Yasunori Suematsu

LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice.

Angiotensin receptor–neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin‐induced diabetic mice.

Optimal kissing balloon inflation after single-stent deployment in a coronary bifurcation model

AIMS To define the optimal kissing balloon inflation (KBI) after single-stent deployment in a coronary bifurcation model. METHODS AND RESULTS We deployed stents in main vessels (MV) followed by KBI in various conditions and compared the stent configurations. A) KBI at the operators discretion vs. under the guidelines of minimal balloon overlapping (MBO). Various stent configurations were observed after the former option, whereas similar maximal dilation points were observed under the MBO guidelines. B) Long balloon overlapping (LBO) vs. MBO with proximal MV dilated by a large balloon. The proximal MV was dilated to an ideal round shape with MBO versus an oval shape with LBO. C) Two-link vs. 3-link stents. Although the 2-link stent was advantageous to open the side branch, it incurred a risk of overdilatation of the proximal struts, whereas the 3-link stent preserved its structure. Computed simulations of coronary flow were analysed in the following left main coronary models: circle with a diameter of 4 and 5.5 mm, ellipse with longitudinal direction and tilt position. They revealed that the overdilated side was exposed to low shear stress regardless of its shape. CONCLUSIONS Optimal KBI can be achieved with MBO and proximal dilatation by an optimally sized balloon.

Newly developed apolipoprotein A-I mimetic peptide promotes macrophage reverse cholesterol transport in vivo

BACKGROUND We elucidated the effect of newly developed Fukuoka Apolipoprotein A-I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms. METHODS AND RESULTS Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of (3)H-tracer. The amount of (3)H-tracer excreted into feces over 48h in the FAMP group was significantly higher than that in the control group. (3)H-cholesterol ester (CE)-HDL was injected intravenously and (3)H-cholesterol in blood was counted. In the FAMP group, plasma (3)H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate. CONCLUSIONS The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential.

Comparison of aldosterone synthesis in adrenal cells, effect of various AT1 receptor blockers with or without atrial natriuretic peptide

Abstract Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10−7 and 10−8 M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10−8 and 10−7 M) without ARBs inhibited Ald synthesis, and the combination of ANP (10−7 M) and ARB (10−8 M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice

OBJECTIVES Rivaroxaban has been shown to reduce overall death from cardiovascular causes in patients with recent acute coronary syndrome. Therefore, we evaluated the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury and its mechanisms in mice. METHODS After myocardial reperfusion injury, C57BL/6J mice were randomized to receive either no treatment or treatment for 14days with low and high doses of rivaroxaban. After 7days, mice were administered tissue factor as a secondary event. RESULTS Based on a Kaplan-Meier curve analysis, the high-dose rivaroxaban group showed a significantly higher % survival than the no-treatment group from day 7 (after the administration of tissue factor) to day 14 (at the end of the experimental period). Left ventricular (LV) ejection fraction in both the low- and high-dose rivaroxaban groups improved compared to that in the no-treatment group. Moreover, mRNA levels of interleukin-6 and collagens 1α2 and 3α1 in the LV in the high-dose group were significantly suppressed compared to those in the no-treatment group. CONCLUSIONS Rivaroxaban improved the survival rate, probably by improving cardiac function through the reduction of inflammatory and fibrotic factors in the LV. This effect may be due to the pleiotropic effects of rivaroxaban beyond its main effect as an anti-coagulant.

A novel inducible cholesterol efflux peptide, FAMP, protects against myocardial ischemia reperfusion injury through a nitric oxide pathway

OBJECTIVE We evaluated whether a novel inducible cholesterol efflux (iCE) peptide [Fukuoka University Apolipoprotein A-I Mimetic Peptide (FAMP)] protects against myocardial ischemia reperfusion injury (IRI) through a nitric oxide (NO) pathway by an improvement of high-density lipoprotein (HDL) functionality. METHODS AND RESULTS Male C57BL6/J mice were intraperitoneally injected with phosphate buffer as a control, low-dose (10 mg/kg) or high-dose (50 mg/kg) of FAMP before 18 h of IRI (n=6-12 in each group). After 30 min of ischemia followed by 6h of reperfusion, blood pressure, and infarct size were measured and cardiac function was evaluated by a Millar catheter. FAMP significantly improved stroke volume, cardiac output, left ventricular ejection fraction, and infarct size. FAMP significantly preserved cytochrome C in the mitochondrial fraction and inhibited its release into the cytosolic fraction in the heart, but did not significantly reduce mRNA levels of monocyte chemoattractant protein-1 or interluekin-6. In a TdT-mediated dUTP nick end labeling (TUNEL) assay, FAMP significantly suppressed the appearance of TUNEL-positive nuclear. We also performed same experiments with endothelial nitric oxide synthase-knockout (eNOS-KO) mice and FAMP-induced improvements of cardiac function were not observed in eNOS-KO mice. CONCLUSIONS FAMP activated HDL-functionality and improved cardiac function in a model of myocardial IRI. It may have anti-apoptotic effects by protecting mitochondria through a NO pathway as a pleiotropic effect.

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line.

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT1) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT1 receptor was greater than that of valsartan alone in an AT1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT1 receptor-induced Ald synthesis in human adrenocortical cells.

Ability of the new AT1 receptor blocker azilsartan to block angiotensin II-induced AT1 receptor activation after wash-out

Introduction: The recently approved angiotensin II (Ang II) type 1 (AT1) receptor blocker (ARB) azilsartan strongly reduces blood pressure (BP) in patients with hypertension. We previously reported that azilsartan showed unique binding behavior to the AT1 receptor because of its 5-oxo-1,2,4-oxadiazole moiety. However, the ability of azilsartan to block Ang II-dependent AT1 receptor activation is not yet clear. Materials and methods: Azilsartan and a derivative of azilsartan (azilsartan-7H) that lacks a carboxyl group at the benzimidazole ring were used. Ang II-induced inositol phosphate (IP) production and extracellular signal-regulated kinase (ERK) activation were analyzed in a cell-based wash-out assay. Results: Azilsartan, but not azilsartan-7H, completely blocked Ang II-induced IP production and ERK activation. Our previous report demonstrated that azilsartan mainly interacts with Tyr113, Lys199, and Gln257 in the AT1 receptor. The interactions between azilsartan and Tyr113 and Gln257, but not Lys199, were critical for blocking Ang II-induced IP production and ERK activation after wash-out. Conclusions: Although our findings regarding the molecule-specific effects of azilsartan are based on basic research, they may lead to an exciting insight into the mechanism of azilsartan.

Visit-to-Visit Variability and Seasonal Variation in Blood Pressure With Single-Pill Fixed-Dose Combinations of Angiotensin II Receptor Blocker/Calcium Channel Blocker and Angiotensin II Receptor Blocker/Diuretic in Hypertensive Patients

Background The visit-to-visit variability in blood pressure (BP) has been shown to be a strong predictor of cardiovascular events. It is not known whether anti-hypertensive therapy using a single-pill fixed-dose combination of angiotensin II receptor blocker (ARB)/calcium channel blocker (CCB) or ARB/diuretic (DI) in hypertensive patients affects the visit-to-visit variability and seasonal variation of BP. Methods We enrolled 47 hypertensive patients who had received a single-pill fixed-dose combination of either ARB/CCB (n = 30) or ARB/DI (n = 17) for 15 months. Beginning 3 months after the start of ARB/CCB or ARB/DI treatment, we determined the visit-to-visit variability in BP expressed as the standard deviation (SD) of average BP and the seasonal variation in BP expressed as the SD of average BP in each season (spring, summer, fall and winter were defined as lasting from March to May, June to August, September to November and December to February, respectively) for a year. Results There were no significant differences in baseline patient characteristics except for the prevalence of coronary artery disease and the percentage of CCB excluding amlodipine in the ARB/CCB group between the ARB/CCB and ARB/DI groups. There were no significant differences in the 1-year time course of systolic and diastolic BP (SBP and DBP) between the groups, although there were significant differences in SBP in August and November and DBP in December. Interestingly, the visit-to-visit variability and seasonal variation of BP in the ARB/CCB group were similar to those in the ARB/DI group. Conclusion Single-pill fixed-dose combinations of ARB/CCB and ARB/DI had similar effects on visit-to-visit variability and seasonal variation in BP in hypertensive patients.

Associations between glycated albumin or hemoglobin A1c and the presence of coronary artery disease.

OBJECTIVE We investigated the associations between serum levels of glycated albumin (GA) or hemoglobin A1c (HbA1c) and the presence of coronary artery disease (CAD) in patients who underwent coronary computed tomography angiography (CTA). METHODS AND RESULTS The study consisted of 244 consecutive patients who underwent CTA and in whom we could measure the levels of both GA and HbA1c. Any narrowing of the normal contrast-enhanced lumen to >50% that could be identified in multiplanar reconstructions or cross-sectional images by CTA was defined as significant stenosis in CAD. We divided the patients into two groups: CAD group (n=72) and non-CAD group (n=172), as assessed by CTA. The CAD group showed significantly higher GA and HbA1c than the non-CAD group. GA and HbA1c showed a positive correlation (r=0.551, p<0.0001). A multivariate logistic regression analysis was performed to examine the associations between the presence of CAD and age, gender, body mass index, and coronary risk factors (hypertension, dyslipidemia, and smoking), in addition to GA and HbA1c. Age [odds ratio (OR): 1.04, p=0.02], gender (OR: 2.84 p=0.01), hypertension (OR: 3.20, p=0.01), and GA (OR: 1.16, p=0.03) were identified as significant independent variables that predicted the presence of CAD. In particular, GA (OR: 1.30, p=0.02) was the only predictor of the presence of CAD in the diabetes mellitus group by a multivariate logistic regression analysis. We defined the cut-off value of GA for the prediction of CAD in patients with diabetes as 17.9% (sensitivity 0.639, specificity 0.639) by a receiver-operating characteristic curve analysis. CONCLUSION GA may be superior to HbA1c as a marker for evaluating the presence of CAD.