Minimal Intimal Thickening Research Articles

Initial Intravascular Ultrasound Without a Routine Early Baseline Study in the Evaluation of Cardiac Transplant Vasculopathy has Prognostic Valve.

Abnormal minimal intimal thickening (MIT) on intravascular ultrasound (IVUS) defined as difference of ≥0.5 mm between baseline and one-year post-transplantation has been shown to have prognostic value. The goal of this retrospective cohort study was to evaluate whether abnormal MIT found on routine IVUS studies in cardiac transplant patients after 6 months without an early baseline study (modified MIT or MMIT), has any prognostic value. Furthermore, we evaluated the prognostic effect of serial IVUS performed beyond one year. A cohort of 149 cardiac transplant patients who underwent IVUS examination > 6 months post-transplant were evaluated retrospectively. Of these 149 patients, 109 patients underwent a subsequent IVUS study approximately 1 year following the initial study. MMIT values of ≥0.5 mm without an early baseline study were correlated with major adverse cardiac event (MACE). The all-cause mortality was 4.7% (5/107) in patients with MMIT of <0.5 mm vs. 14.6% (6/41) in patients with MMIT of ≥0.5 mm [hazards ratio (HR): 3.2; 95% confidence interval (CI): 1.002-12.17; p = 0.039]. The overall MACE rate was 8.4% (9/107) in patients with MMIT of <0.5 mm vs. 24.4% (10/41) in patients with MMIT of ≥0.5 mm [HR: 6.7; 95% CI: 1.30-9.42; p = 0.009]. After adjusting for age, abnormal MMIT remained a significant independent predictor of MACE (HR: 3.93; CI 1.21-12.81; p = 0.023). The presence of abnormal MMIT noted on IVUS performed after 6 months post-transplantation without a routine baseline IVUS carries important prognostic value.

TCT-633 Prognostic Valve of Initial Intravascular Ultrasound without a Routine Early Baseline Study in the Evaluation of Cardiac Transplant Vasculopathy

Abnormal minimal intimal thickening (MIT) on Intravascular ultraousnd (IVUS) defined as difference of > 0.5 mm between baseline and one-year post-transplantation has been shown to have prognostic value. We evaluated whether performing first IVUS more than 6 months after transplantation without a

Expression of urotensin-II in human coronary atherosclerosis

The vasoactive peptide urotensin-II (U-II) is best known for its ability to regulate peripheral vascular and cardiac contractile function in vivo, and recent in vitro studies have suggested a role for the peptide in the control of vascular remodeling by inducing smooth muscle proliferation and fibroblast-mediated collagen deposition. Therefore, U-II may play a role in the etiology of atherosclerosis. In the present study we sought to determine the expression of U-II in coronary arteries from patients with coronary atherosclerosis and from normal control subjects, using immunohistochemistry and in situ hybridization. In normal coronary arteries, there was little expression of U-II in all types of cells. In contrast, in patients with coronary atherosclerosis, endothelial expression of U-II was significantly increased in all diseased segments (P<0.05). Greater expression of U-II was noted in endothelial cells of lesions with subendothelial inflammation or fibrofatty lesion compared with that of endothelial cells underlined by dense fibrosis or minimal intimal thickening. Myointimal cells and foam cells also expressed U-II. In most diseased segments, medial smooth muscle cells exhibited moderate expression of U-II. These findings demonstrate upregulation of U-II in endothelial, myointimal and medial smooth muscle cells of atherosclerotic human coronary arteries, and suggest a possible role for U-II in the pathogenesis of coronary atherosclerosis.

Initial clinical cases of the use of a NF-kappaB decoy at the site of coronary stenting for the prevention of restenosis.

Nuclear factor-kappaB (NF-kappaB) plays a pivotal role in restenosis after percutaneous coronary intervention (PCI) and the aim of the present clinical trials was to evaluate the effectiveness of a NF-kappaB decoy for preventing restenosis. The initial case was a patient suffering from effort angina who had stenoses in the proximal and middle portions of the right coronary artery. The patient received 2 stents; the NF-kappaB decoy was delivered to the distal site, but not the proximal site. Six months after the PCI, the NF-kappaB decoy had suppressed restenosis in comparison with the no-decoy transfection site. The second case was a patient who underwent single-stent insertion and decoy transfection at the same site, and minimal intimal thickening was observed at 6 month after PCI. No systemic adverse effects were observed in either case. These results indicate the clinical usefulness and safety of NF-kappaB decoy transfection after PCI, but further evaluations are necessary to confirm its clinical effectiveness.

Posttransplant administration of allochimeric major histocompatibility complex class-I-molecules induces true transplantation tolerance.

Allochimeric class-I major histocompatibility complex (MHC) molecules that contain donor-type immunogenic epitopes displayed on recipient-type sequences were shown to induce transplantation tolerance when administered at the time of transplantation. Here, we investigated the ability of posttransplant allochimeric administration to induce tolerance and concomitantly inhibit chronic rejection. Allochimeric (alpha1h(1/u))-RT1.Aa class-I MHC antigenic extracts were administered by way of the portal vein into ACI recipients of Wistar-Firth (WF) hearts at days +3, +7, and +10 posttransplantation in conjunction with subtherapeutic oral cyclosporine. Delayed posttransplant allochimeric administration induced donor-specific transplantation tolerance to rat cardiac allografts. In contrast, delayed delivery of unaltered donor- or recipient-type MHC extracts failed to prolong allograft survival. In addition, histopathologic examination or estimation of transplant vascular sclerosis by neointimal index assessment, following delayed allochimeric therapy, revealed intact global architecture and minimal intimal thickening, respectively. Allochimeric MHC class-I therapy is a unique and novel clinically applicable approach for induction of "true" transplantation tolerance where chronic rejection is concomitantly abrogated.

ALLOCHIMERIC CLASS I MHC MOLECULES PREVENT CHRONIC REJECTION AND ATTENUATE ALLOANTIBODY RESPONSES1

We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection. Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6). WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium. Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.

Adeno-associated virus vector transduction of vascular smooth muscle cells in vivo.

Adeno-associated virus (AAV) vectors might offer solutions for restenosis and angiogenesis by transducing nondividing cells and providing long-term gene expression. We investigated the feasibility of vascular cell transduction by AAV vectors in an in vivo rabbit carotid artery model. Time course of gene expression, inflammatory reaction to the vector, and effects of varying viral titer, exposure time, and intraluminal pressures on gene expression were examined. Recombinant AAV vectors with an Rous sarcoma virus promoter and alkaline phosphatase reporter gene were injected intraluminally into transiently isolated carotid segments. Following transduction, gene expression increased significantly over 14 days and then remained stable to 28 days, the last time point examined. Medial vascular smooth muscle cells were the main cell type transduced even with an intact endothelial layer. Increasing the viral titer and intraluminal pressure both enhanced transduction efficiency to achieve a mean of 34 +/- 7% of the subintimal layer of smooth muscle cells expressing gene product. A mild inflammatory reaction, composed of T cells with only rare macrophages, with minimal intimal thickening was demonstrated in 40% of transduced vessels; inflammatory cells were not detected in sham-operated control arteries. These findings demonstrate that AAV is a promising vector for intravascular applications in coronary and peripheral vascular diseases.

Pathologic Correlates of Aortic Plaques, Thrombi and Mobile “Aortic Debris” Imaged In Vivo With Transesophageal Echocardiography

This study sought to evaluate the pathologic correlates of aortic atheromas, thrombi and mobile "aortic debris" imaged in vivo by transesophageal echocardiography (TEE). Atherosclerotic plaques with various complexity, thrombi and debris are frequently identified by TEE during imaging of the aorta. However, pathologic data to characterize these lesions imaged in vivo are lacking. Intraoperative TEE was performed prospectively in 31 patients undergoing repair of aortic aneurysm or dissection. TEE was used to guide the surgeon to mark aortic areas of interest that were sent for pathologic examination. A four-point scoring system was used for both TEE and pathologic evaluation to grade the degree of involvement of the aortic wall with atheroma. Ultrasound video intensity of the aortic wall lesions was measured and compared with quantitative measures of wall composition at pathologic examination. The presence of thrombi and mobile aortic debris by TEE was noted and compared with pathologic findings. Histologic-TEE correlations were possible in 62 aortic segments. There was 73% exact agreement between TEE and pathologic grading. Discrepancies were mostly in the inability of TEE to detect superficial ulcerations. However, separation of normal aorta and minimal intimal thickening (grades I and II) from more complex atheromas (grades III and IV) was observed in 93%. For identification of thrombus, TEE had a sensitivity of 91% (29 of 32 segments) and a specificity of 90% (27 of 30 segments). Mobile aortic debris were identified in six aortic segments and were confirmed at pathologic examination to be thrombi. Ultrasound video intensity increased with worsening complexity of atheroma and related significantly to aortic plaque composition at pathologic evaluation (r = 0.80, p < 0.0001). Ultrasound intensity of thrombi and mobile debris was similar and was lower than that of complex atheromas. Thus, in the evaluation of aortic pathologic segments, TEE can assess aortic plaque complexity and identify thrombus formation, findings that may have important therapeutic implications.

βig-h3, a Transforming Growth Factor–β–Inducible Gene, Is Overexpressed in Atherosclerotic and Restenotic Human Vascular Lesions

Transforming growth factor-beta (TGF-beta) plays an important role in vascular lesion formation and possibly the renarrowing process ("restenosis") that occurs after balloon angioplasty. Secreted in a latent form by most cells, TFG-beta requires enzymatic conversion before it is biologically active. TGF-beta-inducible gene h3 (beta ig-h3) is a novel molecule that is induced when cells are treated with TGF-beta1. This study examined the expression of beta ig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of beta ig-h3 in human arteries, immunocytochemistry was performed on tissue sections from (1) normal internal mammary arteries, (2) the proximal left anterior descending coronary artery (with minimal intimal thickening) of 15 patients aged 18 to 40 years, (3) primary and restenotic coronary lesions from 7 patients, and (4) fresh directional atherectomy tissue from 11 patients. A polyclonal antibody consistently immunodetected beta ig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, beta ig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening. In diseased arteries beta ig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable beta ig-h3 protein, especially in areas of dense fibrous connective tissue. Beta ig-h3 protein was immunodetected in the cytoplasm of plaque macrophages as well as smooth muscle and endothelial cells. By using in situ hybridization on fresh directional atherectomy specimens, we found beta ig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed beta ig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of beta ig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-beta plays a role in atherogenesis and restenosis.

Intimal thickening and fragmentation of the internal elastic lamina in the mesenteric arteries.

To evaluate the intimal thickness and continuity of the internal elastic lamina (IEL) in the mesenteric arteries, proximal segments of the coeliac artery (CA), superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were studied light microscopically in 123 consecutive postmortem examinations. The mean age of the subjects was 62 years. Arterial segments were fixed in formalin, embedded in paraffin blocks, sectioned, and stained with Masson's trichrome. Fifty-one per cent of the samples examined showed at least minimal intimal thickening. The occurrence of significant luminal narrowing increased with age. We found a positive correlation between defects in the IEL and thickness of the intima in the mesenteric arteries, which is in harmony with previous observations showing marked fragmentation of the IEL in atherogenesis.

Surgical implications of transesophageal echocardiography to grade the atheromatous aortic arch

Stroke is an especially serious complication of cardiopulmonary bypass with an incidence of 2% to 5%. This prospective study used transesophageal echocardiography (TEE) in 97 patients more than 65 years of age (mean age, 73 years) to identify those at high risk for aortic atheroemboli. The atheromatous disease of the aorta was graded by TEE: grade I = minimal intimal thickening (n = 29); II = extensive intimal thickening (n = 33); III = sessile atheroma (n = 15); IV = protruding atheroma (n = 10); V = mobile atheroma (n = 10). Clinical evaluation was also performed by intraoperative aortic palpation. Four patients who were graded as having normal aortas by palpation had intraoperative strokes. In contrast, 3 of these 4 patients were in grade V on TEE. The relationship of TEE to incidence of stroke was statistically significant (p less than 0.006), whereas there was no significant correlation between clinical grade and stroke incidence. Four of 10 TEE grade V patients were treated with hypothermic circulatory arrest and aortic arch debridement, and none suffered strokes. The other 6 patients were treated with standard techniques, and 3 had strokes. These results suggest that patients with mobile atheromatous disease are at high risk for embolic strokes that are not predicted by routine clinical evaluation. Selective use of circulatory arrest in the presence of TEE-detected mobile arch atheromas may reduce the risk of intraoperative stroke.

Hepatic inferior vena cava obstruction: treatment of two types with Gianturco expandable metallic stents.

Gianturco expandable metallic stents were used for treating six patients with inferior vena cava (IVC) obstruction due to compression by large hepatic tumors and three patients with idiopathic obstruction of the hepatic IVC and Budd-Chiari syndrome who showed reocclusion or stenosis 3-21 months after previously performed percutaneous transluminal angioplasty (PTA). In all six patients with compression by hepatic tumors, stents dilated the IVC and debilitating edema of the lower body disappeared. In the three patients with idiopathic obstruction, stents were placed after repeat dilation of the lesions and Budd-Chiari syndrome did not recur during a follow-up period of 7-10 months. In two of the three, cavograms obtained 8 months after placement showed the channels to be open with minimal intimal thickening. Gianturco expandable metallic stents can correct IVC obstruction due to compression by hepatic tumors and are useful in preventing reocclusion of the IVC after PTA for the treatment of idiopathic obstruction. The authors recommend using tanem stents connected by at least two struts.