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Biomedical subjects

R Virmani

Publications and source records attributed to R Virmani.

At least 163 records · Page 9Linked to original sources
PubMed1994

Hyperoxic reperfusion is required to reduce infarct size after intravenous therapy with perfluorochemical (Fluosol-DA 20%) or its detergent component (poloxamer 188) in a poorly collateralized animal model. Absence of a role of polymorphonuclear leukocytes.

OBJECTIVES: The aim of this study was to assess whether hyperoxic reperfusion contributes to the efficacy of Fluosol 20% or poloxamer 188 for infarct size reduction and whether suppression of polymorphonuclear leukocyte function is responsible for cardioprotection. BACKGROUND: The perfluorochemical Fluosol and its detergent component poloxamer 188 limit myocardial reperfusion-induced injury; however, the underlying mechanism(s) are uncertain. METHODS: A series of in vivo and ex vivo studies were performed in a 30-min temporary coronary occlusion rabbit model. Before reperfusion, rabbits received a 25-ml/kg infusion of 1) Fluosol; 2) poloxamer 188 (equivalent % w/v to Fluosol, 675 mg/kg body weight); or 3) 5% dextrose (control). In protocol A, animals were subjected to either normoxic or hyperoxic reperfusion; in protocols B and C, hyperoxic reperfusion was studied. In protocol B, myocardial blood flow was assessed. In protocol C, polymorphonuclear leukocyte function and myocardial myeloperoxidase were determined. RESULTS: In rabbits subjected to normoxic reperfusion, infarct size (normalized to risk region weight) was not significantly different among groups. In rabbits subjected to hyperoxic reperfusion, infarcts were significantly reduced with both poloxamer 188 and Fluosol treatment compared with control animals (p = 0.05 and p = 0.0004, respectively). Blood flow at 3 h of reperfusion within the ischemic endocardium was greater in the Fluosol and poloxamer 188 groups than in the control group (p = 0.001 and p = 0.08, respectively). Myeloperoxidase activity was not affected by treatment, nor was there suppression of polymorphonuclear leukocyte function. CONCLUSIONS: Fluosol and poloxamer 188 reduce infarct size in rabbits subjected to hyperoxic reperfusion. Suppression of polymorphonuclear leukocyte function was not demonstrated, suggesting a greater role for increased arterial oxygen delivery in salvaging ischemic myocardium.

Animals↗
PubMed1994

Adenoviral vector-mediated gene transfer into sheep arteries using a double-balloon catheter.

The potential for catheter-based in vivo delivery of genetic material to the arterial wall is incompletely explored. We evaluated the level of recombinant protein production as well as the anatomic distribution and duration of gene expression following adenoviral vector-mediated gene transfer into sheep arteries via a double balloon catheter. Catheters were positioned in the carotid or femoral arteries of 20 sheep via a combined percutaneous and surgical approach, and virions infused over a 30-min period. Three days later, recombinant gene expression was identified in approximately 30% (range 0-80%) of the luminal endothelial cells within the targeted area of the artery. Persistent recombinant protein expression was identified histochemically for up to 4 weeks, although the number of positive cells decreased steadily. High levels of both beta-galactosidase (beta-Gal) activity and protein (mean 20 mU and 44 ng per vessel) were measured in vessel extracts 3 days after gene transfer, again decreasing significantly over a 4-week period. Transgene expression was limited almost entirely to the intima and adventitia; adventitial gene transfer occurred virtually exclusively along the vasa vasorum. In comparison to previous studies of catheter-based gene transfer, adenoviral vectors delivered by double balloon catheter resulted in a particularly high efficiency of endothelial cell gene transfer. The efficiency and amount of recombinant gene expression achieved in this study suggest that catheter-based gene delivery may eventually be applicable to the treatment of focal human arterial disease.

Adenoviridae↗
PubMed1994

Persistence of replicating coxsackievirus B3 in the athymic murine heart is associated with development of myocarditic lesions.

Coxsackievirus B3 (CVB3)-induced myocarditis was studied in euthymic (nu/+) and athymic (nu/nu) C3H/HeN (H-2k) mice. Mice were inoculated intraperitoneally with 10(6) p.f.u. of CVB3 (Nancy strain) and sacrificed at intervals up to 92 days post-inoculation (p.i.). Viraemia peaked at day 2 to 3 p.i. and ceased at day 5 to 7 p.i. in a synchronized manner in both sets of mice. Very few infectious particles were detected in the blood of nu/nu mice after day 14 p.i. In nu/nu mice, CVB3 persisted in myocardial tissue with constant titres between 2.7 +/- 1.9 x 10(4) and 7.6 +/- 5.2 x 10(4) p.f.u./mg from day 3 to 92 p.i., which were comparable to those of nu/+ mice in the acute phase. In nu/+ mice, the virus was recovered from all animals examined by day 11 p.i. and from three out of 13 mice between days 14 and 21 p.i., yet no virus was recovered from nu/+ mice at day 42 p.i. In nu/nu mice, sense and antisense RNA for CVB3 was detected in the myocardial tissue up to day 42 p.i. by in situ hybridization and up to day 92 p.i. by reverse transcriptase-PCR. Neither sense nor antisense RNA was detected after day 21 p.i. in nu/+ mice with the same techniques. Myocardial tissue damage was analysed morphologically. At day 92 p.i., the area of myocardial injury peaked at 23% of the section in nu/nu mice. In contrast, less than 0.6% of tissue sections contained lesions in nu/+ mice. A neutralizing antibody response to CVB3 was observed in both nu/nu and nu/+ mice. The mean titre of neutralizing antibody was significantly higher at day 21 p.i. in nu/+ mice, but similar at day 42 p.i. with nu/nu and nu/+ mice. Perforin-producing natural killer-like cells, which are considered to play an important role in causing acute myocarditic lesions in immunocompetent mice, were found in the lesions of nu/nu mice persistently infected with CVB3. Prolonged tumour necrosis factor-alpha mRNA synthesis detected in nu/nu mice appears to reflect the continuous activation of macrophages, which extend phagocytic reactions to virus-infected myocytes. These immunological results suggested that the host immune response devoid of antigen-specific T cell function is not sufficient to terminate CVB3 infection in nu/nu mice. Also, it appears that competent cellular immunity, on the whole, plays a role in curing rather than in aggravating myocarditis in nu+mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Anatomic barriers influence the distribution of in vivo gene transfer into the arterial wall. Modeling with microscopic tracer particles and verification with a recombinant adenoviral vector.

We evaluated the extent to which anatomic barriers to vector penetration might influence the distribution of successful in vivo gene transfer into the normal arterial wall. A double-balloon catheter technique with infusion pressures of 100 to 400 mm Hg was used to infuse microscopic tracer particles of the size range of liposomes and viral vectors into normal elastic arteries of sheep. Localization of the tracer particles in tissue sections by light, fluorescence, and electron microscopy suggested that vector-sized particles were delivered to the intima by direct infusion and to the adventitia via the arterial vasa vasorum. Particles were virtually absent from the arterial media. To test the predictions made from the particle studies, we repeated the infusion protocol with high-titer adenoviral vectors. Gene transfer occurred at high levels in the intima and along the adventitial vasa vasorum but again was virtually absent within the media. The ability of medial smooth muscle cells to be transduced was established in separate experiments with a high-pressure (5 atm) porous balloon infusion catheter. We conclude that (1) the anatomy of the normal elastic arterial wall imposes significant limitations on the penetration of particles in the size range of most gene-transfer vectors and (2) the distribution of in vivo gene transfer with adenoviral vectors is correctly predicted by the distribution of inert tracer particles. These findings have important implications for the design of arterial gene-transfer and gene-therapy protocols.

Adenoviridae↗
PubMed1994

Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy.

Animals↗
PubMed1994

Cardiac fibroma: clinicopathologic correlates and surgical treatment.

The clinicopathologic findings of 23 patients with cardiac fibroma are presented. The mean patient age was 13 years, with a range of 1 day to 56 years. The presenting symptoms included heart failure, arrhythmias, sudden death, cyanosis, and chest pain. Some patients had no symptoms, and one patient had Gorlin's syndrome. Echocardiography and magnetic resonance imaging were very sensitive in diagnosis. Nineteen patients underwent tumor resection or biopsy, and four tumors were diagnosed at cardiac transplantation or autopsy on explanted hearts. In five surgical cases, complex operations were necessary, including pericardial or synthetic patches, valve replacement, or coronary artery grafting. Two operative deaths occurred in patients with surgical resections and four operative deaths in patients who at the time of the operation were deemed to have inoperable disease and only biopsy was performed. All deaths but one were in patients younger than 2 years of age. Four patients with subtotal resections did well after the operation. Dense collagen was more frequent in tumors in older patients. We conclude that fibromas are congenital tumors that are frequently discovered in adolescents and adults. Surgical treatment is generally successful, and imaging techniques are helpful in preoperative assessment.

Adolescent↗
PubMed1994

Causes of sudden cardiac death in patients with replacement valves: an autopsy study.

We retrospectively reviewed 52 hearts from patients who had heart valve replacement more than one month prior to death. In 37 cases death was sudden (less than 6 hours after symptoms). These 37 cases were divided as Group I (15 cases, sudden death related to valve prosthesis); and Group II (22 patients, sudden death not related to valve prosthesis). Causes of death in Group I were valve thrombosis (n = 4), embolization of valve thrombi (n = 2), strut fracture (n = 2), anticoagulation-related hemorrhage (n = 2), perivalvular fistula (n = 1) and left ventricular outflow obstruction (n = 1). Causes of death in Group II were presumed arrhythmia in 14, myocardial infarction in six and aortic rupture in two cases. Severe coronary atherosclerosis (> 75% cross-sectional area luminal narrowing) was present in five of 14 cases dying of arrhythmia and in all six cases with myocardial infarction; in the remaining cases, there was marked cardiac hypertrophy (mean weight 728 +/- 177 grams). The mean age (54 +/- 18 vs. 54 +/- 13 years, respectively) was similar in both groups. Seven of 21 deaths after aortic, 6/12 deaths after mitral, 10/25 deaths after mechanical, and 5/11 after porcine valve replacement were secondary to valve complications. The mean left ventricular thickness was 1.7 cm in both groups, the mean left ventricular cavity dimension 2.8 +/- 1.4 cm in Group I vs. 3.5 +/- 1.4 cm in Group II, and the mean heart weight was 550 grams in Group I vs. 734 +/- 211 in Group II (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Sarcomas of the great vessels. A clinicopathologic study.

BACKGROUND: There are few reports comparing the clinicopathologic features of sarcomas of the aorta (SA), sarcomas of the inferior vena cava (SIVC), and sarcomas of the pulmonary artery (SPA). METHODS: The authors retrospectively reviewed 11 SA, 16 SIVC, and 16 SPA, and compared clinical, pathologic, and immunohistochemical findings. RESULTS: The mean age at presentation for SA was 62.3 +/- 17.3 years versus 41.3 +/- 17.1 for SPA; mean age for SIVC was 49.9 +/- 18.8. Nine of 11 SA and 14 of 16 SPA were grossly confined to the lumen, compared with only two SIVC. Luminal sarcomas were classified as poorly differentiated (intimal), angiosarcoma or leiomyosarcoma. Eight SA, 13 SPA, and one SIVC were of the intimal type and were composed of fibroblastic or myofibroblastic cells; five had "storiform" areas typical of malignant fibrous histiocytoma, and all had areas of necrosis. Intimal SPA were more likely myxoid than SA, and osteosarcomatous differentiation was present only in SPA (three cases). Intimal sarcomas were negative for desmin, Factor VIII-related antigen, S-100 protein, and CD34/QBend; all were positive for vimentin and most showed positive cells for smooth muscle actin. One luminal SA and one luminal SPA were histologically typical of angiosarcoma. Two SPA, 2 SA, and 14 SIVC were predominantly mural, most of which were leiomyosarcomas. The mean survival of intimal SA was poor (5 months), compared with 37 months for SIVC and 23 months for intimal SPA. CONCLUSION: SA, SPA, and SIVC differ in their clinical presentation and survival. Most SA and SPA sarcomas are aggressive, probably derived from intimal cells that show myofibroblastic differentiation. SIVC are usually derived from medial smooth muscle and are relatively well differentiated leiomyosarcomas.

Adolescent↗
PubMed1993

Early detection and measurement of experimental myocardial infarcts with horseradish peroxidase.

Current methods of experimental infarct size measurement require tissue analysis several hours after the ischemic event. Electron microscopy identifies irreversibly injured myocytes early after ischemia, but cannot be used to measure myocardial infarct size. Horseradish peroxidase (HRP), a tracer protein that permeates the disrupted sarcolemma of injured myocytes, was used to determine infarct size. New Zealand White rabbits (n = 15) were subjected to 30 min coronary artery occlusion and 24 h reperfusion. Prior to euthanasia, HRP was administered intravenously. The hearts were excised, perfused with triphenyl tetrazolium chloride (TTC), and perfusion fixed. A frozen section was cut from left ventricular slices, and the brown HRP reaction product was developed with 3,3'-diaminobenzidine tetrahydrochloride and H2O2. The areas delineated by intramyocyte HRP (as a percent of the left ventricle) closely correlated with infarct size determined by conventional hematoxylin-eosin (H&E) stain and TTC (means +/- S.E.M.): 29.5 +/- 3.0% vs 27.6 +/- 2.9% vs 28.6 +/- 2.6%, respectively. The coefficient of correlation between HRP and H&E was 0.94. This method was tested for early infarct detection in rabbits subjected to 30 min coronary occlusion followed by intravenous injection of HRP and sacrifice. HRP-delineated infarcts measured 21.4 +/- 3.7% of the left ventricle, and electron microscopic examination from ischemic and non-ischemic areas was used to confirm that cells containing HRP were irreversibly injured. Thus, HRP can be used to accurately measure myocardial infarct size in experimental coronary artery occlusion and reperfusion in infarcts as early as 30 min after coronary occlusion or following 24 h of reperfusion.

Animals↗
PubMed1993

Thermal-perfusion balloon coronary angioplasty: in vivo evaluation.

The goal of this study was to develop and test a new radio frequency thermal balloon system to allow longer balloon inflations at lower temperature levels than have been used with standard (laser) thermal balloon angioplasty. Radio frequency thermal capabilities were combined with perfusion balloon technology, creating a thermal-perfusion balloon catheter system for prolonged thermal inflations. Twenty-five dogs underwent thermal-perfusion angioplasty at 37 degrees, 60 degrees, or 80 degrees C for 1.5, 5, or 15 minutes with angiographic and morphologic assessments at 24 hours (n = 17) or 4-6 weeks later (n = 8). Treated segments and side branches remained patent. No coronary spasm, occlusive thrombus, or ischemic myocardial infarction occurred. Histologic extent of thermal injury in treated segments was proportional to treatment duration. Thus the thermal-perfusion balloon angioplasty system may be safely applied in canine coronary arteries. Integrating thermal and perfusion technologies provides prolonged treatment duration at moderate temperatures without excessive tissue damage.

Anesthesia, General↗
PubMed1993

Myocardial infarct extension during reperfusion after coronary artery occlusion: pathologic evidence.

OBJECTIVES: The goal of this study was to demonstrate myocardial infarct extension during reperfusion within the same animal. BACKGROUND: Whether myocardial reperfusion can result in the extension of myocardial necrosis remains controversial. The transformation of reversibly injured myocytes into irreversibly damaged cells after reperfusion has been difficult to demonstrate pathologically. METHODS: New Zealand White rabbits (Group I, n = 10) were subjected to 30 min of coronary artery occlusion and 180 min of reperfusion. Horseradish peroxidase, a tracer protein that permeates the sarcolemma of irreversibly injured myocytes, was used to quantitate myocyte necrosis at the beginning of reperfusion. Within the same heart, infarct size was measured after 180 min of reperfusion by triphenyltetrazolium chloride (TTC) staining. In separate experiments to demonstrate the validity of the model, rabbits were subjected to 30 min of coronary occlusion, followed by intravenous infusion of horseradish peroxidase and rapid induction of death (Group II) or 30 min of occlusion, 180 min of reperfusion with horseradish peroxidase administered after 180 min of reperfusion and TTC staining after induced death (Group III). RESULTS: In Group I, infarct size at the onset of reperfusion, delineated by horseradish peroxidase, measured 45.3 +/- 2.8% of the area of risk and was significantly less than TTC-delineated infarct size after 180 min of reperfusion (59.8 +/- 3.3%, p = 0.0002). By electron microscopy, border areas within the ischemic bed demonstrated irreversibly injured horseradish peroxidase-positive myocytes adjacent to irreversibly injured horseradish peroxidase-negative myocytes, suggesting that further cell death occurred during reperfusion. In Group II, infarcts delineated by horseradish peroxidase after 30 min of coronary occlusion were similar in size to infarcts measured by this tracer in Group I. In Group III, infarcts delineated by horseradish peroxidase at 180 min of reperfusion were similar in size to infarcts measured by TTC and similar to TTC-delineated infarcts measured at 180 min of reperfusion in Group I. CONCLUSIONS: These results provide evidence that there is a subset of myocytes in border areas within the ischemic region that are viable at the beginning of reperfusion but subsequently progress to irreversible injury during the reperfusion period.

Animals↗
PubMed1993

Nonatherosclerotic narrowing of the atrioventricular node artery and sudden death.

OBJECTIVES: This study was undertaken to determine whether thickening of the atrioventricular (AV) node artery is a cause of sudden cardiac death. BACKGROUND: Thickening of the AV node artery has been implicated as a cause of sudden death primarily on the basis of case reports. Few pathologic studies have compared subjects who died of sudden cardiac death with normal control subjects who died traumatically. METHODS: The AV node artery in 27 patients with unexplained sudden cardiac death (mean age 24.8 +/- 7.4 years) was compared with that in 17 control subjects who died traumatically (mean age 25.6 +/- 7.0 years). No anatomic cause of death was found at autopsy in the subjects with sudden death, all of whom died of presumed cardiac arrhythmias. The conduction system of all hearts was studied by semiserial sections and Movat pentachrome stains. At the point of greatest narrowing of the AV node artery, the outer circumference and lumen outline were traced by computerized morphometry, the ratio of outer vessel area to lumen area was calculated and the histopathologic changes were noted. RESULTS: The rank-sum of ratios was significantly greater in the sudden death group than in the control group (p = 0.031, Wilcoxon rank-sum/Mann-Whitney statistic). A dysplastic AV node artery with significant acid mucopolysaccharide deposition was seen almost exclusively in the sudden death group (12 of 27 vs. 1 of 17, p = 0.006). In 10 subjects with sudden death a dysplastic AV node artery was narrowed > 2 SD over the control value; half of this subgroup died during exercise and one third had a family history of sudden unexplained cardiac death. CONCLUSIONS: Dysplasia of the AV node artery may contribute to death in a substantial portion of patients with unexplained sudden death, and such death is often associated with exercise and a family history of unexplained sudden death.

Adult↗
PubMed1993

Cardiac myxoma. A clinicopathologic study.

The clinicopathologic features of 107 cardiac myxomas are presented. Eighty-one were in the left atrium, 18 in the right atrium, and 8 were biatrial or located in the ventricles. The mean age at presentation was 50 years and did not vary significantly by sex, race, or site in the left or right atrium. Histologically, 41% of tumors had surface thrombus; 41%, fibrosis; 23%, mitotic activity; 20%, calcification; 17%, gamma bodies; 8%, ossification; 7%, extramedullary hematopoiesis; 3%, mucin-forming glands; 3%, atypical cells simulating malignancy; and 1% had thymic rests. A majority of myxomas was immunohistochemically positive for QBEnd throughout the lesion, but in most tumors, factor-VIII related antigen was limited to the surface cells. A minority of myxomas stained for antismooth muscle actin and Ulex europaeus; KP-1 and cytokeratin were always negative. Right atrial tumors were more likely calcified than those in the left atrium. Embolic tumors were less often fibrotic than nonembolic myxomas and were more likely thrombosed and extensively myxoid with an irregular frond-like surface. Fibrotic and non-thrombosed tumors had a longer mean duration of clinical symptoms and were found in older persons. Recurrent, multiple, and familial myxomas were more often found in younger women and, more likely irregular surfaced and histologically myxoid; however, they were not likely to be histologically atypical, cellular, or incompletely excised. Five tumors caused the death of the patient by emboli to the brain or heart, but none metastasized. The histology of myxomas varied by site, clinical presentation, patient age, and immunohistochemical findings.

Adolescent↗
PubMed1993

Feasibility and drug delivery efficiency of a new balloon angioplasty catheter capable of performing simultaneous local drug delivery.

BACKGROUND: Local drug delivery at angioplasty treatment sites may improve acute and long-term results after angioplasty. A new dual-purpose balloon angioplasty catheter containing intramural channels and exterior pores ('channeled balloon') was designed to allow local drug delivery at low pressure without jet streams during simultaneous balloon angioplasty. METHODS: Acute feasibility studies were performed in normal ex-vivo and in-vivo arteries (three canine arteries and three rabbits with normal iliac arteries), in which 2 ml of marker agents were locally infused at 2 atm during simultaneous angioplasty at 6 atm with the channeled balloon. Histology, radioactive counting, and autoradiography were performed to determine the intramural localization of the delivered markers. The in-vitro efficiency of acute local drug delivery was estimated in seven normal canine arteries by infusing 3H-heparin and radioactive counting. RESULTS: Histology revealed the presence of markers in the inner third of the media in all ex-vivo samples, and markers in all in-vivo iliac arteries except for one, whereas control segments had no intramural staining. Autoradiography documented transmural radioactive granules. Radioactive counts were 40- to 263-fold higher in those locally treated with the radioactive marker agent. Efficiency of the acute local delivery was estimated by dividing the actual counts by the expected counts; it ranged from 24 to 48%. CONCLUSION: This study demonstrates that the channeled balloon is capable of delivering drugs locally at low pressure in adequate concentrations during simultaneous high-pressure balloon angioplasty in normal arteries.

Angioplasty, Balloon, Coronary↗
PubMed1993

Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina. A clue to the mechanism of transformation from the stable to the unstable clinical state.

BACKGROUND: The mechanisms responsible for the transformation of stable angina to unstable angina, a major cause of morbidity and mortality, are commonly believed to be plaque rupture and thrombosis. We determined whether additional mechanisms are operative by analyzing the histopathology and immuno-histopathology of coronary plaques retrieved by directional atherectomy of patients with unstable angina in whom no intraluminal thrombus was demonstrated by angiography. METHODS AND RESULTS: The histological findings of atherectomy specimens from 34 patients with unstable angina were compared with those of 24 patients with postangioplasty restenosis, whose lesions are known to be composed of smooth muscle cells (SMCs), and 10 patients with stable angina, whose lesions contain relatively few SMCs. We also studied the expression of acidic and basic fibroblast growth factors (aFGF and bFGF), whose role in the vascular response to injury has been established. Specimens from unstable angina resembled those from postangioplasty restenosis in regard to SMC abundance (scale, 0 to 3; 1.4 +/- 0.9 versus 1.7 +/- 0.9; P = NS), and both differed from those of stable angina. Thrombus and/or hemorrhage occurred in only 34% of patients with unstable angina (compared with 8% of restenosis patients and in none of stable angina patients). Active lesions (defined as lesions (defined as lesions containing one or more of the following: thrombus, hemorrhage, abundant and disorganized SMCs in the presence of loose connective tissue, or inflammatory infiltrate) were observed in 56% of the unstable angina patients and in 50% of the restenosis patients but in none of the stable angina patients. The expression of aFGF and bFGF was detected in 80% to 100% of unstable angina (n = 11) and restenosis (n = 10) specimens but in only 1 of 5 stable angina specimens. CONCLUSIONS: Microscopic evidence of thrombosis and plaque rupture occurred in only one third of unstable angina patients, selected because they had no angiographic evidence of intracoronary thrombus. Moreover, their lesions resembled those of restenosis patients in regard to SMC abundance, lesion activity, and the expression of aFGF and bFGF. Our findings therefore suggest that an alternative mechanism to plaque rupture and thrombus formation may be operative in the precipitation of unstable angina; namely, in a subset of patients, SMC proliferation may lead to gradual plaque expansion and thereby to lumenal narrowing and unstable angina. Our data also suggest a role for aFGF and bFGF in this process.

Adult↗
PubMed1993

Platelets protect against myocardial dysfunction and injury induced by ischemia and reperfusion in isolated rat hearts.

Platelets are a source of vasoactive mediators that regulate vascular tone. Platelets also play a role in intravascular thrombus formation and dynamic coronary constriction that result in myocardial ischemia. However, effects of platelets on myocardial function after ischemia and reperfusion are unknown. In this study, we examined the effects of platelets on myocardial dysfunction caused by ischemia/reperfusion. Buffer-perfused isolated rat hearts, after global ischemia (15 minutes) and reperfusion (10 minutes), developed marked myocardial dysfunction, indicated by a 65 +/- 4% decrease in the force of cardiac contraction (FCC) and a 26 +/- 7% increase in coronary perfusion pressure (CPP). Ischemia/reperfusion was also associated with release of creatine kinase (CK) and ATP metabolites in the coronary effluents. Perfusion of hearts with buffer containing washed rat platelets (3-8 x 10(7) cells/ml) protected hearts against dysfunction from ischemia/reperfusion, indicated by minimal changes in CPP (-1 +/- 1%) and FCC (-1 +/- 3%). Release of CK in the coronary effluent was also reduced, as was the release of ATP metabolites in the platelet-perfused hearts. Perfusion of hearts with serotonin receptor antagonist LY53,857 (10(-6) M), thromboxane A2 receptor antagonist SQ29,548 (10(-6) M), adenine nucleotide scavenger apyrase (0.4 units/ml), or nitric oxide synthetase inhibitor NG-monomethyl-L-arginine (2 x 10(-4) M) attenuated (p < 0.05) the platelet-mediated cardioprotective effects. Perfusion of the hearts with L-arginine (2 x 10(-4) M) instead of platelets also showed modest protective effects on FCC (-4.3 +/- 13%), CPP (+18 +/- 7%), and CK release. Prolongation of the ischemic period to 30 minutes and reperfusion to 20 minutes also demonstrated marked cardiac dysfunction (FCC, -58 +/- 10%; CPP, +36 +/- 8%) in buffer-perfused hearts. Perfusion of hearts with platelets in this setting of prolonged ischemia/reperfusion also exhibited protective effects on FCC (-24 +/- 10%), CPP (+12 +/- 6%), and CK release. Thus, platelets protect myocardium from ischemia/reperfusion-induced injury, and these protective effects of platelets are evident regardless of the duration of ischemia/reperfusion. Furthermore, these cardioprotective effects of platelets seem to be related to the release of serotonin, thromboxane A2, and adenine nucleotides. These substances most likely elicit release of endothelium-derived relaxing factor, with its attendant tissue-protective effects, from the microvascular endothelium of hearts.

Adenosine Triphosphate↗
PubMed1993

In vivo adenoviral vector-mediated gene transfer into balloon-injured rat carotid arteries.

We studied the ability of adenoviral vectors to achieve gene transfer into injured arteries. A recombinant adenoviral vector expressing a nuclear-targeted beta-galactosidase gene was constructed and infused into balloon-injured rat carotid arteries. Three days after gene transfer, recombinant gene expression was assessed quantitatively by (1) measuring beta-galactosidase antigen and activity in tissue extracts and (2) histochemical staining and counting of cells expressing beta-galactosidase. Exposure of injured carotid arteries to increasing concentrations of the vector (10(8) to 10(10) plaque-forming units per milliliter) resulted in a dose-responsive increase in beta-galactosidase expression, with peak expression of approximately 43 mU or 25 ng beta-galactosidase per vessel. Microscopic examination of histochemically stained arteries demonstrated gene transfer limited to the vascular media; transduced cells were identified immunohistochemically as smooth muscle cells. Counting of both histochemically stained and total nuclei in the media revealed that approximately 30% of the cells in the media of the injured vessels were transduced. Calculations based on both counting cells and on the level of beta-galactosidase expression in tissue extracts suggested the presence of 5000 to 10,000 transduced cells per 10 mm of vessel. Arteries infused with either vehicle only, a control adenoviral vector, or liposomes combined with the vector plasmid contained little or no evidence of beta-galactosidase expression. High levels of in vivo beta-galactosidase expression persisted for at least 7 days after gene transfer but declined significantly by day 14. We conclude that adenoviral vector-mediated gene transfer into the injured rat carotid artery results in efficient gene transfer into the vascular media, with levels of recombinant protein production significantly higher than any previously reported in arterial gene transfer studies. Adenoviral vectors appear to be particularly useful agents for in vivo arterial gene transfer.

Adenoviridae↗