Karl R. Karsch

Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography

OBJECTIVESnThe aim of the present study was to evaluate the accuracy in determining coronary lesion configuration by multislice computed tomography (MSCT). The results were compared with the findings of intracoronary ultrasound (ICUS).nnnBACKGROUNDnThe risk of acute coronary syndromes caused by plaque disruption and thrombosis depends on plaque composition rather than stenosis severity. Thus, the reliable noninvasive assessment of plaque configuration would constitute an important step forward for risk stratification in patients with known or suspected coronary artery disease. Just recently, MSCT scanners became available for general purpose scanning. Due to improved spatial and temporal resolution, this new technology holds promise to allow for differentiation of coronary lesion configuration.nnnMETHODSnThe ICUS and MSCT scans (Somatom Volume Zoom, Siemens, Forchheim, Germany) were performed in 15 patients. Plaque composition was analyzed according to ICUS (plaque echogenity: soft, intermediate, calcified) and MSCT criteria (plaque density expressed by Hounsfield units [HU]).nnnRESULTSnThirty-four plaques were analyzed. With ICUS, the plaques were classified as soft (n = 12), intermediate (n = 5) and calcified (n = 17). Using MSCT, soft plaques had a density of 14 +/- 26 HU (range -42 to +47 HU), intermediate plaques of 91 +/- 21 HU (61 to 112 HU) and calcified plaques of 419 +/- 194 HU (126 to 736 HU). Nonparametric Kruskal-Wallis test revealed a significant difference of plaque density among the three groups (p < 0.0001).nnnCONCLUSIONSnOur results indicate that coronary lesion configuration might be correctly differentiated by MSCT. Since also rupture-prone soft plaques can be detected by MSCT, this noninvasive method might become an important diagnostic tool for risk stratification in the near future.

Influence of heart rate on vessel visibility in noninvasive coronary angiography using new multislice computed tomography: experience in 94 patients.

OBJECTIVESnInitial reports indicate that coronary artery lesions might be visualized with high sensitivity and specificity by the use of recently introduced multislice computed tomography (MSCT). Current CT technology offers a temporal resolution of 250 ms. In case of heart rates (HRs) >65 beats/min (bpm), however, the reconstruction software switches from a single-phase algorithm (using data from one heart cycle only) to a biphase algorithm using image data of two consecutive heart cycles, improving temporal resolution to down to 125 ms. Thus, it was the aim of the present study to evaluate the influence of the patients (pts) HR on image quality expressed by vessel segment visibility.nnnMETHODS AND RESULTSnMSCT scans (Somatom VZ) were performed in 94 pts. Ten coronary segments were analyzed in each patient with regard to image quality (RCA: segments [sgts] 1-4, LMS: sgt 5, LAD: sgts 5-8, LCX: sgts 11, 12). A total of 697 of 940 (74.1%) sgts were accurately visualizable (RCA: 244/376 [64.9%], LMS: 94/94 [100%], LAD: 232/283 (82.3%), LCX: 146/188 [77.7%]). Beta-blocker therapy had a significant influence on mean HR (65 pts on beta-blocker, HR 65.1+/-10.7 bpm vs. 29 pts, HR 71.6+/-12.2 bpm, P=.01). A significant inverse correlation between HR and segmental visibility was found (r=-.48, P<.0001), with best visibility in pts with lower HRs (n=14 pts with 10 analyzable sgts, HR 60+/-10.1 vs. n=8 pts with 4 analyzable sgts, HR 79.9+/-6.9, P<.0001).nnnCONCLUSIONSnOur results indicate that vessel visibility is highly dependent on the pts HR. Best vessel visibility was found in pts with HR <65 bpm with single-phase image reconstruction. Thus, it appears to be advisable to evaluate, and if needed, to lower the pts HRs before undergoing MSCT coronary angiography in order to achieve best image quality.

All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells

OBJECTIVEnThe vitamin-A derivative all-trans retinoic acid (atRA) is a potent regulator of cell growth, differentiation, and matrix formation of various cell types and plays an important role in embryogenesis. However, sparse data are available about its effects on human vessel diseases. Thus, we studied the effects of atRA on human arterial smooth muscle cell (haSMC) and endothelial cell (haEC) proliferation, migration, differentiation and extracellular matrix (ECM) turnover in mono- and transfilter cocultures.nnnMETHODSnEffects of atRA on human arterial cells in monocultures were determined using cell counting assays, BrdU-ELISA and MTT-tests. In transfilter cocultures haSMC-growth was studied under the stimulatory effect of proliferating haEC. Using Northern blot analysis, effects of atRA on mRNA expression of ECM-proteins were examined while protein expression and activity of matrix metalloproteinases were determined by Western blotting and zymography.nnnRESULTSnatRA caused a dose dependent inhibition of haSMC-growth in monocultures (IC(50) at 0.022 microM) whereas haEC-growth was inhibited less potently (IC(50) at 97 microM). In addition, proliferation and migration of haSMC through a porous membrane were inhibited dose dependently by micromolar atRA-doses after non-stop and single dose application of atRA on the endothelial side of the complex transfilter coculture system. Immunostainings and Northern blotting demonstrated an enhanced alpha-smooth muscle actin and heavy chain myosin expression in haSMC after atRA-treatment. Whereas mRNA-expression of the glycoproteins thrombospondin-1 and fibronectin were decreased, collagen-1 mRNA expression was even slightly stimulated. Transcription of biglycan and TGF-beta1 were not influenced in a specific manner. Finally, protein expression and activity of the matrix metalloproteinases MMP-2 and MMP-9 were inhibited significantly by atRA.nnnCONCLUSIONSnatRA was found to be a potent inhibitor of both haSMC-proliferation and -migration, even in coculture with haEC releasing growth factors. In addition, redifferentiation, ECM synthesis and ECM degradation were regulated by atRA which also influence haSMC migration and intima formation. Thus, atRA-treatment seems to be a promising strategy for the inhibition of processes involved both in atherosclerosis and restenosis.

Stent-based antirestenotic coatings (sirolimus/paclitaxel)

Although several clinical trials show that stent placement reduces restenosis compared with balloon angioplasty, in-stent restenosis is a growing clinical problem [1–4]. Histological and angiographic studies suggest that stents trigger the development of neointimal hyperplasia, which is related to the degree of arterial injury. Cell proliferation is prolonged in stented arteries compared with balloon angioplasty and is associated with late inflammation and monocyte/macrophage invasion. In-stent restenosis occurs in 20%–50% of patients in the setting of complex lesion types, which constitute the majority (around 80%) in daily clinical practice [5]. Hence, viewed overall, the incidence of restenosis is comparable in patients with conventional balloon angioplasty to those undergoing stenting. Moreover, recurrent restenosis is more common after percutaneous treatment of in-stent restenosis. Stent-based local drug delivery is an attractive therapeutic option because stent coatings can optimize the surface properties of the metallic device and serve as a vehicle for local drug delivery. This review will focus on the data for the most promising compounds that are now out in the clinical arena.

Effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery

BACKGROUNDnRetinoids regulate a variety of biological processes and play an important role in cell differentiation and proliferation. All-trans retinoid acid (atRA) is known to inhibit smooth muscle cell growth and thus is supposed to have favorable effects on the incidence of restenosis after percutaneous coronary interventions. The broad biological spectrum, however, leads to numerous severe side effects which limit the clinical use of a systemic application of atRA. In order to avoid systemic side effects, local delivery of atRA is preferable. The aim of this study was to evaluate the effects of atRA on the response to injury in a second-injury model of experimental balloon angioplasty.nnnMETHODSnAfter induction of a fibromuscular plaque in the right carotid artery of 40 New Zealand rabbits, 35 animals underwent balloon angioplasty of the preformed plaque formation. Subsequent local atRA delivery (10 ml, 10 microM) with the double-balloon catheter was performed in 15 animals. Five animals received vehicle only as sham controls, and five animals were solely electrostimulated, 15 animals served as control group with balloon angioplasty only. Vessels were excised 7 days (n=15) and 28 days (n=30) after intervention. Immunocytochemistry with antibodies against smooth muscle alpha-actin and myosin, bromodeoxyuridine, macrophages, collagen I and III and von Willebrand factor was performed. Quantitative analysis was done by computerized morphometry.nnnRESULTSnAfter local atRA delivery in vivo, the extent of stenosis was markedly reduced with 21.7+/-8.3% (mean+/-S.D.) 4 weeks after intervention compared to 31.8+/-13.4% in balloon-dilated animals (P=0.0937). Both a reduced early neointimal proliferation (P=0.0002) and an increase in overall vessel diameter (4 weeks after intervention, P=0.0264) contributed to a limitation of restenosis in atRA-treated animals. Immunocytochemistry revealed a more intense alpha-actin staining pattern after local atRA therapy indicating redifferentiating effects of atRA on vascular smooth muscle cells.nnnCONCLUSIONSnLocal delivery of atRA led to limitation of restenosis formation in this animal model. The concept of a local atRA therapy might be a promising way to exploit the potential of atRA for vascular indications while minimizing the severe side effects of systemic retinoid therapy.

Effects of atorvastatin on in-stent stenosis in normo- and hypercholesterolemic rabbits

BACKGROUNDnIn-stent stenosis is characterized by a prolonged proliferation and inflammatory reactions around the stent struts. Potentially the antiproliferative and lipid-lowering effects of atorvastatin can synergistically limit neointima formation after stenting.nnnMETHODSnPalmaz-Schatz stents were placed in the iliac arteries of white New Zealand rabbits. One half of the animals was fed an 0.5% hypercholesterolemic diet, the other half was normocholesterolemic. Both groups received either atorvastatin (3 mg/kg bodyweight) daily or placebo (n=10 each in the four groups). After 28 days the segments were excised.nnnRESULTSnInjury scores as a result of vessel trauma induced by stent-overstretch injury differed significantly between the four groups (median 1.0-1.9) and the stent-induced injury outweighed the beneficial effects of statin therapy on neointima formation by far. Smooth-muscle-cell proliferation was significantly increased in both hypercholesterolemic groups. Intimal and medial proliferation as well as inflammatory infiltrates around the stent strut were reduced by 20-40% in animals that received statin therapy although the injury score in both statin groups was 19 and 60% higher than in control animals.nnnCONCLUSIONnThus, the data of this study indicate that smooth muscle cell proliferation and inflammation in stented vessels can be reduced by atorvastatin both in hypercholesterolemic rabbits and in animals with normal lipid levels.

The Genomics of Restenosis

Interventional cardiology took off in 1977, with the development of percutaneous coronary balloon angioplasty (1). Despite immediate success in regaining vessel patency, long-term results were undermined by luminal loss secondary to the vessel injury induced by the balloon (2,3). A decade later a new technique involving stent deployment had been designed to overcome vessel recoil (4), initially, considered the major contributor to the loss of lumen diameter. Rather than ridding interventional cardiology of restenosis, a purely iatrogenic process, stents have shifted the focus of attention toward the phenomenon of intimal hyperplasia (5).