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D Hasdai

Publications and source records attributed to D Hasdai.

At least 19 recordsLinked to original sources
PubMed2001

Evaluation of long-term survival after successful percutaneous coronary intervention among patients with chronic renal failure.

We studied the long-term outcomes after percutaneous coronary intervention in dialysis patients and in patients with chronic renal failure (CRF) (serum creatinine > or = 3.0 mg/dl). All-cause mortality at 1 year was 2.9% for the control group, 16.2% for the group with CRF, and 14.1% for dialysis patients. Cardiac mortality at 1 year was 1.9% for ther control group, 15.2% for the group with CRF, and 10.0% for dialysis patients.

Aged↗
PubMed2001

Glycemic control and outcome of diabetic patients after successful percutaneous coronary revascularization.

OBJECTIVE: Our purpose was to examine whether the outcome of diabetic patients after successful percutaneous coronary revascularization (PCR) is influenced by the degree of control of hyperglycemia at the time of revascularization. BACKGROUND: Diabetic patients have a worse outcome after PCR. METHODS: We examined whether the degree of glycemic control (HbA(1c) levels) affected the occurrence of all-cause death and death/myocardial infarction among diabetic patients after successful PCR from October 1979 through December 1998. HbA(1c) was analyzed both as a continuous and a categorical variable (good [HbA(1c) <8.0%, n = 700], moderate [8.0% < or = HbA(1c) < or =10%, n = 442], or poor [HbA(1c) >10%, n = 231] control). RESULTS: HbA(1c) levels were determined at a median (25th, 75th interquartiles) of 3 (1, 10) days after the index procedure for patients with good control, 2 (1, 7) days for moderate control, and 2 (1, 6) days for poor control. Median follow-up after successful PCR was 3.2 (1.2, 6.1) years, 3.9 (1.7,6.3) years, and 4.7 (2.1, 7.1) years, respectively. HbA(1c) as a continuous variable did not have an impact on either death (hazard ratio [95% confidence interval] 1.04 [0.98-1.10]) or death/myocardial infarction (1.02 [0.98-1.07]). As a categorical variable, patients with moderate and poor control had a similar hazard of death (0.99 [0.78-1.26] and 1. 14 [0.86-1.52], respectively) and death/myocardial infarction (1.01 [0.82-1.24] and 1.12 [0.87-1.45], respectively) relative to those with good control. CONCLUSIONS: The degree of glycemic control among diabetic patients at the time of their index intervention did not have an impact on long-term outcomes after successful PCR.

Aged↗
PubMed2000

Cardiogenic shock complicating acute coronary syndromes.

Cardiogenic shock remains the major cause of death among patients with all types of acute coronary syndromes. Thus, there is a growing interest in the identification of patients who are at risk for developing cardiogenic shock, in the exploration of different therapeutic approaches to preventing its development, and in the improvement of outcome when it occurs. This article reviews the aetiology and pathophysiology of cardiogenic shock, its epidemiology, its treatment (including pharmaceutical agents, counterpulsation, and revascularisation), and its outcome. Algorithms are presented that predict its occurrence in both ST-segment-elevation myocardial infarction and unstable angina or non-ST-elevation myocardial infarction, and that predict its mortality in patients with ST-segment-elevation acute myocardial infarction. Such new areas as metabolic therapy and glycoprotein IIb/IIIa inhibitors are discussed, as are the economic implications of shock.

Acute Disease↗
PubMed2000

Microparticle-containing oncotic solutions augment in-vitro clot disruption by ultrasound.

Echocardiographic contrast agents enhance blood clot disruption by ultrasound. It has been suggested that the microbubbles add nuclei for the enhancement of cavitation by ultrasound. However, microbubbles are rapidly destroyed by the ultrasound energy. We assessed whether non-gas filled colloidal solutions (hyperoncotic medium molecular hydroxyethyl starch and degraded gelatin polypeptides) will facilitate clot disruption by ultrasound. In two separate experiments human blood clots, 200-400 mg in weight, were weighed and then immersed for 15 seconds in 10 ml normal saline solution containing 0%, 0.1%, 1%, 2%, and 5% of hyperoncotic medium molecular hydroxyethyl starch or 0%, 0.035%, 0.175%, 0.35%, and 0.7% degraded gelatin polypeptides. Clots were randomized to 10 seconds 20 kHz ultrasound or immersion without ultrasound. After treatment, the clots were reweighed, and the percent difference in weight was calculated. Non-gas filled microparticle-containing solutions such as hyperoncotic medium molecular hydroxyethyl starch and degraded gelatin polypeptides significantly augmented blood clot disruption by ultrasound. The effect is dependent on the colloidal solution concentration with maximal effect achieved with 1% hyperoncotic medium molecular hydroxyethyl starch and 0.35% degraded gelatin polypeptides.

Blood Coagulation↗
PubMed2000

Coronary stenting without predilatation (SWOP): applicable technique in everyday practice.

To evaluate the feasibility of stenting without predilatation, we registered all interventional procedures over a 6-month period. Six hundred patients were registered, and 684 lesions were treated. Interventions were divided into four groups: stenting without predilatation (SWOP), 221 lesions (32.4%); primary stenting with predilatation (PDS), 161 lesions (23.5%); provisional stenting (PRS), 131 lesions (19.2%); and plain-old balloon angioplasty (POBA), 171 lesions (25%). Interventional strategy was at the discretion of the operator based on few simple angiographic criteria and his clinical judgment. Procedural success was similar in all stent groups. We conclude that when primary stenting is planned, about 60% of lesions can be treated by SWOP effectively with excellent procedural results and considerable cost saving.

Adult↗
PubMed2000

Reduced thrombus burden with abciximab delivered locally before percutaneous intervention in saphenous vein grafts.

BACKGROUND: Existing thrombus can complicate percutaneous saphenous vein graft (SVG) intervention. Local delivery of thrombolytics has been used to reduce the thrombus burden often associated with these interventions. We sought to determine whether local delivery of a platelet glycoprotein IIb/IIIa inhibitor is feasible and can reduce thrombus burden before percutaneous SVG intervention. METHODS: We performed a multicenter pilot study of abciximab (0.25 mg/kg) given by local delivery catheter before percutaneous intervention for de novo SVG stenoses followed by intravenous infusion. All patients (n = 58) had >/=60% stenosis and Thrombolysis In Myocardial Infarction (TIMI) grade >0 flow in an SVG of 3 to 4 mm in diameter. Percent diameter stenosis, TIMI thrombus grade, and TIMI flow grade were measured before and after delivery of abciximab and after intervention. RESULTS: Median percent diameter stenosis improved from 69% to 45% (P =.0001) after local delivery, and TIMI thrombus grade >/=1 incidence reduced from 68% to 34% (P =.0001). TIMI flow grade was not significantly affected (P =.12). All patients had a successful intervention (</=50% residual stenosis). CONCLUSIONS: Local abciximab delivery before percutaneous SVG intervention is associated with significantly reduced thrombus burden, significantly improved percent diameter stenosis, and excellent acute procedural results. Further studies of this approach are warranted to define its clinical utility.

Abciximab↗
PubMed2000

Age and outcome after acute coronary syndromes without persistent ST-segment elevation.

BACKGROUND: Although age is the most important variable associated with death among patients with persistent ST-segment elevation, its impact on outcome among patients without persistent ST-segment elevation remains unknown. Moreover, the impact of age on the efficacy of antiplatelet therapy with eptifibatide is unknown. METHODS: We analyzed the impact of increased age on outcome (death or [re]infarction) among patients enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy), a prospective, randomized study comparing placebo versus eptifibatide therapy in acute coronary syndromes without persistent ST-segment elevation. The 9461 patients were divided into 10-year age groups: <50, 50-59, 60-69, 70-79, and >/=80. In addition, we examined whether age had an impact on the efficacy of eptifibatide therapy. RESULTS: Eptifibatide improved outcome at 30 days (P =.04). There was no interaction among age and treatment (placebo vs eptifibatide) and adjusted outcome (P =.16 for death or [re]infarction at 30 days). Despite their worse clinical profile, older patients were less likely to undergo coronary angiography at 30 days: 936 (71%), 1489 (68%), 1969 (65%), 1357 (57%), and 193 (38%) in the respective age groups. Death or (re)infarction at 30 days occurred in 121 (9%), 255 (12%), 447 (15%), 460 (19%), and 134 (26%) in the respective age groups, and at 6 months in 149 (11%), 301 (14%), 547 (18%), 575 (24%), and 162 (32%). For a 10-year difference in age group, the adjusted odds for death or (re)infarction were greater by 33% within 30 days and by 34% within 6 months. These trends persisted for patients with or without myocardial infarction on presentation. CONCLUSIONS: Age did not significantly affect the efficacy of eptifibatide. Older age among patients with acute coronary syndromes was associated with worse baseline characteristics, fewer invasive procedures, and worse outcome.

Age Factors↗
PubMed2000

Cigarette smoking status and outcome among patients with acute coronary syndromes without persistent ST-segment elevation: effect of inhibition of platelet glycoprotein IIb/IIIa with eptifibatide. The PURSUIT trial investigators.

BACKGROUND: Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers. METHODS: The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain </=24 hours and having either ischemic electrocardiographic changes without persistent ST-segment elevation or elevated creatine kinase MB levels. Patients were randomly assigned to receive a bolus and infusion of either eptifibatide or placebo in addition to standard therapy. The primary end point was a composite of death or nonfatal myocardial infarction within 30 days. RESULTS: Of the 9406 patients with known smoking status, 2677 were current smokers, 3086 were former smokers, and 3643 were nonsmokers. Cigarette smokers had better 30-day outcomes (12.3%, 16.8%, and 15.4% for smokers, former smokers, and nonsmokers, respectively; P =.001). However, after adjusting for differences in baseline clinical variables, smoking status was not a predictor of 30-day outcome (P =.45). There was a reduction in the composite end point overall with eptifibatide compared with placebo (14.3% vs 15. 7%, P =.054) but no interaction between smoking status and treatment strategy (P =.68). CONCLUSIONS: Among patients with ACS without persistent ST-segment elevation, cigarette smokers had better short-term outcomes because of their more favorable clinical profile. Although prior studies have suggested that smokers more commonly have platelet-rich thrombi than nonsmokers, eptifibatide did not result in more improvement in their outcome compared with former smokers or nonsmokers.

Acute Disease↗
PubMed2000

Diabetes mellitus and outcome after primary coronary angioplasty for acute myocardial infarction: lessons from the GUSTO-IIb Angioplasty Substudy. Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes.

OBJECTIVES: We sought to compare the efficacy of primary angioplasty in diabetics versus nondiabetics and to evaluate the relative benefits of angioplasty over thrombolytic therapy among diabetics. BACKGROUND: Primary angioplasty for myocardial infarction is at least as effective as thrombolytic therapy in the general population. However, the influence of diabetic status on outcome after primary angioplasty versus thrombolysis remains unknown. METHODS: Patients in the Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) Angioplasty Substudy were randomized to receive either primary angioplasty or accelerated alteplase. The interaction of diabetic status (diabetics n = 177, nondiabetics n = 961) and treatment strategy with the occurrence of the primary end point (death, nonfatal reinfarction or nonfatal, disabling stroke at 30 days) was analyzed (power to detect a 40% relative reduction in the primary end point with alpha = 0.05 and beta = 0.20). Among patients who were randomized to and underwent primary angioplasty, procedural success (defined as residual stenosis <50% and TIMI grade 3 flow) was assessed based on diabetic status. RESULTS: Compared with nondiabetics, diabetics had worse baseline clinical and angiographic profiles. Despite more severe stenosis and poorer flow in the culprit artery, procedural success with angioplasty was similar for diabetics (n = 81; 70.4%) and nondiabetics (n = 391; 72.4%). Outcome at 30 days was better for nondiabetics randomized to angioplasty versus alteplase (adjusted odds ratio, 0.62; 95% confidence interval, 0.41-0.96) with a similar trend for diabetics (0.70, [0.29-1.72]). We noted no interaction between diabetic status and treatment strategy on outcome (p = 0.88). CONCLUSIONS: Primary angioplasty was similarly successful in diabetics and nondiabetics and appeared to be more effective than thrombolytic therapy among diabetics with acute infarction.

Aged↗
PubMed2000

Platelet glycoprotein IIb/IIIa blockade and outcome of cardiogenic shock complicating acute coronary syndromes without persistent ST-segment elevation.

OBJECTIVES: The study examined whether antiplatelet treatment with eptifibatide affected the frequency and outcome of shock among patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial who had acute coronary syndromes but not persistent ST-segment elevation. BACKGROUND: Preliminary reports suggest a salutary effect of antiplatelet agents when shock complicates acute myocardial infarction. METHODS: We analyzed the impact of antiplatelet treatment with eptifibatide on the frequency and outcome of cardiogenic shock developing after enrollment. PURSUIT was a double-blind, randomized trial that examined the efficacy of eptifibatide (180 microg/kg bolus + continuous infusion of 2.0 microg/kg/min for < or =96 h) versus placebo among patients who had acute coronary syndromes but not persistent ST-segment elevation. RESULTS: Shock developed in 2.5% of the 9,449 patients at a median (25th, 75th interquartiles) of 94.0 (38, 206) h. Death by 30 days occurred in 65.8% of shock patients. Patients who had acute myocardial infarction upon enrollment had a greater incidence of shock (2.9% vs. 2.1%, p = 0.01), developed shock earlier (40.2% <48 h vs. 20.9%, p = 0.001), and had higher 30-day mortality from shock (77.2% vs. 52.7%, p = 0.001). Randomization to eptifibatide did not affect the occurrence of shock (p = 0.71, adjusted odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.72-1.25). However, shock patients treated with eptifibatide had significantly reduced adjusted odds of 30-day death (p = 0.03, adjusted OR = 0.51, 95% CI = 0.28-0.94). CONCLUSIONS: Patients with shock treated with eptifibatide had significantly reduced adjusted odds of death, suggesting a salutary effect of antiplatelet therapy on shock. This finding warrants verification in specifically designed studies.

Aged↗
PubMed2000

Predictors of cardiogenic shock after thrombolytic therapy for acute myocardial infarction.

OBJECTIVES: This study characterized clinical factors predictive of cardiogenic shock developing after thrombolytic therapy for acute myocardial infarction (AMI). BACKGROUND: Cardiogenic shock remains a common and ominous complication of AMI. By identifying patients at risk of developing shock, preventive measures may be implemented to avert its development. METHODS: We analyzed baseline variables associated with the development of shock after thrombolytic therapy in the Global Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial. Using a Cox proportional hazards model, we devised a scoring system predicting the risk of shock. This model was then validated in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) cohort. RESULTS: Shock developed in 1,889 patients a median of 11.6 h after enrollment. The major factors associated with increased adjusted risk of shock were age (chi2 = 285, hazard ratio [95% confidence interval] 1.47 [1.40, 1.53]), systolic blood pressure (chi2 = 280), heart rate (chi2 = 225) and Killip class (chi2 = 161, hazard ratio 1.70 [1.52, 1.90] and 2.95 [2.39, 3.63] for Killip II versus I and Killip III versus I, respectively) upon presentation. Together, these four variables accounted for >85% of the predictive information. These findings were transformed into an algorithm with a validated concordance index of 0.758. Applied to the GUSTO-III cohort, the four variables accounted for > 95% of the predictive information, and the validated concordance index was 0.796. CONCLUSIONS: A scoring system accurately predicts the risk of shock after thrombolytic therapy for AMI based primarily on the patient's age and physical examination on presentation.

Aged↗
PubMed2000

Persistent ST segment depression in precordial leads V5-V6 after Q-wave anterior wall myocardial infarction is associated with restrictive physiology of the left ventricle.

OBJECTIVES: To examine the relationship between the persistence of ST segment depression in leads V5-V6 after Q-wave anterior wall myocardial infarction (MI) and the filling pattern of the left ventricle (LV). BACKGROUND: Precordial ST segment depression predominantly in leads V5-V6 is associated with increased in-hospital morbidity and mortality after acute myocardial ischemia, perhaps due to reduced diastolic distensibility of the LV. METHODS: We prospectively studied 19 patients after Q-wave anterior wall MI (>6 months). All patients underwent 12-lead ECG recording, symptom-limited treadmill exercise testing with single photon emission computed tomography thallium-201 imaging, transthoracic Doppler echocardiography, cardiac catheterization and measurement of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels. Patients were classified based on the presence of ST segment depression in leads V5-V6: Group I = ST segment depression <0.1 mV (n = 10); Group II = ST segment depression > or =0.1 mV (n = 9). RESULTS: Patients in Group II had greater LV end diastolic pressures (32.4 +/- 6.5 mm Hg vs. 14.8 +/- 6.1 mm Hg; p = 0.0001), higher plasma ANP (44.4 +/- 47.1 pg/ml vs. 10.7 +/- 14 pg/ml; p = 0.04) and BNP levels (89.4 +/- 62.7 pg/ml vs. 23.6 +/- 33.1 pg/ml; p = 0.01), greater left atrium area (20.6 +/- 3.1 cm2 vs. 17.8 +/- 2.4 cm2; p = 0.05), lower peak atrial (A), higher early (E) mitral inflow velocities, a higher E/A ratio and a lower deceleration time (167 +/- 44 ms vs. 220 +/- 40 ms; p = 0.05). Lung thallium uptake during exercise was more common in Group II (78% vs. 10%, p = 0.04). CONCLUSIONS: Persistent ST segment depression in leads V5-V6 in survivors of Q-wave anterior wall MI is associated with increased LV filling pressure and a restrictive LV filling pattern.

Atrial Natriuretic Factor↗
PubMed2000

Lack of progress in cardiogenic shock: lessons from the GUSTO trials.

AIMS: We used the GUSTO-I and GUSTO-III databases to evaluate our performance in treating cardiogenic shock patients over much of the 1990s. METHODS AND RESULTS: GUSTO-I (1990-1993) and GUSTO-III (1995-1997) prospectively identified all patients with cardiogenic shock complicating acute myocardial infarction. Demographics, clinical presentation and outcomes for cardiogenic shock patients in the two trials were compared. Only patients enrolled with cardiogenic shock in countries common to both trials were included in these analysis. The 695 patients with cardiogenic shock in GUSTO-III were compared with the 2814 patients with cardiogenic shock in GUSTO-I. GUSTO-III patients were older (P=0.0001) and more likely to be diabetic (P=0.009) and hypertensive (P=0.025). They had a higher Killip class (P=0.002) and significantly greater index anterior infarction than cardiogenic shock patients enrolled in GUSTO-I. Time to treatment, presentation heart rate, and diastolic blood pressure were similar; however, systolic blood pressure at presentation was higher among GUSTO-III patients (P=0.002). Rates of coronary angiography, pulmonary artery catheterization, and mechanical ventilation declined in GUSTO-III compared with GUSTO-I (P=0.001); rates of angioplasty and bypass surgery were similar. Cardiogenic shock mortality in GUSTO-III was significantly higher than in GUSTO-I (62 vs 54%, P=0.001), as were rates of reinfarction (14 vs 11%, P=0.013) and recurrent ischaemia (35 vs 27%, P=0.00001). Mortality at non-U.S. sites (68 and 64%) was higher than at U.S. sites (53 and 50%) in both GUSTO-I and GUSTO-III studies, respectively. Angioplasty, bypass surgery, and balloon pump rates were lower for non-U.S. patients. CONCLUSIONS: Cardiogenic shock continues to be associated with high mortality in thrombolytic-treated patients. Lower mortality observed in the U.S.A. supports consideration for percutaneous and surgical revascularization.

Aged↗
PubMed2000

Insulin and insulin-like growth factor-I cause vasorelaxation in human vessels in vitro.

BACKGROUND: Insulin and insulin-like growth factor-I (IGF-I) are endogenous peptides with vasoactive activities. OBJECTIVE: To evaluate the vasodilatory effects of insulin and IGF-I on human vessels taken from patients with and without noninsulin-dependent diabetes mellitus (NIDDM) and to elucidate their mechanisms of action. METHODS: Vascular rings of human internal mammary artery (IMA) and saphenous vein harvested from 54 patients with and without NIDDM undergoing coronary bypass surgery were studied in vitro. RESULTS: For samples from patients without NIDDM both insulin and IGF-I (10(-12)-10(-7) mol/l) evoked greater relaxation in IMA rings (30 +/- 4 and 29 +/- 6%, maximal relaxation +/- SEM, respectively) than they did in saphenous-vein rings (43 +/- 4 and 42 +/- 5%, respectively, P < 0.05 both for insulin and for IGF-I). Similar results were obtained with vessels from patients with NIDDM. Relaxation was not affected by the removal of the endothelium and by inhibition of the production of nitric oxide. However, the vascular relaxation caused by insulin and IGF-I was completely abolished by KCI, and was attenuated by the nonspecific potassium-channel blocker tetraethylammonium (for IMA rings, to 77 +/- 8 and 66 +/- 4% with insulin and IGF-I, respectively; for saphenous vein rings, 73 +/- 2 and 77 +/- 1% for insulin and IGF-I, respectively, P < 0.001). CONCLUSIONS: Both insulin and IGF-I induced endothelial-independent, nitric oxide-independent vasorelaxation of rings from human IMA and saphenous veins, through a mechanism involving activation of potassium channels. This response remained intact in vessels from patients with NIDDM. This result supports the hypothesis that insulin and IGF-I play roles in the regulation of vascular tone in human vessels.

Diabetes Mellitus, Type 2↗
PubMed2000

Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia.

BACKGROUND: Vasoconstriction in response to endothelin-1 has been shown to be primarily related to its effects on the endothelin-A receptor. Experimental hypercholesterolemia is associated with an increase in coronary vasoconstrictor response to endothelin-1 in vivo, although the relative contributions of subtypes of endothelin receptor in this model remain unknown. OBJECTIVE: To test the hypothesis that there is an increase in coronary vasoconstriction in response to stimulation of endothelin-B receptor in hypercholesterolemia, which might be related to attenuation of activity of endothelin-derived relaxing factor. METHODS: We infused 5 ng/kg/min sarafotoxin, a specific endothelin-B receptor agonist, or 50 micrograms/kg/min NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase, into the left anterior descending coronary arteries of pigs before and after feeding them a cholesterol-rich diet for 10 weeks. RESULTS: There was a significant increase in serum level of cholesterol. After 10 weeks, infusion of sarafotoxin resulted in an accentuated decrease in coronary blood flow (CBF) compared with baseline (decreases by 60 +/- 7 versus 34 +/- 6%, P < 0.05). There was no significant difference between the effects on diameter of coronary arteries for the two time periods. The effect of L-NMMA on CBF was attenuated after 10 weeks (by 5 +/- 10.1 versus 45.6 +/- 4.7%, P < 0.05). Endothelin-receptor status of epicardial coronary arteries remained unchanged. Sarafotoxin and L-NMMA were co-infused at the above-mentioned doses into normolipidemic animals; the decrease in CBF in response to this co-infusion was comparable to the decrease observed with sarafotoxin alone in hypercholesterolemic animals (decreases of 67 +/- 5 versus 60 +/- 7, NS). CONCLUSIONS: The present results demonstrate that selective stimulation of the endothelin-B receptor increases coronary vasoconstriction in experimental hypercholesterolemia, primarily at the level of the microvasculature. These findings may be related to the attenuation of activity of endothelin-derived relaxing factor in this model, and support the hypothesis that endothelin-B receptor plays a role in the regulation of coronary vascular tone in pathophysiologic states.

Animals↗
PubMed1999

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.

Administration, Oral↗