Akira Matsuki

Effect of Repeated Sauna Treatment on Exercise Tolerance and Endothelial Function in Patients With Chronic Heart Failure

Repeated sauna treatment, known as Waon therapy, has been shown to improve cardiac function as well as exercise tolerance in patients with chronic heart failure. However, the underlying mechanisms of this therapy regarding these improvements remain to be elucidated. Forty-one patients with chronic heart failure (mean age 68.3 ± 13.5 years old) underwent Waon therapy 5 times a week for 3 weeks. Before and after treatment, a number of assessments were performed in all subjects: 6-minute walk test, echocardiography, determination of neurohumoral factors and number of circulating CD34(+) cells, and a flow-mediated dilation (FMD) test of endothelial function. Cardiopulmonary exercise testing was also performed in 20 patients. Waon therapy increased the left ventricular ejection fraction (from 30.4 ± 12.6% to 32.5% ± 12.8%, p = 0.023) and reduced plasma levels of norepinephrine (from 400 ± 258 to 300 ± 187 pg/ml, p = 0.015) and brain natriuretic peptide (from 550 ± 510 to 416 ± 431 pg/ml, p = 0.035). Waon therapy increased the 6-minute walk distance (from 337 ± 120 to 379 ± 126 m, p <0.001) in association with an improvement in FMD (from 3.5 ± 2.3% to 5.5% ± 2.7%, p <0.001) and an increase in the number of circulating CD34(+) cells (p = 0.025). Changes in 6-minute walk distance were correlated positively with those in the left ventricular ejection fraction and FMD and negatively with those in plasma levels of norepinephrine and brain natriuretic peptide levels. A multivariate analysis revealed that an increase in FMD was the only independent determinant of 6-minute walk distance improvement. Finally, Waon therapy significantly increased peak Vo(2), and this increase was also correlated with changes in FMD. In conclusion, repeated sauna therapy in patients with chronic heart failure improves exercise tolerance in association with improvement in endothelial function.

Repeated sauna therapy improves myocardial perfusion in patients with chronically occluded coronary artery-related ischemia

BACKGROUND Repeated low-temperature sauna (Waon) therapy relieves ischemic symptoms in patients with peripheral arterial disease. We investigated whether Waon therapy could improve myocardial perfusion in patients with ischemia related to chronic total occlusion (CTO) of coronary arteries. METHODS Twenty-four patients who had ischemia in the CTO-related area were examined. The severity of ischemia was quantified by thallium-201 myocardial perfusion scintigraphy with adenosine. The Waon group (n=16) was treated daily for three weeks with a 60 °C far infrared-ray dry sauna bath for 15 min and then kept in a bed covered with blankets for 30 min. The control group (n=8) underwent myocardial perfusion scintigraphy twice with a three-week interval. RESULTS In the control group, neither summed stress score (SSS) nor summed difference score (SDS) of myocardial scintigraphy changed. However, Waon therapy improved both SSS (16 ± 7 to 9 ± 6, p<0.01) and SDS (7 ± 4 to 3 ± 2, p<0.01), and the improvement was greater in patients with higher SSS and SDS scores at the baseline. Waon therapy extended treadmill exercise time (430 ± 185 to 511 ± 192s, p<0.01) and improved flow-mediated dilation of the brachial artery (4.1 ± 1.3 to 5.9 ± 1.8%, p<0.05), but tended to decrease the number of circulating CD34-positive bone marrow-derived cells. CONCLUSIONS Waon therapy improves CTO-related myocardial ischemia in association with improvement of vascular endothelial function. This therapy could be a complementary and alternative tool in patients with severe coronary lesions not suitable for coronary intervention.

Repeated sauna therapy attenuates ventricular remodeling after myocardial infarction in rats by increasing coronary vascularity of noninfarcted myocardium

Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P < 0.01) and end-systolic (8.6 ± 0.5 vs. 9.6 ± 0.6 mm, P < 0.01) dimensions and attenuated MI-induced increases in LV end-diastolic pressure. Cross-sectional areas of cardiomyocytes were smaller in ST rats and associated with a significant reduction in myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for α-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI.

Combination therapy of candesartan with statin inhibits progression of atherosclerosis more than statin alone in patients with coronary artery disease.

ObjectivesBoth statins and renin–angiotensin system (RAS) inhibitors inhibit atherosclerotic progression and reduce cardiovascular events. However, it remains unclear whether combination therapy of RAS inhibitor with statin could inhibit plaque progression more than statin alone. MethodsUsing 64 multislice computed tomography, vessel wall areas (VWAs) and total vascular areas of the left main trunk (LMT) and proximal right coronary artery (RCA) and the thoracic descending aorta (TDA) were determined in patients with coronary artery disease before and after 2.0-year treatment with atorvastatin and candesartan (n=20) or with atorvastatin alone (n=16), although these patients had been treated with the combination therapy or statin alone at the study enrollment. Plasma levels of high sensitive C-reactive protein, matrix metalloproteinase-9, and urinary 8-iso-prostaglandin F2&agr; were determined at the baseline. ResultsThere were no significant differences in low-density lipoprotein and high-density lipoprotein cholesterol, C-reactive protein, matrix metalloproteinase-9, or urinary 8-iso-prostaglandin F2&agr; levels between the two groups. Two years later, total vascular areas of TDA and RCA increased significantly in the atorvastatin group but not in the combination group. Moreover, increases in VWAs were less in the combination group than in the atorvastatin group in TDA (3.6±23.1 vs. 28.6±25.5 mm2, P=0.004), RCA (−1.6±1.6 vs. 0.6±2.5 mm2, P=0.005), and left main trunk (−0.9±3.5 vs. 1.3±2.4 mm2, P=0.095). Biomarker levels at the baseline did not affect the progression of VWA. ConclusionCombination therapy of RAS inhibitor with statin is more effective than statin alone in inhibiting atherosclerotic progression of coronary arteries and the aorta in patients with coronary artery disease.

Impact of myocardial perfusion abnormality on prognosis in patients with non-ischemic dilated cardiomyopathy

BACKGROUND Myocardial perfusion imaging shows various patterns in patients with non-ischemic dilated cardiomyopathy (DCM). However, influences of regional abnormalities of myocardial perfusion or ventricular wall motion on prognosis in DCM patients remains to be clarified. Accordingly, we investigated a relation between myocardial perfusion patterns and long-term prognosis in DCM patients. METHODS AND RESULTS Sixty-two patients were divided into 2 groups according to patterns of (99m)Tc-Tetrofosmin scintigraphy, i.e. large focal defects (focal) and minimally impaired perfusion or multiple small defects (non-focal). There were no differences between the 2 groups in left ventricular (LV) end-diastolic dimensions (63.4 ± 9.1 and 63.8.4 ± 7.5mm, respectively) and LV ejection fraction (30.3 ± 9.2 and 27.9 ± 7.8%, respectively), indicating LV systolic dysfunction was comparable between the groups. The focal group had a higher prevalence of brain natriuretic peptide ≧ 200 ng/dl and plasma norepinephrine ≧ 500 pg/ml than the non-focal group (p<0.05), and had longer QRS durations (p<0.05). The focal group had non-sustained ventricular tachycardia (VT) (p<0.05) on 24-h electrocardiogram recording and a history of VT/ventricular fibrillation more frequently (p<0.05), and had higher New York Heart Association functional class than the non-focal group (p<0.05). The mortality was significantly higher in the focal group (56.0%) than in the non-focal group (28.6%) and the survival curves revealed worse prognosis in the focal group during a follow-up period of 5.3 ± 2.8 years. CONCLUSIONS Non-ischemic DCM patients with focal defects are accompanied by more advanced heart failure and poor prognosis compared to those with minimally impaired perfusion or multiple small defects, despite comparable LV systolic dysfunction.

Ischemic preconditioning accelerates the fatty acid oxidation of rat hearts.

BACKGROUND Ischemic preconditioning (IPC) reduced myocardial ATP depletion during sustained ischemia and has a powerful protective effect on the myocardium. The purpose of the present study was to clarify the effects of IPC on myocardial accumulation of fatty acid (FA) tracer and its intracellular metabolism. METHODS Myocardial ischemia-reperfusion (MI-R) injury was induced by the left coronary artery ligation for 15 min followed by reperfusion in Wistar rats. IPC was achieved with a single cycle of 5-minute coronary ligation followed by 5-minute reperfusion before MI-R. Three days after ischemia-reperfusion, FA metabolism was evaluated in rats with or without IPC using (131)I- and (125)I-15-(p-iodophenyl)-9-methylpentadecanoic acid (9MPA) and thin-layer chromatography. RESULTS IPC attenuated a reduction of 9MPA accumulation in ischemic region (IR). The metabolite fraction of 9MPA including both early and late metabolites was less in IR as compared to non-IR in rats without IPC. IPC increased the final metabolic product of 9MPA processed via alpha- and beta-oxidation in both IR and non-IR. CONCLUSIONS IPC accelerated fatty acid oxidation in both IR and non-IR. This alteration in fatty acid metabolism would inhibit an intracellular accumulation of detrimental fatty acid metabolites.

Nicorandil Attenuates Ischemia-Reperfusion Injury Via Inhibition of Norepinephrine Release From Cardiac Sympathetic Nerve Terminals

A large amount of norepinephrine (NE) released from cardiac sympathetic nerve terminals might accelerate myocardial ischemic injury. Nicorandil (NICO), KATP channel opener, could attenuate cardiac NE release from the sympathetic nerve terminals during ischemia. The present study aimed to investigate the effects of NICO-induced attenuation of cardiac NE release on myocardial ischemia-reperfusion (I/R) injury in rats, by comparison with the effect of cardiac sympathetic denervation on I/R injury.Cardiac interstitial NE (iNE) concentrations were determined using a microdialysis method. Rats were divided into 3 groups; control, NICO, and denervation groups. Cardiac sympathetic denervation was performed by painting 10% phenol on the left ventricular epicardium 7 days before producing ischemia. The left coronary artery was ligated for 30 minutes and then re-perfused for 120 minutes. NICO (50 μg/kg/minute) was infused intravenously starting 20 minutes before the coronary occlusion to the end of the ligation.The infarct size of the left ventricle was smaller in rats treated with NICO than in control rats (20.2 ± 3.0 versus 50.6 ± 14.7%, P < 0.01). Sympathetic denervation also reduced infarct size (28.5 ± 10.4 %, P < 0.01), which was not significantly different from that in the NICO group. At the end of 30-minute ischemia, iNE increased markedly in control rats (0.1 ± 0.1 to 20.6 ± 5.3 × 103 pg/mL), whereas the increase was completely inhibited in denervated rats. NICO markedly attenuated the increase (4.9 ± 3.0 × 103 pg/mL, P < 0.01) during ischemia.NICO-induced attenuation of neural NE release during ischemia might, at least in part, contribute to myocardial protection against I/R injury.

Transient hypercapnic stress causes exaggerated and prolonged elevation of cardiac and renal interstitial norepinephrine levels in conscious hypertensive rats

The responses of sympathetic nerve activity to transient stress can be exaggerated in salt-sensitive (SS), hypertensive subjects. Cardiac and renal interstitial norepinephrine (iNE) levels during and after transient hypercapnia were investigated in conscious SS rats. Dahl SS and salt-resistant (SR) 6-wk-old rats were fed a high-salt diet, and at 12 wk iNE levels in the heart and kidney were determined using microdialysis with probes inserted in the left ventricular (LV) wall and kidney. A telemetry system determined blood pressure and heart rate (HR) in separate animals. After recovery from the operation, data were collected before, during, and after exposure to normoxic 10% CO(2) for 25 min under unanesthetized conditions. The plasma NE concentrations at baseline did not differ between the two strains. Both cardiac and renal iNE levels were much higher in SS rats than in SR rats at baseline as well as during hypercapnic stress. After stress, the markedly increased iNE levels of SS rats were prolonged in the LV as well as in the kidney. During hypercapnic stress, HR decreased in both SS and SR rats, while sudden increases in HR immediately after the withdrawal from stress were followed by its slower reduction in SS rats compared with SR rats. In conclusion, transient hypercapnic stress causes exaggerated and prolonged elevation of iNE levels in the heart as well as in kidneys of SS animals.