Selection of patients with atherosclerotic carotid stenosis for revascularization is mainly based on the degree of luminal narrowing of the carotid artery. However, identification of other features of plaque apart from the degree of stenosis could enable better selection for intervention if they are also associated with the occurrence of stroke. Before these risk factors can possibly play a role in treatment decisions, their prognostic value needs to be proven. The purpose of this narrative review is to summarize current knowledge regarding the risk factors for stroke in patients with carotid stenosis, how they can be determined, and to what extent they predict stroke, based on recent literature. References for this review were identified by searches of PubMed between 1995 and October, 2016 and references from relevant articles. For each topic in this review different relevant search terms were used. The main search terms were ‘carotid stenosis’, ‘atherosclerosis’, ‘stroke risk’, and ‘vulnerable plaque’. Language was restricted to English. The final reference list was generated on the basis of relevance to the topics covered in this review.

Type A acute aortic dissection (AAD) is a serious cardiovascular emergency requiring urgent surgery. Timely accurate diagnosis is essential, but often challenging, because of the wide spectrum of clinical presentations. In patients with type A AAD, chest pain is the most common symptom; furthermore, ischemic ST-T changes such as ST-segment elevation or depression or negative T waves are frequently observed on presentation ECG. These clinical presentations of type A AAD are difficult to differentiate from those of acute coronary syndrome (ACS), which could lead to delayed diagnosis and treatment of type A AAD or misdiagnosis of ACS followed by inappropriate treatment. Of note, ischemic ST-T changes have been shown to be associated with poor outcomes in patients with type A AAD. Because ECG is simple, inexpensive, noninvasive, readily available, and rapidly interpretable at the time of presentation, risk stratification based on ECG findings is considered very useful clinically. ECG findings of type A AAD thus have clinically important diagnostic, therapeutic, and prognostic implications; however, the relationships among these factors remain poorly understood. We review the prevalence of ECG abnormalities, clinical features associated with such changes, and the prognostic importance in patients with type A AAD.

The 81^stAnnual Scientific Meeting of the Japanese Circulation Society was held in Kanazawa, Japan, on March 17–19, 2017 under a miraculously clear sky. The frontlines of healthcare and medicine are dramatically changing. Thus, “Cardiovascular Medicine for Next Generation” was chosen as the main theme of this meeting. The program was constructed around major identified issues, including renewal of our understanding of basic cardiovascular medicine, translational research, and preventive molecular medicine, all of which are anticipated to transcend the medical field over the next generation. Despite the provincial location, 15,672 participants, including more than 400 from overseas countries, attended the 3-day meeting, and there were in-depth discussions in the various sessions. In particular, to our great pleasure, Her Imperial Highness Princess Takamado kindly attended the opening ceremony and extended congratulations to us. The meeting successfully completed and we sincerely appreciate the great cooperation and support from all affiliates.

Background:Shocks delivered by implanted anti-tachyarrhythmia devices, even when appropriate, lower the quality of life and survival. The new SmartShock Technology^®(SST) discrimination algorithm was developed to prevent the delivery of inappropriate shock. This prospective, multicenter, observational study compared the rate of inaccurate detection of ventricular tachyarrhythmia using the SST vs. a conventional discrimination algorithm.

Methods and Results:Recipients of implantable cardioverter defibrillators (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) equipped with the SST algorithm were enrolled and followed up every 6 months. The tachycardia detection rate was set at ≥150 beats/min with the SST algorithm. The primary endpoint was the time to first inaccurate detection of ventricular tachycardia (VT) with conventional vs. the SST discrimination algorithm, up to 2 years of follow-up. Between March 2012 and September 2013, 185 patients (mean age, 64.0±14.9 years; men, 74%; secondary prevention indication, 49.5%) were enrolled at 14 Japanese medical centers. Inaccurate detection was observed in 32 patients (17.6%) with the conventional, vs. in 19 patients (10.4%) with the SST algorithm. SST significantly lowered the rate of inaccurate detection by dual chamber devices (HR, 0.50; 95% CI: 0.263–0.950; P=0.034).

Conclusions:Compared with previous algorithms, the SST discrimination algorithm significantly lowered the rate of inaccurate detection of VT in recipients of dual-chamber ICD or CRT-D.

Background:The current status and outcomes of direct oral anticoagulant (DOAC) use have not been widely evaluated in unselected patients with atrial fibrillation (AF) in the real world.

Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients who visited the participating medical institutions (n=80) in Fushimi, Kyoto, Japan. Follow-up data with oral anticoagulant (OAC) status were available for 3,731 patients by the end of November 2015. We evaluated OAC status and clinical outcomes according to OAC status. The number (incidence rate) of stroke/systemic embolism (SE) and major bleeding events during the median follow-up of 3.0 years was 224 (2.3%/year) and 177 (1.8%/year), respectively. After the release of DOAC, the prevalence of DOAC use increased gradually and steadily, and that of warfarin, DOAC and no OAC was 37%, 26% and 36%, respectively in 2015. On Cox proportional hazards modeling incorporating change in OAC status as a time-dependent covariate for stroke/SE and major bleeding events, use of DOAC compared with warfarin was not associated with stroke/SE events (HR, 0.95; 95% CI: 0.59–1.51, P=0.82) or major bleeding events (HR, 0.82; 95% CI: 0.50–1.36, P=0.45).

Conclusions:In real-world clinical practice, there were no significant differences in stroke/SE events or major bleeding events for DOAC compared with warfarin in patients with AF.

Background:Although paclitaxel-coated balloon (PCB) angioplasty is an effective procedure for in-stent restenosis (ISR) after coronary stenting, recurrent ISR after PCB angioplasty still occurs. The aim of this study was to evaluate the predictors of recurrent ISR after PCB angioplasty for ISR.

Methods and Results:A total of 157 ISR lesions treated with PCB angioplasty from January 2014 to May 2015 were retrospectively examined. Recurrent ISR was judged on 6-month follow-up angiography. Clinical, angiographic and procedural parameters were evaluated as possible predictors of recurrent ISR. Recurrent ISR occurred in 13.9% of lesions after PCB angioplasty. On multivariate analysis the following independent predictors of recurrent ISR were identified: (1) smaller acute gain after initial ballooning (OR, 3.06; 95% CI: 1.08–8.71; P=0.04); (2) geographic mismatch between PCB position and initial ballooning (OR, 5.59; 95% CI: 1.64–19.1; P=0.006); and (3) use of percutaneous transluminal coronary rotational atherectomy (PTCRA) at primary percutaneous coronary intervention (PCI; OR, 5.53; 95% CI: 1.89–16.2; P=0.002).

Conclusions:Optimal expansion at initial ballooning before PCB angioplasty and careful positioning of PCB are important technical tips to prevent recurrent ISR after PCB angioplasty. Recurrent ISR occurred more frequently in severely calcified lesions that required PTCRA at primary PCI.

Background:Both inflammation and malnutrition have been reported to be closely linked to atherosclerosis, especially in patients with chronic kidney disease (CKD). The combined effects of serum albumin and C-reactive protein (CRP) on clinical outcomes after percutaneous coronary intervention (PCI) were investigated.

Methods and Results:A total of 2,164 all-comer patients with coronary artery disease who underwent their first PCI and had data available for preprocedural serum albumin and hs-CRP levels between 2000 and 2011 were studied. Patients were assigned to 4 groups according to their median serum albumin and CRP levels (4.1 g/dL and 0.10 mg/dL, respectively). The incidence of major adverse cardiac events (MACE), including all-cause death and non-fatal myocardial infarction (MI), was evaluated. During a median follow-up period of 7.5 years, 331 cases of MACE (15.3%), including 270 deaths and 61 non-fatal MIs, occurred. Kaplan-Meier curves showed that the rates of MACE differed significantly among the groups (log-rank P<0.0001), even stratified by with or without CKD (both log-rank P<0.0001). After adjustment for established cardiovascular risk factors, low serum albumin with high CRP levels was associated with adverse cardiac events (hazard ratio 2.55, 95% confidence interval 1.72–3,88, P<0.0001, high albumin/low CRP group as reference).

Conclusions:The presence of both low serum albumin and high CRP levels conferred a synergistic adverse effect on the risk for long-term MACE in patients undergoing PCI.

Background:Clinical use of fractional flow reserve (FFR) has been rapidly increasing, but outcomes after FFR-based coronary intervention in Japanese daily clinical practice have not been well investigated.

Methods and Results:The prospective multicenter cardiovascular intervention therapeutics registry (CVIT)-DEFER enrolled consecutive patients for whom FFR measurement was clinically indicated. This study comprised 3,857 vessels in 3,272 patients. Lesions were categorized into 4 groups according to FFR result and revascularization strategy: group 1: FFR >0.8, and deferral of PCI (n=1992); group 2: FFR >0.8, then PCI (n=230); group 3: FFR ≤0.8, and deferral of PCI (n=506); and group 4: FFR ≤0.8, then PCI (n=1,129). The event rate for deferred lesions was significantly low compared with that for PCI lesions (3.5% vs. 6.6%; P<0.05). Vessel-related events occurred in 62 (3.1%), 11 (4.8%), 25 (4.9%), and 79 (7.0%) patients in groups 1, 2, 3, and 4, respectively. PCI for lesions in which FFR was >0.8 (group 2) showed no improvement in the event rate compared with a defer-strategy. On the other hand, deferred lesions with lower FFR values had a higher risk of vessel-related events.

Conclusions:A FFR-based revascularization strategy in daily clinical practice was safe with regard to vessel-related events.

Background:The efficacy of exercise training (ET) programs and its relationship with long-term clinical outcomes in advanced heart failure (HF) patients with high levels of B-type natriuretic peptide (BNP) remain uncertain.

Methods and Results:We studied 340 consecutive HF patients with ejection fraction (EF) <45% who completed a 3-month ET program. Patients with BNP ≥200 pg/mL (High-BNP, n=170) had more advanced HF characteristics, including lower EF (25.0±8.6% vs. 28.1±8.0%, P=0.0008), than those with BNP <200 pg/mL. In the High-BNP patients, peak oxygen uptake (V̇O₂) was significantly increased by 8.3±16.2% during the ET program, and changes in peak V̇O₂inversely correlated with changes in BNP (R=−0.453, P<0.0001) and changes in ventilatory efficiency (V̇E/V̇CO₂slope) (R=−0.439, P<0.0001). During a median follow-up of 46 months, patients in the upper tertile of changes in peak V̇O₂(≥13.0%), compared with those in the lower tertile (<1.0%), had lower rates of the composite of all-cause death or HF hospitalization (37.9% vs. 54.4%, P=0.036) and all-cause death (8.6% vs. 24.6%, P=0.056). In the multivariate analysis, change in peak V̇O₂was a significant independent predictor of the composite outcome and all-cause death.

Conclusions:Even among advanced HF patients with high BNP level, an ET program significantly improved exercise capacity, and a greater improvement in exercise capacity was associated with greater decreases in BNP level and V̇E/V̇CO₂slope and more favorable long-term clinical outcomes.

Background:Few studies have investigated the association between serum vitamin D levels and mortality in general Asian populations.

Methods and Results:We examined the association of serum 1,25-dihydroxyvitamin D (1,25(OH)₂D) levels with the risk of all-cause and cause-specific death in an average 9.5-year follow-up study of 3,292 community-dwelling Japanese subjects aged ≥40 years (2002–2012). The multivariable-adjusted hazard ratio (HR) for all-cause death increased significantly with lower serum 1,25(OH)₂D levels (HR 1.54 [95% confidence interval, 1.18–2.01] for the lowest quartile, 1.31 [0.99–1.73] for the 2nd quartile, 0.94 [0.70–1.25] for the 3rd quartile, 1.00 [Ref.] for highest quartile; P for trend <0.001). A similar association was observed for cardiovascular and respiratory infection death (both P for trend <0.01), but not for cancer death or death from other causes. In the stratified analysis, the association between lower serum 1,25(OH)₂D levels and the risk of respiratory infection death was stronger in subjects with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²than in those with eGFR ≥60 mL/min/1.73 m²; there was a significant heterogeneity in the association between eGFR levels (P for heterogeneity=0.04).

Conclusions:The findings suggested that a lower serum 1,25(OH)₂D level is a potential risk factor for all-cause death, especially cardiovascular and respiratory infection death, in the general Japanese population, and that lower serum 1,25(OH)₂D levels greatly increase the risk of respiratory infection death in subjects with kidney dysfunction.

Background:The development of both electrical reverse remodeling and mechanical reverse remodeling (ERR+MRR) after cardiac resynchronization therapy (CRT) implantation could reduce the incidence of lethal arrhythmia, hence the prediction of ERR+MRR is clinically important.

Methods and Results:Eighty-three patients (54 male; 67±12 years old) with CRT >6 months were enrolled. ERR was defined as baseline intrinsic QRS duration (iQRSd) shortening ≥10 ms in lead II on ECG after CRT, and MRR as improvement in LVEF ≥25% on echocardiography after CRT. Acute ECG changes were measured by comparing the pre-implant and immediate post-implant ECG. Ventricular arrhythmia episodes, including ventricular tachycardia and ventricular fibrillation, detected by the implanted device were recorded. Patients were classified as ERR only (n=12), MRR only (n=23), ERR+MRR (n=26), or non-responder (ERR− & MRR−, n=22). On multivariate regression analysis, difference between baseline intrinsic QRS and paced QRS duration (∆QRSd) >35 ms was a significant predictor of ERR+MRR (sensitivity, 68%; specificity, 64%; AUC, 0.7; P=0.003), and paced QTc >443 ms was a negative predictor of ERR+MRR (sensitivity, 78%; specificity, 60%; AUC, 0.7; P=0.002). On Cox proportional hazard modeling, ERR+MRR may reduce risk of ventricular arrhythma around 70% compared with non-responder (HR, 0.29; 95% CI: 0.13–0.65).

Conclusions:Acute ECG changes after CRT were useful predictors of ERR+MRR. ERR+MRR was also a protective factor for ventricular arrhythmia.

Background:Very little data is available to evaluate the gender-specific role of N-terminal pro-B type natriuretic peptide (NT-proBNP). This study was performed to investigate whether there is a gender difference in the prognostic value of NT-proBNP in patients hospitalized for heart failure (HF).

Methods and Results:A total of 2,280 patients hospitalized with HF (67.9±14.3 years, 50.9% women) from the nationwide registry database were analyzed. Composite events including all-cause mortality and HF readmission were assessed. During the mean follow-up period of 1,245±824 days, there were 1,067 cases of composite events (49.7%). NT-proBNP levels were significantly higher in patients with events than those without in both genders (P<0.001 for each). A higher NT-proBNP level was an independent predictor of events (highest vs. lowest tertile: hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.25–2.43; P=0.001) in men, even after controlling for potential confounders. However, NT-proBNP was not associated with the occurrence of composite events in women in the same multivariable analysis (P>0.05).

Conclusions:In patients with HF, the NT-proBNP level seems to be a more valuable marker in the prediction of long-term mortality and HF readmission in men than in women.

Background:Dynamic diurnal changes in 24-h ambulatory systolic blood pressure (SBP) are associated with increased cardiovascular risk. We compared ambulatory BP dynamics in Japanese and American black and white populations with treatment-resistant hypertension.

Methods and Results:Both HTN-Japan (n=41) and SYMPLICITY HTN-3 (n=384 white and n=140 black patients) enrolled patients with office SBP ≥160 mmHg and 24-h ambulatory SBP ≥135 mmHg while on ≥3 antihypertensive medications. Indices of circadian variation in ambulatory BP, including morning and nighttime dynamic surges, were retrospectively compared. All 3 cohorts had similar baseline office SBP. The Japanese cohort had significantly lower body mass index, less obstructive sleep apnea, and less hypercholesterolemia than the black and white cohorts, but significantly greater morning SBP levels, including moving peak morning SBP (183 vs. 169 vs. 169 mmHg, P<0.001), morning dynamic surge (37.9 vs. 28.6 vs. 24.2 mmHg, P<0.001) and nighttime dynamic surge (24.9 vs. 8.3 vs. 7.7 mmHg, P<0.001). These racial differences in SBP surge parameters persisted despite adjustment for baseline demographic population differences through multivariate regression.

Conclusions:Greater diurnal BP variability, including dynamic surges, in Japanese compared with black and white patients may indicate ethnic differences in the underlying BP regulatory mechanism of resistant hypertension. These differences may be important to take into consideration for more specific drug and device-based therapy strategies based on ethnicity.

Background:The association between the early repolarization pattern (ERP) and ventricular arrhythmias in patients with ST-segment elevation myocardial infarction (STEMI) remains uncertain. We hypothesized that ERP predicts the risk of sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) during the acute phase of anterior STEMI.

Methods and Results:We enrolled 1,460 consecutive patients with acute anterior STEMI. We identified an ERP-positive group and a 1:6 propensity-matched ERP-negative group of 183 and 471, respectively. Comparisons of sustained VT/VF, heart failure, major adverse cardiovascular events and all-cause death were based on Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression with adjustment for unmatched confounding factors. In our full matching propensity score cohorts, there were 8 out of 28 variables not matching between the 2 groups. The Kaplan-Meier curves showed ERP increased the risk of sustained VT/VF in 30 days (log-rank test P=0.00065). Adjusted for baseline unmatched confounding risk, the Cox hazards regression analysis showed sustained VT/VF was associated with the present of ERP (hazard ratio=2.915, 95% CI: 1.520–5.588, P=0.001).

Conclusions:In a propensity score-adjusted cohort the presence of ERP had a multivariable-adjusted association with increased risk of sustained VT/VF in patients with anterior STEMI in the early 30 days.

Background:In Ebstein’s anomaly (EA) current surgical criteria may not translate into better long-term survival. The aim of this study was therefore to determine if surgical treatment for EA increases survival, and to analyze factors associated with mortality.

Methods and Results:A retrospective study was carried out involving 103 patients with surgical indication using current criteria, comparing operated (n=49; 47.5%) and non-operated patients (n=54; 52.4%); the severity of disease was similar in all cases. Overall follow-up was 12 years (range, 1–49 years). There were no differences in mortality: in the surgical and non-surgical groups, survival at 10 years was 92.8% vs. 90.7%; 20 years, 85.7% vs. 81.0%; and 30 years, 78.5% vs. 72.2%, respectively. On multivariate analysis right ventricular fractional shortening (RVFS) was associated with mortality in both groups. Decreasing RVFS was associated with worse survival according to severity: when RVFS was <20%, survival at 20, 40 and 60 years was 58%, 39%, and 12.5%, respectively (P<0.0013). Left ventricular ejection fraction also correlated with survival (P<0.0013).

Conclusions:Surgery did not translate into benefit in terms of survival, and this was clearly associated with RV function; therefore this should be a key factor in the surgical decision making.

Background:Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.

Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm⁵(P<0.0001). For the secondary endpoint, the 6-min walk distance (6MWD) increased from 445.0±102.2 to 459.1±112.8 m (P=0.0324); World Health Organization functional class improved in 4 patients (12.1%), and was maintained in 29 patients (87.9%). A decrease in PVR was also shown in patients treated with selexipag, on top of a phosphodiesterase inhibitor and endothelin receptor antagonist. Most of the commonly reported adverse events were consistent with those reported for other PGI₂formulations. Thirty-four patients attained the individual maximum tolerated dose (maintenance dose).

Conclusions:The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].)