Improvements in the long-term survival of cancer patients have led to growing awareness of the clinical importance of cancer therapeutics-related cardiac dysfunction (CTRCD), which can have a considerable effect on the prognosis and quality of life of cancer patients and survivors. Under such circumstances, onco-cardiology/cardio-oncology has emerged as a new discipline, with the aim of best managing cardiovascular complications, including CTRCD. Despite the recent accumulation of epidemiological and clinical information regarding CTRCD, the molecular mechanisms underlying the pathogenesis of CTRCD by individual drugs remain to be determined. To achieve the goal of preventing cardiovascular complications in cancer patients and survivors, it is important to elucidate the pathogenic mechanisms and to establish diagnostic strategies with risk prediction and mechanism- and evidence-based therapies against CTRCD.

Background:The purpose of this study was to elucidate the effect of the temporal relationship between atrial fibrillation (AF) and heart failure (HF) on clinical outcomes after catheter ablation.

Methods and Results:We included 129 consecutive patients with AF and HF who underwent catheter ablation in hospital from December 2014 to September 2017. The patients were divided into 2 groups based on the temporal relationship between AF and HF. Group 1 consisted of 42 patients with AF following HF while Group 2 consisted of 87 patients with AF preceding HF or those who developed both of them simultaneously at the timing of first visit to a doctor. The primary endpoint was a composite of death and hospitalization due to HF during a 2-year follow-up. AF recurrence was more common in Group 1 (45% vs. 23%; hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.25–4.94; P=0.009). Death and HF hospitalization were more frequent in Group 1 (19 [45%], 6 [7%] patients, respectively, P<0.0001). After adjustment for several covariates, patients in Group 1 were independently associated with poorer outcomes after AF ablation (HR, 8.66; 95% CI, 2.942–5.5; P<0.0001).

Conclusions:Adverse clinical outcomes of death, HF hospitalization and AF recurrence were more frequent in patients with AF following HF than in those with AF preceding HF.

Background:In the Japanese clinical setting, the prevalence, potential cofounders of gastrointestinal (GI) bleeding from anticoagulant therapy, including direct oral anticoagulants (DOACs) and warfarin, and prognosis after GI bleeding are unclear.

Methods and Results:We examined about GI bleeding from anticoagulant therapy using data from the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 48.8% (n=1,561) were warfarin users and 51.2% (n=1,676) DOAC users. GI bleeding was identified in 68 patients (2.1%). No incidental differences in GI bleeding were observed between the DOAC and warfarin users (32 [1.9%] patients [0.67 events per 100 person-years] vs. 36 [2.3%] patients [0.75 events per 100 person-years], respectively; P=0.43). Multivariate Cox proportional hazard model analysis revealed that creatinine (hazard ratio [HR] 1.379, 95% confidence interval [CI] 1.091–1.743 P=0.007) and hemoglobin (HR 0.814, 95% CI 0.705–0.941, P=0.005) remained independent determinants of GI bleeding. Patients experiencing GI bleeding events had a higher risk of all-cause death (18%) than those without GI bleeding (6%) (P=0.045).

Conclusions:GI bleeding was strongly associated with anemia and renal impairment. Patients experiencing GI bleeding had higher risk for all-cause death than those without GI bleeding.

Background:There is a scarcity of data on short-duration dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy as compared with aspirin monotherapy after percutaneous coronary intervention (PCI).

Methods and Results:STOPDAPT-1 is a prospective trial enrolling patients who agreed to 3-month DAPT followed by aspirin monotherapy after everolimus-eluting stent (EES) implantation. STOPDAPT-2 is a randomized trial comparing 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT after EES implantation. We compared the clinical outcomes of patients assigned to the 1-month DAPT group in STOPDAPT-2 and the 3-month DAPT group enrolled in STOPDAPT-1. The current study population consisted of 1,480 patients in STOPDAPT-2 and 1,339 patients in STOPDAPT-1. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis and TIMI major/minor bleeding. Cumulative 1-year incidence of the primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 (2.3% vs. 2.3%, P=0.98). After adjusting for confounders, there was no excess risk of STOPDAPT-2 relative to STOPDAPT-1 for the primary endpoint. Between 3 and 12 months, the cumulative incidence of primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 (1.7% vs. 1.6%, P=0.77).

Conclusions:The effect of 1-month DAPT followed by clopidogrel monotherapy on clinical outcomes was similar to that of 3-month DAPT followed by aspirin monotherapy in patients receiving PCI.

Background:Although mitral valve repair is recommended over replacement due to better outcomes, repair rates vary significantly among centers. This study examined the effect of institutional mitral valve repair volume on postoperative mortality.

Methods and Results:All cases of adult mitral valve repair performed in Korea between 2009 and 2016 were analyzed. The association between case volume and 1-year mortality was analyzed after categorizing centers according to the number of mitral valve repairs performed as low-, medium-, or high-volume centers (<20, 20–40, and >40 cases/year, respectively). The effect of case volume on cumulative all-cause mortality was also assessed. In all, 6,041 mitral valve repairs were performed in 86 centers. The 1-year mortality in low-, medium-, and high-volume centers was 10.1%, 8.7%, and 4.7%, respectively. Low- and medium-volume centers had increased risk of 1-year mortality compared with high-volume centers, with odds ratios of 2.80 (95% confidence interval [CI] 2.15–3.64; P<0.001) and 2.66 (95% CI 1.94–3.64; P<0.001), respectively. The risk of cumulative all-cause mortality was also worse in low- and medium-volume centers, with hazard ratios of 1.96 (95% CI 1.68–2.29; P<0.001) and 1.77 (95% CI 1.47–2.12; P<0.001), respectively.

Conclusions:Lower institutional case volume was associated with higher mortality after mitral valve repair. A minimum volume standard may be required for hospitals performing mitral valve repair to guarantee adequate outcome.

Background:Although there is an increase in the use of mechanical circulatory support devices to rescue patients with acute myocardial infarction (AMI) complicated by refractory cardiogenic shock (CS), the optimal timing of the application remains controversial. Therefore, this study aimed to compare the clinical outcomes between venoarterial-extracorporeal membrane oxygenation (VA-ECMO) insertion before and after coronary revascularization in AMI patients with refractory CS.

Methods and Results:A total of 253 patients with AMI who underwent revascularization therapy with VA-ECMO were included. The study population was stratified into extracorporeal cardiopulmonary resuscitation (E-CPR) before revascularization (N=106, reference cohort) and refractory CS without E-CPR before revascularization (n=147, comparison cohort). Patients with refractory CS but without E-CPR before revascularization were further divided into VA-ECMO before revascularization (N=50) and VA-ECMO after revascularization (n=97). The primary endpoint was a composite of in-hospital mortality, left ventricular assist device implantation, and heart transplantation. The primary endpoint occurred in 60 patients (40.8%) of the comparison cohort and 51 patients (48.1%) of the reference cohort. Among the comparison cohort, the primary endpoint was significantly lower in VA-ECMO before revascularization than in VA-ECMO after revascularization (32.0% vs. 49.5%, OR 0.480, 95% CI 0.235–0.982, P=0.045). A similar trend was observed after a 1-year follow up.

Conclusions:Early initiation of VA-ECMO before revascularization therapy might improve clinical outcomes in patients with AMI complicated by refractory CS.

Background:Characteristics and treatment outcomes of acute myocardial infarction (AMI) patients have been studied; however, those of recent myocardial infarction (RMI) patients remain unclear. This study aimed to clarify characteristics, treatment strategy, and in-hospital outcomes of RMI patients in the Tokyo CCU network database.

Methods and Results:In total, 1,853 RMI and 12,494 AMI patients from the Tokyo CCU network database during 2013–2016 were compared. Both RMI and AMI were redefined by onset times of 2–28 days and ≤24 h, respectively. The RMI group had a higher average age (70.4±12.9 vs. 68.0±13.4 years, P<0.001), more women (27.6% vs. 23.6%, P<0.001), lower proportion of patients with chest pain as the chief complaint (75.2% vs. 83.6%, P<0.001), higher prevalence of diabetes mellitus (35.9% vs. 31.0%, P<0.001), and higher mechanical complication incidence (3.0% vs. 1.5%, P<0.001) than did the AMI group. Thirty-day mortality was comparable (5.3% vs. 5.8%, P=0.360); major causes of death were cardiogenic shock and mechanical complications in the AMI and RMI groups, respectively. Death from mechanical complications (not onset time) in the AMI group plateaued almost 1 week after hospitalization, whereas it continued to increase in the RMI group.

Conclusions:Both RMI and AMI patients have distinctive clinical features, sequelae, and causes of death. Although treatment of RMI patients adhered to guidelines, it was insufficient, and death from mechanical complications continues to increase.

Background:The increase in stroke volume during inotropic stimulation in patients with heart failure with reduced ejection fraction (HFrEF) is called the “pump function reserve.” Few studies have reported on the relationship between pump function reserve and HF prognosis. In HFrEF patients who have pump function reserve, stroke volume increases during exercise. Simply put, the pulse pressure change (∆PP) during cardiopulmonary exercise testing (CPX) is closely related to the prognosis of patients with HFrEF. We hypothesized that ∆PP could predict disease severity and cardiovascular death in patients with HFrEF.

Methods and Results:A total of 224 patients with HFrEF who underwent symptom-limited maximal CPX between 2012 and 2016 were enrolled. During a median follow-up of 1.5 years, cardiovascular death occurred in 54 participants (24%). Patients who died demonstrated a lower ∆PP between rest and peak exercise (∆PP [peak−rest]) than those who survived (P<0.001). Cox regression analyses revealed that ∆PP, slope of the relationship between minute ventilation and carbon dioxide production, and B-type natriuretic peptide level were independent predictors of cardiovascular death in patients with HFrEF (P=0.001, 0.021, and <0.001, respectively).

Conclusions:∆PP (peak−rest) can accurately predict cardiovascular death in patients with HFrEF and may be a useful new prognostic indicator in these patients.

Background:In Japan, the long-term care insurance (LTCI) system has an important role in helping elderly people, but there have been no clinical studies that have examined the relationship between the LTCI and prognosis for patients with acute heart failure (HF).

Methods and Results:This registry was a prospective multicenter cohort, 1,253 patients were enrolled and 965 patients with acute HF aged ≥65 years were comprised the study group. The composite endpoint included all-cause death and hospitalization for HF after discharge. We divided the patients into 4 groups: (i) patients without LTCI, (ii) patients requiring support level 1 or 2, (iii) patients with care level 1 or 2, and (iv) patients with care levels 3–5. The Kaplan-Meier analysis identified a lower rate of the composite endpoint in group (i) than in the other groups. After adjusting for potentially confounding effects using a Cox proportional regression model, the hazard ratio (HR) of the composite endpoint increased significantly in groups (iii) and (iv) (adjusted HR, 1.62; 95% confidence interval [CI], 1.22–1.98 and adjusted HR, 1.62; 95% CI, 1.23–2.14, respectively) when compared with group (i). However, there was no significant difference between groups (i) and (ii).

Conclusions:The level of LTCI was associated with a higher risk of the composite endpoint after discharge in acute HF patients.

Background:Right ventricular dysfunction (RVD) in the setting of left ventricular (LV) myocardial damage is a major cause of morbidity and mortality, and the pulmonary artery pulsatility index (PAPi) is a novel hemodynamic index shown to predict RVD in advanced heart failure. However, it is unknown whether PAPi can predict the long-term prognosis of dilated cardiomyopathy (DCM) even in the mild to moderate phase. This study aimed to assess the ability of PAPi to stratify DCM patients without severe symptoms.

Methods and Results:Between April 2000 and March 2018, a total of 162 DCM patients with stable symptoms were evaluated, including PAPi, and followed up for a median of 4.91 years. The mean age was 50.9±12.6 years and the mean LV ejection fraction (EF) was 30.5±8.3%. When divided into 2 groups based on median value of PAPi (low, L-PAPi [<3.06] and high, H-PAPi [≥3.06]), even though there were no differences in B-type natriuretic peptide or pulmonary vascular resistance, the probability of cardiac event survival was significantly higher in the L-PAP than in the H-PAP group by Kaplan-Meier analysis (P=0.018). Furthermore, Cox’s proportional hazard regression analysis revealed that PAPi was an independent predictor of cardiac events (hazard ratio: 0.782, P=0.010).

Conclusions:Even in patients identified with DCM in the mild to moderate phase, PAPi may help stratify DCM and predict cardiac events.

Background:Determinants of poor outcome in atherosclerotic cardiovascular disease (ASCVD) according to left ventricular ejection fraction (LVEF) are unclear. The renal resistive index (RRI) correlates well with atherosclerotic vascular damage, which, in turn, is correlated with cardiovascular outcomes. This study investigated whether high RRI is associated with poor cardiovascular outcomes in ASCVD patients classified by LVEF.

Methods and Results:Records of 1,598 acute coronary syndromes (ACS) and acute decompensated heart failure (ADHF) patients, categorized into preserved (p), mid-range (mr), and reduced (r) ejection fraction (EF) groups (EF ≥50% [n=1,130], 40–50% [n=223], and <40% [n=245], respectively), were analyzed retrospectively. The primary endpoint was any cardiovascular-related event: fatal and non-fatal ACS, ADHF, stroke, and sudden cardiac death. Over 1.9-years follow-up (3,030 person-years), 233 events occurred: 122, 37, and 74 in the pEF, mrEF, and rEF groups, respectively. Adjusted Cox regression analysis revealed RRI ≥0.8 was associated with the primary endpoint in the pEF group (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.09–2.56), but not in the mrEF or rEF groups. The primary endpoint risk of pEF patients with an RRI ≥0.8 was comparable to that of mrEF patients using the pEF+RRI <0.8 group as the reference (HR 1.89 [95% CI 1.26–2.83] and 1.77 [95% CI 1.19–2.63], respectively).

Conclusions:RRI was associated with the risk of cardiovascular events in ASCVD patients with pEF.

Background:Interruption in Doppler intrarenal venous flow (IRVF) has been used in assessing renal congestion and in the prediction of prognosis of cardiovascular diseases. However, there is a paucity of pathophysiological knowledge, so we aimed to clarify the determinants of IRVF interruption.

Methods and Results:Intrarenal Doppler studies were performed within 24 h before right-side catheterization studies. The interruption in IRVF in 73 patients was divided into a continuous pattern, and 4 discontinuous types based on the timing of interruption. Type 1, with an interruption in early systole, was associated with a-wave elevation of right atrial pressure (RAP). Type 2, with an interruption in early diastole, was associated with v-wave elevation, tricuspid regurgitation (TR), and right ventricular dysfunction. Both Type 1 and 2 were observed even in the normal range of mean RAP. Type 3, with an interruption throughout systole, was observed in advanced right heart failure patients with markedly elevated RAP, particularly elevated x-descend and atrial fibrillation. Finally, Type 4, with limited flow at systole, was observed in 2 of the patients with pulmonary arterial hypertension.

Conclusions:IRVF interruption was closely related to RAP elevation at each specific point of the cardiac cycle rather than to mean RAP levels, suggesting that the characteristics of IRVF mirror right-sided heart hemodynamics, not mean RAP.

Background:The Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria have been suggested as the standard definition of HBR. However, the prevalence of individual criteria and their prognostic value for long-term bleeding events after percutaneous coronary intervention are scarcely studied.

Methods and Results:The study population comprised 1,193 patients treated with everolimus-eluting stents between 2010 and 2011. Data on all 17 major and minor criteria of the ARC-HBR definition were retrospectively collected, and applied to this study population. Major bleeding was defined as the occurrence of a BARC type 3 or 5 bleeding event. A simplified definition was developed by excluding the low-frequency criterion, and the prognostic value was assessed by a receiver-operating characteristic curve. Mean follow-up was 2,996±433 days and there were 656 HBR patients (55.0%). The cumulative incidence of major bleeding was significantly higher in the HBR group than in the non-HBR group (16.2% vs. 5.7% at 8 years, P<0.001). The frequencies of 6 of the 17 criteria were less than 1%. The prognostic value of the simplified definition made by excluding these 6 criteria for major bleeding was comparable to that of the original (c-statistic=0.598 and 0.600, P=0.08).

Conclusions:Some risk criteria of the ARC-HBR definition are observed infrequently. Our simplified definition identified patients with long-term bleeding risk as successfully as the original definition.

Background:Stent thrombosis (ST) is a serious complication after drug-eluting stents (DES) implantation. To identify the risk factors of mortality following ST, we evaluated adverse event reports used for safety measures after approval.

Methods and Results:Between July 2004 and August 2019, 2,887 ST case reports were submitted to the Pharmaceutical and Medical Device Agency. Reports of probable or possible ST (n=604), with insufficient data regarding in-hospital outcome or duration between procedure and ST occurrence (n=37) or duplicate reports (n=191) were excluded. Accordingly, 2,045 reports with definite ST were analyzed. Among the subjects, there were 286 in-hospital deaths (14.0%). Multivariate logistic regression analysis revealed that left main trunk (LMT) (odds ratio [OR]: 4.76, 95% confidence interval [CI]: 3.26–6.96), chronic heart failure (CHF) (OR: 2.88, 95% CI: 1.61–5.14), hemodialysis (OR: 2.69, 95% CI: 1.66–4.36), prior stroke (OR: 2.28, 95% CI: 1.15–4.51), over 70 years old (OR: 1.62, 95% CI: 1.22–2.16), and right coronary artery (OR: 0.41, 95% CI: 0.27–0.63) were independent factors for in-hospital death after DES-ST.

Conclusions:LMT, CHF, hemodialysis, prior stroke, and older age were independently associated with higher risk of in-hospital death following DES-ST. If target patients have these factors, maximum preventive strategies against ST occurrence, including adequate dual-antiplatelet therapy duration and optimal DES deployment procedures, are required.

Background:The association between cytochrome P450 (CYP) 2C19 genotypes and adverse events in patients treated with clopidogrel or prasugrel after percutaneous coronary intervention (PCI) in the Japanese population is unclear.

Methods and Results:This study consisted of 1,580 patients whoseCYP2C19genotypes were assessed at Shiga University of Medical Science Hospital, and 193 clopidogrel-treated and 217 prasugrel-treated patients who were followed more than 1 year after receiving PCI were analyzed. Among 1,580 patients, the prevalence of normal, intermediate, and poor metabolizers was 32%, 49%, and 17%, respectively. Overall incidence of the primary outcome, defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic stroke, or major bleeding was not significantly different between the clopidogrel and prasugrel groups (adjusted hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.85–4.61, P=0.12). Among patients with theCYP2C19loss-of-function (LOF) allele, however, the incidence of the primary outcome was significantly higher in the clopidogrel group (adjusted HR 3.19, 95% CI 1.10–9.24, P=0.03), whereas no difference was observed among patients without theCYP2C19LOF allele (adjusted HR 0.67, 95% CI 0.14–3.26, P=0.62).

Conclusions:Among patients with theCYP2C19LOF allele, the use of clopidogrel was significantly associated with increased adverse events. Thus, further investigation is needed to establish the practical use ofCYP2C19genotyping.

Background:Dual antiplatelet therapy is commonly used for patients with acute coronary syndrome (ACS). This study aimed to evaluate the safety and efficacy of aspirin and prasugrel at standard dosages in Korean patients using clinical outcome data.

Methods and Results:For this prospective multicenter phase IV post-marketing surveillance (PMS) study, ACS patients from 29 July 2012 to 28 July 2016 were recruited. Patients received aspirin at a dose of 75–150 mg daily and a standard dose of prasugrel. Bleeding events were recorded and summarized to evaluate safety. Data on adverse events (AEs) and composite events such as cardiovascular (CV) death, myocardial infarction (MI), and stroke were recorded and summarized to assess efficacy. Of the 3,283 patients recruited, data from 3,110 and 3,044 patients were included in the safety and efficacy analyses, respectively (median treatment duration, 172 days). The most frequently reported AE was ecchymosis (2.8%). The number of patients with major bleeding was 29/3,110 (0.93%). The discontinuation rate for any reason was 12.6%. The number of cases that ended in CV death, MI, stroke, stent thrombosis, or unplanned coronary revascularization was 26/3,044 (0.85%).

Conclusions:The present results are similar to those observed in clinical trials where administration of low-dose aspirin plus prasugrel was associated with a low rate of major bleeding and CV events.

Background:G protein coupled receptor kinase 2 (GRK2) inhibitor, paroxetine, has been approved to ameliorate diabetic cardiomyopathy (DCM). GRK2 is also involved in regulating T cell functions; the potential modifications of paroxetine on the immune response to DCM is unclear.

Methods and Results:DCM mouse was induced by high-fat diet (HFD) feeding. A remarkable reduction in the regulatory T (Treg) cell subset in DCM mouse was found by flow cytometry, with impaired cardiac function evaluated by echocardiography. The inhibited Treg differentiation was attributable to insulin chronic stimulation in a GRK2-PI3K-Akt signaling-dependent manner. The selective GRK2 inhibitor, paroxetine, rescued Treg differentiation in vitro and in vivo. Furthermore, heart function, as well as the activation of excitation-contraction coupling proteins such as phospholamban (PLB) and troponin I (TnI) was effectively promoted in paroxetine-treated DCM mice compared with vehicle-treated DCM mice. Blockade of FoxP3 expression sufficiently inhibited the proportion of Treg cells, abolished the protective effect of paroxetine on heart function as well as PLB and TnI activation in HFD-fed mice. Neither paroxetine nor carvedilol could effectively ameliorate the metabolic disorder of HFD mice.

Conclusions:The impaired systolic heart function of DCM mice was effectively improved by paroxetine therapy, partially through restoring the population of circulating Treg cells by targeting the GRK2-PI3K-Akt pathway.

Background:Transcatheter aortic valve replacement (TAVR) has been performed more and more frequently in elderly patients with aortic stenosis. We investigated the association of in-hospital availability of TAVR on outcomes of surgical aortic valve replacement (SAVR) in the era of TAVR.

Methods and Results:We utilized data from the Japan Adult Cardiovascular Surgery Database. Between October 2013 and December 2016, 9,330 patients aged ≥80 years underwent isolated SAVR or SAVR with coronary artery bypass grafting in 557 centers in Japan. We assessed the associations of in-hospital TAVR availability with operative mortality and composite complications adjusting for each patient’s characteristics, JapanSCORE predicted the risk scores, and hospital volumes of SAVR using generalized estimation equation methods. Observed operative mortality rates were 3.4% in all centers, 2.0% in TAVR centers and 4.0% in non-TAVR centers. The multivariable analyses showed that TAVR centers had statistically significantly lower operative mortality compared with non-TAVR centers among all patients (odds ratio 0.60, 95% confidence interval 0.41–0.89, P=0.01) and among intermediate/high-risk patients (odds ratio 0.52, 95% confidence interval 0.32–0.85, P<0.01) but not among low-risk patients (odds ratio 0.82, 95% confidence interval 0.44–1.51, P=0.52).

Conclusions:In-hospital TAVR availability was associated with better outcomes of SAVR among elderly patients. This association was statistically significant among intermediate/high-risk patients but not significant among low-risk patients.