脳卒中様発作を伴ったミトコンドリア脳筋症および乳児致死型心筋症におけるミトコンドリアDNA点変異

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1012号,学位授与年月日：平成3年9月30日,学位授与年：199

Intravascular ultrasound appearance of scattered necrotic core as an index for deterioration of coronary flow during intervention in acute coronary syndrome

In acute coronary syndrome (ACS) patients with deterioration of coronary flow during percutaneous coronary intervention (PCI), a scattered necrotic core pattern (SNC) is observed by intravascular ultrasound virtual histology (VH-IVUS). The purpose of this study was to evaluate the impact of SNC on deterioration of coronary flow during PCI in ACS. A total of 38 ACS patients were imaged using VH-IVUS before PCI. In addition to conventional definitions of thin-cap fibroatheroma by VHIVUS (ID-TCFA), the SNC was defined as necrotic core foci with a maximum diameter of 50% plaque burden except in the ID-TCFA frame. Patients were divided into deterioration of coronary flow group (n = 15) and normal-reflow group (n = 23). The incidence of residual thrombus and plaque rupture, the external elastic membrane, plaque and fibrous volumes, the incidence of IDTCFA and the average number of SNC per frame was significantly greater in deterioration of coronary flow group than in normal-reflow group (all parameters P < 0.05). Multivariate analysis revealed that the average number of SNC per frame was independently associated with deterioration of coronary flow in ACS patients (odds ratio 1.18, P < 0.05). In conclusion, an increased number of SNC is associated with deterioration of coronary flow during PCI in ACS patients. © Springer 2011

Heterogeneity of cardiac sympathetic nerve activity and systolic dysfunction in patients with hypertrophic cardiomyopathy

金沢大学大学院医学系研究科Cardiac sympathetic nerve activity is changed in patients with hypertrophic cardiomyopathy (HCM). However, the relationship between heterogeneity of this activity and systolic left ventricular dysfunction in patients with HCM is not well established. This study was performed to evaluate the sympathetic nerve activity in various cardiac regions and to investigate the relationship between cardiac dysfunction and heterogeneity of the cardiac sympathetic nerve activity in patients with HCM. Methods: Cardiac sympathetic nerve activity was evaluated in 25 patients with HCM and 10 control subjects using planar imaging and SPECT by 123l-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. With planar 123I-MIBG imaging, the heart-to-mediastinum activity ratios (H/M), at early (20 min) and delayed (3 h) acquisition, and the washout rate were calculated. Polar maps of the left ventricular myocardium were divided into 20 segments, and the dispersion (maximal to minimal values) and SD of uptake and the washout rate in 20 segments were calculated. Results: The early H/M did not differ between the 2 groups. The delayed H/M was significantly lower and the washout rate of the whole heart was significantly higher in the HCM group than those in the control group. In patients with HCM, the delayed H/M, early uptake dispersion, and SD of early uptake showed good correlation with the left ventricular end-diastolic and end-systolic dimensions and the percentage of fractional shortening. A stepwise regression analysis revealed that the SD of early uptake was a powerful determinant for the percentage of fractional shortening in patients with HCM. Conclusion: These results suggest that the heterogeneity of regional cardiac sympathetic nerve activity may be correlated with cardiac dysfunction in patients with HCM

Oxidative Stress Correlates with Left Ventricular Volume after Acute Myocardial Infarction

It has been suggested that oxidative stress may play a role in the pathophysiology of heart failure. However, little is known about the clinical relationship between oxidative stress and left ventricular dilatation after acute myocardial infarction (AMI). We prospectively studied 28 consecutive patients, successfully treated with primary coronary angioplasty, after their first AMI. To evaluate oxidative stress, plasma oxidized low-density LDL levels (U/mL) were measured serially 1 day, 7 days, 14 days, 30 days, and 90 days after the onset of AMI using a specific sandwich enzyme-linked immunosorbent assay. Left ventriculography and coronary angiography were obtained in all patients 3 months after the AMI and infarct-related arteries were all patent. Peak plasma oxidized LDL levels were seen 7 days after AMI (after 1 day: 14.71.5, 7 days: 21.02.8, 14 days: 20.22.8, 30 days: 18.32.5, 90 days: 16.52.3 U/mL). Plasma oxidized LDL levels 7 days after AMI were significantly correlated with left ventricular end-diastolic volume (1157 mL; r=0.54, P=0.0025) and end-systolic volume (585 mL; r=0.49, P=0.008) 3 months after the AMI. Moreover, they were also correlated with end-diastolic volume index (684 mL/m2, r=0.40, P<0.05). However, no correlation was seen between peak plasma oxidized LDL levels and ejection fraction. These findings suggest that oxidative stress may play an important role in the development and progression of left ventricular remodeling after AMI

Diagnostic usefulness of the post-exercise systolic blood pressure response for the detection of coronary artery disease in patients with diabetes mellitus

金沢大学大学院医学系研究科Patients with diabetes mellitus (DM) often have a positive result on exercise testing despite a normal coronary arteriogram, which indicates that exercise-induced ST depression is not always an accurate indicator of the presence of coronary artery disease (CAD) in such patients. The present study evaluated the usefulness of the post-exercise systolic blood pressure (SBP) response for the detection of CAD in 47 consecutive patients with DM. Significant stenotic lesions were detected by angiography in 25 patients; 18 of these had true positive (TP) exercise testing results, and 7 had false negative (FN) results. No significant stenotic lesions were detected in the remaining 22 patients and of these 10 had true negative (TN) exercise testing results, and 12 had false positive (FP) results. The SBP ratio (SBP after 3 min of recovery divided by the SBP at peak exercise) was significantly higher in patients with coronary stenoses than in those without. Analysis of the relative cumulative frequency revealed that a SBP ratio greater than 0.87 was associated with significant stenoses. The sensitivity, specificity, and accuracy of ST change combined with a SBP ratio greater than 0.87 for detecting stenoses in patients with DM were 68%, 82%, and 74%, respectively. These results suggest that calculating the SBP ratio, in combination with monitoring for ST depression, improves the accuracy of treadmill exercise testing for the detection of CAD in patients with DM

Changes in cardiac sympathetic nerve innervation and activity in pathophysiologic transition from typical to end-stage hypertrophic cardiomyopathy

金沢大学大学院医学系研究科Left ventricular (LV) systolic function in hypertrophic cardiomyopathy (HCM) is usually normal. Late in the disease, however, LV systolic dysfunction and dilatation are recognized. Although abnormalities in cardiac sympathetic nerve activity in patients with HCM have been demonstrated using 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, the changes of cardiac sympathetic nerve activity throughout the clinical course from typical to end-stage HCM are unclear. The objective of this study was to evaluate the relationship between abnormalities on 123I-MIBG myocardial scintigraphy and pathophysiologic changes in patients with HCM. Methods: We performed 123I-MIBG scintigraphy on 46 patients with HCM and 18 age-matched control subjects. The patients were categorized into 3 groups: 28 patients with normal LV systolic function (group A), 9 patients with LV systolic dysfunction (group B), and 9 patients with LV systolic dysfunction and dilatation (group C). With planar 123I-MIBG imaging, the heart-to-mediastinum ratio for early and delayed acquisitions and the washout rate were calculated. With SPECT, polar maps of the LV myocardium were divided into 20 segments. The regional uptake and washout rate were calculated from semiquantitative 20-segment bull\u27s-eye analysis. Results: The early uptake was significantly lower in group C than in the control group (P < 0.01). The washout rate was progressively higher in group A, group B, and group C (P < 0.01). Reduced regional early uptake was found in 2.9 ± 3.4 (group A), 4.1 ± 4.7 (group B), and 7.4 ± 4.3 (group C) segments, respectively. In group C, regional early uptake was significantly reduced, predominantly in the interventricular septal wall, and regional washout rate was increased in the apex and lateral wall. Conclusion: These results suggest that cardiac sympathetic nerve abnormalities in patients with HCM may advance with development of LV systolic dysfunction and dilatation and that 123I-MIBG myocardial scintigraphy may be a useful tool for the evaluation of pathophysiologic changes in HCM

In-hospital Outcome in Octogenarians with Acute Coronary Syndrome Undergoing Emergent Coronary Angiography

金沢大学附属病院臨床試験管理センターVery elderly patients have higher mortality rates than younger patients after acute coronary syndrome (ACS). However, the mechanism by which increasing age contributes to such mortality remains unclear. In addition, the efficacy and safety of invasive coronary procedures for octogenarians with ACS have not been well established. We compared the clinical characteristics and in-hospital outcome of 193 octogenarians (mean age, 83 years) with those of 1,462 younger patients (mean age, 64 years) with ACS who underwent emergent coronary angiography. Octogenarians included a greater number of females, had higher rates of cerebrovascular disease and multivessel disease, a higher Killip class, a higher Forrester class, and lower rates of smoking, diabetes, and hypercholesterolemia than the younger subjects. Interventions, including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), were performed less frequently in octogenarians than in younger patients (88.0% versus 90.8%). The procedural success rate in octogenarians did not differ from that in younger patients. However, the in-hospital mortality rate for the octogenarians was about three times higher than for the younger patients (19.2% versus 6.9%). Multivariate analysis revealed that the predictors of in-hospital mortality in the octogenarians were a higher Killip class and a higher Forrester class. Octogenarians with ACS had fewer coronary risk factors and a similar success rate for the intervention, but had more greatly impaired hemodynamics and higher in-hospital mortality than the younger patients. Therefore, impaired myocardial reserve may contribute to a large portion of in-hospital deaths in octogenarians with ACS

Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues

金沢大学医薬保健研究域医学系Objective: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins