Atsuo Yanagisawa

Clinical and Prognostic Significance of Atrial Fibrillation in Acute Myocardial Infarction

The clinical significance of the time of onset of atrial fibrillation (AF) was investigated in patients with acute myocardial infarction (AMI). Among 1,039 patients with AMI, 100 (9.6%) had AF. These patients were divided into 3 groups: AF group 1 (n = 45), who developed AF within 24 hours of the onset of AMI; AF group 2 (n = 41), who developed AF >24 hours after the onset of AMI; and AF group 3 (n = 14), who developed AF before the onset of AMI. The infarct-related lesion was most frequent (67%) in the proximal right coronary artery in AF group 1 (p <0.01). Right atrial pressure was most significantly increased in AF group 1. The left atrial dimension and pulmonary arterial wedge pressure were most significantly increased, and left ventricular ejection fraction was most significantly decreased in AF group 2. In the acute phase, the frequencies of heart failure, cardiogenic shock, and in-hospital mortality were higher for all 3 AF groups than the sinus group (p <0.01). The long-term survival rate was significantly lower in AF group 1 and AF group 2 than in the sinus group. AF was an independent predictor of cardiac death in both AF group 1 (odds ratio 2.5; 95% confidence interval 1.2 to 5.0; p = 0.0012) and AF group 2 (odds ratio 3.7; 95% confidence interval 1.8 to 7.5; p = 0.0005), but not in AF group 3. The onset time of AF appears to be a useful parameter for evaluating the cardiac status and prognosis of patients with AMI.

Platelet-dependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes.

OBJECTIVES This study sought to assess the usefulness of platelet-dependent thrombin generation as an index of coagulability in diabetes and to determine the effect of glycemic control on coagulability in diabetes. BACKGROUND It is important to investigate the interaction of platelets and the coagulation factors to clarify the processes of the coagulation system in detail. METHODS Platelet-rich plasma (150 X 10(9)/liter), 0.5 ml, was prepared, and 40 mmol/liter of calcium chloride was added to initiate clotting. S-2238 was added to each sample in a microtiter plate every 10 min, and the absorbance of the released color product at 2 min was measured spectrophotometrically at a wavelength of 405 nm using a microtiter plate reader as thrombin generation. We measured the platelet-independent thrombin generation in patients with non-insulin-dependent diabetes mellitus grouped according to glycemic control. RESULTS Platelet-dependent thrombin generation at 30 min after calcium chloride addition was significantly higher in 23 patients with poorly glycemic-controlled non-insulin-dependent diabetes mellitus without complications, such as diabetic retinopathy, nephropathy and neuropathy (hemoglobin [Hb] A1c >/= 9.0%) than in 46 healthy normal subjects (448 +/- 75 vs. 165 +/- 28 mU/min, p < 0.001). Thrombin generation in 31 well controlled diabetic patients without complications (Hb A1c < 9.0%) was intermediate (240 +/- 72 mU/min) between those of the poorly controlled group and healthy normal subjects. Platelet-poor plasma from diabetic patients increased platelet-dependent thrombin generation in normal subjects. CONCLUSIONS Coagulability is evidently enhanced in patients with non-insulin-dependent diabetes mellitus compared with that in healthy normal subjects on the basis of assessments of the platelet-dependent thrombin generation, and good glycemic control may help to correct a hypercoagulable state in diabetic patients.

Platelet-Dependent Thrombin Generation in Patients With Hyperlipidemia

OBJECTIVES We evaluated coagulability as determined by platelet-dependent thrombin generation in hypercholesterolemic patients before and after treatment with pravastatin and in hypertriglyceridemic patients to investigate the usefulness of coagulability as an index of atherosclerosis and to determine the importance of treating hyperlipidemia. BACKGROUND An understanding of the interaction between platelets and the plasma coagulation system is important for clarifying the mechanism of the procoagulant process. METHODS We assessed coagulability in 58 patients with hypercholesterolemia (serum total cholesterol level > or = 220 mg/dl, age 56.5 +/- 1.5 years [mean +/- SEM]), 37 patients with hypertriglyceridemia (serum triglyceride level > or = 200 mg/dl, age 59.5 +/- 1.7 years), 13 patients with hypercholesterolemia plus hypertriglyceridemia (age 51.4 +/- 3.1 years) and 75 normal subjects (age 52.2 +/- 1.7 years). We also studied platelet-dependent thrombin generation in patients with hypercholesterolemia before and after treatment with pravastatin. Calcium chloride was added to 0.5 ml of platelet-rich plasma (150 x 10(9)/liter) to initiate coagulation. Ten microliters of the sample was transferred into 90 microliters of 3.8% sodium citrate at 10-min intervals for 30 min. A chromogenic substrate, S-2238, was added to each sample, and absorbance was measured spectrophotometrically at a wavelength of 405 nm to determine thrombin generation. RESULTS Platelet-dependent thrombin generation was increased in patients with hypercholesterolemia and patients with hypercholesterolemia plus hypertriglyceridemia (p < 0.01) compared with patients with hypertriglyceridemia and control subjects. Treatment with pravastatin normalized thrombin generation. CONCLUSIONS Hypercholesterolemia, but not hypertriglyceridemia, was associated with increased platelet-dependent thrombin generation. Pravastatin normalized the generation of thrombin.

The prevalence and prognostic significance of arrhythmias in Duchenne type muscular dystrophy

To investigate the prevalence and prognostic significance of cardiac arrhythmias in Duchenne type muscular dystrophy 24-hour ambulatory ECG was performed in 80 patients with Duchenne type muscular dystrophy, and they were followed up for 5 years. Various arrhythmias were observed in 63.8% (51 of 80) of the patients. Ventricular premature beats were found in 30% (24 of 80), and the incidence of ventricular premature beats increased as the clinical severity of skeletal muscle involvement advanced. Forty-seven patients survived for 5 years, but the incidence of arrhythmias increased from 38.3% (18 of 47) to 74.5% (35 of 47) (p < 0.001). During the 5-year period, four of 33 deaths were sudden. Malignant ventricular premature beats (ventricular couplets, ventricular tachycardia, and R-on-T-type ventricular premature beats) were observed in three of these four patients. It appears that cardiac arrhythmias are a common complication of Duchenne type muscular dystrophy and that the incidence of ventricular arrhythmias increases with the progression of myocardial involvement. There is an association between ventricular arrhythmias and sudden death, but the reduction of ventricular arrhythmias may not reduce the incidence of episodes of sudden death.

Early Detection of Anthracycline-Induced Cardiotoxicity by Radionuclide Angiocardiography

For the early detection of myocardial damage associated with anthracycline therapy, electrocardiography, echocardiography, and radionuclide angiocardiography were used to assess cardiac function in 37 patients receiving anthracyclines (ie, adriamycin and daunorubicin at a total dose of 100-2,030 mg/m2). None of the patients developed clinical congestive heart failure. There were no significant changes of electrocardio graphic and echocardiographic parameters after anthracycline administration. The left ventricular ejection fraction did not change significantly on radionuclide angiocardiog raphy. However, the 1/3 peak filling rate (PFR) corrected by the end-diastolic count (EDC) (1/3 PFR/EDC) and the 1/3 filling fraction (1/3 FF), the indices of early diastolic function, showed a significant decrease. These findings suggest that the 1/3 PFR/EDC and 1/3 FF determined by radionuclide imaging are useful for detecting silent myocardial damage induced by anthracyclines.

Possible involvement of a chloride-bicarbonate exchanger in apoptosis of endothelial cells and cardiomyocytes.

We examined the role of ion movement in staurosporine‐induced apoptosis of vascular endothelial cells. Cultured vascular endothelial cells from bovine carotid arteries were used. Apoptosis was determined by propidium iodide assay. Treatment of the endothelial cells with staurosporine (10nmol/l‐1μmol/l) for 6h induced nuclear fragmentation in a dose‐dependent manner. Staurosporine (1μmol/l) elicited apoptosis in 70.5±1.5% of cells. Concomitant treatment of endothelial cells with 1mmol/l of 4,4‐diisothiocyanatostilbene‐2,2‐disulfonic acid (DIDS), a chloride—bicarbonate exchange blocker, completely inhibited staurosporine‐induced apoptosis. Other ion transporter inhibitors such as dimethyl amiloride and anthracene‐9 carboxylic acid were less effective inhibitors of staurosporine‐induced apoptosis of endothelial cells. DIDS prevented staurosporine‐induced apoptosis of endothelial cells as well as cardiomyocytes. Next, we determined whether chloride ions or bicarbonate are involved in apoptosis. Incubation with a chloride ion removal buffer did not inhibit staurosporine‐induced apoptosis of endothelial cells. However, endothelial cell apoptosis was completely suppressed by an inhibitor of caspase, benzyloxycarbonyl‐Asp‐CH2‐O(C)O‐dichlorobenzene (zD‐dcb, 50μmol/l). Staurosporine (1μmol/l) increased the intracellular pH of endothelial cells, and DIDS (1mmol/l), but not a caspase inhibitor, inhibited this increase in pH caused by staurosporine. Our findings suggest that endothelial cell apoptosis induced by staurosporine may be associated with the Cl−and bicarbonate (HCO−3) ions. Thus, Cl−efflux from cells or HCO−3 influx to cells (which increases pH) may play an important role in signal transduction leading events such as activation of caspase in staurosporine‐induced apoptosis.

Prognostic value of Doppler transmitral flow velocity patterns in acute myocardial infarction.

Doppler transmitral flow patterns are partially dependent on age. We investigated the correlations between the age-adjusted transmitral flow patterns, hemodynamic indexes, and the coronary and clinical outcome in 206 patients with acute myocardial infarction (AMI) and 102 normal control subjects. The peak flow velocity at atrial contraction was significantly lower in 50 of the 206 patients (24%) (low-A group) than in the 102 normal controls. Pulmonary capillary wedge pressure was significantly higher in the low-A group than in the remaining 156 patients with AMI (20 +/- 7 vs 11 +/- 5 mm Hg, p <0.001), and the cardiac index and left ventricular ejection fraction were significantly lower (2.2 +/- 0.6 vs 2.9 +/- 0.7 L/min/m2, p <0.001; 38 +/- 15% vs 52 +/- 13%, p <0.001). The incidence of cardiogenic shock was significantly higher in the low-A group than in the other patients with AMI (42% vs 19%, p <0.001). Regression analysis demonstrated a significant association between decreased atrial filling velocity and increased in-hospital mortality as well as the incidence of heart failure in AMI (p <0.001). The 5-year mortality rate was also significantly higher in the low-A group (p <0.001). The age-adjusted transmitral flow pattern in AMI can identify patients with left ventricular dysfunction, which can lead to a poor prognosis.

Beneficial effects of tissue-type plasminogen activator in acute myocardial ischemia in cats

Tissue-type plasminogen activator is a new thrombolytic agent that dissolves intravascular thrombi in coronary and peripheral vessels with less pronounced systemic lysis than that produced by streptokinase. Plasminogen activator was shown to induce reperfusion, and to salvage ischemic myocardium, by lysing experimentally induced coronary artery thrombi. The effect of a melanoma cell-derived tissue-type plasminogen activator was studied in cat myocardium rendered ischemic by coronary artery ligation for 2 hours and reperfused for another 4 hours. Plasminogen activator was infused at a rate of 500 IU X kg-1 X min-1 for the first 30 minutes of reperfusion. The marked increase in plasma creatine kinase activity during reperfusion was significantly lower in plasminogen activator-treated cats at 4, 5 and 6 hours, with 7.7 +/- 1.5 X 10(-3) IU X mg protein-1 (n = 8) in the plasminogen activator group versus 17.8 +/- 3.5 X 10(-3) IU X mg protein-1 (n = 7) in the vehicle group at 6 hours (mean +/- SEM). The area at risk in the two ischemic groups was not different, being 14.6 +/- 1.5 and 16.6 +/- 1.4% of total left ventricular mass for the treated and untreated groups, respectively. However, the mass of necrotic tissue determined histochemically was significantly lower in the plasminogen activator-treated group, accounting for 29.5 +/- 3.9% of the area at risk compared with 46.8 +/- 4.2% of area at risk in cats receiving only the vehicle (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic significance of persistent right ventricular dysfunction as assessed by radionuclide angiocardiography in patients with inferior wall acute myocardial infarction.

We evaluated cardiac hemodynamics and long-term prognosis in patients with right ventricular (RV) acute myocardial infarction (AMI) using Fourier phase and amplitude analysis of radionuclide angiocardiographic scanning. In 143 patients with RV AMI, delayed phase and low amplitude in radionuclide RV images persisted in 54 patients (persistent RV dysfunction group) 3 months after AMI, but disappeared in the remaining 89 patients (improved RV function group). No significant differences were present in RV dimensions, left ventricular (LV) wall motion, LV ejection fraction, or RV ejection fraction between these groups during the acute phase. At 3 months, RV dimension and LV and RV wall motion indexes were significantly higher (p = 0.0292, p = 0.0124, p<0.0001, respectively), and LV and RV ejection fractions were lower (p = 0. 0174 and p = 0.0008, respectively) in the persistent RV dysfunction group. Percutaneous transluminal coronary angioplasty in the acute phase was performed in a smaller group of patients (15% vs. 34%, p = 0.0223), and the degree of residual stenosis in the proximal right coronary artery was significantly greater in the persistent RV dysfunction group than in the improved RV function group (82+/-22% vs. 53+/-30%, p<0.0001). The 8-year survival rate was significantly lower in the persistent RV dysfunction group (p<0.0001). Persistent abnormality of phase and amplitude in radionuclide RV images was a significant independent predictor of long-term survival (odds ratio 10.42; 95% confidence interval 3.65 to 29.71; p<0.0001). Radionuclide angiocardiographic Fourier phase and amplitude scanning can detect persistent RV dysfunction in patients with RV AMI and can predict patient outcome.

Cardioprotective actions of specific thromboxane receptor antagonist in acute myocardial ischemia

Summary: Thromboxane A2 (TxA2) has been implicated as a potential mediator of myocardial damage during acute ischemia. A potent and specific TxA2 receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg/h) was tested in a cat acute coronary ligation model of myocardial ischemia over a 5-h observation period. Those cats given the TxA2 receptor antagonist had a significant reduction in elevated S-T segment from 0.32 to 0.17 mV (p < 0.01) in contrast to cats given only vehicle which showed a progressive increase in S-T segment elevation over the 5-h course of the experiment. Furthermore, the rise in plasma creatine kinase (CK) activity during myocardial ischemia was significantly attenuated after SQ-29,548 administration (p < 0.05). This was confirmed by direct myocardial biopsies which demonstrated a reduction in the loss of myocardial CK and nitrogenous compounds from the ischemic region. Because heart rate (HR), mean arterial blood pressure (MABP), and the pressure rate index (PRI) were unaffected by SQ-29,548 administration, its mechanism of protection probably does not occur through reduction of myocardial oxygen demand. Furthermore, specificity of SQ-29,548 for thromboxane/endoperoxide receptors was demonstrated in the isolated cat coronary arteries. These data suggest that SQ-29,548 reduces the damage associated with myocardial ischemia through direct TxA2 receptor antagonism. The data are also consistent with an important role of TxA2 in the pathophysiology of myocardial ischemia.