Coronary Artery Remodeling Research Articles

Everolimus Prevents Endomyocardial Remodeling After Heart Transplantation

Endomyocardial remodeling is characterized by progressive fibrosis and scars and may develop after heart transplantation. The role of everolimus in preventing this process has not been evaluated as yet. We prospectively studied 132 patients at baseline pretransplant and at 4 weeks, 1 year, and 3 years after heart transplantation. Fibrosis, scars (Zeiss Vision, in Sirius), and acute cellular rejection (hematoxylin-eosin) were studied in biopsy. Transplant vasculopathy was assessed by coronary angiography (focal stenoses, peripheral obliterations, negative vascular remodeling defined by peripheral obliterations, and diffusely narrowed proximal and mid vessel segments). Patients on everolimus versus patients on mycophenolate mofetil presented with significantly less fibrosis at 4 weeks (3.8%±0.3% vs. 5.5%±0.3%, P=0.007), 1 year (4.1%±0.3% vs. 4.8%±0.3%, P=0.015), and 3 years (4.2%±0.3% vs. 5.5%±0.7%, P=0.049) posttransplant and showed less scarring at 3 years posttransplant (19.9±1.9% vs. 31.9±4.6% vs. baseline biopsy 26.0±2.8%; P=0.017). Angiographic peripheral obliterations correlated with higher amounts of endomyocardial fibrosis. The negative correlation of everolimus and the positive correlation of peripheral obliterations with fibrosis were confirmed by regression analysis. Angiographic stenoses or acute cellular rejection had no effect on the development of fibrosis. Negative vascular remodeling in 1-year follow-up tended to be less frequent in everolimus-treated patients (24% vs. 76%; P=0.053). Everolimus prevents endomyocardial remodeling after heart transplantation and might have beneficial effects on vascular remodeling of epicardial coronary arteries too. Angiographic peripheral obliterations correlate with increased amounts of endomyocardial fibrosis, suggesting a relevant effect on microvascular perfusion.

Abstract 17781: Relationship Between Epicardial Adipose Tissue and Coronary Arterial Remodeling as Assessed by Intravascular Ultrasound in Patients with Coronary Artery Disease

Background: Recently, the interest in epicardial adipose tissue (EAT) is rapidly growing. Several study suggest that EAT induces inflammation of the artery wall by secretion of pro-inflammatory proteins and plays a role in the pathogenesis of coronary artery disease. However, there is no information regarding the impact of EAT on coronary arterial remodeling and plaque vulnerability. Objectives: The aim of this study was to evaluate the relationship between EAT and intravascular ultrasound (IVUS) findings, mainly remodeling, in patients with coronary artery disease. Methods: One hundred and eight consecutive patients with de novo lesions located in native coronary artery were studied. The EAT thickness on the right ventricle was measured using transthoracic echocardiography, and arterial remodeling of culprit lesion was assessed by preinterventional IVUS. The remodeling index (RI) was calculated as lesion divided by the reference external elastic membrane cross-sectional area, Positive remodeling (PR) was defined as RI>1.05, intermediate remodeling (IR) as between 0.95 and 1.05, and negative remodeling (NR) as <0.95. IVUS findings included plaque characteristics-lipid rich, mixed and calcified plaque and plaque eccentricity. Results: There was significant relationship between EAT thickness and RI(r= 0.36, p=0.0001). Higher EAT thickness (≥10mm, n=55) were associated with higher BMI(25.2±3.6 kg/m 2 vs. 23.9±2.8 kg/m 2 , p=0.04), plasma triglyceride level (189.1±103.8 mg/dl vs. 146.1±80.9 mg/dl, p=0.02), and plasma urinary acid level(6.8±1.5mg/dl vs. 5.9±1.5 mg/dl, p=0.02). PR and more lipid rich and mixed plaque were observed in patients with higher EAT thickness than lower EAT thickness (PR ;43.6% vs. 18.9%,p=0.02. lipid rich and mixed plaque; 89% vs.66%,p=0.004). Multivariate analysis showed high EAT thickness was independent factor affecting coronary positive remodeling (OR3.05,p=0.02).There was no significant association EAT thickness and plaque eccentricity. Conclusion; High EAT thickness was significantly correlated with the coronary positive remodeling and non calcified plaque characteristics.

Possibility of assessment of atherosclerotic coronary artery remodeling by spectral analysis of differences of heart and pulse rhythms variability

Objective. We propose assessment of coronary artery stenoses by estimating the difference in heart and pulse rhythm variability during the controlled respiratory rate test. Design and methods. The study included 30 patients with chronic coronary artery disease, divided into groups according to coronary angiography data: I group — 10 patients with intact coronary arteries, II group — 20 patients with coronary artery stenoses (summary index 3-21). All patients were examined by simultaneous recording of electrocardiogram (ECG) and digital arterial pulse in the supine position. First record was made during 5 minutes of spontaneous breathing, second record followed by 5 minutes under controlled breathing, with subsequent analysis of heart and pulse rate variability. Results. We propose two coefficients K 1 and K 2 for evaluation of coronary artery stenoses, which based on the spectral differences of heart and pulse rhythms as a result of myocardial ischemic impact on the activity of cardiopulmonary baroreceptors. Conclusion. Simultaneous recording of heart and pulse rhythms during the controlled respiratory rate test with subsequent spectral analysis could be used as a method for assessment of atherosclerotic coronary artery remodeling.

Association of coronary plaque composition and arterial remodelling: A optical coherence tomography study

BackgroundConflicting data have been reported about the association between plaque composition and remodelling index (RI). The aim of this study is to evaluate the relationship between plaque morphology obtained by optical coherence tomography (OCT) and arterial remodelling. Methods and resultsOCT and intravascular ultrasound imaging pull back was performed at corresponding sites on 94 lesions in 47 patients. OCT plaque characteristics for lipid content, fibrous cap thickness, thin-cap fibroatheroma (TCFA), plaque rupture, thrombus, calcification and erosion were derived using validated criteria. Compared with intermediate/negative remodelling (RI<1.0), positive remodelling (RI>1.0) was associated with presence of higher lipid pool (2.86±0.42 vs. 2.20±0.78; p<0.001), thin fibrous cap (47.86±25.43μm vs. 74.41±32.41μm; p<0.001), TCFA>3mm (82.1% vs. 22.7%; p<0.0001), plaque rupture and thrombus (42.8% vs. 19.7%; p=0.024), and higher plaque burden (73.70 vs. 70.70; p=0.048). No difference was observed in the presence of calcification and plaque erosions. ConclusionsCoronary lesions with positive remodelling show higher incidences of vulnerable plaque and plaque rupture across the lesion length. This potentially explains the correlation between unstable coronary syndromes and positive remodelling.

Endothelial dysfunction after right coronary artery remodeling: a new pathogenetic role of eNOS uncoupling?

lu et al. ([2][1]) reported in the Journal of Applied Physiology by using a swine model of pulmonary artery banding-induced right ventricular hypertrophy (RVH) that the outward remodeling of the right coronary artery (RCA) induces reactive oxygen species (ROS) generation, an increase in basal

Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity

Experimental and clinical data support the notion that peroxisome proliferator-activated receptor γ (PPARγ) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPARγ agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPARγ activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPARγ antagonist), and losartan with no PPARγ activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NFκB) activation and tumor necrosis factor α. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPARγ activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPARγ in db/db mice and this effect of telmisartan was cancelled by the coadministration of GW9662. Our data provided the first evidence indicating that PPARγ activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. PPARγ activity of telmisartan was involved in the normalization of vascular PPARγ downregulation in diabetic mice. Thus, telmisartan seems to exert vascular protective effects in hypertensive patients with diabetes.

Long-Term Positive Remodeling of the Right Coronary Artery after Reimplantation from the Pulmonary Artery to the Ascending Aorta

A 53-year-old woman, nonsmoking patient, with a history of surgically corrected anomalous origin of the right coronary artery from the pulmonary artery 17 years prior to admission, presented to our department complaining of mild, left-sided exertional chest pain for the past 3 months. She underwent a computed tomography examination of the heart and coronary angiography revealing postsurgical changes to the coronary vasculature and severe stenosis of the left circumflex artery, which was successfully treated by percutaneous stent implantation.

Assessment of coronary artery remodelling by dual-source CT: a head-to-head comparison with intravascular ultrasound

BackgroundWhile it is widely assumed that coronary CT angiography permits detection and quantification of ‘positive remodelling’ of coronary atherosclerotic lesions, there is a paucity of data comparing CT with established...

AS-247 Relation between Remodeling Pattern and Coronary Plaque Components: Virtual Histology-Intravascular Ultrasound Analysis

Plaque components according to the remodeling pattern were not fully assessed. We used virtual histology-intravascular ultrasound (VH-IVUS) to evaluate the relation between coronary artery remodeling pattern and plaque components in 1,133 patients.

Elevated oxidative stress and endothelial dysfunction in right coronary artery of right ventricular hypertrophy

Remodeling of right coronary artery (RCA) occurs during right ventricular hypertrophy (RVH) induced by banding of the pulmonary artery (PA). The effect of RVH on RCA endothelial function and reactive oxygen species (ROS) in vessel wall remains unclear. A swine RVH model (n = 12 pigs) induced by PA banding was used to study RCA endothelial function and ROS level. To obtain longitudinal coronary hemodynamic and geometric data, digital subtraction angiography was used during the progression of RVH. Blood flow in the RCA increased by 82% and lumen diameter of RCA increased by 22% over a 4-wk period of RVH. The increase in blood flow and the commensurate increase in diameter resulted in a constant wall shear stress in RCA throughout the RVH period. ROS was elevated by ∼100% in RCA after 4 wk of PA banding. The expressions of p47(phox), NADPH oxidase (NOX1, NOX2, and NOX4) were upregulated in the range of 20-300% in RCA of RVH. The endothelial function was compromised in RCA of RVH as attributed to insufficient endothelial nitric oxide synthase cofactor tetrahydrobiopterin. In vivo angiographic analysis suggests an increased basal tone in the RCA during RVH. In conclusion, stretch due to outward remodeling of RCA during RVH (at constant wall shear stress), similar to vessel stretch in hypertension, appears to induce ROS elevation, endothelial dysfunction, and an increase in basal tone.

Non-dimensional modeling in flow simulation studies of coronary arteries including side-branches: A novel diagnostic tool in coronary artery disease

AimsBlood flow, vascular shape and size and local remodeling of the vascular wall are linked through wall shear stress (WSS) signaling. Inter-individual comparison of shape and WSS is hampered by large differences in size of flow and shape. We performed non-dimensional modeling to discriminate different types of coronary artery remodeling based on WSS patterns and vessel morphology. Methods and resultsBlood flow was simulated in three-dimensional reconstructed right coronary artery trees from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) classified by expert visual diagnosis. A discriminant model using low WSS area, a remodeling index, and cross-correlation of WSS in main trunks and complete trees (K) as non-dimensional parameters classified CAD and AnCAD correctly and identified three patients with high risk profile and functional disease in controls. The new model was compared with discriminant analysis of identical cases simulated without side-branches. The inclusion of K (information from side-branches) and replacement of the mean diameter by a non-dimensional remodeling index improved the model. We found significant (p<0.005) gender differences in the remodeling index. ConclusionThe combination of non-dimensional modeling and WSS profiling should be further investigated as a novel diagnostic tool in CAD beyond local stenosis.

Serum lipid profiles are independent determinants of coronary artery remodeling

Serum lipid profiles are independent determinants of coronary artery remodeling

Correlation between high density lipoprotein-cholesterol and remodeling index in patients with coronary artery disease: IDEAS (IVUS diagnostic evaluation of atherosclerosis in Singapore)-HDL study

Serum level of high density lipoprotein (HDL)-cholesterol is associated with risk of coronary artery disease. We correlated the serum level of cholesterol with coronary artery remodeling index of patients with coronary artery disease. A total of 120 patients with de novo lesions located in native coronary artery were studied. Remodeling index was based on intravascular ultrasound (IVUS) interrogation of the lesions using the static approach, and was defined as external elastic membrane (EEM) area at lesion/average EEM area at proximal and distal reference segments. The average remodeling index was 0.9 (SD: 0.2). The remodeling index was not associated with any of the demographic and coronary risk factors. Stable angina was associated with a low remodeling index. Remodeling index correlated with white blood cell count and HDL-cholesterol, but not with total cholesterol, LDL-cholesterol and triglyceride. In the multiple linear regression analysis, HDL-cholesterol and procedure indication were the only 2 significant predictors of remodeling index. An increase of 1 mg/dL of HDL-cholesterol resulted in a decrease of 0.003 (95% CI: 0.0001, 0.007; P = 0.046) in remodeling index, after adjusting for procedural indications. When stratified according to diabetic status, the negative correlation persisted in non-diabetic (P = 0.023), but not in diabetic, patients (P = 0.707). We found a negative correlation between HDL-cholesterol level and remodeling index. Diabetic status may have an influence on the observed relationship.

TCT-343: Plasma Pentraxin 3 is associated with Thin-cap Fibroatheroma and Positive Remodeling in Coronary Arteries Determined by Optical Coherence Tomography and Intravascular Ultrasound

TCT-343: Plasma Pentraxin 3 is associated with Thin-cap Fibroatheroma and Positive Remodeling in Coronary Arteries Determined by Optical Coherence Tomography and Intravascular Ultrasound

Does Abciximab Promote Coronary Artery Remodeling in Patients With Kawasaki Disease?

Standard therapy, consisting of intravenous immunoglobulin and aspirin, reduces, but does not eliminate, coronary artery aneurysms (CAAs) in patients with Kawasaki disease. Large CAAs can persist or undergo varying degrees of regression. The treatment of large CAAs using abciximab has been associated with short-term regression; however, longer term data are unavailable. We sought to obtain longer term follow-up data regarding the changes in the diameters of large CAAs in patients receiving both abciximab and standard therapy and to compare these changes to those of a similar group receiving standard therapy alone. All patients with Kawasaki disease and large CAAs (diameter >5 mm or Z score >10) treated from 1986 to 2007 were identified and divided into 2 groups. The abciximab group received abciximab plus standard therapy and the no-abciximab group received standard therapy alone. The maximum diameters of the proximal right and left anterior descending CAAs were obtained from echocardiograms. The Z scores were calculated for 3 points: the acute/subacute phase (<8 weeks) and at 1 and 3 to 5 years of follow-up. The patients in the abciximab (n = 11) and no-abciximab (n = 7) groups were similar in age, interval to treatment, gender, and largest CAA Z score at diagnosis (19.6 +/- 6.2 vs 25.8 +/- 9.5, p = 0.11). The change in CAA Z score was similar between the 2 groups at 1 year (p = 0.99). At 3 to 5 years of follow-up, compared to baseline, the abciximab group had a greater decrease in the CAA Z score than did the no-abciximab group (-14.0 +/- 4.0 vs -8.2 +/- 5.9, p = 0.04). In conclusion, abciximab treatment might be associated with vascular remodeling in patients with large CAAs.

Progressive Coronary Artery Remodeling in Diabetic db/db Mice

Type 2 diabetes is associated with vascular dysfunction and remodeling. The aim of this study was to determine the progression of coronary artery remodeling in Type 2 diabetes. Septal coronary arteries from 12, 16, and 20‐wk‐old heterozygous Db/db and Type 2 diabetic db/db mice were isolated and mounted on a pressure myograph containing Ca2+‐free physiological saline solution, EGTA and sodium nitroprusside. Passive structural measurements across a range of pressures revealed no changes in coronary structure in 12‐wk db/db mice, a time at which endothelial dysfunction is reported. However, wall thickness in diabetic arteries at 16 and 20‐wks was augmented (Db/db‐16: 6.9±0.6 μm vs. db/db‐16: 9.7±0.5 μm and Db/db‐20 6.7±0.8 μm vs. db/db‐20 9.2±0.7 μm at 100 mmHg, p &lt; 0.05, respectively) while internal lumen diameters tended to be reduced (Db/db‐16: 117.6±4.6 μm vs. db/db‐16: 102.9±4.3 μm and Db/db‐20 112.3±9.1 μm vs. db/db‐20 106.2±6.7 μm at 100 mmHg). The wall/lumen ratio at the same ages was augmented in diabetic coronary arteries (Db/db‐16: 6.0±0.6 μm vs. db/db‐16: 9.5±0.4 μm and Db/db‐20 6.1±0.6 μm vs. db/db‐20 8.9±0.7 μm at 100 mmHg, p &lt; 0.01). Despite these structural changes, no change in compliance was observed between control and diabetic groups. These data indicate that diabetic coronary arteries undergo progressive inward remodeling that may lead to impaired cardiac perfusion and coronary flow reserve. Supported by NIH RO1‐HL056046 (PAL).

Specification and Differentiation of Coronary Smooth Muscle

Lineage mapping studies have shown that progenitors for coronary smooth muscle enter the heart following epithelial to mesenchymal transition (EMT) of epicardial cells. Primary explant culture experiments show that loss of epicardial cell‐cell adhesion is a prerequisite for transcriptional activation of coronary smooth muscle cell (CoSMC) differentiation marker genes. Thus a majority of epicardial cells are specified for a CoSMC fate, but do not express that fate while resident within the intact epicardium. Our studies suggest that epicardial cell‐cell contacts activate Notch‐dependent pathways that oppose receptor tyrosine kinase (PDGFBB, FGF2)‐mediated signals for EMT and thereby maintain the CoSMC progenitor phenotype in the intact epicardium. Later steps in coronary development produce three distinct layers of artery wall. The outer layer is known as the adventitia and is composed of epicardium‐derived cells. We observed that formation of adventitia is accompanied by local activation of sonic hedgehog (Shh) signaling that is restricted to the adventitial layer. Moreover, we found a population of stem cell antigen 1‐positive cells (AdvSca1) resident within this novel domain of Shh signaling with intrinsic potential to differentiate to pericytes and CoSMCs. The role of AdvSca1 progenitors in coronary artery maturation, remodeling and disease will be discussed. Support: HL19242, HL93594.

Involvement of NADPH oxidase in age-associated cardiac remodeling

Increased activation of the renin–angiotensin–aldosterone system (RAAS) and an increase in oxidative stress are both implicated in age-related cardiac remodeling but their precise interrelationship and linkage to underlying molecular and cellular abnormalities remain to be defined. Recent studies indicate that NADPH oxidases are major sources of oxidative stress and are activated by the RAAS. This study investigated the relationship between the NADPH oxidase system, age-related cardiac remodeling and its underlying mechanisms. We studied male Fisher 344 cross Brown Norway rats aged 2 months (young rats), 8 months (young adult rats) or 30 months (old rats). Aging-dependent increases in blood pressure, cardiomyocyte area, coronary artery remodeling and cardiac fibrosis were associated with increased myocardial NADPH oxidase activity attributable to the Nox2 isoform. These changes were accompanied by evidence of local RAAS activation, increased expression of connective tissue growth factor (CTGF) and TGF-β1, and a significant activation of MMP-2 and MT1-MMP. The changes in old rats were replicated in 8 month old rats that were chronically treated with angiotensin II for 28 days. Increased RAAS activation may drive age-related cardiac remodeling through the activation of Nox2 NADPH oxidase and subsequent increases in MMP activation, fibrosis and cardiomyocyte hypertrophy.

Treatment with Nesiritide, A Recombinant B-Type Natriuretic Peptide, Reduces Vascular Remodeling Following Balloon-Induced Endothelial Injuries in Rabbits

Re-stenosis or remodeling of coronary and peripheral arteries remains a major complication following balloon-angioplasty or stenting. This study was designed to investigate the effect of nesiritide, a recombinant B-type natriuretic peptide (BNP), on vascular remodeling following balloon-induced endothelial injuries. Twenty-eight male New Zealand rabbits were divided into nesiritide-treated (0.1 mg/kg/day, sc, for 4 weeks, n = 10), saline-treated control (n = 10) and sham-operated groups (n = 8). In the nesiritide and control groups, a balloon catheter was inserted to the right iliac artery to induce injuries. Vascular endothelial growth factor (VEGF) was measured by immunohistochemistry. The area under internal elastic membrane of the arterial wall (643.2 ± 134.1 vs 493.7 ± 139.3 µm(2), p < 0.05) and the area under external elastic membrane (1495.1 ± 204.9 vs 1265.9 ± 232.6 µm(2), p < 0.05) in the nesiritide group were greater than those in the control group, but were smaller than those in the sham-operated group (p < 0.05). The stenosis ratio was lower in the nesiritide group than in the control group (18.7 ± 7.7% vs 38.0 ± 8.3%, p < 0.01). Importantly, the VEGF expression rate was significantly lower in the nesiritide group than in the control group (42.2 ± 8.8% vs 56.1 ± 13.1%, p < 0.05), while there were no signs of VEGF expression in the non-injured arteries of the three groups. In conclusion, nesiritide treatment reduces the stenosis of the rabbit iliac artery following balloon-induced endothelial injuries probably by decreasing VEGF expression.

Abstract 4893: Selective Aldosterone Blocker Enhances Protective Effects of Calcium Channel Blocker (CCB) Against Salt-sensitive Hypertension-induced Cardiovascular Injury, Independently of Blood Pressure

Purpose : The effects of aldosterone blocker against hypertension (HTN)-induced cardiovascular injury are still unclear. We compared the protective effects of eplerenone (EPL), an aldosterone blocker and amlodipine (AML), a CCB on salt-sensitive HTN-induced cardiovascular injury, and examined these combined effects on cardiovascular protection. Methods : Dahl salt-sensitive rats fed on 8% NaCl containing diet were divided into vehicle, EPL (100mg/kg), AML (10mg/kg), and EPL combined with AML. Results : EPL monotherapy, without affecting blood pressure (BP) and plasma renin activity, significantly suppressed HTN-induced cardiac macrophage infiltration and interstitial fibrosis, coronary arterial remodeling, and improved HTN-induced vascular endothelial dysfunction, to a similar extent to strongly BP lowering AML. Beneficial effects of the combination therapy against HTN-induced cardiac inflammation, fibrosis, and vascular endothelial dysfunction were greater than AML monotherapy despite no lowering BP. Moreover, combination of EPL and AML markedly improved HTN-induced cardiac diastolic dysfunction compared with vehicle. These additive amelioration by the combination against hypertensive cardiac injury compared with AML monotherapy were associated with more attenuation of cardiac MCP-1, IL-6 and TGF- β 1 expressions, and more reduction of cardiac superoxide partially derived from NADPH oxidase. Furthermore, improvement of vascular endothelial dysfunction by the combination compared with AML monotherapy was attributed to not only more reduction of vascular NADPH oxidase-mediated superoxide but also more increase of NO by vascular endothelial NO synthase phosphorylation. It is interesting that the amelioration of endothelial fucntion by EPL was associated with the attenuation of HTN-induced vascular apoptosis signal-regulating kinase 1 (ASK1) activation. Actually, we found that vascular ASK1 deficiency markedly reduced vascular superoxide, and improved vascular endothelial dysfunction caused by aldosterone/salt-induced HTN in ASK1 deficient mice. Conclusions : Without lowering BP, aldosterone blocker enhanced protective effects of CCB against salt sensitive HTN-induced cardiovascular injury.