Dataset Information

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis.

ABSTRACT:

Aim

The purpose of the current study was to determine if long term treatment with an endothelin-A (ETA) receptor antagonist attenuates the progression of coronary plaques in patients with coronary endothelial dysfunction.

Methods

Thirty-five patients with non-obstructive coronary disease and coronary endothelial dysfunction were randomized in a double blind manner to treatment with placebo or ETA receptor antagonist Atrasentan (10 mg) for six months. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Normalized mean total atheroma volume (TAVMEAN), percent atheroma volume (PAV) and changes of atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and 6-month follow-up.

Results

In segments with coronary endothelial dysfunction, there was a significant decrease in normalized TAVMEAN and PAV at six months from baseline in the Atrasentan group compared to the placebo group median (IQR) -2.00 mm(3) (-7.28, 2.53.) vs 9.11 mm(3) (1.23, 14.05), p=0.0024 and 0.955% (-3.43, 1.70) vs 3.85% (-0.39, 14.59) p=0.010. There was no change in normalized TAV or PAV in the segments with normal endothelial function.

Conclusion

This study demonstrates that 6-month treatment with Atrasentan attenuates progression of coronary plaque in segments with endothelial dysfunction.

SUBMITTER: Yoon MH

PROVIDER: S-EPMC3795901 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis.

Yoon Myeong Ho MH Reriani Martin M Mario Gössl G Rihal Charanjit C Gulati Rajiv R Lennon Ryan R Tilford Jonella M JM Lerman Lilach O LO Lerman Amir A

International journal of cardiology 20130103 2

<h4>Aim</h4>The purpose of the current study was to determine if long term treatment with an endothelin-A (ETA) receptor antagonist attenuates the progression of coronary plaques in patients with coronary endothelial dysfunction.<h4>Methods</h4>Thirty-five patients with non-obstructive coronary disease and coronary endothelial dysfunction were randomized in a double blind manner to treatment with placebo or ETA receptor antagonist Atrasentan (10 mg) for six months. Endothelial function was asses ...[more]

PMID: 23290081

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Project description:BackgroundEndothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.Methods and resultsForty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.ConclusionsThis study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Project description:Patient-specific phenotyping of coronary atherosclerosis would facilitate personalized risk assessment and preventive treatment. We explored whether unsupervised cluster analysis can categorize patients with coronary atherosclerosis according to their plaque composition, and determined how these differing plaque composition profiles impact plaque progression. Patients with coronary atherosclerotic plaque (n = 947; median age, 62 years; 59% male) were enrolled from a prospective multi-national registry of consecutive patients who underwent serial coronary computed tomography angiography (median inter-scan duration, 3.3 years). K-means clustering applied to the percent volume of each plaque component and identified 4 clusters of patients with distinct plaque composition. Cluster 1 (n = 52), which comprised mainly fibro-fatty plaque with a significant necrotic core (median, 55.7% and 16.0% of the total plaque volume, respectively), showed the least total plaque volume (PV) progression (+ 23.3 mm3), with necrotic core and fibro-fatty PV regression (- 5.7 mm3 and - 5.6 mm3, respectively). Cluster 2 (n = 219), which contained largely fibro-fatty (39.2%) and fibrous plaque (46.8%), showed fibro-fatty PV regression (- 2.4 mm3). Cluster 3 (n = 376), which comprised mostly fibrous (62.7%) and calcified plaque (23.6%), showed increasingly prominent calcified PV progression (+ 21.4 mm3). Cluster 4 (n = 300), which comprised mostly calcified plaque (58.7%), demonstrated the greatest total PV increase (+ 50.7mm3), predominantly increasing in calcified PV (+ 35.9 mm3). Multivariable analysis showed higher risk for plaque progression in Clusters 3 and 4, and higher risk for adverse cardiac events in Clusters 2, 3, and 4 compared to that in Cluster 1. Unsupervised clustering algorithms may uniquely characterize patient phenotypes with varied atherosclerotic plaque profiles, yielding distinct patterns of progressive disease and outcome.

Project description:ObjectivesThe aim of this study was to identify the determinants of plaque structural stress (PSS) and the relationship between PSS and plaques with rupture.BackgroundPlaque rupture is the most common cause of myocardial infarction, occurring particularly in higher risk lesions such as fibroatheromas. However, prospective intravascular ultrasound-virtual histology studies indicate that <10% higher risk plaques cause clinical events over 3 years, indicating that other factors also determine plaque rupture. Plaque rupture occurs when PSS exceeds its mechanical strength; however, the determinants of PSS and its association with plaques with proven rupture are not known.MethodsWe analyzed plaque structure and composition in 4,053 virtual histology intravascular ultrasound frames from 32 fibroatheromas with rupture from the intravascular ultrasound-virtual histology in Vulnerable Atherosclerosis study and 32 fibroatheromas without rupture on optical coherence tomography from a stable angina cohort. Mechanical loading in the periluminal region was estimated by calculating maximum principal PSS by finite element analysis.ResultsPSS increased with increasing lumen area (r = 0.46; p = 0.001), lumen eccentricity (r = 0.32; p = 0.001), and necrotic core ≥10% (r = 0.12; p = 0.001), but reduced when dense calcium was ≥10% (r = -0.12; p = 0.001). Ruptured fibroatheromas showed higher PSS (133 kPa [quartiles 1 to 3: 90 to 191 kPa] vs. 104 kPa [quartiles 1 to 3: 75 to 142 kPa]; p = 0.002) and variation in PSS (55 kPa [quartiles 1 to 3: 37 to 75 kPa] vs. 43 kPa [quartiles 1 to 3: 34 to 59 kPa]; p = 0.002) than nonruptured fibroatheromas, with rupture primarily occurring either proximal or immediately adjacent to the minimal luminal area (87.5% vs. 12.5%; p = 0.001). PSS was higher in segments proximal to the rupture site (143 kPa [quartiles 1 to 3: 101 to 200 kPa] vs. 120 kPa [quartiles 1 to 3: 78 to 180 kPa]; p = 0.001) versus distal segments, associated with increased necrotic core (19.1% [quartiles 1 to 3: 11% to 29%] vs. 14.3% [quartiles 1 to 3: 8% to 23%]; p = 0.001) but reduced fibrous/fibrofatty tissue (63.6% [quartiles 1 to 3: 46% to 78%] vs. 72.7% [quartiles 1 to 3: 54% to 86%]; p = 0.001). PSS >135 kPa was a good predictor of rupture in higher risk regions.ConclusionsPSS is determined by plaque composition, plaque architecture, and lumen geometry. PSS and PSS variability are increased in plaques with rupture, particularly at proximal segments. Incorporating PSS into plaque assessment may improve identification of rupture-prone plaques.

Dataset Information

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis.

Aim

Methods

Results

Conclusion

Publications

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis.

Similar Datasets

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