Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.

Quantitative evaluation of regional myocardial blood flow by videodensitometric analysis of digital subtraction coronary arteriography in humans.

Videodensitometric analysis of digital subtraction coronary arteriography, a new approach for calculating contrast disappearance half-life (T1/2), was assessed in determining regional myocardial blood flow quantitatively. Forty-one patients with coronary artery disease and 12 with angiographically normal coronary arteries underwent digital subtraction coronary arteriography by manual injection of contrast medium into the left main coronary artery. The T1/2 was calculated from a time-density curve generated in the four sectors of the myocardium perfused by the left anterior descending coronary artery. The mean T1/2 value of the four sectors correlated inversely with the great cardiac vein flow measured by the thermodilution method (r = -0.89), and appeared to be a reliable index of myocardial blood flow. The relation of mean T1/2 with percent stenosis of the left anterior descending coronary artery was curvilinear (r = 0.88) and an abnormally high T1/2 occurred in patients with coronary stenosis greater than 75%. In patients with comparable stenosis of the left anterior descending artery, the apical T1/2 was significantly increased in those with impaired apical wall motion, while it was significantly decreased in those with coronary collateral vessels. These findings suggest that regional myocardial blood flow begins to decrease in vessels with greater than 75% stenosis, and that myocardial contraction and collateral flow are additional factors that modify regional myocardial blood flow. Thus, the contrast disappearance half-life (T1/2) derived by computerized washout analysis of digital subtraction coronary arteriograms proved useful as an index for quantitative evaluation of regional myocardial blood flow.

Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy.

OBJECTIVES: The present study investigated the long-term changes in the electrocardiographic (ECG) hallmarks of the Japanese form of apical hypertrophy. BACKGROUND: Giant negative T waves and tall R waves in the left precordial leads are the ECG hallmarks of the Japanese form of apical hypertrophy. However, the long-term course is largely unknown. METHODS: Twenty-nine patients with apical hypertrophy (26 men, 3 women, mean age +/- SD 50.4 +/- 8.2 years) who showed left precordial giant negative T waves (< or = -10 mm) and tall R waves (> or = 26 mm) and spade configuration in the left ventriculogram were followed up for 10.9 +/- 3.7 years. RESULTS: The intermediate follow-up ECGs (5 to 9 years) showed disappearance of giant negative T waves in 31% and of tall R waves in lead V5 in 6%. At the long-term follow-up study (> or = 10 years), loss of giant negative T waves increased to 71%, with average T wave negativity in lead V4 or V5 decreasing from -16.5 +/- 5.1 to -6.9 +/- 4.2 mm. These T wave changes were associated with decreases in R wave amplitude in lead V5 from 40.7 +/- 9.6 to 26.1 +/- 13.8 mm, with loss of tall R waves in lead V5 in 38% of patients and development of abnormal Q waves in two patients. CONCLUSIONS: During the long-term follow-up of the Japanese form of apical hypertrophy, giant negative T waves disappeared in association with decreases in R wave amplitude in lead V5, indicating that these ECG hallmarks are clinical features that evolve progressively during the natural course of the disease.

Cyclic flow variations in a conscious dog model of coronary artery stenosis and endothelial injury correlate with acute ischemic heart disease syndromes in humans.

OBJECTIVES: The purpose of this study was to test the hypothesis that episodes of cyclic flow variations (CFVs) in conscious dogs with coronary stenoses and endothelial injury correlate with acute ischemic heart disease syndromes in humans. BACKGROUND: Although the canine model with CFVs has proved to be a useful model of coronary thrombosis, whether CFVs progress to these syndromes has not been clearly described. METHODS: Cyclic flow variations were produced by an external constrictor placed at the site of the left anterior descending coronary artery with injured endothelium. Blood flow in this artery and 24-h Holter electrocardiogram (ECG) were recorded during the 1st 5 postoperative days. RESULTS: Of 41 dogs that underwent the initial operative procedure successfully, 29 developed an episode of CFVs. In five dogs in which CFVs persisted throughout the monitoring period, the left anterior descending coronary artery flow decreased until day 3 and thereafter increased through day 5. Transient coronary occlusion during CFVs induced ST segment changes that returned to baseline after reflow. In 12 dogs, CFVs progressed to persistent coronary occlusion, and histologic examination revealed thrombus formation at the stenotic site and evidence of myocardial infarction. Four of these 12 dogs died suddenly of ventricular arrhythmias during persistent coronary occlusion; another 5 dogs died of reperfusion arrhythmias during CFVs with no evidence of myocardial infarction. CONCLUSIONS: Conscious dogs with CFVs closely correlated with clinical acute ischemic heart disease syndromes, suggesting them to be a useful model for investigating the complex mechanisms of cellular interactions in the pathogenesis of these syndromes.

Free oxygen radicals contribute to platelet aggregation and cyclic flow variations in stenosed and endothelium-injured canine coronary arteries.

OBJECTIVES: The purpose of this study was to test the hypothesis that free oxygen radicals contribute to platelet aggregation and cyclic flow variations in stenosed and endothelium-injured coronary arteries. BACKGROUND: Although free oxygen radicals, such as superoxide anion and hydrogen peroxide, have been shown to alter platelet function in vitro, the potential role of free oxygen radicals has not been fully described in an in vivo model of coronary artery thrombosis. METHODS: Cyclic flow variations were produced in dogs by an external constrictor placed at the site of the left anterior descending coronary artery with injured endothelium. Blood flow in this artery was monitored by a pulsed Doppler flow probe. If cyclic flow variations were observed during postoperative days, dogs intravenously received superoxide dismutase plus catalase. In anesthetized dogs that did not develop an episode of cyclic flow variations, the effect of intracoronary infusion of xanthine plus xanthine oxidase or hydrogen peroxide on arterial blood flow velocity was studied. In platelet studies, the effect of free oxygen radicals and radical scavengers on platelet aggregation was examined. RESULTS: In conscious dogs with cyclic flow variations, superoxide dismutase plus catalase significantly reduced cyclic flow variations (n = 7), whereas saline infusion had no effect (n = 7). The infusion of xanthine plus xanthine oxidase or hydrogen peroxide significantly induced cyclic flow variations in four of six dogs or in five of seven dogs, respectively. In vitro platelet studies showed that xanthine plus xanthine oxidase or hydrogen peroxide significantly enhanced platelet aggregation, and superoxide dismutase or catalase significantly inhibited such aggregation. CONCLUSIONS: Reduction of free radical formation decreases platelet aggregation and may eliminate cyclic flow variations, whereas promotion of free radical generation enhances platelet aggregation and may induce cyclic flow variations. Thus, free oxygen radicals are an important mediator in this model.

Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats.

Nitric oxide inhibits proliferation and migration of vascular smooth muscle cells and contractility of cardiomyocytes in vitro. In spontaneously hypertensive rats (SHR), evidence suggests intrinsic abnormalities of the L-arginine-nitric oxide axis, such as low cGMP-dependent protein kinase in the heart and abnormal L-arginine metabolism. To investigate the in vivo effect of L-arginine on cardiac hypertrophy, 30 SHR and 30 Wistar-Kyoto rats (WKY) were randomly grouped to receive L-arginine (7.5 g/L in drinking water) or vehicle for 12 weeks. L-Arginine treatment did not affect body weight or arterial pressure in either strain. In vehicle-treated animals, the heart/body weight ratio was significantly higher in SHR than in WKY (P < .01). L-Arginine treatment decreased the heart/body weight ratio in SHR (P < .05) but did not affect it in WKY. Expression of skeletal alpha-actin mRNA, known to be expressed in the hypertrophied myocardium, was attenuated in L-arginine-treated SHR compared with vehicle-treated SHR. Cardiac cGMP content and nitrate/nitrite content were less in SHR than WKY. L-Arginine treatment increased these levels only in SHR, suggesting enhanced nitric oxide production. Thus, chronic L-arginine administration attenuated cardiac hypertrophy independently of blood pressure and increased myocardial content of cGMP and nitrate/nitrite. Our results suggest that abnormality of the cardiac L-arginine-nitric oxide axis may play an important role in the pathogenesis of cardiac hypertrophy in SHR.

Hypertension induced by nitric oxide synthesis inhibition is renal nerve dependent.

Recent studies have indicated that chronic administration of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, produces marked hypertension. Although the mechanism of this form of hypertension is not well understood, several studies have demonstrated that sympathetic nerve activity is at least acutely elevated after L-NAME administration. To evaluate the potential role of the renal sympathetic nerves in L-NAME-induced hypertension, we compared the blood pressure response to L-NAME in four groups of Sprague-Dawley rats (n = 8 each): (1) sham-operated vehicle-treated, (2) sham-operated L-NAME-treated, (3) denervated vehicle-treated, and (4) denervated L-NAME-treated. After renal denervation or sham surgery, L-NAME was added to the drinking water (70 mg/100 mL) for 4 weeks, and arterial pressure was measured weekly by the tail-cuff method. L-NAME treatment caused a progressive increase in arterial pressure in sham-operated rats, rising to 154 +/- 6 mm Hg by week 4 of treatment compared with 115 +/- 2 mm Hg in the vehicle-treated sham-operated group (P < .005). In contrast, the development of hypertension was significantly delayed and attenuated in renal-denervated rats treated with L-NAME. The results of our study suggest that L-NAME-induced hypertension may be partly mediated by or is at least dependent on the integrity of the renal nerves.

Decreased coronary vasodilatory capacity in hypertrophic cardiomyopathy determined by split-dose thallium-dipyridamole myocardial scintigraphy.

Split-dose thallium-dipyridamole myocardial scintigraphy was performed in patients with nonobstructive hypertrophic cardiomyopathy (HC) who had angiographically normal coronary arteries. The dipyridamole-induced increases in thallium-201 uptake, calculated to evaluate coronary vasodilatory capacity, were significantly lower in 30 patients with HC than in 13 control subjects (177 +/- 58 vs 281 +/- 46%) and the reductions were observed in both the septal and lateral segments. The reductions of the septal segment in HC patients were significantly greater than those in 10 hypertensive patients with comparable degrees of septal hypertrophy. Of patients with HC, 16 had increases in thallium uptake well below the normal range. Compared with those having normal increases, these patients had significantly lower exercise duration (11 vs 15 minutes), with 33% having ST depression develop at a workload less than or equal to 80 watts. These data indicate that approximately one-half of patients with HC have impaired coronary vasodilatory capacity that could be an important pathophysiologic abnormality of HC resulting in the development of myocardial ischemia and the impairment of cardiac performance during exercise.

Increased left ventricular function as an adaptive response in vibration disease.

Vibration disease results from the long-term use of vibrating tools. Vibration, noise, and cold are stressors that impair the human body, inducing vibration disease. From echocardiographic methods, the left ventricular ejection fraction in vibration disease was 79 +/- 4%, a significantly higher value than that in control subjects (75 +/- 6%) (p less than 0.01). The increase in ejection fraction appeared to be due mainly to an increase in left ventricular end-diastolic dimension. The value of the ejection fraction was proportional to the activity of the autonomic nerves. The stroke volume index in patients with vibration disease was also significantly larger than that in the control subjects (p less than 0.001). Electrocardiograms revealed a significantly lower heart rate at rest and an increase in the ratio of T waves to R waves in precordial lead V6. These data suggest that the cardiovascular system in patients with vibration disease provides an adaptive response to the stressors.

Postoperative erythroderma after cardiac operations. The possible role of depressed cell-mediated immunity.

Erythroderma as a manifestation of graft-versus-host disease after cardiac operations with blood transfusion may occur more frequently in Japan than in other countries. We have seen this problem in five patients who, after heart operations, died with symptoms and signs characteristic of graft-versus-host disease: cutaneous eruption, fever, diarrhea, leukopenia associated with agranulocytosis, and liver dysfunction. In the three patients seen most recently, skin biopsy showed findings similar to those of graft-versus-host disease after bone marrow transplantation. In addition, immunologic investigation showed remarkable differences in the findings in these patients and in those who did not have a graft-versus-host disease-like syndrome after cardiac operations. In particular, interleukin-2 production in response to mitogen stimulation was markedly diminished after operation in our patients, and the ratio of OKT4+ cells to OKT8+ cells in peripheral blood was low, reflecting increased numbers of OKT8+ cells after the occurrence of symptoms. The results raise the possibility that transient depression of cellular immunity after cardiac operations with blood transfusion may contribute to the occurrence of postoperative acute graft-versus-host disease.

Association of hyperinsulinemia and serum free fatty acids with serum high density lipoprotein-cholesterol.

A total of 155 Japanese subjects (79 men and 76 women) who were classified as having normal or borderline glucose tolerance, according to the criteria for the 50-g oral glucose tolerance test (GTT) of the Japanese Diabetes Society, were analyzed for factors related to serum high density lipoprotein (HDL)-cholesterol concentration, especially the responses of insulin and free fatty acid (FFA) after a glucose challenge. In men, significant negative univariate correlations were observed with body mass index (P < 0.01), the summed values of triceps and subscapular skin-folds (P < 0.01), serum insulin concentration at all time intervals, and serum FFA at 30 and 60 min of GTT. Serum insulin at 60, 120, and 180 min, sum insulin, and FFA at 30 and 60 min of GTT were significantly related to serum HDL-cholesterol after adjustment for body mass index and triglyceride concentration. Multiple linear regression analysis with the step-forward method showed that sum insulin (P < 0.01), FFA at 60 min of GTT (P < 0.001), and alcohol consumption (P < 0.01) were independently related to serum HDL-cholesterol concentration. Only the triglyceride concentration was inversely correlated (P < 0.05) with HDL-cholesterol concentration in women. These data indicate that both insulin and FFA concentration, as markers of insulin resistance, apparently influence on HDL kinetics in men, but not in women. The lack of this association in women was appeared to related to the degree of obesity.

Soluble form of P-selectin in patients with acute myocardial infarction.

BACKGROUND: P-selectin, an integral membrane glycoprotein of platelets and endothelial cells, is rapidly redistributed to the cell surface after cellular activation. The soluble form of P-selectin has been shown to be present in people with normal circulation. The purpose of the present study was therefore to examine the soluble form of P-selectin in patients with acute myocardial infarction (AMI). METHODS: Whole blood was obtained from nine patients with AMI and from 10 volunteers who made up the control group. Plasma concentrations of the soluble form of P-selectin were examined with a monoclonal antibody-based enzyme immunoassay. RESULTS: Plasma P-selectin levels in control volunteers were 178 +/- 44 ng/ml. In patients with AMI, plasma P-selectin levels on days 1, 2 and 3 were 743 +/- 374, 627 +/- 267, and 588 +/- 223 ng/ml, respectively (P < 0.001)--significantly higher than the levels in the control volunteers. CONCLUSION: Plasma concentrations of the soluble form of P-selectin were markedly higher in patients with AMI, suggesting the activation of platelets, or endothelial cells, or both. Thus, quantitative measurements of plasma P-selectin concentrations may help to assess the pathophysiology of inflammatory reactions in patients with AMI.

Indium-111 antimyosin monoclonal antibody Fab imaging in patients with cardiomyopathy.

Six patients with cardiomyopathy were imaged following intravenous injection of an indium-111 labeled monoclonal antibody directed against the heavy chain of cardiac myosin. Two patients had hypertrophic non-obstructive cardiomyopathy (HNCM), two patients had dilated cardiomyopathy (DCM), and two patients had specific heart muscle disease. One of 2 patients with HNCM and one of 2 patients with DCM had a positive antimyosin scan. The 2 patients with specific heart muscle disease manifested persistent blood pool activity of the antibody, thereby precluding interpretation of the images. The present report demonstrates that antimyosin antibody imaging may provide evidence of myocardial injury, or necrosis in some patients with cardiomyopathy.

Noninvasive assessment of the autonomic nervous tone in angina pectoris: an application of digital plethysmography with auditory stimuli.

To assess the relationship between autonomic nerve activity and the anginal attack, we examined the daily variation of the autonomic tones employing digital plethysmography with auditory stimuli, and also tested the daily variation of exercise capacity. Thirteen of 45 cases (28.9%) of spontaneous angina, excluding Prinzmetal's angina, complained of typical chest discomfort or pain especially in the morning. They manifested an augmented level of the autonomic nerve activity and positive stress testing. The remainder did not demonstrate these abnormal findings in the morning. For the 13 cases, calcium antagonists were given orally immediately after awakening. This resulted in the complete relief from chest discomfort or pain. These findings suggest that an autonomic imbalance plays an important role in the pathogenesis of this type of anginal attack. Thus, the estimation of the daily variation of autonomic nervous tone would be valuable for the diagnosis and treatment of angina pectoris.

Further observations of the digital plethysmography in response to auditory stimuli and its clinical applications.

Further observations of the digital plethysmography with auditory stimuli and its clinical applications were performed in patients with vibration disease and heart diseases. The responsive pattern to the auditory stimuli in the digital plethysmogram could be faithfully reproducible if it elapses more than 5 minutes apart between the first stimulus and the second one. The responsive patterns were divided into four types: normal (N), hyperreactive (I and D) types and hyporeactive (P) type. The values of urinary catecholamine increased in parallel to the activity level of the autonomic nerve. The hyperreactive type (D) had the highest value of urinary catecholamine, and vice versa. With regard to the age, the elderly was prone to show hyporeactive (P) type, and the young tended to be hyperreactive (D) type. Psychologic factors were examined by Cornell medical index. Neurosis was not necessarily related to the hyperreactive type. In clinical applications, it was observed by this method that the autonomic imbalance in patients with vibration disease, angina pectoris, or hypertension was recovered by the treatment, and the abnormal types of the response recovered to N type. In conclusion, the digital plethysmography with auditory stimuli as one of the autonomic nerve function tests would be much useful and non-invasive method for observation of clinical course and decision of the severity.

Aneurysm of the ductus arteriosus.

A 59-year-old man with an aneurysm of the ductus arteriosus is described. Macroscopically and histologically it was ascertained that the aneurysm had originated from the ductus arteriosus itself. We suggest the following pathogenesis: after obliteration of the pulmonary end, the aneurysm was formed, and as a result of a gradual increase in pressure in the lumen, the obliterated pulmonary end, the aneurysm was formed, and as a result of a gradual increase in pressure in the lumen, the obliterated pulmonary end recanalized.

Evaluation of the intramembrane particle count in biopsied myocardium from patients with idiopathic cardiomyopathy.

To clarify the abnormalities of myocardial membrane structure in cardiomyopathy, the density of intramembranous particles (IMP) of mitochondria, sarcoplasmic reticulum and sarcolemma, and the number of caveolar necks was evaluated by freeze-fracture morphology. The subjects consisted of 17 patients with hypertrophic cardiomyopathy (HCM), 6 patients with dilated cardiomyopathy (DCM), and 7 patients as controls. The results showed that the numbers of IMPs on the membrane faces of mitochondria, sarcoplasmic reticulum and sarcolemma were significantly decreased in HCM and DCM, and that they were decreased more markedly in DCM than in HCM. The number of caveolar necks was significantly decreased in DCM. Thus, the decreased numbers of IMPs on myocardial membranes and the decrease in caveolar necks may be important characteristics resulting from abnormal myocardial membrane metabolism in cardiomyopathies, HCM and DCM.

Alterations in beta-adrenergic receptor density and cyclic-AMP level in the myocardium of rats chronically treated with alcohol.

An impaired function of the myocardial beta-adrenergic receptor system has been reported in patients with end-stage heart failure and this impairment has been postulated to be a factor in further deterioration of cardiac contractile function. As ventricular dysfunction is often associated with prolonged alcohol abuse, we investigated whether or not chronic administration of ethanol could induce alterations in the beta-adrenergic receptor adenylate-cyclase system in rats. Male Wistar rats of 8 weeks of age received 33% ethanol in drinking water for 3 months. As compared with control rats drinking water, the ethanol-treated rats showed weight loss and an increase in the heart/body weight ratio. Chronic ethanol increased myocardial contents of norepinephrine and epinephrine, possibly resulting from sympathoadrenal activation. The beta-adrenergic receptor density (Bmax) of the myocardial membrane was significantly decreased in the ethanol-treated rats (27.7 +/- 9.9 vs 39.0 +/- 6.0 fmol/mg protein, p < 0.01), while the affinity (Kd) did not differ between the two groups. The myocardial content of cyclic-AMP was also reduced in the ethanol rats (865 +/- 59 vs 1055 +/- 83 pmol/g w.w., p < 0.01). These observations indicate that chronic ethanol administration depresses the function of the beta-adrenergic receptor adenylate-cyclase system. The decreased beta-adrenergic receptor density was partly attributed to down-regulation due to increased sympathetic stimulation. This impaired function may contribute to the cardiac contractile dysfunction observed in chronic alcoholics.

[Field epidemiological investigation on an outbreak of Chlamydia pneumoniae infection--first recognized incidence in a nursing home for elderly in Japan].

Chlamydia pneumoniae (C. pneumoniae) is an emerging pathogen recognized in 1989. Although C. pneumoniae infection is known to give a great impact on public health in western countries, many aspects remain unclarified in Japan. During December 1999 and March 2000, respiratory symptoms among residents and employees in a nursing home for elderly implicated an outbreak of C. pneumoniae infection. Field epidemiological investigation confirmed that this is the first outbreak recognized in a nursing home setting in Japan, involving 31/59 (15 confirmed) residents and 9/41 (2 confirmed) employees. Fifteen residents developed severe C. pneumoniae infections including one fatal outcome with pneumonia. Epidemiological analysis did not identify risk factors which induce infection or severe illness by C. pneumoniae for the residents. However, for the employees, frequent contact with the residents was demonstrated as a significant risk factor for the infection. None of 13 employees who had no contact with the residents presented C. pneumoniae infection, while nine out of 28 employees who had frequent contact developed C. pneumoniae infections (RR infinite, P = 0.04). These results indicated that C. pneumoniae infection spread gradually by human-to-human droplet transmission without specific risk factors. This study raised current problems in diagnosing and treating the C. pneumoniae infection and the need to enhance the awareness of this disease.

[Detection and localization of multiple metastases from differentiated thyroid carcinoma with 99mTc-MIBI whole body scintigraphy: a case report].

A 79-year-old male with a history of total thyroidectomy due to follicular thyroid carcinoma developed multiple metastases in the lung, bone, and lymph nodes. In order to detect and localize every metastases, 99mTc-MIBI whole body scintigraphy was performed, and clearly depicted all metastatic lesions except tiny pulmonary nodules. 99mTc-MIBI whole body scintigraphy may be useful in detecting metastases from differentiated thyroid carcinoma, because of a good quality of scintigram and no need of patient preparation. This article is the first report on 99mTc-MIBI localization in multiple metastases from differentiated thyroid carcinoma.