For several decades, most physicians have believed that acute coronary syndrome (ACS) is caused by coronary thrombosis resulting from rupture of vulnerable plaque characterized by a thin fibrous cap overlying a large necrotic core and massive inflammatory cell infiltration. However, nearly one-third of ACS cases are caused by plaque erosion characterized by intact fibrous cap, less or absent necrotic core, less inflammation, and large lumen. Because of the limitations of current imaging modalities, including angiography and intravascular ultrasound, the importance of plaque erosion as a cause of acute coronary events is less well known. Optical coherence tomography (OCT) as an emerging modality with extremely high resolution is the only intravascular imaging modality available for identification of plaque erosion in vivo, which provides new insight into the mechanism of ACS. More importantly, the introduction of OCT to clinical practice enables us to differentiate the patients with ACS caused by plaque erosion from those caused by plaque rupture, thereby providing precise and personalized therapy based on the different underlying mechanisms. We systematically review the morphological characteristics of plaque erosion identified by OCT and its implications for the management of ACS.

Type 2 myocardial infarction (T2MI) refers to myocardial necrosis caused by an imbalance in myocardial oxygen supply and demand and in the absence of acute coronary thrombosis. Despite growing recognition of this entity, there remains little understanding of the pathophysiology and uncertainty over the diagnostic criteria for this subtype of MI. Alarmingly, recent studies suggest that a diagnosis of T2MI pertains a prognosis similar to, if not worse than, type 1 MI. With increasing clinical use of high-sensitivity cardiac troponin assays, the frequency of recognition of T2MI is expected to increase. Yet, there remains a scarcity of prospective studies examining this cohort of patients, let alone randomized clinical trials identifying optimum treatment strategies. Further evaluation of the prevalence, pathophysiology and management of this patient cohort is warranted by the scientific community.

Background:The current state of evaluating patients with peripheral artery disease and more specifically of evaluating medical devices used for peripheral vascular intervention (PVI) remains challenging because of the heterogeneity of the disease process, the multiple physician specialties that perform PVI, the multitude of devices available to treat peripheral artery disease, and the lack of consensus about the best treatment approaches. Because PVI core data elements are not standardized across clinical care, clinical trials, and registries, aggregation of data across different data sources and physician specialties is currently not feasible.

Methods and Results:Under the auspices of the U.S. Food and Drug Administration’s Medical Device Epidemiology Network initiative—and its PASSION (Predictable and Sustainable Implementation of the National Registries) program, in conjunction with other efforts to align clinical data standards—the Registry Assessment of Peripheral Interventional Devices (RAPID) workgroup was convened. RAPID is a collaborative, multidisciplinary effort to develop a consensus lexicon and to promote interoperability across clinical care, clinical trials, and national and international registries of PVI. The current manuscript presents the initial work from RAPID to standardize clinical data elements and definitions, to establish a framework within electronic health records and health information technology procedural reporting systems, and to implement an informatics-based approach to promote the conduct of pragmatic clinical trials and registry efforts in PVI.

Conclusions:Ultimately, we hope this work will facilitate and improve device evaluation and surveillance for patients, clinicians, health outcomes researchers, industry, policymakers, and regulators.

On November 11–15, the American Heart Association (AHA) Scientific Sessions 2017 were held in Anaheim, California, for the first time in 16 years. The annual sessions attracted nearly 18,000 attendees, with a global presence from more than 100 countries, and featured 5 days of programming for cardiovascular basic scientists, clinicians, and researchers. As usual, activities of participants from Japan were prominent. From the exciting sessions, I report the topics and key presentations including the late-breaking clinical trials.

Background:Detection of aortic aneurysm (AA) prior to rupture is crucial to decreasing its mortality. Towards this purpose, a novel detection algorithm was developed from pulse volume recording (PVR), analyzing the propagation loss of pulse waves caused by expansion of the aortic wall. The diagnostic ability of the algorithm was evaluated in this prospective study.

Methods and Results:PVR were measured for 30 s using the oscillometric device designed for automatic measurement of the ankle-brachial index (ABI). The algorithm processed the data automatically and assessed whether the patient had an AA. CT angiography was used as the reference standard. Sensitivity and specificity of the algorithm were evaluated. A total of 152 AA patients, including 21 patients with thoracic AAs (TAA), and 64 non-aneurysm control subjects were enrolled. The mean diameter of all AAs was 47.2±10.3 mm. After measurements, 121 AA patients and 33 control subjects were judged by the algorithm as having or not having AAs, resulting in sensitivity of 80% and specificity of 52%. The sensitivity was higher for larger AAs. There was no sensitivity difference according to the location of the AA.

Conclusions:The new diagnostic algorithm installed in the oscillometric device detected AAs with high sensitivity, especially larger aneurysms. For application as a screening tool, the specificity needs to be improved.

Background:Aneurysm expansion, and consequent endoleaks, after endovascular aneurysm repair (EVAR) is a major problem. Accurate prediction of aneurysm expansion is demanding for surgeons and remains difficult.

Methods and Results:We retrospectively analyzed 157 cases of EVAR for abdominal aortic aneurysm (AAA) using a bifurcated main-body stent-graft. There were 62 cases of aneurysm shrinkage after EVAR, 63 cases of stable aneurysm, and 32 cases of aneurysm expansion. Type I endoleaks were significantly increased in the aneurysm expansion group (EXP) compared with the stable (STB) and shrinkage (SHR) groups (EXP: 15.6% vs. STB: 4.8% vs. SHR: 0%, P=0.005). Type II endoleaks were also significantly increased in EXP (EXP: 65.6% vs. STB: 36.5% vs. SHR: 6.5%, P<0.001). Aneurysm wall enhancement (AWE) on imaging, however, was significantly decreased in the EXP group (EXP: 18.8% vs. STB: 23.8% vs. SHR: 53.2%, P<0.001). In multivariate analysis, the occurrence of type II endoleaks significantly decreased (P<0.001) and that of AWE significantly increased the likelihood of aneurysm shrinkage (P=0.032).

Conclusions:AWE following EVAR may be associated with aneurysm shrinkage.

Background:The JACRE-R Registry, in which 42 Japanese institutions participated, monitored the efficacy and safety of rivaroxaban in catheter ablation (CA) of atrial fibrillation (AF). In the present analysis, we sought to elucidate the effects and risks of heparin bridging and different patterns of interruption/resumption of rivaroxaban on complications of CA.

Methods and Results:We administered rivaroxaban during the perioperative period and recorded the incidence of complications up to 30 days after CA. A total of 1,118 patients were registered; 546 received heparin bridging and 572 did not. The bridging group showed a significantly higher incidence of non-major bleeding than the no-bridging group (4.03% vs. 0.87%; P=0.001). In the group receiving their last dose of rivaroxaban at 8–28 h before CA, neither thromboembolism nor major bleeding was observed during or after CA and the incidence of non-major bleeding was low (4/435, 0.92%). The incidence of non-major bleeding was significantly higher in the group resuming rivaroxaban ≥12 h after CA than in the group resuming <12 h (1.79% vs. 0.27%, P=0.045).

Conclusions:Heparin bridging increased the risk of non-major bleeding perioperatively. It was safe to stop rivaroxaban 8–28 h before the CA procedure, whereas resumption of the drug within 12 h of CA was associated with a lower incidence of non-major bleeding.

Background:Prasugrel has been shown to provide more potency and less variability than clopidogrel, but its potential temporal variability has not been described.

Methods and Results:We conducted a prospective open-label study, evaluating platelet reactivity overtime in acute coronary syndrome (ACS) patients on aspirin and clopidogrel (n=60) or prasugrel (n=61), after a percutaneous coronary intervention (PCI). Blood samples were taken at discharge and at 3 and 6 months. Platelet function tests included VerifyNow (VN-P2Y12), and Multiplate Aggregometry (MEA). By means of VN-P2Y12, prasugrel patients displayed significantly (P<0.001) higher platelet inhibition than clopidogrel patients over time, although there were not significant differences using MEA. Prasugrel patients showed higher platelet inhibition at baseline than at 3 months (59.3±8.1 vs. 105.0±49.2; P<0.001), without significant change at 6 months (107.9±72.0; P=0.919 vs. 3 months). Clopidogrel patients showed a similar trend (160.1±65.1, 184.8±62.7 and 185.0±53.3; baseline vs. 3 months P=0.060; 3 months vs. 6 months P=0.974). High platelet reactivity (HPR) was shown in 16.3% prasugrel patients, with no patient consistently remaining in HPR over time. HPR was detected in 36.6% of the clopidogrel patients, being consistently observed in 15.0% of them. Low platelet reactivity (LPR) was detected in 60.5% prasugrel and 9.8% clopidogrel patients.

Conclusions:Prasugrel patients showed less temporal variation than patients on clopidogrel in terms of HPR. In contrast, higher variability in LPR was detected in prasugrel patients for up to 6 months’ follow-up.

Background:The European Society of Cardiology recommends a risk-based antithrombotic strategy for patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) based on CHA₂DS₂-VASc and HAS-BLED scores. However, because it is unclear if that strategy can be generalized to Asians, we aimed to describe antithrombotic therapies among Japanese patients.

Methods and Results:Using a nationwide claims database in Japan, this retrospective cohort study identified AF patients who underwent PCI from April 1, 2014 to March 31, 2015. The primary outcome was utilization of anticoagulant and antiplatelet agents before PCI, at discharge, and 6, 9, and 12 months after PCI. The secondary outcome was incidence of stroke after PCI. We identified 10,862 patients and 87.5% of them had high CHA₂DS₂-VASc and HAS-BLED scores. There were no significant differences in antithrombotic therapies across the risk strata. More than 30% of patients at high risk of thrombosis did not receive oral anticoagulant prescriptions at discharge. The hazard ratio of incidence of stroke in patients with prior stroke compared with patients without prior stroke was 9.09 (95% confidence interval 7.86–10.50, P<0.01).

Conclusions:Among Japanese AF patients who underwent PCI, prescriptions for antiplatelet agents were more common than those for anticoagulant agents. The majority of study participants were classified as high risk, suggesting a need for a new risk classification that reflects the risk profiles of Japanese patients.

Background:Rotational atherectomy (RA) is an adjunct tool for the management of heavily calcified coronary lesions during percutaneous coronary intervention (PCI), but the long-term clinical outcomes of RA use remain unclear in this drug-eluting stent era.

Methods and Results:This multi-center registry assessed the characteristics and outcomes of patients treated by RA for calcified coronary lesions between 2004 and 2015. Among 1,090 registered patients, mean age was 70±10 years and 815 (75%) were male. Sixty percent of patients had diabetes mellitus and 27.7% were receiving hemodialysis. The procedure was successful in 96.2%. In-hospital death occurred in 33 patients (3.0%), and 14 patients (1.3%) developed definite/probable stent thrombosis. During the median follow-up period of 3.8 years, the incidence of major adverse cardiac events (MACE), defined as all-cause death, acute coronary syndrome, stent thrombosis, target vessel revascularization and stroke, was 46.7%. On multivariable Cox hazard analysis, hemodialysis (HR, 2.08; 95% CI: 1.53–2.86; P<0.0001) and age (HR, 1.03; 95% CI: 1.01–1.04; P<0.0001) were strong independent predictors of MACE. Conversely, statin treatment was associated with lower incidence of MACE (P=0.035).

Conclusions:This study has provided the largest Japanese dataset for long-term follow-up of RA. Although RA in calcified lesions appears feasible with a high rate of procedural success, a high incidence of MACE was observed.

Background:The comparative efficacy of second-generation (G2) vs. first-generation (G1) drug-eluting stents (DES) for calcified coronary lesions is unknown.

Methods and Results:We compared the 3-year clinical outcomes of patients with G1- or G2-DES according to the presence or absence of calcified coronary lesions as assessed in an angiographic core laboratory using data from 2 large-scale prospective multicenter randomized trials, RESET and NEXT. G1-DES and G2-DES were implanted in 299 and 1,033 patients, respectively, in the Calc stratum (≥1 lesion with moderate/severe calcification), and 1,208 and 3,550 patients, respectively, in the Non-calc stratum (no/mild calcification). The patients in the Calc stratum had a significantly higher adjusted risk for the primary outcome measure (any target-lesion revascularization (TLR)) than those in the Non-calc stratum (HR: 1.38, 95% CI: 1.11–1.71, P=0.004). The cumulative 3-year incidence of any TLR was not significantly different between the G1-DES and G2-DES groups in both the Calc and Non-calc strata (12.1% vs. 9.7%, P=0.22, and 6.8% vs. 6.1%, P=0.44, respectively). After adjusting for confounders, the effect of G2DES relative to G1-DES for any TLR remained insignificant in both the Calc and Non-calc strata (HR: 0.78, 95% CI: 0.48–1.25, P=0.3, and HR: 0.84, 95% CI: 0.61–1.17, P=0.31, respectively, P interaction=0.55).

Conclusions:The effect of G2-DES relative to G1-DES for TLR was not significantly different regardless of the presence or absence of lesion calcification.

Background:Elevated serum phosphorus level is an important risk factor for cardiovascular death in general patients on hemodialysis (HD). However, the effect of serum phosphorus levels on outcomes after drug-eluting stent (DES) implantation in HD patients is unknown.

Methods and Results:This was a post-hoc study of the OUCH study series, a series of prospective multicenter registries of HD patients who underwent DES implantation comprising 359 patients from 31 centers in Japan. Patients were categorized into 3 groups according to their preprocedural serum phosphorus levels. The 1-year clinical outcomes of the 336 patients treated for de novo lesions were evaluated. Compared with patients with high (>5.5 mg/dL; n=65) or normal (3.5–5.5 mg/dL; n=219) serum phosphorus levels, those with low serum phosphorus levels (<3.5 mg/dL; n=52) had significantly fewer target lesion revascularization events (13.9% vs. 16.9% vs. 1.9%; P=0.0090) and major adverse cardiac and cerebrovascular events (29.2% vs. 31.1% vs. 13.5%; P=0.032). Multivariate logistic regression analysis revealed that low serum phosphorus level was an independent negative predictor for major adverse cardiac and cerebrovascular events (adjusted odds ratio, 0.31; 95% confidence interval, 0.12–0.70; P=0.0036).

Conclusions:Lowering of serum phosphorus levels beyond the current recommended range may be considered in HD patients who undergo DES implantation.

Background:This study aimed to evaluate the safety and feasibility of transaortic mitral pannus removal (TMPR).

Methods and Results:Between 2004 and 2016, 34 patients (median age, 57 years; 30 women) with rheumatic disease underwent pannus removal on the ventricular side of a mechanical mitral valve through the aortic valve during reoperation. The median time interval from the previous surgery was 14 years. TMPR was performed after removal of the mechanical aortic valve (n=21) or diseased native aortic valve (n=11). TMPR was performed in 2 patients through a normal aortic valve. The mitral transprosthetic mean pressure gradient (TMPG) was ≥5 mmHg in 11 patients, including 3 with prosthetic valve malfunction. Prophylactic TMPR was performed in 23 patients. There were no early deaths. Concomitant operations included 22 tricuspid valve surgeries (13 replacements, 15 repairs) and 32 aortic valve replacements (24 repeats, 8 primary). The mean gradient in patients who had mitral TMPG ≥5 mmHg was significantly decreased from 6.46±1.1 to 4.37±1.17 mmHg at discharge (P<0.001). No mechanical valve malfunction was apparent on last echocardiography.

Conclusions:TMPR is a safe and effective procedure for patients with malfunction or stenosis of a mechanical mitral valve and may be considered an alternative approach in patients with pannus overgrowth in such valves.

Background:Current surgical outcomes of congenital heart surgery for patients with Down syndrome are unclear.

Methods and Results:Of 29,087 operations between 2008 and 2012 registered in the Japan Congenital Cardiovascular Surgery Database (JCCVSD), 2,651 were carried out for patients with Down syndrome (9%). Of those, 5 major biventricular repair procedures [ventricular septal defect repair (n=752), atrioventricular septal defect repair (n=452), patent ductus arteriosus closure (n=184), atrial septal defect repair (n=167), tetralogy of Fallot (TOF) repair (n=108)], as well as 2 major single ventricular palliations [bidirectional Glenn (n=21) and Fontan operation (n=25)] were selected and their outcomes were compared. The 90-day and in-hospital mortality rates for all 5 major biventricular repair procedures and bidirectional Glenn were similarly low in patients with Down syndrome compared with patients without Down syndrome. On the other hand, mortality after Fontan operation in patients with Down syndrome was significantly higher than in patients without Down syndrome (42/1,558=2.7% vs. 3/25=12.0%, P=0.005).

Conclusions:Although intensive management of pulmonary hypertension is essential, analysis of the JCCVSD revealed favorable early prognostic outcomes after 5 major biventricular procedures and bidirectional Glenn in patients with Down syndrome. Indication of the Fontan operation for patients with Down syndrome should be carefully decided.

Background:Advanced age has an adverse impact on clinical results in left ventricular assist device (LVAD) patients. We compared the clinical results of patients aged >60 years with younger patients using a national Japanese database.

Methods and Results:Between April 2013 and December 2016, 300 patients underwent HeartMateII implantation. Of these, 37 patients were ≥60 years at LVAD implantation, and the clinical results of these patients were compared with the other younger 263 patients. At 1 and 3 years the on-device survival was 95%, 91% in younger patients, and 85%, 75% in older patients, respectively (P=0.016), although age was not a risk factor on the multivariate analysis. There was no significant difference between the groups in incidence of various adverse events except stroke. In the propensity-matching cohort, the incidence of stroke was significantly higher in patients aged >60 years (P=0.047). In patients aged >60 years, improvement of renal function was transient and there was no improvement later than 3 months, and recovery of serum albumin level to preoperative value was delayed.

Conclusions:There were significant differences in the stroke incidence and recovery of end-organ functions after LVAD implantation. This may have important implications for patient selection in future destination therapy in Japan, where quality of life is an important issue in LVAD support.

Background:Habitual speed eating is a risk factor of obesity but evidence of this in children is limited. We examined the association between speed-eating habit and subsequent body mass index (BMI) and blood pressure (BP) among Japanese children.

Methods and Results:The community-based study comprised 1,490 Japanese boys and girls who were born in 1989, involved in the Ibaraki Children’s Cohort Study at age 3 years, and had returned questionnaires at both ages 6 and 12 years. In a subsample, we measured BP (n=263). Speed-eating habit was categorized into 4 groups: Never, Quit, Newly, and Continuous. Sex-specific mean values of questionnaire-based BMI and measured BPs at age 12 were examined according to speed-eating habit. Children with continuous speed eating had a higher BMI at age 12 than those who had never had a speed-eating habit (20.0 vs. 17.9 kg/m²for boys (P<0.001); 20.0 vs. 18.4 kg/m²(P<0.001) for girls). Systolic BP at age 12 was higher in boys with continuous speed eating than in those without (117 vs. 110 mmHg, P=0.01), but such a difference was not observed in girls (112 vs. 111 mmHg, P=0.95).

Conclusions:Habitualspeed eating was positively associated with subsequent BMI among boys and girls as well as with systolic BP among boys.

Background:Satisfaction among early-career cardiologists is a key performance metric for cardiovascular (CV) educational programs. To assess the time trend in the interest and activities of early-career cardiologists regarding their training, we conducted web-based surveys in 2011 and 2015.

Methods and Results:Early-career cardiologists were defined as physicians who planned to attend Japanese Circulation Society (JCS) annual meetings within 10 years of graduation. A total of 272 and 177 participants completed the survey for the years 2011 and 2015, respectively. Survey questions were designed to obtain core insights into the workplace, research interests, and demographic profile of respondents. Main outcome measures were satisfaction levels with their training program. The overall satisfaction rate for training was lower in 2015 than 2011; this was largely affected by decreases in the rates of satisfaction for valvular heart disease, ischemic heart disease, advanced heart failure, and congenital heart disease. Moreover, satisfaction with CV training was associated with the volume of invasive procedures such as coronary angiography and percutaneous coronary interventions in 2011 but not 2015.

Conclusions:Early-career cardiologists’ satisfaction with their training decreased during the study period, especially in the field of evolving subspecialties (e.g., valvular heart disease or advanced heart failure), suggesting that prompt reevaluation of the current educational curriculum is needed to properly adapt to progress in cardiology.

Background:We investigated the risk of cardiovascular disease (CVD) with duration of metabolic syndrome (MetS) for the past 4 years before the CVD event.

Methods and Results:We performed a nested case-control study within the Japan Epidemiology Collaboration on Occupational Health Study. A total of 139 registered cases of CVD and 561 self-reported cases of CVD were identified and matched individually on age, sex, and worksite with 695 and 2,803 controls, respectively. MetS was defined by the Joint Interim Statement definition. The odds ratio (95% confidence interval) for registered CVD was 4.7 (2.9, 7.5) for people with persistent MetS (positive for MetS for ≥3 assessments) and 1.9 (1.1, 3.3) for those with intermittent MetS (positive for MetS for 1–2 assessments), compared with people without MetS during the past 4 years before the event/index date (P for trend <0.001). The corresponding odds ratio for self-reported CVD was 2.7 (2.2, 3.5) and 1.8 (1.4, 2.3) (P for trend <0.001). The association with MetS duration was stronger for myocardial infarction than for other CVD subtypes. Similar results were obtained when using the Japanese MetS criteria.

Conclusions:The risk of CVD increases with increasing MetS duration. These findings contribute to risk stratification and encourage lifestyle modification for people with MetS to minimize their health risk.

Background:Recently, it was reported that angiopoietin-like protein 2 (ANGPTL2) secreted from a pathologically stressed heart accelerates cardiac dysfunction in an autocrine/paracrine manner, and that suppression of ANGPTL2 production in the heart restored cardiac function and myocardial energy metabolism, thereby blocking heart failure (HF) development. Interestingly, circulating ANGPTL2 concentrations reportedly increase in HF patients, suggesting a possible endocrine effect on cardiac dysfunction. However, it remains unclear why circulating ANGPTL2 increases in those subjects and whether circulating ANGPTL2 alters cardiac function in an endocrine manner.

Methods and Results:It was found that circulating ANGPTL2 levels are positively correlated with left atrial diameter and pulmonary capillary wedge pressure, and are inversely proportional to the percent of ejection fraction in patients with dilated cardiomyopathy. Furthermore, in mice, circulating ANGPTL2 concentrations increased as HF developed following transverse aorta constriction (TAC), and were inversely correlated with the percent of fractional shortening. Interestingly, although circulating ANGPTL2 concentrations significantly increased in transgenic mice overexpressing keratinocyte-derived ANGPTL2, no pathological cardiac remodeling was seen. Furthermore, it was observed that there was no difference in HF development between transgenic mice and controls following TAC surgery.

Conclusions:Circulating ANGPTL2 levels increase in subjects experiencing cardiac dysfunction. However, circulating ANGPTL2 does not promote cardiac dysfunction in an endocrine manner, and increased levels of circulating ANGPTL2 seen during HF are a secondary effect of increased ANGPTL2 secretion from stressed hearts in HF pathologies.

Background:Blood stream infection is thought to increase the risk of hemorrhagic stroke, a major adverse event with devastating outcome, in patients with continuous-flow left ventricular assist devices (LVADs). We analyzed the risk factors of hemorrhagic stroke in LVAD patients, as well as the time relationship between systemic bacteremia and hemorrhagic stroke.

Methods and Results:We evaluated the incidence of systemic bacteremia and stroke in 164 patients who underwent continuous-flow LVAD implantation between 2005 and 2016. At 1 and 2 years after implantation, the incidence of bacteremia was 29% and 36%, and the incidence of hemorrhagic stroke was 22% and 22% in patients without bacteremia, and 32% and 44% in those with bacteremia, respectively (P=0.035). This higher prevalence of hemorrhagic stroke in patients with bacteremia was notable particularly in the chronic phase (>90 days after implantation). Multivariate analysis revealed that bacteremia was an independent risk factor of hemorrhagic stroke in the chronic phase [hazard ratio, 2.36 (1.02–5.62); P=0.044]. The hazard rate was the highest immediately after the onset of bacteremia, and the risk steadily declined by 90 days after the last episode of bacteremia and flattened thereafter.

Conclusions:Bacteremia was an independent risk factor of hemorrhagic stroke in patients in the chronic phase, with the highest risk seen in the early phase following an episode of bacteremia.

Background:The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; β-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/β-blocker group than in the benidipine/thiazide group.

Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups.

Conclusions:This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, β-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.

Background:Because infective endocarditis (IE) carries a high risk of morbidity and mortality, rapid diagnosis and effective treatment are essential to achieving a good patient outcome. However, the diagnosis of IE is often difficult in patients presenting with nonspecific clinical manifestations. An association between IE and hypointense signal spots on brain T2*-weighted magnetic resonance imaging (MRI) has been reported, but the clinical significance remains unclear.

Methods and Results:To assess the clinical importance of silent lesions in the brains of IE patients, hypointense signal spots detected on their brain T2*-weighted MRI scans were investigated in a retrospective review of 44 consecutive patients with definite or suspected IE evaluated by MRI between June 2006 and January 2014. Hypointense signal spots on T2*-weighted MRI were detected in 37 (84%) patients; of these, 21 (46%) had ischemic lesions, 10 (22%) had subarachnoid hemorrhage, 4 (9%) had intraparenchymal hemorrhage, and 4 (9%) had infectious aneurysm. The hypointense signal spots on T2*-weighted images were preferentially distributed in cortical areas.

Conclusions:T2*-weighted hypointense signal spots are highly frequent in patients with IE and their presence may be informative in the monitoring of IE-associated brain lesions, even those that are neurologically asymptomatic. The strong association between IE and T2*-weighted hypointense signal spots supports the need to consider additional criteria in the diagnosis of IE.

Background:Little is known about the impact of stent type on the prognosis of vasospastic angina (VSA) in patients who undergo stent implantation.

Methods and Results:We evaluated consecutive patients undergoing coronary angiography with positive (n=650; VSA) and negative (n=2,872; non-VSA) ergonovine testing. Among them, 304 patients undergoing stent implantation for organic stenosis were classified for comparison into 3 respective VSA and non-VSA groups based on stent type (68 and 78 with bare-metal stent [BMS]; 21 and 49 with sirolimus-eluting stent [SES]; 26 and 62 with newer generation drug-eluting stent [N-DES]). The primary outcome was defined as target lesion revascularization, target vessel revascularization, emergency coronary angiography, and cardiac death. The 2-year cumulative incidence of the primary outcome was significantly higher in the VSA group than non-VSA group after SES implantation (38.1% vs. 16.1%, P=0.03), whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation. The difference in the percent diameter stenosis from mid-term to late-term follow-up was significantly higher in the VSA group than non-VSA group (10.0% vs. 2.3%, P=0.045) after SES implantation, whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation.

Conclusions:The impact of VSA on clinical and angiographic outcomes was observed only in SES implantation, but not after N-DES or BMS implantation.

Background:A novel bare metal stent with an SiO₂coating was developed to prevent excessive neointimal hyperplasia by inertization of the metallic stent surface. The efficacy of the device was demonstrated in a preclinical model. The aim of this first-in-man trial was to assess the safety and feasibility of the new device.

Methods and Results:This prospective non-randomized single-arm trial was designed to enroll 35 patients with a de novo coronary lesion. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at the baseline procedure and at the 6-month follow-up. Stent implantation was performed with OCT guidance according to optimal stent implantation criteria. The trial was terminated upon the advice of the data safety monitoring board after enrolling 14 patients due to the high incidence of re-intervention. Optimal OCT implantation criteria were achieved in only 8.3% of lesions. At 6 months, angiographic in-stent late lumen loss as the primary endpoint was 0.77±0.44 mm, and binary restenosis occurred in 33.3% of lesions. At the 6-month OCT, neointimal volume obstruction was 32.8±15.6% with a neointimal thickness of 237±117 µm. At 12 months, the device-oriented composite endpoint (defined as cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization rate) was 33.3%.

Conclusions:In contrast with the preclinical study, the Axetis stent did not efficiently suppress neointimal hyperplasia in humans in this trial.

Background:This study aimed to evaluate the diagnostic performance of coronary flow reserve (CFR), hyperemic myocardial blood flow (hMBF), and CFR ratio for detecting significant coronary artery disease (CAD) on ¹³N-ammonia positron emission tomography (PET).

Methods and Results:We analyzed 63 patients (mean age, 71±9 years; 43 males) with suspected CAD who underwent both pharmacological stress/rest ¹³N-ammonia PET and coronary angiography. CFR and hMBF for PET were calculated automatically using quantitative PET software, and the CFR ratio was defined as the ratio of per-vessel CFR to maximum CFR in a standard 17-segment model. We compared the diagnostic performance among the 3 quantitative values. In the per-vessel analysis, 55 vessels were diagnosed as significant CAD (≥70% stenosis and/or fraction flow reserve ≤0.8). CFR, hMBF, and CFR ratio of significant CAD were significantly lower than for non-significant CAD (1.85±0.69 vs. 2.38±0.69; P<0.01, 1.67±0.54 vs. 2.19±0.52 mL·min⁻¹·g⁻¹; P<0.01, and 0.66±0.15 vs. 0.82±0.09; P<0.01, respectively). In the receiver-operating characteristic curve analysis, CFR, hMBF, and CFR ratio had areas under the curve of 0.71, 0.75, and 0.85 respectively, and the CFR ratio was significantly higher than CFR and hMBF (P<0.05). The sensitivity, specificity, and accuracy of the CFR ratio with an optimal cutoff value of 0.75 were 75%, 85%, and 82%, respectively.

Conclusions:Clinically, the CFR ratio in ¹³N-ammonia PET was more effective in detecting significant CAD.

Background:Levels of triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to endothelial dysfunction through renin-angiotensin system (RAS) activation and oxidative stress. The present study investigated how systemic FFA loading affected myocardial microcirculation during hyperemia via RAS.

Methods and Results:Eight healthy men received candesartan, perindopril, or a placebo for 2 days in a double-blind crossover design, and then myocardial microcirculation during hyperemia induced by a 2-h infusion of lipid/heparin was assessed using dipyridamole stress-myocardial contrast echocardiography (MCE). Leukocyte activity and hemorheology were also assessed ex vivo using a microchannel flow analyzer, serum levels of oxidative stress markers, and IκB-α expression in mononuclear cells. Serum FFA elevation by the infusion of lipid/heparin significantly decreased myocardial capillary blood velocity and myocardial blood flow during hyperemia. Both candesartan and perindopril significantly prevented the FFA-induced decrease in capillary blood velocity and myocardial blood flow during hyperemia. Systemic FFA loading also caused an increase in the number of adherent leukocytes and prolonged the whole blood passage time. These effects were blocked completely by candesartan and partially by perindopril. Both agents prevented the FFA-induced enhancement of oxidative stress and IκB-α degradation in mononuclear cells.

Conclusions:Both candesartan and perindopril can prevent FFA-induced myocardial microcirculatory dysfunction during hyperemia via modulation of leukocyte activation and microvascular endothelial function.

Background:Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat.

Methods and Results:Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm²) and was also reduced in the high EFV group (EFV ≥80 cm³). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis.

Conclusions:Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.

Background:The 4th heart sound (S4) is commonly heard in patients with hypertrophic cardiomyopathy (HCM). The 3rd heart sound (S3) is also audible in HCM patients regardless of the presence or absence of heart failure. These extra heart sounds may be associated with myocardial fibrosis because myocardial fibrosis has been suggested to affect left ventricular compliance.

Methods and Results:The present retrospective study evaluated 53 consecutive HCM patients with sinus rhythm who had no symptoms of heart failure and underwent an initial assessment including phonocardiography, echocardiography, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). S3 was detected on phonocardiography in 13% of all patients, and S4 was recorded in 75% of patients. Patients with S3 had a higher incidence of LGE and larger LGE volumes (86% and 11.5±2.4 g/cm, respectively) than patients without S3 (33% and 2.5±0.8 g/cm, respectively; P=0.02 and P=0.002). The presence of S4 was not associated with MRI findings, including the incidence of LGE and LGE volume. The diagnostic value of S3 for the detection of LGE was highly specific (97%), with a low sensitivity (29%).

Conclusions:Myocardial fibrosis, as assessed by LGE, was associated with S3 but not with S4 in patients with HCM. These results may contribute to the risk stratification of patients with HCM.

Background:This purpose of this study was to investigate whether Kawasaki disease (KD) increases the risk of cognitive impairment. In this clinical study, cognitive profiles were compared between KD patients, control subjects, and a nationwide population-based cohort to determine the potential correlation between KD and a subsequent diagnosis of an intellectual disability.

Methods and Results:The clinical study consisted of 168 KD patients (mean age 5.6 years, 62.5% male) and 81 healthy controls (mean age 6.4 years, 54.3% male). The nationwide cohort consisted of 4,286 KD patients and 50,038 controls retrieved from the Taiwan National Health Insurance Research Database between 1996 and 2000. The clinical study sample revealed no significant difference in any developmental index or cognitive function between KD patients and controls across various age groups (P>0.05). In the nationwide cohort, Cox regression analysis showed that a diagnosis of KD did not significantly affect the likelihood of developing an intellectual disability (adjusted hazard ratio 0.87, 95% confidence interval 0.68–1.11).

Conclusions:Both the clinical data and the population-based cohort consistently demonstrated that KD does not increase a child’s risk of future cognitive impairment. Although the outcome of the present study is negative, caregivers and patients with KD can be reassured that KD will have no effect on developmental milestones or cognitive function later in life.

Background:The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA.

Methods and Results:The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR₁₀-AUC₃₀) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR₁₀-AUC₃₀was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045).

Conclusions:The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors.

Background:The effect of lipid-lowering agents on progression of coronary artery calcification (CAC) remains unclear. We evaluated the effects of pitavastatin 2 mg/day (PIT2), pitavastatin 4 mg/day (PIT4), and PIT2 combined with eicosapentaenoic acid (PIT2+EPA) on CAC progression.

Methods and Results:This prospective multicenter study in Japan included patients with an Agatston score of 1–999, hypercholesterolemia, and no evidence of cardiovascular disease. Patients were allocated into PIT2, PIT4, or PIT2+EPA groups. The primary outcome was the annual percent change in Agatston score in all patients. In total, 156 patients who had multi-detector row computed tomography without any artifacts were included in the primary analysis. Pitavastatin did not significantly reduce the annual progression rate of the Agatston score (40%; 95% CI: 19–61%). The annual progression rate of Agatston score in the PIT2 group was not significantly different from that in the PIT4 group (34% vs. 42%, respectively; P=0.88) or the PIT2+EPA group (34% vs. 44%, respectively; P=0.80). On post-hoc analysis the baseline ratio of low- to high-density lipoprotein cholesterol was a significant predictor of non-progression of Agatston score by pitavastatin (OR, 2.17; 95% CI: 1.10–44.12; P=0.02).

Conclusions:Pitavastatin does not attenuate progression of CAC. Intensive pitavastatin treatment and standard treatment with EPA does not reduce progression of CAC compared with standard treatment.

Background:Few studies have investigated the clinical impact of pulmonary artery (PA) dilatation on outcomes in pediatric pulmonary arterial hypertension (PAH).

Methods and Results:This study investigated the clinical outcomes of idiopathic or heritable PAH in 66 children aged <18 years at diagnosis. Main PA/thorax (MPA/T) ratio was measured on chest radiography in PAH patients. Patients were divided into 2 groups based on MPA/T ratio, and compared with a control group of 166 age- and gender-matched healthy children. Group A had higher MPA/T ratio than normal, and group B had normal MPA/T ratio. Composite outcomes included cardiac death, lung transplantation, and hospitalization due to heart failure. Group A consisted of 27 patients and group B, 39 patients. At diagnosis, group A had significantly higher brain natriuretic peptide (BNP), cardiothoracic ratio, PA pressure, and pulmonary vascular resistance index compared with group B. The number of patients with New York Heart Association (NYHA) functional class III and IV was significantly higher in group A than in group B. Cumulative event-free survival rate was significantly lower in group A.

Conclusions:MPA dilatation correlated with BNP, NYHA functional class, and hemodynamics with regard to disease severity, and may be a potential prognostic factor in pediatric idiopathic and heritable PAH.

Background:The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment.

Methods and Results:This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjögren’s syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants.

Conclusions:Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short- and long-term outcomes.

Background:This study aimed to determine the incidence, characteristics and management of venous thromboembolism (VTE) in Japan during 2011.

Methods and Results:A retrospective study assessed responses to a questionnaire regarding treating newly diagnosed VTE at all admitting hospitals throughout Japan during 2011. More individuals were diagnosed with VTE than ever before, with 16,096 cases of diagnosed pulmonary embolism (PE) and 24,538 cases of diagnosed deep vein thrombosis (DVT). Almost half (47.2%) of the PE patients had a relatively mild condition with no right ventricular overload. Similarly, almost half (43.8%) of the DVT patients had a relatively mild condition with isolated calf thrombus. Most of PE patients were treated by anticoagulation, and fewer were treated using thrombolytic agent or inferior vena cava (IVC) filter.

Conclusions:The present study showed a remarkable increase in the incidence of VTE in Japan during 2011. Relatively mild conditions such as non-massive PE and isolated calf DVT were frequently diagnosed. Among PE patients, thrombolytic therapy or IVC filter implantation decreased compared with previous surveys. The appropriate management of isolated calf DVT requires further investigation.

Background:Multilineage differentiating stress-enduring (Muse) cells are SSEA3⁺and CD105⁺double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling.

Methods and Results:In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 μL) than in the CAD (167±89 cells/100 μL) and Control (164±125 cells/100 μL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase.

Conclusions:Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.

Background:Prior studies have shown an association between high blood urea nitrogen (BUN) and an elevated risk of mortality in heart failure patients, but data on the prognostic significance of BUN and other markers of kidney function in acute ischemic stroke (AIS) patients are sparse.

Methods and Results:A total of 3,355 AIS patients were enrolled from December 2013 to May 2014, across 22 hospitals. Admission BUN was divided into quartiles (Q1, <4.39 mmol/L; Q2, ≥4.39 and <5.40 mmol/L; Q3, ≥5.40 and <6.70 mmol/L and Q4, ≥6.70 mmol/L) and estimated glomerular filtration rate (eGFR), creatinine (Cr) and BUN/Cr were also categorized. Cox proportional hazard and logistic regression models were used to estimate the effect of BUN, eGFR, Cr and BUN/Cr on all-cause in-hospital mortality and poor outcome on discharge (modified Rankin Scale score ≥3) in AIS patients. During hospitalization, 120 patients (3.6%) died from all causes and 1,287 (38.4%) had poor outcome at discharge. BUN was independently associated with all-cause in-hospital mortality (adjusted HR for Q4 vs. Q1, 3.75; 95% CI: 1.53–9.21; P-trend=0.003) but not poor outcome at discharge (P-trend=0.229). No significant association was found, however, between reduced eGFR, increased Cr and BUN/Cr and all-cause in-hospital mortality and poor outcome at discharge (all P-trend ≥0.169).

Conclusions:Increased BUN at admission is a significant prognostic factor associated with in-hospital mortality in AIS patients, but not with poor discharge outcome.

Background:There is a consensus that overactivation of the cardiac sympathetic nervous system (CSN) proportionately increases the severity of heart failure and is accompanied by worse prognosis. Because it is unknown whether patients with aortic valve stenosis (AS) have similar CSN activation, we investigated the effect of transcatheter aortic valve implantation (TAVI).

Methods and Results:We enrolled 31 consecutive patients with AS treated by TAVI. ¹²³I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy was performed at baseline and at 2 weeks after TAVI. At baseline, the early heart-mediastinum ratio (H/M) was within normal limits (3.0±0.5), but the delayed H/M was low (2.6±0.6) and the washout rate (WR) was high (34±13%). WR negatively correlated with aortic valve area (r=−0.389, P<0.01) and cardiac output (r=−0.595, P<0.01) and positively correlated with norepinephrine (r=0.519, P<0.01) and log NT-proBNP level (r=0.613, P<0.01). After TAVI, there were significant decreases in the norepinephrine level (366±179 ng/mL vs. 276±125 ng/mL, P<0.01) and WR (34±13 vs. 26±11%, P<0.01).

Conclusions:The WR of MIBG was a useful marker of CSN activity and severity of AS. Immediate improvement of CSN activity after TAVI implied that AS hemodynamics per se enhanced CSN.

Background:The aim of this study was to assess the echocardiographic characteristics of chronic hemodialysis (HD) patients with end-stage renal disease (ESRD) in a multicenter prospective cohort study.

Methods and Results:Three hundred and fifteen patients with ESRD (67.9±10.6 years, 47.6% male) on chronic HD for ≥1 year were examined on transthoracic echocardiography, including Doppler-derived aortic valve area (AVA) measurement. Only 11.5% and 3.4% of all patients had normal left ventricular (LV) geometry and normal LV filling pattern, respectively. The majority of patients had aortic and mitral valvular calcification, and approximately 50% of all 315 patients had aortic valve narrowing with AVA <2.0 cm². Patients were divided into 3 groups according to AVA index tertile: group 1, highest tertile; group 2, middle tertile; and group 3, lowest tertile. Group 3 was older, had a greater cardiothoracic ratio on chest X-ray, higher plasma brain natriuretic peptide and total LV afterload, and lower stroke volume index than the other 2 groups. Age and intact parathyroid hormone (PTH) level were independently associated with low AVA index.

Conclusions:Patients with ESRD on chronic HD have a high prevalence of cardiac structural and functional abnormalities including calcified aortic sclerosis. High age and PTH were associated with aortic valve narrowing in these patients.

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.