Echocardiography has a central role in the diagnosis and management of cardiovascular disease. Precise and reliable echocardiographic assessment is required for clinical decision-making. Even if the development of new technologies (3-dimentional echocardiography, speckle-tracking, semi-automated analysis, etc.), the final decision on analysis is strongly dependent on operator experience. Diagnostic errors are a major unresolved problem. Moreover, not only can cardiologists differ from one another in image interpretation, but also the same observer may come to different findings when a reading is repeated. Daily high workloads in clinical practice may lead to this error, and all cardiologists require precise perception in this field. Artificial intelligence (AI) has the potential to improve analysis and interpretation of medical images to a new stage compared with previous algorithms. From our comprehensive review, we believe AI has the potential to improve accuracy of diagnosis, clinical management, and patient care. Although there are several concerns about the required large dataset and “black box” algorithm, AI can provide satisfactory results in this field. In the future, it will be necessary for cardiologists to adapt their daily practice to incorporate AI in this new stage of echocardiography.

Background:Antiplatelet therapy is the corner stone of treatment following acute myocardial infarction (AMI). Prasugrel, a new and potent antiplatelet agent, was recently introduced to clinical practice. We compared the clinical outcomes of patients with AMI treated with prasugrel with those treated with clopidogrel in real-world clinical practice in Japan.

Methods and Results:The Japan AMI Registry (JAMIR) is a multicenter, nationwide, prospective registry enrolling patients with AMI from 50 institutes. Between December 2015 and May 2017, a total of 3,411 patients were enrolled. Among them, 3,069 patients were treated with either prasugrel (n=2,607) or clopidogrel (n=462) during hospitalization. Median follow-up period was 12 months. Prasugrel-treated patients were predominantly male, younger, more often showed ST-elevation AMI, and had fewer comorbidities. After adjustment using inverse probability of treatment weighting, the primary endpoint, defined as a composite of cardiovascular death, non-fatal MI and non-fatal stroke, was comparable between the prasugrel and clopidogrel groups (adjusted hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.67–1.72), whereas the risk of major bleeding (BARC type 3 or 5 bleeding) was significantly lower in the prasugrel group (adjusted HR 0.62, 95% CI 0.39–0.99).

Conclusions:The present real-world database of the JAMIR demonstrated that the potent P2Y12-inhibitor prasugrel showed comparable rates of 1-year ischemic events to clopidogrel, but the risk of bleeding was lower with prasugrel than with clopidogrel.

Background:Because the influence of digitalis use on the death of patients with non-valvular atrial fibrillation (NVAF) remains controversial, a subanalysis of the J-RHYTHM Registry was performed.

Methods and Results:A consecutive series of outpatients with AF from 158 institutions was enrolled and followed for 2 years or until the occurrence of an event. Among 7,406 patients with NVAF, 7,018 (age, 69.7±10.0 years; men, 71.1%) with information on antiarrhythmic drug and digitalis use at baseline were divided into 2 groups based on digitalis use. The influence of digitalis on death was investigated using a propensity score-matching model. In 802 patients treated with digitalis, all-cause death was significantly higher than in 6,216 patients with no digitalis use during the 2-year follow-up period (4.4% vs. 2.4%, unadjusted P<0.001). Digitalis use was significantly associated with all-cause death in the crude model (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.28–2.68, P=0.001). However, after propensity score-matching, the association was not significant (HR 1.31, 95% CI 0.70–2.46, P=0.405). Older age, male sex, heart failure, coronary artery disease, and lower body mass index were significantly associated with all-cause death in NVAF patients treated with digitalis.

Conclusions:Digitalis use was not independently associated with all-cause death, and several clinical confounding factors might contribute to increased mortality in NVAF patients treated with digitalis.

Background:Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging results in the treatment of atrial fibrillation (AF). This study sought to assess data on the safety, efficacy and clinical success of CB2-based PVI in patients with heart failure (HF) and reduced ejection fraction (HFrEF).

Methods and Results:CB2-based PVI was performed in 551 consecutive patients in 3 highly experienced EP centers. Patients with HF and LVEF ≤40% were included (HFrEF group, n=50/551, 9.1%). Data were compared with propensity score-matched patients without HF and preserved left ventricular EF (LVEF) (n=50, control group). The median LVEF was HFrEF: 37% (35, 40) and control: 55% (55, 55), P<0.0001. Major periprocedural complications were registered in 4/50 (8%, HFrEF group) and 3/50 (6%, control group), P=0.695. The 12-month freedom from AF recurrence was 73.1% (95% confidence interval (CI): 61–88, HFrEF group) and 72.6% (95% CI: 61–87, control group), P=0.25. NYHA class decreased from 2.4±0.8 (baseline) to 1.7±0.8 at 12-month follow-up (P<0.0001). LVEF improved from a median of 37% (35, 40) prior to ablation to a median of 55% (40, 55), P<0.0001.

Conclusions:CB2-based PVI in patients with HFrEF appeared to be safe, was associated with comparable periprocedural complications and showed promising clinical success rates equal to those for patients with preserved LVEF. NYHA class and LVEF significantly improved at 12-month follow-up.

Background:Balloon pulmonary angioplasty (BPA) is a percutaneous treatment option for patients affected by chronic thromboembolic pulmonary hypertension (CTEPH) and either judged inoperable or with persistent symptoms after pulmonary endoarteriectomy. Current data regarding BPA are sparse and results vary according to local center experience. A systematic review of the literature was performed to better understand the effectiveness and safety of BPA in the treatment of CTEPH.

Methods and Results:PubMed and EMBASE were searched for studies reporting BPA results in patients with CTEPH. Differences in clinical and hemodynamic parameters before and after the procedure were analyzed. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were calculated. In total, 14 studies were included (725 patients). BPA was associated with a reduction in mean pulmonary artery pressure (from 43 to 32.5 mmHg), reduction in pulmonary vascular resistance (from 9.94 to 5.06 Woods units), increase in cardiac index (from 2.35 to 2.62 L/min/m²), and improvement of 6-minute walking distance (from 345 to 442 m). Periprocedural mortality occurred in 2.1% of patients (95% CoI 0.8–4.1) while reperfusion and pulmonary vessel injuries occurred in 9.3% (95% CoI 3.1–18.4) and 2.3% (95% CoI 0.9–4.5) of total BPA sessions, respectively.

Conclusions:Our systematic review suggested that BPA for CTEPH patients was an effective and relatively safe treatment option.

Background:In 2018, Japan became the first country to have robotic cardiac surgery covered under the national health insurance. The number of patients undergoing robotic mitral valve (MV) repair has been estimated to increase remarkably, but no reports in Japan have yet described the outcomes of robotic MV repair. This study aimed to analyze the early clinical outcomes of patients undergoing totally endoscopic robotic MV repair (TERMVR) as a landmark national study for this procedure.

Methods and Results:A total of 213 patients (152 men; mean age, 55±11 years) underwent TERMVR during May 2014 to December 2018. Preoperative demographics, operative profiles, and postoperative outcomes, including follow-up echocardiography, were analyzed. Successful TERMVR was achieved in all patients. Operation, cardiopulmonary bypass, and aortic cross-clamp times were 192±49.8, 127±23.8, and 70.1±16.2 min, respectively. Intraoperative transfusion was performed in 20 patients (10%). There were no in-hospital deaths. All patients were alive during the median follow-up period of 255 days (interquartile range, 32.5–208 days). Freedom from recurrence of MR >grade 2+ was 97.3%, 95.0%, and 90.7% at 6, 12, and 24 months, respectively.

Conclusions:TERMVR is an effective and safe procedure with acceptable early postoperative outcomes.

Background:Although minimally invasive mitral valve surgery via a right minithoracotomy (MICS-mitral) is widely performed, no tool to evaluate its risk has been reported. We sought to establish MICS-mitral risk calculators using a national clinical database for selection of appropriate patients.

Methods and Results:Between 2008 and 2015, 3,240 patients (mean age 59±14 years, males 1,950) underwent a MICS-mitral procedure in Japan and were registered in a national clinical database. We examined mortality and composite outcome (operative mortality, stroke, reoperation for bleeding) using multivariate analysis, then developed a risk calculator for each using stepwise analysis. Operative mortality was 1.1% and the composite outcome rate was 5%. In multivariate analysis, risk factors for operative mortality were shown to be age, respiratory dysfunction, thoracic aortic disease, myocardial infarction, body mass index >30, NYHA class IV, moderate or severe aortic regurgitation, mitral valve replacement, multiple valve surgery, and annual cases <10. ROC curve analysis of our prediction formulas for mortality and composite outcome revealed an area under the curve for operative mortality of 0.877 (95% confidence interval: 0.82–0.94, P<0.01) and for composite outcome of 0.665 (95% confidence interval: 0.62–0.71, P<0.01).

Conclusions:We developed risk calculator formulas using risk factors associated with both operative mortality and composite outcome. The present risk calculator formula is useful for patient selection and may influence future applications for this procedure.

Background:This study assessed whether the dissemination of public-access defibrillation (PAD) at the population level is associated with an increase in neurologically favorable outcomes among patients experiencing ventricular fibrillation (VF) in public vs. residential locations in Japan.

Methods and Results:We enrolled adult patients with bystander-witnessed VF between 2013 and 2015. The primary outcome measure was 1-month neurologically favorable outcome defined by cerebral performance category 1 or 2. The number of survivors with neurologically favorable outcome attributed to PAD after VF arrest was estimated by location of arrest. A total of 16,252 adult patients with bystander-witnessed VF arrest were analyzed. In public locations, 29.3% (2,334/7,973) of out-of-hospital cardiac arrest (OHCA) patients received PAD, whereas 1.1% (89/8,279) of OHCA patients received PAD in residential locations. OHCA patients with PAD had significantly better neurological outcomes compared with those without PAD in public locations (51.8% vs. 25.5%, P<0.001), whereas there were no significant differences in neurologically favorable outcome between patients with or without PAD in residential locations (22.5% vs. 18.6%, P=0.357). The total number of patients with neurologically favorable outcomes attributed to PAD was estimated at 615 in public locations, but only 3 in residential locations.

Conclusions:In Japan, when compared with residential locations, PAD works more successfully in public locations for adults with bystander-witnessed VF arrest.

Background:This study aimed to identify potential predictors of medication adherence and persistence with statin-ezetimibe combinational lipid-lowering therapy (LLT) as a separate pill combination in a real-world setting in Japan.

Methods and Results:Patients newly switched to statin-ezetimibe combinational LLT from statin monotherapy were identified within a Japanese national pharmacy claims database during January 2015 to April 2018. Adherence and persistence were measured by the proportion of days covered (PDC), time to treatment discontinuation and persistence rate at 1 year. A stepwise multivariate logistic regression model and Cox proportional hazards regression model were used to explore potential predictors associated with adherence and persistence, respectively. Among 6,921 patients, 71.9% were adherent (PDC ≥80%), and 83.6% were persistent at 1 year after initiation. Patients aged ≤54 years and ≥75 years were prone to be more non-adherent. Secondary prevention was associated with better adherence and longer persistence. Concomitant use of medications for depression/anxiety was associated with shorter persistence, whereas use of antihypertensive drugs was associated with better adherence and persistence.

Conclusions:Age, concomitant use of certain classes of medications (or the existence of these diseases) and secondary prevention were associated with adherence and persistence of statin-ezetimibe combinational LLT. Given that dyslipidemia is a chronic disease requiring life-long control, active interventions are required for patients with poor adherence and persistence.

Background:A recent study revealed a high prevalence of transthyretin (TTR) cardiac amyloidosis (CA) in elderly patients. ^{99 m}Tc-labeled pyrophosphate (^{99 m}Tc-PYP) scintigraphy is a remarkably sensitive and specific modality for TTR-CA, but is only available in specialist centres; thus, it is important to raise the pretest probability. The aim of this study was to evaluate the characteristics of patients with ^{99 m}Tc-PYP positivity and make recommendations about patient selection for ^{99 m}Tc-PYP scintigraphy.

Methods and Results:We examined 181 consecutive patients aged ≥70 years who underwent ^{99 m}Tc-PYP scintigraphy at Kumamoto University Hospital between January 2012 and December 2018. Logistic regression analyses showed that high-sensitivity cardiac troponin T (hs-cTnT) ≥0.0308 ng/mL, left ventricular posterior wall thickness ≥13.6 mm, and wide QRS (QRS ≥120 ms) were strongly associated with ^{99 m}Tc-PYP positivity. We developed a new index for predicting ^{99 m}Tc-PYP positivity by adding 1 point for each of the 3 factors. The ^{99 m}Tc-PYP positive rate increased by a factor of 4.57 for each 1-point increase (P<0.001). Zero points corresponded to a negative predictive value of 87% and 3 points corresponded to a positive predictive value of 96% for ^{99 m}Tc-PYP positivity.

Conclusions:The combination of biochemical (hs-cTnT), physiological (wide QRS), and structural (left ventricular posterior wall thickness) findings can raise the pretest probability for ^{99 m}Tc-PYP scintigraphy. It can assist clinicians in determining management strategies for elderly patients with suspected CA.

Background:Heart failure (HF) and cancer (CA) are becoming increasingly prevalent as the population ages. We aimed to evaluate prior history and occurrence of CA and its prognostic impact on HF.

Methods and Results:Consecutive hospitalized HF patients (n=2,103) were divided into 2 groups according to prior history of CA: non-prior-CA group (n=1,828) and prior-CA group (n=275). Compared with the non-prior-CA group, the prior-CA group were older, and had higher prevalence of chronic kidney disease, anemia, and atrial fibrillation (P<0.05). In contrast, sex, other comorbidities, levels of natriuretic peptide and ejection fraction were comparable between groups. We focused on newly diagnosed CA after discharge for HF. In the follow-up period (median 623 days), 114 (6.2%) patients in the non-prior-CA and 17 (6.2%) patients in the prior-CA groups were newly diagnosed as having CA. Additionally, 83 (3.9%) CA-related patient deaths occurred (median 776 days). In the Kaplan-Meier analysis (median 1,037 days), not only all-cause death but also cardiac event rate was significantly higher in the prior-CA group than in the non-prior-CA group (log-rank P<0.01). In the Cox proportional hazard analysis, CA history was a predictor of cardiac event rate (HR 1.450, 95% CI 1.134–1.822), as well as all-cause death (HR 2.483, 95% CI 2.034–3.030).

Conclusions:Prior-CA history was associated with high cardiac event and mortality rates. CA is notable comorbidity in HF patients.

Background:The cardiopulmonary exercise test (CPX) is a tool for evaluating disease severity and limitations in activities of daily living in patients with cardiac disorders. However, few studies have evaluated the association between exercise oscillatory ventilation (EOV) severity and prognosis in heart failure (HF) patients with EOV. EOV severity can be evaluated by detecting endtidal CO₂pressure (PETCO₂, an indicator of the arterial partial pressure of CO₂(PaCO₂)) and minute ventilation, which is a reflection of the respiratory response to elevated CO₂. We hypothesized that the magnitude of EOV severity can predict the severity and prognosis of cardiac disorders and aimed to validate this hypothesis.

Methods and Results:In total, 2,043 patients who underwent symptom-limited maximal CPX between 2010 and 2016 were evaluated. We enrolled 70 patients who had HF with reduced ejection fraction (HFrEF) and EOV. The endpoint was cardiovascular death. During a median follow-up of 4.3 years, 34 participants died (48%). Those who died showed significantly larger EOV loop size and lower hemoglobin (Hb) levels than those who survived (17.3±7.0 cm²vs. 12.8±6.1 cm², P<0.001; 12.2±1.2 g/dL vs. 13.2±2.9 g/dL, P=0.004). Cox regression analyses revealed Hb levels and EOV loop size as independent predictors of cardiovascular death in HFrEF patients with EOV.

Conclusions:EOV loop size was associated with cardiovascular death of HFrEF patients with EOV.

Background:Withaferin A (WFA), an anticancer constituent of the plant Withania somnifera, inhibits tumor growth in association with apoptosis induction. However, the potential role of WFA in the cardiovascular system is little-studied and controversial.

Methods and Results:Two different doses of WFA were tested to determine their cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury through evaluation of cardiofunction in wild-type and AMP-activated protein kinase domain negative (AMPK-DN) gentransgenic mice. Surprisingly, cardioprotective effects (improved cardiac function and reduced infarct size) were observed with low-dose WFA (1 mg/kg) delivery but not high-dose (5 mg/kg). Mechanistically, low-dose WFA attenuated myocardial apoptosis. It decreased MI/R-induced activation of caspase 9, the indicator of the intrinsic mitochondrial pathway, but not caspase 8. It also upregulated the level of AMP-activated protein kinase (AMPK) phosphorylation and increased the MI/R inhibited ratio of Bcl2/Bax. In AMPK-deficient mice, WFA did not ameliorate MI/R-induced cardiac dysfunction, attenuate infarct size, or restore the Bcl2/Bax (B-cell lymphoma2/Mcl-2-like protein 4) ratio.

Conclusions:These results demonstrated for the first time that low-dose WFA is cardioprotective via upregulation of the anti-apoptotic mitochondrial pathway in an AMPK-dependent manner.

Background:Left ventricular non-compaction (LVNC) is a heritable cardiomyopathy characterized by hypertrabeculation, inter-trabecular recesses and thin compact myocardium, but the genetic basis and mechanisms remain unclear. This study identified novel LVNC-associated mutations inNOTCH-dependent genes and investigated their mutational effects.

Methods and Results:High-resolution melting screening was performed in 230 individuals with LVNC, followed by whole exome and Sanger sequencing of available family members. Dimerization of bone morphogenetic protein 10 (BMP10) and its binding to BMP receptors (BMPRs) were evaluated. Cellular differentiation, proliferation and tolerance to mechanical stretch were assessed in H9C2 cardiomyoblasts, expressing wild-type (WT) or mutant BMP10 delivered by adenoviral vectors. Rare variants, p.W143*-NRG1and p.V407I-BMP10, were identified in 2 unrelated probands and their affected family members. Although dimerization of mutant V407I-BMP10 was preserved like WT-BMP10, V407I-BMP10 pulled BMPR1a and BMPR2 receptors more weakly compared with WT-BMP10. On comparative gene expression and siRNA analysis, expressed BMPR1a and BMPR2 receptors were responsive to BMP10 treatment in H9C2 cardiomyoblasts. Expression of V407I-BMP10 resulted in a significantly lower rate of proliferation in H9C2 cells compared with WT-BMP10. Cyclic stretch resulted in destruction and death of V407I-BMP10 cells.

Conclusions:The W143*-NRG1and V470I-BMP10variants are associated with LVNC. Impaired BMPR-binding ability, perturbed proliferation and differentiation processes and intolerance to stretch in V407I-BMP10 mutant cardiomyoblasts may underlie myocardial non-compaction.

Background:There is limited information about the clinical profiles of patients with hypertrophic cardiomyopathy (HCM) and thromboembolic events in a community-based Japanese patient cohort.

Methods and Results:In 2004, we established a cardiomyopathy registration network in Kochi Prefecture that comprised 9 hospitals, and finally 293 patients with HCM were followed. The mean age at registration was 63±14 years, and 197 patients (67%) were men. At registration, 86 patients (29%) had documented atrial fibrillation (AF). During a mean follow-up period of 6.1±3.2 years, thromboembolic events, including 3 embolic stroke deaths, occurred in 23 patients. The 5-year embolic event rate was 5.5%. During the follow-up period, an additional 31 patients (11%) had documentation of AF and finally a total of 117 patients (40%) developed AF. The 5-year embolic event rate in those 117 patients with AF was 12.3%. Of the 23 patients with embolic events, 12 had AF prior to the embolic complications and another 6 had documented AF after thromboembolism. AF was not detected in the remaining 5 patients. The CHADS₂score did not correlate with the embolic outcome in HCM patients.

Conclusions:In this community-based registry, thromboembolic events were not rare in patients with HCM. All patients with HCM in whom AF develops should be given anticoagulation therapy regardless of their CHADS₂score.

Background:The purpose of this study was to investigate if the transcatheter aortic valve replacement (TAVR) risk score can independently predict outcomes following TAVR, and to evaluate its predictive performance.

Methods and Results:This retrospective multicenter study comprised 682 patients with severe aortic stenosis who underwent TAVR. The primary endpoint was all-cause death following TAVR. The clinical model was established using variables identified as independent predictors in the multivariate analysis. Incremental values were assessed after adding atrial fibrillation, body mass index (BMI), and serum albumin to the TAVR risk score in receiver-operating characteristic analysis. The median TAVR risk score was 2.1% with a mean follow-up of 505 days. On Kaplan-Meier analysis, a TAVR risk score >4% had lowest survival rate, whereas TAVR risk score ≤2% had the highest survival rate at 3 years (log-rank P<0.001). The multivariate Cox regression analysis found the TAVR risk score was independently associated with all-cause death, and demonstrated moderate predictive performance for predicting all-cause death at 3 years. However, if each independent predictor is added to the model, it significantly increased discriminatory performance, particularly with BMI and serum albumin level.

Conclusions:We demonstrated that the TAVR risk score could independently predict mid-term death following TAVR, and had greater predictive performance for predicting all-cause death at 3 years with BMI and serum albumin level.