Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca²⁺ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure. (Jpn Circ J 1999; 63: 231 - 243)

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Changes in P-wave morphology in inferior leads during atrial pacing at the margins of the carvo-tricuspid isthmus have been reported to be useful for predicting the creation of isthmus block in radiofrequency (RF) ablation of type 1 atrial flutter (AFL). However, it is not known whether these changes in P-wave morphology allow the clinician to differentiate between complete isthmus block and slow isthmus conduction. P-wave morphology during low lateral right atrial (LLRA) pacing, as well as during coronary sinus ostium (PCS) pacing, was evaluated prior to ablation, during slow isthmus conduction, and after complete isthmus block in 30 patients with AFL. Changes in P-wave morphology during LLRA pacing were not sufficient to differentiate between complete isthmus block and slow isthmus conduction. While changes in P-wave morphology in lead II from inverted to biphasic during PCS pacing were observed in both slow isthmus conduction and complete isthmus block, the ratio of the positive component to the total P-wave amplitude (P-wave ratio) was significantly different between slow isthmus conduction (20±17%) and complete isthmus block (40±11%) (P<0.0001). When the P-wave ratio in lead II during PCS pacing was more than 75% of the F-wave ratio in lead II during AFL, bilateral complete isthmus block was predicted with a sensitivity of 88%, a specificity of 71%, a positive predictive value of 75%, and a negative predictive value of 85%. These results indicate that a P-wave ratio greater than 20% or a P-wave ratio during PCS pacing greater than 75% of the F-wave ratio during AFL may predict a bidirectional complete isthmus block. (Jpn Circ J 1999; 63: 244 - 248)

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Coronary arteriosclerosis is an underlying condition in acute myocardial infarction (AMI), unstable angina pectoris (UAP) and stable angina pectoris (SAP), and is also related to restenosis (RS) following coronary intervention. To investigate the pathogenesis of this condition, a quantitative reverse transcriptase polymerase chain reaction was used to determine relative levels of mRNA for interleukin (IL)-1β, IL-6, IL-8, transforming growth factor β (TGF-β), intercellular adhesion molecule (ICAM)-1, E-selectin and vascular cell adhesion molecule (VCAM)-1 using directional coronary atherectomy (DCA) specimens. Eleven patients with AMI, 7 with UAP, 10 with SAP and 6 with RS following a previous coronary intervention underwent DCA. The mRNA intensity for each molecule was expressed by comparing it with that of β-actin mRNA. The AMI and UAP patients showed high frequencies of mRNA for IL-1β, IL-8, TGF-β, and ICAM-1 together with strong intensities of expression, whereas SAP patients showed decreased mRNA expression for these molecules. Increased IL-6 mRNA expression was observed only in AMI samples. Specimens from RS patients revealed an accumulated expression of proinflammatory cytokines, except for IL-6, as well as of TGF-β. The study suggests that variation in mRNA expression may reflect the pathophysiology of specific types of coronary artery disease, and remodeling following vascular injury. (Jpn Circ J 1999; 63: 249 - 254)

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Vascular endothelial function is abnormal in patients with congestive heart failure (CHF). Exhaled nitric oxide (NO) output is a marker of pulmonary endothelial NO release. The present study examined the relation between exhaled NO output and oxygen uptake (VO₂) kinetics at the onset of exercise, which reflects blood flow response. Sixteen patients with CHF and 7 volunteers underwent constant bicycle exercise. Oxygen deficit and time constant for VO₂ increment at the onset of exercise were analyzed. Exhaled NO concentration was measured by a chemiluminescence analyzer and exhaled NO output was calculated by multiplexing ventilation. Exhaled NO output was significantly greater in the CHF group than in the control group at rest (86±65 nl min^-1 m ^-2 vs 298±135 nl min^-1 m ^-2, p<0.001) and during exercise (152±98 nl min^-1 m^-2 vs 455±190 nl min^-1 m^-2, p<0.001). However, the %increase of NO output was significantly smaller in the CHF group than in the control group (70±26% vs 109±85%, p<0.05). Oxygen deficit was significantly greater in the CHF group than in the control group (240±70 ml vs 372 ±107 ml, p<0.01) and the time constant for VO₂ increment was also significantly prolonged in the CHF group (35.1±8.0 s vs 50.1±16.3 s, p<0.05). Exhaled NO output during exercise significantly correlated with oxygen deficit (r=0.67, p<0.001) and the time constant for VO₂ increment (r=0.74, p<0.001). Increased NO output played a counter-regulatory role in the impaired blood flow in CHF. (Jpn Circ J 1999; 63: 255 - 260)

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The contribution of venous return to the increase in anaerobic threshold (AT) in patients with acute myocardial infarction (AMI) was investigated. Twenty-seven patients with uncomplicated AMI underwent supine and sitting cardiopulmonary exercise testing, and 10 out of these 27 patients performed constant-workload tests in which cardiac output before and after a phase II program was measured. Data from 8 patients were eliminated because of restenosis after direct percutaneous transluminal coronary angioplasty. The increase in AT was significantly greater in the sitting position than in the supine position, 15.0±9.9% and 6.3±6.0% respectively. Average O₂ pulse at AT changed non-significantly from 8.6±1.5 to 8.7±1.2 ml min^-1 beat ^-1 in the supine position, but it showed a significant increase from 8.1±1.3 to 9.2±1.3 ml min^-1 beat^-1 when mesured in the sitting position. In the constant-workload studies, stroke index showed a significant increase during both supine and sitting exercise. Percent increase in the stroke index from rest to exercise did not differ significantly in the supine position, but did differ significantly in the sitting position. These results strongly suggest that increased venous return as well as improvement in cardiac pump function play a major role in the mechanism of AT increase in an upright position throughout the recovery phase in AMI patients. (Jpn Circ J 1999; 63: 261 - 266)

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This study was undertaken in patients with heart failure to investigate the relation between plasma norepinephrine (NE) concentration and Mg dynamics. The study subjects comprised 16 patients with chronic heart failure (mean age 64.9±10.0 years). Cardiopulmonary exercise testing was performed on all patients, and anaerobic threshold (AT), peak oxygen uptake (peak VO₂) and peak exercise time were measured. Resting and peak values of plasma NE concentration and serum and erythrocyte magnesium concentration were also measured. The results were as follows: the serum Mg concentration was increased significantly immediately after exercise (p<0.01), and the erythrocyte Mg concentration showed a tendency to decrease (p<0.1). The resting plasma NE level was inversely correlated with AT (p<0.05, r=-0.57), peak VO₂ (p<0.05, r=-0.55) and peak exercise time (p<0.01, r=-0.62). When the plasma NE concentration at rest was analyzed in 2 groups of patients, ie, those with higher than average and those with lower than average concentrations, the resting erythrocyte Mg concentration was significantly lower in the high-NE group (2.2±0.3 mg/dl) than in the low-NE group (2.7±0.5 mg/dl) (p<0.05). The data indicate that patients with chronic heart failure associated with high NE levels at rest who showed low exercise tolerance have intracellular hypomagnesemia, which may be caused by Mg migration from intracellular to extracellular spaces. (Jpn Circ J 1999; 63: 267 - 273)

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The significance of the time from anaerobic threshold to respiratory compensation point (RCP-AT time) in patients with chronic heart failure was investigated. Thirty-seven patients with chronic heart failure (New York Heart Association class II or III) were enroled into the study. Cardiopulmonary exercise testing was performed using breath-by-breath gas sampling. A bicycle ergometer was used, and incremental exercise testing was carried out. Anaerobic threshold, respiratory compensation point (RCP), and the slope of oxygen uptake (VO₂) as a function of work rate (ΔVO ₂/ΔWR) were measured. A positive correlation (r=0.53) between RCP-AT time and ΔVO₂/ ΔWR was found. RCP-AT time was corrected for the whole exercise period (ramp exercise-RCP point), and the correlation between corrected RCP-AT time and ΔVO₂/ΔWR was still present (r=0.46). There was no correlation between RCP-AT time and anaerobic threshold. These findings suggest that RCP-AT time is a new parameter that reflects the rate of the aerobic and anaerobic metabolism after AT. (Jpn Circ J 1999; 63: 274 - 277)

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While the role of heat shock protein 72 (HSP72) in protection of the ischemic heart has been studied extensively, the expression and localization of HSP72 in the ischemic and reperfused heart remains poorly understood. This study examined the expression and distribution of HSP72 after various periods of ischemia and reperfusion in the non-stress-pretreated rat heart. The distribution of HSP72 in the myocardium was examined immunohistochemically using a specific monoclonal antibody for detection of this protein. The levels of HSP72 mRNA in the myocardium were estimated by the reverse transcriptase polymerase chain reaction (RT-PCR) method. Rats were subjected to either permanent occlusion of the left coronary artery or 30 min of occlusion followed by reperfusion, and they were sacrificed 30 min, 4 h, 24 h and 7 days thereafter. Both permanent ischemia and reperfusion induced expression of HSP72 mRNA in the ischemic myocardium from 30 min to 24 h after the onset of ischemia/reperfusion. The maximum mRNA level, which appeared at 4 h, was much higher in the reperfusion group than in the permanent ischemia group. Myocytes exhibited definite immunoreactivity of HSP72 at 4 h and 24 h in both groups, and microvessels exhibited strong immunoreactivity at 4 h in the reperfusion group. This study revealed the time course of expression and distribution of HSP72 in the ischemic and reperfused hearts in vivo. (Jpn Circ J 1999; 63: 278 - 287)

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We performed photodynamic therapy (PDT) using the Yttrium Aluminium Garnet-Optical Parametric Oscillated (YAG-OPO) laser in cases of atherosclerosis, and examined its efficacy in vivo. We also performed PDT using an Argon-dye (Ar-dye) laser with the same output, and compared the efficacies. Following balloon denudation injury of the thoracoabdominal aorta, rabbits were raised on a cholesterol diet for 16 weeks, producing atheroma in that region. At 24 h following the administration of Photofrin 5 mg/kg, PDT was performed, and animals were sacrificed at 1 day, 1 week, and 2 weeks following the procedure to examine its efficacy. This was compared with the efficacy of PDT using the Ar-dye laser. Following PDT using a YAG-OPO laser, an increase in the vessel lumen was seen due to reduction of the hypertrophic intima and media, without the appearance of inflammatory cells. This result was seen more strongly in PDT using the pulse wave YAG-OPO laser than with the continuous wave Ar-dye laser, affecting not just the intima but also the media. These data demonstrated that PDT can effectively regress atherosclerotic lesions. (Jpn Circ J 1999; 63: 288 - 295)

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We tested whether acute pressure overloading of the left ventricle (LV) had spatially different effects on repolarization, thereby causing arrhythmias. The effects of gadolinium (Gd³⁺), a nonspecific blocker of stretch-activated channels were also examined. In anesthetized dogs, 5 s clamping of the ascending aorta (AC), separated by 5-min intervals, was repeated while monophasic action potentials (MAPs) were recorded from the LV endocardium and epicardium. Gd³⁺ was injected into the left atrium before the second (500 μmol) and third AC (2500 μmol) (n=10). In a separate group (n=7), the effects of Gd³⁺ in the presence of verapamil were examined. Epicardial MAP durations at 50% and 90% repolarization (APD₅₀; APD₉₀) shortened in response to LV pressure rise and elongation of the segment length induced by the first AC, whereas endocardial MAP durations remained unchanged. Thus, the difference in APD₅₀ and APD₉₀ increased. Consistent with these changes, premature ventricular contractions (PVCs) developed. Gd³⁺ had no effect on baseline MAP durations, however it prevented an AC-induced increase in the difference by suppressing epicardial MAP shortening. Gd³⁺ also reduced PVCs in a dose-dependent manner at plasma concentrations of 1-4 μmol/L. The effects were also evident after administration of verapamil. Thus, gadolinium suppressed an increase in the spatial dispersion of repolarization and arrhythmias via a mechanism of action different from that of verapamil. (Jpn Circ J 1999; 63: 296 - 302)

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Graft coronary arteriosclerosis (GCA) that results in proliferative and obstructive lesions limits the long-term success of cardiac transplantation. Despite extensive study, the pathogenic mechanisms underlying GCA are still unclear and therapeutic strategies for this condition have been inadequate. In this study, we compared the therapeutic effectiveness of cyclosporine A (CsA), 15-deoxyspergualin (DSG), and Multiglycosidorum tripterygii (MT) on GCA. In addition, we studied the correlation between the extent of GCA and the degree of platelet-derived growth facter (PDGF)-A chain mRNA expression in cardiac grafts. Lewis rats receiving heterotropic heart transplants from Wistar King donors were treated with 10 mg kg^-1 day ^-1 of CsA (n=7), 5 mg kg^-1 day^-1 of DSG (n=7) or 30 mg kg^-1 day^-1 of MT (n=7) respectively. Histological evaluation of coronary arteriosclerosis and Northern blot analysis of cardiac allograft PDGF-A chain mRNA expression were conducted on day 60 after transplantation. Varying levels of GCA were observed in the 21 transplanted hearts. Significant differences in both the degree of PDGF-A mRNA expression and the extent of GCA were found among the 3 groups. GCA was significantly reduced in allografts treated with MT or DSG in comparison with the level seen in CsA-treated grafts. A significant correlation was found between PDGF-A chain mRNA expression and the grade of arterial intimal thickening (r=0.76, p<0.05) as well as with the incidence of diseased vessels (r=0.82, p<0.01). Our results indicate that both MT and DSG are more effective in the treatment of GCA than CsA. In our cardiac allografts, the degree of PDGF-A chain mRNA expression correlated well with the extent of GCA, suggesting that PDGF-A may play an important role in the development of transplant-related GCA. (Jpn Circ J 1999; 63: 303 - 308)

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To the best of our knowledge, only 3 cases of coronary artery bypass grafting (CABG) performed under cardiopulmonary bypass (CPB) on patients in the chronic phase after renal transplantation have been reported in Japan. The first case of a patient who underwent CABG in the acute phase after renal implantation in Japan is herein described. Perioperatively, oral immunosuppressive agents were discontinued and they were given intravenously. Cyclosporin A (Cy-A) was administered via a continuous intravenous infusion in the acute phase after renal transplantation and closely monitored, because the blood concentration of Cy-A can vary a great deal during the perioperative period. This case report serves to demonstrate that as long as appropriate immunosuppressive drugs are perioperatively administered, CABG under CPB can be safely performed on patients who have undergone renal transplantation without subsequent rejection, infection, or renal damage, even during the acute phase. (Jpn Circ J 1999; 63: 309 - 311)

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A chronic, large thrombus in the right main pulmonary artery (PA) was detected in a 54-year-old woman with a history of surgical repair of atrial septal defect. Color flow imaging revealed a prominent red signal along the right border of the markedly dilated PA. Pulsed Doppler echocardiography showed that the red signal was caused by flow reversal occurring during systole. According to the physics of blood flow, flow reversal probably represents secondary, helical flow, which may be related to thrombus formation. (Jpn Circ J 1999; 63: 312 - 314)

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A Gianturco-Roubin II (GR-II) stent was inserted in a 75-year-old man who developed restenosis of the right coronary artery (RCA) after percutaneous transluminal coronary angioplasty (PTCA). Although the vessel became partially occluded after 7 months, it was redilated by PTCA. Follow-up angiography of the RCA and left coronary artery (LCA) was performed 3 months later. Chest pain with bradycardia and hypotension occurred immediately after this examination, and ST elevation appeared in ECG leads II, III, and aV_F. Repeat angiography of the RCA confirmed complete occlusion due to a spasm at a site proximal to the GR-II stent. The spasm was resolved by intracoronary infusion of isosorbide dinitrate (ISDN), and PTCA was carried out for extensive recurrent restenosis of the RCA; however, vascular dissection developed at the distal end of the GR-II stent. Therefore, a Palmaz-Schatz (P-S) stent was placed such that its proximal end overlapped the distal end of the GR-II stent. Follow-up angiography 3 months later showed no restenosis, but an episode of vasospasm similar to the previous one occurred immediately after left ventriculography. The RCA was completely occluded proximal to the GR-II stent because of spasm. Although this spasm was gradually relieved by intracoronary infusion of ISDN, marked spasm was also observed distal to the P-S stent; complete relief was achieved by infusion of additional ISDN. (Jpn Circ J 1999; 63: 315 - 318)

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The mechanism of cardiac uptake of long-chain free fatty acids has not been fully determined. We encountered a hypertrophic cardiomyopathy patient who showed a lack of cardiac uptake of 2 different types of long-chain fatty acid analogues on the scintigraphic images. Flow cytometric analysis revealed no platelet or monocyte CD36 molecule expression (type I CD36 deficiency) and his CD36 gene showed homozygous mutation for ⁴⁷⁸C to T substitution, leading to an abnormal CD36 amino acid sequence. These findings strongly suggest that a specific transporting system rather than a simple diffusion is commonly involved in the cardiac uptake of long-chain free fatty acids in humans, and that the CD36 protein is the most likely candidate for the specific transporter and to explain scintigraphic defects on fatty acid imaging. (Jpn Circ J 1999; 63: 319 - 322)

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Sustained monomorphic ventricular tachycardia (VT) developed in a 58-year-old man with acute myocardial infarction and end-stage renal disease. Amiodarone was effective in preventing VT recurrence. Sustained VT was not induced during an electrophysiologic study. However, VT recurred during accidental hyperkalemia, which was caused by the change of dialysis therapy from peritoneal dialysis to hemodialysis. VT subsided with correction of hyperkalemia. Thereafter, VT did not recur as long as the serum potassium concentration was kept within the normal range. Several months later, the patient died suddenly because poor dietary compliance resulted in an increase in his potassium concentration. This case suggests that hyperkalemia may reverse the potent antiarrhythmic effects of amiodarone. (Jpn Circ J 1999; 63: 323 - 325)

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A patient with Cowden disease and multiple arteriovenous malformations (AVMs) that resulted in high output heart failure is described. Cowden disease is a familial syndrome characterized by endodermal, mesodermal and ectodermal dysplasia causing benign and malignant tumors of the skin, breast, gastrointestinal tract, and thyroid gland. Our patient had gastrointestinal polyposis, a right renal tumor, a left lung tumor, an adenomatous goiter, and typical dermatologic findings such as facial papules, acral keratosis, gingival papillomatosis and hemangiomas. AVMs were observed in the pelvis, cervical vertebra, liver, and right supraclavicular area. Transcatheter embolization was performed 7 times for the pelvic AVMs, but the effect decreased with repetition and the patient died of heart failure 2 years after the first embolization. The serum levels of tissue plasminogen activator (t-PA), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β₁ were high, suggesting that these angiogenic molecules may play a role in the pathogenesis of AVMs in Cowden disease. (Jpn Circ J 1999; 63: 326 - 329)

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We report a case of a 19-year-old woman with a primary pericardial synovial sarcoma that extended from the right ventricular free wall to the posterior aspect of the left anterior thoracic wall. Synovial sarcoma was diagnosed by the detection of the chimeric transcript SYT-SSX using reverse transcriptase-polymerase chain reaction (RT-PCR). This transcript is generated by reciprocal translocation between chromosomes X and 18, and is specific to synovial sarcoma that usually occurs in the extremities of young adults. When pathological and immunohistochemical diagnosis of synovial sarcoma is difficult, the molecular biological technique using RT-PCR becomes a powerful method of confirmation of this neoplasm. (Jpn Circ J 1999; 63: 330 - 332)

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