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Biomedical subjects

R D Simari

Publications and source records attributed to R D Simari.

At least 37 records · Page 2Linked to original sources
PubMed1998

Clinical outcomes after successful percutaneous coronary angioplasty of saphenous vein graft disease and the importance of long-term assessment.

We examined the short- and long-term outcome of 327 patients at Mayo Clinic who had undergone coronary angioplasty of saphenous vein graft stenoses to determine whether the traditional 6-month assessment of clinical end points after coronary angioplasty is as useful as it is for patients who have had angioplasty of native vessel disease. Follow-up over 3.3+/-2.7 years was performed. At 6 months, 96+/-1% of the patients were alive, whereas at the 1- and 5-year end points, survival had deteriorated to 92+/-2 and 67+/-3%, respectively. Only 80+/-2% were free of severe angina at 6 months and 62+/-3 and 36+/-3% after 1 and 5 years. Combined event-free rate for death, Q-wave myocardial infarction or repeat coronary artery bypass surgery was 86+/-2% at 6 months, 78+/-2% at 1 year, and 45+/-4% at 5 years. Independent predictors of mortality included advancing age, diabetes mellitus, target vein grafts >5 years old and left ventricular ejection fraction <40%. In conclusion, despite reasonable 6- to 12-month outcomes following vein graft angioplasty, significant attrition in survival and event-free survival was observed. These observations have important implications for the interpretation of results of trials comparing conventional angioplasty and coronary bypass surgery with newer interventional devices if only the traditional 6-month follow-up interval is used.

Aged↗
PubMed1998

Nonviral vector-mediated thymidine kinase gene transfer and ganciclovir treatment in leiomyoma cells.

OBJECTIVE: To test the hypotheses that ganciclovir is cytotoxic to leiomyoma cells transfected with herpes simplex virus thymidine kinase and that estrogen modulates the responsiveness of tumor cells to this gene therapy approach. METHODS: Human and rat cultured uterine leiomyoma cells were transfected with plasmids encoding the beta-galactosidase gene, thymidine kinase gene, or a control plasmid. Transfection efficiency was monitored by measuring beta-galactosidase enzyme activity. Ganciclovir cytotoxicity in thymidine kinase-transfected cells was assessed by monitoring cell viability using trypan blue exclusion. The "bystander effect," a phenomenon in which thymidine kinase-expressing cells exposed to ganciclovir are toxic to adjacent thymidine kinase-nonexpressing cells, was assessed when thymidine kinase vector-transfected cells were cocultured with control plasmid-transfected cells at various percentages before exposure to ganciclovir. The effect of estradiol on ganciclovir-thymidine kinase-mediated cytotoxicity was assessed in estrogen-responsive rat leiomyoma cells. RESULTS: A thymidine kinase-ganciclovir-mediated "bystander effect" was demonstrated, with 48.6% (human) and 65.6% (rat) cell death when 5% of the leiomyoma cells were transfected with the pNGVL1-tk vector, with 0.84% and 1.9% of the cells expected to express thymidine kinase as based on the 16.7% and 39.8% transfection efficiency determined by the reporter gene assay in human and rat leiomyoma cells, respectively. Estradiol promoted cell growth and enhanced the "bystander effect" in rat leiomyoma cells. CONCLUSION: These findings demonstrate the feasibility of using thymidine kinase gene therapy as a novel treatment for uterine leiomyomas. The effect of estrogen may provide a mechanism to enhance the tumor-suppressive effect of this approach.

Animals↗
PubMed1998

Autocrine role for the endothelin-B receptor in the secretion of adrenomedullin.

Adrenomedullin, originally discovered in human pheochromocytoma, is a vasodilating and natriuretic peptide of vascular endothelial and smooth muscle cell origin. Although endothelin-1 (ET-1) has been implicated as a vasoconstricting and growth-promoting peptide of endothelial origin, it may more importantly function as an autocrine factor and release vasodilatory substances such as nitric oxide by mechanisms linked to the endothelin-B (ETB) receptor subtype. The present study was designed to establish that the ETB receptor stimulates the secretion of adrenomedullin from cultured canine aortic endothelial cells. We first sought to determine the presence and production of adrenomedullin in canine aortic endothelial cells using immunohistochemistry and Northern blot analysis, which revealed that adrenomedullin immunoreactivity and adrenomedullin mRNA were present in canine aortic endothelial cells. Second, adrenomedullin was time-dependently secreted from canine aortic endothelial cells, with a secretion rate of 15.7+/-1.5 pg/10(5) cells per 24 hours. Furthermore, immunohistochemistry revealed the presence of the ETB receptor in canine aortic endothelial cells, and ETB receptor stimulation by sarafotoxin S6c increased adrenomedullin production and secretion from canine aortic endothelial cells. Such actions were blocked with the ETB receptor antagonist IRL-2500 but not with ETA receptor antagonist FR-139317. These studies are the first to report an additional autocrine role of the ETB receptor in the release of vasodilating and natriuretic peptide adrenomedullin, and they suggest another important vasoactive system regulated by the ET receptor subtype.

Adrenomedullin↗
PubMed1998

Requirements for enhanced transgene expression by untranslated sequences from the human cytomegalovirus immediate-early gene.

BACKGROUND: The cytomegalovirus immediate early (CMV IE) promoter has been widely used for heterologous expression. Further enhancements of gene expression from this potent promoter may allow for the development of improved gene transfer strategies. We aimed to determine whether inclusion of the first exon (5' untranslated) and first intron of the CMV IE gene would increase heterologous transgene expression in primary target cells and to determine the sequences required for any observed increases. MATERIALS AND METHODS: Comparisons of reporter gene expression were made following transient transfection of vascular smooth muscle cells (VSMCs) with plasmids containing the first exon and intron from the CMV IE gene or deletional mutations. Comparisons were also made using a heterologous promoter (RSV). RESULTS: Gene expression from the CMV IE promoter was increased 5.7-fold in VSMC with the inclusion of the first exon and intron. Similar increases were seen with other target cells and from the heterologous RSV promoter. This increase was associated with an increase in steady-state mRNA. Deletion analyses demonstrated that the enhancement was dependent on the presence of the 5' portion of the first exon while deletion of large segments within the intron was associated with similar levels of expression compared with the parental plasmid. CONCLUSIONS: Inclusion of the first exon and intron from the CMV IE gene increases expression from the CMV IE promoter. This enhancement is seen with the heterologous RSV promoter and is associated with an increase in steady-state mRNA. Deletion analyses suggest that this enhancement is associated with inclusion of sequences within the 5' portion of the first exon and inclusion of an intron.

Animals↗
PubMed1997

Enhanced angiogenesis and unfavorable remodeling in injured porcine coronary artery lesions: effects of local basic fibroblast growth factor delivery.

There is interest in the role of growth factors in the genesis of arterial remodeling. We studied local administration of basic fibroblast growth factor (bFGF) to coronary lesions to determine whether there is a difference in remodeling and whether neovascularization could be induced in such stenoses and distal myocardium. Pigs were randomized to balloon infusion of either saline or bFGF at each thermally injured arterial site. After the animals were killed, their internal elastic lamina, neointima, and lumen areas were measured. Capillaries were counted in the arteries and myocardium. There was a greater loss of lumen and internal elastic in the bFGF group. The neointima, media, and myocardium in the bFGF treated arteries had statistically more capillaries. This study showed that local intracoronary bFGF, at a dose that results in arterial luminal revascularization in injured segments, adversely affects arterial remodeling. Thus, the angiogenic response to exogenous bFGF may be offset by concomitant shrinkage of injured arterial segments.

Animals↗
PubMed1996

A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo.

An important goal of gene therapy for cardiovascular diseases and cancer is the development of effective vectors for catheter-based gene delivery. Although adenoviral vectors have proven effective for this purpose in animal models, the ability to achieve comparable gene transfer with nonviral vectors would provide potentially desirable safety and toxicity features for clinical studies. In this report, we describe the use of a new cationic DNA-liposome complex using an improved expression vector and lipid, N-(3-aminopropyl)-N, N-dimethyl-2,3-bis(dodecyloxy)-1-propaniminium bromide/dioleyl phosphatidylethanolamine (GAP-DL-RIE/DOPE) to optimize catheter-mediated gene transfer in porcine arteries. The efficiency of this vector was compared to DNA alone, DNA with a previously described cationic liposome complex, (+/-)-N-(2-hydroxyethyl)-N, N-dimethyl-2,3-bis(tetradecyloxy)-1-propanaminium bromide (DMRIE/DOPE), and a replication-defective adenoviral vector in a porcine artery gene transfer model. When used in optimal ratios, GAP-DL-RIE/DOPE liposomes provided a 15-fold higher level of gene expression in arteries compared to DNA alone or DMRIE/DOPE. Gene expression was observed in intimal and medial cells. However, when compared to adenoviral vectors (10(10) pfu/ml), gene expression following GAP-DLRIE/DOPE transfection was approximately 20-fold lower. Following intravenous injection of GAP-DLRIE/DOPE in mice, biochemical, hematological, and histopathological abnormalities were not observed. Significant improvements in the efficacy of arterial gene expression can be achieved by optimization of transfection condition with DNA-liposome complexes in vivo that may prove useful for arterial gene delivery in cardiovascular diseases and cancer.

Animals↗
PubMed1996

Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury.

Arterial injury induces a series of proliferative, vasoactive, and inflammatory responses that lead to vascular proliferative diseases, including atherosclerosis and restenosis. Although several factors have been defined which stimulate this process in vivo, the role of specific cellular gene products in limiting this response is not well understood. The p21 cyclin-dependent kinase inhibitor affects cell cycle progression, senescence, and differentiation in transformed cells, but its expression in injured blood vessels has not been investigated. In this study, we report that p21 protein is induced in porcine arteries following balloon catheter injury and suggest that p21 is likely to play a role in limiting arterial cell proliferation in vivo. Vascular endothelial and smooth muscle cell growth was arrested through the ability of p21 to inhibit progression through the G1 phase of the cell cycle. Following injury to porcine arteries, p21 gene product was detected in the neointima and correlated inversely with the location and kinetics of intimal cell proliferation. Direct gene transfer of p21 using an adenoviral vector into balloon injured porcine arteries inhibited the development of intimal hyperplasia. Taken together, these findings suggest that p21, and possibly related cyclin-dependent kinase inhibitors, may normally regulate cellular proliferation following arterial injury, and strategies to increase its expression may prove therapeutically beneficial in vascular diseases.

Adenoviridae↗
PubMed1996

Regulation of cellular proliferation and intimal formation following balloon injury in atherosclerotic rabbit arteries.

Injury to atherosclerotic arteries induces the expression of growth regulatory genes that stimulate cellular proliferation and intimal formation. Intimal expansion has been reduced in vivo in nonatherosclerotic balloon-injured arteries by transfer of genes that inhibit cell proliferation. It is not known, however, whether vascular cell proliferation can be inhibited after injury in more extensively diseased atherosclerotic arteries. Accordingly, the purpose of this study was to investigate whether expression of recombinant genes in atherosclerotic arteries after balloon injury could inhibit intimal cell proliferation. To test this hypothesis, we examined the response to balloon injury in atherosclerotic rabbit arteries after gene transfer of herpesvirus thymidine kinase gene (tk) and administration of ganciclovir. Smooth muscle cells from hyperlipidemic rabbit arteries infected with adenoviral vectors encoding tk were sensitive to ganciclovir, and bystander killing was observed in vitro. In atherosclerotic arteries, a human placental alkaline phosphatase reporter gene was expressed in intimal and medial smooth muscle cells and macrophages, identifying these cells as targets for gene transfer. Expression of tk in balloon-injured hyperlipidemic rabbit arteries followed by ganciclovir treatment resulted in a 64% reduction in intimal cell proliferation 7 d after gene transfer (P = 0.004), and a 35-49% reduction in internal area 21 d after gene transfer, compared with five different control groups (P < 0.05). Replication of smooth muscle cells and macrophages was inhibited by tk expression and ganciclovir treatment. These findings indicate that transfer of a gene that inhibits cellular proliferation limits the intimal area in balloon-injured atherosclerotic arteries. Molecular approaches to the inhibition of cell proliferation in atherosclerotic arteries constitute a possible treatment for vascular proliferative diseases.

Adenoviridae↗
PubMed1996

A proliferation analysis of arterial neointimal hyperplasia: lessons for antiproliferative restenosis therapies.

Medial smooth muscle cell proliferation is frequently implicated as the major cause of coronary restenosis. Although antiproliferative agents have shown efficacy in animal studies, they are ineffective in human trials. To better understand these discrepancies, we performed a mathematical kinetic analysis of cellular proliferation in the neointimal hyperplasia of rats, pigs, and patients. A model was derived using a differential expression for proliferation, proportional to the number of cells present. Additional terms were included for inhibition of proliferation proportional to neointimal mass and time. The resulting equation was solved in closed form for the number of cells and proliferation rate. These equations were validated in the rat carotid artery injury model from published data. The model was then applied to the porcine coronary injury model, and then to clinical data obtained from angiographic human studies. Peak cellular proliferative activity in patients occurs at 16 days and continues at lower levels for much longer periods of time. Less than 10 generations of cells are sufficient to develop clinically significant restenosis. Conversely, proliferation rates in the two animal models (rats and pigs) are maximal at roughly 2 and 6 days, respectively, also continuing at low levels for extended time periods. Cell proliferation in restenosis is a highly controlled process, with comparatively few cell generations causing enough neointima for arterial obstruction to occur. Substantial cell kinetic differences occur across species. The rat exhibits high proliferation rates and rapid doubling times compared to patients and pigs, and is thus a highly 'proliferative' model. Such differences may be responsible for discrepant animal model and clinical trial results. These data may help determine the timing and strategy of therapy against clinical restenosis.

Animals↗
PubMed1996

Genetic therapy.

Vascular gene transfer is the introduction of foreign DNA into host cells within the vessel wall. Expression of recombinant genes within vascular cells has been demonstrated in normal, injured and atherosclerotic arteries. Transfer of genes with biological activity has provided insights into the role of specific genes in normal and pathological states. The development of gene transfer as a form of vascular therapy will require safe and effective vectors and intravascular delivery systems. Viral and non-viral vectors and several delivery catheters are being evaluated to determine their clinical applicability. The current applications of vascular gene transfer to cardiovascular diseases are the prevention of restenosis following arterial injury and induction of angiogenesis in occlusive vascular disease.

Animals↗
PubMed1996

Gene transfer approaches to the regulation of vascular cell proliferation.

Considerable progress has been made in identifying potential targets for treating vascular proliferative diseases. In this review, we discuss gene transfer approaches to regulating smooth muscle cell proliferation after vascular injury using the cell cycle specific proteins, p21, delta Rb and HSV-tk. Results from these studies suggest that replicating smooth muscle cells and macrophages are inhibited in vivo in several animal models of restenosis, including hyperlipidaemic vessels. Identification of appropriate vascular diseases and improvements in gene delivery and vectors will require careful optimization in order to develop effective molecular therapies for human vascular diseases.

Animals↗
PubMed1995

A novel approach to the placement of Palmaz-Schatz biliary stents in saphenous vein grafts.

The placement of Palmaz-Schatz biliary stents has become a successful method to treat stenoses in large saphenous vein grafts. Unlike coronary stents, the biliary stents are not routinely delivered with a selective delivery sheath and may be more difficult to deliver and prone to detachment from the balloon and even embolization during delivery. In order to enhance the ability to deliver these stents, a guide-within-a-guide system was developed. A 7F guiding catheter was used as a selective delivery sheath within a standard guiding catheter. Nineteen biliary stents were successfully placed in vein grafts in 15 patients using this system. One procedure was complicated by an embolic event documented angiographically following intragraft delivery of urokinase but prior to stent implantation.

Aged↗
PubMed1994

Coronary angioplasty in acute myocardial infarction: primary, immediate adjunctive, rescue, or deferred adjunctive approach?

OBJECTIVE: To address the current clinical applications, outcomes, and limitations of coronary angioplasty in the setting of acute myocardial infarction. DESIGN: We review the results of several large trials in which various strategies of thrombolysis and primary, immediate adjunctive, rescue, or deferred adjunctive coronary angioplasty were used in patients with acute myocardial infarction. MATERIAL AND METHODS: Four strategies for the utilization of angioplasty in myocardial infarction have been developed and are based on the timing and concurrent use of thrombolytic therapy. RESULTS: Primary coronary angioplasty without prior thrombolytic therapy is as effective as thrombolytic therapy for salvaging myocardium. Results of a meta-analysis of recent trials suggest potential benefits of increased survival and decreased reinfarction in comparison with the results of thrombolysis in recent trials. Immediate adjunctive angioplasty after thrombolytic therapy has been tested in three large, randomized trials. The results suggest that this strategy is associated with increased risks without benefits of increased survival or improved left ventricular function. Rescue angioplasty may be helpful after failed thrombolytic therapy. Ongoing randomized trials might further clarify the benefits of rescue angioplasty. Because of the inherent difficulty in the noninvasive identification of patients with persistent reocclusion, diagnostic coronary angiography early after thrombolytic therapy may be necessary. Deferred adjunctive angioplasty during the weeks after infarction to prevent recurrent ischemia was not shown to decrease mortality or reinfarction in two large trials. CONCLUSION: Primary coronary angioplasty is the treatment of choice for patients with contraindications to thrombolytic therapy. Certain high-risk subgroups may also benefit from primary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1992

Ventricular relaxation and myocardial ischemia: a comparison of different models of tau during coronary angioplasty.

This study compares the sensitivity and variability of four models of tau, the time constant of ventricular relaxation, to detect the presence of myocardial ischemia. High fidelity left ventricular pressure recordings were obtained in ten patients undergoing coronary angioplasty at baseline, during balloon inflation, and at recovery. Four models of tau were considered: 1) a semilogarithmic, zero asymptote model (TL), 2) a semilogarithmic model using data from the first 40 ms of isovolumic relaxation (T40), 3) an exponential non-zero asymptote model (TE), and 4) a derivative non-zero asymptote model (TD). TL, T40, and TE increased significantly during inflation and returned to near baseline values at recovery. TD showed no change during inflation. Comparisons of TL, T40, and TE using the derived relaxation half-time (T1/2), failed to reveal significant differences between the models at baseline, during inflation, or at recovery. The non-zero asymptote models were associated with a greater beat-to-beat variability than the semilogarithmic models. Thus, T1/2 using the semilogarithmic zero asymptote models (TL and T40) may be more useful and consistent when measuring the rate of isovolumic relaxation during myocardial ischemia.

Angioplasty, Balloon, Coronary↗
PubMed1992

Percutaneous transluminal coronary angioplasty and the changing indications for coronary artery bypass grafting for single-vessel coronary artery disease.

Patients with single-vessel coronary artery disease have a good long-term prognosis with either medical or surgical therapy. Because percutaneous transluminal coronary angioplasty has become widely available for treating patients with symptomatic single-vessel coronary artery disease, those who currently undergo coronary artery bypass grafting may be a select group. In this study, we examined the effects of the increasing use of percutaneous transluminal coronary angioplasty on the indications for coronary artery bypass grafting in patients with symptomatic single-vessel coronary artery disease and reviewed the type of procedures performed in such patients at our institution between 1983 and 1988. During this period, 115 patients underwent coronary artery bypass grafting for single-vessel coronary artery disease. The indication for revascularization was angina in 111 patients (88% were in class III or IV, Canadian Cardiovascular Society classification), acute myocardial infarction in 3, and a strongly positive result of an exercise test in 1. The number of surgical revascularization procedures annually for single-vessel coronary artery disease remained consistent throughout the study period. In a comparison of the first 3 years of the study with the last 3 years, the number of patients who underwent coronary artery bypass grafting for restenosis after coronary angioplasty increased, but the number who had surgical revascularization because of failure of coronary angioplasty decreased. In addition, more patients received internal mammary grafts during the second half of the study (42 or 72%) than during the first half (24 or 42%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Capabilities of supine exercise electrocardiography versus exercise radionuclide angiography in predicting coronary events.

The ability of supine exercise electrocardiography and exercise radionuclide angiography to predict time to subsequent cardiac events (cardiac death, nonfatal myocardial infarction or late coronary bypass grafting or angioplasty) were compared in 265 patients with normal resting electrocardiograms who were not taking digoxin. All patients had undergone coronary catheterization and were initially treated medically. Follow-up study was performed at a median of 51 months. Separate logistic regression models, which had been previously developed to predict 3-vessel or left main coronary artery disease (CAD), were compared using a Cox regression analysis to predict time to a subsequent cardiac event. The exercise electrocardiography model, consisting of the magnitude of ST depression, exercise heart rate and patient gender, was a powerful predictor (chi-square = 30.8, p less than 0.0001) of subsequent events. The exercise radionuclide angiography model, which included the exercise response of the pressure-volume ratio in addition to the exercise electrocardiography variables, had similar prognostic power (chi-square = 31.8, p less than 0.0001). In a separate analysis considering only cardiac death and nonfatal myocardial infarction, the exercise electrocardiography model remained a significant predictor of events (chi-square = 12.2, p less than 0.001). None of the radionuclide angiography variables added significantly to the prognostic power of the exercise electrocardiography model. Thus, in patients with a normal resting electrocardiogram who are not taking digoxin, the supine exercise electrocardiography model that predicts 3-vessel or left main CAD also predicts future cardiac events. Exercise radionuclide angiography does not provide any additional prognostic information in such patients.

Coronary Disease↗