Sodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients. Twenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time. Two weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = −0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = −0.60, P = 0.0014), but not increased urinary glucose excretion. SGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Waon therapy is a form of thermal treatment in a dry sauna maintained at a temperature of 60 degrees C, which differs from the traditional sauna. Waon therapy reportedly improves the hemodynamics, cardiac function, ventricular arrhythmias, vascular endothelial function, neurohormonal factors, sympathetic nervous system function, and symptoms in patients with chronic heart failure (CHF). It has also been demonstrated that the molecular mechanism by which Waon therapy improves vascular flow and endothelial function involves increased expression of endothelial nitric oxide synthase (eNOS). Furthermore, in a mouse model of hindlimb ischemia, repeated Waon therapy increased eNOS protein expression, blood flow, and capillary density. Moreover, Waon therapy did not increase blood flow and capillary density in eNOS-deficient mice, indicating that eNOS is a critical regulator of the angiogenesis induced by this therapy. Moreover, repeated Waon therapy is effective for patients with severe peripheral arterial disease (PAD), as evidenced by substantial decrease in pain scores, increases in both ankle-brachial pressure index and blood flow assessed by laser Doppler perfusion imaging, and by formation of new collateral vessels on angiography. In addition, ischemic ulcers heal or improve markedly. In conclusion, Waon therapy is an innovative and highly promising strategy for treating CHF and PAD.

Aim: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease, although it has yet to be established whether CKD is an independent risk factor for arterial stiffness in community residents. The purpose of this study was to determine the correlation between the cardio-ankle vascular index (CAVI) and estimated glomerular filtration rate (eGFR) in the general population. Methods: We studied 881 consecutively enrolled subjects undergoing health checkups. CAVI was calculated automatically from the pulse volume record, blood pressure and the vascular length from the heart to the ankle. CKD was evaluated by the eGFR. Results: The distribution of eGFR was as follows: 241 with eGFR (mL/min/1.73m²) ≥90; 572 with eGFR 60-89; 65 with eGFR 30-59; 3 with eGFR 15-29; 0 with eGFR <15. Linear regression analysis showed that CAVI was negatively correlated significantly with eGFR, while multiple regression analysis using CAVI as an objective variable, adjusted for conventional atherosclerotic risk factors and eGFR as explanatory variables, demonstrated that CAVI was an independent determinant of eGFR. We also showed that stepwise increments of CAVI occurred with progressive deterioration of CKD. Conclusion: CAVI was independently correlated with eGFR indicating that CKD is associated with arterial stiffness in the general population.

Background: Thermal therapy, namely Waon therapy, has previously been reported to regulate nitric oxide (NO) and endothelial NO synthase (eNOS) and augment ischemia-induced angiogenesis in mice and improve limb ischemia in patients with peripheral artery disease. The aim of this study was to clarify the precise mechanism by which Waon therapy augments angiogenesis in mice with hindlimb ischemia. Methods and Results: Unilateral hindlimb ischemia was induced in apolipoprotein E-deficient mice and Waon therapy was performed for 5 weeks. Heat shock protein 90 (Hsp90), phosphorylated-Akt, and phosphorylated-eNOS were detected in arterial endothelial cells of ischemic hindlimbs and all were upregulated by Waon therapy compared to controls. Waon therapy also increased serum concentrations of nitrite and nitrate. Capillary density and the ischemic limb/normal side blood perfusion ratio monitored by laser Doppler perfusion imaging in the Waon therapy group were significantly increased beyond those in the control group. The effect of Waon therapy on angiogenesis through the activation of the Hsp90/Akt/eNOS pathway was attenuated by the administration of a Hsp90 inhibitor. Conclusions: It is suggested that Waon therapy upregulates Hsp90, which contributes to the activation of the Akt/eNOS/NO pathway, and induces angiogenesis in mice with hindlimb ischemia. (Circ J 2012; 76: 1712–1721)

Low-density lipoprotein cholesterol (LDL-C) is routinely estimated using the Friedewald equation [LDL-C(F)]. A novel method for LDL-C [LDL-C(M)] estimation recently proposed by Martin et al. was reported to be more accurate than the Friedewald formula in subjects in the United States. The validity of LDL-C(M) in different races and patients with diabetes mellitus (DM) has not been elucidated. The purpose of this study was to validate the LDL-C(M) estimates in Japanese population with type 2 DM by comparing with LDL-C(F) and directly measured LDL-C [LDL-C(D)]. Both LDL-C(M) and LDL-C(F) levels were compared against LDL-C(D) measured by selective solubilization method in 1,828 Japanese patients with type 2 DM. On linear regression analysis, LDL-C(M) showed a stronger correlation than that shown by LDL-C(F) (R=0.979 vs. R=0.953, respectively) with LDL-C(D). We further analyzed the effect of serum triglyceride (TG) concentrations on the accuracy of LDL-C(F) and LDL-C(M). Although LDL-C levels showed a positive correlation with TG levels, the LDL-C(F) levels tended to show a greater divergence from LDL-C(D) levels than that shown by LDL-C(M) with changes in TG levels. We for the first time demonstrated a more useful measurement of LDL-C levels estimated by Martin's method than that estimated by the Friedewald equation in Japanese patients with DM.