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Background: Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques., Methods and Results: Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively)., Conclusions: AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

The 88 th Annual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8 th to Sunday, March 10 th in Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.

Background: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR)., Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis., Conclusions: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

In Japan, cerebrovascular diseases and cardiovascular diseases (CVDs) are major causes of death and long-term care. Against this, the Cerebrovascular and Cardiovascular Disease Control Act was passed by a legislative body and promulgated in December 2018, and enacted on December 1, 2019. Based on the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease (Japanese National Plan), prefectural plans have been formulated and published from March 2021 to January 2023. Although the majority of individual measures were comprehensively articulated in accordance with the Japanese National Plan, some prefectures did not describe individual measures such as research, collection of medical information, consultation support for patients with CVD, palliative care, assistance for patients with sequelae, support for maintaining a balance between treatment and work, and measures from childhood and adolescence. Furthermore, a few specific indicators were set for these measures and those related to chronic care. This review identifies the current status of prefectural plans and discusses future challenges and directions.

Background: Detection of left ventricular (LV) abnormalities is essential for patients with preclinical heart failure (HF) to delay progression to clinical HF. Global longitudinal strain (GLS) is a sensitive marker for the early occurrence of subtle abnormalities in LV function, but not all echocardiographic instruments can measure GLS., Methods and results: We studied 853 preclinical HF patients to devise a scoring system for predicting low GLS (<16%). The associations of medical history and echocardiographic parameters with low GLS were evaluated using Cox proportional hazards analysis. Model 1 of the system consisted of medical history; for Model 2, conventional echocardiographic parameters were added to Model 1. For Model 1, a score ≥5 points meant prediction of low GLS with 90.2% sensitivity and 62.9% specificity (male=1 point, hypertension=4 points, dyslipidemia=1 point, atrial fibrillation=2 points, history of cardiac surgery=2 points). For Model 2, a score ≥4 points denotes prediction of low GLS with 80.3% sensitivity and 76.5% specificity (male=1 point, hypertension=2 points, atrial fibrillation=2 points, LV mass index >116 g/m 2 [male] or >96 g/m 2 [female]=1 point, LV ejection fraction <59%=2 points, E/e' >14=1 point)., Conclusions: Our scoring system provides an easy-to-use evaluation of LV longitudinal myocardial dysfunction, and may prove useful for risk stratification of patients with preclinical HF.

Background: Early detection and intervention for preclinical heart failure (HF) are crucial for restraining the potential increase in patients with HF. Thus, we designed and conducted a single-center retrospective cohort study to confirm the efficacy of B-type natriuretic peptide (BNP) for the early detection of preclinical HF in a primary care setting., Methods and results: We investigated 477 patients with no prior diagnosis of HF who were under the care of general practitioners. These patients were categorized into 4 groups based on BNP concentrations: Category 1, 0 pg/mL≤BNP≤35 pg/mL; Category 2, 35 pg/mL200 pg/mL. There was a marked and statistically significant increase in the prevalence of preclinical HF with increasing BNP categories: 19.9%, 57.9%, 87.5%, and 96.0% in Categories 1, 2, 3, and 4, respectively. Compared with Category 1, the odds ratio of preclinical HF in Categories 2, 3, and 4 was determined to be 5.56 (95% confidence interval [CI] 3.57-8.67), 23.70 (95% CI 8.91-63.11), and 171.77 (95% CI 10.31-2,861.93), respectively., Conclusions: Measuring BNP is a valuable tool for the early detection of preclinical HF in primary care settings. Proactive testing in patients at high risk of HF could play a crucial role in addressing the impending HF pandemic.

Background: We investigated the efficacy of left ventricular (LV) myocardial damage by native T 1 mapping obtained with cardiac magnetic resonance (CMR) for patients undergoing transcatheter edge-to-edge repair (TEER)., Methods and results: We studied 40 symptomatic non-ischemic heart failure (HF) patients and ventricular functional mitral regurgitation (VFMR) undergoing TEER. LV myocardial damage was defined as the native T 1 Z-score, which was converted from native T 1 values obtained with CMR. The primary endpoint was defined as HF rehospitalization or cardiovascular death over 12 months after TEER. Multivariable Cox proportional hazards analysis showed that the native T 1 Z-score was the only independent parameter associated with cardiovascular events (hazard ratio 3.40; 95% confidential interval 1.51-7.67), and that patients with native T 1 Z-scores <2.41 experienced significantly fewer cardiovascular events than those with native T 1 Z-scores ≥2.41 (P=0.001). Moreover, the combination of a native T 1 Z-score <2.41 and more severe VFMR (effective regurgitant orifice area [EROA] ≥0.30 cm 2 ) was associated with fewer cardiovascular events than a native T 1 Z-score ≥2.41 and less severe VFMR (EROA <0.30 cm 2 ; P=0.002)., Conclusions: Assessment of baseline LV myocardial damage based on native T 1 Z-scores obtained with CMR without gadolinium-based contrast media is a valuable additional parameter for better management of HF patients and VFMR following TEER.

Background: Fractional flow reserve-computed tomography (FFR CT ) has not been validated in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) for coronary artery disease due to theoretical difficulties in using nitroglycerin for such patients., Methods and results: In this single-center study, we prospectively enrolled 21 patients (34 vessels) and performed pre-TAVR FFR CT without nitroglycerin, pre-TAVR invasive instantaneous wave-free ratio (iFR) measurements, and post-TAVR FFR measurements using a pressure wire. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of pre-TAVR FFR CT ≤0.80 to predict post-TAVR invasive FFR ≤0.80 were 82%, 83%, 82%, 71%, and 90%, respectively. A receiver operating characteristic analysis demonstrated an optimal cutoff of 0.78 for pre-TAVR FFR CT to indicate post-TAVR FFR ≤0.80, with an area under the curve (AUC) of 0.84, and the counterpart cutoff of pre-TAVR iFR was 0.89 with an AUC of 0.86., Conclusions: FFR CT without nitroglycerin could be a useful non-invasive imaging modality for assessing the severity of coronary artery lesions in patients with severe AS.

Background: Diabetes increases the risk of heart failure (HF). 3-Hydroxyisobutyric acid (3-HIB) is a muscle-derived metabolite reflecting systemic insulin resistance. In this study, we investigated the prognostic impact of 3-HIB in patients with chronic HF., Methods and results: The KUNIUMI Registry chronic cohort is a community-based cohort study of chronic HF in Awaji Island, Japan. We analyzed the association between serum 3-HIB concentrations and adverse cardiovascular (CV) events in 784 patients from this cohort. Serum 3-HIB concentrations were significantly higher in patients with than without diabetes (P=0.0229) and were positively correlated with several metabolic parameters. According to Kaplan-Meier analysis, rates of CV death and HF hospitalization at 2 years were significantly higher among HF patients without diabetes in the high 3-HIB group (3-HIB concentrations above the median; i.e., >11.30 μmol/L) than in the low 3-HIB group (log-rank P=0.0151 and P=0.0344, respectively). Multivariable Cox proportional hazard models adjusted for established risk factors for HF revealed high 3-HIB as an independent predictor of CV death (hazard ratio [HR] 1.82; 95% confidence interval [CI] 1.16-2.85; P=0.009) and HF hospitalization (HR 1.72; 95% CI 1.17-2.53, P=0.006) in HF patients without diabetes, whereas no such trend was seen in subjects with diabetes., Conclusions: In a community cohort, circulating 3-HIB concentrations were associated with prognosis in chronic HF patients without diabetes.

Background: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD)., Methods and results: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92-139] vs. 142 [121-165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110-157] vs. 142 [123-174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman's r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76-0.96, P=0.033), whereas HDL-C was not., Conclusions: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.

Background: The efficacy of a therapy for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has not been proven, but tafamidis has been associated with favorable outcomes. However, echocardiographic details of the association of tafamidis with cardiac morphology remain undetermined. Moreover, whether the efficacy of tafamidis varies with the degree of cardiac involvement remains unknown. Using echocardiography, this study investigated the impact of tafamidis on the cardiac morphology of patients with ATTR-CM., Methods and results: Of 52 consecutive patients with biopsy-proven ATTR-CM at Kobe University Hospital, we included 41 for whom details of follow-up echocardiographic examinations after the administration of tafamidis were available. All patients underwent standard and speckle-tracking echocardiography before and a mean (±SD) of 16±8 months after the administration of tafamidis. No significant changes were observed in any representative echocardiographic parameters after the administration of tafamidis. Furthermore, there were no significant changes observed in subgroup analyses (e.g., left ventricular [LV] ejection fraction ≥50% vs. <50%; LV mass index <150 vs. ≥150 g/m 2 ; New York Heart Association Class I-II vs. Class III; age ≥80 vs. <80 years)., Conclusions: Tafamidis may prevent worsening of various representative echocardiographic parameters of patients with ATTR-CM. This effect is also seen in patients with relatively advanced disease and in those who are elderly.

Background: The mechanism underlying the sex differences in atrial fibrillation (AF) recurrence following pulmonary vein (PV) isolation is not fully understood. We hypothesized that non-PV foci and epicardial adipose tissue (EAT) play a key role., Methods and results: Data from 304 consecutive patients (75% males) who underwent contrast-enhanced computed tomography and catheter ablation of AF were reviewed. The EAT around the atrium was measured separately in 4 parts of the atrium. All patients underwent high-dose isoproterenol infusions to assess the non-PV foci. Significantly more non-PV foci and less EAT around the atrium were observed in female patients than in male patients. In males, those with non-PV foci on the left atrial (LA) anterior wall had significantly greater EAT for the same lesions than those without non-PV foci. During a median follow-up of 27 months, the predictors of AF recurrence after first catheter ablation were female sex, presence of non-PV foci, LA diameter, and septal EAT index. A sex-specific analysis revealed that LA diameter was a predictor only in males and that the presence of non-PV foci in the septal region was a strong predictor in males (hazard ratio [HR]: 2.24) and females (HR: 3.65)., Conclusions: Sex-specific differences were observed in non-PV foci sites and local EAT and in regard to the predictors of AF recurrence.

Background: Most patients with acute myocardial infarction (AMI) present in the emergency department in a hemodynamically stable condition (i.e., non-cardiogenic shock) (AMI-NCS). However, few studies specifically focused on the clinical characteristics and outcomes of AMI-NCS patients. Temporal trends in clinical characteristics, in-hospital occurrence of in-hospital adverse outcomes, and the effect of primary percutaneous coronary intervention (PPCI) were examined., Methods and results: Between April 2012 and March 2018, 176,275 AMI-NCS patients (67.7% of the total AMI population; 25.4% female; mean age 68.6±13.1 years) were identified in a nationwide Japanese administrative database. During the 6-year study period, AMI-NCS patients have been getting older and had an increasing burden of comorbidities. The rates of 30-day all-cause mortality and in-hospital complications were 2.6% and 30.5%, respectively. Thirty-day all-cause mortality did not change significantly over time, whereas in-hospital complications, especially major non-cardiac events, increased progressively. On multivariable analyses, higher age, higher Killip class, atrial fibrillation, chronic renal failure, and malignancy were independently associated with both increased 30-day mortality and in-hospital complications. PPCI was independently associated with lower mortality and in-hospital complications., Conclusions: The clinical background of AMI-NCS patients has been becoming more complex with increasing age and the burden of comorbidities, with increased in-hospital complications. More active and appropriate application of PPCI may further decrease adverse events and improve survival of AMI-NCS patients.

Background: Several algorithms have been proposed for differentiating the right and left outflow tracts (RVOT/LVOT) arrhythmia origins from 12-lead electrocardiograms (ECGs); however, the procedure is complicated. A deep learning (DL) model, a form of artificial intelligence, can directly use ECGs and depict the importance of the leads and waveforms. This study aimed to create a visualized DL model that could classify arrhythmia origins more accurately., Methods and results: This study enrolled 80 patients who underwent catheter ablation. A convolutional neural network-based model that could classify arrhythmia origins with 12-lead ECGs and visualize the leads that contributed to the diagnosis using a gradient-weighted class activation mapping method was developed. The average prediction results of the origins by the DL model were 89.4% (88.2-90.6) for accuracy and 95.2% (94.3-96.2) for recall, which were significantly better than when a conventional algorithm is used. The ratio of the contribution to the prediction differed between RVOT and LVOT origins. Although leads V1 to V3 and the limb leads had a focused balance in the LVOT group, the contribution ratio of leads aVR, aVL, and aVF was higher in the RVOT group., Conclusions: This study diagnosed the arrhythmia origins more accurately than the conventional algorithm, and clarified which part of the 12-lead waveforms contributed to the diagnosis. The visualized DL model was convincing and may play a role in understanding the pathogenesis of arrhythmias.

Background: Few registries have provided precise information concerning incidence rates for acute heart failure syndrome (AHFS) in Japan., Methods and results: All hospitals with acute care beds in Awaji Island participated in the Kobe University heart failure registry in Awaji Medical Center (KUNIUMI Registry), a retrospective, population-based AHFS registration study, enabling almost every patient with AHFS in Awaji Island to be registered. From 1 January 2015 to 31 December 2017, 743 patients with de novo AHFS had been registered. Mean age was 82.1±11.5 years. Using the general population of Japan as of 2015 as a standard, age- and sex-adjusted incidence rates for AHFS were 133.8 per 100,000 person-years for male and 120.0 for female. In 2015, there were an estimated 159,702 new-onset patients with AHFS, which was predicted to increase to 252,153 by 2040, and reach a plateau. The proportion of patients aged >85 years accounted for 42.6% in 2015, which was predicted to increase up to 62.5% in 2040. The proportion of patients with heart failure with preserved ejection fraction was estimated at 52.0% in 2015, which was predicted to increase gradually to 57.3% in 2055., Conclusions: The present analysis suggested that the number of patients with de novo AHFS keeps increasing with progressive aging in Japan. Establishment of countermeasures against the expanding burden of HF is urgently required.

Background: A thorough understanding of the anatomy of the aortic valve is necessary for aortic valve-sparing surgery. Normal valvar dimensions and their relationships in the living heart, however, have yet to be fully investigated in a 3-dimensional fashion., Methods and results: In total, 123 consecutive patients (66±12 years, Men 63%) who underwent coronary computed tomographic angiography were enrolled. Mid-diastolic morphology of the aortic roots, including height of the interleaflet triangles, geometric height, free margin length of each leaflet, effective height, and coaptation length were measured using multiplanar reconstruction images. Average height of the interleaflet triangle, geometric height, free margin length, effective height, and the coaptation length were 17.3±1.8, 14.7±1.3, 32.6±3.6, 8.6±1.4, and 3.2±0.8 mm, respectively. The right coronary aortic leaflet displayed the longest free margin length and shortest geometric height. Geometric height, free margin length, and effective height showed positive correlations with aortic root dimensions. Coaptation length, however, remained constant regardless of aortic root dimensions., Conclusions: Diversities, as well as characteristic relationships among each value involving the aortic root, were identified using living-heart datasets. The aortic leaflets demonstrated compensatory elongation along with aortic root dilatation to maintain constant coaptation length. These measurements will serve as the standard value for revealing the underlying mechanism of aortic regurgitation to plan optimal aortic valve-sparing surgery.

Background: Cardiovascular diseases and/or risk factors (CVDRF) have been reported as risk factors for severe coronavirus disease 2019 (COVID-19)., Methods and results: In total, we selected 693 patients with CVDRF from the CLAVIS-COVID database of 1,518 cases in Japan. The mean age was 68 years (35% females). Statin use was reported by 31% patients at admission. Statin users exhibited lower incidence of extracorporeal membrane oxygenation (ECMO) insertion (1.4% vs. 4.6%, odds ratio [OR]: 0.295, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, P=0.004) despite having more comorbidities such as diabetes mellitus., Conclusions: This study suggests the potential benefits of statins use against COVID-19.

Background: The impact of antiplatelet drug effects on mid-term local arterial responses following percutaneous coronary intervention (PCI) remains uncertain. We evaluated the impact of the platelet reactivity of prasugrel on mid-term vascular healing between acute coronary syndrome (ACS) and stable coronary artery disease (CAD)., Methods and results: We conducted a prospective, 12-center study in 125 patients with ACS and 126 patients with stable CAD who underwent PCI with an everolimus-eluting stent (EES) and received dual antiplatelet therapy (DAPT) with prasugrel and aspirin. Serial optical coherence tomography (OCT) was performed immediately after PCI and at the 9-month follow-up to assess the association of P2Y 12 reaction units (PRU) with the frequency of malapposed or uncovered struts and intrastent thrombi (IST). The incidence of abnormal mid-term OCT findings did not different between the ACS and CAD arms, regardless of clinical presentation, except that uncovered struts were more frequent in the ACS than CAD arm. PRU at PCI was significantly associated with the frequency of IST at follow-up, but not with uncovered and malapposed struts. PRU at PCI was the only independent predictor of IST detected at follow-up (odds ratio 1.009)., Conclusions: In patients undergoing EES implantation and receiving prasugrel, achieving an adequate antiplatelet effect at the time of stent implantation may regulate thrombus formation throughout the follow-up period.

Background: This study investigated the effects of age on the outcomes of coronavirus disease 2019 (COVID-19) and on cardiac biomarker profiles, especially in patients with cardiovascular diseases and/or risk factors (CVDRF)., Methods and results: A nationwide multicenter retrospective study included 1,518 patients with COVID-19. Of these patients, 693 with underlying CVDRF were analyzed; patients were divided into age groups (<55, 55-64, 65-79, and ≥80 years) and in-hospital mortality and age-specific clinical and cardiac biomarker profiles on admission evaluated. Overall, the mean age of patients was 68 years, 449 (64.8%) were male, and 693 (45.7%) had underlying CVDRF. Elderly (≥80 years) patients had a significantly higher risk of in-hospital mortality regardless of concomitant CVDRF than younger patients (P<0.001). Typical characteristics related to COVID-19, including symptoms and abnormal findings on baseline chest X-ray and computed tomography scans, were significantly less prevalent in the elderly group than in the younger groups. However, a significantly (P<0.001) higher proportion of elderly patients were positive for cardiac troponin (cTn), and B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) levels on admission were significantly higher among elderly than younger patients (P<0.001 and P=0.001, respectively)., Conclusions: Elderly patients with COVID-19 had a higher risk of mortality during the hospital course, regardless of their history of CVDRF, were more likely to be cTn positive, and had significantly higher BNP/NT-proBNP levels than younger patients.

Background: Coronary artery spasms (CASs), which can cause angina attacks and sudden death, have been recently reported during catheter ablation. The aim of the present study was to report the incidence, characteristics, and prognosis of CASs related to atrial fibrillation (AF) ablation procedures., Methods and results: The AF ablation records of 22,232 patients treated in 15 Japanese hospitals were reviewed. CASs associated with AF ablation occurred in 42 of 22,232 patients (0.19%). CASs occurred during ablation energy applications in 21 patients (50%). CASs also occurred before ablation in 9 patients (21%) and after ablation in 12 patients (29%). The initial change in the electrocardiogram was ST-segment elevation in the inferior leads in 33 patients (79%). Emergency coronary angiography revealed coronary artery stenosis and occlusions, which were relieved by nitrate administration. No air bubbles were observed. A comparison of the incidence of CASs during pulmonary vein isolation between the different ablation energy sources revealed a significantly higher incidence with cryoballoon ablation (11/3,288; 0.34%) than with radiofrequency catheter, hot balloon, or laser balloon ablation (8/18,596 [0.04%], 0/237 [0%], and 0/111 [0%], respectively; P<0.001). CASs most often occurred during ablation of the left superior pulmonary vein. All patients recovered without sequelae., Conclusions: CASs related to AF ablation are rare, but should be considered as a dangerous complication that can occur anytime during the periprocedural period.

Background: In-stent neoatherosclerosis (NA) is a risk for future cardiovascular events through atherosclerotic progression in non-stented lesions. Using optical coherence tomography, this study assessed the efficacy of intensive therapy with 10 mg/day rosuvastatin plus 1,800 mg/day eicosapentaenoic acid (EPA) vs. standard 2.5 mg/day rosuvastatin therapy on native coronary plaques in patients with NA., Methods and results: This was a subgroup analysis of the randomized LINK-IT trial, which was designed to compare changes in the lipid index in NA between intensive and standard therapy for 12 months. In all, 42 patients with native coronary plaques and NA were assessed. Compared with standard therapy, intensive therapy resulted in greater decreases in serum low-density lipoprotein cholesterol concentrations and greater increases in serum 18-hydroxyeicosapentaenoic acid concentrations, with significantly greater decreases in the lipid index and macrophage grade in both NA (-24 vs. 217 [P<0.001] and -15 vs. 24 [P<0.001], respectively) and native coronary plaques (-112 vs. 29 [P<0.001] and -17 vs. 1 [P<0.001], respectively) following intensive therapy. Although there was a greater increase in the macrophage grade in NA than in native coronary plaques in the standard therapy group, in the intensive therapy group there were comparable reductions in macrophage grade between NA and native coronary plaques., Conclusions: Compared with standard therapy, intensive therapy prevented atherosclerotic progression more effectively in native coronary plaques in patients with NA.

Background: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH)., Methods and results: This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm 5 , whereas that in the placebo group was 26±180 dyn·s/cm 5 . Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm 5 (P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index., Conclusions: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).

Background: The underlying mechanism of mitral regurgitation (MR) in atrial fibrillation (AF) is an isolated annulus dilation caused by left atrial (LA) remodeling. However, the association of mitral valve (MV) geometry with MR in AF patients remains unclear., Methods and results: We studied 96 AF patients with preserved left ventricular ejection fraction (LVEF). MV geometry was evaluated with 3-dimensional transesophageal echocardiography (3D-TEE). Mitral annulus area of the MR group (n=11, ≥ moderate) was significantly larger (10.6±1.8 vs. 8.2±1.5 cm 2 , P<0.0001), and relative posterior mitral leaflet (PML) area (PML area / mitral annulus area) was significantly smaller (0.51±0.06 vs. 0.57±0.01, P=0.002) than in the non-MR group (n=85,

Background: Trans-fatty acid (TFA) intake increases the risk of coronary artery disease (CAD). Our previous cross-sectional survey showed that middle-aged patients with CAD in Japan have elevated serum TFA. In this study, we longitudinally investigated whether elevated TFA is a risk factor in the secondary prevention of CAD for the same-age patients. Methods and Results: A total of 112 patients (age, 21-66 years) who underwent percutaneous coronary intervention were followed up for up to 2 years. Serum elaidic acid was measured using gas chromatography/mass spectrometry as a marker of TFA intake and divided into quartiles. The primary endpoint was ischemia-driven target lesion revascularization (TLR). The hazard ratio (HR) for TLR increased significantly with higher serum elaidic acid (P<0.01). The significant positive trend remained unchanged after adjusting for conventional lipid profile and bare-metal stent usage. In contrast, although triglycerides and low-density lipoprotein cholesterol were positively correlated with elaidic acid, they were not associated with TLR. On multivariable Cox proportional hazard analysis, elevated elaidic acid was independently associated with TLR risk after adjusting for conventional coronary risks (HR, 10.7, P<0.01)., Conclusions: Elevated elaidic acid is associated with higher TLR rate in middle-aged patients with CAD, suggesting that excessive TFA intake is becoming a serious health problem in Japan.

Background: Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030)., Conclusions: Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.

Background: Our aim was to investigate the baseline clinical and echocardiographic parameters for predicting left ventricular (LV) dysfunction after anthracycline chemotherapy and heart failure (HF) hospitalization in a single cancer disease. Methods and Results: We studied 73 patients with malignant lymphoma and preserved LV ejection fraction (LVEF). Echocardiography was performed before and after anthracycline chemotherapy. Global longitudinal strain (GLS) was determined from 3 standard apical views. LV dysfunction after anthracycline chemotherapy was defined according to the current definition of cancer therapeutics-related cardiac dysfunction. Long-term (50-month) unfavorable outcome was prespecified as hospitalization for HF. A total of 10 patients had LV dysfunction after anthracycline chemotherapy. Multivariate logistic regression analysis showed that baseline GLS was the only independent predictor of this dysfunction. Receiver-operating characteristic curve analysis identified the optimal GLS cutoff for predicting LV dysfunction after anthracycline chemotherapy as ≤19% (P=0.008). Furthermore, the Kaplan-Meier curve indicated that fewer patients with GLS >19% were hospitalized for HF than among those with GLS ≤19% (log-rank P=0.02). For sequential logistic models, a model based on baseline clinical variables (χ 2 =2.9) was improved by the addition of baseline LVEF (χ 2 =9.0; P=0.01), and further improved by the addition of baseline GLS (χ 2 =13.1, P=0.04)., Conclusions: Watchful observation or early therapeutic intervention with established cardioprotective medications may be necessary for patients with malignant lymphoma and preserved LVEF but with abnormal GLS.

Background: It has previously been reported that oral administration of purified eicosapentaenoic acid (EPA) generates EPA-rich high-density lipoprotein (HDL) particles with a variety of anti-inflammatory properties. In this study, the mechanism underlying the anti-atherogenic effects of EPA-rich HDL using reconstituted HDL (rHDL) was investigated.Methods and Results:rHDL was generated by the sodium cholate dialysis method, using apolipoprotein A-1 protein, cholesterol, and various concentrations of EPA-phosphatidylcholine (PC) or egg-PC. Increased EPA-PC contents in rHDL resulted in decreased particle size. Next, the effects of rHDL containing various amounts (0-100% of total PC) of EPA-PC on vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical vein endothelial cells (HUVECs) was examined. Cytokine-stimulated VCAM-1 expression was inhibited in a dose-dependent manner based on the amount of EPA-PC in rHDL. Surprisingly, the incubation of HUVECs with EPA-rich rHDL resulted in the production of resolvin E3 (RvE3), an anti-inflammatory metabolite derived from EPA. Incubation with EPA-PC alone did not adequately induce RvE3 production, suggesting that RvE3 production requires an endothelial cell-HDL interaction. The increased anti-inflammatory effects of EPA-rich HDL may be explained by EPA itself and RvE3 production. Furthermore, the increase in EPA-PC content enhanced cholesterol efflux., Conclusions: The EPA-enriched HDL particles exhibit cardioprotective properties via the production of anti-inflammatory lipid metabolites and the increase in cholesterol efflux.

Background: Although aortic valve intervention is recommended for virtually all symptomatic patients with aortic stenosis (AS), how urgently the intervention should be performed remains controversial. The aim of this study was thus to determine whether the preload reserve in response to leg-positive pressure (LPP) maneuver could serve for decision-making for AS patients awaiting aortic valve intervention.Methods and Results:Sixty-eight patients with symptomatic AS, who were referred for aortic valve intervention, were recruited. Stroke volume (SV) was assessed by means of pulsed-wave Doppler, and the ratio between transmitral E wave and mitral annular velocity (e') was calculated to estimate ventricular filling pressure. While waiting for intervention, 11 patients experienced preoperative cardiac events. During acute preload stress, forward SV for patients without cardiac events increased significantly (from 43±9 to 49±10 mL/m 2 , P<0.01) along with a minimal change in filling pressure (E/e': from 20±8 to 21±9, NS). For patients with cardiac events, the Frank-Starling mechanism was significantly impaired (SVi: from 40±9 to 38±7 mL/m 2 , NS), while filling pressure increased to the critical level (E/e': from 24±8 to 31±8, P<0.001). Both the patients without flow reserve (∆SVi <4.5 mL/m 2 ) and those without diastolic reserve (∆E/e' ≥2.9) exhibited significantly worse event-free survival than the others (P<0.05, respectively)., Conclusions: Assessment of preload reserve during LPP stress could facilitate risk stratification of patients with severe AS waiting for aortic valve intervention.

Background: Hyogo Prefecture is the 2nd prefecture in Japan, after Kanagawa, to enact a ban with penal code on smoking in public places, although the restriction is partial.Methods and Results:This study included consecutive patients with acute coronary syndrome (ACS) who were admitted to 33 major hospitals in the Hyogo District during the 12 months before implementation of the legislation and during the 24 months thereafter. Consecutive patients with ACS from Gifu Prefecture who were admitted to 20 major hospitals were enrolled as geographical controls. The number of ACS admissions did not change from the years 2012-2015 in both Hyogo District (1,774 in the pre-year, 1,784 in the 1st year, and 1,720 in the 2nd year) and Gifu Prefecture (1,226 in the pre-year, 1,174 in the 1st year, and 1,206 in the 2nd year). However, a clear reduction was observed in the subanalysis for Kobe City (895 in the preceding year, 830 (-7.3%) in the 1st year, and 792 (-11.5%) in the 2nd year), where adherence to the smoking ban was higher than in other Hyogo districts., Conclusions: The primary endpoint did not show a significant change. However, the subanalysis showed a significant decrease in ACS admissions in Kobe City. These results suggest that ACS reduction may depend on the degree of adherence to a smoking ban. (Circ J 2016; 80: 2528-2532).