Tadaaki Arimura

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.

Safety and efficacy of antihypertensive therapy with add-on angiotensin II type 1 receptor blocker after successful coronary stent implantation

This study was performed to evaluate the safety and efficacy of additional antihypertensive therapy with angiotensin II type 1 receptor blocker (ARB; olmesartan or valsartan) after successful stent implantation in patients with coronary artery disease (CAD). Fifty patients with CAD after successful stent implantation were included in this study. They were divided into an ARB group, which initially received olmesartan (n=20, 14±8 mg day−1) or valsartan (n=20, 60±23 mg day−1) immediately after stent implantation, and a non-ARB group (n=10) according to their blood pressure (BP). Follow-up coronary angiography, measurement of BP and blood sampling were performed before (at baseline) and 6–8 months after stent implantation (at follow-up). There were no significant differences in the baseline characteristics between the groups, except for BP. Although there were no changes in % diameter restenosis between the groups, the BP level in the ARB group at follow-up showed a significant reduction (125±12/69±9 mm Hg) and reached the target BP. There were no critical adverse effects in the ARB group throughout the study period. In addition, serum high-sensitive C-reactive protein (hs-CRP) and pentraxin 3 were significantly decreased in the ARB group but not in the non-ARB group. Although olmesartan and valsartan induced similar BP-lowering effects, olmesartan but not valsartan induced a significant decrease in hs-CRP, but did not increase serum uric acid. In conclusion, antihypertensive therapy with add-on low-dose ARB after stent implantation was safe and achieved the target BP. In particular, olmesartan had an anti-inflammatory effect.

Association between cardiac function and metabolic factors including adiponectin in patients with acute myocardial infarction

BACKGROUND Although several clinical studies have evaluated plasma adiponectin levels in response to chronic heart failure, little is known about the relation between cardiac function and metabolic factors including adiponectin in patients with acute myocardial infarction (AMI). METHODS AND RESULTS We analyzed 50 consecutive patients with AMI who had undergone successful coronary stent implantation. Echocardiography and blood sampling were performed at 1 week and 6 months after AMI. Blood was analyzed with regard to brain natriuretic peptide (BNP) and metabolic factors including plasma levels of adiponectin, lipid profile, and hemoglobin A1c (HbA1c). Plasma adiponectin levels were significantly increased at 6 months (7.3 ± 4.9 μg/ml) compared to those at 1 week (6.1 ± 3.7). BNP (from 156 ± 151 to 96 ± 124 pg/ml) significantly decreased. In addition, BNP at 6 months was positively correlated with plasma adiponectin levels at 1 week (y = 0.019 x -23.1, r = 0.537, P = 0.002), while BNP at 6 months was not associated with maximal creatinine kinase after AMI. A multiple regression analysis was performed to analyze the relationship between BNP at 6 months and metabolic factors (plasma levels of adiponectin, lipid profile, HbA1c, blood pressure, age, sex, and body mass index) at 1 week after AMI. BNP at 6 months was most closely correlated with plasma levels of adiponectin at 1 week (P = 0.045). CONCLUSIONS Among the metabolic factors examined, a higher adiponectin level at 1 week is the predictor of a higher BNP as one marker of cardiac dysfunction at 6 months after AMI.

Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension

Objective: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. Methods: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. Results: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. Conclusion: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.

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.

Comparison of the efficacy and safety of statin and statin/ezetimibe therapy after coronary stent implantation in patients with stable angina

Little is known about the efficacy and safety of intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statin/ezetimibe therapy after coronary stent implantation in patients with stable angina. Fifty patients with stable angina were randomly divided into an atorvastatin (10 mg/day) (A) group and an atorvastatin (10 mg/day)/ezetimibe (10 mg/day) (A+E) group after stent implantation. Follow-up coronary angiography was performed at 6-9 months after stenting. The A and A+E groups showed significant reductions in LDL-C. The levels of LDL-C in the A+E group were significantly lower than those in the A group at follow-up, whereas there were no differences in major adverse cardiac events, in-stent restenosis, or in-stent % diameter stenosis (DS) between the groups. Only the A+E group showed a significant decrease in the levels of highly sensitive C-reactive protein. In a sub-analysis, %DS in the non-target vessel significantly decreased in both groups. Moreover, Δ%DS (Δ=the value at baseline minus that at follow-up) in the A+E group was more closely associated with LDL-C levels at follow-up than that in the A group. There were no significant differences in adverse effects between the A and A+E groups. In conclusion, although statin/ezetimibe therapy was effective and safe for intensive lipid-lowering in patients with stable angina after successful coronary stent implantation, improvement in clinical outcomes with the combination therapy remains unclear.

Comparison of the Efficacy and Safety of Irbesartan and Olmesartan in Patients With Hypertension (EARTH Study)

Fifty-four patients were randomly divided into irbesartan and olmesartan groups. Blood pressure (BP) was significantly decreased in all patients at 12 weeks. In particular, BP in patients who initially received irbesartan showed significant reductions. The equality of variance of BP in the irbesartan group was significantly smaller than that in the olmesartan group at 12 weeks. Blood concentrations of adiponectin were significantly increased in the irbesartan group at 12 weeks. Log [pentraxin-3] in the irbesartan group were significantly decreased. In conclusion, the ability of irbesartan to reduce BP is comparable to that of olmesartan with equivalent safety.

Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Association between plasma levels of pigment epithelium-derived factor and renal dysfunction in patients with coronary artery disease.

BACKGROUND Although plasma pigment epithelium-derived factor (PEDF) levels have been shown to be significantly correlated with the levels of creatinine (Cr) in type 2 diabetes, little is known about the association between PEDF levels and renal dysfunction in patients with coronary artery disease (CAD). METHODS We enrolled 134 consecutive patients with diagnosed CAD and measured plasma levels of PEDF, serum Cr, uric acid (UA) and high-sensitive C-reactive protein (hsCRP). RESULTS Plasma PEDF levels were positively correlated with serum Cr (p 〈 0.0001) and UA (p 〈 0.0001) and negatively correlated with the estimated glomerular filtration rate (eGFR) (p 〈 0.0001), whereas there was no association between plasma PEDF and age or hsCRP. When the subjects were divided into five groups (0-4) according to the number of metabolic factors (obesity, diabetes, hypertension and dyslipidemia), PEDF levels in patients with four factors were significantly higher than those in patients without factors. Next, we divided the patients into quartiles according to their plasma PEDF levels (〈 9.9 μg/mL, 9.9-12.8, 12.9- -15.7, 〉 15.7). The eGFR in the first group was significantly higher than those in the third and fourth groups. Multivariate logistic analysis indicated that eGFR (p 〈 0.0001) and age (p = 0.030) were significant independent variables that correlated with the quartile classification according to PEDF levels. CONCLUSIONS This study revealed that PEDF may play a role in renal dysfunction in CAD patients.

Effects of Tolvaptan With or Without the Pre-Administration of Renin-Angiotensin System Blockers in Hospitalized Patients With Acute Decompensated Heart Failure

We examined whether tolvaptan combined with an angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACE-I) is more effective than tolvaptan alone in the treatment of patients with heart failure (HF). Sixty-five hospitalized patients with acute decompensated HF were included in this study. They were divided into 2 groups; an ARB/ACE-I group (n = 44, who received ARB or ACE-I before the use of tolvaptan) and a non-ARB/ACE-I group (n = 21). There were no significant differences in patient characteristics including medications at baseline between the non-ARB/ACE-I and ARB/ACE-I groups with the exception of the percentages of hypertension and ischemic heart disease. Urinary volume (UV) at baseline in the ARB/ACE-I group was slightly higher than that in the non-ARB/ACE-I group. The increase in UV after the use of tolvaptan in the non-ARB/ACE-I group was significantly higher than that in the ARB/ACE-I group. The cardiothoracic ratio and the reduction in body weight were similar between the groups after tolvaptan use. Finally, in a logistic regression analysis, a response to the use of tolvaptan was independently associated with the non-use of ARB/ACE-I, but not with age, gender, body mass index, loop diuretic, or human arterial natriuretic peptide. In conclusion, tolvaptan alone might induce an increase in UV in decompensated HF patients without ARB/ ACE-I, although the treatment of HF with ARB/ACE-I is the first choice strategy.