Atherosclerotic Coronary Segments Research Articles

Discovering pericoronary adipose tissue differences between normal and atherosclerotic coronary segments with radiomics analysis

Abstract Introduction Pericoronary adipose tissue (PCAT) extracted from coronary CT angiography (CCTA) is a novel marker for coronary inflammation. Establishing correlation between PCAT changes and the vascular lesion itself is essential for using PCAT to monitor clinical and subclinical disease status. Past studies focused on patient-level and vessel-level PCAT differences. However, lesion-level PCAT differences beyond mean attenuation values are not well understood. Purpose To investigate the differences between PCAT adjacent to atherosclerotic plaques and PCAT adjacent to normal coronary segments using radiomics analysis. Material and Methods This study enrolled 100 consecutive patients who underwent CCTA. A total of 446 plaques were successfully annotated in 89 patients. The PCAT of these 446 plaques and also their normal segment counterparts were extracted. Following prior literature, adipose tissue was defined as voxels with attenuation ranging -190 to -30 HU. PCAT was extracted within 3 mm distance from the vessel wall, along the middle 10 mm of each plaque. The PCAT of normal coronary artery segments were extracted both proximal and distal with distance D mm to the plaque with 10 mm length. We used 3 different distances to define the normal segments (D={10, 20, 30}). PyRadiomics was used to generate radiomics features and the random forest classifier from Scikit-Learn was used to distinguish PCAT extracted adjacent to atherosclerotic plaques and PCAT adjacent to normal coronary segments. To minimize bias due to vessel diameter or shape and focus on the texture of PCAT, we included only the First Order, GLCM, GLDM, GLRLM, GLSZM and NGTDM features (total 93 features) from PyRadiomics. We used 5-fold cross validation splitted at patient-level to develop the classifier. Result The radiomics model achieved acceptable discrimination for D=30 mm (mean AUROC = 0.70), borderline discrimination for D=20 mm (mean AUROC=0.68) and D=10 mm (mean AUROC = 0.60). These results suggest a trend toward greater differences between PCAT further away from the lesion compared with PCAT adjacent to the lesion. The feature "Gray Level Size Zone Matrix (GLSZM): Low Gray Level Zone Emphasis" had the highest importance in 4 out of 5 folds in our D = 30 mm experiment. The mean value of this feature is significantly different for the PCAT adjacent to the lesions compared to PCAT extracted from the normal segments (0.152 vs 0.166, p=0.001). Conclusion We investigated the difference between PCAT adjacent to atherosclerotic plaques and PCAT adjacent to normal coronary segments using radiomics analysis. We found greater discrimination when the normal segments were extracted further away from the lesion, suggesting PCAT changes due to atherosclerosis may exist beyond the length of the plaque. Moreover, "Gray Level Size Zone Matrix (GLSZM): Low Gray Level Zone Emphasis" could serve as a novel radiomic biomarker to correlate PCAT changes to atherosclerosis.

Influence of wall shear and structural stress on plaque progression of different phenotype in human coronary arteries

Abstract Introduction Atherosclerotic plaque progression is affected by local wall shear stress (WSS), .i.e. the frictional force of the blood at the vessel wall [1,2]. However, the blood pressure also induces stress inside the vessel wall (wall stress, WMS) and is mainly studied for plaque rupture [3]. Little is known on the impact of WMS on plaque progression. Purpose In order to have a comprehensive understanding of the involvement of the biomechanical factors (WSS and WMS) in atherosclerotic artery disease, we studied the individual and combined effects of WMS and WSS in plaque free as well as in atherosclerotic coronary segments. Methods Forty non-stented, non-culprit human coronary arteries (IMPACT study) were imaged with near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) at the baseline and after 12 months [3]. The 2D and 3D lumen, vessel wall and lipid-rich necrotic core (LRNC) geometries were reconstructed based on the co-registration of NIRS-IVUS and OCT. WSS was computed with Computational Fluid Dynamics [3]. The WMS on the peri-luminal region was calculated via ABAQUS with hyperelastic material models [4] using intraluminal pressure of 120mmHg. The vessels were divided into 1.5mm/45° sectors. In each sector wall growth was quantified as plaque burden (plaque area/total vessel area*100%) change over time. Plaque was defined as wall thickness > 0.5 mm. The sectors were categorized as "plaque with lipid rich necrotic core (LRNC)", "plaque w/o lipid rich necrotic core (LRNC)", or "plaque free wall". The individual and combined effect of WSS and WMS on plaque progression was evaluated using Linear Mixed Model in SPSS and all stress metrics were divided into artery-based tertiles. Results Vessel sectors exposed to low WSS at baseline demonstrated a higher plaque burden increase over the follow up period compared to the vessel sectors exposed to mid or high WSS (Fig.1), which was significantly different for all the 3 categories (Plaque free wall, Plaque without LRNC, Plaque with LRNC). Vessel sectors exposed to increasing WMS demonstrated increasing plaque progression (Fig.1) Sectors that were simultaneously exposed to low WSS and high WMS revealed the highest change in plaque size and in particular in plaque sectors that were lipid rich (Fig.2). Conclusion Our findings suggest that the local atherosclerotic disease progression in coronary arteries is not only associated with the well-known WSS, but also with WMS. Moreover, our results show that there is an complex interplay between WSS, WMS and plaque composition, such that lipid rich plaques exposed to low WSS and high WMS demonstrated the highest plaque progression.Figure 1Figure 2

CT Attenuation of Pericoronary Adipose Tissue in Normal Versus Atherosclerotic Coronary Segments as Defined by Intravascular Ultrasound.

The factors influencing genesis of atherosclerosis at specific regions within the coronary arterial system are currently uncertain. Local mechanical factors such as shear stress as well as metabolic factors, including inflammatory mediators released from epicardial fat, have been proposed. We analyzed computed tomographic (CT) attenuation of pericoronary adipose tissue in normal versus atherosclerotic coronary segments as defined by intravascular ultrasound (IVUS). We evaluated the data sets of 29 patients who were referred for invasive coronary angiography and in whom IVUS of 1 coronary vessel was performed for clinical reasons. Coronary CT angiography was performed within 24 hours from invasive coronary angiography. Computed tomographic angiography was performed using dual-source CT (Siemens Healthcare; Forchheim, Germany). A contrast-enhanced volume data set was acquired (120 kV, 400 mA/rot, collimation 2 × 64 × 0.6 mm, 60-80 mL intravenous contrast agent). Intravascular ultrasound was performed using a 40-MHz IVUS catheter (Atlantis; Boston Scientific Corporation, Natick, Mass) and motorized pullback at 0.5 mm/s. Sixty corresponding coronary artery segments within the coronary artery system were identified in both dual source computed tomography and IVUS using bifurcation points as fiducial markers. In dual source computed tomography data sets, 8 serial parallel cross sections (2-mm slice thickness) were rendered orthogonal to the center line of the coronary artery for each segment. For each cross section, pericoronary adipose tissue within a radius of 3 mm from the coronary artery and enclosed within the epicardium (excluding coronary veins and myocardium) was manually traced and mean CT attenuation values were obtained. Intravascular ultrasound was used to define coronary segments as follows: presence of predominantly fibrous atherosclerotic plaque (hyperechoic), presence of predominantly lipid-rich atherosclerotic plaque (hypoechoic), and absence of atherosclerotic plaque. In IVUS, 20 coronary segments with fibrous plaque, 20 segments with lipid-rich plaque, and 20 coronary segments without plaque were identified. The mean CT attenuation of pericoronary adipose tissue for segments with any coronary atherosclerotic plaque was -34 ± 14 Hounsfield units (HU), as compared with -56 ± 16 HU for segments without plaque (P = 0.005). The density of pericoronary fat in segments with fibrous versus lipid-rich plaque as defined by IVUS was not significantly different (-35 ± 19 HU vs -36 ± 16 HU, P = 0.8). Mean CT attenuation of pericoronary adipose tissue is significantly lower for normal versus atherosclerotic coronary segments. This supports a hypothesis of different types of pericoronary adipose tissue, the more metabolically active of which might exert local effects on the coronary vessels, thus contributing to atherogenesis.

High susceptibility of atherosclerotic coronary arteries to the onset of vasospasm and angina pectoris-like symptoms due to coronary spasm in WHHLMI rabbits.

We examined the relationship between atherosclerosis and the provocation of coronary spasm as well as the influence of coronary spasm on the onset of acute ischemic myocardial disease. Coronary spasm was provoked in anesthetized normal Japanese white (JW) rabbits and myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for coronary atherosclerosis and myocardial infarction, by injecting ergonovine during the infusion of norepinephrine through a marginal ear vein. A decrease in contrast flow in the left circumflex artery was observed on coronary angiograms. Ischemic changes were observed on the electrocardiograms of 29% (2/7) of JW and 79% (27/34, P=0.007) of WHHLMI rabbits. The frequency of coronary spasm was significantly high in rabbits with severe coronary plaques showing diffuse lesions. Left ventricle motility in vasospasm-positive rabbits, which was evaluated with echocardiograms, was decreased by 29% following the ergonovine injection (P<0.001), and every serum ischemic marker markedly increased 4 h after the provocation of vasospasm. These results demonstrate that atherosclerotic coronary arteries are positively related to the provocation of vasospasm, and vasospasm in severe atherosclerotic coronary segments evokes angina pectoris-like findings and/or non-fatal myocardial infarction. WHHLMI rabbits may be a novel animal model for angina pectoris and acute ischemic heart disease.

High Susceptibility of Atherosclerotic Coronary Arteries to the Onset of Vasospasm and Angina Pectoris-like Symptoms due to Coronary Spasm in WHHLMI Rabbits

Objectives: We examined the relationship between atherosclerosis and provocation of coronary spasm as well as influence of coronary spasm on the onset of acute ischemic myocardial disease. Methods and Results: Coronary spasm was provoked in anesthetized normal Japanese white (JW) rabbits and WHHLMI rabbits, an animal model for coronary atherosclerosis and myocardial infarction, by injecting ergonovine during the infusion of norepinephrine through a marginal ear vein. A decrease in contrast flow in the left circumflex artery was observed on coronary angiograms. Ischemic changes were observed on the electrocardiogram of 29% (2/7) of JW and 79% (27/34) of WHHLMI rabbits. The frequency of coronary spasm was significantly high in rabbits with severe coronary plaques showing diffuse lesions. In addition, the degree of contraction of coronary strips with atherosclerotic plaques was higher than that of normal coronary strips excised from JW rabbits stimulated by a combination of ergonovine and norepinephrine. Left ventricle motility in these vasospasm-positive rabbits, which was evaluated with echocardiograms was decreased by 29% following the ergonovine injection (P<0.001), and every serum ischemic marker examined markedly increased 4 hours after the provocation of vasospasm. Conclusions: The results of the present study demonstrated that atherosclerotic coronary arteries were positively related to the provocation of vasospasm, and vasospasm in severe atherosclerotic coronary segments evoked angina pectoris and/or non-fatal myocardial infarction.

Effect of Metabolic Syndrome on Coronary Artery Stenosis and Plaque Characteristics as Assessed with 64–Detector Row Cardiac CT

To investigate the prevalence and severity of subclinical coronary atherosclerosis and plaque characteristics in asymptomatic subjects according to the presence or absence of metabolic syndrome (MS) with multidetector computed tomography (CT). This study was approved and the requirement for informed patient consent was waived by the local institutional review board. Degree of coronary artery stenosis, multivessel involvement, and plaque characteristics, as well as coronary artery calcium score (CACS), were assessed with 64-detector row CT in 3000 age- and sex-matched asymptomatic individuals (mean age, 50.2 years ± 8.9 [standard deviation]; age range, 30-79 years). Anthropometric and metabolic profiles were also measured. Multivariate logistic regression analyses were performed to identify variables related to coronary atherosclerosis and plaque types. Subjects with MS had significant coronary artery stenosis (>50% stenosis), multivessel involvement, more positive remodeling, more atherosclerotic coronary segments, and higher CACS than subjects without MS (P < .01 for all). Mixed and noncalcified plaques were also more prominent in subjects with MS than in those without MS (14.2% ± 4.4 vs 7.6% ± 3.1 and 13.1% ± 4.3 vs 7.3% ± 2.8, respectively; P < .01 for both). After adjustment for confounding factors, MS was strongly associated with significant coronary artery stenosis, multivessel involvement, and mixed plaque. Multidetector CT is useful in the early diagnosis and evaluation of subclinical coronary atherosclerosis in asymptomatic patients with MS; however, future prospective studies are needed to address the clinical implications of these findings.

Vanilloid receptor TRPV1, sensory C-fibers, and activation of adventitial mast cells: A novel mechanism involved in adventitial inflammation

The immunological mechanisms on adventitial inflammation has received much attention, while the contribution of nerves to adventitial inflammation has largely been ignored. Although the mechanism of initial chemotaxis of the adventitial inflammatory cells remains unknown, vascular nerves were frequently found in the inflammatory lesions of coronary adventitia and adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries. The sensory nerves in contact with adventitial mast cells contained the neuropeptides SP and CGRP. These neuropeptides play an important role in the amplification of tissue injury by the increase of both vascular permeability and neutrophil recruitment, and the term ''neurogenic inflammation'' has been coined. Activation of adventitial mast cells, with ensuing release of vasoactive compounds, may cause vasoconstriction in atherosclerotic coronary segments. Therefore, we hypothesize that adventitial vanilloid receptor TRPV1 and sensory C-fibers may play a pistol role for adventitial inflammation.

Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator.

Intraplaque neovascularization and hemorrhage may facilitate plaque progression. We studied expression of basic fibroblast growth factor (bFGF), a potent angiogenic mediator, by mast cells (MCs) in human coronary plaques with increasing degrees of atherosclerosis. Normal and atherosclerotic coronary segments were collected from 30 autopsied subjects. Immunohistochemical methods were used to detect MCs, bFGF, and microvessels. Both adventitial and intimal MCs showed intracytoplasmic granular staining for bFGF, and bFGF-positive extracellular granules were observed close to the MCs. Increased numbers of bFGF-positive MCs were detected in neovascularized areas of plaques, and there was a positive correlation between numbers of bFGF-positive MCs and microvessels in both the intima and adventitia. In plaques, the highly neovascularized areas contained increased numbers of bFGF-positive MCs compared with the adjacent nonvascularized areas, where only few MCs were present. Importantly, the proportion of intimal MCs expressing bFGF increased with increasing severity of atherosclerosis. The present work reveals a novel source of bFGF in human coronary arteries, the intimal and adventitial MCs. The association of bFGF-positive MCs with microvessels and with the severity of atherosclerosis suggests that coronary MCs, by releasing bFGF, may play a role in angiogenesis and progression of coronary plaques.

Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries.

The number of activated mast cells is increased in the adventitia of coronary segments with plaque rupture and in spastic atherosclerotic coronary segments. Neurogenic activation of mast cells has been demonstrated previously in other tissues. Here we identified and quantified contacts between mast cells and nerves in the adventitia of normal and atherosclerotic coronary segments. Normal (types 0 or I) and atherosclerotic (lesion types II, III, and IV) coronary segments from 22 unselected autopsy cases were stained for mast cells and sensory nerves by a histochemical double-labeling method. Contacts between mast cells and sensory nerves were quantified morphometrically and also identified by confocal microscopy. Coronary arteries obtained during heart transplantation were stained for the neuropeptides capable of stimulating mast cells, ie, substance P and calcitonin gene-related peptide. In the adventitia of atherosclerotic coronary segments with type IV lesions, the numbers of mast cells and mast cell-nerve contacts (104+/-15 mast cells/mm(2) and 30+/-5 nerve contacts/mm(2); mean+/-SEM) were significantly greater than in segments with type III lesions (79+/-12 [P<0.001] and 24+/-6 [P<0.001]), those with type II lesions (54+/-4 [P<0.001] and 12+/-2 [P<0.001]), or those with normal intima (31+/-3 [P<0.001] and 4+/-1 [P<0.001]). The nerve fibers connected with mast cells contained both substance P and calcitonin gene-related peptide, which identified them as sensory nerves. Neurogenic stimulation of mast cells in the adventitia of coronary arteries may release vasoactive compounds, such as histamine and leukotrienes, which can contribute to the complex neurohormonal response that leads to abnormal coronary vasoconstriction.

Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis.

Vascular endothelial growth factor (VEGF) is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. VEGF expression in cultured cells (smooth muscle cells, macrophages, endothelial cells) is controlled by growth factors and cytokines. Hence, the question arises of whether VEGF could play a role in atherogenesis. Frozen sections from 38 coronary artery segments were studied. The specimens were characterized as normal with diffuse intimal thickening, early atherosclerosis with hypercellularity, and advanced atherosclerosis (atheromatous plaques, fibrous plaques, and totally occlusive lesions). VEGF expression as well as the expression of 2 VEGF receptors, flt-1 and Flk-1, were studied with immunohistochemical techniques in these samples at the different stages of human coronary atherosclerosis progression. The expression of VEGF mRNA was also studied with reverse transcription-polymerase chain reaction. Normal arterial segments showed no substantial VEGF expression. Hypercellular and atheromatous lesions showed distinct VEGF positivity of activated endothelial cells, macrophages, and partially differentiated smooth muscle cells. VEGF positivity was also detected in endothelial cells of intraplaque microvessels within advanced lesions. In totally occlusive lesions with extensive neovascularization, intense immunostaining for VEGF was observed in accumulated macrophages and endothelial cells of the microvessels. Furthermore, VEGF mRNA expression was detected in atherosclerotic coronary segments but not in normal coronary segments. The immunostainings for flt-1 and Flk-1 were detected in aggregating macrophages in atherosclerotic lesions and also in endothelial cells of the microvessels in totally occlusive lesions. These results demonstrate distinct expression of VEGF and its receptors (flt-1 and Flk-1) in atherosclerotic lesions in human coronary arteries. Considering the multipotent actions of VEGF documented experimentally in vivo and in vitro, our findings suggest that VEGF may have some role in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.

ECG-Gated Three-dimensional Intravascular Ultrasound

Automated systems for the quantitative analysis of three-dimensional (3D) sets of intravascular ultrasound (IVUS) images have been developed to reduce the time required to perform volumetric analyses; however, 3D image reconstruction by these nongated systems is frequently hampered by cyclic artifacts. We used an ECG-gated 3D IVUS image acquisition workstation and a dedicated pullback device in atherosclerotic coronary segments of 30 patients to evaluate (1) the feasibility of this approach of image acquisition, (2) the reproducibility of an automated contour detection algorithm in measuring lumen, external elastic membrane, and plaque+media cross-sectional areas (CSAs) and volumes and the cross-sectional and volumetric plaque+media burden, and (3) the agreement between the automated area measurements and the results of manual tracing. The gated image acquisition took 3.9+/-1.5 minutes. The length of the segments analyzed was 9.6 to 40.0 mm, with 2.3+/-1.5 side branches per segment. The minimum lumen CSA measured 6.4+/-1.7 mm2, and the maximum and average CSA plaque+media burden measured 60.5+/-10.2% and 46.5+/-9.9%, respectively. The automated contour-detection required 34.3+/-7.3 minutes per segment. The differences between these measurements and manual tracing did not exceed 1.6% (SD<6.8%). Intraobserver and interobserver differences in area measurements (n=3421; r=.97 to.99) were <1.6% (SD<7.2%); intraobserver and interobserver differences in volumetric measurements (n=30; r=.99) were <0.4% (SD<3.2%). ECG-gated acquisition of 3D IVUS image sets is feasible and permits the application of automated contour detection to provide reproducible measurements of the lumen and atherosclerotic plaque CSA and volume in a relatively short analysis time.

Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity

Recent evidence suggests that high-density lipoprotein (HDL) cholesterol has important vasoactive properties which may contribute to its beneficial effects on atherosclerotic coronary artery disease. The endothelium-dependent vasodilator acetylcholine has been used in a number of experimental studies to assess endothelial function. The relation between serum lipoproteins and acetylcholine-induced coronary vasoreactivity was investigated in patients (n = 27) undergoing elective coronary arteriography. Mean serum cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglyceride levels were 189 ± 7 (4.84 ± 0.18 mmol/liter), 134 ± 6 (3.47 ± 0.15 mmol/liter), 41 ± 3 (1.06 ± 0.08 mmol/ liter) and 106 ± 30 mg/dl (1.20 ± 0.03 mmol/ liter), respectively. After a baseline arteriogram, acetylcholine was infused into the left main coronary artery and percent change from baseline dimension was determined in 27 angiographically smooth coronary artery segments and in 14 arterial segments with evidence of mild atherosclerotic disease. Intact vascular smooth muscle function was then confirmed in all segments by dilation to intracoronary nitroglycerin. Acetylcholine produced significant vasoconstriction of both angiographically smooth (13 ± 4%, p < 0.05 vs baseline) and diseased (19 ± 4%, p < 0.05 vs baseline) coronary segments. A positive correlation was observed between HDL cholesterol and normal acetylcholine-induced coronary vasoreactivity in both angiographically smooth (r = 0.59, p < 0.001) and diseased (r = 0.62, p < 0.02) coronary segments. No significant correlation was observed, however, between total and low-density lipoprotein cholesterol, or between total cholesterol to HDL ratio and the response of coronary artery diameter to acetylcholine infusion. These findings suggest that HDL cholesterol promotes normal endothelial cell function in both normal and atherosclerotic coronary segments. This beneficial effect may be related to a direct effect of HDL on release of endothelial-derived relaxing factor or may be secondary to its effects on endothelial cell proliferation. Thus, while HDL has important antiatherogenic properties, the clinical benefit of HDL elevation may be related, in part, to its effects on endothelial function and coronary vasoreactivity.

ST/HR slope during prostacyclin treatment: An improved method to identify patients with advanced coronary artery disease

Constriction of atherosclerotic coronary segments during exercise may further reduce coronary flow reserve in patients with coronary artery disease. This could influence the linear regression analysis of the heart rate-related changes in ST-segment depression (ST/HR slope) thereby limiting the accuracy of this method in identifying the severity of the disease. To test this hypothesis, the exercise related ST/HR slopes on placebo were compared with those obtained during coronary vasodilation induced by a prostacyclin analogue (iloprost 6 ng kg-1 min-1) in 42 anginal patients with documented coronary artery disease. In seven of these, the same protocol was repeated during right heart catheterization. The overall diagnostic accuracy of the ST/HR slope on iloprost was better than on placebo in patients with advanced coronary artery disease. This was due mainly to a consistent rightward shift of the ST/HR slope in patients with one- and two-vessel, but not three-vessel disease or left main stem disease. The reason for the greater effects of iloprost on ST/HR slopes in patients with a lesser degree of atherosclerosis remains unclear. However, coronary blood flow was higher during drug infusion, which suggests that iloprost may prevent the occurrence of dynamic coronary events able to reduce the maximum coronary flow reserve during exertion. This mechanism may be predominant in patients with minor coronary artery disease.

Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries.

We studied quantitative aspects of coronary artery contraction in isolated epicardial coronary ring segments from 49 human hearts. The order of maximal tension developed by drugs in normal calcium (ionized calcium, 1.26 mM) solution was U-44069 (a prostaglandin endoperoxide analog) greater than histamine greater than carbachol greater than serotonin greater than phenylephrine greater than ergonovine. In Ca2+-free solution these same drugs mediated a lesser degree of contraction, which demonstrates that the human coronary artery uses both "intracellular" and "extracellular" calcium in hormone receptor-activated contraction. U-44069, histamine, carbachol, and phenylephrine produced calcium-free/normal calcium maximal responses of 62.9% 48.7%, 39.8%, and 37.2%, respectively. Morphologic characteristics of the atherosclerotic plaques within the vessel lumen and the degree of myocardial dysfunction did not qualitatively alter these contractile responses. However, severely atherosclerotic coronary segments were supersensitive to histamine, but not to carbachol or calcium. In conclusion, the human epicardial coronary artery is a highly reactive vessel that uses at least two calcium pools to couple contraction. Receptor-coupled agonists differ in their abilities to mediate contraction and in the degree to which each calcium pool is used, and the presence of atherosclerosis potentiates the contractile response to histamine.