Traditionally the therapy for coronary heart disease has been focused on the "how-to" problem. However, the clustering of cardiovascular events around the specffic time of the day has been clarified. To solve the problems of the clustering would give us the clue to treat the coronary heart disease timely and in time. Therefore, the research has been stressed to solve "when-to" problem.
The circadian variabilities in coronary heart disease has been clarified to be the function of the biologic time. Therefore, three problems were discussed in this paper. 1) The circadian variabilites in biology should be assessed based on the biologic zero hour rather than the mid-night of the mechanical clock. Our concept of the biologic zero hours has been proposed to answer this problem. 2) Daily health care with circadian order and harmony for the prevention of the coronary risk factors should be recommended as the prevention of the acute coronary risk factors as the trigger mechanism of the cardiovascular events. 3) The chronotherapy to chronic coronary risk factors such as hypertension was discussed, In hypertension the anti-hypertensive therapy should be customized individually adjusting the circadian variability of blood pressure with the proper selection of agents and time of the administration.

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In response to a paper written by Drs. Toshima and Kawai trying to refute my earlier article on the movement for cardiac transplantation in Japan, I present the results of my survey of the opinions of medical students and student nurses to prove that polls showing a majority of people supporting organ transplantation from so-called brain-dead persons, to which transplant protagonists rely heavily, merely reflect the failure of the mass media to distrib-ute information on the negative aspects of organ transplantation to the public. Several major flaws in the logic of the proponents are pointed out to show how fragile their theoretical background is. Thus, the need for the distribution of better-balanced information to the public and continued debate on this most serious medical, ethical, social and cultural issue is emphasized.

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This study was retrospectively designed to examine if the Wiktor stent, a balloon-expandable tantalum coil stent, provides a more favorable procedural and long-term clinical and angiographic outcome than does conventional coronary balloon angioplasty (POBA). From April 1995 to April 1996, we implanted 56 Wiktor stents in 46 lesions (LAD: 23, RCA: 16, CX: 7) in 42 patients (average age 53±10 years). Coronary lesions from the stent group were matched with similar lesions of another 42 POBA patients whose characteristics were identical to the Wiktor group. Revascularization indications in the Wiktor and POBA groups, respectively, were recent myocardial infarction (RMI) (45%, 40%), unstable (31%, 39%) and stable (24%, 21%) angina pectoris. 7% of the stents and 17% of the POBA balloons were less than 3mm in diameter (p>0.05). Procedural success was significantly greater in the Wiktor group than in the POBA group (100% vs. 92%, p<0.05). Neither major cardiac event (death, CABG, acute myocardial infarction) nor (sub) acute occlusion was encountered in the Wiktor group during the hospitalization period and 1 month follow-up. There was 1 urgent CABG and 4 subacute occlusions in the POBA group. Control angiography at 8 months was performed in patients of both groups, of whom some were symptomatic at long-term follow-up or completely event free for 8 months. Angiographic restenosis (>50% diameter stenosis) occurred in 25% of the Wiktor patients and in 43% of those in the POBA group (p<0.05). For an 18 month clinical follow-up, 91% of the patients in the Wiktor group were asymptomatic and without ischemia in radionuclide imaging (RI), whereas 79% of the POBA patients were angina-free and 74% were without ischemia in the RI study.
In conclusion, Wiktor stent implantation, with no major cardiac event or subacute occlusion, provides a more favorable procedural and long-term clinical and angiographic outcome than does conventional POBA.

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ACE (angiotensin converting enzyme) gene genotypes have been shown to be a risk factor for development of left ventricular hypertrophy and cardiomyopathy, upon the assumption that the DD genotype is linked to higher cellular ACE activity leading to myocardial fibrosis. To test an analogous hypothesis that the DD genotype favors myocardial fibrosis in the atrium and thus promotes atrial fibrillation without any structural heart diseases, we determined the distribution of the ACE gene genotypes in 77 patients with lone atrial fibrillation and investigated the effects of the ACE genotypes on the clinical characteristics of atrial fibrillation. The distribution of ACE genotypes was not significantly different between the patients and healthy volunteers. Also, the ACE gene genotypes did not affect the types of atrial fibrillation and the age at the onset of atrial fibrillation. Thus, these results refuted the hypothesis of possible relationships between ACE genotypes and lone atrial fibrillation through myocardial fibrosis, and indicated some unknown differences between the atrium and ventricle.

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49 patients with 51 left-sided accessory pathways underwent radiofrequency catheter ablation for symptomatic supraventricular tachycardia via the transeptal route using specialised long vascular sheaths with compound curves. The procedure was successful in 45 patients (92%). The mean fluroscopic time was 22.5±15.2 mins and the mean procedure time was 1.7±0.5 hours. Pericardial tamponade occurred in 2 patients (4%) and 2 patients (4%) required switching to the retrograde transaortic route for successful ablation of the pathways. During the period of follow-up of 16.8±6.9 months, clinical recurrence occurred in 2 patients (4%). In conclusion, , the transeptal route of radiofrequency catheter ablation is a useful alternative strategy to the transaortic approach with good long term results. The use of specialised sheaths may help in stabilisation of the catheter during the procedure which can generate more adequate lesions and consequently a lower recurrence rate.

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We characterized the influence of the size of the left ventricular (LV) chamber (LV diastolic diameter, LVDD) and LV end-diastolic pressure (LVEDP) on left atrial active stroke index (LAASI) in patients with old myocardial infarction (OMI) (n=118) and controls (n=25). Patients with OMI were classified into four groups according to the grade of LVDD (≥55 or <55mm) and LVEDP (≥18 or <18mmHg). LAASI was determined by multiplying the LV stroke index by the fraction of left atrial active contraction of the velocity-time integral on the pulsed-wave Doppler echocardiogram. LAASI in the "LVDD≥55& LVEDP≥18" group was less than that in the groups with normal LVEDP. LAASI did not differ among the normal LV dimension groups. The combination of LV enlargement and high LVEDP was related to the decrease in LAASI in patients with OMI.

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To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 59 Indian patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 58 of these patients. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 59 years old (mean 32.9 years). No significant differences in HLA-A, HLA-B, HLA-DR and HLA-DQ frequencies between patients and controls were noted. The role of genetically determined immune-response factors in the pathogenesis of chronic rheumatic heart disease was not evident in this study.

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A total of 168 consecutive patients with predominant rheumatic mitral stenosis were evaluated by transthoracic (TTE) and transesophageal echocardiography (TEE). Of the 168 patients, 35 had previous embolic events (group I) and 133 had no emboli (group II). A total of 77 (45.8%) patients had atrial fibrillation. The frequency of atrial fibrillation was higher in group I than group II (68.6% vs 39.8%, p<0.001). The incidence of left atrial enlargement was greater in group I (p<0.001). Mitral valve area was found to be smaller in group I compared to group II (p<0.001). In group I 83.3% and 29.2% of the patients with atrial fibrillation had left atrial spontaneous echo contrast (SEC) and left atrial thrombus, respectively, and 72.7% of the patients with sinus rhythm had left atrial SEC. In group II 79.2% and 20.8% of the patients with atrial fibrillation had left atrial SEC and left atrial thrombus whereas 28.6% and 2.6% of the patients with sinus rhythm had left atrial SEC and left atrial thrombus, respectively. The incidence of left atrial thrombus was significantly different in those patients with compared to those without embolic events (20% vs 9.7%, p<0.01). In groups I and II, 28 of 35 (80%) and 64 of 133 (48.1%) patients had left atrial SEC (p<0.01). Patients with left atrial SEC had a greater left atrial size (p<0.01) and smaller mitral valve area (p<0.01). Left atrial size was normal in 2 patients with left atrial SEC and SEC was not found in 55 patients with enlarged left atrium. Multiple logistic regression analysis showed that atrial fibrillation, mitral valve area and left atrial enlargement were independent predictors of the SEC (p<0.001) and left atrial SEC was the principal determinant of thromboembolism.
These data suggest that regardless of rhythm and atrial size, left atrial SEC is a principal determinant of thromboembolic risk in mitral stenosis. TEE may be able to detect those patients with mitral stenosis at risk for emboli and guide appropriate therapy.

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Atrial septal defect (ASD) is the most common congenital heart anomaly encountered in adults. For patients over 60 years old, acceptable operative mortality and symptomatic improvement following surgery have been reported. We reviewed patients with ASD aged over 70 years and studied their preoperative hemodynamics, the surgical procedures used and the results.
Between January 1994 and December 1996, 18 patients over the age of 40 years underwent surgical repair of ASD. Four patients were over 70 years of age (Group A). The other 14 patients were studied as a control group (Group B). We compared the preoperative clinical status, hemodynamic data, and surgical results between the two groups. The postoperative clinical status of Group A was studied during the follow-up period.
The NYHA functional class of the elderly patients was greater than that of the middle-aged patients. None of the elderly patients had pulmonary hypertension. Moderate or severe tricuspid valve regurgitation (TR) due to annular dilatation was found, and tricuspid annuloplasty was performed in all four elderly patients. There were no operative or hospital deaths in either group. The NYHA functional class and TR improved in all the aged patients after surgery.
In order to prevent progressive tricuspid annular dilatation due to an intraatrial left to right shunt, surgical closure of ASD should be performed for physically active adult patients.

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In addition to obesity, abnormalities in glucose and lipid metabolism are common in hypertensives, indicating a possible link between hypertension and hyperinsulinemia. Since the frequency of obesity in Japanese is lower than that in Caucasians, the present study was designed to clarify the frequen-cies of hyperinsulinemia, glucose and lipid abnormalities, and obesity.
We surveyed consecutively 470 men without a history of gastrectomy who visited a health clinic after excluding previously known hypertensives receiving hypotensive agents (4.2%) and diabetics (6.1%). Hypertensives with a blood pressure exceeding 150 and/or 90mmHg (n=62) had a significantly higher frequency of diabetes mellitus (6.5%) associated with hypercholesterolemia (24.2%) and mild obesity with a body mass index (BMI) of more than 25 (24.2%) than those of normotensives. When reanalyzed according to the presence or absence of hyperinsulinemia after 75g oral glucose loading, hyperinsulinemic men demonstrated a higher blood pres-sure. The incidences of impaired glucose tolerance (67.1%), hypertri-glyceridemia (64.4%), low HDL-cholesterol (53.4%), hypercholesterolemia (21.9%) and mild obesity (37.0%) were also significantly higher than those of normoinsulinemic subjects. Subjects with either hypertension and/or hyperinsulinemia had a significantly higher incidence of coexistence of these risk factors. Multiple regression analysis revealed that not only BMI, but also the plasma glucose and insulin response during the 75g glucose loading test independently correlated with mean blood pressure. These results suggest that hypertensive and/or hyperinsulinemic subjects may be associated with excess cardiovascular risk and should be managed more carefully.

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The effect of additional abdominal aortic banding on parameters of heart failure was studied in male Wistar rats with myocardial infarction. Contractile function was studied 8-9 weeks after operation, with an isoprenaline dose response protocol, in a retrograde Langendorff perfusion. Also, plasma noradrenaline concentration, infarct size and morphology were determined. Compared with controls, myocardial infarction/aortic banding animals showed a decreased contractile function, both at baseline and after maximal isoprenaline stimulation, and elevated noradrenaline levels (1316±94 vs 1909±174pg/ml, both p<0.05). In myocardial infarction rats, baseline values, but not those after inotropic stimulation were decreased, when compared with controls, while the calculated E_max was significantly decreased. In aortic banding rats, contractile parameters were not significantly impaired, compared with controls. Both myocardial infarction and the myocardial infarction/aortic banding animals, but not aortic banding rats, had a significantly increased heart weight (1.4±0.04g for controls vs 1.7±0.08g for myocardial infarction and 2.0±0.12g for myocardial infarction/aortic banding), and left ventricular cavity volume (19±1.4mm³ for controls vs 49±5.5mm³ for myocardial infarction and 48±4.3mm³ for myocardial infarction/aortic banding) compared to control animals. Infarct size was 36.0% and 39.4% for the myocardial infarction and myocardial infarction/aortic banding animals, respectively.
We conclude that myocardial infarction/aortic banding provides a new experimental model, which may yield important information and pathophysiology which allow evaluation of changes that may mimic clinical myocardial infarction with concomitant hypertension.

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Numerous investigators have attempted to measure regional wall stress directly. However, the measurement systems and devices employed have been too complex for accurate quantification in situ. We have developed a new tactile sensor system for measuring accurately myocardial stiffness in situ and validated its use for estimation of myocardial contractile function.
The tactile sensor was placed on the left ventricle of five mongrel dogs, (weighing 12-17kg) and myocardial stiffness (g/mm²) was measured. Dobutamine (5.0μg/kg/min) and propranolol (0.25mg/kg) were sequentially administrated intravenously, and the change in myocardial stiffness was monitored.
Myocardial stiffness followed a time course similar to that of left ventricular pressure, indicating a close relationship with wall stress. Baseline end-systolic stiffness in 5 dogs was 2.38±0.19g/mm². After administration of dobutamine, end-systolic stiffness increased to 3.26±0.32g/mm² (p<0.01). After the administration of propranolol, end-systolic stiffness decreased significantly to 1.83±0.19g/mm² (p<0.01), compared with the baseline values.
Regional myocardial stiffness of a beating heart can be measured precisely using our new tactile sensor system. End-systolic stiffness is a useful index for accurate quantification of the regional myocardial contractile state.

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We investigated the intrinsic cardiac mechanics of myocardium and changes in titin in insulin-resistant rats. Microsonometry and micromanometry were used to evaluate the maximal elastance (E_max) and myocardial stiffness constant (K_m) of the left ventricle, in addition to the traditional systolic and diastolic cardiac function, with an isolated working heart preparation. Thirty 150g Wistar rats were divided into three groups of 10. Group A was fed rat chow, while groups B and C were fed a 66% fructose diet for 7-8 months. Group C also received clonidine. Group B rats developed insulin resistance, as well as elevated plasma glucose and blood pressure. Group C rats also had insulin resistance and elevated plasma glucose, but not higher blood pressure. Group B rats had decreased Emax, decreased peak-dp/dt, prolonged Tau and increased Km compared to normal control rats. Group C rats, which mimicked the clinical condition of diabetic cardiomyopathy, maintained normal global left ventricular function as revealed by cardiac output, peak+dp/dt, peak-dp/dt and Tau of relaxation. However, they had a lower Emax slope (355±51 vs 535±56mmHg•mm than group A rats, p<0.05) and increased Km (81.6±9.9 vs 25.5±4.8 in group A, p<0.001), even though the extent of elevation of plasma glucose was only mild (71.3±2.0 to 108.9±4.4mg/dl, p<0.001). Their left ventricular mass, myocyte size, interstitial fibrosis and vascular picture did not change. However, the content of myocardial titin decreased significantly (intensity ratio of titin/actin was 0.23±0.01 and 0.29±0.02 in group C and group A rats respectively, p<0.05). These findings suggest that changes in titin play a role in the change in myocardial functional characteristics and may be one of the causes of diabetic cardiomyopathy.

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Norepinephrine (NE) is one of the most potent positive inotropic drugs available for the treatment of low-output state following open-heart surgery. However, its inotropic effect is often masked by a significant increase of periph-eral vascular resistance due to marked vasoconstriction. The purpose of the present study was to investigate whether the use of nicardipine (Nc) and phentolamine (Ph) in combination with NE could ameliorate the adverse vaso-constrictive action of NE. A low-output-state (LOS) model was produced by global myocardial ischemia due to electrically induced intermittent ventricular fibrillations in open-chest dogs. Twenty-eight dogs were divided into 6 groups according to the drugs infused after producing LOS. In the control group, hemodynamic changes similar to the clinical low-output state were observed, e.g., a decrease in cardiac output (CO) and left ventricular dp/dt, and an increase in the systemic vascular resistance (SVR). The use of NE alone pro-duced marked increases in the systemic arterial pressure (SAP), heart rate, and SVR, with a slight increase in CO. The infusion of Nc alone produced de-creases in SVR and SAP with a slight increase in CO. The concomitant infu-sion of NE and Nc produced increases in SV and CO, and decreases in SAP and SVR. The infusion of Ph alone produced no significant hemodynamic changes. The combined use of NE and Ph produced increases in CO, SAP and heart rate, but not to a significant extent. These results suggest that there are major advantages in the concomitant use of NE and Nc for the control of LOS.

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We describe the case of a 21-year-old Italian male who presented with giant negative T-waves and left ventricular hypertrophy on the electrocardiogram suggestive of apical hypertrophic cardiomyopathy.
Clinically, he suffered from new onset of exertional angina, dyspnea and palpitations during soccer playing or heavy exercise beginning one week before admission.
Echocardiography and cardiac catheterization confirmed the rare combination of a nonobstructive apical hypertrophic cardiomyopathy of the "Japanese" type coexistent with an extensive muscular bridge involving almost the entire anterior interventricular branch of the left coronary artery.
Although the patient complained of exertional angina pectoris, absence of objective evidence of myocardial ischemia by means of treadmill stress test, exercise thallium scan, dobutamine stress echocardiography as well as atrial pacing stress emphasized the benign nature of this complex anomaly.

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Two cases of familial porphyria cutanea tarda (PCT) with constrictive pericarditis are described. A 50-year-old woman and her 48-year-old younger brother were admitted because of right ventricular heart failure. Constrictive pericarditis was diagnosed by RV pressure waveform and echocardiogram. The patients were diagnosed as PCT based on clinical symptoms, histologic findings and elevated urinary excretion levels of uroporphyrin. Even to this day, over 40% of the etiology of constrictive pericarditis remains unknown. There is a possibility of overlooking porphyria cutanea tarda in constrictive pericarditis patients. This report describes the first documented cases of famil-ial PCT with constrictive pericarditis.

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