Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

Validation of the obesity paradox by body mass index and waist circumference in patients undergoing percutaneous coronary intervention.

BACKGROUND: The paradoxical association of obesity with mortality, named the "obesity paradox", has been inconsistent, possibly due to a difference between body mass index (BMI) and central obesity, estimated by waist circumference (WC) as patterns of adiposity. SUBJECTS/METHODS: We enrolled 8513 participants from the Kumamoto Intervention Conference Study, a multicenter registry that included consecutive patients undergoing percutaneous coronary intervention (PCI) at 18 centers between 2008 and 2017 in Japan. Patients were divided into quartiles in ascending order of the BMI or WC. The primary endpoints were all-cause mortality and cardiovascular death within a year. RESULTS: There were 186 deaths (case fatality rate, 22.1/1000 person-years) during the follow-up period. The lowest group (1st quartile) of BMI or WC had the worst prognosis among the quartiles (1st quartile, 4.2%; 2nd quartile, 1.9%; 3rd quartile, 1.5%; 4th quartile, 1.1%; P < 0.001 (χ2) and 1st quartile, 4.1%; 2nd quartile, 2.3%; 3rd quartile, 1.2%; 4th quartile, 1.5%; P < 0.001 (χ2), respectively). Similar results were obtained for cardiovascular death. In a multivariable analysis adjusted by nine conventional factors, the lowest group (1st quartile) of BMI (hazards ratio, 2.748; 95% confidence interval [CI], 1.712-4.411) and WC (hazards ratio, 2.340; 95% CI, 1.525-3.589) were independent prognostic factors for all-cause mortality. By dividing the participants into two groups according to either the BMI or WC based on the National Cholesterol Education Program Adult Treatment Panel III and World Health Organization classification, the highest mortality was observed in the lower group. However, the C-statistic after adding BMI (quartile) to conventional factors was found to be slightly higher than BMI (two categories) and WC (two categories) (0.735 vs. 0.734). CONCLUSIONS: The obesity paradox was observed in patients after PCI, and single-use of BMI (or WC) was sufficient to predict the prognosis of patients after PCI.

Impact of cerebrovascular comorbidity on prognosis in Japanese patients undergoing PCI: 1-year data from Japanese multicenter registry (KICS).

Cardiovascular and cerebrovascular diseases are considered the principal cause of morbidity and mortality worldwide; the effect of stroke-induced cardiac manifestations is well recognized; however, not enough clinical data have been found about the impact of stroke with underlying cardiac disease. This study's objective is to assess the impact of stroke on the prognosis of patients with underlying IHD, who underwent PCI treatment. This was a multicenter, 1-year observational study in patients undergoing PCI in one of the 17 participating centers across Japan. 18,495 patients were registered on the PCI list; 2481 patients had a prior stroke experience, whereas 15,979 were stroke-free. Our study revealed that stroke patients were significantly older (mean age 73.5 ± 9.6, 69.7(± 11.5), respectively), and suffered from more comorbidities (diabetes, hypertension, and chronic kidney disease, p < 0.0001). During the 1-year period, subjects with stroke showed higher incidence of clinical events compared to those without stroke; to illustrate, all-cause death accounted for 6.2% in patients with stroke, in contrast to only 2.8% in stroke-free patients (p < 0.0001), cardiac death amounted for 2.2 and 1.2%, respectively (p < 0.0001), recurrent stroke for 3.1% and 1.2% (p < 0.0001), non-cardiac death for 3.6 and 1.54% (p < 0.0001), and finally, hemorrhagic complications with 2.6 and 1.3% (p < 0.0001). Kaplan-Meier analysis revealed that stroke patients had a higher probability of all-cause mortality, cardiac death, and recurrent stroke (log-rank p < 0.0001). Cox hazard analysis also showed that the presence of stroke is a significant indicator in determining the outcome of cardiac death (HR = 1.457, 95% CI 1.036-2.051, p = 0.031); hence, proving it to be a crucial predictor on cardiac prognosis. History of prior stroke was common in PCI patients, and independently associated with a higher rate of subsequent cardiovascular and cerebrovascular events recurrence. Thus, highlighting an urgent need for comprehensive prevention of cardiac and cerebrovascular diseases.

Temporal trends in coronary intervention strategies and the impact on one-year clinical events: data from a Japanese multi-center real-world cohort study.

Percutaneous coronary intervention (PCI) has significantly advanced over the last 40 years, but it is not clear whether there have been any changes in prognosis in recent years. The Kumamoto Intervention Conference Study Real-World Registry is a multi-center registry that enrolls consecutive patients undergoing PCI in 17 centers in Kyushu, Japan. To elucidate the clinical impact of recent changes in treatment strategies, 8841 consecutive participants (historical PCI: n = 4038, enrolled between January 2013 and December 2014, and current PCI: n = 4803, between January 2015 and March 2017) with 1-year follow-up data were analyzed. The incidences of major adverse cardiovascular and other clinical events were comparable between historical PCI and current PCI, even though complex lesions were more frequent during the more recent period. During this period, the use of radial approaches, drug eluting stents, and coronary imaging was greater. The use of prasugrel was more frequent (P < 0.001) during the time periods. Comparable event rates were associated with the use of clopidogrel (52.7%) and prasugrel (47.3%). In the sub-analysis for acute coronary syndrome (n = 5047), similar clinical event rates were recorded for historical and current PCI. Although the lesions to be treated are becoming more severe and complex, equivalent clinical outcomes have been maintained in recent years, possibly due to advances in the devices and medication used.

Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial.

AIM: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. METHODS: This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. RESULTS: Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. CONCLUSIONS: This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Fabrication of Porous α-TCP/Gellan Gum Scaffold for Bone Tissue Engineering.

α-tricalcium phosphate (α-TCP, α-Ca3(PO4)2) receives great attention for bone repairing due to its biodegradability and capability of transformation to human bone's main inorganic components, hydroxyapatite (HAp). α-TCP porous scaffold is easily procurable by sintering of the low-temperature polymorph of TCP, ß-TCR Still, porous body of α-TCP is too brittle to being handled and shaped, limiting its clinical application as implant materials. To improve mechanical properties of α-TCP porous scaffold, the present study focused on coating of a type of polysaccharides on α-TCP scaffolds. Gellan gum was chosen as the polysaccharide for coating because of its biodegradability as well as the potential acting as substrate for HAp deposition during hydration of α-TCP after exposure to body fluid. After coating of gellan gum on α-TCP scaffolds with porosity of 75 vol%, the compressive strength increased from 0.45 MPa to around 2.00 MPa. Among the coated scaffold, the maximum compressive strength, 3.97 MPa, was obtained on the scaffold with porosity of 63 vol%. Improvement of mechanical properties of α-TCP/gellan gum composites was achieved to show easy handling performance for a bone substitute for tissue repairing. The dissolving rate of the coated scaffolds was also controlled by adjusting the concentration of GG solutions.

Impact of candesartan on cardiovascular events after drug-eluting stent implantation in patients with coronary artery disease: The 4C trial.

OBJECTIVE: The purpose of this study was to examine the cardiovascular protective effects of candesartan in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). BACKGROUND: Candesartan has been reported to reduce cardiovascular events when therapy was started 6 months after PCI with bare-metal stents in patients who survived restenosis. Candesartan started immediately after PCI with DESs was also effective in preventing cardiovascular events. METHODS: The 4C trial was a multicenter, prospective, randomized, open-label study. A total of 1145 patients at 39 centers in Japan were randomly assigned to receive candesartan plus standard medical treatment or standard medical treatment alone. The primary endpoints were all-cause death, and a composite of non-fatal myocardial infarction (MI), unstable angina pectoris (uAP), congestive heart failure (CHF), and non-fatal cerebrovascular events. The follow-up period was up to 3 years after the index PCI (ClinicalTrials.gov NCT00139386). RESULTS: The incidence of total death, one of the primary endpoints, was comparable between the two treatment groups (3.8% each, p=0.9702). Another primary endpoint, non-fatal major cardiovascular events, tended to occur more often in the control group than in the candesartan group (9.2% vs. 12.5%, p=0.0985). In contrast, candesartan significantly reduced one of the pre-specified secondary endpoints: cardiovascular events that included non-fatal MI, uAP, and CHF (4.4% vs. 6.7%, p=0.0136). Furthermore, candesartan significantly reduced another secondary endpoint that included cardiovascular events and cardiovascular death (5.0% vs. 7.7%, p=0.0493). CONCLUSIONS: The 4C trial showed that candesartan administered immediately after PCI with DESs did not improve the prognosis after the index procedure, but did reduce some cardiac-related events for 3 years.

Rationale, design and baseline characteristics of a study to evaluate effects of candesartan on cardiovascular events after drug-eluting stent implantation in patients with ischemic heart disease.

AIM: Few multicenter studies have assessed the effects of angiotensin receptor blockers on cardiovascular events after drug-eluting stent implantation in patients with ischemic heart disease. METHODS: An open-label multicenter randomized prospective study is in progress to evaluate the effects of candesartan on cardiovascular events in patients with ischemic heart disease after implantation of sirolimus- and/or paclitaxel-eluting stents. RESULTS: A total of 1,145 patients were enrolled at 39 institutes in the Candesartan for prevention of Cardiovascular events after CYPHER or TAXUS Coronary stenting (4C trial). Patients were randomized into a group treated with candesartan (n=602) and a group treated with standard medical therapy without candesartan (n=543). The primary endpoint of the 4C trial is a composite of all-cause death, successful resuscitation after cardiopulmonary arrest and cardiovascular events including non-fatal myocardial infarction, unstable angina requiring emergent hospitalization, congestive heart failure requiring emergent hospitalization and cerebrovascular attacks. All patients will be followed-up for 36 months. CONCLUSIONS: The 4C trial will be the first multicenter study to elucidate the effects of candesartan after drug-eluting stent implantation and may provide new information to optimize medical therapy after percutaneous coronary interventions.

Formation of octacalcium phosphates with co-incorporated succinate and suberate ions.

Octacalcium phosphates (OCPs) co-incorporated with various molar ratios of succinate and suberate ions were synthesized by wet processing. The interplanar spacings of the (100) planes (d(100)) of OCPs formed in the presence of succinic acid (Suc) or suberic acid (Sub) were larger than those of OCPs formed without addition of a dicarboxylic acid to the reaction solvent. The increases in the interplanar spacings of the (100) planes were caused by substitution of HPO(4)(2-) by dicarboxylate ions. The OCPs with co-incorporated succinate and suberate ions, i.e. solid solutions of OCP with incorporated Suc and Sub, were formed by reactions in the presence of Suc and Sub. When the Suc/(Suc + Sub) values in the starting compositions were in the range 0.45-1.0, Suc was preferentially incorporated into the OCP. In contrast, when the Sub/(Suc + Sub) values in the starting compositions were in the range 0.60-1.0, Sub was preferentially incorporated into the OCP crystals.

Effect of ammonium carbonate on formation of calcium-deficient hydroxyapatite through double-step hydrothermal processing.

Double-step hydrothermal processing is a process where powder compacts of calcium phosphates are exposed to vapor of solvent solution, followed by being immersed in the solution. In the present study, we investigated the effects of ammonium carbonate on formation of calcium-deficient hydroxyapatite (CDHA) through double-step hydrothermal processing. The synthesized CDHA has high crystallinity when the solution has relatively low concentration of the ammonium carbonate ranging from 0.01 to 0.25 mol dm(-3). Carbonate content in the prepared samples were distinctly increased with increasing the concentration of ammonium carbonate to indicate formation of carbonate-containing calcium-deficient hydroxyapatite (CHAp) with low crystallinity. Morphology of the CHAp formed on the compacts varied progressively from rods and rosette-like shape to irregular shape with increase in the initial concentration of the ammonium carbonate in the solution. Application of ammonium carbonate in the double-step hydrothermal processing allows fabrication of irregular-shaped CDHA containing carbonate ions in both phosphate and hydroxide site, with low crystallinity, when the initial concentration of ammonium carbonate was 0.5 mol dm(-3) and more.

A case of newly demonstrated coronary spasm 4 months after paclitaxel-eluting stent implantation for in-stent restenosis.

A 56-year-old woman with hypertension and hypercholesterolemia was admitted to our hospital with acute inferior myocardial infarction. The patient had total occlusion of the right coronary artery (RCA) segment 2, and bare-metal stents were placed. Four months later, plain old balloon angioplasty was performed for in-stent restenosis. Follow-up coronary angiography (CAG) 6 months later showed in-stent total occlusion, so a stent-in-stent procedure was performed using paclitaxel-eluting stents (PESs). Four months later, the patient began complaining of early morning chest pain at rest. CAG showed no in-stent restenosis, so coronary spastic angina was suspected. Intracoronary infusion of ergonovine to the right and left coronary arteries revealed spasm of the RCA with total occlusion just proximal to the PES in segment 1. Her chest pain was reproduced with ST-elevation in leads II, III, and aVF, so the diagnosis of coronary spastic angina was made. Treatment with a Ca-channel blocker and nitrates relieved the symptoms. The PES was the probable cause of the coronary spasm.

In vitro apatite formation on organic-inorganic hybrids in the CaO-SiO(2)-PO (5/2)-poly(tetramethylene oxide) system.

The osteoconduction potential of artificial materials is usually evaluated in vitro by apatite formation in a simulated body fluid (SBF) proposed by Kokubo and his colleagues. This paper reports the compositional dependence of apatite formation on organic-inorganic hybrids in the CaO-SiO(2)-PO(5/2)-poly(tetramethylene oxide) system, initiated from tetraethoxysilane (TEOS), triethyl phosphate (OP(OEt)(3)), calcium chloride (CaCl(2)) and poly(tetramethylene oxide)(PTMO) modified with alkoxysilane. Formation of an apatite layer was observed on the surface of the organic-inorganic hybrids with molar ratios of TEOS/OP(OEt)(3) ranging from 100/0 to 20/80. The rate of apatite formation remarkably decreased when the hybrids were synthesized with TEOS/OP(OEt)(3) ratios of 40/60 or less. Hybrids without TEOS showed no apatite formation in SBF for up to 14 days. Addition of small amounts of OP(OEt)(3) to TEOS in the hybrids led to the high dissolution of calcium and silicate, while addition of large amounts of OP(OEt)(3) decreased the dissolution of calcium and silicate ions and resulted in reduced apatite formation regardless of the dissolution of phosphate ions from the hybrids.

Bioactive composites consisting of PEEK and calcium silicate powders.

Bioactive bone-repairing materials with mechanical properties analogous to those of natural bone can be obtained through the combination of bioactive ceramic fillers with organic polymers. Previously, we developed novel bioactive microspheres in a binary CaO-SiO2 system produced through a sol-gel process as filler for the fabrication of composites. In this study, we fabricate bioactive composites in which polyetheretherketone is reinforced with 0-50 vol% 30CaO x 70SiO2 (CS) microspheres. The prepared composites reinforced with CS particles form hydroxyapatite on their surfaces in simulated body fluid. The induction periods of hydroxyapatite formation on the composites decrease with increasing amount of CS particles. The mechanical properties of the composites are evaluated by three-point bending test. The composites reinforced with 20 vol% CS particles show 123.5 MPa and 6.43 GPa in bending strength and Young's modulus, respectively.

Relationship between apatite-forming ability and mechanical properties of bioactive PMMA-based bone cement modified with calcium salts and alkoxysilane.

Polymethylmethacrylate (PMMA)-based bone cement is used for the fixation of artificial joints in orthopaedics. However, the fixation is liable to loosen in the body, because the cement does not bond to living bone. So-called bioactive ceramics bond directly to living bone through the apatite layer formed on their surfaces in the body. We previously revealed that modification using gamma-methacryloxypropyltrimethoxysilane (MPS) and water-soluble calcium salts such as calcium acetate and calcium hydroxide was effective for providing the PMMA-based bone cement with apatite-forming ability in a simulated body fluid (SBF, Kokubo solution) that closely reproduces the body environment. However, the effect of the chemical reaction forming the apatite on the mechanical properties of the cements has not been clarified. The present work aimed to investigate this issue from the viewpoint of the interface structure between the apatite and the cement. The surface of the cement modified with calcium acetate and MPS was fully covered with newly formed apatite after soaking in Kokubo solution within 7 days, while half of the surface area of the cement modified with calcium hydroxide and MPS was covered with the apatite. The bending strength of the modified cements decreased after soaking in Kokubo solution. Porous structure was observed in the region about 50-100 microm in depth from the top surface because of release of the Ca2+ ions by both modified cements after soaking in Kokubo solution. The decrease in bending strength of the modified cements could be attributed to the formation of the pores. In addition, the pores on the top surfaces of the cements were filled with the newly formed apatite. The apatite formation would be effective not only for bioactivity but also for decreasing the reduction of mechanical strength.