Background: Selecting an appropriate cannula size is crucial for achieving an adequate extracorporeal membrane oxygenation (ECMO) flow rate. However, the association between ECMO cannula size and the prognosis of patients with out-of-hospital cardiac arrest (OHCA) has not been fully elucidated. We examined the associations between ECMO cannula size and neurological outcomes and survival at discharge in patients with OHCA who received ECMO.

Methods and Results: This is a secondary analysis of the Study of Advanced life support for Ventricular fibrillation with Extracorporeal circulation in Japan (SAVE-J II study). The primary and secondary outcomes were favorable neurological outcomes and survival at discharge, respectively. In all, 918 patients were included in the analysis. There were no statistically significant differences between cannula sizes and neurological outcomes. Multivariable analysis showed that increasing body weight (BW)-adjusted sizes of arterial cannulas (odds ratio [OR] 1.04 per 0.01-Fr/kg increase; 95% confidence interval [CI] 1.01–1.07; P=0.011) and venous cannulas (OR 1.04 per 0.01-Fr/kg increase; 95% CI 1.01–1.06; P=0.005) were significantly associated with the survival rate at discharge. Increasing BW-adjusted sizes of arterial cannulas were significantly associated with cannulation site bleeding.

Conclusions: There were no significant associations between favorable neurological outcomes and cannula size, whereas larger-sized arterial and venous cannulas were significantly associated with higher survival rates at discharge in patients with OHCA who received ECMO.

Time-space network hypertension is a data science approach that connects diverse information related to hypertension within a time-space framework. This field of academic research aims to predict disease onset and direct effective, individualized, optimized treatments by integrating and analyzing the variability of multiple internal biological and external environmental signals as they relate to blood pressure variability across different time phases. By linking time series changes in blood pressure and biological distribution with multi-environmental and physiological information, enabled by advances in digital technology, the time-space network hypertension approach contributes to “digital hypertension” research. This article from Jichi Medical University provides an update on research relating to the time-space network hypertension approach, which is designed to progress hypertension management towards achieving net zero cardiovascular events.

Background: Although sudden cardiac death (SCD) generally occurs more frequently in men than in women, there are limited data on sex differences in SCD in patients with chronic heart failure (HF) across a range of left ventricular ejection fraction (LVEF).

Methods and Results: We examined sex differences in SCD incidence, timing, and risk factors in 4,683 patients with chronic HF (3,186 men, 1,497 women) from a multicenter prospective observational cohort study (CHART-2). Over a median follow-up of 8.8 years after study enrollment, there were 215 SCDs (160 in men, 55 in women). The SCD incidence rates in men and women were 6.1 and 4.6 per 1,000 person-years, respectively (P=0.088). Among women, more than half the SCDs occurred in the first 5 years of follow-up. Beyond 5 years, the SCD incidence rate was significantly lower in women than in men (3.6 vs. 5.9 per 1,000 person-years, respectively; P=0.044). After adjusting for confounders, age, increased B-type natriuretic peptide, and LVEF <50% were common prognostic factors. After 5 years of follow-up, left ventricular (LV) enlargement was a risk factor for SCD in both sexes.

Conclusions: These results indicate that there are sex differences in SCD, especially beyond 5 years of follow-up, with a lower prevalence in women. LV enlargement is a common long-term prognostic factor in both sexes, suggesting the importance of preventing LV remodeling in HF management.

Background: Selexipag, an oral prostacyclin (PGI₂) receptor agonist, is approved for adult patients with pulmonary arterial hypertension (PAH). This study evaluated the efficacy and safety of selexipag for Japanese pediatric patients with PAH.

Methods and Results: The study enrolled 6 patients who received selexipag twice daily at an individualized dose based on body weight; maintenance doses were determined for each patient by 12 weeks after starting administration. Efficacy, including pulmonary hemodynamics, was evaluated after 16 weeks, and efficacy and safety were further evaluated 52 weeks after treatment was initiated in the last enrolled patient. The mean (±SD) change in the pulmonary vascular resistance index from baseline to Week 16 (the primary endpoint of the study) was −5.55±6.88 Wood units·m²; improvements were also seen in other pulmonary hemodynamic parameters. The 6-min walk distance increased and N-terminal pro-B-type natriuretic peptide decreased up to Week 64, but the between-subject variability was large. The World Health Organization functional class was improved in 1 of 6 patients at Week 16 and in 2 of 4 patients at Week 64. No patient worsened. The major side effects of selexipag were those characteristic of PGI₂, and the safety profile of selexipag was similar to that in adult patients.

Conclusions: The efficacy and safety of selexipag in Japanese pediatric patients with PAH were demonstrated.

Background: Previous randomized clinical trials did not support a benefit of screening for occult cancer after diagnosis of venous thromboembolism (VTE), although screening may be of potential benefit for selected high-risk patients.

Methods and Results: The COMMAND VTE Registry-2 enrolled consecutive patients with acute symptomatic VTE between 2015 and 2020 from 31 centers across Japan. The 3,706 patients in the registry without known active cancer at the time of VTE diagnosis were divided into 2 groups: those with (n=250) and without (n=3,456) newly diagnosed cancer during the follow-up period. The cumulative incidence of newly diagnosed cancer was 1.5% at 30 days, 3.7% at 1 year, and 7.0% at 3 years. The multivariable Cox proportional hazard model demonstrated that older age (hazard ratio [HR] 1.02 per 1 year increase; 95% confidence interval [CI] 1.01–1.03; P<0.001), a history of cancer (HR 3.57; 95% CI 2.73–4.64; P<0.001), autoimmune disorders (HR 1.48; 95% CI 1.06–2.02; P=0.02), a history of major bleeding (HR 1.64; 95% CI 1.04–2.48; P=0.04), and the absence of transient provoking risk factors for VTE (HR 1.44; 95% CI 1.08–1.92; P=0.01) were independently associated with newly diagnosed cancer.

Conclusions: The incidence of newly diagnosed cancer after VTE diagnosis was 3.7% at 1 year, and several independent risk factors for newly diagnosed cancer after VTE diagnosis were identified.

Background: There is a paucity of data on safety of calcium channel blockers (CCB) in patients with severe aortic stenosis (AS) and hypertension.

Methods and Results: Among 2,460 patients with severe AS and hypertension receiving antihypertensive therapy in the CURRENT AS registry-2, we compared the clinical outcomes between patients taking antihypertensive therapy with CCB (CCB group) and without CCB (no CCB group). In the entire study population, CCB was prescribed in 1,763 patients (71.7%), which was the most commonly prescribed antihypertensive agents. The prescription rates of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and thiazides were 61.9%, 25.6%, and 7.3% in the CCB group, and 75.8%, 54.4%, and 6.0% in the no CCB group. In the propensity score matched cohort, the cumulative 3-year incidence of all-cause death or hospitalization for heart failure was not different between the CCB and no CCB groups (38.3% vs. 38.7%, log-rank P=0.65; HR, 0.94; 95%CI, 0.77–1.15; P=0.56). The cumulative 3-year incidence of syncope was low regardless of CCB prescription (1.1% vs. 1.0%, P=0.74).

Conclusions: Among patients with severe AS and hypertension, CCB was the most commonly prescribed antihypertensive agents, and antihypertensive therapy with CCB was associated with comparable clinical outcomes to antihypertensive therapy without CCB. Syncope was rarely seen in patients with severe AS and hypertension receiving antihypertensive therapy regardless of CCB prescription.

Background: The association between blood urea nitrogen (BUN) levels and incident heart failure (HF) in the general population is still unclear.

Methods and Results: We assessed the association of BUN level with incident HF in 14,167 ARIC participants without a history of HF at baseline (1987–1989) (mean age 54.1 years, 54.4% female, 25.2% Black). BUN levels (mg/dL) were divided into quartiles, with the highest quartile further divided into tertiles (Q1 ≤13, Q2 13–15, Q3 15–17, Q4a 17–19, Q4b 19–21, Q4c >21). HF events were identified through to December 31, 2019, using diagnostic codes on discharge records or death certificates. Hazard ratios (HRs) were estimated using multivariable Cox models. During a median follow-up of 26.2 years, 3,482 participants developed HF (incidence rate 10.7 per 1,000 person-years). In a multivariable Cox model adjusted for sociodemographic variables, the highest BUN quartile (Q4) had a HR of 1.19 (95% confidence interval [CI] 1.09, 1.31) compared with Q1. HRs for Q4a, Q4b, and Q4c were 1.14 (95% CI 1.02, 1.28), 1.11 (0.96, 1.28), and 1.42 (1.22, 1.63), respectively. After further adjustment for clinical factors, the association remained significant for Q4c (HR 1.23 [1.06, 1.43]). Associations were consistent across demographic and clinical subgroups.

Conclusions: In this community-based cohort, higher BUN levels were significantly associated with incident HF. BUN, routinely measured in clinical care, may help identify individuals at risk of HF.

Background: This study aimed to identify risk factors associated with the implementation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with acute myocarditis and to develop a predictive model.

Methods and Results: This retrospective study included 841 patients from 7 hospitals in Korea with biopsy-proven or clinically suspected acute myocarditis. Logistic regression analysis was used to identify the clinical characteristics of patients who required VA-ECMO and to construct a scoring system to predict the implementation of VA-ECMO. Among the study population, 217 (25.8%) patients underwent VA-ECMO. The study population was divided into training (n=621) and testing (n=220) cohorts according to participating center. The final predictive model of VA-ECMO insertion derived from the training cohort included the following: initial mean blood pressure <65 mmHg, cardiac arrest, Glasgow Coma Scale score ≤12, platelet count <100×10³/mL, pulmonary congestion on chest X-ray, QRS interval ≥120 ms, left or right bundle branch block, and left ventricular ejection fraction <40%. Using this predictive model, a β coefficient-weighted Korean Acute Myocarditis (KAM) score was developed. External validation of the predictive model and KAM score using the testing cohort showed excellent discriminant ability (areas under the curve of 0.945 and 0.921, respectively).

Conclusions: A risk scoring system based on simple clinical and laboratory parameters at initial presentation could predict the implementation of VA-ECMO and clinical course in patients with acute myocarditis.

Medicine, and human healing more generally, have been constantly evolving for millennia as part of humanity’s persistent efforts to heal its injuries and diseases, to maintain wellbeing, and to delay the inevitable: death. The philosophy underlying medicine has always been closely intertwined with the prevailing ideas in each historical period. Prejudices, religious beliefs, even magical herbs, as well as rational thought and advanced sciences, make up the fabric of over 2,000 years of western medicine. Hippocrates (460–377 BC), a physician from ancient Greece, is considered the father of western medicine. Almost 2,000 years later, Andreas Vesalius (1514–1564), by being the first to explore anatomical dissections of humans, significantly challenged the views of Galen, thus ushering in modern medicine, which, by the mid-19th century, had evolved into clinical medicine, a holistic approach that remains relevant today. The rapid advances in artificial intelligence, and more broadly in digital health, are shifting clinical medicine towards a new perspective, that of metaclinical medicine, where human doctors will need to work closely with non-human physicians, delegating a significant part of their traditional role in diagnosis and treatment. This article outlines the existing realities regarding the role of artificial intelligence in diagnosing various diseases, and speculates on the collaboration between human and non-human physicians in the metaclinical era.

Background: Transcatheter closure of paravalvular leak (PVL) has become an established treatment for patients at prohibitive surgical risk. However, few studies have examined the feasibility of transcatheter closure using Amplatzer occluders in Japanese patients with mitral PVL.

Methods and Results: Twelve patients (mean [±SD] age 78±7 years) with heart failure, hemolytic anemia, or both after surgical mitral prosthetic valve replacement (mechanical valve, 75%) underwent transcatheter PVL closure with Amplatzer Vascular Plug II (AVP-II)/Amplatzer Duct Occluder II (ADO-II) between 2014 and 2021 at Toho University Ohashi Medical Center. We examined procedural, in-hospital, 30-day, and 1-year outcomes. All procedures were performed under general anesthesia using an antegrade transseptal approach, and the procedures were successful in all cases. The mean (±SD) number of Amplatzer occluders deployment per patient was 2.9±1.1, and in 2 patients the combined use of ADO-II was required. The mitral PVL grade decreased notably from 3+ to 1+, with residual PVL being mild or absent in 9 patients. There were no all-cause mortalities, major adverse events, or device-related complications at the 30-day follow-up. At 1 year, all-cause mortality was 16.7% and 3 (25%) patients required reintervention because of the recurrence of clinical symptoms.

Conclusions: Our findings suggest that transcatheter PVL closure with AVP-II/ADO-II can be feasible and safe in Japanese patients with mitral PVL, leading to satisfactory early clinical outcomes.

Background: Vascular complications are common and can be fatal even after successful decannulation in patients with peripherally cannulated veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Therefore, we aimed to accurately determine the incidence of arterial complications assessed by Duplex ultrasound following peripheral VA-ECMO decannulation. In addition, we investigated the predictors of severe complications requiring intervention.

Methods and Results: We retrospectively reviewed 1,350 adult patients who underwent ECMO between January 2012 and April 2023. Of 839 patients treated with peripherally cannulated VA-ECMO, 596 were successfully weaned off and 212 underwent Duplex ultrasound for final analysis. The primary outcome was arterial complications requiring vascular intervention. Thirty-three (15.6%) patients experienced such complications after decannulation. Acute limb ischemia due to thrombotic occlusion was the most common complication, occurring in 23 (10.8%) patients, followed by stenosis (3.8%), pseudoaneurysm (3.8%), arteriovenous fistula (0.9%), and dissection (0.9%). No significant differences in complication rates were found between the percutaneous and surgical decannulation groups in the propensity score-matched population (12.7% vs. 15.9%, respectively; P=0.799). Multivariable analysis revealed disseminated intravascular coagulation (DIC; odds ratio 2.6; 95% confidence interval 1.17–5.69; P=0.019) as the only predictor of arterial complications after decannulation.

Conclusions: Arterial complications requiring vascular intervention frequently occur following successful weaning from VA-ECMO regardless of the decannulation strategy. In this setting, DIC appears to be associated with an increased rate of arterial complications.

Takayasu arteritis (TAK) is classified as a large vessel vasculitis and often causes vascular stenosis, occlusion, and aneurysm formation. Although the principal treatment for TAK involves suppressing inflammation with glucocorticoids, the emergence of biological disease-modifying antirheumatic drugs has considerably changed the treatment landscape of TAK in recent years. Several biological disease-modifying antirheumatic drugs, such as tocilizumab (TCZ), have shown promising effects on TAK in clinical studies. Cardiologists and cardiovascular surgeons encounter patients receiving these drugs who require catheterization, endovascular treatment, or cardiovascular surgery. However, in patients treated with glucocorticoids and TCZ, there needs to be greater awareness of more complications than usual after surgery, such as delayed wound healing, systemic infection, and surgical site infection. In addition, in patients receiving TCZ, inflammatory markers, such as C-reactive protein, may not increase when complications arise from infection. Unfortunately, there are no guidelines or solid evidence that have clearly defined the optimal perioperative treatment strategy for patients with TAK who require cardiovascular surgery. This article reviews the evidence and our recent experience supporting the perioperative use of TCZ, and proposes a protocol that can reduce complications in patients with TAK undergoing invasive cardiovascular treatment.

Background: Our study investigated the prognostic impacts of the interval between collapse and the initiation of cardiopulmonary resuscitation (CPR), and subsequent intervals to defibrillation or epinephrine administration, on 30-day favorable neurological outcomes following out-of-hospital cardiac arrest (OHCA).

Methods and Results: This nationwide population-based cohort study used the All Japan Utstein Registry, encompassing OHCA patients in Japan between January 2006 and December 2021. The primary outcome was 30-day favorable neurological outcomes, defined as Cerebral Performance Category 1 or 2. Three-dimensional plots and multivariable logistic regression models were used to assess the time-dependent prognostic impacts of prehospital CPR interventions. In all, 184,731 OHCA patients (86,246 with shockable rhythm and 98,485 with non-shockable rhythm) were included in the study. Three-dimensional plots revealed that the interval between collapse and initiation of CPR, and subsequent intervals to defibrillation or epinephrine, were independently associated with 30-day favorable neurological outcomes in the groups with shockable and non-shockable rhythms, respectively (P<0.05 for all).

Conclusions: Among patients with witnessed OHCA, there was a dose-response relationship between delays in the collapse-CPR initiation interval, and subsequent intervals to defibrillation or epinephrine administration, and 30-day favorable neurological outcomes. Our findings provide valuable insights into OHCA management.

Background: The short-term mortality associated with veno-arterial extracorporeal membrane oxygenation combined with the Impella device (termed ECPELLA) for acute myocardial infarction complicated by cardiogenic shock (AMI-CS) remains unclear.

Methods and Results: The Japanese Registry for Percutaneous Ventricular Assist Devices (J-PVAD) includes data on all patients treated with an Impella in Japan. We extracted data for 922 AMI-CS patients who underwent ECPELLA support and conducted an exploratory analysis focusing on 30-day mortality. The median age of patients was 69 years, and 83.8% were male. The overall 30-day mortality was 46.1%. Factors associated with mortality included age >80 years, in-hospital cardiac arrest, systolic blood pressure <90 mmHg, serum creatinine >1.5 mg/dL, and serum lactate >4.0 mmol/L. In patients aged >80 years with any of these factors, mortality was significantly higher than in those without, ranging from 57.5% to 64.9%. The J-PVAD score assigns 1 point per predictor, with a C-statistic of 0.620 (95% confidence interval 0.586–0.654). The 30-day mortality was 20.0% for a J-PVAD score of 0, increasing to 70.0% for a score of 5.

Conclusions: The J-PVAD data indicate high short-term mortality in AMI-CS patients treated with ECPELLA, particularly among older patients. Further studies are needed to validate this risk stratification in this patient subset.

Background: The ONCO DVT study demonstrated potential benefits of extended edoxaban treatment in patients with isolated distal deep vein thrombosis in terms of thrombotic risk. However, the risk-benefit balance in patients with anemia remains unclear.

Methods and Results: This prespecified subgroup analysis included 601 patients, divided into anemia (n=402) and no-anemia (n=199) groups. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) or VTE-related death. Anemia was defined as hemoglobin <12 g/dL for women and <13 g/dL for men. In the anemia subgroup, the primary endpoint occurred in 3 (1.5%) and 17 (8.4%) patients in the 12- and 3-month edoxaban treatment groups, respectively (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05–0.58), compared with 0 and 5 (4.9%) patients, respectively, in the no-anemia subgroup (P interaction=0.997). Major bleeding occurred in 26 (13.1%) and 17 (8.4%) patients with anemia in the 12- and 3-month edoxaban treatment groups, respectively (OR 1.64; 95% CI 0.86–3.14), compared with 2 (2.1%) and 5 (4.9%) patients without anemia (OR 0.67; 95% CI 0.26–1.73; P interaction=0.13).

Conclusions: Regardless of the presence of anemia, edoxaban treatment for 12 months was superior to treatment for 3 months in reducing thrombotic events, whereas the risk of major bleeding did not differ significantly between the 2 treatment groups.

Background: Possible etiologies of out-of-hospital cardiac arrest (OHCA), including aortic dissection, ruptured aortic aneurysms, and pulmonary embolism, may be classified as non-cardiac causes. We investigated whether cardiac and non-cardiac OHCAs increased following the Kumamoto earthquake and whether the impact on OHCAs extended to regions far from the epicenter.

Methods and Results: We prospectively analyzed a nationwide registry of patients who experienced OHCAs between January 2013 and December 2019. Data from cases registered in 7 prefectures, including Kumamoto (Kyushu region; n=82,060), in the All-Japan Utstein Registry were analyzed for OHCAs of cardiac and non-cardiac origin. The numbers of OHCAs before and after the Kumamoto earthquake were compared using an interrupted time series analysis. The incidence of both cardiac (rate ratio [RR] 1.22) and non-cardiac (RR 1.27) OHCAs in Kumamoto Prefecture increased after the earthquake. The difference disappeared when the analysis was limited to patients with non-cardiac OHCAs with a clear cause of cardiac arrest. The number of cardiac and non-cardiac OHCAs did not increase in other prefectures within the Kyushu region.

Conclusions: The Kumamoto earthquake led to an increase in the incidence of cardiac and non-cardiac OHCAs. However, this was attenuated by increasing distance from the epicenter. Except for cardiac causes, cases complicated by earthquake-related events may include non-cardiac OHCAs due to vascular diseases that might be overlooked.

Background: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.

Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0–9.6%]) in the home treatment group and in 2 patients (1.8% [0.0–4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0–9.6%]), and 2 patients (3.0% [0.0–7.2%]) required hospitalization due to bleeding events.

Conclusions: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.