Images in cardiology: diffuse aneurysmal disease.
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Aged↗
Biomedical subjects
Ramtin Agah
Publications and source records attributed to Ramtin Agah.
Transforming growth factor beta 1 induces neointima formation through plasminogen activator inhibitor-1-dependent pathways.
OBJECTIVE: The mechanisms through which transforming growth factor (TGF)-beta1 promotes intimal growth, and the pathways through which TGF-beta1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-beta1-induced intimal growth. METHODS AND RESULTS: Adenovirus-mediated overexpression of TGF-beta1 in uninjured carotid arteries of wild-type mice induced formation of a cellular and matrix-rich intima. Intimal growth appeared primarily due to cell migration and matrix accumulation, with only a negligible contribution from cell proliferation. Overexpression of TGF-beta1 also stimulated expression of plasminogen activator inhibitor type 1 (plasminogen activator inhibitor [PAI]-1) in the artery wall. To test the hypothesis that PAI-1 is a critical downstream mediator of TGF-beta1-induced intimal growth, we transduced carotid arteries of PAI-1-deficient (Serpine1(-/-)) mice with the TGF-beta1-expressing vector. Overexpression of TGF-beta1 in Serpine1(-/-) arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-beta1-transduced arteries of Serpine1(-/-) mice secreted 6- to 10-fold more TGF-beta1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-beta1-expressing vector. CONCLUSIONS: PAI-1 is both a critical mediator of TGF-beta1-induced intimal growth and a key negative regulator of TGF-beta1 expression in the artery wall.
Adenoviridae↗
In vivo expression of a conditional TGF-beta1 transgene: no evidence for TGF-beta1 transgene expression in SM22alpha-tTA transgenic mice.
Transforming growth beta-1 (TGF-beta1) appears to play a critical role in the regulation of arterial intimal growth and the development of atherosclerosis. TGF-beta1 is expressed at increased levels in diseased arteries; however, its role in disease development remains controversial. Experiments in which TGF-beta1 is overexpressed in the artery wall of transgenic mice could clarify the role of TGF-beta1 in the development or prevention of vascular disease. However, constitutive overexpression of a TGF-beta1 transgene in the mouse artery wall is embryonically lethal. Therefore, to overexpress TGF-beta1 in the artery wall of adult mice, we generated mice that were transgenic for a conditional, tetracycline operator (tetO)-driven TGF-beta1 allele. These mice were viable, and when crossed with mice expressing a tetracycline-regulated transactivator (tTA) in the heart, expressed the TGF-beta1 transgene in a cardiac-restricted and doxycycline-dependent manner. Nevertheless, breeding of the tetO-TGF-beta1 transgene into three lines of mice transgenic for a smooth muscle-targeted tTA (SM22alpha-tTA mice; reported elsewhere to transactivate tetO-driven alleles in smooth muscle cells of large arteries) did not yield expression of the TGF-beta1 transgene. Moreover, tTA expression was not detected in aortae of the SM22alpha-tTA mice. Transgenic mice that express tTA at high levels in vascular smooth muscle and reliably transactivate tetO-driven transgenes would be useful for deciphering the role of TGF-beta1 (or other proteins) in normal arterial physiology and in the development of arterial disease. Currently available SM22alpha-tTA mice were not useful for this purpose. Generation of higher-expressing lines of SM22alpha-tTA mice appears warranted.
Alleles↗
Regulated transgene expression in vascular smooth muscle.
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Animals↗
Comparison of the safety and efficacy of emboli prevention devices versus platelet glycoprotein IIb/IIIa inhibition during carotid stenting.
Distal embolization is the main potential risk of carotid stenting, and techniques to minimize this risk are evolving. Between July 1998 and March 2002, 305 consecutive patients who underwent elective or urgent percutaneous carotid intervention at The Cleveland Clinic were prospectively followed. During this period, the clinical practice of carotid stenting evolved from the routine use of glycoprotein IIb/IIIa inhibitors (GPIs) to routine emboli-prevention device (EPD) placement. A total of 199 patients received adjunctive GPIs (91% abciximab), and 106 patients underwent the procedure with an EPD (85% filter design, 15% occlusive balloon). At 30 days, the composite end point of neurologic death, nonfatal stroke, and major bleeding, including intracranial hemorrhage, was significantly lower among patients treated with EPDs compared with those treated with GPIs (0% vs 5.1%, p = 0.02). EPDs may provide an overall safer and more effective means of neuroprotection during carotid stenting than GPIs.
Abciximab↗
Creation of a large-scale genetic data bank for cardiovascular association studies.
BACKGROUND: A prerequisite for undertaking genetic association studies is the need for a genetic data bank with adequate DNA samples and a well-described clinical cohort. METHODS: We initiated a prospective single-center study enrolling 6,273 patients referred for cardiac catheterization in a genetic data bank (with eventual goal of 10,000 enrollees). Using a prescreening tool, the patients had comprehensive clinical phenotyping, including angiogram, electrocardiogram, echocardiogram, clinical history, and medication profile (Appendix A). Along with this clinical information, DNA, serum, plasma, basic metabolic panel, inflammation, and lipid panel were collected and stored in the database. RESULTS: Mean age of the patients enrolled was 64 +/- 12 years; 69% are men, 26% have diabetes, 79% have dyslipidemia, and 72% have coronary artery disease (CAD) > or = 50%. We undertook extensive quality-control measures to ensure the validity of both the clinical and DNA samples acquired into our GenBank. As part of this validation, we undertook a genetic association study to discern the effect of the apoE4 polymorphism on the risk for atherosclerosis. We are able to show that the apoE4 polymorphism is an independent risk factor for CAD. CONCLUSIONS: We have been able to create a large-scale genetic data bank as a resource to undertake genetic association studies. Key elements in implementation of this GenBank and baseline characteristics of our patient cohort are summarized. Lastly, as a "proof of concept" for the utility of this resource to discern gene variants associated with disease, we validated apoE4 polymorphism as an independent risk factor for CAD.
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LightTyper platform for high-throughput clinical genotyping.
DNA sequence variations due to single nucleotide changes or polymorphisms (SNPs) have demonstrated an association with certain diseases as causative agents or surrogate biomarkers. Identification and genotyping of SNPs requires reliable and robust technologies. Multiple genotyping platforms are available to detect SNPs. Although many of these platforms meet the requirements of the research environment, technologies have also emerged for high-throughput clinical genotyping as well. The LightTyper is one such platform, providing SNP identification by employing melting curve analysis of fluorescently labeled probes. The LightTyper has been used to identify SNPs associated with myocardial infarction, developing and validating assays for approximately 100 SNPs in 30 candidate genes. The LightTyper is also amenable to the use of assays already developed for the LightCycler, which is widely used in clinical laboratories. The initial experience presented here suggests the potential use of the LightTyper for high-throughput clinical genotyping.
Animals↗
Genetic testing for coronary heart disease: the approaching frontier.
The prospect for genetic testing to better delineate the risk for coronary heart disease will become a reality in the next decade. Advances in this area will follow the accelerated trajectory in our ability to dissect the genetics of complex diseases including coronary heart disease. A brief overview of the present state of knowledge will follow the discussion of present approaches in discovering these genetic predispositions. The key issues that will likely shape the field in the near future will also be presented.
Arteriosclerosis↗