Biomedical subjects

Rainer Wessely

Publications and source records attributed to Rainer Wessely.

24 records · Page 2Linked to original sources

PubMed2004

Local cyclin-dependent kinase inhibition by flavopiridol inhibits coronary artery smooth muscle cell proliferation and migration: Implications for the applicability on drug-eluting stents to prevent neointima formation following vascular injury.

In-stent restenosis is a hyperproliferative disease which can be successfully treated by drug-eluting stents releasing compounds that exhibit cell-cycle inhibitory properties to inhibit coronary smooth muscle cell (CASMC) proliferation and migration, resembling the key pathomechanisms of in-stent restenosis. Cyclin-dependent kinases (CDK) are key regulators of the eukaryotic cell cycle. CDK activity may be blocked by novel compounds such as flavopiridol. Therefore, CDK inhibitors are attractive drugs to be used for the local prevention of in-stent restenosis. In this study, we demonstrate that flavopiridol leads to potent inhibition of CASMC proliferation and migration. Molecular effects on cell-cycle regulatory mechanisms and distribution were evaluated by post-transcriptional assessment of distinct cyclins and cyclin-dependent kinase inhibitor (CKI) levels and flow cytometry. Cellular necrosis and apoptosis was assessed in CASMC and coronary endothelial cells. Flavopiridol induced a potent antiproliferative effect by cell-cycle inhibition in G1 and G2/M and led to increased protein levels of CKIs p21cip1 and p27kip1 as well as p53 in CASMC. Hyperphosphorylation of retinoblastoma protein was abrogated and mitogen-mediated smooth muscle cell migration significantly reduced. No accelerated cytotoxicity or increased apoptosis was detectable. Flavopiridol-coated stents, implanted in rat carotid arteries, led to significant decrease of neointima formation. As proof of principle, our results demonstrate that stents eluting CDK inhibitors such as flavopiridol effectively inhibit neointima formation. Therefore, this new class of therapeutics may be suitable for further clinical investigations on drug-eluting stents to prevent in-stent restenosis.

Animals↗

PubMed2004

A comprehensive approach to visual and functional assessment of experimental vascular lesions in vivo.

The rat carotid injury model is the most widely used model to study the pathophysiology of neointimal hyperplasia as well as the value of novel therapeutic approaches to limit vasoproliferative diseases such as restenosis. For lesion assessment, the current gold standard of histomorphometry neither provides integral insight into the vascular lesion in vivo nor assesses of functional lesion-associated flow alterations and the time course of lesion development. To overcome these limitations, we applied and validated duplex sonography as a novel tool for comprehensive lesions assessment in vivo. Left rat common carotid arteries (CCA) were balloon injured. Duplex sonography was performed in both injured and noninjured CCAs before and up to 14 days postinjury. Sham-operated animals served as controls. The parameters determined were vessel lumen diameter as well as systolic and end-diastolic flow velocity, time-dependent lesion development, and intra- and interobserver variability. Subsequently, the model was applied to validate the therapeutic effect of gene transfer into the vessel wall and compared with histomorphometry. We show that duplex sonography in the experimental carotid injury model allows accurate follow-up of lesion development in vivo with low intra- and interobserver variability. It can be easily adopted to assess the efficacy of therapeutic approaches even with limited technical experience and adds valuable functional data to mere postmortem histomorphometric analysis, thereby closing the gap between experimental approaches and clinical importance of vascular lesions.

Angioplasty, Balloon↗

PubMed2003

Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy.

BACKGROUND: Transplant vasculopathy (TVP) is the most common cause of death and retransplantation after heart transplantation. Human cytomegalovirus (HCMV) infection has been linked to atherosclerosis and to the development of TVP. A prospective study evaluating the relation between CMV infection and progression of TVP is lacking thus far. The purpose of the present study was to investigate the influence of CMV infection status on the progression of TVP within 1 year. METHODS: We enrolled 103 consecutive heart-transplant recipients who underwent routine cardiac catheterization and intracoronary ultrasound examination at study entry and after 1 year. Plaque progression determined by quantitative intracoronary ultrasound was used to define the severity of disease at baseline and at 1-year follow-up. At study entry, HCMV infection status was evaluated by immunological assays and reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: HCMV immunoglobulin (Ig)G/IgM seropositivity was found in 34 (33%) of transplant recipients, 11 of whom were HCMV PCR positive. The HCMV-positive group showed more advanced, calcified lesions (64.7% vs. 27.5%, P=0.002), and the maximal plaque thickness was significantly different from the HCMV IgG/IgM-negative group (median [quartile] 1.36 [0.85, 1.88] vs. 1.05 [0.58, 1.34], P=0.02). In a logistic regression model, we demonstrate that HCMV IgG/IgM positivity is a predictor for the progression of TVP independent of cardiovascular risk factors, inflammatory markers, and platelet activation (P=0.038). In addition, HCMV PCR positivity even increases the risk for accelerated TVP (P=0.017) and, consecutively, transplant failure. CONCLUSIONS: HCMV infection status in transplant patients detects patients with increased risk for transplant failure caused by TVP.

Cytomegalovirus Infections↗

PubMed2003

Coxsackieviral replication and pathogenicity: lessons from gene modified animal models.

Coxsackieviruses have been implicated in the pathogenesis of human myocarditis and some forms of dilated cardiomyopathy. A considerable portion of our knowledge about the pathophysiology of viral heart disease is derived from animal studies. In particular, investigations utilising gene-targeted mice provide valuable new insights into various aspects of viral pathogenicity and host factors involved in the control of viral replication. This review focuses on models in cell culture and transgenic animals mimicking coxsackieviral persistence, demonstrating that remarkably low persisting levels of replication-restricted coxsackieviral genomes are associated with an induction of a cytopathic effect in cardiac myocytes, leading to dilated cardiomyopathy in a transgenic mouse model. In this particular animal model, a phenotype is revealed which closely resembles the major hallmarks of human dilated cardiomyopathy. The impact of the innate immune system on coxsackieviral replication is demonstrated by studies in gene-targeted mice deficient of either type I or type II interferon signalling, which have indicated that type I but not type II interferons are essential for the control of early viral replication and survival of coxsackieviral infection.

Animals↗

PubMed2003

A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia.

Neointima formation, the leading cause of restenosis after catheter angioplasty, is a paradigm for vascular proliferative responses. Neointima formation is self-limiting after a variable degree of tissue growth, causing significant renarrowing in a substantial number of patients. To investigate the mechanisms that limit neointima formation we studied the role of the transcription factor IRF-1, which is a regulator of interferons and a tumor suppressor. We demonstrate that IRF-1 is highly regulated in human vascular lesions and exhibits a growth inhibitory function in coronary artery smooth muscle cells (CASMC). IRF-1 deficient mice display a high grade of susceptibility towards neointima formation following vessel injury. IRF-1 leads to G(1) cell cycle arrest in CASMC and induces the CDK inhibitor p21. In addition, IRF-1 induces NO production, which is known to attenuate endothelial dysfunction. Mitogen-mediated cellular migration is abrogated by IRF-1. In conclusion, IRF-1 displays pleiotropic anti-restenotic activities in vascular restenosis through transcriptional activation of several relevant mechanisms that limit neointima formation. These findings suggest an important role of this transcription factor as an endogenous inhibitor of neointimal growth following vessel injury and it is likely that IRF-1 regulation also plays a role in the pathophysiology of primary atherosclerosis. In addition, IRF-1 may be an interesting target for interventions to prevent neointimal hyperplasia.

Angioplasty, Balloon↗

PubMedDate not supplied

Late constrictive involvement of the pericardium in a case of previous myocarditis.

Constrictive pericarditis (CP) is a highly relevant disease clinically because pericardiectomy represents the only curative therapeutic approach. Previous cardiac surgery or mediastinal radiation may cause CP, however, infectious agents account for a substantial portion of CP. In this report, we present a patient with previous biopsy-proven myocarditis and positive seroconversion against coxsackievirus B3 without clinical evidence of acute pericardial involvement who developed CP after a prolonged period of time. This suggests that infectious particles primarily infecting the myocardium may lead to chronic inflammatory responses of the pericardium, thus causing CP even at late clinical stages. This case emphasizes the important fact that primary myocarditis may not only cause systolic ventricular impairment but may also induce diastolic dysfunction of the heart, either as restrictive cardiomyopathy or, as in this case, through inflammatory involvement of the pericardium, leading to CP.

Antibodies, Viral↗