松本 鉄也

The renin-angiotensin system regulates the vascular fibrinolytic balance. In the human forearm vasculature, angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) increase the release of t-PA through endogenous bradykinin. We tested the hypothesis that ACE inhibition and sex modulate the endogenous coronary release of tissue plasminogen activator (t-PA) in hypertensive patients. Seventy-three patients underwent diagnostic coronary angiography and had normal coronary angiograms. Thirty-three patients (21 men and 12 women) were treated with imidapril (5 mg/day) for 4 weeks (ACE-I group), and 40 (23 men and 17 women) were not treated with ACE-I (non-ACE-I group). All of the women were postmenopausal. Coronary blood flow in the left anterior descending artery was evaluated by measuring Doppler flow velocity. Net coronary t-PA release was determined as (coronary sinus-aorta gradient of t-PA)X(coronary blood flow)X[(100-hematocrit)/100]. Age, arterial pressure, heart rate, lipid levels, coronary flow, and the plasma level of t-PA at either aorta or coronary sinus were comparable among the 4 groups. In women, net t-PA release in the ACE-I group was significantly higher than that in the other groups (P<0.05; man non-ACE-I group: 1.4 +/- 2.6 ng/mL; woman non-ACE-I group: 1.4 +/- 3.1 ng/mL; man ACE-I group: -1.8 +/- 2.8 ng/mL; woman ACE-I group: 14.8 +/- 3.6 ng/mL). Correction for smoking status gave similar results. There was a significant negative correlation between serum ACE activity and coronary t-PA release in women (r=-0.38; P<0.05) but not in men. ACE inhibition increases coronary release of t-PA in women but not in men. (Hypertension. 2010;56:364-368.)

Echocardiographic studies have suggested an association between diastolic dysfunction and exercise intolerance. The aim of this study was to examine the relationship between exercise capacity and left ventricular (LV) function during stress myocardial scintigraphy, and to investigate whether or not this relationship is caused by ischemia during exercise. The studied patients underwent technetium-99m sestamibi quantitative gated SPECT, including treadmill exercise. Myocardial stress images were acquired 30 min after the first tracer injection (370 MBq) during maximal exercise. Three hours later, the second tracer (740 MBq) was injected, and resting images were acquired 30 min after this injection. The presence of ischemia was determined by tracer accumulation. From the same data source, LV diastolic parameters [first third filling fraction (1/3FF), first third filling rate (1/3FR), peak filling rate (PFR) and time to PFR (TPF)], and systolic parameters [ejection fraction (EF), peak ejection rate (PER), time to PER (TPE) and first third ejection fraction (1/3EF)] were analyzed. Subjects with exercise inability (< 6 METs) were excluded. In 45 patients, diastolic parameters 1/3FF, 1/3FR, PFR and TPF correlated significantly with exercise duration (r = 0.32*, 0.37*, 0.37* and -0.40(#), respectively; *p < 0.05, (#) p < 0.01), but systolic parameters EF, PER, TPE and 1/3EF did not. At rest, 1/3FF, PFR and PER were significantly increased, suggesting functional deterioration during exercise. Even after 3 h, 1/3FR, PFR and TPF still correlated significantly with exercise duration (r = 0.29*, 0.36* and -0.30*, respectively; *p < 0.05). Such findings were observed even when the 10 patients who exhibited ischemia during exercise were excluded (1/3FR: r = 0.34*; PFR: r = 0.37*; TPF: r = -0.36*; *p < 0.05, n = 35). Our findings suggested that LV diastolic dysfunction, not systolic dysfunction, is associated with limited exercise capacity independent of the occurrence of ischemia.

The aim of this study was to determine the impact of pitavastatin on low-density lipoprotein cholesterol (LDL-C) and lectin-like oxidized LDL receptor-1 (LOX-1) in patients with hypercholesterolemia. Twenty-five hypercholesterolemic patients (8 male, 17 female; age 66 +/- 13, 21-80 years) who had not received anti-dyslipidemic agents and had LDL-C levels of more than 160 mg/dL were examined. Biochemical factors were measured at baseline and after treatment with pitavastatin (2 mg/day) for 6 months. Serum levels of LOX-1 with apolipoprotein B-100 particle ligand and a soluble form of LOX-1 (sLOX-1) were measured by ELISA. All subjects completed the study with no adverse side effects. Total-C (268 +/- 26 vs. 176 +/- 17 mg/dL), LDL-C (182 +/- 21 vs. 96 +/- 14 mg/dL), and LOX-1 ligand (867 +/- 452 vs. 435 +/- 262 ng/mL) were reduced with pitavastatin treatment (P < 0.0001 for each). Significant decreases in triacylglycerols were noted (P < 0.0001), but there were no changes in high-density lipoprotein cholesterol. After 6 months, there were no significant changes in high-sensitivity CRP or soluble LOX-1. At baseline, there were no significant correlations between LOX-1 ligand and either LDL-C or sLOX-1. The decrease in LOX-1 ligand was not correlated with the decrease in LDL-C, but was correlated with the decrease in sLOX-1 (r = 0.47, P < 0.05). In conclusion, pitavastatin therapy had beneficial effects on markers of oxidative stress in hypercholesterolemic subjects. Serum levels of LOX-1 ligand may be a useful biomarker of the pleiotropic effects of statins.

心室細動(ventricular fibrillation;VF)を発生後に自動体外式除細動器(automated external defibrillator;AED)より救命された重症心疾患例が下肢血行障害を合併し下肢を切断したが、心臓リハビリテーションを工夫して施行したことによって家庭に退院できるまでの日常生活動作(activities of daily living;ADL)が獲得できた2症例を報告する。症例1:74歳、男性。心筋虚血による心室細動(VF)に対して、体育館に設置してあった自動体外式除細動器(AED)が使用された。心不全に対して大動脈バルーンパンピング(IABP)が使用された。下肢の血行障害を生じて、右下腿切断を施行された。下腿装具を装着し、心臓リハビリテーションを実施しADLが向上した。致死性不整脈の再発はなく、家庭復帰した。症例2:16歳、男性。心筋炎によると考えられるVFの発作を繰り返した。初回のVFに対して、学校に設置してあったAEDが使用された。心不全に対して経皮的心肺補助装置(PCPS)が使用された。下腿の血行障害による壊死を生じたため、下腿切断を施行された。下腿装具を作製し、心臓リハビリテーションを行った。VFを繰り返したため植込み型除細動器(implantable cardioverter defibrillator;ICD)を植え込み、その後も心臓リハビリテーションを行い、家庭復帰と復学が可能となった。(著者抄録)

A 49-year-old female cardiomyopathic patient with heart, hepatic, and renal failure and lactic acidosis was transferred to the intensive care unit without a unifying diagnosis. She was of short stature ( 145 cm tall), had difficulty in hearing, a past history of complete atrioventricular block, and had received a permanent pacemaker. She had been diagnosed and treated as dilated cardiomyopathy by her primary doctor. Treatment in the intensive care unit for 21 days including plasma exchange, continuous hemodiafiltration, artificial ventilation, and administration of catecholamine, carperitide, and a large amount of coenzyme Q10 ( 210 mg/day) improved the symptoms. Genetic analysis using mitochondrial DNA from leukocytes and sternocleidomastoid muscle revealed a 3243A>G mutation in the mitochondrial tRNA(Leu (UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes ( MELAS). The patient recovered through intensive care and could be discharged from hospital without any sequelae. This case was mitochondrial cardiomyopathy diagnosed from the symptoms of multiple organ dysfunction syndrome. Cardiomyopathy due to the mutation of mitochondrial DNA is not a common disease. However, it should be considered as a possible cause of heart failure. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

The authors examine the clinical significance of radial augmentation index (rAI) and brachial-ankle Pulse wave velocity (baPWW). In 78 hypertensive patients, rAI correlates inversely with pulse rate (PR; r = -0.57, P < .001), but baPWV does not. A weak correlation between rAI and systolic blood pressure (SBP) is observed (r = 0.28, P <. 05). rAI has no significant correlation with diastolic blood pressure (DBP). In contrast, baPWV correlates positively with both SBP (r = 0.54, P < .001) and DBP (r = 0,43, P < .001). In 56 of these patients, baPMV correlates with the diastolic parameters-the mitral E/A ratio (r = -0.35, P < .01), pulmonary vein S/D ratio (r = 0.41, P < .01), and deceleration time 0.28, P < .05) by echocardiography, but AI.P75 (rAI corrected for PR 75 bpm because of PR dependence) does not. Therefore, for detection of diastolic dysfunction, baPWV may be more sensitive than rAI.

背景,目的:習慣的な運動は血管内皮機能を改善させ,心血管病のリスクを減少させる.その機序は血管内皮に作用するシェアストレスによると考えられている.そこで,臥床した状態で全身を上下に周期的に振動させる運動負荷ベッドを用いて,全身の周期的加速運動の血管内皮機能の改善効果について上腕動脈の反応性充血反応(FMD)を評価して検討した.<BR>方法:運動習慣のない成人ボランティア20名(平均年齢43±4歳,女性12名,男性8名)を対象とした.対象者を無作為に2群に分け,4週間の運動療法期間,4週間の非運動療法期間の順番をクロスオーバーにて割りつけた.1日1回,45分間の2～3Hz,±0.22gの運動を4週間の間に計20回施行した.<BR>結果:すべての対象者において運動装置による合併症は生じなかった.運動療法期間,非運動療法期間の前後で血圧,脈拍,脂質,血糖,Body Mass Index(BMI)に変化は認めなかった.運動療法群でFMDは73±0.6%から8.2±0.7%に有意に増加した(P<0.05).非運動療法群ではFMDに変化は認めなかった(7.2±0.6%から7.7±0.5%).硝酸薬による血管拡張作用は運動療法期間,非運動療法期間の前後で同様であった.<BR>結論:運動習慣のない成人において,全身の受動的な周期的加速運動は血管内皮機能を改善した.QOL向上・生命予後改善効果も含めた運動療法として期待される.

Background: Cigarette smoking is a major risk factor for acute coronary thrombosis. Bradykinin (BK) can induce the release of tissue plasminogen activator (tPA) from the coronary vasculature. The purpose of this study was to investigate whether smoking reduces BK-stimulated tPA release in human coronary circulation. Materials and methods: We examined two groups: 20 current smokers and 19 nonsmokers. By cardiac catheterization, graded doses of BK (0.2, 0.6 and 2.0 mu g/min) and papaverine (PA) (12 mg) were administered into the coronary artery. Coronary blood flow (CBF) was measured using a Doppler flow wire. Blood samples from the aorta (Ao) and coronary sinus (CS) were assayed. Results: BK increased both coronary artery diameter (CD) and CBF to a similar extent in the two groups. The net coronary tPA release was dose-dependently increased by BK in the two groups, but the degree of this increase in current smokers was significantly lower than that in nonsmokers. BK did not change plasminogen activator inhibitor type 1 (PAI 1) levels in either group. PA did not alter either tPA or PAI-1 levels in either group. Conclusions: These results suggest that cigarette smoking deteriorates coronary fibrolytic activity, independent of changes in CBE These findings can at least partly explain the higher risk of coronary thrombosis in smokers. (C) 2007 Elsevier Ltd. All rights reserved.

A 70-year-old man with alcoholic cardiomyopathy underwent 99mtechnetium-sestamibi (MIBI), iodine-123-labeled metaiodobenzylguanidine (MIBG) scintigraphy and Iodine-123-labeled beta-methyl-iodophenyl pentadecanoic acid (BMIPP) scintigraphy. 99mTechnetium-MIBI identified myocardial damage in the inferior wall of left ventricle. 123I BMIPP showed low uptake in the inferior wall of the myocardium, concordant to perfusion. 123I BMIPP and 123I MIBG showed reduced uptake in the inferior segment of the myocardium, indicating impairment of fatty acid metabolism and sympathetic abnormalities. Damaged myocardium was demonstrated in alcoholic cardiomyopathy. Beta blocker (carvedilol) and angiotensin-receptor blocker (valsartan) were started at low doses, then increased gradually, leading to the improvement of cardiac performance. Cardiac sympathetic nerve function, impaired due to alcoholic cardiomyopathy, was improved with beta-blocker therapy. Cardiac scintigraphy may be useful to assess the extent of myocardial improvement and the response to therapy. © 2006 The Japanese Society of Internal Medicine.

We illustrate pulmonary vein anatomy in 2 patients undergoing multi-slice computed tomography (MSCT) scanning prior to atrial fibrillation ablation, including anomaly of the pulmonary vein. The anomalous variations need to be investigated before catheter procedure, because of the anomalous variations. Non-invasive imaging using MSCT could have important clinical implications and provide the physicians useful information on morphological feature in patients with atrial fibrillation before catheter ablation. © Springer 2005.

The study evaluated the feasibility of determining coronary lesion configuration, including coronary plaque, stenosis and calcification, by ECG-gated MSCT. The results were compared with the characteristics of intravascular ultrasound (IVUS). The overall sensitivity for diagnosing significant coronary stenosis was 80.2%, and the specificity was 95.6%. There were significant differences in plaque density among three groups (p&lt 0.01). MSCT was feasible for the detection of coronary artery stenosis. And plaque composition could be clearly differentiated and classified by MSCT, which is a promising method of non-invasive risk assessment in patients with known or suspected coronary artery disease. © 2005 Elsevier Ltd. All rights reserved.

Creatine depletion in the non-viable infarcted human heart was previously demonstrated with proton magnetic resonance (MR) spectroscopy (¹H MRS). In the present study, we assessed total creatine (CR) in human hearts with non-ischemic dysfunctions such as cardiomyopathy. Using cardiac-gated ¹H MRS with MR image-guided PRESS localization, we measured septal CR in healthy and diseased human hearts. Fifteen patients with chronic heart failure (CHF, left ventricular ejection fraction <45%) and 14 age-matched normal subjects were examined. Myocardial CR was significantly (p<0.001) lower in failing hearts (15.1±SD 5.0 μmol/g wet weight, range 8.0-22.9) than in normal hearts (27.6±4.1 μmol/g wet weight, range 20.8-36.2). Myocardial CR concentrations in six heart failure patients with plasma B-type natriuretic peptide (BNP) levels of >200 pg/ml (11.5±0.9 μmol/g wet weight, range 9.9-12.3) were significantly lower than those in four heart failure patients with plasma BNP levels of <200 pg/ml (19.8±2.5 μmol/g wet weight, range 17.7-22.9, p<0.001). Thus, our study showed that myocardial CR was decreased in non-ischemic dysfunctional hearts. Noninvasive measurements of myocardial CR by ¹H MRS may be useful in the assessment of the severity of heart failure.<br>

We investigated the endothelial modulations in nitrate tolerance in isolated rabbit aorta. Nitrate tolerance was induced by a 72-h treatment with transdermal nitroglycerin (NTG, 0.4 mg/h) in conscious rabbits, which was verified by a 20-fold increase in the EC50 values [NTG tolerance (6.1+/-0.8) x 10(-7) M vs control (3.0 +/- 0.6) x 10(-8) M]. The relaxations to NTG in tolerant and nontolerant aortic strips were enhanced when their endothelia were denuded [E(-)]. In the presence of endothelium [E(+)], NTG-tolerant vessels were not tolerant to acetylcholine (ACh), which can release endothelial nitric oxide (NO), exogenous NO or 8-bromo (Br)-cGMP. In NTG-tolerant and nontolerant vessels with endothelium, concentration-response curves for NO were the same as those in endothelium-absent tolerant vessels. In both NTG-tolerant and nontolerant vessels, treatment with superoxide dismutase (SOD, 20 units/ml), an O-2-. scavenger, unaffected the responses to NTG reduced in the presence of endothelium, but treatment with N-G-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), an NO synthase (NOS) inhibitor, reversed these reductions. Thus, our data did not indicate that an increased endothelial superoxide O-2-. production contributes to nitrate tolerance. Our study suggested that (i) an impaired biotransformation process from NTG to NO is responsible for the occurrence of nitrate tolerance and (ii) vascular response to NTG enhanced by endothelial removal is related to blocked endothelial NO release. (C) 2003 Elsevier Inc. All rights reserved.

Background - Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE) however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-β in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling Methods and Results - We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I 10 mg/kg twice a day n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with the normal group however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of τ. Chy I suppressed collagen-type I and III and transforming growth factor-β mRNA levels and decreased fibrosis in the LV compared with the vehicle. Conclusion - The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF.