A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over th... more A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over the entire coronary artery tree had been treated with several kinds of lipid-lowering single or combined drug therapies using clofibrate, compactin, cholestyramine, probucol, and pravastatin, and LDL-apheresis. During the 19-year follow-up, he suffered myocardial infarction three times and some of the ectatic coronary segments became enlarged, others narrowed, and one of them occluded in spite of the treatment. At the age of 58, he died after a fourth cardiac attack and subsequent cardiogenic shock. The autopsy indicated that his three coronary arteries showed diffuse ectatic changes and the largest lumen diameter of the left anterior descending artery was 25 mm, of the circumflex artery 12 mm, and of the right coronary artery 13 mm. The ectatic artery wall was not thick and the major part of the lumen was occupied by organized thrombi. Microscopic examinations showed that the larger the diameter of the lumen, the more severe the structural damage of the intima and tunica media and the larger the number of infiltrated cells, including lymphocytes, macrophages, and plasma cells. Immunoreactivity against matrix metalloproteinase (MMP)-1, and MMP-2 was observed in smooth muscle cells, macrophages, lymphocytes, and endothelial cells of the vasa vasorum or neovasculature. MMP-9 immunoreactivity was also localized in intimal foamy macrophages and round cells (macrophages and lymphocytes) of the media and adventitia. MMP-1 increased with the lumen diameter of the ectatic arteries. The ratio of immunoreactivity against both MMP-2 and MMP-9 to that against tissue inhibitor of metalloproteinase (TIMP)-2 also increased with the lumen diameter, but it no longer increased when the diameter was over 10 mm. These observations suggest that the MMP-TIMP system appears to play a significant role in the development of coronary ectasia
Journal of International Medical Research, Aug 1, 2022
ObjectiveTo assess the determinants of target lesion revascularization (TLR) after drug-coated ba... more ObjectiveTo assess the determinants of target lesion revascularization (TLR) after drug-coated balloon (DCB) angioplasty for de novo small coronary artery lesions.MethodsThis retrospective study enrolled consecutive lesions from patients that were in a stable condition and had undergone successful DCB treatment for de novo small coronary artery lesions. The study endpoint was TLR and major adverse cardiac events at 12 months.ResultsA total of 68 patients with 83 lesions were enrolled in the study. Of these, 11 (13.3%) lesions required TLR. Mean ± SD pre-dilatation balloon diameters were similar in the non-TLR (2.33 ± 0.72 mm) and TLR (2.18 ± 0.36 mm) groups. A comparison of the two groups showed that post/pre-lumen area ratio during pre-dilatation (%) by plain old balloon angioplasty (POBA) was significantly and negatively associated with TLR and the optimal cut-off point was 170%. Cox proportional hazard and multivariate regression analyses showed that post/pre-lumen area ratio was the only independent predictor of TLR (hazard ratio 0.9318; 95% confidence interval 0.9001, 0.9645).ConclusionGreater pre-dilatation using POBA, assessed as the post/pre-lumen area ratio, may be independently associated with a lower 12-month TLR rate in patients undergoing DCB angioplasty for de novo small coronary lesions.
Clinical Chemistry and Laboratory Medicine, Jan 6, 2001
To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and thei... more To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (<65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p<0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.
To elucidate the effects of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (... more To elucidate the effects of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (Ala to Val) on the development of coronary artery disease (CAD) in familial hypercholesterolemia (FH), we studied 128 consecutive male heterozygous FH patients, 65 with CAD and 63 without CAD. The frequency of genotype W in the CAD group was 15% and in the non-CAD group was 11%. The mean ages of onset in the CAD group were 53-, 53-, and 42- years, for genotypes AA, AV, and W, respectively (p<.05); the age of onset of CAD in genotype W was significantly lower than in the other two genotypes. The oldest patients in the non-CAD group were 80-, 68-, and 48- years, for genotypes AA, AV, and W, respectively. In the stepwise multiple regression analysis, only MTHFR genotype W was shown to be an independent predictor of the early onset of CAD. The mean plasma Hcy level of genotype W was significantly higher than those of the other two genotypes. These results suggest that he MTHFR mutation may accelerates the onset of CAD through elevation of plasma Hcy levels in male heterozygous FH patients.
Backgrounds Circulating levels of some amino acids are significantly decreased in heart failure p... more Backgrounds Circulating levels of some amino acids are significantly decreased in heart failure patients. However, relationship between their levels and cardiac function remains unclear. We therefore examined association between amino acid levels and cardiac function as prognostic predictor in DCM patients. Methods Consecutive 59 patients with DCM (M/F: 46/13, mean age: 59 years) were enrolled. We measured 25 kinds of plasma AA concentration, derivative of reactive oxygen metabolites (d-ROMs) as marker of oxidative stress, and washout rate of Tc-99m Sestamibi (WOR) as function of mitochondria and LVEF as LV function parameters. The occurrence of rehospitalization for cardiac events or cardiac death were followed during mean 1101 days (13-2626). Results Histidine, arginine and Fischer ratio (FR) showed a significant positive association with LVEF (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Threonine and asparagine showed a significant negative association with WOR (P &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Histidine and arginine showed a significant negative association with levels of d-ROMs (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05).Rehospitalization for cardiac events and cardiac death were recorded in 16 patients (27%) and 6 patients (10%), respectively. Kaplan-Meier curves analysis showed similar trend of rehospitalization in subjects with lower FR and those with higher values. However, cardiac death in subjects with lower FR was observed more frequently as compared to those with higher values (22.2% vs 5.3% p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). ConclusionsThe plasma FR could be a novel prognostic biomarker in DCM patients.
Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in... more Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in the non-enzymatic reaction with intracellular proteins, are highly cytotoxic and have been implicated in the pathogenesis of various diseases. However, the mechanisms underlying the degradation and removal of TAGE remain largely unknown. In the present study, we identified the checkpoint kinase-1 (CHK1) mutant, d270KD, which was rapidly degraded intracellularly by GA, and showed that its degradation was mainly mediated by the ubiquitin-proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of TAGE. The knockdown of p62/SQSTM1 reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of TAGE aggregates. The present results suggest that the ubiquitin-proteasome pathway and p62 play a role in the degradation and aggregation of intracellular TAGE formed by GA. This study provides new insights into the mechanisms underlying TAGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with TAGE accumulation.
A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over th... more A 39-year-old male heterozygous familial hypercholesterolemia patient with marked ectasia over the entire coronary artery tree had been treated with several kinds of lipid-lowering single or combined drug therapies using clofibrate, compactin, cholestyramine, probucol, and pravastatin, and LDL-apheresis. During the 19-year follow-up, he suffered myocardial infarction three times and some of the ectatic coronary segments became enlarged, others narrowed, and one of them occluded in spite of the treatment. At the age of 58, he died after a fourth cardiac attack and subsequent cardiogenic shock. The autopsy indicated that his three coronary arteries showed diffuse ectatic changes and the largest lumen diameter of the left anterior descending artery was 25 mm, of the circumflex artery 12 mm, and of the right coronary artery 13 mm. The ectatic artery wall was not thick and the major part of the lumen was occupied by organized thrombi. Microscopic examinations showed that the larger the diameter of the lumen, the more severe the structural damage of the intima and tunica media and the larger the number of infiltrated cells, including lymphocytes, macrophages, and plasma cells. Immunoreactivity against matrix metalloproteinase (MMP)-1, and MMP-2 was observed in smooth muscle cells, macrophages, lymphocytes, and endothelial cells of the vasa vasorum or neovasculature. MMP-9 immunoreactivity was also localized in intimal foamy macrophages and round cells (macrophages and lymphocytes) of the media and adventitia. MMP-1 increased with the lumen diameter of the ectatic arteries. The ratio of immunoreactivity against both MMP-2 and MMP-9 to that against tissue inhibitor of metalloproteinase (TIMP)-2 also increased with the lumen diameter, but it no longer increased when the diameter was over 10 mm. These observations suggest that the MMP-TIMP system appears to play a significant role in the development of coronary ectasia
Journal of International Medical Research, Aug 1, 2022
ObjectiveTo assess the determinants of target lesion revascularization (TLR) after drug-coated ba... more ObjectiveTo assess the determinants of target lesion revascularization (TLR) after drug-coated balloon (DCB) angioplasty for de novo small coronary artery lesions.MethodsThis retrospective study enrolled consecutive lesions from patients that were in a stable condition and had undergone successful DCB treatment for de novo small coronary artery lesions. The study endpoint was TLR and major adverse cardiac events at 12 months.ResultsA total of 68 patients with 83 lesions were enrolled in the study. Of these, 11 (13.3%) lesions required TLR. Mean ± SD pre-dilatation balloon diameters were similar in the non-TLR (2.33 ± 0.72 mm) and TLR (2.18 ± 0.36 mm) groups. A comparison of the two groups showed that post/pre-lumen area ratio during pre-dilatation (%) by plain old balloon angioplasty (POBA) was significantly and negatively associated with TLR and the optimal cut-off point was 170%. Cox proportional hazard and multivariate regression analyses showed that post/pre-lumen area ratio was the only independent predictor of TLR (hazard ratio 0.9318; 95% confidence interval 0.9001, 0.9645).ConclusionGreater pre-dilatation using POBA, assessed as the post/pre-lumen area ratio, may be independently associated with a lower 12-month TLR rate in patients undergoing DCB angioplasty for de novo small coronary lesions.
Clinical Chemistry and Laboratory Medicine, Jan 6, 2001
To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and thei... more To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (&amp;amp;lt;65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p&amp;amp;lt;0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.
To elucidate the effects of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (... more To elucidate the effects of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (Ala to Val) on the development of coronary artery disease (CAD) in familial hypercholesterolemia (FH), we studied 128 consecutive male heterozygous FH patients, 65 with CAD and 63 without CAD. The frequency of genotype W in the CAD group was 15% and in the non-CAD group was 11%. The mean ages of onset in the CAD group were 53-, 53-, and 42- years, for genotypes AA, AV, and W, respectively (p<.05); the age of onset of CAD in genotype W was significantly lower than in the other two genotypes. The oldest patients in the non-CAD group were 80-, 68-, and 48- years, for genotypes AA, AV, and W, respectively. In the stepwise multiple regression analysis, only MTHFR genotype W was shown to be an independent predictor of the early onset of CAD. The mean plasma Hcy level of genotype W was significantly higher than those of the other two genotypes. These results suggest that he MTHFR mutation may accelerates the onset of CAD through elevation of plasma Hcy levels in male heterozygous FH patients.
Backgrounds Circulating levels of some amino acids are significantly decreased in heart failure p... more Backgrounds Circulating levels of some amino acids are significantly decreased in heart failure patients. However, relationship between their levels and cardiac function remains unclear. We therefore examined association between amino acid levels and cardiac function as prognostic predictor in DCM patients. Methods Consecutive 59 patients with DCM (M/F: 46/13, mean age: 59 years) were enrolled. We measured 25 kinds of plasma AA concentration, derivative of reactive oxygen metabolites (d-ROMs) as marker of oxidative stress, and washout rate of Tc-99m Sestamibi (WOR) as function of mitochondria and LVEF as LV function parameters. The occurrence of rehospitalization for cardiac events or cardiac death were followed during mean 1101 days (13-2626). Results Histidine, arginine and Fischer ratio (FR) showed a significant positive association with LVEF (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Threonine and asparagine showed a significant negative association with WOR (P &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Histidine and arginine showed a significant negative association with levels of d-ROMs (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05).Rehospitalization for cardiac events and cardiac death were recorded in 16 patients (27%) and 6 patients (10%), respectively. Kaplan-Meier curves analysis showed similar trend of rehospitalization in subjects with lower FR and those with higher values. However, cardiac death in subjects with lower FR was observed more frequently as compared to those with higher values (22.2% vs 5.3% p &amp;amp;amp;amp;amp;amp;amp;lt; 0.05). ConclusionsThe plasma FR could be a novel prognostic biomarker in DCM patients.
Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in... more Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in the non-enzymatic reaction with intracellular proteins, are highly cytotoxic and have been implicated in the pathogenesis of various diseases. However, the mechanisms underlying the degradation and removal of TAGE remain largely unknown. In the present study, we identified the checkpoint kinase-1 (CHK1) mutant, d270KD, which was rapidly degraded intracellularly by GA, and showed that its degradation was mainly mediated by the ubiquitin-proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of TAGE. The knockdown of p62/SQSTM1 reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of TAGE aggregates. The present results suggest that the ubiquitin-proteasome pathway and p62 play a role in the degradation and aggregation of intracellular TAGE formed by GA. This study provides new insights into the mechanisms underlying TAGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with TAGE accumulation.
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Papers by Kouji Kajinami