Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Clinical outcomes and predictors of delayed echocardiographic response to cardiac resynchronization therapy.

INTRODUCTION: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. METHODS: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end-systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two-dimensional speckle-tracking radial strain analysis. RESULTS: Seventy-eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non-responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non-responders after 3 years. During the follow-up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non-responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036-1.222; p = .005), non-exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101-973.518; p = .044), and pre-QRS duration (OR: 0.901; 95% CI: 0.827-0.981; p = .016) were independent predictors of delayed response to CRT compared with early response. CONCLUSION: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre-QRS duration were related to delayed response than early response.

Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

Evaluation of microembolic signals on carotid ultrasound during pulmonary vein isolation with high-power short-duration and cryoballoon ablations: When and where do bubble and solid emboli arise?

INTRODUCTION: The underlying risks of asymptomatic embolization during high-power short-duration (HPSD) ablation for atrial fibrillation remain unclear. We aimed to evaluate microembolic signals (MESs) during HPSD ablation with power settings of 50 and 90 W in comparison with those during cryoballoon (CB) ablation using a novel carotid ultrasound-Doppler system that classifies solid and air bubble signals using real-time monitoring. METHODS AND RESULTS: Forty-seven patients underwent HPSD ablation using radiofrequency (RF), and 13 underwent CB ablation. MESs were evaluated using a novel pastable soft ultrasound probe equipped with a carotid ultrasound during pulmonary vein isolation. We compared the detailed MESs and their timing between RF and CB ablations. The number of MESs and solid signals were significantly higher in the RF group than in CB group (209 ± 229 vs. 79 ± 32, p = .047, and 83 ± 89 vs. 28 ± 17, p = .032, respectively). In RF ablation, the number of MESs, solid, and bubble signals per ablation point, or per second, was significantly higher at 90 W than at 50 W ablation. The MESs, solid, and bubble signals were detected more frequently in the bottom and anterior walls of the left pulmonary vein (LPV) ablation. In contrast, many MESs were observed before the first CB application and decreased chronologically as the procedure progressed. Signals were more prevalent during the CB interval rather than during the freezing time. Among the 28 patients, 4 exhibited a high-intensity area on postbrain magnetic resonance imaging (MRI). The MRI-positive group showed a trend of larger signal sizes than did the MRI-negative group. CONCLUSION: The number of MESs was higher in the HPSD RF group than in the CB group, with this risk being more pronounced in the 90 W ablation group. The primary detection site was the anterior wall of the LPV in RF and the first interval in CB ablation.

Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis.

Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial for improving patient outcomes and quality of life. Although HFpEF is the predominant heart failure type among older individuals, its prognosis is often poor owing to the lack of effective therapies. The roles of the spleen and bone marrow are often overlooked in the context of HFpEF. Recent studies suggest that the spleen and bone marrow could play key roles in HFpEF, especially in relation to inflammation and immune responses. The bone marrow can increase production of certain immune cells that can migrate to the heart and contribute to disease. The spleen can contribute to immune responses that either protect or exacerbate heart failure. Extramedullary hematopoiesis in the spleen could play a crucial role in HFpEF. Increased metabolic activity in the spleen, immune cell production and mobilization to the heart, and concomitant cytokine production may occur in heart failure. This leads to systemic chronic inflammation, along with an imbalance of immune cells (macrophages) in the heart, resulting in chronic inflammation and progressive fibrosis, potentially leading to decreased cardiac function. The bone marrow and spleen are involved in altered iron metabolism and anemia, which also contribute to HFpEF. This review presents the concept of an interplay between the heart, spleen, and bone marrow in the setting of HFpEF, with a particular focus on extramedullary hematopoiesis in the spleen. The aim of this review is to discern whether the spleen can serve as a new therapeutic target for HFpEF.

Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Hyperkalaemia-related reduction of RAASi treatment associates with more subsequent inpatient care.

BACKGROUND: Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and number of hospitalized days in patients with CKD and/or HF in Sweden and Japan. METHODS: Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASi who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity-score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD-, and HF-related hospitalized days per patient-year during 6 months before versus after index, and the number of days alive and out of hospital (DAOH) during 6 months post-index were described. RESULTS: Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization (95% confidence intervals) increased by 18.2 (17.0-19.2) days per person-year in Sweden and 17.9 (17.4-18.5) days per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 (8.6-10.4) and 8.5 (8.0-9.0) days per person-year, respectively, among patients with maintained RAASi treatment. Mean (standard deviation) DAOH were 121.5 (75.0) in Sweden and 141.7 (54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (51.3) and 157.5 (31.6) days, respectively, among patients with maintained RAASi treatment. CONCLUSION: Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained.

Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI.Methods and Results: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537-14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034-8.347; P=0.043) events. CONCLUSIONS: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.

The Balance of CD8-Positive T Cells and PD-L1 Expression in the Myocardium Predicts Prognosis in Lymphocytic Fulminant Myocarditis.

INTRODUCTION: The clinical significance and prognostic value of T cell involvement and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) have not been established in lymphocytic fulminant myocarditis (FM). We investigated the prognostic impact of the number of CD4+, CD8+, FoxP3+, and PD-1+ T cells, as well as PD-L1 expression, in cardiomyocytes in lymphocytic FM. METHODS: This is a single-center observational cohort study. Myocardial tissue was obtained from 16 consecutive patients at lymphocytic FM onset. The median follow-up was 140 days. Cardiac events were defined as a composite of cardiac death and left ventricular-assist device implantation. CD4, CD8, FoxP3, PD-1, and PD-L1 immunostaining were performed on myocardial specimens. RESULTS: The median age of the patients was 52 years (seven men and nine women). There was no significant difference in the number of CD4+ cells. The number of CD8+ cells and the CD8+/CD4+ T cell ratio were higher in the cardiac event group (Event+) than in the group without cardiac events (Event-) (p = 0.048 and p = 0.022, respectively). The number of FoxP3+ T cells was higher in the Event+ group (p = 0.049). Although there was no difference in the number of PD-1+ cells, cardiomyocyte PD-L1 expression was higher in the Event+ group (p = 0.112). Event-free survival was worse in the group with a high CD8+ cell count (p = 0.012) and high PD-L1 expression (p = 0.049). When divided into three groups based on the number of CD8+ cells and PD-L1 expression (CD8highPD-L1high [n = 8], CD8lowPD-L1high [n = 1], and CD8lowPD-L1low [n = 7]), the CD8highPD-L1high group demonstrated the worst event-free survival, while the CD8lowPD-L1high group had a favorable prognosis without cardiac events (p = 0.041). CONCLUSION: High myocardial expression of CD8+ T cells and PD-L1 may predict a poor prognosis in lymphocytic FM.

Cathepsin S activity controls chronic stress-induced muscle atrophy and dysfunction in mice.

Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS-/-) mice were randomly assigned to non-stress and variable-stress groups. CTSS+/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS+/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C2C12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

Clinical outcomes and risk factors associated with drug-coated balloon treatment for femoropopliteal artery disease in patients on maintenance hemodialysis.

The effect of drug-coated balloons (DCB) on hemodialysis (HD) in patients with femoropopliteal (FP) disease remains uncertain. This study aimed to investigate the outcomes of DCB therapy in patients with FP artery disease on HD. A total of 185 patients with FP lesions (140 HD patients) who underwent DCB treatment were included in the study. The incidence of restenosis and target lesion revascularization (TLR) at 12 months were measured. Risk factors for TLR were also investigated. The mean age was 71.7 years, and diabetes was observed in 82.3% of patients. The mean duration of receiving dialysis was 8.8 years. The mean lesion length was 11.0 cm, and approximately half of the lesions were severely calcified. Severe dissection after DCB therapy was observed in 19.5% of patients. During the follow-up period, 74 restenosis, 68 TLRs, 8 major amputations, and 28 deaths were observed. The freedom rates from restenosis and TLR at 12 months were 63.8% and 71.3%, respectively. The freedom rates after low- and high-dose DCB at 12 months were 61.9% and 70.6% for restenosis (P = 0.49) and 66.4% and 79.4% for TLR (P = 0.095), respectively. Independent risk factors for TLR at 12 months of age were diabetes, chronic limb-threatening ischemia, and severe calcification. When patients were divided into four groups according to the number of these three risk factors, the rates of freedom from TLR at 12 months were 100%, 94.8%, 76.7%, and 30.3% in the groups with no risk factors, any one risk factor, any two risk factors, and all risk factors, respectively (P < 0.0001). Clinical outcomes after endovascular therapy in HD patients with FP disease remain unsatisfactory, even if they are treated with DCB. In particular, patients on HD with diabetes, chronic limb-threatening ischemia, and severe calcification have poor outcomes.

Clinical features, future cardiac events, and prognostic factors following percutaneous coronary intervention in young female patients.

BACKGROUND: The proportion of young females among the patients who undergo percutaneous coronary intervention (PCI) is relatively small, and information on their clinical characteristics is limited. This study investigated the clinical characteristics and prognostic factors for future cardiac events in young females who underwent PCI. METHODS: This multicenter observational study included 187 consecutive female patients aged < 60 years who underwent PCI in seven hospitals. The primary composite endpoint was the incidence of cardiac death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The mean patient age was 52.1 ± 6.1 years and 89 (47.6%) had diabetes, and renal dysfunction (an estimated glomerular filtration rate < 60 mL/min/1.73 m2) was observed in 38 (20.3%). During a median follow-up of 3.3 years, the primary endpoint occurred in 28 patients. The Cox proportional hazards models showed that renal dysfunction was an independent predictor for the primary endpoint (hazard ratio 3.04, 95% confidence interval 1.25-7.40, p = 0.01), as well as multivessel disease (hazard ratio 2.79, 95% confidence interval 1.12-6.93, p = 0.03). Patients with renal dysfunction had a significantly higher risk for the primary endpoint than those without renal dysfunction. CONCLUSIONS: Renal dysfunction was strongly associated with future cardiac events in young females who underwent PCI.

Combined Prognostic Impact of Two Quick Frailty Assessments in Acute Heart Failure.

INTRODUCTION: We aimed to investigate the prognostic impact of frailty (defined by the Study of Osteoporotic Fracture [SOF] index and the Clinical Frailty Scale [CFS]) in hospitalized patients with acute decompensated heart failure (HF). METHODS: A total of 1,053 patients over 75 years of age, who were primarily admitted to hospital with a diagnosis of acute decompensated HF, were enrolled. The prognostic value of frailty by the two tools for predicting all-cause mortality was analyzed using multivariate Cox regression models. RESULTS: The incidence of frailty was 57.1% when using the SOF index, 37.6% when using the CFS, and 23.3% when using both tools. Frailty, via the SOF index or CFS, was an independent predictor of all-cause mortality in model 1, after adjustment for significantly associated factors by univariate analysis (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.04-1.84, p = 0.027; HR 1.53, 95% CI 1.15-2.05, p = 0.003, respectively), and in model 2, after adjustment for previously reported prognostic factors (HR 1.42, 95% CI 1.07-1.89, p = 0.015; HR 1.56, 95% CI 1.17-2.07, p = 0.002, respectively). Compared to non-frail patients, frail patients via both tools had a significantly higher incidence of all-cause mortality in models 1 (adjusted HR 2.16, 95% CI 1.42-3.29, p < 0.001) and 2 (adjusted HR 2.30, 95% CI 1.51-3.50, p < 0.001). CONCLUSIONS: Combined frailty screening using the SOF index and CFS contributed to stratify the risk of mortality in patients with acute decompensated HF.

Usefulness of bicarbonate-based Impella purge solution in a patient with heparin-induced thrombocytopenia: the first case report of long-term management in Japan.

Percutaneous mechanical circulatory support utilizing micro-axial flow pumps, such as the Impella group of devices, has become a life-saving technique in the treatment of refractory cardiogenic shock, with ever-increasing success rates. A 30-year-old man presented with acute decompensated heart failure and a severely reduced left ventricular ejection fraction (17%). Despite initial treatment with inotropic drugs and intra-aortic balloon pump support, his hemodynamic status remained unstable. Transition to Impella CP mechanical circulatory support was made on day 6 owing to persistently low systolic blood pressure. A significant decline in platelet count prompted suspicion of heparin-induced thrombocytopenia (HIT), later confirmed by positive platelet-activated anti-platelet factor 4/heparin antibody and a 4Ts score of 6 points. Argatroban was initially used as the purge solution, but owing to complications, a switch to Impella 5.0 and a bicarbonate-based purge solution (BBPS) was performed. Despite additional veno-arterial extracorporeal membrane oxygenation support on day 24, the patient, aiming for ventricular assist device treatment and heart transplantation, died from infection and multiple organ failure. Remarkably, the Impella CP continued functioning normally until the patient's demise, indicating stable Impella pump performance using BBPS. This case highlights the usefulness of BBPS as an alternative to conventional Impella heparin purge solution when HIT occurs.

Clinical Value of Troponin Levels to Cardiac Function and Prognosis in Patients with Fulminant Myocarditis.

Troponin (Tn) is a biomarker related to myocardial necrosis and is elevated in patients with myocarditis. This study aimed to investigate the association between cardiac Tn levels and the course of cardiac function, and prognosis in patients with fulminant myocarditis (FM) receiving percutaneous mechanical circulatory support (MCS).We used data from a multicenter retrospective registry, CHANGE PUMP 2, which included 216 patients with FM who required MCS. Among them, 141 patients whose Tn levels were available were analyzed. The patients were divided into low and high Tn groups according to the median values of TnT and TnI.The median age was 54 years, and 59.6% were male. The TnT and TnI on day 1 (at MCS initiation) were 3.8 (1.4-10.0) and 21.4 (8.4-68.8) ng/mL. While the left ventricular ejection fraction (LVEF) was similar on day 1 (25.0% versus 24.5%), the low Tn group showed better LVEF improvement on day 7 than the high Tn group (45.0% versus 25.3%, P < 0.001). LVEF at 1 year after admission was higher in the low Tn group (65.0% versus 59.7%, P = 0.039). The low Tn group had a better 90-day composite endpoint in death, durable left ventricular assist device implantation, and heart transplantation compared to the high Tn group (hazard ratio 0.47, 95% CI 0.23-0.95).Tn levels were associated with short- and long-term cardiac recovery and adverse outcomes in patients with FM receiving MCS due to cardiogenic shock.

Relationship between the volume of cases and in-hospital mortality in patients with cardiogenic shock receiving short-term mechanical circulatory support.

BACKGROUND: We examined the relationship between annual case volume at each hospital and outcome in cardiogenic shock (CS) patients receiving mechanical circulatory support (MCS) devices. METHODS: This cross-sectional study used the Japanese nationwide database to identify patients receiving short-term MCS for CS between April 2012 and March 2020. Of 65,837 patients, 3 subcohorts were created; the intra-aortic balloon pump (IABP) alone (n = 48,643), the extracorporeal membrane oxygenation (ECMO) (n = 16,871), and the Impella cohorts (n = 696). RESULTS: The median annual case volume was 13.5 (7.4-22.1) in the IABP alone cohort, 6.4 (3.4-11.0) in the ECMO cohort, and 7.5 (4.0-10.7) in the Impella cohort. The highest quintile for the volume of cases in the IABP alone and ECMO had the lowest in-hospital mortality (IABP alone, 25.1% in quintile 1 vs 15.2% in quintile 5; ECMO, 73.7% in quintile 1 in 67.4% in quintile 5). Adjusted ORs for in-hospital mortality decreased as case volume increased (IABP alone, 0.63 [0.58-0.68] in quintile 5; ECMO, 0.73 [0.65-0.82] in quintile 5, with the lowest quintile as reference) but did not decrease significantly in the Impella (0.90 [0.58-1.39] in tertile 3, with the lowest tertile as reference). In the continuous models with the case volume as a continuous variable, adjusted ORs for in-hospital mortality decreased to 28 IABP cases/year and 12 ECMO cases/year. They did not decrease or became almost flat above that. CONCLUSIONS: Higher volumes of IABP and ECMO are associated with a lower mortality. There is an upper limit to the decline. Centralizing patients with refractory CS in a particular hospital might improve patient outcomes in each region.

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan. METHODS: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction. RESULTS: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577. CONCLUSIONS: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

A novel practical algorithm using machine learning to differentiate outflow tract ventricular arrhythmia origins.

INTRODUCTION: Diagnosis of outflow tract ventricular arrhythmia (OTVA) localization by an electrocardiographic complex is key to successful catheter ablation for OTVA. However, diagnosing the origin of OTVA with a precordial transition in lead V3 (V3TZ) is challenging. This study aimed to create the best practical electrocardiogram algorithm to differentiate the left ventricular outflow tract (LVOT) from the right ventricular outflow tract (RVOT) of OTVA origin with V3TZ using machine learning. METHODS: Of 498 consecutive patients undergoing catheter ablation for OTVA, we included 104 patients who underwent ablation for OTVA with V3TZ and identified the origin of LVOT (n = 62) and RVOT (n = 42) from the results. We analyzed the standard 12-lead electrocardiogram preoperatively and measured 128 elements in each case. The study population was randomly divided into training group (70%) and testing group (30%), and decision tree analysis was performed using the measured elements as features. The performance of the algorithm created in the training group was verified in the testing group. RESULTS: Four measurements were identified as important features: the aVF/II R-wave ratio, the V2S/V3R index, the QRS amplitude in lead V3, and the R-wave deflection slope in lead V3. Among them, the aVF/II R-wave ratio and the V2S/V3R index had a particularly strong influence on the algorithm. The performance of this algorithm was extremely high, with an accuracy of 94.4%, precision of 91.5%, recall of 100%, and an F1-score of 0.96. CONCLUSIONS: The novel algorithm created using machine learning is useful in diagnosing the origin of OTVA with V3TZ.