB (TIMI major and Bleeding Academic Research Consortium (BARC) ≥ 3) were compared in 2 subsequent trials with similar inclusion criteria but different DAPT duration, that is, BASKET (6 months; n = 557) and BASKET-PROVE (12 months; n = 2,314), between months 0 to 6 (DAPT in both trials), 7 to 12 (DAPT in BASKET-PROVE only), and 13 to 24 (aspirin in both trials) using propensity score-adjusted, time-stratified Cox proportional hazard models. RESULTS: Overall, event rates were low with fewer ST but similar MB in prolonged DAPT. Analysis of the 3 periods showed a uniform pattern for ST (interaction DAPT/period; P = .145) but an inconsistent pattern for MB (interaction DAPT/period; P < .001 for TIMI major and P = .046 for BARC ≥ 3), with more MB occurring during months 7 to 12 with prolonged DAPT. Considering observed case fatality rates of 31% with ST and 11% with MB, the extrapolated prevention of 27 ST deaths and the excess of 5 MB deaths resulted in an expected benefit of 22 survivors/10,000 patients treated over 2 years with prolonged DAPT. CONCLUSION: Despite overall low event rates, prolonged DAPT was associated with more MB during months 7 to 12 according to the interaction DAPT/period. Given the higher observed case fatality rates of ST versus MB, 12- versus 6-month DAPT was associated with an extrapolated reduction in mortality. Effective treatment periods and case fatality rates seem important in the analysis of different DAPT durations, specifically with regard to ongoing trials.

[Important classifications and scores in cardiology]. / Wichtige Stadieneinteilungen und Scores in der Kardiologie.

Classifications and scores play a fundamental role in clinical cardiology. While classification systems may help to quantify symptoms and stages of disease, specific scores enable risk stratification and may facilitate decision-making in various cardiac disorders. The present article reviews some of the most frequently used cardiologic classifications and scores. Frequently used classification systems are the NYHA classification for staging patients with cardiac diseases according to their symptoms and functional capacity, and the CCS classification for grading the severity of symptoms in patients with stable angina pectoris. The Killip classification represents a simple clinical tool to estimate mortality risk in patients with acute coronary syndromes. While there is no controversy about the acute management of patients with STEMI - i. e. reperfusion therapy by fibrinolysis or, preferably, primary percutaneous coronary intervention - the diagnostic and therapeutic strategy in patients with NSTE-ACS depends on their individual risk. Various scores have been developed for early risk stratification in patients with NSTE-ACS. Of these, the TIMI risk score and the GRACE score are the most frequently used. Prevention of thromboembolic events represents a primary therapeutic goal in patients with atrial fibrillation. In affected patients, scores such as the CHA2DS2-VASc-Score and the HAS-BLED score are helpful in assessing individual risk of thromboembolic and bleeding complications. Herewith, these scores aid in decision-making for anticoagulation and, thereby, improve prognosis of patients with atrial fibrillation.

Incidence and time frame of life-threatening arrhythmias in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Life-threatening arrhythmias may complicate the hospital course of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). The optimal duration of electrocardiographic monitoring in such patients is not well established. We aimed to determine the incidence and the time of occurrence of life-threatening arrhythmias in STEMI patients undergoing PPCI. METHODS: Data of 382 consecutive patients with STEMI undergoing PPCI were analysed regarding the occurrence of ventricular fibrillation (VF), sustained ventricular tachycardia (sVT) or bradycardia necessitating temporary or permanent pacing. RESULTS: Of these patients, 55% had inferior STEMI, 41% anterior and 4% lateral STEMI. The infarct-related arteries were the right in 41%, the left anterior descending in 41%, the left circumflex in 16%, the left main stem in 1% and a vein graft in <1%. During hospitalisation, 27 (7.0%) patients developed 29 life-threatening arrhythmias (incidence 7.6%): 19 episodes occurred during PPCI (VF n = 11, bradycardia n = 8), 9 episodes during the first 24 hours after PPCI (VF n = 7, sVT n = 2), and 1 sVT episode in a hypokalemic patient on the 4th post-procedural day. A total of 17 patients (4.5%) died within the first 30 days, and 3 of these died during the PPCI procedure. CONCLUSIONS: Life-threatening arrhythmias occur in a considerable proportion of STEMI patients undergoing PPCI during hospitalisation. Most of these arrhythmias occur during the PPCI procedure. Post-procedural life-threatening arrhythmias are virtually limited to the first 24 hours after PPCI. Thus, routine electrocardiographic monitoring beyond the first 24 hours after PPCI might not be required in most patients with uncomplicated STEMI.

Incidence of acute myocardial infarction after implementation of a public smoking ban in Graubünden, Switzerland: two year follow-up.

QUESTION UNDER STUDY: In the first year after implementation of a public smoking ban a significant decrease in the incidence of acute myocardial infarction (AMI) was observed in Graubünden. In the present study we analyzed the incidence of AMI in the second year of the ban. In addition, we investigated the contribution of smoking ban-unrelated factors to the reduced incidence of AMI incidence observed after enactment of the ban. METHODS: Data of all AMI patients who underwent coronary angiography at the Kantonsspital Graubünden, the only tertiary care hospital with a cardiac catheterization laboratory in Graubünden, between March 1st, 2009 and February 28th, 2010 were collected prospectively. Data were compared with those of the three preceding 12-month periods. We also estimated AMI incidence during the corresponding time period in Lucerne, a region with no smoke-free legislation, using data of the AMIS Plus registry. The influence of outdoor air pollution was analyzed with the help of official measurements of PM(10)- and NO(2)-concentrations in Graubünden. The prescription of lipid-lowering drugs was estimated by using sales figures in Graubünden and Lucerne. RESULTS: In Graubünden, the number of patients with AMI in the second year after adoption of the smoking ban was similar to that in the first year of the ban (188 vs. 183; P = ns) and significantly lower than in each of the two years preceding the ban (229 and 242, respectively; P <0.05 vs. each of the 12-month periods after the ban). Overall, the number of AMI patients in the two post-ban years was 21% lower than in the two pre-ban years. The reduction in the number of patients with AMI was most pronounced in non-smokers and individuals with known coronary artery disease. During the corresponding time period, no similar decrease in the incidence of AMI was observed in Lucerne. No association was found between the magnitude of outdoor air pollution and the incidence of AMI. During the observation period, the use of lipid-lowering drugs increased similarly in Graubünden and Lucerne. CONCLUSIONS: Compared with the two years preceding the implementation of a smoking ban, the incidence of AMI remained significantly reduced in the second year of the ban in Graubünden, whereas no similar reduction was seen in a comparable area without smoke-free legislation. Changes in outdoor air pollution or the use of lipid-lowering drugs did not substantially contribute to the decrease in the incidence of AMI that occurred after adoption of the ban in Graubünden.

Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect.

OBJECTIVE: Isolated diastolic dysfunction is present in 40% of heart failure patients. It has been attributed to myocardial fibrosis and related to cardiovascular risk factor exposure. We hypothesized that simvastatin will improve these dynamics in experimental hypercholesterolemia (HC). METHODS: Three groups of pigs were studied after 12 weeks of normal (N) diet, HC diet, or HC diet with simvastatin (80 mg/day) treatment. Cardiac function was assessed by electron beam computed tomography (EBCT) and percentage of myocardium occupied by microvessels (myocardial vascular fraction) was calculated by micro-CT. Collagen content was determined by Sirius red staining and confirmed by a quantitative, hydroxyoproline-based assay. RESULTS: Compared with N, LDL serum concentration was higher in HC and HC+simvastatin (1.0±0.1 vs. 7.9±1.7 and 9.6±1.2 mmol/L, p<0.05 for both). Cardiac early diastolic filling was reduced in HC compared with N (102.4±11.3 vs. 151.1±12.1 mL/s; p<0.05) but restored in HC+simvastatin (176.8±21.3 mL/s, p<0.05 vs. HC). Compared with N, myocardial vascular fraction was higher in HC but not in HC+simvastatin (1.98±0.84 vs. 4.48±0.31 and 2.95±0.95%; p<0.05 for HC vs. N). Myocardial collagen content was higher in HC than in HC+simvastatin and N (4.72±1.03 vs. 1.62±0.12 and 1.21±0.24% area staining; p<0.05 for HC vs. N), which was attributable mainly to an increase in collagen III (2.90±0.48 vs. 1.62±0.12 and 1.21±0.24% area staining; p<0.05 for HC vs. N). CONCLUSIONS: Simvastatin is able to prevent diastolic dysfunction in experimental HC independent of its lipid lowering effect. This beneficial effect is, at least partially, due to a decrease in myocardial fibrosis and angiogenesis.

Effect of brief secondhand smoke exposure on endothelial function and circulating markers of inflammation.

OBJECTIVE: In contrast to the well defined detrimental consequences of long-term secondhand smoke (SHS) exposure, little is known about the acute effects of passive smoking on endothelial function and inflammation. The aim of the present study was to assess the acute effects of short-term SHS exposure on endothelial function and circulating markers of inflammation. METHODS: Peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) index, circulating markers of endothelial function (von Willebrand factor antigen, Thrombomodulin, E-selectin) and circulating inflammatory markers (high sensitivity C-reactive protein (hsCRP), Interleukin-6 (IL-6)) were measured in eighteen male, non-smoking volunteers before and 12h after a 1-h SHS exposure. RESULTS: Twelve hours after passive smoking, average RH-PAT index was significantly lower than before SHS exposure (1.54±0.49 vs 2.01±0.55 (mean±SD), p=0.01) indicating deterioration of peripheral microvascular endothelial function. von Willebrand factor antigen as a marker of endothelial activation was significantly increased after SHS exposure (93.0±25.5% vs 78.4±17.9%, p=0.03). Levels of Thrombomodulin, E-selectin, hsCRP, and IL-6 were unaffected by SHS exposure. CONCLUSION: Short-term SHS exposure leads to a measurable disturbance of endothelial function. However, 1h of passive smoking appears to be too short to elicit a significant inflammatory response.

Complement inhibition to treat myocardial infarction?

The authors describe the case of a middle-aged women who presented with an acute myocardial infarction due to thrombotic occlusion of angiographically normal coronary arteries. Coronary thrombosis was caused by a hypercoagulable state related to a haemolytic crisis of paroxysmal nocturnal haemoglobinuria and the patient was treated conservatively with antithrombotic agents. The clinical course was complicated by both severe bleeding and thrombotic complications and the patient eventually died of a massive intracerebral haemorrhage. The rapid occurrence of complications inhibited a timely administration of a specific treatment for complement-mediated haemolysis (eculizumab).

Drug-eluting stents compared with bare metal stents improve late outcome after saphenous vein graft but not after large native vessel interventions.

OBJECTIVES: To define long-term efficacy of different stent types in saphenous vein graft (SVG) interventions. METHODS: In BASKET (Basel Stent Cost Effectiveness Trial), major adverse cardiac events (MACE), i.e. cardiac death, myocardial infarction and symptom-driven target vessel revascularization (TVR) were assessed after 18 months comparing drug-eluting stents (DES) versus bare metal stents (BMS), and SVG and large native vessels (> or =3.0 mm). RESULTS: Large vessel interventions were performed in 605 patients. Patients with SVG interventions (n = 47, 8%) were older and had more often hypertension, prior myocardial infarction, prior revascularization and multivessel disease and less frequent ST-elevation myocardial infarction than patients with large native vessel interventions (n = 558, 92%). Stent number and length were higher in SVG than in large native vessel interventions. Baseline characteristics were similar for DES and BMS. In SVG stenting, long-term outcome was better in DES- than in BMS-treated patients (MACE 21 vs. 62%, p = 0.007, mainly due to TVR 18 vs. 46%, p = 0.045), but for large native vessel stenting, no significant difference was noted (MACE: 13 vs. 16%, p = 0.40). CONCLUSIONS: Among patients with SVG disease, treatment with DES resulted in a better long-term outcome than treatment with BMS. In contrast, no DES benefit was found in similarly sized native vessels regarding MACE.

Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design.

BACKGROUND: Based on a subgroup analysis of 18-month BAsel Stent Kosten Effektivitäts Trial (BASKET) outcome data, we hypothesized that very late (> 12 months) stent thrombosis occurs predominantly after drug-eluting stent implantation in large native coronary vessel stenting. METHODS: To prove or refute this hypothesis, we set up an 11-center 4-country prospective trial of 2260 consecutive patients treated with > or = 3.0-mm stents only, randomized to receive Cypher (Johnson & Johnson, Miami Lakes, FL), Vision (Abbott Vascular, Abbott Laboratories, IL), or Xience stents (Abbott Vascular). Only patients with left main or bypass graft disease, in-stent restenosis or stent thrombosis, in need of nonheart surgery, at increased bleeding risk, without compliance/consent are excluded. All patients are treated with dual antiplatelet therapy for 12 months. The primary end point will be cardiac death/nonfatal myocardial infarction after 24 months with further follow-up up to 5 years. RESULTS: By June 12, 229 patients (10% of the planned total) were included with a baseline risk similar to that of the same subgroup of BASKET (n = 588). CONCLUSIONS: This study will answer several important questions of contemporary stent use in patients with large native vessel stenting. The 2-year death/myocardial infarction-as well as target vessel revascularization-and bleeding rates in these patients with a first- versus second-generation drug-eluting stent should demonstrate the benefit or harm of these stents compared to cobalt-chromium bare-metal stents in this relevant, low-risk group of everyday patients. In addition, a comparison with similar BASKET patients will allow to estimate the impact of 12- versus 6-month dual antiplatelet therapy on these outcomes.

Endothelial function and cerebrovascular disease: implications for diagnosis and treatment.

Cerebrovascular disease remains one of the most common causes of morbidity and mortality in the United States. There is strong evidence to implicate endothelial dysfunction in the initiation and progression of atherosclerosis and its complications. It is now well known that endothelial dysfunction represents a systemic syndrome involving multiple vascular beds, including the cerebral vasculature. Currently, no gold standard treatment for endothelial dysfunction exists. Nonetheless, several treatment strategies have been found to be helpful in improving endothelial function. A few of these strategies have been implicated in stroke risk reduction as well, adding another line of evidence to the relationship between endothelial function and cerebrovascular disease.

Bosentan preserves endothelial function in mice overexpressing APP.

This study was designed to test the hypothesis that Alzheimer's disease (AD) is associated with endothelial dysfunction and that chronic endothelin-1 antagonism preserves endothelial function in mice overexpressing the AD amyloid precursor protein (APP). Three groups of mice were studied: C57BL/6 (normal control, n = 6), transgenic mice overexpressing APP (Tg2576, n = 5), and Tg2576 mice fed Bosentan (100 mg/(kg day)(-1)), a combined endothelin A and B receptor antagonist, for 4 months (Tg2576+Bosentan, n = 5). Mice were sacrificed at the age of 7 months. In vitro, the endothelium-dependent aortic vasorelaxation was significantly attenuated in Tg2576 mice as compared to C57BL/6 and Tg2576+Bosentan mice. In contrast, Tg2576+Bosentan and C57BL/6 mice showed similar endothelium-dependent aortic vasorelaxation. Similarly, endothelium-dependent carotid vasorelaxation was significantly attenuated in Tg2576 mice compared to C57BL/6 and Tg2576+Bosentan mice. There was no difference between the three groups in the response to nitroprusside. The current study demonstrates the presence of endothelial dysfunction in both carotid and aortic arteries in mice overexpressing APP and suggests a pathophysiological role for the endogenous endothelin system in AD.

Coronary stent infection: a rare but severe complication of percutaneous coronary intervention.

During the last two decades, the number of percutaneous coronary interventions (PCI) has steadily increased in Switzerland, as has the use of coronary stents. However, reports of coronary stent infections are very rare. In the present article we review all published cases of coronary stent infections. All patients presented with symptoms of infection within the first four weeks after PCI. Clinical hallmarks of stent infection were fever and chest pain. Blood cultures were positive in all patients. Despite the use of intravenous antibiotics in all except one patient and surgical drainage of the infectious focus in the majority of affected individuals mortality was high (40%). Thus, coronary stent infection, although exceedingly rare, represents a life-threatening complication and should be considered in the differential diagnosis of patients presenting with fever during the first few weeks after PCI.

Incremental cost-effectiveness of drug-eluting stents compared with a third-generation bare-metal stent in a real-world setting: randomised Basel Stent Kosten Effektivitäts Trial (BASKET).

BACKGROUND: No prospective trial-based data are available for incremental cost-effectiveness of drug-eluting stents (DES) compared with bare-metal stents (BMS) in unselected patients, as treated in everyday practice. METHODS: The Basel stent cost-effectiveness trial (BASKET) included 826 consecutive patients treated with angioplasty and stenting for 1281 de-novo lesions, irrespective of indication for angioplasty. Patients were randomised to one of two DES (Cypher, n=264; Taxus, n=281) or to a cobalt-chromium-based BMS (Vision, n=281) and followed up for 6 months for occurrence of major adverse cardiac events and costs. Analysis was by intention-to-treat. The primary endpoint was cost-effectiveness after 6 months, with effectiveness defined as reduction of major adverse cardiac events. FINDINGS: Cardiac death, myocardial infarction, or target vessel revascularisation occurred in 39 of 544 (7.2%) patients with DES and 34 of 280 (12.1%) with BMS (odds ratio 0.56, 95% CI 0.35-0.91; p=0.02), without significant differences between the two DES. Total costs at 6 months were higher with DES (mean 10,544, SD 6849) than with BMS (9639, 9067; p<0.0001); higher stent costs of DES were not compensated for by lower follow-up costs. Incremental cost-effectiveness ratio of DES compared with BMS to avoid one major event was 18,311, and costs per quality-adjusted life-year gained were more than 50 000. Subgroup analyses showed that DES were more cost-effective for elderly patients in specific high-risk groups. INTERPRETATION: In a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. Use of these stents could be restricted to patients in high-risk groups.

Influence of revascularization on long-term outcome in patients > or =75 years of age with diabetes mellitus and angina pectoris.

Little is known about the effect of revascularization in patients > or =75 years of age with symptomatic coronary artery disease (CAD) and diabetes mellitus (DM) for whom periprocedural risk and overall mortality are increased. Therefore, we examined the 301 patients of the Trial of Invasive versus Medical therapy in the Elderly with symptomatic CAD (TIME) with special regard to diabetic status. Patients were randomized to an invasive versus optimized medical strategy. The median follow-up was 4.1 years (range 0.1 to 6.9). Patients with DM (n = 69) had a greater incidence of hypertension (73% vs 58%, p = 0.03), > or =2 risk factors (93% vs 46%, p <0.01), previous heart failure (22% vs 12%, p = 0.04), and previous myocardial infarction (59% vs 43%, p = 0.02), and a lower left ventricular ejection fraction (48% vs 54%, p = 0.02) than did patients without DM. Mortality was greater in patients with DM than in those without DM (41% vs 25%, p = 0.01; adjusted hazard ratio 1.86, p = 0.01). Revascularization improved the overall survival rate from 61% (no revascularization) to 79% (p <0.01; adjusted hazard ratio 1.68, p = 0.03), an effect similarly observed in patients with and without DM. The event-free survival rate was 11% in nonrevascularized patients with DM compared with 40% in nonrevascularized patients without DM and 41% and 53% in revascularized patients with and without DM, respectively (p <0.01). Angina severity and antianginal drug use were similar for patients with and without DM, but those with DM performed worse in daily activities and physical functioning. In conclusion, elderly diabetic patients with chronic angina have a worse outcome than those with DM but benefit similarly from revascularization regarding symptom relief and long-term outcome. However, physical functioning related to daily activities is reduced in those with DM and may need special attention.

Long-term benefits and limitations of combined antianginal drug therapy in elderly patients with symptomatic chronic coronary artery disease.

BACKGROUND: Chronic angina is a common and disabling disorder in the elderly. Combined antianginal drug treatment represents the mainstay of therapy in this population. However, there is a paucity of data regarding the effect of this strategy on long-term outcome in the elderly. METHODS: To assess the long-term effect of combined antianginal drug therapy in elderly individuals, we performed a long-term follow-up analysis of all 148 patients of the Trial of Invasive versus Medical therapy in Elderly (TIME) patients with chronic symptomatic coronary-artery disease assigned to an optimized medical therapy strategy. Angina severity, measures of quality of life (QOL), and survival were assessed after a median of 3.7 (0.1-6.9) years. RESULTS: At baseline, patients were 79.8 +/- 3.5 years old with Canadian Cardiovascular Society (CCS) class angina 3.0 +/- 0.7 despite the use of 2.4 +/- 0.6 antianginal drugs. Although antianginal drugs were increased to 2.8 +/- 0.9 (P < .01), 63 (43%) patients needed revascularization for refractory symptoms during the first year of observation (REVASC). At baseline, REVASC patients had more frequently CCS class 4 angina (37% vs 20%, P < 0.05) but reported less prior heart failure (5% vs 20%, P < 0.01), fewer prior cerebral events (3% vs 13%, P < .05) and a lower rate of two or more comorbidities (10% vs 33%, P < .01) than patients on continued drug therapy (DRUG). At long-term follow-up, angina severity was still higher in DRUG compared to REVASC patients (CCS class, 1.8 +/- 1.6 vs 1.0 +/- 1.4, P < .05) despite more antianginal drugs (2.1 +/- 1.1 vs 1.5 +/- 1.0, P < .01), whereas measures of QOL had improved similarly in both groups. In addition, long-term mortality was significantly higher in DRUG than in REVASC patients (38% vs 13%, P < .01). CONCLUSION: Combined antianginal drug therapy successfully relieved symptoms in most elderly patients with chronic angina but failed to do so in 43%. Patients who needed revascularization for refractory symptoms reported less angina, despite lower drug use during long-term follow-up and had a better long-term survival. Thus, the widely used strategy to increase antianginal drug therapy in elderly patients instead of evaluating them for revascularization should be reconsidered.

Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.

OBJECTIVES: We investigated the value of reactive hyperemia peripheral arterial tonometry (RH-PAT) as a noninvasive tool to identify individuals with coronary microvascular endothelial dysfunction. BACKGROUND: Coronary endothelial dysfunction, a systemic disorder, represents an early stage of atherosclerosis; RH-PAT is a technique to assess peripheral microvascular endothelial function. METHODS: Using RH-PAT, digital pulse volume changes during reactive hyperemia were assessed in 94 patients without obstructive coronary artery disease and either normal (n = 39) or abnormal (n = 55) coronary microvascular endothelial function; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at baseline. RESULTS: Average RH-PAT index was lower in patients with coronary endothelial dysfunction compared with those with normal coronary endothelial function (1.27 +/- 0.05 vs. 1.78 +/- 0.08: p < 0.001). An RH-PAT index <1.35 was found to have a sensitivity of 80% and a specificity of 85% to identify patients with coronary endothelial dysfunction. CONCLUSIONS: Digital hyperemic response, as measured by RH-PAT, is attenuated in patients with coronary microvascular endothelial dysfunction, suggesting a role for RH-PAT as a noninvasive test to identify patients with this disorder.

Successful treatment of symptomatic coronary endothelial dysfunction with enhanced external counterpulsation.

Enhanced external counterpulsation (EECP) is a valuable therapeutic option for patients with coronary artery disease and refractory angina. Although the exact mechanisms by which this technique exerts favorable effects remain unclear, improvement in endothelial function is considered a potential mechanism contributing to the clinical benefit associated with EECP. We describe a young woman with severely symptomatic coronary endothelial dysfunction in the absence of obstructive coronary artery disease who experienced a dramatic and sustained reduction in symptoms in response to a standard 35-hour course of EECP.

Endothelin type A receptor antagonism restores myocardial perfusion response to adenosine in experimental hypercholesterolemia.

Experimental hypercholesterolemia is characterized by increased endothelin-1 (ET-1) activity and is associated with an attenuated myocardial perfusion response and an inappropriate increase in coronary microvascular permeability during episodes of increased myocardial demand. This study was designed to determine the effect of chronic selective ET type A (ET(A)) receptor antagonism on coronary vascular response to simulated cardiac stress in experimental hypercholesterolemia. Twenty-one pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC), and HC diet plus ABT-627, a selective ET(A) receptor antagonist, (HC+ABT-627). After 12 weeks, cardiac electron beam computed tomography (EBCT) was performed before and during intravenous infusion of adenosine, and myocardial perfusion (ml/min per g) and coronary microvascular permeability index (arbitrary units) were calculated. Basal myocardial perfusion was similar in all groups (N: 0.91+/-0.10; HC: 0.95+/-0.08; HC+ABT-627: 1.03+/-0.09; P=0.64). Adenosine infusion led to a significant increase in myocardial perfusion in the N (1.32+/-0.15; P<0.001) but not in the HC (0.95+/-0.07) group. However, in the HC+ABT-627 group, adenosine also significantly increased myocardial perfusion (1.33+/-0.12; P=0.001). Basal permeability index did not differ between the groups (N: 1.56+/-0.13; HC: 1.34+/-0.19; HC+ABT-627: 1.62+/-0.10; P=0.38). Adenosine infusion significantly increased permeability index in HC pigs (2.29+/-0.22; P<0.001) but not in N (1.71+/-0.21) and HC+ABT-627 (1.82+/-0.08) pigs. We conclude that chronic selective ET(A) receptor antagonism preserves myocardial perfusion response and coronary microvascular integrity during episodes of increased myocardial demand in experimental hypercholesterolemia, indicating an important role for the endogenous endothelin system in this disorder.