At present, atherosclerosis is one of the most important field in clinical and research medicine. Because it is closely related to cardiovascular (CV) and endocrine disorders such as coronary artery disease, cardiometabolic disorders, much research on how to manage atherosclerosis has been performed. The low-density lipoprotein cholesterol (LDL-C) concentration has been established as an independent risk factor for developing atherosclerosis, and considerable effort has been committed to educating both physicians and the general public on the importance of lowering LDL-C with statins. Although statins have already significantly improved CV outcomes, patients with LDL-C target levels achieved by intense statin therapy still have significant remaining CV risk. Statins already play a central role in managing hyperlipidemia; however, residual risk with statins is an important field of managing remaining CV risk. Recent studies have suggested residual cholesterol and inflammation risks in causing CV events. In the current review, we will discuss residual risk and suggest strategies to overcome it in the statins era.
Tobacco smoking continues to be a major risk factor for cardiovascular disease (CVD) and the leading avoidable cause of death worldwide. Tobacco smoking has declined in high-income countries, but the average smoking rate in Japan remains high: 29.4% for men and 7.2% for women in 2017. Of note, the average smoking rate among middle-aged men remains approximately 40%, indicating that a high incidence of smoking-related CVD will continue for a couple of decades in Japan. The adverse effects of tobacco smoking on CVD are more extensive than previously thought. Physicians should be particularly alert to the development and progression of heart failure, atrial fibrillation, and venous thromboembolism, as well as ischemic CVD among tobacco smokers. Increasing use of heat-not-burn tobacco as cigarette alternatives is an emerging issue. Harmful effects do not disappear just by changing the delivery system of tobacco.
Background:Atrial fibrillation (AF) is the most common arrhythmia with serious complications and a high rate of recurrence after catheter ablation. Recently, mutation ofMYL4was reported as responsible for familial atrial cardiomyopathy and AF. This study aimed to determine the association between polymorphism inMYL4with the onset and recurrence of AF.
Methods and Results:A total of 7 single-nucleotide polymorphisms were selected by linkage disequilibrium and genotyped in 510 consecutive AF patients and 192 controls without structural heart disease. A total of 246 AF patients who underwent cryoballoon ablation had a 1-year scheduled follow-up study for AF recurrence. C allele and CC genotype of rs4968309 and A allele of rs1515751were associated with AF onset both before and after adjustment of covariation (age, sex, hypertension, and diabetes). AF type and left atrial size were different among the genotypes of rs4968309. Moreover, CC genotype of rs4968309 increased susceptibly of AF recurrence after cryoballoon ablation. The prevalence of hypertension was associated with rs1515752, and left atrial size was associated with the genotype of rs2071438.
Conclusions:C allele and CC genotype of rs4968309 inMYL4were associated with AF onset and recurrence. Moreover, the A allele of rs1515751 had a significant association with AF onset. The polymorphisms ofMYL4can predict AF onset and prognosis after ablation in AF patients without structural heart disease.
Background:An adaptive cardiac resynchronization therapy (aCRT) algorithm has been described for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT). However, there are few algorithmic data on the effect of changes during exercise.
Methods and Results:We enrolled 27 patients with availability of the aCRT algorithm. Eligible patients were manually programmed to optimal atrioventricular (AV) and interventricular (VV) delays by using echocardiograms at rest or during 2 stages of supine bicycle exercise. We compared the maximum cardiac output between manual echo-optimization and aCRT-on during each phase. After initiating exercise, the optimal AV delay progressively shortened (P<0.05) with incremental exercise levels. The manual-optimized settings and aCRT resulted in similar cardiac performance, as demonstrated by a high concordance correlation coefficient between the LV outflow tract velocity time integral (LVOT-VTI) during each exercise stage (Ex.1: r=0.94 P<0.0008, Ex.2: r=0.88 P<0.001, respectively). Synchronized LV-only pacing in patients with normal AV conduction could provide a higher LVOT-VTI as compared with manual-optimized conventional biventricular pacing at peak exercise (P<0.05).
Conclusions:The aCRT algorithm was physiologically sound during exercise by patients.
Background:Intracoronary (IC) administration of nicorandil has been proposed as an alternative choice of hyperemic agent for fractional flow reserve (FFR) measurements. This study evaluated the utility and validity of IC nicorandil administration alone to induce maximal hyperemia.
Methods and Results:Two-hundred-seven patients with coronary artery disease listed for coronary angiography with FFR were prospectively enrolled. FFR was measured after (1) IC administration of nicorandil 2 mg (ICNIC2 mg); (2) continuous intravenous (IV) adenosine triphosphatase (ATP) infusion at 150 μg/kg/min (IVATP150); (3) IV ATP infusion at 210 μg/kg/min (IVATP210); (4) IC administration of 0.5 mg nicorandil during IVATP150 (ICNIC0.5 mg+IVATP150); (5) IC administration of 1 mg nicorandil during IVATP150 (ICNIC1 mg+IVATP150); and (6) IC administration of 2 mg nicorandil during IVATP150 (ICNIC2 mg+IVATP150). The average FFR values and the rate of achieving maximum hyperemia after ICNIC2 mg, IVATP150, IVATP210, ICNIC0.5 mg+IVATP150, ICNIC1 mg+IVATP150, and ICNIC2 mg+IVATP150 were 0.85±0.08, 0.89±0.08, 0.85±0.09, 0.84±0.08, 0.83±0.08, 0.83±0.08 (P<0.01), and 92%, 54%, 91%, 96%, 99%, 99% (P<0.01), respectively. The incidence of systolic aortic pressure drop, chest discomfort, and transient atrioventricular block increased in a dose-dependent manner after IV ATP infusion, but almost no adverse effects were observed after ICNIC2 mg.
Conclusions:ICNIC2 mg produced a more pronounced hyperemia than continuous IV ATP, and might be the preferred method for assessment of FFR.
Background:The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF).
Methods and Results:We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban.
Conclusions:The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.
Background:In patients with acute coronary syndrome (ACS), alirocumab reduced the risk of recurring ischemic events. ODYSSEY J-IVUS assessed the effect of alirocumab on coronary atheroma volume in Japanese patients recently hospitalized with ACS and hypercholesterolemia, using intravascular ultrasound imaging analysis.
Methods and Results:Patients (n=206) who at index ACS diagnosis either had low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (≥100 mg/dL) despite stable statin therapy, or were not on statins with LDL-C levels above target after statin initiation, were randomized (1:1) to alirocumab (75 mg every 2 weeks [Q2 W]/up to 150 mg Q2 W), or standard of care (SoC; atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary efficacy endpoint (week [W] 36 mean [standard error] percent change in normalized total atheroma volume [TAV] from baseline) was −3.1 (1.0)% with SoC vs. −4.8 (1.0)% with alirocumab (between-group difference: −1.6 [1.4]; P=0.23). W36 absolute change from baseline in percent atheroma volume was −1.3 (0.4)% (SoC) and −1.4 (0.4)% (alirocumab; nominal P=0.79). At W36, LDL-C was reduced from baseline by 13.4% (SoC) vs. 63.9% (alirocumab; nominal P<0.0001). In total, 61.8% (SoC) and 75.7% (alirocumab) of patients reported treatment-emergency adverse events.
Conclusions:In Japanese patients with ACS and hypercholesterolemia inadequately controlled despite statin therapy, from baseline to W36, a numerically greater percent reduction in normalized TAV was observed with alirocumab vs. SoC, which did not reach statistical significance.
Background:We aimed to clarify the predictors of death or heart failure (HF) in elderly patients who undergo transcatheter aortic valve replacement (TAVR).
Methods and Results:We prospectively enrolled 83 patients (age, 83±5 years) who underwent transthoracic echocardiography (TTE) and cardiopulmonary exercise testing (CPET) with impedance cardiography post-TAVR. We investigated the association of TTE and CPET parameters with death and the combined outcome of death and HF hospitalization. Over a follow-up of 19±9 months, peak oxygen uptake (V̇O2) was not associated with death or the combined outcome. The minimum ratio of minute ventilation (V̇E) to carbon dioxide production (V̇CO2) and the V̇E vs. V̇CO2slope were higher in patients with the combined outcome. After adjusting for age, sex, Society of Thoracic Surgeons score and peak V̇O2, ventilatory efficacy parameters remained independent predictors of the combined outcome (minimum V̇E/V̇O2: hazard ratio, 1.108; 95% confidence interval, 1.010–1.215; P=0.031; V̇E vs. V̇CO2slope: hazard ratio, 1.035; 95% confidence interval, 1.001–1.071; P=0.044), and had a greater area under the receiver-operating characteristic curve. The V̇E vs. V̇CO2slope ≥34.6 was associated with higher rates of the combined outcome, as well as lower cardiac output at peak work rate during CPET.
Conclusions:In elderly patients, lower ventilatory efficacy post-TAVR is a predictor of death and HF hospitalization, reflecting lower cardiac output at peak exercise.
Background:Decreased light reception because of cataracts leads to potential circadian misalignment, resulting in exacerbation of atherosclerosis; however, little is known about the association between cataracts and atherosclerosis in populations.
Methods and Results:In this cross-sectional study, cataracts were graded using slit lamp biomicroscopy with the Lens Opacities Classification System III and carotid atherosclerosis was assessed based on carotid intima-media thickness (IMT) measured using ultrasonography of the common carotid artery in 442 elderly participants (mean age, 70.0 years). Cataract was defined as nuclear cataract grade ≥3.0, cortical cataract grade ≥2.0, or posterior subcapsular cataract grade ≥2.0 in both eyes. The mean and maximal carotid IMT was 0.86±0.15 mm and 1.07±0.29 mm, respectively. In multivariable analysis adjusted for potential confounders, the mean and maximal carotid IMT were significantly greater in the cataract group than in the non-cataract group by 0.04 mm (95% confidence interval (CI), 0.01–0.06) and 0.07 mm (95% CI, 0.01–0.12), respectively. Logistic regression analysis adjusted for confounders revealed a significantly higher odds ratio for carotid atherosclerosis (maximal carotid IMT ≥1.1 mm) in the cataract group than in the non-cataract group (odds ratio, 1.78; 95% CI, 1.14–2.78).
Conclusions:Cataracts may be independently associated with subclinical carotid atherosclerosis in the elderly population, indicating a need for further prospective studies.
Background:Increased heart rate (HR) is an independent risk factor for cardiovascular outcomes in chronic heart failure (HF). Ivabradine, anIfinhibitor, improved outcomes in patients with HF and reduced ejection fraction (HFrEF) in the SHIFT study. We evaluated its efficacy and safety in Japanese HFrEF patients in a randomized, double-blind, placebo-controlled phase III study: the J-SHIFT study. The main objective was to confirm a hazard ratio of <1 in the primary composite endpoint of cardiovascular death or hospital admission for worsening HF.
Methods and Results:Patients with NYHA functional class II–IV, left ventricular EF ≤35%, and resting HR ≥75 beats/min in sinus rhythm under optimal medical therapy received ivabradine (n=127) or placebo (n=127). Mean reduction in resting HR was significantly greater in the ivabradine group (15.2 vs. 6.1 beats/min, P<0.0001). However, symptomatic bradycardia did not occur. A total of 26 (20.5%) patients in the ivabradine group and 37 (29.1%) patients in the placebo group had the primary endpoint event (hazard ratio 0.67, 95% CI 0.40–1.11, P=0.1179) during median follow-up of 589 days. Mild phosphenes were reported in 8 (6.3%) patients in the ivabradine group and 4 (3.1%) patients in the placebo group (P=0.3760).
Conclusions:The J-SHIFT study supported the efficacy and safety of ivabradine for Japanese HFrEF patients, in accord with the SHIFT study.
Background:In patients with severe coronary artery disease (CAD) requiring coronary revascularization, the prevalence of surgical ineligibility and its clinical effect on long-term outcomes remain unclear.
Methods and Results:Among 15,939 patients with first coronary revascularization in the CREDO-Kyoto percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) registry cohort-2, we identified 3,982 patients with triple-vessel or left main disease (PCI: n=2,188, and CABG: n=1,794). Surgical ineligibility as documented in hospital charts was present in 142 (6.5%) of 2,188 PCI-patients, which was mainly related to comorbidities and advanced age. The cumulative 5-year incidence of the primary outcome measure (all-cause death/myocardial infarction/stroke) was much higher in PCI-patients with surgical ineligibility than in PCI-patients without surgical ineligibility and in CABG-patients (52.5%, 27.6%, and 24.0%, respectively, log-rank P<0.001). After adjusting for confounders, the excess risk of PCI-patients with surgical ineligibility relative to CABG-patients was substantial (hazard ratio [HR] 1.97, 95% CI 1.51–2.58, P<0.001), while the excess risk of PCI-patients without surgical ineligibility relative to CABG-patients was modest, but remained significant (HR 1.37, 95% CI 1.19–1.59, P<0.001).
Conclusions:Among patients with severe CAD, PCI-patients with surgical ineligibility had worse long-term outcomes as compared with those without surgical ineligibility and CABG-patients.
Background:Kawasaki disease (KD) severely threatens young children’s health worldwide. The pathogenic mechanism of KD has not yet been solved, so there is still debate over whether KD is an infectious disease or an autoimmune disease.
Methods and Results:To solve this problem, an immune repertoire analysis of KD was conducted. We collected blood cell RNA samples and prepared them into amplicons with iRepertoire kits. The amplicons were sequenced and analyzed with the iRepertoire pipeline. We first identified KD-specific VJ and VDJ forms that had the potential to serve as biomarkers of KD. In addition, the KD-specific VDJ forms were contributed mostly by immunoglobulin G. The D50 value analysis showed that B-cell diversity in KD is decreased, suggesting unique immunoglobulins are produced in KD. Moreover, V, D and J segment usage in IgA, IgG and IgM was consistent with previous KD studies. Further comparison showed no difference in CDR3 peptide length between KD and fever controls (subjects with fever but not diagnosed as KD), indicting KD had B-cell selection phenomenon that has a non-autoimmune pattern. The comparison of amino acid usage of the CDR3 region demonstrated a preference for hydrophilic amino acids in KD.
Conclusions:The results of D50 value, VDJ usage and CDR3 peptide length analyses suggested the characteristics of infectious disease for KD.