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Shafie Fazel

Publications and source records attributed to Shafie Fazel.

At least 19 recordsLinked to original sources
PubMed2006

c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes.

Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2), a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE(2) biosynthesis. In neonatal cardiomyocytes, interleukin-1beta and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE(2) release induced by interleukin-1beta or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1(-/-) or jnk2(-/-) mice. In contrast, infection of jnk1(-/-) cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2(-/-) cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE(2) release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE(2) biosynthesis by cardiomyocytes.

Animals↗
PubMed2005

Cell transplantation preserves matrix homeostasis: a novel paracrine mechanism.

OBJECTIVES: Cell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation. METHODS: Smooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (14C-proline uptake). RESULTS: Left ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% +/- 42% of CON, P = .02; TIMP-3, 118% +/- 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% +/- 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% +/- 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation. CONCLUSIONS: These data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis.

Animals↗
PubMed2005

Cell transplantation preserves cardiac function after infarction by infarct stabilization: augmentation by stem cell factor.

OBJECTIVE: We hypothesized that implantation of adult mesenchymal stem cells after acute myocardial infarction mobilizes bone marrow precursor cells by activating the stem cell factor pathway, and that overdriving this pathway would enhance the beneficial effects of cell transplantation. METHODS: After coronary ligation, medium, mesenchymal stem cells, or stem cell factor-overproducing mesenchymal stem cells were injected into the anterior left ventricle. Cells from beta-galactosidase transgenic mice enabled tracking of injected cells. The global and local impact of the cells was evaluated by measuring cytokine levels, endothelial progenitor cells, and myocardial angiogenesis, and by addressing cardiomyogenesis with confocal microscopy. The impact on cardiac function was evaluated by pressure-volume loops. Ventricular morphometrics were measured after in situ perfusion-fixation of the hearts at physiologic pressures. RESULTS: Implantation of mesenchymal stem cells increased myocardial stem cell factor levels 2.0-fold, endothelial progenitor cell mobilization 2.7-fold, and myocardial angiogenesis 2.3-fold (P < .05), but did not induce mitogenesis in host cardiomyocytes or give rise to beta-galactosidase-expressing cardiomyocytes. Cell-transplanted groups had improved indices of cardiac function, including preload recruitable stroke work and end-systolic elastance (P < .001). Cell transplantation resulted in 2.0-fold smaller ventricular volumes (P = .001) and 2.0-fold reduced infarct scar area (P = .056), but had no effect on the volume of spared myocardium. Stem cell factor overproduction imparted greater functional benefit without inducing detectable histologic cardiomyocyte regeneration. CONCLUSION: Mesenchymal stem cell implantation after myocardial infarction facilitates functional cardiac regeneration without myocyte regeneration through augmentation of endogenous infarct repair, which is enhanced by stem cell factor.

Animals↗
PubMed2005

Cardiac restoration: frontier or fantasy?

Heart failure is reaching epidemic proportions in Canada. The current medical and surgical therapies are inadequate to restore cardiac function. Increasingly, cell therapy has been investigated as a novel approach to regenerate the heart and to restore function. Animal studies have been promising and clinical trials are proceeding. Early results suggest that cell therapy may be efficacious in humans as well, but adverse events have been noted. Although the optimal cell type, mode of delivery and ideal patient population have not been identified, the bulk of the evidence suggests that both cardiologists and cardiac surgeons will use cellular therapy to treat heart failure in the future.

Animals↗
PubMed2005

Current status of cellular therapy for ischemic heart disease.

Cellular therapy for acute myocardial infarction and ischemic cardiomyopathy has entered clinical trials across the globe. Early promising results have now provided the justification for larger randomized and blinded trials to address the efficacy of cellular therapy. A variety of fresh or cultured autologous cells have been delivered by catheter-guided endocardial, catheter-guided intracoronary, catheter-guided transvenous, and direct epicardial routes. This review will summarize the clinical data and highlight salient basic science data that support the ongoing efforts to identify the optimal cellular therapy both for acute myocardial infarction and chronic ischemic cardiomyopathy patients.

Bone Marrow Cells↗
PubMed2005

Heart cell implantation after myocardial infarction.

In the last 15 years, heart cell implantation to regenerate infarcted myocardium has gone from the bench to clinical trial. Several phase I and II controlled randomized trials showed the feasibility, the side effects and the potential efficacy of cell implantation after myocardial infarction in humans. Preclinical experiments investigating the mechanisms of heart function improvement after cell implantation showed controversial results regarding implanted cell differentiation into cardiomyocytes and highlighted other effects including neovascularization and modifications of the extra cellular matrix remodelling. Ongoing clinical and experimental studies should pave the way for cell implantation to become a therapeutic option to prevent and treat post-myocardial infarction congestive heart failure in a near future.

Animals↗
PubMed2005

Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy.

We evaluated the impact of donor age on the efficacy of myocardial cellular therapy for ischemic cardiomyopathy. Characteristics of smooth muscle cells (SMC), bone marrow stromal cells (MSCs), and skeletal muscle cells (SKMCs) from young, adult, and old rats were compared in vitro. Three weeks after coronary ligation, 3.5 million SMCs (n = 11) or MSCs (n = 9) from old syngenic rats or culture medium (n = 6) were injected into the ischemic region. Five weeks after implantation, cardiac function was assessed by echocardiography and the Langendorff apparatus. In the in vitro study, the numbers and proliferation of MSCs from fresh bone marrow and SKMCs from fresh tissue but not SMCs were markedly diminished in old animals (P < 0.05 both groups). SKMCs from old animals did not reach confluence. After treatment with 5-azacytidine (azacitidine), the myogenic potential of old MSCs was decreased compared with young MSCs. In the in vivo study, both SMC and MSC transplantation induced significant angiogenesis compared with media injections (P < 0.05 both groups). Transplantation of SMCs but not MSCs prevented scar thinning (P = 0.03) and improved ejection fraction and fractional shortening (P < 0.05). Load-independent indices of cardiac function in a Langendorff preparation confirmed improved function in the aged SMC group (P = 0.01) but not in the MSC group compared with the control group. In conclusion, donor age adversely impacts the efficacy of cellular therapy for myocardial regeneration and is cell-type dependent. SMCs from old donors retain their ability to improve cardiac function after implantation into ischemic myocardium.

Aging↗
PubMed2004

Invited commentary.

Explore the source record for details and available documents.

Coronary Artery Bypass, Off-Pump↗
PubMed2004

Neovascularization derived from cell transplantation in ischemic myocardium.

Myocardial ischemia triggers a limited angiogenic response, part of the remodeling process that is insufficient to avoid further functional impairment. Several strategies have been evaluated to regenerate myocardial vascularization after ischemic injury such as transmyocardial laser revascularization and gene therapy. Attention has recently been focused on the potential of cell therapy to induce angiogenesis. Enhancing myocardial neovascularization is a major goal of myocardial cell transplantation because it would provide patients, who cannot undergo conventional revascularization, with an alternative therapy. Additionally, neovascularization would provide the implanted cells with adequate microenvironment to enhance survival and function. This short review gives an overview of the effect of various cell transplantation strategies on myocardial neovascularization. It suggests that in order to optimize myocardial neovascularization induced by cell therapy, future experiments should focus on the contribution of exogenous and endogenous stem cells to new vessels formation, and on the identification of the molecular pathways involved in the process.

Animals↗
PubMed2003

Radial artery use is safe in patients with moderate to severe left ventricular dysfunction.

BACKGROUND: Using radial artery grafts in patients with moderate to severe left ventricular dysfunction (LVD; ejection fraction < 35%) has been discouraged for the fear that postoperative vasopressor support may cause graft spasm and lead to ischemic complications. We, therefore, examined the safety of radial grafts in aortocoronary bypass (ACB) patients with LVD. METHODS: Data were collected from 5,455 patients who underwent isolated ACB between January 1995 and September 2001. One thousand eight hundred three patients received a radial artery graft (RadACB), and 3,652 patients did not (NoRadACB). Three hundred seven RadACB, and 819 NoRadACB operations were performed in LVD patients. A matched (age, sex, urgency of operation, diabetes, and renal insufficiency) cohort analysis was performed in LVD patients. Univariate and logistic regression analyses were performed in the entire population and the unmatched RadACB and NoRadACB patient subgroups to examine the effect of radial artery use on postoperative death or myocardial infarction rate. RESULTS: The matched cohort analysis revealed a similar rate of death or myocardial infarction (RadACB, 11 of 242 patients; NoRadACB, 16 of 242 patients; p = 0.32). Left ventricular dysfunction was associated with a higher rate of death or myocardial infarction in both unmatched groups (RadACB, odds ratio, 2.36; 95% confidence interval, 1.38 to 4.58; p = 0.004; NoRadACB, odds ratio, 1.62; 95% confidence interval, 1.18 to 2.24; p < 0.001) and in the entire population (odds ratio, 1.77; 95% confidence interval, 1.32 to 2.35; p = 0.003). An interaction term for patients with LVD and a radial artery graft, which was forced into the logistic regression model for the entire population, was not predictive of death or myocardial infarction (odds ratio, 1.52; 95% confidence interval, 0.75 to 3.10; p = 0.25). CONCLUSIONS: Left ventricular dysfunction carries similar risk for postoperative death or myocardial infarction in RadACB and NoRadACB patients. The presence of LVD in isolation is not a contraindication to the use of radial grafting.

Aged↗
PubMed2002

Early experience with robotically assisted internal thoracic artery harvest.

We sought to determine the efficacy of using robotic assistance to facilitate endoscopic harvesting of internal thoracic arteries (ITAs). A total of 104 patients had ITAs harvested endoscopically with use of both the AESOP 3000 system (Computer Motion, Goleta, CA, U.S.A.) and Zeus robotic telesurgical system (Computer Motion). All ITAs were harvested with a harmonic scalpel (Ethicon Endosurgery, Cincinnati, OH, U.S.A.). With the left lung collapsed, ITAs were harvested with CO2 insufflation through three 5-mm ports in the left chest. All patients tolerated insufflation without hemodynamic compromise. Average ITA harvest time was 61.3 +/- 20.9 minutes. Intraoperative graft flows averaged 36.3 +/- 22.4 mL/min. There were three distal ITA injuries; all other vessels were patent after harvesting and demonstrated no angiographic evidence of injury. This article demonstrates a technique by which ITA can be safely harvested totally endoscopically with use of computer-enhanced robotic systems and a harmonic scalpel, allowing complete pedicle dissection through 5-mm ports with minimal ITA manipulation.

Aged↗
PubMedDate not supplied

Contemporary trends in aortic valve surgery: a single centre 10-year clinical experience.

The purpose of this study is to present a comprehensive profile of the trends in aortic valve replacement at a single institution over the past decade. Prospectively collected data concerning 873 patients undergoing aortic valve replacement (AVR), with and without coronary artery bypass grafting (CABG), were analysed. The patients were divided into three time periods: period I, (1990 to 1993); period II, (1994 to 1996); and period III, (1997 to 2000). Actuarial survival of AVR patients with and without CABG at 7 years was 82.9 +/- 2.4% and 79.1 +/- 3.3% (p = 0.17), respectively. Actuarial survival at 7 years for stentless, mechanical, and stented valve patients were 89.5 +/- 2.7%, 85.5 +/- 2.8%, and 76.0 +/- 3.2%, respectively. There was a significant difference in survival between the stentless and stented valve groups (p = 0.014). Age (63.8 +/- 12.9 yrs, 66.2 +/- 11.0 yrs, 67.9 +/- 10.3 yrs; p = 0.01), the incidence of peripheral vascular disease (5.1%, 10.8%, 16.6%; p = 0.001), and the extent of coronary artery disease necessitating CABG (34.0%, 38.8%, 41.0%; p = 0.05) have increased significantly in the later time period. However, operative mortality has remained constant (4.7%, 4.8%, 4.5%; p = 0.9). Moreover, perioperative complications have decreased significantly (27.4%, 18.0, 16.0%; p = 0.001). Multivariate analysis identified more recent time period as independent protective factor for early mortality and morbidity (period I, RR 1.00; period II, RR 0.47; period III, RR 0.40).

Aged↗