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Biomedical subjects

D R Holmes

Publications and source records attributed to D R Holmes.

At least 91 records · Page 5Linked to original sources
PubMed2000

Percutaneous coronary interventions in patients with prior coronary artery bypass surgery: changes in patient characteristics and outcome during two decades.

PURPOSE: Patients who develop recurrent myocardial ischemia after coronary artery bypass graft (CABG) surgery are often referred for percutaneous coronary interventions. The objective of this study was to evaluate the changing demographic and clinical characteristics, and procedural and long-term outcomes, in patients with prior CABG referred for percutaneous coronary interventions during a 20-year period. METHODS: We prospectively collected data on patients who underwent coronary interventional procedures following CABG surgery. We compared angiographic and procedural success, and long-term event-free survival, among patients who had procedures from 1979 to 1989 (n = 393), from 1990 to 1994 (n = 811), and from 1995 to 1998 (n = 937). RESULTS: Patients in the 1995 to 1998 cohort were older, had a lower mean left ventricular ejection fraction, and were more likely to have diabetes, hypertension, and hyperlipidemia, but less likely to smoke. They were more likely to have treatment of complex lesions, including vein graft lesions, and had more prior CABG surgeries. More patients received intracoronary stents in 1995 to 1998. Both angiographic success rates (78% from 1979 to 1989, 88% from 1990 to 1994, and 91% from 1995 to 1998, P < 0.0001) and procedural success rates (78%, 86%, and 91%, P < 0.0001) improved with time. Long-term mortality was greater in the pre-1990 group (relative risk = 1.8, 95% confidence interval: 1.3 to 2.4) and 1990 to 1994 group (relative risk = 1.7, 95% confidence interval: 1.3 to 2.2) compared with the 1995 to 1998 group, as were the likelihoods of repeat revascularization and recurrent severe angina. CONCLUSION: Although the demographic and clinical characteristics of patients who underwent percutaneous intervention following CABG surgery indicate that they are at increasingly greater risk of adverse cardiac events, success rates and long-term survival have improved with time. The rates of recurrent severe angina as well as of subsequent revascularization have also decreased, probably as a result of improvements in technique and greater use of stents and adjunctive medications.

Aged↗
PubMed2000

Activated nuclear factor-kappaB is present in the coronary vasculature in experimental hypercholesterolemia.

BACKGROUND: Experimental hypercholesterolemia (HC) is characterized by a decrease in nitric oxide (NO) bioavailability and cellular proliferation. Nuclear factor-kappaB (NF-kappaB) is a transcriptional factor which plays a coordinating role in inflammation and cellular proliferation and may be involved in early atherosclerosis. We examined whether activated NF-kappaB was present in experimental hypercholesterolemia in the coronary vasculature in association with a decrease in NO bioavailability. METHODS: A total of 14 juvenile domestic crossbred pigs were placed on a HC diet and six pigs on a normal diet for 10-12 weeks. A monoclonal antibody to the activated form of the p65 subunit of NF-kappaB was used to detect immunoreactivity in coronary artery sections. Coronary tissue homogenates were analyzed for activated NF-kappaB and endothelial nitric oxide synthase (eNOS) using Western blotting. In vitro coronary endothelium-dependent relaxation was performed in response to bradykinin, as a measure of NO bioavailability. RESULTS: Intimal staining for activated NF-kappaB was present in 12/14 HC pigs as compared with 0/6 controls (P<0.001). Confocal microscopy confirmed the presence of NF-kappaB in the nucleus of intimal cells although the majority of the staining was cytoplasmic. In the HC group, Western blotting revealed an increase in activated NF-kappaB in the vessel wall compared to the normal group, in association with a decrease in the presence of eNOS protein and an attenuated vasorelaxation response to bradykinin. CONCLUSION: This study suggests a potential role for activation of NF-kappaB, in association with a decrease in NO bioavailability, in the initial stages of atherosclerosis in the coronary vasculature.

Animals↗
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

Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy.

OBJECTIVES: The purpose of this study was to evaluate the association between hypertension and left ventricular hypertrophy (LVH) with both coronary vascular remodeling and endothelial function. BACKGROUND: The association between endothelial and nonendothelial coronary flow reserve with vascular remodeling in patients with hypertension and LVH is still unclear. METHODS: One hundred and eleven patients with normal or mildly diseased coronary arteries at angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Patients were divided into three groups: group 1: n = 13, hypertensive patients with LVH; group 2: n = 30, hypertensive patients without LVH; group 3: n = 68, normotensive patients. Vessel and lumen area and atherosclerotic plaque area were evaluated. Vascular reactivity was examined using intracoronary adenosine and acetylcholine. RESULTS: Vessel area in group 1 (with LVH) was significantly (p < 0.01) greater than that in group 2 (without LVH), whereas, vessel area in both groups 1 and 3 was similar (12.8 +/- 0.8 mm2, 10.7 +/- 0.4 mm2 and 11.5 +/- 0.3 mm2). Coronary blood flow at baseline for patients in group 1 (with LVH) was significantly greater than it was for patients in groups 2 and 3 (81.1 +/- 9.9 ml/min, 56.5 +/- 6.2 ml/min and 48.1 +/- 3.2 ml/min, both p < 0.05). In comparison with groups 2 and 3, the response to both acetylcholine and adenosine was significantly impaired in patients with LVH. CONCLUSIONS: The current study demonstrates that hypertension with LVH is associated with both coronary vascular remodeling and attenuated endothelial and nonendothelial coronary flow reserve.

Acetylcholine↗
PubMed2000

Improving outcome over time of percutaneous coronary interventions in unstable angina.

OBJECTIVE: This study was performed to evaluate the recent changes in the outcome of coronary interventions in patients with unstable angina (UA). BACKGROUND: An early invasive strategy has not been shown to be superior to conservative treatment in patients with UA. Earlier studies had utilized older technology. Interventional approaches have changed in the recent past, but to our knowledge, no large studies have addressed the impact of these changes on the outcome of coronary interventions. METHODS: We analyzed the in-hospital and intermediate-term outcome in 7,632 patients with UA who underwent coronary interventions in the last two decades. The study population was divided into three groups: group 1, n = 2,209 who had coronary intervention from 1979 to 1989; group 2, n = 2,212 with interventions from 1990 to 1993; and group 3, n = 3,211 treated from 1994 to 1998. RESULTS: Group 2 and 3 patients were older and sicker compared with group 1 patients. The clinical success improved significantly in group 3 (94.1%) compared with group 2 (87%) and group 1 (76.5%) (p < 0.001). There was a significant reduction in in-hospital mortality, Q-wave myocardial infarction and need for emergency bypass surgery in group 3 compared with the earlier groups. One-year event-free survival was also significantly higher in the recent group compared with the earlier groups: 77% in group 3, 70% in group 2 and 74% in group 1 (p < 0.001). With the use of multivariate models to adjust for clinical and angiographic variables, treatment during the most recent era was found to be independently associated with improved in-hospital and intermediate-term outcomes. CONCLUSIONS: There has been significant improvement in the in-hospital and intermediate-term outcome of coronary interventions in patients with UA in recent years; newer trials comparing conservative and invasive strategies are therefore needed.

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

American College of Cardiology/European Society of Cardiology International Study of Angiographic Data Compression Phase I: The effect of lossy data compression on recognition of diagnostic features in digital coronary angiography.

OBJECTIVES: This study intended to determine the effect of varying degrees of lossy Joint Photographic Experts Group (JPEG) compression on detection of coronary angiographic features. BACKGROUND: Compression of digital coronary angiograms facilitates playback of images and decreases cost. There are little data on the effect of compression on the accuracy of coronary angiography. METHODS: At six centers, 71 angiographers each reviewed a set of 100 angiographic sequences. The 100 sequences were divided into four, 25-sequence subsets. Each subset of 25 was displayed either as original images or at one of three compression ratios (CRs) (6:1, 10:1 or 16:1). The effect of lossy compression on the sensitivity and specificity for detection of diagnostic features was determined. The effect of compression on subjective measures of image quality graded by the angiographers was also examined. RESULTS: Lossy compression at a ratio of 16:1 decreased the sensitivity for the detection of diagnostic features (76% vs. 80% p = 0.004). The largest effect was in the detection of calcification (52% vs. 63% at 16:1 compression vs. original images, p < 0.001). Subjective indicators of image quality indicated a reduction in confidence in interpretation at CRs of 10:1 and 16:1. CONCLUSIONS: With increased ratios of lossy compression, a degradation of digital coronary angiograms occurs that results in decreased diagnostic accuracy. The sensitivity for detection of common diagnostic features was decreased, and subjective assessment of image quality was impaired. Caution is warranted in the interpretation of coronary angiograms that have been subjected to lossy JPEG compression beyond a ratio of 6:1.

Adult↗
PubMed2000

American College of Cardiology/ European Society of Cardiology international study of angiographic data compression phase I. The effects of lossy data compression on recognition of diagnostic features in digital coronary angiography.

OBJECTIVES: This study intended to determine the effect of varying degrees of lossy Joint Photographic Experts Group (JPEG) compression on detection of coronary angiographic features. Background Compression of digital coronary angiograms facilitates playback of images and decreases cost. There are little data on the effect of compression on the accuracy of coronary angiography. METHODS: At six centers, 71 angiographers each reviewed a set of 100 angiographic sequences. The 100 sequences were divided into four, 25-sequence subsets. Each subset of 25 was displayed either as original images or at one of three compression ratios (CRs) (6:1, 10:1 or 16:1). The effect of lossy compression on the sensitivity and specificity for detection of diagnostic features was determined. The effect of compression on subjective measures of image quality graded by the angiographers was also examined. RESULTS: Lossy compression at a ratio of 16:1 decreased the sensitivity for the detection of diagnostic features (76% vs. 80%P=0.004). The largest effect was in the detection of calcification (52% vs. 63% at 16:1 compression vs. original images, P<0.001). Subjective indicators of image quality indicated a reduction in confidence in interpretation at CRs of 10:1 and 16:1. CONCLUSIONS: With increased ratios of lossy compression, a degradation of digital coronary angiograms occurs that results in decreased diagnostic accuracy. The sensitivity for detection of common diagnostic features was decreased, and subjective assessment of image quality was impaired. Caution is warranted in the interpretation of coronary angiograms that have been subjected to lossy JPEG compression beyond a ratio of 6:1.

Adult↗
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

Prediction of death after percutaneous coronary interventional procedures.

BACKGROUND: The prediction and comparison of procedural death after percutaneous coronary interventional procedures is inherently difficult because of variations in case mix and practice patterns. The impact of modern, expanded patient selection criteria, and newer technologic approaches is unknown. Our objective was to determine whether a risk equation based on patient-related variables and derived from an independent data set can accurately predict procedural death after percutaneous coronary intervention in the current era. METHODS AND RESULTS: An analysis was made of the Mayo Clinic Coronary Interventional Database January 1, 1995, to October 31, 1997. Expected mortality rate was calculated with the use of the New York State multivariate risk score. In 3387 patients, 3830 procedures (55.1% stents) were performed, with an expected mortality rate of 2.32% and observed mortality rate of 2.38% (P = not significant). The risk score derived from the New York multivariate model was highly predictive of death (chi-square = 213.8; P <.0001). The presence of a high-risk lesion characteristic such as calcium, thrombus, or type C lesion was modestly associated with death. CONCLUSIONS: The New York State multivariate model accurately predicted procedural death in our database.

Angina, Unstable↗
PubMed2000

Race, baseline characteristics, and clinical outcomes after coronary intervention: The New Approaches in Coronary Interventions (NACI) registry.

BACKGROUND: The impact of race and sex on clinical outcomes after percutaneous coronary interventions remains incompletely understood. Specific data on patient demographics, lesion characteristics, and outcomes of black versus white patients are poorly described. To further evaluate these issues, we analyzed the New Approaches in Coronary Interventions (NACI) registry. METHODS: Patients (200 black, 4279 white) undergoing coronary interventions in the NACI trial were compared. A Cox proportional hazards model was used to determine which baseline demographics were independent risk factors for the combined end point of death, Q-wave myocardial infarction, and coronary artery bypass grafting at 1 year. RESULTS: Black patients were significantly younger (age 59 +/- 11 vs 63 +/- 11 years; P <.001), more often obese (29.6 +/- 6 vs 27.5 +/- 4.8 kg/m(2); P <.001), female (50% vs 34%; P <.001), diabetic (34% vs 21%; P <.001), and hypertensive (71% vs 52%; P <.001). Black patients were significantly more likely to have single-vessel disease (48% vs 40%; P <.05) and less likely to have undergone coronary artery bypass grafting (26% vs 34%; P <.05). Blacks were significantly more likely to have a discrete lesion (85% vs 62%; P <. 001) with less thrombus (7% vs 12%; P <.05), tortuosity (17% vs 25%; P <.05), and an ulcerated appearance (5% vs 10%; P <.05). Despite these significant baseline differences, no significant difference was seen in the procedural success (80% vs 82%) or major adverse events (death, Q-wave myocardial infarction, any revascularization) at 1 year (39% vs 34%). Predictors of adverse events for white patients included diabetes (relative risk [RR] = 1.24; confidence intervals [CI], 1.0-1.5) and high-risk status (RR = 1.58; CI, 1.26-1. 91). Predictive characteristics of adverse events for black patients included only sex (RR = 3.45; CI, 1.27-9.35; P =.02). CONCLUSIONS: There are significant differences in baseline characteristics of black patients compared with white patients. Despite these differences in traditional risk factors, they do not affect procedural success or 1-year outcome. In black patients, only sex predicted adverse events. Additional investigation is required to understand the mechanisms for this difference.

Adult↗
PubMed2000

Immediate and one-year outcome of intracoronary stent implantation in small coronary arteries with 2.5-mm stents.

BACKGROUND: The role of coronary stenting in the treatment of stenoses in small coronary arteries with use of 2.5-mm stents is not well defined. METHODS AND RESULTS: Between January 1995 and August 1999, 651 patients with stenoses in small coronary arteries were treated with 2.5-mm stents (n = 108) or 2.5-mm conventional balloon angioplasty (BA) (n = 543). Patients who received treatment with both 2.5-mm and > or =3.0-mm stent placement or balloons were excluded. Procedural success and complication rates as well as 1-year follow-up outcomes were examined. Baseline clinical characteristics were similar between the two groups, except patients in the stent group were more likely to have hypertension and a family history of coronary artery disease and less likely to have prior myocardial infarction. Angiographic success rates were higher in the stent group (97.2% vs 90.2%, P =.02). In-hospital complication rates were comparable between the two groups. Among successfully treated patients, 1-year follow-up revealed no significant differences in the survival (96.2% vs 95.2%, P =.89) or the frequency of Q-wave myocardial infarction (0% vs 0.4%, P =.60) or coronary artery bypass grafting (8.4% vs 6.8%, P =.89) between the stent and BA groups, respectively. However, patients in the stent group were more likely to have adverse cardiac events (35.4% vs 22.1%, P =.05). Stent use after excluding GR II stent use, however, was not independently associated with reduced cardiac events at follow-up (relative risk 1. 3 [95% confidence interval 0.8-2.3], P =.30). CONCLUSIONS: Intracoronary stent implantation of stenoses in small coronary arteries with 2.5-mm stents can be carried out with high success and acceptable complication rates. However, compared with BA alone, stent use was not associated with improved outcome through 1 year of follow-up.

Aged↗
PubMed2000

Primary angioplasty for acute myocardial infarction in the elderly.

Elderly patients with acute myocardial infarction present a formidable therapeutic challenge. Although there appears to be a survival benefit from thrombolytic therapy for the eligible elderly patient, persistent concerns regarding the risk of intracranial hemorrhage impedes utilization in this age group. Primary or direct angioplasty of the infarct artery has been proven to be an effective modality for reperfusion. Randomized comparisons suggest an advantage over thrombolysis in terms of achieving superior patency and mitigating recurrent ischemic events. Primary angioplasty expands the reperfusion population by including many patients ineligible for thrombolysis and is more effective for treating patients at high risk, such as those with cardiogenic shock. Acute angiography accumulates important prognostic and decision-facilitating information. The benefits of primary angioplasty are more impressive for the aging patient. The survival gain and reduction in intracranial hemorrhage may combine to magnify the advantages of performing angioplasty on patients in this group. Emerging evidence concerning the aging population validates continued examination of this invasive reperfusion approach.

Aged↗
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↗
PubMed2000

Cholesterol-lowering treatment is associated with improvement in coronary vascular remodeling and endothelial function in patients with normal or mildly diseased coronary arteries.

Coronary vascular remodeling and altered endothelial function have been described in the early stages of native atherosclerosis. The purpose of this study was to evaluate the association between cholesterol-lowering therapy and coronary vascular remodeling and endothelial function in patients with normal or mildly diseases coronary arteries. Patients (N=101) with normal or mildly diseased coronary arteries by coronary angiography underwent intravascular ultrasound examination of the left anterior descending coronary artery. Vessel and lumen area, atherosclerotic plaque area, and plaque morphology were evaluated. Vascular reactivity was examined with the use of intracoronary adenosine, acetylcholine, and nitroglycerin. Patients were divided into 3 groups based on the total cholesterol levels: group 1 (n=25), patients with a history of hypercholesterolemia adequately treated (total cholesterol <240 mg/dL); group 2 (n=26), patients with hypercholesterolemia not adequately controlled (total cholesterol >/=240 mg/dL); and group 3 (n=50), patients without hypercholesterolemia. Vessel area and lumen area were significantly greater in groups 1 and 3 than in group 2 (for respective values in groups 1, 2, and 3: vessel area 11.9+/-0.5, 10.6+/-0.4, and 11.8+/-0.4 mm(2), both P<0.05; lumen area 8.3+/-0.4, 6.9+/-0.3, and 8.9+/-0.3 mm(2), both P<0.01). However, plaque areas in groups 1 and 2 were similar. Furthermore, acetylcholine-induced percent increases in coronary blood flow were significantly greater in groups 1 and 3 than in group 2 (for respective values in groups 1, 2, and 3: 70.5+/-20.1%, 22.8+/-13.7%, and 68.6+/-14.8%, both P<0. 05). Cholesterol-lowering treatment is associated with an improvement in coronary lumen area that results not from a decrease in plaque area but from an increase in vessel area, reflecting vascular remodeling. Additionally, this adaptive process may occur in association with an improvement of endothelium-dependent vasodilation of the resistance coronary artery.

Anticholesteremic Agents↗