Genetic forms of human dilated cardiomyopathy (DCM) are briefly discussed, and a variety of animal models of genetic DCM are presented, some of which are caused by the gene mutations that also cause DCM in humans. The forms of DCM related to mutations or deletion of genes coding for extrasarcomeric or intrasarcomeric proteins, as well as to overexpression or knockout of genes in the β-adrenergic signaling pathway, are included. Finally, novel approaches to treatment in experimental animal models are discussed, including double transgenesis and newer recombination methods, as well as in vivo somatic gene transfer which, based on initial experiments in animals, seems likely to find eventual application in human cardiac failure. (Circ J 2002; 66: 219 -224)

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Therapy for heart failure has traditionally been directed to such short-term functional abnormalities as low cardiac output, high filling pressures, and fluid retention. More recently, it has become clear that therapy must also inhibit the proliferative responses that contribute to the progressive deterioration of the failing heart. That heart failure is more than a hemodynamic disorder became apparent when clinical trials showed that drugs that improve such functional abnormalities as high venous pressure and low cardiac output failed to improve long-term prognosis. Most vasodilators, in spite of alleviating short-term problems caused by excessive afterload, increase long-term mortality; the notable exceptions are ACE inhibitors, the ability of which to prolong survival and inhibit remodeling can be attributed to inhibition of proliferative signaling. Other clinical trials showed that inotropic drugs, while providing immediate relief of symptoms, generally shorten long-term survival, whereas β-adrenergic receptor blockers, which inhibit proliferative signaling by norepinephrine, improve prognosis. These findings can be explained by crossovers between functional and proliferative signaling, among the most important of which is the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious proliferative responses in the failing heart. The emerging understanding of the role of cytoskeletal and cell adhesion molecules in activating maladaptive proliferative responses suggests additional targets for therapy, and the rapid pace of discovery in molecular biology promises additional opportunities to inhibit this abnormal signaling, which causes progressive ventricular dilatation (remodeling) and cardiac cell death, now recognized to be major problems in this syndrome. (Circ J 2002; 66: 225 - 231)

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The purpose of this study was to clarify the activities that trigger the onset of acute aortic dissection (AAD) and their relation to the occurrence of AAD. The study group comprised 444 consecutive patients referred for spontaneous AAD. From the hospital medical records, the activities that triggered AAD could be identified in 307 of these: most (86.6%) AAD episodes occurred in relation to physical (73.6%) or mental (13%) activities. In the older (≥61 years) population, AAD occurred significantly more frequent during sleep or rest than in the younger (≤60 years) population (16.9% vs 7.6%, p=0.020). The relationship between the time of onset and the triggering activity of AAD could be assessed in 267 patients. The onset of AAD was predominantly during the day: 63.3% of the episodes occurred between 06.00 h and 18.00 h, and were significantly more related to physical or mental activities than the nighttime events (95.3% vs 70.4%, p<0.0001). Most (86.6%) of the AAD episodes were related to physical or mental stress, particularly those that occurred during the day. (Circ J 2002; 66: 232 - 235)

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Electrocardiographic recognition of the P' wave during tachycardia is very useful in the diagnosis of supraventricular tachycardias. In slow/fast (S/F) atrioventricular nodal reentrant tachycardia (AVNRT), no discrete P' waves are observed on ECG and pseudo r' deflection in lead V₁ (pseudo r') is commonly recognized. However, the atrial components that contribute to the genesis of pseudo r' in lead V₁ have not been described and this study aimed to clarify them by analysis of the whole activation sequence of the right atrium using Basket catheter isochronal mapping. The study group comprised 48 patients with AVNRT. Pseudo r' was defined as an upward deflection in the terminal portion of the QRS complex during tachycardia that was not recognized during sinus rhythm and it occurred in 45 patients (94%). During S/F AVNRT, the retrograde atrial activation was earliest on His bundle electrogram, followed by the coronary sinus ostium, distal coronary sinus and high right atrium. Only the high lateral aspect of the right atrium was activated after the end of the QRS complex. The interval between the onset of QRS in multiple surface ECG leads and the atrial activities on high right atrium was similar to the V-r' interval in lead V₁ (111 ±20 ms, 117±11 ms) and correlated with the V-r' interval (r=0.56). Pseudo r' deflection in lead V₁ is a highly sensitive indicator of S/F AVNRT, and appears to result from the activation of the superolateral aspect of the right atrium. (Circ J 2002; 66: 236 - 240)

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Cilostazol, a novel cyclic adenosine monophosphate phosphodiesterase type III inhibitor, has been developed as an antiplatelet drug with a vasodilating action on peripheral arteries. The present study was designed to test, in humans, whether cilostazol can dilate the epicardial coronary arteries and what are its hemodynamic effects. Eight patients with chest pain syndrome were subjected to serial quantitative coronary arteriography immediately before and at 30, 60 and 150 min after a single oral dose of cilostazol (200 mg). Luminal cross-sectional areas (mm²) at the proximal and distal sites of major coronary arteries (6 segments at each sampling time) were significantly increased at 150 min after taking the drug. The percent increases relative to the baseline values were 25±7 (6.8±0.8 →8.3±1.0*) and 42±7% (2.1±0.3→3.0±0.4*) in the right coronary artery, 24±5 (5.1±0.7 →6.1±0.8*) and 28±10% (1.6±0.3→1.9±0.3*) in the left anterior descending artery, and 14±6 (5.9±0.9→6.6±0.9*) and 24±10% (1.3±0.2→1.5 ±0.2*) in the left circumflex artery, respectively (*p<0.05 vs baseline). This action, relative to that of nitroglycerine, was between 27% and 54%. Moreover, small but sustained decreases in systolic pulmonary pressure and stroke work index were observed. Thus, cilostazol has a mild coronary vasodilating action with minimal hemodynamic effects, thereby giving it a possible role in the treatment of coronary artery disease. (Circ J 2002; 66: 241 - 246)

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The relationship between baroreceptor sensitivity (BRS) and cardiac sympathetic nerve function after acute myocardial infarction (AMI) was investigated in 34 patients. BRS was measured during the Valsalva maneuver and cardiac sympathetic function was assessed by the washout rate (WR) of I-123 meta-iodo-benzyl guanidine (¹²³I-MIBG) with planar image (global WR) and polar map analysis (regional WR). Gated left ventricular ejection fraction (LVEF) measured by left ventriculography as a parameter of ventricular function was measured with quantitative gated SPECT (QGS). The gated LVEF correlated with global WR (r=-0.36, p=0.034) and regional WR of normal area (r=-0.46, p=0.006), but not with BRS, although BRS correlated with global WR (r=-0.43, p=0.015) and regional WR of normal area (r=-0.72, p<0.0001). After AMI, baroreceptor function is linked to sympathetic activation, as elucidated by the regional WR of normal area, which suggests that separation of the infarcted area from the non-infarcted myocardium is necessary for evaluating sympathetic activation after AMI and that the regional kinetics of ¹²³I-MIBG in the normal area are a more suitable marker of activated cardiac nerve function than global ¹²³I-MIBG kinetics. (Circ J 2002; 66: 247 - 252)

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Hepatocyte growth factor (HGF) is a well-known powerful proliferative factor of vascular endothelial cells and it has been reported that plasma HGF concentrations are increased in acute myocardial infarction (AMI), although the mechanisms are not yet well delineated. Serum HGF levels and C-reactive protein (CRP) were measured in 22 patients with unstable angina pectoris (UAP) (15 males, 7 females; class IIb or IIIb of the Braunwald classification), 60 patients with AMI (37 males, 23 females; average time from the onset of symptoms to admission 4.6±0.7 h, range, 0.5-12 h), and 20 normal subjects. Immediate angioplasties were performed in 51 patients with AMI, and the time course of the HGF levels were measured in 31 patients among them. Heparin dramatically increased the HGF level and it declined to the normal range 18 h after heparin injection. Blood samples were taken before heparin treatment, or at least 24 h after. Serum HGF levels on admission was significantly increased in UAP (mean ± SE: 0.30±0.03 ng/ml, p<0.01), and AMI (0.27±0.02 ng/ml, p<0.01) compared with the normal subjects (0.19±0.01 ng/ml). Even in the early stage (within 3 h of onset of symptoms to admission, average time was 1.8±0.1 h), serum HGF levels were already elevated (0.25±0.02 ng/ml, p<0.05). There was no significant difference between the HGF levels in UAP and AMI. Fifty-one of the 60 patients with AMI underwent immediate percutaneous transluminal coronary angioplasty and blood samples were obtained from 31 of them on days 7, 14, and 21 after MI. Serum HGF levels peaked on day 7 (0.34±0.04 ng/ml, p<0.01) and there was a weak relationship between peak creatine kinase and serum HGF levels at that time. A statistically significant correlation was found between peak CRP and serum HGF levels on day 7 (r=0.62: p<0.001). Serum HGF levels decreased to nearly normal by day 21 (0.22±0.01 ng/ml). The study shows that serum HGF levels during the early stage of AMI increased significantly and peaked by day 7 after the onset, at which time there was a strong correlation with peak CRP levels. These data suggest that HGF production may be related to the inflammatory response in AMI. (Circ J 2002; 66: 253 - 256)

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The incidence of acute pulmonary thromboembolism (APTE) in Japan is quoted as being extremely low compared with the United States, and the incidence and clinical characteristics of chronic pulmonary thromboembolism (CPTE) in Japan is unknown, so this study investigated these aspects of CPTE in 309 patients with APTE and 68 patients with CPTE. The ratio of the incidence of CPTE to APTE was 0.22 and there was no significant difference in age or sex between the APTE and CPTE patients. All of the predisposing factors for pulmonary thromboembolism, except for thrombophilia, were more frequently seen in the patients with APTE. There are some differences in the incidence and clinical characteristics of CPTE compared with APTE between Japanese and American patients in Japan, suggesting that the pathogenesis of CPTE in Japan may differ from that in the USA. (Circ J 2002; 66: 257 - 260)

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The present study was designed to determine whether exercise plasma noradrenaline (NA) levels could predict cardiac death in patients with mild heart failure in whom the plasma NA levels were only minimally elevated. Treadmill exercise testing with serial measurement of plasma NA and plasma adrenaline were performed in 142 patients with heart failure (New York Heart Association class I-II; age, 58±12 years) and 26 age-matched normal subjects. During a median follow-up of 9.6 years, 27 cardiac deaths occurred among the patients. By univariate Cox proportional hazard analysis, left ventricular end-systolic dimension (p<0.001), age (p<0.01), peak exercise heart rate (p<0.01), exercise plasma NA level (p<0.01) and left ventricular ejection fraction (p<0.001) were identified as significant prognostic markers. In a multivariate analysis, exercise plasma NA level was identified as the most powerful prognostic marker (p<0.001), followed by left ventricular end-systolic dimension and peak exercise heart rate. In addition, from the Kaplan-Meier analysis, patients with a supramedian level of exercise plasma NA concentration (NA ≥840 pg/ml) had a significantly lower survival rate than those with an inframedian level (p<0.01). Exercise plasma NA levels can provide prognostic information in patients with mild heart failure, which suggests an important role of exercise-induced activation of sympathetic nervous system activity in the prognosis of patients with mild heart failure. (Circ J 2002; 66: 261 - 266)

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The present study was designed to examine whether elevated levels of lipoprotein(a) (Lp(a)) are related to the impairment of the endothelium-dependent vasoresponse to acetylcholine (ACh) in normocholesterolemic and non-diabetic human normal coronary arteries. ACh (30 μg) was injected into the left main coronary artery of 31 patients (serum low-density cholesterol <160 mg/dl and fasting plasma glucose <126 mg/dl) with angiographically normal coronary arteries, and the relation between diameter change and lipid levels was analyzed. The mean diameter change of all coronary segments examined (segments 6, 8, 11 and 13) was reduced by 14.6±26.5% in response to ACh, but increased by 23.3±6.0% in response to nitroglycerin, suggesting endothelial dysfunction in those arteries. The mean diameter change of the left anterior descending artery or left circumflex artery in each patient was negatively correlated only with the level of Lp(a). Stepwise multiple regression analysis also revealed that only Lp(a) among the lipids showed significant correlation with impaired vasodilation (p=0.033). These findings suggest that elevated levels of plasma Lp(a) might be a strong predictor of endothelial dysfunction in normocholesterolemic and non-diabetic subjects. (Circ J 2002; 66: 267 -271)

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Apolipoprotein E-knockout (apoE-KO) mice have been used for studying atherogenesis, but the in vivo features including cardiovascular function have not yet been reported. This study aimed to noninvasively evaluate cardiovascular lesions in 6 apoE-KO mice and 6 control (C57BL/6) mice using transthoracic echocardiography performed using an originally developed linear scanner that permits a high-speed scan with wideband high-frequency ultrasound. Two independent observers evaluated and scored the degree of atherosclerotic changes in the aortic root from 2-dimensional long-axis and short-axis images. M-mode measurements included left ventricular end-diastolic dimension (LVDd), posterior wall thickness (LVPWT), fractional shortening, aortic root dimension and rate of systolic expansion of the aorta (%SEAo). The wall thickness of the aortic root was measured from the serial histological sections. Significant differences between apoE-KO and C57BL/6 mice were found in the atherosclerotic score, %SEAo, LVDd and LVPWT. The atherosclerotic score and %SEAo were significantly correlated with the aortic wall thickness. Transthoracic echocardiography with a high-frequency ultrasound system can detect atherosclerotic lesions and the decreased distensibility of the ascending aorta, as well as secondary changes in left ventricular geometry, in apoE-KO mice. (Circ J 2002; 66: 272 -276)

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To examine the effect of vasopressin on the sarcolemmal ATP-sensitive K (K_ATP) channel, cell-attached, inside-out and open-cell-attached methods of patch clamp techniques were used in isolated guinea pig ventricular myocytes. Suppressing both glycolytic and oxidative ATP production attained K_ATP channel activation. In the cell-attached mode, vasopressin inhibited K_ATP channels in a concentration-dependent manner with an IC₅₀ of 15.1 ±1.8 nmol/L. In the inside-out configuration, vasopressin failed to block K_ATP channels. In the cell-attached mode, manning compound (1 μmol/L), a V₁ receptor-selective antagonist, blocked the inhibitory action of vasopressin, although OPC-31260 (1 μmol/L), a V₂ receptor-selective antagonist could not affect the action of vasopressin. In addition, vasopressin lost its inhibitory action on K_ATP channels when the channel was activated by pinacidil, a K channel opener and in the open-cell-attached mode effected by streptolysin-O. Thus, the inhibitory action of vasopressin K_ATP channels may occur via V₁ receptor related mechanism. (Circ J 2002; 66: 277 - 282)

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The present study compared autonomic nervous function in Kob [Spontaneously Diabetic, Bio-Breeding (BB)] rats with control Wistar rats to determine the development of cardiac neuropathy in diabetic rats. Telemetric ECG signals were obtained from an ECG radio-transmitter placed in a dorsal subcutaneous pouch of male Kob and Wistar rats for 30 min every 6 h at a sample rate of 5 kHz. Heart rate (HR) and HR variability (HRV) were analyzed in each group by power spectrograms obtained by a fast Fourier transform algorithm. RR interval, total power (TP), low frequency (LF) power (0.04-0.67 Hz), high frequency (HF) power (0.79-1.48 Hz) and LF/HF ratio were also measured. The Kob rats had lower HRV than the control Wistar rats; HR, TP, and HF power, but not the LF/HF ratio, in the Kob rats were significantly lower than those of the control rats (p<0.001). However, in the Kob rats the response of these parameters to a muscarinic antagonist (atropine: 2 mg/kg) was left intact, but their response to a β-adrenergic antagonist (propranolol: 4 mg/kg) was impeded. Autonomic nervous control of HR in spontaneously diabetic rats was inhomogeneously deranged in terms of the balance in sympathetic and parasympathetic tone, not only in the baseline condition, but also in the regulatory systems, including postsynaptic receptor function. (Circ J 2002; 66: 283 - 288)

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The purpose of this study was to examine the effects of nipradilol on the cardiac function and mRNA expression in Wistar rats with a myocardial infarction (MI) that was created by ligation of the anterior descending coronary. Ten mg · kg ^-1 · day^-1 of nipradilol were administrated to the rats in random order, and hemodynamic and Doppler-echocardiographic findings and myocardial mRNA expression were analyzed at 4 weeks after MI. Although left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) were increased in the MI rats, nipradilol significantly reduced the degree of the increase in both parameters. MI also significantly increased the weight of the left and right ventricles, and increased the left ventricular end-diastolic dimension (LVDd), effects that were attenuated by nipradilol. The MI rats showed decreased fractional shortening as systolic dysfunction and decreased E wave deceleration rate as diastolic dysfunction, and nipradilol significantly prevented these. Nipradilol significantly suppressed the increase in the non-infarcted myocardial mRNA expression of atrial natriuretic peptide, brain natriuretic peptide and collagen I and III. In conclusions, nipradilol prevents the cardiac remodeling that is accompanied by systolic and diastolic dysfunction, and inhibits abnormal myocardial gene expression after MI. (Circ J 2002; 66: 289 - 293)

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Legislation for brain death and organ transplantation was passed in Japan in 1997, but there is still a great shortage of brain-death donors. Primary pulmonary hypertension (PPH) is a progressive disease that is usually followed by death within 5 years of diagnosis. Continuous infusion of prostacyclin is effective, but some patients will ultimately require heart - lung or lung transplantation. The first case of bilateral living-donor lobar lung transplantation (LDLLT) for PPH in Japan is reported. The recipient was a 19-year-old woman who was diagnosed as PPH at the age of 14 years and began intravenous prostacyclin therapy. Initially her symptoms improved, but she returned to New York Heart Association class IV in 2000. In January 2001, she underwent bilateral LDLLT. Postoperative echocardiography showed that the right ventricular diameter had decreased and septal wall motion had normalized, resulting in a round-shaped left ventricle. Right heart catheterization demonstrated that cardiac output and pulmonary arterial pressure had normalized. The right ventricular ejection fraction improved from 15% to 77%. The patient was discharged from hospital after 60 days postoperatively. LDLLT will become one of the options in Japan for end-stage PPH. (Circ J 2002; 66: 294 - 296)

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Renovascular hypertension occasionally manifests clinically as electrolyte disorders and albuminuria in addition to elevated blood pressure. A 49-year-old man who had renovascular hypertension also had severe hypokalemia, hyponatremia, polyuria and polydipsia that were treated by an angiotensin-converting enzyme inhibitor and resection of an atrophic kidney with a compromised blood supply. This is a case of hyponatremic - hypertensive syndrome related to renovascular hypertension and occurring as an additional abnormality. (Circ J 2002; 66: 297 - 301)

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A 37-year-old woman had progressive shortness of breath and mitral stenosis was diagnosed. Despite the unusual finding of undegenerated septum primum on echocardiography and angiography, percutaneous transseptal mitral commissurotomy was successfully performed in this patient with rheumatic mitral stenosis under the guidance of online transesophageal echocardiography. (Circ J 2002; 66: 302 - 304)

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A 61-year-old woman had intermittent fever of 2 months' duration following a dental extraction. On admission, her body temperature was 39.2°C. A mid-systolic murmur was heard at the apex on ausculation. A 2-dimensional echocardiogram revealed a mobile, heavy stick-like mass with vegetation (5.0×1.5 cm) attached to the left atrial septum. Multiple blood cultures grew Streptococcus constellatus. On diagnosis of an infected left atrial myxoma, antibiotics were administered daily and 4 weeks later, the left atrial tumor was resected. The tumor was 5.3 cm long, 1.5 cm in diameter at the inter-atrial wall and had vegetation on the free edge. On microscopic examination, colonies of Gram-positive cocci were found in the thrombus, on the papillary fibroelastoma. After treatment with antibiotics for a further 4 weeks, the patient was discharged. This is the first report of infected papillary fibroelastoma. (Circ J 2002; 66: 305 - 307)

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