Fibrinogen promotes early atherosclerotic changes of the carotid artery in young, healthy adults.

AIM: To determine whether high plasma levels or activities of different hemostatic proteins contribute to the development of early atherosclerotic vessel wall changes. Elevated levels of various hemostatic proteins and markers of inflammation have been linked to an increased risk of ischemic cardiovascular events; however, the mechanisms by which these molecules might contribute to this increased risk is not clear. METHODS: The intima-media thickness of the common carotid arteries (CCA-IMT) of 125 healthy young volunteers without known cardiovascular risk factors was measured by high-resolution ultrasound. Plasma concentrations of fibrinogen, thrombomodulin, protein Z and CRP were quantified, and the plasma activities of protein C, plasminogen and factor VIII were measured. Other established risk factors, such as body mass index (BMI) and plasma levels of cholesterol, triglycerides and homocysteine, were also determined. Furthermore, the carotid arteries were examined for the presence of plaques and stenoses. RESULTS: Univariate analysis showed a significant negative correlation between CCA-IMT and HDL cholesterol, and positive correlations with age, BMI, LDL cholesterol, triglycerides, homocysteine, fibrinogen and thrombomodulin, but not with total cholesterol, lipoprotein(a) and hsCRP. CCA-IMT was also statistically independent of the activities of protein C, factor VIII and plasminogen. Multivariate analysis revealed a significant correlation of CCA-IMT with age, BMI and fibrinogen. CONCLUSION: Our data suggest that fibrinogen levels correlate with early atherosclerotic changes of the carotid artery in a population with very low cardiovascular risk.

Inhibition of matrix deposition: a new strategy for prevention of restenosis after balloon angioplasty.

Restenosis after balloon angioplasty or stent placement is characterized by local accumulation of mainly vascular smooth muscle cells and the synthesis of extracellular matrix molecules (ECM).We hypothesized that inhibition of ECM synthesis represents a strategy to prevent trauma-induced neointima formation. Rats were treated with pirfenidone (1 g/kg of body weight orally.), an inhibitor of growth factor-induced collagen synthesis, and subjected to balloon denudation of the carotid artery. Two weeks later, computer-aided morphometry was done and compared with untreated controls (each n = 6). Neointimal proliferative activity was quantified immunohistochemically by counting PCNA-positive nuclei, and collagen deposition was visualized by picrosirius red staining and semi-quantified by Northern blot. Control-injured animals developed marked neointimal thickening within 2 weeks (I/M, mean intima to media ratio: 2.42 +/- 0.15) resulting in an 89.2% luminal narrowing. The neointima mainly consisted of vascular smooth muscle cells embedded in collagen. Neointima formation was strongly reduced when balloon-injured animals had been treated with pirfenidone (I/M ratio 0.22 +/- 0.08, P < 0.001), resulting in a minimal residual narrowing of the lumen (7.9%). I/M ratio did not further increase even after discontinuation of the drug for 14 days (0.35 +/- 0.13). Proliferative activity within the neointima was unaffected by the drug, 4.4% versus 4.8% of neointimal cells stained positive for PCNA in carotid arteries of treated versus untreated animals, respectively. However, picrosirius red staining demonstrated marked attenuation of collagen deposition, a finding that was further confirmed by Northern blot of homogenized vessels. Pirfenidone, currently being investigated clinically for the treatment of various fibrotic diseases, is able to prevent neointimal lesion formation most likely through inhibition of local ECM deposition. Targeting matrix deposition may have an intriguing potential for the prevention of vascular proliferative diseases.

Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice.

BACKGROUND: Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. METHODS: Mice were held either at normoxia (N; 21% O2) or at hypobaric hypoxia (H; 0.5 atm; ~10% O2). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for alpha-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy. RESULTS: Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H +/- RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined. CONCLUSION: Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.

Comparison between pulsed and continuous radiofrequency delivery.

INTRODUCTION: Potentials arising in the pulmonary veins (PV) have been proposed to be a trigger of atrial fibrillation. Percutaneously, the best results for curative treatment of atrial fibrillation have been achieved by segmental or circumferential isolation of the PV. The purpose of our study was to determine the feasibility of ostial pulmonary vein isolation and to compare continuous radiofrequency (RF) with pulsed RF concerning homogeneity and transmurality of produced lesions. MATERIALS AND METHODS: In vivo tests were performed in seven anesthetized and ventilated pigs. Under fluoroscopy and guided by intracardiac electrograms each of the 28 pulmonary veins was targeted for circumferential isolation near its ostium. After the continuous energy application in one PV-ostium the catheter was placed into the next PV-ostium and the same procedure was repeated using pulsed energy. The ablations were performed with an octapolar circumferential ablation catheter, with either continuous RF energy delivery to each electrode for 120 s or pulsed energy delivery to four electrodes simultaneously with a 5 ms duty cycle. Lesion diameter was measured with a microcaliper and homogeneity classified from 1 (highest) to 4 (least). RESULTS: More homogeneous lesions were produced in significantly less time with pulsed rather than with continuous energy delivery. There were no significant differences in impedance or temperature of the electrodes. We did not observe tissue carbonization or "popping," pulmonary vein stenosis, pericardial effusion/perforation at any time. CONCLUSION: Ostial ablation of the PV with pulsed energy delivery proved feasible. It was the faster and more reliable method of creating linear circumferential lesions with a maximum amount of homogeneity and transmurality. We observed no elevated risk of PV stenosis during our experiments.

Proportion of candidates for cardiac resynchronization therapy.

Biventricular pacing has been used as an adjunct to standard heart failure therapy in symptomatic patients with left bundle branch block (LBBB). Estimates of the number of patients for whom this treatment is appropriate are unavailable, but are of clinical and socioeconomic importance. LBBB combined with a low (< 0.35) ejection fraction was found in 7,121 consecutive patients referred for elective diagnostic angiography in 1996 through 2000 from a total population of about 125,000 residents. Patients with LBBB (n = 289, 4%) had lower ejection fractions (0.53 +/- 0.23) in comparison with patients without LBBB (P < 0.0001). The ejection fraction was < 0.35 in 558 (8%) patients. LBBB was combined with a low ejection fraction in 96 (1.4%) patients (i.e., 19 patients per year and about 15 patients per year per 100,000 residents). Of these 96 patients, 80 had normal sinus rhythm, 82 had mitral regurgitation (grade > II), 86 were < 75 years of age, and 68 had coronary artery disease. Holter recordings performed in 47 of 96 patients showed nonsustained VT in 28 (60%). LBBB, low ejection fraction, sinus rhythm, and age < 75 years were found in 71 (1%) patients (i.e., 11 patients per year per 100,000 residents). The prevalence of LBBB combined with severely impaired left ventricular ejection function is about 1-2% in patients who undergo cardiac catheterization. The authors estimate that biventricular pacing might be considered as an adjunct to standard heart failure therapy in five to ten patients per year per 100,000 residents in industrial countries. About half of these patients are potential candidates for implantation of cardioverter defibrillators combined with permanent pacing.

Cerebral infection with Rhodococcus equi in a heart transplant recipient.

Iatrogenic immunosuppression following organ transplantation leads to an increased number of opportunistic bacterial and viral infections. Similar to patients with human immunodeficiency virus (HIV) infection transplant recipients may suffer from rare infectious diseases. Herein we report on a patient presenting with a cerebral infection who had previously undergone orthotopic cardiac transplantation. Rhodococcus equi was isolated.