In cardiac muscle, the contraction-relaxation cycle is tightly controlled by the regulated release and uptake of intracellular Ca²⁺ between sarcoplasmic reticulum and cytoplasm. A major protein controlling Ca²⁺ cycling is Ca²⁺-ATPase (SERCA2a) located in the sarcoplasmic reticulum membrane. The function of SERCA2a protein is regulated by the phosphorylatable protein, phospholamban. Phosphorylation of phospholamban releases its inhibitory effect on SERCA2a through direct molecular interaction. Recently, mice whose SERCA2a function is increased (overexpression of the gene) or lost (knock out) were developed. These mice demonstrated that SERCA2a pump levels are a major determinant of cardiac muscle contractility and relaxation. These studies open the prospect that the overexpression of SERCA2a can correct cardiac dysfunction seen in heart failure. Advances in knowledge concerning the function and gene regulation of SERCA2a are discussed in this review. (Jpn Heart J 2000; 41: 1-13)

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Takayasu arteritis is an acute and sometimes chronic form of vasculitis involving the aorta, its main branches and pulmonary arteries. Although its etiology is still unknown, immunopathologic analyses revealed that the infiltrating cells mainly consisted of γδ T-cells as well as αβ T-cells and NK cells. The infiltrating γδ T-cells, cytotoxic T-lymphocytes (CTLs), and natural killer (NK) cells directly injured the vascular cells by releasing a cytolytic factor, perforin. Expression of heat-shock protein (HSP)-65 as well as human leukocyte antigen (HLA) class I and II was enhanced in Takayasu arteritis lesions, supporting the pathogenic role of γδ T-cells and αβ T-cells. T-cell receptor (TCR) αβ gene usage by the infiltrating cells was restricted, strongly suggesting that a specific antigen was targeted. TCR γδ gene usage by the infiltrating cells was also restricted. Furthermore, it has been reported that a strong association with a specific haplotype of major histocompatibility complex (MHC) class I chain-related (MIC), MICA gene with Takayasu arteritis, suggesting that the HLA-linked gene susceptible to the disease is mapped near the MICA gene. This also supports a pathogenic role of γδ T-cells in Takayasu arteritis because γδ T-cells were shown to recognize MICA molecule, which can be stress-induced. These findings suggest that unknown stress, such as infection, may trigger the autoimmune process of inflammation involved in Takayasu arteritis. Jpn Heart J 2000; 41: 15-26)

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We have previously reported that pulsatile mechanical stretch in vitro induced rapid secretion of vascular endothelial growth factor (VEGF) by cultured cardiac myocytes and that the stretch-induced secretion of VEGF was mainly mediated by secretion of transforming growth factor (TGF)-β1 by cardiac myocytes in an autocrine fashion. To investigate whether tachycardia-induced mechanical overload increases serum levels of VEGF and TGF-β1, we investigated the serum levels of VEGF and TGF-β1 in patients with atrial fibrillation undergoing defibrillation therapy. The serum VEGF level before defibrillation was significantly increased in 13 out of 20 patients (89.48±16.09 pg/ml [mean±SE]). After defibrillation, the serum VEGF level in these 13 patients significantly (p=0.019) decreased (65.04±16.61 pg/ml [mean± SE]), although it increased slightly in one patient. The serum TGF-β1 level before defibrillation therapy (13.01±1.97 pg/ml [mean±SE]) in these 12 patients also decreased after defibrillation therapy (11.47±2.06 pg/ml [mean±SE]). The changes in serum VEGF level significantly correlated with those in the serum TGF-β1 level in these 12 patients (r=0.73, p<0.05, n=12). Our data suggest that tachyarrhythmia-induced mechanical overload can increase the serum VEGF level, which can be a useful clinical marker for relative myocardial oxygen shortage in such patients. (Jpn Heart J 2000; 41: 27-32)

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The aim of this study was to assess the long term efficacy of DDD pacing mode in selected patients with idiopathic dilated cardiomyopathy (IDCM) and drug refractory heart failure. The patients were evaluated according to the long term alteration of the sympathovagal balance (SVB). Patients with IDCM were considered eligible for DDD pacing if during temporary VDD pacing a 15% or more increase in the resting cardiac output was demonstrated. From the 29 patients studied, finally 20 patients (15M, 5F, 69±10 years) fulfilled the aforementioned criterion and therefore were considered candidates for permanent DDD pacing (NYHA class:3.5±0.3, Ejection fraction:27±7%, Resting cardiac index (CI) 2.6±0.4l/min). The ECG of the patients demonstrated LBBB in 13, RBBB in 4 and RBBB+LAH in 3, with a PR interval of 232±28 ms and QRS duration of 138±15ms. The pacemaker was programmed at 40-150 bpm, and AV delay of 105±20 ms. The lower heart rate programmed, in conjunction with the heart failure state of these patients, was responsible for essentially continuous atrial tracking, ventricular pacing. We evaluated the SVB in the pre- and post-implant periods (3rd and 6th month), using the hourly power spectral analysis (PSA) of heart rate variability during 24 hour Holter monitoring. As SVB we considered the ratio: low (0.04-0.15Hz) to high frequency (0.15-0.40Hz). We compared the SVB (LF/HF) during the day and night time for the pre- and post-implant periods. Post-pacing, the NYHA class was significantly improved (2.9±0.2 and 2.7± 0.3 the 3rd and 6th month respectively). The mean heart rate was 78±8 bpm in the 3rd and 80±7 bpm in the 6th month postoperatively, which was lower than the 84±9 bpm preoperatively, but this difference did not reach statistical significance. During the night time the LF/HF decreased from 1.45±0.2 (LF:7.19±0.43, HF: 4.95±0.54) in the pre-implant period to 0.9±0.09 (p (LF : 6.96±0.63, HF:7.73±0.48) in the 3rd month. No further changes were observed in the 6th month (0.82±0.05, p=NS) (LF:6.83±0.51, HF:8.53±0.86) compared to the 3rd month. During the day time the LF/HF decreased from 1.5±0.5 (LF:7.87±0.67, HF:5.24±0.32) to 1.43±0.6 (p=NS) (LF:7.34±0.71, HF: 5.24±0.42) in the 3rd month and to 1.41±0.09 in the 6th month (p=NS) (LF:7.51±0.74, HF:5.36±0.63). Comparing the LF/ HF of day and the night time period, while in the pre-implant period there was no significant difference (1.5±0.5 vs 1.45±0.2, p=NS), the difference became significant in the 3rd (1.43±0.6 vs 0.9±0.09, p<0.001) and 6th month (1.41±0.09 vs 0.82±0.05, p<0.001). In conclusion, DDD pacing with individualized AV delay as an adjunct therapy could be a valuable method in selected patients with IDCM and drug refractory heart failure. DDD pacing improves the SVB over the long term. This improvement is attributed to sympathetic activity withdrawal and is more pronounced during night and less during day time. (Jpn Heart J 2000; 41: 33-40)

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The prognosis of patients with lymphocytic myocarditis (LM) is poor with the combined endpoint of death or transplant in the Myocarditis Treatment trial being 56% at 5 years. Physicians often have difficulty determining the prognosis in an individual patient. Patients with LM may have ongoing myocardial inflammation. We evaluated the ability of a serum marker of inflammation to predict prognosis in patients with LM. Serum concentrations of C-reactive protein (CRP) were measured in patients with LM. Thiry-one patients with clinical and histologic evidence of LM were evaluated. Patients with coronary artery disease, and idiopathic dilated and secondary cardiomyopathies were excluded. Overall mortality and morbidity from congestive heart failure was assessed at 28 days. The mean plasma CRP concentrations in the five patients who died within the 28-day follow-up period were significantly higher than in those patients who survived (17.4±5.6 vs 5.9±3.3 mg/ml, p<0.05). The CRP concentration was positively correlated with plasma levels of lactic dehydrogenase and the New York Heart Association functional class. Routine measurement of CRP may be a useful tool for determining the prognosis in patients with LM. (Jpn Heart J 2000 ; 41 : 41-47)

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Variations of systolic and diastolic blood pressure in patients with normotension at rest after successful surgical repair of coarctation of the aorta were examined using 24 hour ambulatory monitoring at mid-term follow-up. Ambulatory blood pressure monitoring, m-mode measurements of left ventricle and transmitral Doppler spectrals in 18 patients aged 7.6±4.5 years after 9 months to 6.1 years (2.5±1.9 years) following operation were compared with the findings in 18 matched controls. Patients had significantly higher mean systolic blood pressures (24 hours:115±10 mmHg, awake:119±11 mmHg and asleep:106±8 mmHg) than controls (24 hours:108±6 mmHg, awake: 112±7 mmHg and asleep:101±7 mmHg) (p=0.04, 0.03 and 0.03, re spectively). Patients had also more systolic blood pressure readings above the 95^th percentile for age (24 hours:28±20%, awake:39±27% and asleep : 12 ±14%) than controls (24 hours:10±9%, awake:14±13% and asleep: 1± 4%) (p=0.03, 0.002 and 0.007, respectively). No significant difference was found in diastolic blood pressure profiles. There were no significant differences in left ventricular m-mode measurements and diastolic function parameters. Left ventricular mass index was significantly increased in patients (81.7±28.7 g/m²) compared with controls (64.5±20.9 g/m²) (p=0.03). Operation age and post-surgical period did not affect ambulatory blood pressure profiles at mid-term follow-up. Patients who are normotensive at rest after successful surgical repair of coarctation of the aorta show higher systolic blood pressure profiles than healthy children with ambulatory blood pressure monitoring at mid-term follow-up. Ambulatory blood pressure monitoring in patients operated on for coarctation of the aorta despite their good clinical status is useful to detect and monitor subtle abnormalities of blood pressure. (Jpn Heart J 2000; 41: 49-58)

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In order to testify the hypothesis that unknown mechanisms are involved in the process of cardiac remodeling after myocardial infarction (MI), we employed differential display reverse transcription-polymerase chain reaction (DDRT-PCR) as our primary inspection tool. An animal model of MI was established by ligation of the left anterior descending coronary artery (LAD) in rat. Fifty upregulated candidate cDNA fragments were obtained in the right ventricle (RV) of the heart six weeks after MI. Eight cDNA fragments isolated from DD denaturing gel were extracted and reamplified, cloned into pCR II vector and sequenced. A Genbank search of these clones showed that three of them have a high homology with known genes not previously associated with cardiac remodeling, i.e., mouse interleukin-4 receptor gene, rat ferritin mRNA, and T-cell receptor beta chain V beta 5. The remaining clones have no similarity to known sequences. These data suggest that certain genes which were not previously being associated with cardiac hypertrophy are turned on during the process of cardiac remodeling after MI. (Jpn Heart J 2000; 41: 59-66)

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Whole cardiac myosin induced experimental autoimmune myocarditis (EAM) in animals. The identification of the epitope causing EAM is expected to elucidate the mechanism leading to the onset of this autoimmune disease. Until now such studies have been done mostly with synthetic oligo-peptides. We employed recombinant technology to produce the immunogenic fragment of the self-cardiac myosin heavy chain (CMHC) for EAM in Lewis rats, and successfully induced severe myocarditis with short recombinant peptide fragment CMHC residues 1107 to 1186. The immunogenicity was completely abolished from the fragment with futher excision of 12 amino acids from residues 1131 to 1143. This recombinant technology clearly has advantages in the ease of manipulation and the purity for the creation of immunogenic epitopes. (Jpn Heart J 2000; 41: 67-77)

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Endothelin-1 (ET-1) is a potent vasoconstrictor. This peptide exerts numerous effects on the heart, including regulation of cardiomyocyte growth during hypertrophy. The effects of the structurally novel, nonpeptide, ET-1-selective, competitive antagonist (ETA) 97-139 were investigated in mice with congestive heart failure (CHF) and myocardial hypertrophy. Morphological and microscopical analyses were conducted on day 56 after viral inoculation following 28 day treatment with 99-139. Eight week-old DBA2 mice were intraperitoneally inoculated with encephalomyocarditis virus at a dose of 500 pfu/mouse. The 30 mice were divided into two groups-an ETA treated group and an untreated group. Heart weight (HW) in the infected group was significantly (p<0.05) increased compared to that in the uninfected group. HW and the HW/body weight (BW) ratio were significantly (p<0.05) reduced in the ETA treated group compared with the untreated group (HW; 127.7±6.2mg vs 144.3±4.2 mg, HW/BW; 4.9±0.9×10^-3 vs 5.4±0.5×10^-3). Myofiber diameter in the ETA treated group was significantly reduced compared with the untreated group (12.1±1.5μm vs 14.3±1.9μm). These results suggest the ET-1 receptor antagonist 97-139 has an effect on the reduction of cardiac mass and myofiber hypertrophy, and that 97-139 may be a useful agent for CHF due to viral myocarditis. (Jpn Heart J 2000; 41: 79-85)

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The efficacy of local treatment of thrombosis with low-dose antithrombotic drugs (heparin:30 U/kg, or argatroban:0.02 mg/kg) was investigated using a novel porous balloon catheter. This novel balloon catheter can deliver drug into arterial walls without causing vascular trauma. Thrombus formation was significantly inhibited in balloon-injured and locally-treated iliac arteries compared with control balloon-injured arteries in 12 dogs. In the systemic high-dose delivery group (ten times as high as the low dose), thrombus formation in injured arteries was significantly less than that of controls in 7 dogs. Low-dose systemic delivery was not effective at inhibiting this thrombus formation. Thus, local treatment with an antithrombotic drug using this novel porous balloon catheter can prevent thrombosis without influencing systemic coagulability. (Jpn Heart J 2000; 41: 87-95)

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A 75-year-old woman presented with recurrent ventricular tachycardia (VT) compatible with torsades de pointes (TdP) based on sinus bradycardia and QT prolongation. Previously she had received pirmenol, at a serum concentration within therapeutic range, for her paroxysmal atrial fibrillation. Emergent cardiac catheterization identified a ventricular aneurysm of the anteroapical and inferior wall along with angiographically normal coronary arteries. A right ventricular endomyocardial biopsy revealed postmyocarditic change. The left ventricular contraction improved after 5 weeks of conservative treatment. A follow-up echocardiogram revealed transient thickening of partial left ventricular wall consistent with the segment of the aneurysm. Several months later, almost all abnormal findings had improved except for sustained deep negative T waves in precordial leads. Acute myocarditis was primarily suspected as the cause of her clinical presentation. (Jpn Heart J 2000; 41: 97-102)

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