Overview of the 87th Annual Scientific Meeting of the Japanese Circulation Society (JCS2023)　- New Challenge With Next Generation.

The 87thAnnual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of "New Challenge With Next Generation" the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.

Mapping of Purkinje-related ventricular arrhythmias by a multispline catheter with small and close-paired electrodes: Comparison with conventional catheters.

BACKGROUND: Precise mapping of the Purkinje fiber network is essential in catheter ablation of Purkinje-related ventricular arrhythmias (PrVAs). We sought to evaluate the mapping ability of a multi-spline duodecapolar catheter (PentaRay) for PrVAs. METHODS: Mappings of Purkinje fibers by PentaRay catheters were compared with those by conventional mapping catheters in consecutive patients undergoing catheter ablation of PrVAs from 2015 to 2022. RESULTS: Sixteen PrVAs (7 premature ventricular contractions or non-reentrant fascicular tachycardias [PVCs/NRFTs] and 9 fascicular ventricular tachycardias [FVTs]) were retrospectively studied. In PVCs/NRFTs, earliest preceding Purkinje potentials (PPs) could be recorded by the PentaRay catheters but not by the mapping and ablation catheters in 5 cases. At the earliest PP sites, the precedence from the QRS onset was greater, and the amplitude of the preceding potentials was higher in the PentaRay catheter compared with those in the mapping and ablation catheter (-62.0 ± 42.8 vs. -29.4 ± 34.2 ms, P = 0.02; 0.45 ± 0.43 vs. 0.09 ± 0.08 mV, P = 0.02). In FVTs, late diastolic potentials (P1) were recorded by the PentaRay catheters but not by the mapping and ablation catheters or the linear duodecapolar catheter in 2 cases. The amplitude of P1 was higher in the PentaRay catheter compared with that in the linear duodecapolar catheter and the mapping and ablation catheters (0.72 ± 0.49 vs. 0.17 ± 0.18 vs. 0.27 ± 0.21 mV, P = 0.0006, P = 0.002). The localized critical PPs, defined as the earliest preceding potentials in PVCs/NRFTs and P1 in FVTs, could be recorded in all the patients by the PentaRay catheter. The mapping ability of critical PPs of PrVAs was better with the PentaRay catheter than with the conventional mapping catheters (16/16 vs. 9/16, P = 0.004 by McNemar exact test). CONCLUSIONS: The PentaRay catheter has clinical advantages in mapping of the Purkinje fiber network to reveal critical PPs as ablation targets of PrVAs.

One-year outcomes of patients undergoing percutaneous coronary intervention with the revived directional coronary atherectomy catheter: Insights from the J-PCI OUTCOME registry.

OBJECTIVES: We sought to investigate the 1-year outcomes, including all-cause and cardiovascular mortality, major adverse cardiovascular events (MACEs), and major bleeding, of patients undergoing percutaneous coronary intervention (PCI) with or without the revived directional coronary atherectomy (DCA) catheter in a Japanese nationwide registry. BACKGROUND: Clinical data regarding the midterm outcomes of patients undergoing PCI with DCA are scarce in contemporary real-world practice. METHODS: We analyzed the data of 74,764 patients who underwent PCI at 179 hospitals from January 2017 to December 2018. The baseline characteristics and 1-year outcomes of patients with stable coronary artery disease or unstable angina who underwent PCI with or without DCA were assessed. RESULTS: Overall, 431 patients (0.6%) underwent PCI with DCA. Patients in the DCA group were younger and predominantly male, with fewer comorbidities than patients in the non-DCA group. Stentless PCI with DCA following additional drug-coated balloon (DCB) angioplasty was the dominant strategy in the DCA group (43.6%). One-year outcomes, including all-cause mortality (1.2% in the DCA group vs. 2.5% in the non-DCA group, respectively, p = 0.075), cardiovascular death (0.9% vs. 1.0%, p = 0.69), MACEs (1.9% vs. 1.8%, p = 0.96), and nonfatal major bleeding requiring readmission (1.2% vs. 1.4%, p = 0.62), were comparable between the two groups. In the DCA group, 1-year outcomes were comparable, regardless of whether the stent or DCB was used. CONCLUSIONS: One-year clinical outcomes after PCI with DCA in patients with stable coronary artery disease or unstable angina are acceptable, regardless of stent use.

Sex Differences in Long-Term Outcomes in Patients With Chronic Coronary Syndrome After Percutaneous Coronary Intervention　- Insights From a Japanese Real-World Database Using a Storage System.

BACKGROUND: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI).Methods and Results: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312-1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97-1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men. CONCLUSIONS: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.

Relationships Among Heart Rate, ß-Blocker Dosage, and Prognosis in Patients With Coronary Artery Disease in a Real-World Database Using a Multimodal Data Acquisition System.

BACKGROUND: The optimal heart rate (HR) and optimal dose of ß-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system.Methods and Results: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60-66 beats/min), Q3 (HR 67-74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates. CONCLUSIONS: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.

Clinical picture of the duration of venoarterial extracorporeal membrane oxygenation: analysis from JROAD-DPC.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been widely used for critically ill patients all over the world; however, comprehensive survey regarding the relationship between VA-ECMO duration and prognosis is limited. We conducted a survey of VA-ECMO patients in the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC), which was a health insurance claim database study among cardiovascular centers associated with the Japan Circulation Society, between April 2012 and March 2016. Out of 13,542 VA-ECMO patients, we analyzed 5766 cardiovascular patients treated with VA-ECMO. 68% patients used VA-ECMO only for 1 day and 93% had VA-ECMO terminated within 1 week. In multivariate analysis, the hazard ratio of 1-day support was significantly high at 1.72 (95% confidence intervals; 95% CI 1.53-1.95) (p < 0.001), while that of 2-day [0.60 (95% CI 0.49-0.73)], 3-day [0.75 (95% CI 0.60-0.94)], 4-day [0.43 (95% CI 0.31-0.60)] and 5-day support [0.62 (95% CI 0.44-0.86)] was significantly low. Comprehensive database analysis of JROAD-DPC revealed that cardiovascular patients who were supported with VA-ECMO for 2-5 days showed lower mortality. The optimal VA-ECMO support window should be investigated in further studies.

Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease.

BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority). CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial.

BACKGROUND: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy. METHODS: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events. RESULTS: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group. CONCLUSIONS: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.

Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis.

BACKGROUND: In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. METHODS: In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. RESULTS: Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. CONCLUSIONS: The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.

Macrophage (Drp1) Dynamin-Related Protein 1 Accelerates Intimal Thickening After Vascular Injury.

OBJECTIVE: Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynamin-related protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury. METHOD AND RESULTS: To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors. CONCLUSIONS: Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.

Institutional Characteristics and Prognosis of Acute Myocardial Infarction With Cardiogenic Shock in Japan　- Analysis From the JROAD/JROAD-DPC Database.

BACKGROUND: The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. CONCLUSIONS: A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.

Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols.

OBJECTIVE: Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. APPROACH AND RESULTS: Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. CONCLUSIONS: We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols.

Prognostic Value of Neurological Status on Hospital Arrival for Short-Term Outcome in Patients With Cardiovascular Shock　- Sub-analysis of the Japanese Circulation Society Cardiovascular Shock Registry.

BACKGROUND: Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1-3 (not fully alert but awake without any stimuli); arousable, JCS 10-30 (arousable with stimulation); and coma JCS 100-300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P<0.001). Similar trends were observed in etiologically divergent subgroups (acute coronary syndrome, non-ischemic arrhythmia, and aortic disease). On multivariate Cox regression analysis, arousable (hazard ratio [HR], 1.82; 95% CI: 1.16-2.85, P=0.009) and coma (HR, 2.72; 95% CI: 1.76-4.22, P<0.001) (reference: alert) independently predicted 30-day mortality. CONCLUSIONS: Neurological status upon hospital arrival was useful to predict 30-day mortality in cardiovascular shock patients without OHCA.

Clinical characteristics and prognostic factors in acute coronary syndrome patients complicated with cardiogenic shock in Japan: analysis from the Japanese Circulation Society Cardiovascular Shock Registry.

Cardiogenic shock frequently leads to death even with intensive treatment. Although the leading cause of cardiogenic shock is acute coronary syndrome (ACS), the clinical characteristics and the prognosis of ACS with cardiogenic shock in the present era still remain to be elucidated. We analyzed clinical characteristics and predictors of 30-day mortality in ACS with cardiogenic shock in Japan. The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 495 ACS patients with cardiogenic shock were analyzed. The primary endpoint was 30-day all-cause mortality. The median [interquartile range; IQR] age was 71.0 [63.0, 80.0] years. The median [IQR] value of systolic blood pressure (SBP) and heart rate were 75.0 [50.0, 86.5] mm Hg and 65.0 [38.0, 98.0] bpm, respectively. Multivariable analysis showed an odds ratio (OR) of 4.76 (confidence intervals; CI 1.97-11.5, p < 0.001) in the lowest SBP category (< 50 mm Hg) for SBP ≥ 90 mm Hg. Moreover, age per 10 years increase (OR 1.38, CI 1.18-1.61, p = 0.002), deep coma (OR 3.49, CI 1.94-6.34, p < 0.001), congestive heart failure (OR 3.81, CI 2.04-7.59, p < 0.001) and left main trunk disease (LMTD) (OR 2.81, CI 1.55-5.10, p < 0.001) were independent predictors. Severe hypotension, older age, deep coma, congestive heart failure, and LMTD were independent unfavorable factors in ACS complicated by cardiogenic shock in Japan. A prompt assessment of high-risk patients referring to those predictors in emergency room could lead to appropriate treatment without delay.

Architecture of the Japan Ischemic Heart Disease Multimodal Prospective Data Acquisition for Precision Treatment (J-IMPACT) System.

The utilization of electronic medical records and multimodal medical data is an ideal approach to build a real-time and precision registry type study with a smaller effort and cost, which may fill a gap between evidence-based medicine and the real-world clinical practice. The Japan Ischemic heart disease Multimodal Prospective data Acquisition for preCision Treatment (J-IMPACT) project aimed to build an clinical data registry system that electronically collects not only medical records, but also multimodal data, including coronary angiography and percutaneous coronary intervention (PCI) report, in standardized data formats for clinical studies.The J-IMPACT system comprises the standardized structured medical information exchange (SS-MIX), coronary angiography and intervention reporting system (CAIRS), and multi-purpose clinical data repository system (MCDRS) interconnected within the institutional network. In order to prove the concept, we acquired multimodal medical data of 6 consecutive cases that underwent PCI through the J-IMPACT system in a single center. Data items regarding patient background, laboratory data, prescriptions, and PCI/cardiac catheterization report were correctly acquired through the J-IMPACT system, and the accuracy of the multimodal data of the 4 categories was 100% in all 6 cases.The application of J-IMPACT system to clinical studies not only fills the gaps between randomized clinical trials and real-world medicine, but may also provide real-time big data that reinforces precision treatment for each patient.

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial.

OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. CONCLUSIONS: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels.

Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats.

Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP) -mediated targeting of pitavastatin could attenuate the progression of established PAH.We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35.NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.

Safety, Tolerability, and Pharmacokinetics of NK-104-NP.

Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.