Tsunehiro Yasuda

Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.

To begin to dissect atherogenesis as a complex genetic disorder affected by genetic makeup and environment, we have (a) generated a reproducible mouse model of neointimal growth; (b) evaluated the effect of disruption of a single gene, endothelial nitric oxide synthase, believed to be central to intimal growth, and (c) examined the modifying effects of gender and pregnancy upon the vascular response. Cuff placement around the femoral artery causes reproducible intimal growth. We assessed the response to injury by quantitative morphometry, measuring the intimal to medial (I/M) volume ratio. In wild-type mice, cuff placement causes pronounced intimal proliferation without affecting the media, resulting in I/M ratios of 31% (SV129 males) and 27% (C57BL/6 males). eNOS mutant male mice have a much greater degree of intimal growth (I/M ratio of 70%). Female mice show less intimal response than do males, although eNOS mutant female mice still have more response than do wild-type females. Most dramatic, however, is the effect of pregnancy, which essentially abolishes the intimal response to injury, even overriding the effect of eNOS mutation. We conclude that eNOS deficiency is a genetic predisposition to intimal proliferation that is enhanced by male gender, and that may be overridden by pregnancy.

Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion.

Twenty-nine patients with acute myocardial infarction were treated with recombinant human tissue-type plasminogen activator (rt-PA). The incidence of acute coronary reocclusion and its prevention by a maintenance infusion of rt-PA were studied. Intravenous rt-PA was given at a rate of 0.4 to 0.75 mg/kg over 60 to 120 min after angiographic documentation of complete coronary occlusion. Reperfusion was accomplished within 1 hr in 24 of 29 patients (83%) and was associated with a decrease of the plasma fibrinogen level by 20%. In a first group of 13 patients, 11 of whom were successfully reperfused, prevention of reocclusion was attempted with heparin anticoagulation. However, acute reocclusion within 1 hr after cessation of rt-PA was demonstrated angiographically in five of these patients (45%). Quantitative angiographic analysis indicated that acute reocclusion only occurred in patients with 80% or greater residual stenosis. In patients with less than 80% residual stenosis, heparin anticoagulation was sufficient to maintain patency during the hospital stay in four of five patients. In a second group of patients (n = 16), 13 of whom underwent reperfusion with intravenous rt-PA, seven demonstrated a residual stenosis of 80% or greater. These patients were given heparin and, in addition, 10 mg of rt-PA per hour for 4 hr. None developed acute angiographic reocclusion or clinical signs of reocclusion during the hospital stay. Repeat angiography at 10 to 14 days confirmed persistent patency in six of the seven patients. The maintenance infusion resulted in only a moderate additional drop in fibrinogen, while a steady-state plasma rt-PA level of 750 +/- 250 ng/ml was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphic quantification of myocardial necrosis in patients after intravenous injection of myosin-specific antibody.

The Fab fragments of antimyosin antibodies, labeled with 99mTc, were used in the scintigraphic examination of 30 patients with myocardial infarction. The ability to detect necrosis and determine its extent from the antimyosin scan were compared with the results of quantitative regional wall motion analysis by contrast ventriculography at 10 to 14 days and 99mTc-pyrophosphate imaging. Antimyosin images recorded by planar and single photon-emission computed tomography (SPECT) delineated areas of myocardial necrosis in 27 of 30 patients (90%) compared with a 91% sensitivity of pyrophosphate in 21 of 23 patients. Infarct size was determined by both antimyosin and pyrophosphate SPECT images. Results by both techniques showed a significant correlation with computer-derived hypokinetic segment length (r = .79 for both, p = .002) and peak creatine kinase (r = .9 for both, p less than .01). Although sensitivity for and correlations with markers of necrosis were similar with both techniques, infarct size by pyrophosphate SPECT was 1.7 times larger than infarct size by antimyosin SPECT (p less than .01). Certain zones in the infarct area were differentially labeled; the nature and irreversibility of injury within these zones remains to be clarified.

Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris

OBJECTIVES In a Phase I clinical trial, we studied the antithrombotic and clinical effects of the synthetic competitive thrombin inhibitor, argatroban, in 43 patients with unstable angina pectoris. BACKGROUND Thrombin has a pivotal role in platelet-mediated thrombosis associated with atheromatous plaque rupture in patients with an acute ischemic coronary syndrome. However, the efficacy of conventional heparin therapy to prevent ischemic events is limited and has been surpassed by that of specific thrombin inhibitors in experimental models of arterial thrombosis. METHODS Intravenous infusion of the drug (0.5 to 5.0 micrograms/kg per min) for 4 h was monitored by sequential measurements of coagulation times and of indexes of thrombin activity in vivo followed by a 24-h clinical observation period. RESULTS Significant dose-related increases in plasma drug concentrations and activated partial thromboplastin times (aPTT), but no bleeding time prolongation or spontaneous bleeding, was observed. Myocardial ischemia did not occur during therapy but, surprisingly, 9 of the 43 patients experienced an episode of unstable angina 5.8 +/- 2.6 h (mean +/- SD) after infusion. This early recurrent angina was correlated significantly with a higher argatroban dose and with greater prolongation of aPTT but not with other demographic, clinical, laboratory and angiographic characteristics. Pretreatment plasma concentrations of thrombin-antithrombin III complex and fibrinopeptide A were elevated two to three times above normal values. During infusion, thrombin-antithrombin III complex levels remained unchanged, whereas a significant 2.3-fold decrease in fibrinopeptide A concentrations was observed. By contrast, 2 h after infusion, thrombin-antithrombin III complex concentrations increased 3.9-fold over baseline measurements together with return of fibrinopeptide A levels to values before treatment with argatroban. CONCLUSIONS In patients with unstable angina, argatroban inhibits clotting (aPTT prolongation) and thrombin activity toward fibrinogen (fibrinopeptide A decrease), but in vivo thrombin (thrombin-antithrombin III complex) formation is not suppressed. However, cessation of infusion is associated with rebound thrombin (thrombin-antithrombin III complex) generation and with an early dose-related recurrence of unstable angina. Although the mechanism of this clinical and biochemical rebound phenomenon remains to be determined, its implication for the clinical use of specific thrombin inhibitors in the management of ischemic coronary syndromes may be significant.

Antimyosin antibody cardiac imaging: Its role in the diagnois of myocarditis

Right ventricular endomyocardial biopsy currently remains the procedure of choice for identifying patients with symptomatic heart failure due to myocarditis from the larger population with idiopathic dilated cardiomyopathy. Despite its specificity, the sensitivity of right ventricular biopsy remains uncertain because of the focal or multifocal nature of the disease. Because myocyte necrosis is an obligate component of myocarditis, the use of indium-111 antimyosin imaging was evaluated in 82 patients with suspected myocarditis. Seventy-four patients had dilated cardiomyopathy of less than 1 years duration (mean left ventricular ejection fraction 0.30 +/- 0.02); eight patients had normal left ventricular function (mean ejection fraction 0.59 +/- 0.03). Symptoms at presentation included congestive heart failure (92%), chest pain mimicking myocardial infarction (6%) and life-threatening ventricular tachyarrhythmias (2%). All patients underwent planar and single photon emission computed tomographic (SPECT) cardiac imaging after injection of indium-111-labeled antimyosin antibody fragments and right ventricular biopsy within 48 h of imaging. Antimyosin images were interpreted as either abnormal or normal and correlated with biopsy results. On the basis of the right ventricular histologic examination, the sensitivity of antimyosin imaging was 83%, specificity 53% and predictive value of a normal scan 92%. Improvement in left ventricular function occurred within 6 months of treatment in 54% of patients with an abnormal antimyosin scan compared with 18% of those with a normal scan (p less than 0.01). Antimyosin cardiac imaging may be useful for the initial evaluation of patients with dilated and nondilated cardiomyopathy and clinically suspected myocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)

Indium 111-monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis.

A definitive diagnosis of myocarditis requires right ventricular biopsy. Despite its specificity, however, right ventricular biopsy may lack sensitivity due to the focal nature of the disease. Because indium 111-monoclonal antimyosin antibody imaging can be used to detect myocardial necrosis, this procedure was performed on 28 patients clinically suspected of having myocarditis, 25 of whom had left ventricular ejection fractions of less than 45%, and the results were compared with those of right ventricular biopsy performed within 48 hr of the scan. Antimyosin scans were positive in nine patients who had evidence of myocarditis on right ventricular biopsy, and negative in 11 who had no evidence of myocarditis by biopsy. The remaining eight had positive antimyosin scans but showed no evidence of myocarditis on right ventricular biopsy. On the basis of a right ventricular biopsy standard, the sensitivity of this method was 100%, the specificity 58%. We conclude that antimyosin antibody imaging is a reliable...

Patient management after noninvasive cardiac imaging: Results from SPARC (Study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease)

OBJECTIVES This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging. BACKGROUND Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear. METHODS We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography. RESULTS Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results. CONCLUSIONS Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomys Role in Coronary Artery [CAD] [SPARC]; NCT00321399).

Reproducibility and Accuracy of Quantitative Myocardial Blood Flow Assessment with 82Rb PET: Comparison with 13N-Ammonia PET

82Rb cardiac PET allows the assessment of myocardial perfusion with a column generator in clinics that lack a cyclotron. There is evidence that the quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) with dynamic 82Rb PET is feasible. The objectives of this study were to determine the accuracy and reproducibility of MBF estimates from dynamic 82Rb PET by using our methodology for generalized factor analysis (generalized factor analysis of dynamic sequences [GFADS]) and compartment analysis. Methods: Reproducibility was evaluated in 22 subjects undergoing dynamic rest and dipyridamole stress 82Rb PET studies at a 2-wk interval. The inter- and intraobserver variability of MBF quantitation with dynamic 82Rb PET was assessed with 4 repeated estimations by each of 4 observers. Accuracy was evaluated in 20 subjects undergoing dynamic rest and dipyridamole stress PET studies with 82Rb and 13N-ammonia, respectively. The left ventricular and right ventricular blood pool and left ventricular tissue time–activity curves were estimated by GFADS. MBF was estimated by fitting the blood pool and tissue time–activity curves to a 2-compartment kinetic model for 82Rb and to a 3-compartment model for 13N-ammonia. CFR was estimated as the ratio of peak MBF to baseline MBF. Results: The reproducibility of the MBF estimates in repeated 82Rb studies was very good at rest and during peak stress (R2= 0.935), as was the reproducibility of the CFR estimates (R2 = 0.841). The slope of the correlation line was very close to one for the estimation of MBF (0.986) and CFR (0.960) in repeated 82Rb studies. The intraobserver reliability was less than 3% for the estimation of MBF at rest and during peak stress as well as for the estimation of CFR. The interobserver reliabilities were 0.950 at rest and 0.975 at peak stress. The correlation between myocardial flow estimates obtained at rest and those obtained during peak stress in 82Rb and 13N-ammonia studies was very good (R2 = 0.857). Bland–Altman plots comparing CFR estimated with 82Rb and CFR estimated with 13N-ammonia revealed an underestimation of CFR with 82Rb compared with 13N-ammonia; the underestimation was within ±1.96 SD. Conclusion: MBF quantitation with GFADS and dynamic 82Rb PET demonstrated excellent reproducibility as well as intra- and interobserver reliability. The accuracy of the absolute quantitation of MBF with factor and compartment analyses and dynamic 82Rb PET was very good, compared with that achieved with 13N-ammonia, for MBF of up to 2.5 mL/g/min.

Comprehensive Assessment of Myocardial Perfusion Defects, Regional Wall Motion, and Left Ventricular Function by Using 64-Section Multidetector CT

PURPOSE To evaluate the accuracy of 64-section multidetector computed tomography (CT) for the assessment of perfusion defects (PDs), regional wall motion (RWM), and global left ventricular (LV) function. MATERIALS AND METHODS All myocardial infarction (MI) patients signed informed consent. The IRB approved the study and it was HIPAA-compliant. Cardiac multidetector CT was performed in 102 patients (34 with recent acute MI and 68 without). Multidetector CT images were analyzed for myocardial PD, RWM abnormalities, and LV function. Global LV function and RWM were compared with transthoracic echocardiography (TTE) by using multidetector CT. PD was detected by using multidetector CT and was correlated with cardiac biomarkers and single photon emission CT (SPECT) myocardial perfusion imaging. Multidetector CT diagnosis of acute MI was made on the basis of matching the presence of PD with RWM abnormalities compared with clinical evaluation. RESULTS Correlation between multidetector CT and TTE for global function (r = 0.68) and RWM (kappa = 0.79) was good. The size of PD on multidetector CT had a moderate correlation against SPECT (r = 0.48, -7% +/- 9). There was good to excellent correlation between cardiac biomarkers and the percentage infarct size by using multidetector CT (r = 0.82 for creatinine phosphokinase, r = 0.76 for creatinine phosphokinase of the muscle band, and r = 0.75 for troponin). For detection of acute MI in patients, multidetector CT sensitivity was 94% (32 of 34) and specificity was 97% (66 of 68). Multidetector CT had an excellent interobserver reliability for ejection fraction quantification (r = 0.83), as compared with TTE (r = 0.68). CONCLUSION Patients with acute MI can be identified by using multidetector CT on the basis of RWM abnormalities and PD.

A randomized, blinded, placebo-controlled trial of recombinant human tissue-type plasminogen activator in patients with unstable angina pectoris.

Twenty-four patients with unstable angina pectoris, defined as chest pain at rest with transient ST segment deviation of at least 1 mm, were randomly assigned to blinded treatment with either placebo or intravenous recombinant human tissue-type plasminogen activator (rt-PA). Before randomization, all patients were treated with oral beta-blockers, calcium antagonists, nitrates, and continuous intravenous heparin for a monitoring period of 12 to 28 hr. After this monitoring period the 24 patients were randomly assigned to receive either placebo or 1.75 mg/kg intravenous rt-PA given over 12 hr at a rate of 0.75 mg/kg over 1 hr, 0.5 mg/kg over 4 hr, and 0.5 mg/kg over 7 hr. One patient, assigned to receive placebo, developed acute myocardial infarction after randomization but before receiving the study drug. Ischemic events were recorded during a hospital follow-up period of at least 4 days unless a further intervention was indicated or the coronary angiogram was normal. The follow-up period was 7 +/- 5 days (mean +/- SD) after the placebo infusion and 8 +/- 4 days after the infusion of rt-PA. Unstable angina pectoris persisted after the completion of the infusion in six of 11 patients receiving placebo and only one of 12 patients receiving rt-PA (p less than .03). Coronary angiography, performed 38 +/- 19 hr after the infusion, demonstrated subocclusive thrombus in eight of 11 patients receiving placebo but in none of 11 patients treated with rt-PA (p less than .002). One patient on rt-PA refused coronary angiography.(ABSTRACT TRUNCATED AT 250 WORDS)