This review discusses the evolution in the approach to the therapy of cardiac arrhythmias that has occurred during the past 2 decades. The major changes have been driven by advances in understanding arrhythmia mechanisms, in bioengineering, and in clinical trials. It seems likely that progress in understanding the cellular and molecular basis of arrhythmias and their response to drug therapy may allow further identification of patient subsets in which specific therapies are indicated or contraindicated. (Jpn Circ J 1999; 63: 655 - 658)

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A high serum lipoprotein(a) [Lp(a)] level, which is genetically determined by apolipoprotein(a) [apo(a)] size polymorphism, is an independent risk factor for coronary atherosclerosis. However, the associations among Lp(a) levels, apo(a) phenotypes, and myocardial infarction (MI) have not been studied. Patients with MI (cases, n=101, M/F: 86/15, age: 62±10 y) and control subjects (n=92, M/F: 53/39, age: 58±14 y) were classified into quintile groups (Groups I to V) according to Lp(a) levels. Apo(a) isoform phenotyping was performed by a sensitive, high-resolution technique using sodium dodecyl sulfate-agarose/gradient polyacrylamide gel electrophoresis (3-6%), which identified 26 different apo(a) phenotypes, including a null type. Groups with higher Lp(a) levels (Groups II, III, and V) had higher percentages of MI patients than that with the lowest Lp(a) levels (Group I) (54%, 56%, or 75% vs. 32%, p<0.05). Groups with different Lp(a) levels had different frequency distributions of apo(a) isoprotein phenotypes: Groups II, III, IV, and V, which had increasing Lp(a) levels, had increasingly higher percentages of smaller isoforms (A1-A4, A5-A9) and decreasingly lower percentages of large isoforms (A10-A20, A21-A25) compared to Group I. An apparent inverse relationship existed between Lp(a) and the apo(a) phenotype. Subjects with the highest Lp(a) levels (Group V) had significantly (p<0.05) higher serum levels of total cholesterol, apo B, and Lp(a). Patients with MI and the controls had different distributions of apo(a) phenotypes: ie, more small isoforms and more large size isoforms, respectively (A1-A4/A5-A9/A10-A20/A21-A25: 35.7%/27.7%/20.8%/15.8% and 22.8%/23.9%/29.4%/23.9%, respectively). Lp(a) (parameter estimate ± standard error: 0.70±0.20, Wald χ²=12.4, p=0.0004), apo(a) phenotype (-0.43±0.15, Waldχ²=8.17, p=0.004), High-density lipoprotein-cholesterol, apo A-I, and apo B were significantly associated with MI after adjusting for age, gender, and conventional risk factors, as assessed by a univariate logistic regression analysis. The association between Lp(a) and MI was independent of the apo(a) phenotype, but the association between the apo(a) phenotype and MI was not independent of Lp(a), as assessed by a multivariate logistic regression analysis. This association was not influenced by other MI- or Lp(a)-related lipid variables. These results suggest that apo(a) phenotype contributes to, but does not completely explain, the increased Lp(a) levels in MI. A stepwise logistic regression analysis with and without Lp(a) in the model identified Lp(a) and the apo(a) phenotype as significant predictors for MI, respectively. (Jpn Circ J 1999; 63: 659 -665)

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Insulin resistance (IR) is frequently observed in patients with coronary heart disease (CHD). The relationship between IR and the angiographical characteristics of coronary atherosclerosis were investigated in 66 patients with coronary artery lesions. Insulin resistance was assessed by a 75-g oral glucose tolerance test and homeostasis model assessment (HOMA). The angiographical characteristics of coronary atherosclerosis (ie, the severity of CHD) were defined by both Gensini's score (GS) (a higher degree of coronary artery stenosis or a proximal lesion was assigned a higher score than a distal lesion) and the number of significantly stenosed vessels. When GS was examined as a categorical variable classified by tertile values (Group A, n=22: 1≤ GS ≤14; Group B, n=22: 15≤ GS ≤32; and Group C, n=22: 33 ≤ GS), patients with a high GS (Group C) had significantly (p<0.05) higher values of fasting plasma insulin, insulin response, and HOMA IR than patients with a low GS (Group A) (12.6±1.2μU/ml vs 6.9±1.2μU/ml, 122.2±11.9 μU ml^-1 h^-1 vs 72.9 ±12.9μU ml^-1 h^-1, and 2.9±0.3 vs 1.5±0.3, respectively).The values in Group B patients (9.4±1.2μU/ml, 108.5±12.5μU ml^-1 h ^-1, and 2.1±0.3, respectively) were intermediate between those in Groups A and C. The area of insulin/area of glucose ratio was significantly (p<0.05) higher in Groups B and C than in Group A (0.54±0.06μU/mg, 0.54±0.06μU/mg, and 0.32±0.06 μU/mg, respectively). However, no significant differences were observed in variables of glucose tolerance, serum lipid, lipoproteins, fibrinogen, uric acid, and blood pressure among the 3 groups. Significant (p<0.05) positive associations were found between GS, the number of diseased coronary arteries, and fasting immunoreactive insulin, insulin response, the area of insulin/area of glucose ratio and HOMA IR by logistic regression analysis. After adjusting for the number of diseased coronary arteries, the association between GS and IR was not significant, suggesting that IR contributed to the severity of coronary atherosclerosis but not to the distribution of lesions. In conclusion, IR was associated with the severity of CHD as measured by both Gensini's score and the number of diseased coronary arteries, and increased the risk of CHD regardless of the location of the lesions. (Jpn Circ J 1999; 63: 666 - 673)

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Although an electrophysiologic study (EPS) is the most reliable method for selecting the treatment for a patient with sustained ventricular tachycardia (VT), VT recurrence may occur even during EPS-guided effective therapy. Electrophysiologic parameters were compared between patients with and without arrhythmic events under EPS-guided effective therapy to identify the predictive parameters of VT recurrence during the clinical course. The study population consisted of 77 consecutive patients with sustained VT who were receiving long-term pharmacological therapy that was demonstrated to be effective by the EPS assessment. The VT induction protocol employed 1-3 extrastimuli and rapid ventricular pacing at 2 right ventricular sites and 1 left ventricular site, and isoproterenol was infused when VT was not induced. To determine the `effective' antiarrhythmic drug, all sustained ventricular arrhythmias had to be prevented during the whole induction protocol, but repetitive ventricular responses (RVR) were allowed to remain for up to 5 beats when they were in the same QRS configurations as the clinical VT and up to 12 beats when they were in polymorphic QRS configurations. The effective refractory periods (ERPs) at the 3 ventricular pacing sites and their difference (ie, ERP-dispersion) and the maximum number of RVR beats were evaluated in an EPS during the control state and at the time of drug assessment. In the comparison of patients with and without VT recurrence, there was no significant difference in clinical characteristics or ERPs, but the ΔERP-dispersion (ie, the increase in ERP-dispersion caused by the antiarrhythmic drug) and the maximum number of RVRs were significantly smaller in the group of patients without VT recurrence (ΔERP-dis, -3±8 vs 6±12, p=0.0027; maxRVR, 3±3 vs 5±4, p=0.0160). The VT recurrence rate was significantly lower in the patients with ΔERP-dis ≤0 or maxRVR <6 in comparison with the others (p=0.0114 and p=0.0360). Patients with VT recurrence showed greater ΔERP-disp and a longer duration of RVRs at the time of drug assessment in comparison with the patients without VT recurrence. The prognosis of patients under EPS-guided therapy may be improved by the use of stricter criteria for drug assessment in the EPS, although this may decrease the number of drug responders determined in the EPS. (Jpn Circ J 1999; 63: 674 - 680)

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To assess diastolic function of the right ventricle (RV) in patients with hypertrophic cardiomyopathy (HCM), biplane RV angiograms and RV pressures were analyzed in 19 HCM patients and in 13 normal subjects. RV and left ventricle (LV) pressures were measured using catheter-tip manometers. RV volumes were obtained from frame-by-frame tracings of angiograms. Ventricular relaxation was assessed by the time constant of isovolumic pressure decay (T). The peak filling rate (PFR) and the time to PFR (TPFR) were used as parameters of early diastolic filling, and the right atrial contribution to RV filling (%AF) was used as a parameter of late diastolic filling. The T for the RV was significantly prolonged in HCM patients. However, there was no significant correlation between the T for the RV and LV, nor did the T for the RV correlate with the RV ejection fraction or interventricular septal wall thickness. The TPFR, but not PFR, was significantly greater in HCM patients, and the %AF tended to be increased in HCM, but not significantly. The RV diastolic pressure-volume relations in the HCM patients shifted upward. In conclusion, impaired isovolumic relaxation and delayed diastolic filling and decreased diastolic distensibility are present in the RV of HCM patients. (Jpn Circ J 1999; 63: 681 - 687)

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A woman with coronary artery disease underwent a new imaging technique: dobutamine-stress electrocardiography (ECG)-gated tetrofosmin-single photon emission computed tomography (SPECT). Dobutamine-stress ECG-gated tetrofosmin-SPECT with automatic left ventricular function analysis software programs detected improvement and a biphasic response of dysfunctional myocardium during dobutamine infusion, which suggested viable but hibernating myocardium. Dobutamine-stress ECG-gated tetrofosmin-SPECT with automatic left ventricular function analysis software programs has the potential to detect viable but dysfunctional myocardium with contractile reserve. (Jpn Circ J 1999; 63: 688 - 691)

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Accelerated atherosclerosis is a major risk for uremic patients undergoing long-term hemodialysis. Because hyperhomocysteinemia may influence this condition, 168 such patients were examined for a possible association between plasma total homocysteine concentration (tHcy) and conventional cardiovascular risk factors. Generalized atherosclerosis was indicated by excessive intimal-medial wall thickness (IMT) of the extracranial carotid artery as measured by B-mode ultrasonography. The results documented tHcy in these patients of 33.0±16.9 μmol/L, a significantly higher amount than that of healthy subjects (11.0±3.1μmol/L, p<0.0001). The patients' carotid maximum IMT was 1.79±1.16 mm. In multiple regression analyses with forward elimination procedure, carotid maximum IMT was clearly related to age (r=0.417, p<0.0001), systolic blood pressure (r=0.262, p=0.0043), smoking (r=0.177, p=0.0076), duration of hemodialysis (r=0.083, p=0.0045), and tHcy (r=0.195, p=0.0021). These 5 factors accounted for 36.0% of the variation in carotid maximum IMT. Factors determined as unrelated were male gender, diastolic blood pressure, body mass index, total and HDL cholesterol, triglyceride, lipoprotein(a), uric acid, calcium, inorganic phosphate, and parathyroid hormone. Therefore hyperhomocysteinemia, along with advanced age, systolic hypertension and smoking aggravates atherosclerosis in chronic uremic patients. (Jpn Circ J 1999; 63: 692 - 696)

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Idiopathic right ventricular outflow tract (RVOT) tachycardia is prone to occur when sympathetic nervous activity increases. The effects of catheter ablation on the arrhythmia may be modified by changes in the sympatho-vagal balance induced by the ablation. In 8 patients with RVOT tachycardia, analyses of heart rate variability (HRV) were performed before, early (1-3 days, POST1) and late (7-14 days, POST2) after the ablation. From 24-h ambulatory Holter monitoring, RR intervals of a 2-h period during sleep (00.00-06.00 h) were analyzed. MSSD and pNN50 were increased along with a decrease in the frequency of ventricular arrhythmias at both POST1and POST2 after successful ablation. In contrast, high frequency power (HF) was increased, and low frequency power (LF) and LF/HF were decreased only at POST2 in the 8 patients. In 4 patients in whom the initial ablation had been unsuccessful, the indices of HRV did not change significantly after the unsuccessful ablation, but after successful ablation they changed as in the other 4 patients. After successful catheter ablation of the RVOT tachycardia, sympathetic nervous activity was decreased and parasympathetic nervous activity was increased along with decrease in the frequency of ventricular arrhythmias. The presence of ventricular tachyarrhythmia could, therefore, elicit sympathetic predominance and consequently modify arrhythmogenesis. (Jpn Circ J 1999; 63: 697 - 703)

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As part of studies on the effects, especially the preventive effects, of exercise and psychological factors on cardiovascular diseases, the association between psychological tendencies and immune response was evaluated in patients with coronary heart disease who were receiving exercise therapy. The Pearson's product-moment correlation coefficients between natural killer (NK) cell activity and various psychological scales were obtained. For the Moudsley Personality Inventory, NK cell activity had a significant positive correlation with the extraversion scale and a significant negative correlation with the neuroticism scale. NK cell activity also had a significant positive correlation with the playful humor scale and a significantly negative correlation with the Self-rating Depression Scale. The positive correlation of NK cell activity with the extraversion scale and the humor scale and its negative correlation with the neuroticism scale suggest an association between a positive-feeling tendency and high NK cell activity. The negative correlations of NK activity with the depression scale and neuroticism scale indicate that decreased or excessive expression of feelings inhibits NK cell activity. Thus, high NK activity appears to be associated with optimal expression of feelings. (Jpn Circ J 1999; 63: 704 - 709)

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It is not fully resolved how the chronotropic and inotropic responses alter depending on the strength or duration of stimulation, and how theα-vasoconstrictor effect competes with metabolic vasodilation during sympathetic stimulation. The present study investigated the effects of differential frequency stimuli on these responses in rat hearts during sympathetic stimulation while keeping the left ventricular end-diastolic volume constant. The heart was perfused at a constant flow or pressure with a modified Krebs-Henseleit solution. Electrical stimulation of sympathetic nerves (SNS) was performed at 4 frequencies (0.2, 0.5, 1 and 3 Hz) for 90 s in pithed rats without or with anα₁ or α₂ adrenergic receptor antagonist. The heart rate progressively increased during 3-Hz SNS (33±10% at 30 s, 3814% at 90 s), whereas the inotropic action peaked at about 30 s and then decreased (left ventricular systolic pressure +23±8% at 30 s, -1±13% at 90 s). This phenomenon indicates a negative staircase, in spite of a gradual increase in norepinephrine release. The reduction of contractility did not differ from that shown by constant atrial pacing with an equivalent rate. The coronaryα₁-vasoconstrictor response was competitive with metabolic vasodilation only in the early phase of stimulation and theα₂-vasoconstrictor action had little contribution to the regulation of coronary circulation. The fact that these results differ from previous findings suggests that sympathetic regulation of the heart should be reconsidered, although direct application of the present results to humans is not clear because of species differences. (Jpn Circ J 1999; 63: 710 - 717)

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Myocardial ischemia and reperfusion result in endothelial and ventricular dysfunction. Beta-blockers protect the myocytes from injury by acting as anti-ischemia agents. These anti-ischemic effects of the β-blockers are due not only to their negative inotropic/chronotropic effects but also to a lipid peroxidation reducing mechanism. Thus, β-blockers enhance myocardial recovery. In the present study 20 isolated guinea-pig hearts were perfused with Krebs-Henseleit buffer (KHB) using a Langendorff apparatus. The animals were allocated into 2 groups. In the study group (Group I), metoprolol, as the β-blocker agent, was added into the KHB and in the control group (Group II) perfusion was performed without metoprolol. The percentage change (%change) of heart rate, developed pressure and dP/dtmax; malondialdehyde (MDA) and glutathione (GSH) levels of the perfusate and heart tissue were obtained as data. The %change of heart rate was 70.5±9.2 in the study group and 87.3±8.2 in the control (p=0.003). The %change of developed pressure was 68.7±14.4 and 55.9±8.6 in the study group and control group, respectively (p=0.04). The % change of dP/dt was 63.3±10.0 in the study group and 54.4±5.3 in the control group (p=0.01). The tissue MDA level was 31.0±5.5 nmol/g tissue in the study group and 53.5±4.2 nmol/g tissue in the control group (p=0.0002). The tissue GSH levels were 1.08±0.20 and 0.80±0.07 (mol/g tissue) in Groups I and II, respectively (p=0.001). The levels of the perfusate MDA decreased and the levels of the perfusate GSH increased significantly in the metoprolol group in the postreperfusion period in comparison with the preischemia term (p=0.003 and p=0.03, respectively). Metoprolol reduces ischemic injury via prevention of lipid peroxidation and reduces the myocardial energy demand by decreasing the heart rate. (Jpn Circ J 1999; 63: 718 - 721)

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This report describes 2 cases of a type A acute aortic dissection combined with myocardial infarction caused by a retrograde dissection into the left main trunk of the coronary artery. Successful surgical treatments, including the replacement of the ascending aorta, aortic valve resuspension and coronary artery bypass grafting, were performed in both patients, and they recovered well from cardiogenic shock. However, left ventricular function of both patients remained depressed postoperatively, which limited their quality of life. Because no definite method for salvaging infarcted myocardium has yet been established, either more timely surgery or the preoperative placement of a perfusion catheter in the left main coronary artery is mandatory. (Jpn Circ J 1999; 63: 722 - 724)

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A 42-year-old woman with the diagnosis of aortic regurgitation was admitted to hospital for surgical treatment. Ten years ago, primary antiphospholipid syndrome had been diagnosed, and she had a history of recurrent spontaneous abortions and deep vein thrombosis. She was suffering from moderate exertional dyspnea and chest pain. Catheter investigation revealed progressive dilatation of the left ventricle and a deterioration of the ejection fraction. The aortic valve was excised and replaced with a mechanical valve. A specimen of the aortic valve showed localized thickening and shrinkage of the midportion and base of each cusp, with vegetation on the surface. These localized, specific findings suggest that another mechanism may be involved in the cardiac valve pathology in patients with primary antiphospholipid syndrome. No hemostatic or thromboembolic problems were encountered after the surgery, and her postoperative course was uneventful. (Jpn Circ J 1999; 63: 725 -726)

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A case of neonatal catecholaminergic ventricular tachycardia is reported. Episodes of fetal tachycardia were detected in a female baby and just after birth, sustained monomorphic ventricular tachycardia of complete left bundle branch block pattern and inferior axis were recorded, suggesting a right ventricular outflow origin. Routine examination did not reveal overt heart disease. Ventricular tachycardia was induced by crying or sucking, elicited by isoproterenol infusion, and was suppressed by intravenous injection of ATP or propranolol. The baby's arrhythmia was controlled with oral propranolol. The ventricular tachycardia seemed to be caused by triggered activity. (Jpn Circ J 1999; 63: 727 - 728)

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Scimitar syndrome in infancy is a rare condition, presenting with severe congestive heart failure and pulmonary hypertension. The presence of large systemic-pulmonary collateral arteries may play a role in the cause of heart failure and pulmonary hypertension. A 4-month-old infant underwent coil occlusion of large anomalous systemic arteries supplying the right lower pulmonary lobe. Symptoms of severe congestive heart failure and pulmonary hypertension improved dramatically with coil occlusion, and surgical correction was performed 3 months later without any complications. Coil occlusion of anomalous systemic arteries can improve symptoms of heart failure and pulmonary hypertension in infants and may bring about a good surgical result for this disease. (Jpn Circ J 1999; 63: 729 - 731)

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A 55-year-old woman was admitted to hospital with chest discomfort. Emergency angiography revealed no organic stenosis in the coronary artery, but there was akinesis in the apico-anteroseptal region of the left ventricle. Left ventriculography on the 5th day after admission was normal. On the 2nd day, initial imaging by ¹²³I-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) myocardial single photon emission computed tomography (SPECT) indicated a slight decrease in tracer uptake and delayed imaging revealed fill-in in the apico-anteroseptal regions in spite of akinesis in those areas. On the 4th day, initial imaging by ¹²³I-BMIPP showed a moderate decrease in tracer uptake and delayed imaging revealed a high washout again in those areas. On the 12th day, initial imaging by ¹²³I-BMIPP showed a severely reduced uptake in the apico-anteroseptal regions and delayed imaging disclosed a high washout, in the same areas that showed akinesis during the acute phase. On the 35th day, ¹²³I-BMIPP identified no significant decrease in tracer uptake. It is suggested that these dynamic changes in ¹²³I-BMIPP myocardial SPECT imaging may reflect the metabolic change of fatty acid in the ischemic state, the size and degree of turnover of the triacylglycerol pool. (Jpn Circ J 1999; 63: 732 - 736)

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