Kyozo Ishikawa

A 192Arg Variant of the Human Paraoxonase (HUMPONA) Gene Polymorphism Is Associated With an Increased Risk for Coronary Artery Disease in the Japanese

Recent reports have suggested that polymorphisms in the human paraoxonase (HUMPONA) gene may be a genetic risk factor for coronary artery disease (CAD) in white populations. However, this association has not yet been confirmed in other ethnic populations. We studied 75 Japanese patients with CAD, whose coronary lesions were confirmed by angiography, and 115 Japanese control subjects with no history of CAD and a normal resting electrocardiogram. The assays for genotyping the two polymorphisms in the HUMPONA gene (192Arg/Gln and 55Leu/Met) were based on changes in restriction enzyme digestion patterns. For codon 192, the frequencies of the Arg-coding allele (B allele) in both patients and control subjects were much higher than those from published results of whites (.26 to .31), and the difference between patients (.74) and control subjects (.59) was statistically significant (P = .002). The patient group had a higher proportion of Arg/Arg (B/B) homozygotes (52.0% vs 32.2%, P = .006). For codon 55, the frequencies of the Leu-coding allele in control subjects and patients were much higher (.91 and .93, respectively) than those published results for whites, but there was no difference between Japanese control subjects and Japanese patients. When subjects with the 55Leu/Leu genotype only were analyzed, 192Arg/Arg homozygotes were still significantly more frequent in the patients than in the control subjects (55.4% vs 37.2%, P = .024), and the frequency of the 192Arg allele was also higher in patients than control subjects (P = .013). Logistic regression analysis including conventional coronary risk factors revealed that 192Arg is an independent risk factor for CAD. Thus, in the Japanese, the association of CAD with the 192Arg variant of HUMPONA (B-type enzyme) is similar to that reported for whites, although the allele frequencies for 192Arg and 55Leu are much higher in the former than the latter population.

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.

Coronary Artery Disease and Polymorphisms in a Receptor Mediating Shear Stress–Dependent Platelet Activation

BACKGROUND Platelets play pivotal roles in coronary thrombosis, and antiplatelet therapies are widely used for coronary artery disease (CAD). However, the effects of genetic variation in platelets on CAD are poorly understood. We have assessed the association between CAD and polymorphisms in a platelet receptor for von Willebrand factor, the glycoprotein (GP) Ib/IX complex, which mediates shear stress-dependent platelet activation. METHODS AND RESULTS Genotypes of the alpha-chain of the receptor (GP Ib alpha, 145Thr/Met) were determined in 91 patients with myocardial infarction (MI) or angina pectoris whose lesions were confirmed by coronary angiography as well as in 105 individuals from the general population with no history of angina or other heart diseases and normal resting ECGs. There was no homozygote for Met/Met in either the control or patient groups. The prevalence of the Thr/Met genotype (T/M) in all patients was not significantly different from that in the control group. However, the frequency of T/M was significantly higher in patients aged < or = 60 years (31.8%) than in control subjects aged < or = 60 years (16.0%; P<.05, odds ratio=2.5). An association was also demonstrated between CAD and the other polymorphism of GP Ib alpha, a variable number of tandem repeats of a 13-amino acid sequence, which is known to be linked to the 145Thr/Met polymorphism. There was an association between the frequency of the T/M genotype and the angiographic severity of CAD: 11.1% for Gensini score < 40 versus 50.0% for Gensini score > or = 40 (P=.0015). There was no difference in the distribution of GP Ib alpha genotypes between patients with MI and those with angina pectoris. CONCLUSIONS This study suggests that the presence of the Met allele in GP Ib alpha is a risk factor for the prevalence and severity of CAD in individuals aged < or = 60 years. The results need to be confirmed in a large-scale study of incident case subjects and matching control subjects.

Prognosis of aortic intramural hemorrhage compared with classic aortic dissection

Aortic intramural hemorrhage occurs fairly frequently among patients with aortic dissection, and may not have a poor prognosis if it is Stanford type B. In patients with type A aortic dissection, cardiac tamponade should be ruled out during observation.

Genotype distribution of estrogen receptor polymorphisms in men and postmenopausal women from healthy and coronary populations and its relation to serum lipid levels

The cardiovascular protective effects of estrogen are known to be mediated by its beneficial effects on lipid metabolism and its direct actions on the vessel wall. The latter can be mediated by a specific receptor for estrogen present on smooth muscle cells and endothelial cells. The gene for the receptor (the classic estrogen receptor [ER]) has three known polymorphisms, Pvu II, Xba I, and B-variant polymorphisms, which are reportedly associated with receptor expression and altered receptor function and with some disorders including breast cancer, hypertension, and spontaneous abortion. However, the significance of genetic variations of the ER in vascular diseases has not been reported. We have examined the association between coronary artery disease (CAD) and the three polymorphisms in ER. Genotypes (P1/P2, X1/X2, and B-wild type/B-variant type) were determined in 87 men and postmenopausal women with myocardial infarction or angina pectoris whose lesions were confirmed by coronary angiography, as well as from 94 control individuals from the general population with no coronary heart disease and normal resting ECG. For B-variant polymorphism, all individuals examined had B-wild type, which contrasts with the reported allele frequency for B-variant type (0.1) in the white population. Genotype distributions and allele frequencies of Pvu II or Xba I polymorphisms were not significantly different between control subjects and patients (P > .05 for Pvu II or Xba I genotypes; P > .05 for Pvu II or Xba I allele frequencies). When the allele frequencies were analyzed separately by sex, there was still no statistically significant difference for both polymorphisms (P > .05 for men; P > .05 for women). No association was found between the polymorphisms and the angiographic severity of CAD. Total cholesterol, triglyceride, or HDL-cholesterol levels were not significantly different among ER genotypes. These findings suggest that the three polymorphisms in ER are not associated with the prevalence and severity of CAD and that the polymorphisms are unrelated to the serum lipid levels in control subjects and patients.

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.

Relation of ST-Segment Changes in Inferior Leads During Anterior Wall Acute Myocardial Infarction to Length and Occlusion Site of the Left Anterior Descending Coronary Artery

We investigated the relation between left anterior descending (LAD) coronary artery morphology and inferior lead ST-segment changes to elucidate the clinical significance of such changes in 159 patients with anterior wall acute myocardial infarction (AMI). Patients with 1-vessel LAD artery lesions were divided into an ST depression group (n = 40), an ST elevation group (n = 25), and a no-ST-change group (n = 94) based on ST-segment changes in the inferior leads. The relation between each group and the infarct-related lesion and the presence of a wrapped LAD artery was then investigated. The percentage of patients with the infarct-related lesion in the proximal LAD artery was significantly higher in the ST depression group and significantly lower in the ST elevation group. The percentage of patients with a wrapped LAD artery was significantly higher in the ST elevation group and significantly lower in the ST depression group. The wall motion index determined echocardiographically was significantly higher in the ST depression group and the no-ST-change group than in the ST elevation group. Our findings suggest that inferior lead ST-segment changes during anterior wall AMI arise as a result of competition between reciprocal changes caused by high lateral wall AMI due to lesions of the proximal LAD artery, which depress the ST segment, and inferoapical wall AMI due to a wrapped LAD artery, which elevates the ST segment. In patients with no ST-segment changes, echocardiography was useful for distinguishing the amount of affected LAD artery territory.

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.

Sequential changes in cardiac structure and function in patients with Duchenne type muscular dystrophy : A two-dimensional echocardiographic study

BACKGROUND Most patients with progressive muscular dystrophy of the Duchenne type (DMD) die of respiratory failure at approximately 20 years of age. However, some patients with DMD die of heart failure in relatively short periods of time. We investigated the long-term progression of cardiac impairment in patients with DMD by two-dimensional echocardiography. METHODS We monitored 74 patients for 4 years with two-dimensional echocardiography. Patients were classified into four groups according to the 8-grade Swinyard-Dever system. We also evaluated the echocardiographic features of 22 other patients with DMD with studies performed within 1 year before their deaths. RESULTS During the 4-year follow-up the left ventricle expanded, and regional left ventricular wall motion abnormalities developed in the posterior wall and apex. Almost all patients had myocardial dysfunction that progressed in parallel with their Swinyard-Dever stage. However, in a few patients who died of congestive heart failure, left ventricular dilation and circumferential left ventricular wall motion were severely impaired. CONCLUSIONS Myocardial impairment is accelerated in patients with DMD who died of heart failure. Two-dimensional echocardiography is a useful tool for the early diagnosis of left ventricular dysfunction and provides useful information for the treatment of patients with DMD.

Circadian rhythm and variability of heart rate in Duchenne-type progressive muscular dystrophy

Using 24-hour Holter monitoring and time domain and power spectral measurements, we evaluated the variability of the heart rate and its circadian rhythm in 55 male patients with Duchenne-type progressive muscular dystrophy (DMD) to characterize their autonomic function versus findings in 20 normal controls. Comparisons were also made in patients with mild, moderate, and severe stages of DMD. The percent difference between successive RR intervals that exceeded 50 ms, a measure of parasympathetic tone, was significantly lower even in patients with early stage of DMD than in controls (p < 0.01). This trend became marked with disease progression. Power in the high-frequency (HF) range (0.15 to 0.40 Hz), a measure of parasympathetic tone, was lower (p < 0.01), and the ratio of the power in the low-frequency (LF) range (0.04 to 0.15 Hz) and that of HF range (LF/HF ratio), a measure of sympathetic tone, was higher in DMD patients versus controls (p < 0.01). This trend was also marked with disease progression. Patients with mild or moderate disease had a slight circadian alteration in HF and LF/HF ratio. Patients with severe disease had virtually no circadian rhythm in HF. Their LF/HF ratio was higher at night (p < 0.01), lower in the morning (p < 0.01), and still lower during the day (p < 0.01), the opposite of control findings. The autonomic abnormalities in DMD were thus characterized by a significant increase in sympathetic activity and a significant decrease in parasympathetic activity. Thus, heart rate variability and circadian rhythm were useful in assessing autonomic dysfunction in DMD.