Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases, especially in the Japanese population. Because coronary artery spasm can be induced by a variety of stimuli with different mechanisms of action, the occurrence of the spasm appears to be due to the local hyperreactivity of the coronary artery rather than to an enhanced stimulation with a single mechanism of action. Several lines of evidence indicate that coronary artery spasm is caused primarily by smooth muscle hypercontraction whereas the contribution of endothelial dysfunction may be minimal. In order to elucidate the cellular and molecular mechanisms of the spasm, porcine models of the spasm were developed. In the first model with balloon injury and high-cholesterol feeding, a close topological correlation between the early atherosclerotic lesions and the spastic sites was noted, whereas in the second model with an inflammatory cytokine the potential importance of coronary inflammatory changes, especially at the adventitia, was noted. Subsequent studies in vivo and in vitro demonstrated that protein kinase C (PKC) and Rho-kinase are substantially involved in the intracellular mechanism of the spasm, resulting in increases in the mono- and diphosphorylations of myosin light chain (MLC). Furthermore, molecular biological analyses demonstrated that Rho-kinase is upregulated at the spastic site (at all levels, including mRNA, protein, and activity), resulting in the inhibiton of MLC phosphatase through the phosphorylation of its myosin binding subunit and thereby causing the increase in MLC phosphorylations. Preliminary results also suggest that the long-term inhibition of Rho-kinase is effective in inhibiting the development of arteriosclerotic vascular lesions in several porcine models. Thus, Rho-kinase could be regarded as a novel therapeutic target for coronary arteriosclerosis in general and coronary artery spasm in particular.

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Although the long-term benefits of conventional coronary artery bypass grafting (CABG) are obvious, postoperative morbidity and mortality and the length of recovery associated with cardiopulmonary bypass are the main concerns of cardiac surgeons and cardiologists. The aim of this study was to demonstrate the effectiveness and advantage of the off-pump CABG for patients with concomitant malignant disorders requiring myocardial revascularization. From March 1997 to February 1999, 51 patients underwent off-pump CABG. Of these, there were 9 patients who had concomitant malignant disease requiring noncardiac surgery: gastric cancer (4), urinary bladder cancer (2), cholangioma (1), lung cancer (1) and colon cancer (1). Off-pump CABG was performed through a sternotomy, left thoracotomy or subxiphoid incision. Five patients received single grafting and 4 received double. The mean operative time for the off-pump CABG was 167 min. The total amount of bleeding during the off-pump CABG was 450-890 ml. Simultaneous noncardiac operations were carried out in 5 patients. The other 4 patients underwent subsequent operations for the malignancy uneventfully. In contrast, of the 4 patients with concomitant malignant disorders who underwent standard CABG during the period before the use of off-pump CABG, 2 died without undergoing the subsequent noncardiac operation. Off-pump CABG is quite efficient and is of great advantage in patients with malignancy who require myocardial revascularization in addition to noncardiac surgery for the cancer.

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To evaluate the clinical significance of the plasma and urinary levels of heart fatty acid-binding protein (H-FABP) in patients undergoing cardiac surgery, a prospective study was conducted. Ten patients undergoing coronary artery bypass grafting were enrolled. Blood samples for determination of plasma H-FABP (pH-FABP), the MB isoenzyme of creatine kinase (CK-MB) and troponin-T (TnT), and urine samples for determination of urinary H-FABP (uH-FABP) were collected serially. None of the patients had perioperative myocardial infarction. The time to reach the peak level after aortic declamping was significantly (P<0.05) shorter for pH-FABP (1.4±0.5h) than for CK-MB (2.5±0.5h), TnT (6.6±1.3h) or uH-FABP (3.0±0.6h). Peak levels of pH-FABP correlated with those of CK-MB (r=0.51, p=0.04), TnT (r=0.60, p=0.03) and uH-FABP (r=0.61, p=0.03), and peak levels of uH-FABP correlated with CK-MB (r=0.57, p=0.04). Postoperative uH-FABP levels correlated inversely with the left ventricular stroke work index (r=-0.63, p=0.04). This study demonstrated that H-FABP appears rapidly in plasma after reperfusion and reaches its peak earlier than other available biochemical markers; it appears also in urine and the levels correlated with cardiac function. Plasma and urinary H-FABP may be an early and sensitive biochemical marker for the diagnosis of myocardial injury in patients undergoing cardiac surgery.

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Surgical reduction of pulmonary allografts is being performed because of the shortage of allografts of suitable size for pediatric use. However, the outcome of size-reduced pulmonary allografts for pulmonary conduits is unknown. In the present study, cryopreserved pulmonary allografts harvested from adults at the time of kidney donation were size-reduced and used in 4 children, 2 with pulmonary atresia and ventricular septal defect and 2 with atrioventricular discordance, pulmonary atresia and ventricular septal defect. They all had undergone right and/or left modified Blalock-Taussig shunt operations with a 5-mm synthetic graft prior to the reparative operations. They underwent definitive repair with a size-reduced cryopreserved pulmonary allograft valved conduit and were followed up for 2-5 years. Postoperative echocardiographic and cineangiographic assessments revealed excellent function of the pulmonary bicuspidalized valves with a minimal pressure gradient and no, or only trivial, regurgitation. Although the long-term result of a cryopreserved bicuspid pulmonary valved conduit remains unknown, the remodeled bicuspid pulmonary allograft conduits showed excellent hemodynamic characteristics in mid-term follow-up and appear to be a reasonable alternative to other types of conduits when an appropriate-sized allograft is not available.

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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. However, the role of ET-1 in exercise-induced physiological responses is still to be investigated. The purpose of the present study was to investigate in healthy volunteers whether the ET-1 plasma concentration in nonworking muscles is changed by exercise and to investigate the physiological role of ET-1 during exercise. Bicycle ergometer cardiopulmonary exercise tests were performed in 36 healthy men (mean age, 22.5 years). Blood samples for measuring ET-1 were drawn from the cubital vein during rest and immediately after the exercise test. The ET-1 change ratio was calculated as ET-1 immediately following exercise/ET-1 during the resting state. Cardiac output (CO) was measured during the exercise test by the impedance method. Arterial venous oxygen difference (AVO₂D) when CO reached 10L/min or 15L/min was calculated as AVO₂D=VO₂/CO. Results were as follows: (1) the ET-1 change ratio correlated inversely with exercise time at the anaerobic threshold (r=-0.37, p=0.03) and peak exercise time (r=-0.35, p=0.04); (2) the ET-1 change ratio tended toward an inverse correlation with ΔVO₂/Δwork rate (r=-0.29, p=0.09); (3) the ET-1 change ratio correlated positively with AVO₂D when CO reached 10L/min (r=0.42, p=0.02) and tended toward a positive correlation with AVO₂D when CO reached 15L/min (r=0.32, p=0.08). These results indicate that an increase in ET-1 in nonworking muscles may participate in the exercise-induced redistribution of blood flow and in increasing the blood flow to working muscles.

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The age-adjusted, heart rate variability (HRV) was evaluated as a parameter for the severity of heart failure and its prognosis. HRV was obtained by 24-h Holter monitoring in patients with left ventricular dysfunction (LVD). New York Heart Association (NYHA) functional classification, echocardiography, radioisotope ventriculography, and blood examination were performed, and compared between patients and normal subjects. The evaluation was repeated during the follow-up period. Finally, using the lower limit of HRV, patients were divided into either normal or abnormal group for each low-frequency power (LF) and high-frequency power (HF) (age-adjusted HRV). Other parameters of heart failure and prognosis were compared between these 2 groups. HRV tended to be lower in patients with LVD. HF decreased at the early stage of heart failure, but did not decrease progressively. LF decreased progressively. HRV change paralleled the change of NYHA. The abnormal HRV group showed a poor prognosis for cardiac death, but not for sudden cardiac death. In patients with LVD, HRV was decreased compared with the normal subjects. Change in HRV correlated with the change in NYHA classification. Age-adjusted HRV correlated with cardiac-death prognosis, but not for sudden cardiac death.

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The present study investigated how the RR interval complexity and variability and their circadian rhythms alter for patients with congestive heart failure (CHF). Sixteen patients aged between 41 and 72 years with CHF and 20 control subjects were included. 24-h ambulatory electrocardiographic recordings were analyzed, and digitized data was partitioned into sections of 30-min duration. For each section, time- and frequency-domain indices, and complexity indices of heart rate variability were calculated. For CHF patients, 24-h average values of all indices were significantly decreased. The circadian rhythms of mean RR intervals were preserved and resembled the abnormal circadian rhythms of the low-frequency power. The circadian rhythms of high-frequency power and all complexity indices shown in the normal control were lost. Conclusively, the patients with CHF showed decreased RR interval complexity and loss of its circadian rhythm, in addition to decreased frequency-domain RR interval variability and its abnormal circadian rhythm.

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The present study retrospectively investigated cerebral complications of coronary artery bypass grafting in 205 consecutive patients aged 70 years or older, who underwent elective cardiopulmonary bypass from 1990 to 1997. Computed tomography of the brain and chest was done before surgery. Ten patients had so-called ‘aortic notouch surgery’ and suffered no cerebral complications; the other 195 patients had conventional surgery. Adverse cerebral events occurred in 8.7%, including cerebral infarction (4.1%), diffuse encephalopathy (1.0%), convulsions (1.0%), transient disturbance of consciousness (1.0%), and severe loss of volition (1.5%). Multivariate analysis showed that only the detection of calcification of the ascending aorta was significantly associated with cerebral complications (p=0.029). Total clamping tended to be superior to partial clamping for prevention of cerebrovascular accidents. The mortality rate was 7.3%. In-hospital death was related to age (p=0.0062), cerebral complications (p=0.0032), and a low left-ventricular function (p=0.018). Therefore, chest computed tomography to assess the ascending aorta should be performed preoperatively. Modified techniques like aortic no-touch surgery or other therapies combined with coronary intervention may be needed in elderly patients with severe calcification of the ascending aorta.

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Lipoprotein(a) (Lp(a)) is recognized as a new coronary risk factor, but few studies have quantitatively assessed the relationship of serum Lp(a) levels with other coronary risk factors in many patients undergoing coronary cineangiography. Seventeen coronary risk factors were quantified (ie, age, gender, hypertension, impaired glucose tolerance, cerebrovascular accident, hyperuricemia, smoking, family history of ischemic heart disease (IHD), history of hyperlipidemia, Lp(a), total cholesterol, high density lipoprotein (HDL)-cholesterol, triglyceride, low density lipoprotein-cholesterol, apolipoproteins(apo)A-I, B, E) to determine their relationship with the numbers of involved coronary vessels using multiple regression test in 1, 006 patients who underwent coronary cineangiogram (280 non-IHD patients: 144 men, 136 women; 726 IHD patients: 460 men, 266 women; age 16-84 years, mean 60.5±0.3). Multiple regression test indicated R=0.506 and items that showed high beta weight and significant p level were age, Lp(a), impaired glucose tolerance, total cholesterol, cerebrovascular accidents, HDL-cholesterol, smoking, gender, family history of IHD, and apo-A-I (0.221, p<0.001; 0.174, p<0.001; 0.616, p<0.001; 0.138, p<0.001; 0.122, p<0.001; -0.12, p<0.001; 0.092, p<0.01; 0.091, p<0.01; 0.067, p<0.05; -0.065, p<0.05; respectively). It was concluded that Lp(a) is an independent, potential, and modifiable coronary risk factor, and that reduction of serum Lp(a) is important in the clinical management of patients with IHD.

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Cardiac dendritic cells are considered to play an important role in the immunoresponse of the heart. However, it is unclear whether these cells occur in human myocarditis and whether they function in similar ways to those in rats. Cardiac samples were obtained from 22 autopsied patients with myocarditis, and compared with 20 age- and sex-matched controls. Formalin-fixed hearts were immunostained by the LSAB method. Cardiac dendritic cells were detectable even in the control hearts (1.5 cells/high power field (HPF)). In the acute phase of myocarditis, the number of cardiac dendritic cells increased up to 12.6 cells/HPF (p<0.001). In the subacute phase of myocarditis, T cells (36.6 cells/HPF) and HLA-DR+ cells (10.2 cells/HPF) continued to infiltrate the periphery of the inflammatory lesions, but they had no expression without inflammation. In this study, cardiac dendritic cells were reactive for HLA-DR, but negative for CD68, and were characteristically large monocytes with long, slender, dendritic processes. Accordingly, they were clearly distinguishable from macrophages. In the human heart, cardiac dendritic cells may be recruited in the acute phase of myocarditis, and seem to play an important role in the succeeding immunoresponse.

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Effects of adriamycin (ADR) on the twitch contraction of isolated guinea pig cardiac muscles were examined to elucidate its actions on intracellular Ca²⁺ mobilization. In right ventricular papillary muscles, ADR (100-300μmol/L) caused positive inotropy when the muscles were constantly stimulated at low frequencies (0.1-0.5 Hz), whereas it caused negative inotropy when the muscles were stimulated at higher frequencies (2.0-3.0 Hz). Action potential duration was prolonged significantly by ADR, especially at the lower frequencies. The potentiation of twitch contraction of the first beat (B1) following a short rest period (2-10s) in ventricular muscles was inhibited by ADR. In untreated papillary muscles, B1 contraction showed time-dependent decay in response to a prolongation of the preceding rest period up to 120s. ADR (300μmol/L) caused ryanodin-like acceleration for the early B1 decay with rest period less than 20s, but a substantial deceleration for the later B1 decay (≥30s). In left atrial muscles stimulated constantly, ADR had significant negative inotropy troughout the entire range of stimulation frequencies tested (0.1-4.0 Hz). The post-rest potentiation of B1 contraction of atrial muscle in the presence of nifedipine was also inhibited by ADR. These findings suggest that ADR has dual inotropic effects through a complex modulation of myocardial Ca²⁺ handling, which may involve (1) an increase of Ca²⁺ influx through a prolongation of action potential duration, (2) ryanodine-like inhibition of Ca²⁺ release from the sarcoplasmic reticulum, and (3) inhibition of sarcolemmal Ca²⁺ extrusion probably through the Na⁺/Ca²⁺ exchange.

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Because most anti-arrhythmic drugs are eliminated from the kidney, anti-arrhythmic drug therapy is largely restricted in patients undergoing hemodialysis (HD). Cibenzoline is a widely used antiarrhythmic drug excreted mainly from the kidney. The present study evaluated the safety and efficacy of reduced doses of cibenzoline (25 and 50mg/day chronically) in 8 patients with maintenance HD. Cibenzoline was administered for more than 3 months without any problems in 7 of the 8 patients, although the medication was discontinued in 1 patient due to nausea and anorexia. With cibenzoline administration, the incidence and duration of atrial fibrillation decreased or disappeared in 6 of 7 patients and the frequency of complex ventricular arrhythmias was also reduced in 3 of 4 patients. No adverse side effects were noted. Plasma concentration of cibenzoline ranged from 169 to 220ng/ml with the 25-mg/day dosage, and from 408 to 500ng/ml with the 50-mg/day dosage. The concentrations remained stable during the study. In conclusion, low doses of cibenzoline are safe and effective in patients undergoing maintenance HD. However, intermittent monitoring is essential to ensure therapeutic drug concentrations.

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This report describes a patient with the pulmonary edema after cardioversion for paroxysmal atrial flutter without organic heart disease. A 68-year-old man was admitted to hospital for paroxysmal atrial flutter. Antiarrhythmic agents were not effective, and direct current cardioversion was performed on the 4th hospital day. Three hours after cardioversion, the patient complained of dyspnea, and a chest X-ray showed pulmonary edema. He responded to oxygen, intravenous furosemide and drip infusion of nitroglycerine. During tapering of the medication, his condition remained stable. The patient was discharged on the 7th day after admission. Echocardiographic findings indicated that transient left ventricular diastolic dysfunction due to direct current shock was the most likely cause of the lung edema.

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This report presents a case of multiple myeloma with a mass lesion on the pericardium and pericardial effusion. The response to intrapericardial combination chemotherapy (cisplatin and betamethasone) was evaluated by repeated transesophageal echocardiograms. Following the treatment, complete resolution of the tumor and effusion were observed for 6 months after which the patient died of bacterial pneumonia. Intrapericardial combination chemotherapy can be an effective treatment for myelomatous involvement of the pericardium.

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A 61-year-old female, with a history of uterine and cervical cancer treated with radical hysterectomy and 2 years of postoperative chemotherapy, presented to the emergency department with dyspnea on exertion. Computed tomography of the chest revealed a large pericardial effusion and a sacciform aneurysm of the ascending aorta. The patient subsequently underwent emergency pericardiocentesis with drainage of approximately 330ml of a bloody and turbid effusion. Cultures from the effusion yielded group B streptococcus. Multiple organ failure and disseminated intravascular coagulation syndrome occurred in the acute phase, but gradually improved with continuous antibiotic therapy. On the 194th hospital day, in situ reconstruction of the ascending aorta was successfully performed using a synthetic graft. Although rarely reported, both purulent bacterial pericarditis and mycotic aneurysm can be life-threatening.

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