摘要:

Insulin in physiological concentrations attenuates the agonist-induced intracellular Ca2+([Ca2+]i) transient and inhibits contraction in individual nonproliferated cultured canine femoral artery vascular smooth muscle cells (VSMCs). In the present study, we wished to define the effects of insulin on individual components of Ca2+transport in vascular smooth muscle.Methods and ResultsInsulin (40 μU/mL) attenuated the 5-hydroxytryptamine (5-HT, serotonin; 10−5 mol/L)-induced [Ca2+]itransient (measured by fura 2 fluorescence) in primary confluent canine femoral artery VSMCs in the presence of extracellular Ca2+. In Ca2+-free media, the 5-HT-induced [Ca2+transient was reduced by 42% and was not affected by insulin. This finding suggested that insulin inhibits 5-HTinduced Ca2+influx but does not affect sarcolemmal Call efflux or Ca2+release from intracellular stores. In support of those conclusions, we found that insulin inhibited the 5-HT-induced component of Mn2+(a Ca2+surrogate) influx (measured by fura 2 fluorescence quenching at the Ca2+isosbestic excitation wavelength). In addition, 5-HT stimulated the rates of45Ca2+efflux from intact cells (a measure of sarcolemmal Ca2+efflux) and from saponin-permeabilized cells (a measure of Ca2+release from intracellular stores), but insulin did not affect these rates of45Ca2+efflux.ConclusionsWe conclude that a physiological insulin concentration attenuates the 5-HT- induced [Ca2+]itransient in confluent primary cultured canine femoral artery VSMCs by inhibiting the 5 -HT-induced component of Ca2+influx but not by affecting sarcolemmal Ca2+efflux or Ca2+release from intracellular stores.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThe cardiac renin-angiotensin system has been suggested to be involved in the development of left ventricular hypertrophy. In humans, a strong correlation has been found between plasma angiotensin I-converting enzyme (ACE) activity and the insertion/deletion (I/D) polymorphism of the ACE gene, which has been reported to be associated with myocardial infarction, ischemic and idiopathic dilated cardiomyopathy, sudden death in hypertrophic cardiomyopathy, and restenosis after percutaneous transluminal coronary angioplasty. In the present study, we examined the possibility that the genotype of the ACE gene might influence the development of left ventricular hypertrophy.Methods and ResultsThe study population consisted of 268 subjects randomly selected from our outpatient clinic. In 142 subjects, left ventricular mass (LVM) was determined by echocardiogram. The genotype of the ACE gene was determined by the polymerase chain reaction. ANCOVA revealed that the genotype of the ACE gene had no effect on blood pressure. The percentage of the explained variance of LVM with variables including diastolic blood pressure (DBP,P= .0001), body mass index (BMI,P= .0001), sex (P= .0009), and the genotype of the ACE gene (P= .0017) was 34.61%. Significant differences in the effects of the genotype of the ACE gene on LVM were observed between the II and DD (P= .0004) and between the ID and DD (P= .0077) genotypes. The percentage of the explained variance of the LVM/ht ratio with variables including sex (P= .134), age (P= .3655), the genotype of the ACE gene (P= .0014), BMI (P= .0001), and DBP (P= .0001) was 31.25%. Significant differences in the effects of the genotype of the ACE gene on LVM/ht were observed between the II and DD genotypes (P= .0003) and between the ID and DD genotypes (P= .0091).ConclusionsIn addition to BMI and DBP, the genotype of the ACE gene was a significant predictor of LVM and LVM/ht in our study population.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundMyotonic dystrophy, the most common form of adult dystrophy, has been shown to be caused by amplification of CTG triplet repeat in the 3′ untranslated region of a protein kinase gene located on chromosome 19. Impaired glucose metabolism has been suggested as a possible explanation of brain and skeletal muscle involvement in this multisystem disease. We investigated whether myocardial glucose metabolism is impaired in myotonic dystrophy and whether this impairment is related to the size of the mutation.Methods and ResultsThe myocardial metabolic rate for glucose (MMRGlu, μmol·min−1.g−1), K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood transfer constant), and k3 (phosphorylation rate constant) were determined in 7 control subjects and 12 patients with myotonic dystrophy by using parametric images generated from dynamic cardiac positron emission tomography (PET) and18F-fluoro-2-deoxy-glucose studies. The expansion of the CTG triplet repeats was analyzed in patients with the probe cDNA25 afterEcoRI digestion. Nonparametric tests were used to compare quantitative variables between control subjects and patients. The correlations between the size of the mutation and PET parameters were studied by linear regression. MMRGlu and k3 were significantly decreased in patients compared with control subjects (0.39 ± 0.20 versus 0.64 ± 0.25,P= .03, and 0.09 ± 0.07 versus 0.24 ± 0.21,P= .03, respectively), whereas K1 and k2 were not statistically different between control subjects and patients. MMRGlu and k3 correlate inversely with the length of the CTG triplet repeat (r= −.65 andP= .03 for MMRGlu, andr= −.85 andP= .001 for k3, respectively).ConclusionsIn myotonic dystrophy, the observed reductions in MMRGlu and phosphorylation are inversely linked to the length of the mutation. This observation suggests that impaired modulation of a protein kinase involved in myocardial hexokinase activation may give a pathophysiological schema to relate the molecular defect and the abnormal myocardial metabolism in myotonic dystrophy.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThe Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant inherited trait characterized by prolonged QT interval on ECG, life-threatening arrhythmias, syncope, and sudden death in affected individuals. A gene responsible for this disorder has been shown to be linked to the Harveyras-1 locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosome 11p, whether evidence exists for more than one gene causing LQTS (ie, locus heterogeneity).Methods and ResultsTwenty-three families (262 family members) were clinically evaluated using medical histories, ECGs, and Holter recordings. Each corrected QT interval (QTc) were determined using Bazett's formula. Blood for DNA extraction and cell line immortalization was obtained after informed consent. Southern blotting and polymerase chain reaction were performed, and linkage analysis carried out using the LINKAGE computer program (v 5.03). Genetic heterogeneity was determined using the HOMOG 2 (v 2.51) computer program. Twenty-three families were studied for evidence of linkage to chromosome 11p using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including tyrosine hydroxylase (TH). Two- point linkage analysis using pTBB-2 and TH markers was consistent with linkage in 15 of 23 families, with the maximum single-family LOD score of +3.038 occurring at Θ = 0. However, 8 of 23 families had negative LOD scores, with the values in 4 families being less than −2 at Θ = 0, consistent with exclusion of linkage. Analysis with the HOMOG program was consistent with genetic heterogeneity (P< .0001). Multipoint linkage data using pTBB-2 and TH were also examined for evidence of heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1 locus also supported heterogeneity (P< .001).ConclusionsIn the 23 families with LQTS analyzed for linkage to the H-ras-1 locus on chromosome 11p15.5, 15 of 23 families had LOD scores consistent with linkage. The remaining 8 of 23 families had negative LOD scores, 4 of which were definitively excluded from linkage. Thus, genetic heterogeneity is definitively (P< .001) demonstrated for this disorder.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThis study describes the impact of clinical, angiographic, and demographic characteristics on the long-term survival of Coronary Artery Surgery Study (CASS) patients while they were under medical treatment. Revascularization rates for the population are also provided.Methods and ResultsAll CASS patients who had not received heart surgery before enrollment (23467 patients) were included in this survival analysis while they were under medical treatment or surveillance. Follow-up time ranged from 0 to 17 years (median, 12 years). Long-term vital status is known for 95.8% of these patients. Log-rank tests, Kaplan-Meier survival curves, and Cox proportional- hazards regression are used to describe and assess the impact of patient characteristics on survival. Characteristics that had a significant impact on survival, in order of observed explanatory power, are age, number of diseased vessels, congestive heart failure score, smoking history, ejection fraction, sex, presence of left main coronary artery disease, presence of diabetes, left ventricular wall motion score, presence of other illnesses, history of myocardial infarction, and presence of left main equivalent disease. Overall, 12-year survival for patients with zero-, one-, two- and three-vessel disease is 88%, 74%, 59%, and 40%, respectively. Twelve-year survival for patients with at least one diseased vessel and ejection fractions in the ranges of 50% to 100%, 35% to 49%, and 0% to 34% is 73%, 54%, and 21%, respectively. High myocardial jeopardy, high anginal class, and two or three proximal diseased vessels characterize the profile of patients most likely to have received surgical treatment during follow-up.ConclusionsThese results contribute to the understanding of the natural history of coronary artery disease and are also of historical interest. The poor survival of patients with three-vessel disease and low ejection fractions continues to emphasize the importance of considering revascularization for these patients.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundA paradoxical increased risk of death has been reported during the first 24 hours after thrombolysis for myocardial infarction. The mechanism of this phenomenon is not known, nor is its relation to the success or failure of reperfusion. The present study was a prospectively designed analysis of deaths occurring within the first 24 hours in the GUSTO trial.Methods and ResultsThere were 41021 patients enrolled in GUSTO, a randomized comparison of streptokinase with intravenous or subcutaneous heparin, accelerated tissue-type plasminogen activator (TPA), and combination of streptokinase and TPA. An angiographic mechanistic substudy examined reperfusion (using the TIMI flow grading criteria) 90 minutes after the assigned thrombolytic regimen was begun in 1567 patients. There were 1125 deaths (2.8%) within 24 hours (“early deaths”) and 1726 additional deaths (4.2%) after 24 hours but within 30 days (“later deaths”). At the time of presentation, the most potent predictors of early death were hypotension and sinus tachycardia. In a multiple logistic regression model, lower systolic blood pressure, shorter height, higher heart rate, and the absence of prior smoking distinguished early death from later death. Reinfarction occurred in 26 patients (2.4%), shock in 572 patients (52%), atrioventricular block in 308 patients (28%), and tamponade in 106 patients (10%) dying early compared with 262 (15%), 788 (46%), 396 (23%), and 74 (4%) respective patients dying later. There were no differences in early mortality among the thrombolytic regimens for the first 6 hours after randomization. By 24 hours, however, mortality was 2.89% for streptokinase recipients, 2.84% for combination therapy recipients, and 2.36% for accelerated TPA recipients (P= .005). There was little difference among patients with differing flow grades in the infarct artery during the first 4 hours, although mortality was among patients with grade 2 flow was initially higher. After the fourth hour, there were very few additional deaths during the first day in patients with grade 3 flow. At 24 hours, mortality 2.35% for patients with flow grade 0 or 1, 2.92% for patients with flow grade 2, and 0.89% for patients with flow grade 3.ConclusionsEven with aggressive management regimens, mortality within the first 24 hours accounted for a large proportion of postthrombolytic deaths. Patients dying early were more likely to present with pump failure than were those dying later and were more likely to diet of events related to left ventricular dysfunction, although cardiac tamponade also accounted for a significant minority of these deaths. Thus, the severity of the clinical presentation rather than the underlying risk factors predicts early mortality. Based on the angiographic substudy data, it appears that rather than hastening early mortality, successful restoration of complete antegrade flow in the infarct-related artery protects against early death.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundWe have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents—streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)—on activation of the complement and kinin systems in plasma of patients with AMI.Methods and ResultsForty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b- 9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion.ConclusionsOur results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID