Prevalence of bleeding events in real-world Japanese registry for Percutaneous Ventricular Assist Device.

PURPOSE: Bleeding complication is a critical risk factor for outcomes of acute heart failure patients requiring mechanical circulatory support (MCS), including percutaneous catheter-type heart pumps (Impella). The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) is an ongoing, large-scale, real-world registry to characterize Japanese patients requiring Impella. Here we analyzed bleeding complication profiles in patients who received Impella. METHODS: All consecutive Japanese patients who received Impella from October 2017 to January 2020 were enrolled. The 30-day survival and bleeding complications were analyzed. RESULTS: A total of 1344 patients were included: 653 patients received Impella alone, 685 patients received a combination of veno-arterial extracorporeal membrane oxygenation and Impella (ECPELLA), and 6 patients had failed Impella delivery. Overall 30-day survival was 67.0%, with Impella alone at 81.9% and ECPELLA at 52.7%. Overall bleeding/hematoma adverse events with a relation or not-excluded relation to Impella was 6.92%. Among them, the rates of hematoma and bleeding from medical device access sites were 1.41% and 4.09%, respectively. There was no difference between etiologies for these events. CONCLUSION: This study represents the first 3-year survival and the safety profile focused on bleeding adverse events from the J-PVAD registry. The results show that the real-world frequency of bleeding adverse events for patients who received Impella was an expected range from previous reports, and future real-world studies should aim to expand this data set to improve outcomes and adverse events.

Outcomes of Veno-Arterial Extracorporeal Membrane Oxygenation With Percutaneous Left Ventricular Unloading in Fulminant Myocarditis.

Fulminant myocarditis requiring peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has a high mortality rate. We investigated clinical outcomes of combined use of VA-ECMO and percutaneous left ventricular assist device (VAD) (Impella) for fulminant myocarditis in 104 consecutive patients enrolled in the Japan Registry for Percutaneous VAD (J-pVAD) between October 2017 and January 2020. Patients were followed until hospital discharge and predictors of survival were analyzed with a Cox proportional hazards model. The median support duration of combined use of VA-ECMO and Impella (ECMO/Impella) was 6 days, and the median left ventricular ejection fraction improved from 15% to 52% during support ( p < 0.0001). Overall, 66 patients (63%) survived to discharge. Multivariate analysis revealed ECMO/Impella support at a transplant center as an independent predictor of survival ( p = 0.0231). Patients treated at transplant centers had better 60 days survival rates when compared to nontransplant centers (83% vs. 55%, p = 0.005). However, baseline characteristics and treatment strategies differed between the two groups. This real-world national registry database suggested the difference in survival after ECMO/Impella support for fulminant myocarditis between transplant and nontransplant centers, which may indicate hospital variations regarding patient management, although further controlled studies are needed.

Short-Term Outcomes of Impella Support in Japanese Patients With Cardiogenic Shock Due to Acute Myocardial Infarction　- Japanese Registry for Percutaneous Ventricular Assist Device (J-PVAD).

BACKGROUND: The Impella®percutaneous left ventricular assist device has been available in Japan since 2017. This is the first large-scale registry study to analyze the efficacy and safety of Impella in Japanese patients with acute myocardial infarction with cardiogenic shock (AMICS).Methods and Results: The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) has registered all consecutive Japanese patients treated with Impella. We extracted data for 593 AMICS patients from J-PVAD and analyzed 30-day survival and safety profiles. Overall 30-day survival was 63.1%. The 30-day survival of the Impella alone and Impella plus venoarterial extracorporeal membrane oxygenation (ECPELLA) groups was 80.9% and 45.7%, respectively. The Impella alone group was older and had a lower rate of cardiac arrest, milder consciousness disturbance, less inotrope use, lower serum lactate concentrations, higher B-type natriuretic peptide concentrations, and higher left ventricular ejection fraction (LVEF) than the ECPELLA group. Cox regression analysis revealed that older age and comorbid renal disturbance were common risk factors affecting 30-day mortality in both groups. Major adverse events were hemolysis (10.8%), hemorrhage/hematoma (7.6%), peripheral ischemia (4.4%), stroke (1.3%), and thrombosis (0.7%). LVEF improved in both groups during support. CONCLUSIONS: AMICS treatment with Impella showed favorable 30-day survival and safety profiles. The survival rate of patients treated with Impella alone was particularly high. Further studies are needed to improve outcomes of patients with ECPELLA support.

Three-year experience of catheter-based micro-axial left ventricular assist device, Impella, in Japanese patients: the first interim analysis of Japan registry for percutaneous ventricular assist device (J-PVAD).

Catheter-based micro-axial ventricular assist device Impella® (Abiomed, Danvers, MA) has been used in Japanese patients with drug-refractory acute heart failure (AHF) since 2017. This is the first interim analysis of the ongoing Japan Registry for Percutaneous Ventricular Assist Device (J-PVAD) to investigate the safety and efficacy of Impella support. Between October 2017 and January 2020, 823 Japanese patients, who were treated with the Impella 2.5, CP, or 5.0 pump, were enrolled. The primary endpoints were safety profiles and cumulative 30-day survival. Among them, 44.8% of patients were acute myocardial infarction with cardiogenic shock. The Impella pumps were unable to implant in 4 patients. The Impella 2.5, CP, and 5.0 pumps were used in 72.4%, 6.2%, and 16.6%, respectively, and mean support duration was 8.1 ± 10.2 days. Combination use of Impella and venoarterial extracorporeal membrane oxygenation (VA-ECMO) was applied for 387 patients (47.3%). Pump stop occurred 22 patients (2.7%). Major adverse events included hemolysis (11.2%), hemorrhage/hematoma (6.1%), peripheral ischemia (1.6%), and stroke (1.6%). The overall 30-day survival was 62.2%. Survival of patients with single Impella support was significantly higher than patients with Impella combined with VA-ECMO support (81.1% vs 49.6%; p < 0.01), who had lower blood pressure, lower left ventricular ejection fraction, and higher degree of inotropic support. Results suggest that short-term outcome of Impella support for Japanese patients was favorable with acceptable safety profiles.

Automated analysis method to assess pulmonary blood flow distribution using conventional X-ray angiography.

Quantitative assessment of the right-to-left ratio of pulmonary blood flow distribution is important for determining the clinical indications for treating pulmonary arterial branch stenosis. A novel theory was recently proposed that can be used to quantitatively assess the right-to-left ratio on conventional X-ray angiography images. In the proposal, further developments were indicated, especially automated calculation. In this study, a new automated algorithm was developed. In the X-ray image, regions of interest were set in right and left lung, and time-signal intensity curves were measured. The new automated algorithm is applied to determine the optimal time window for the analysis of the time-signal intensity curve and to calculate the slope of the curve in the optimized time window. The right-to-left ratios in seven consecutive patients calculated by the new automated algorithm were compared to those calculated by lung perfusion scintigraphy. The ratios were in good agreement with linear regression with a slope of 1.27 and a Pearson correlation coefficient of 0.95. The processing time was less than 10 s, which is one-eighth of the manual processing time. The new automated algorithm is accurate, stable, and fast enough for clinical use in the real world.

Identification of metabolomic profile related to adult Fontan pathophysiology.

BACKGROUND: Metabolic disorders are important pathophysiologies that can cause multiple organ dysfunction and worsen prognosis in Fontan patients. This study aimed to comprehensively evaluate the metabolomic profile of adult Fontan patients and characterize its pathophysiology in relation to 2 control groups. METHODS AND RESULTS: We performed metabolomic analysis of 31 plasma samples using capillary electrophoresis time-of-flight mass spectrometry. This observational cross-sectional study compared plasma metabolites of 14 heterogeneous adult Fontan patients with those of control groups, including 9 patients with congenital heart disease after biventricular repair and 8 normal healthy controls. Fontan patients exhibited significant differences in intermediate metabolite concentrations related to glycolysis, the tricarboxylic acid (TCA) cycle, and the urea cycle. The plasma concentrations of lactic acid, 2-oxoglutarate, isocitric acid, malic acid, cis-aconitic acid, arginine, citrulline, and the ratio of ornithine/citrulline showed significantly differences among the groups. Multiple logistic regression analysis with a stepwise selection-elimination method identified 2-oxoglutaric acid (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.05-3.76) and cis-aconitic acid (OR 2.69, 95% CI 1.04-6.99) as independently associated with Fontan patients. After adjustment for the covariates of age and gender, 2-oxoglutaric acid (OR 1.97, 95% CI 0.98-3.93) and cis-aconitic acid (OR 3.88, 95% CI 0.99-15.2) showed remarkable relationships with Fontan patients. CONCLUSIONS: The present findings suggest that abnormalities in the TCA cycle and amino acid metabolism are distinguishing features in the pathophysiology of Fontan patients. Future metabolomic studies will assist in developing biomarkers for the early prediction of "silent" Fontan pathophysiologies.

A novel diagnostic approach for assessing pulmonary blood flow distribution using conventional X-ray angiography.

OBJECTIVE: Quantitative assessment of pulmonary blood flow distribution is important when determining the clinical indications for treating pulmonary arterial branch stenosis. Lung perfusion scintigraphy is currently the gold standard for quantitative blood flow measurement. However, it is expensive, cannot provide a real-time assessment, requires additional sedation, and exposes the patient to ionizing radiation. The aim of this study was to investigate the feasibility of a novel technology for measuring pulmonary blood flow distribution in each lung by conventional X-ray pulmonary angiography and to compare its performance to that of lung perfusion scintigraphy. METHODS: Contrast-enhanced X-ray pulmonary angiography images were acquired at a frame rate of 30 frames per second. The baseline mask image, obtained before contrast agent injection, was subtracted from subsequent, consecutive images. The time-signal intensity curves of two regions of interest, established at each lung field, were obtained on a frame-to-frame basis. The net increase in signal intensity within each region at the torrent period during the second cardiac cycle before contrast agent enhancement over the total lung field was measured, and the right-to-left ratio of the signal intensity was calculated. The right-to-left ratio obtained with this approach was compared to that obtained with scintigraphy. Agreement of the right-to-left ratio between X-ray angiography and lung scintigraphy measurements was assessed using linear fitting with the Pearson correlation coefficient. RESULT: The calculation of the right-to-left ratio of pulmonary blood flow by our kinetic model was feasible for seven children as a pilot study. The right-to-left ratio of pulmonary blood flow distribution calculated from pulmonary angiography was in good agreement with that of lung perfusion scintigraphy, with a Pearson correlation coefficient of 0.91 and a slope of linear fit of 1.2 (p<0.005). CONCLUSION: The novel diagnostic technology using X-ray pulmonary angiography from our kinetic model can feasibly quantify the right-to-left ratio of pulmonary blood flow distribution. This technology may serve as a substitute for lung perfusion scintigraphy, which is quite beneficial for small children susceptible to radiation exposure.

Ventricular myocardial response to exercise in patients with Fontan circulation.

BACKGROUND: Exercise stress echocardiography has been used to assess myocardial reserve in various heart diseases. This study examined the ventricular myocardial response to exercise in Fontan patients using exercise stress echocardiography. METHODS: Twenty-five Fontan patients and 19 control subjects underwent semi-supine bicycle exercise stress echocardiography in this prospective, single-center, cross-sectional study. Pulsed-wave Doppler tissue imaging peak systolic (s') and diastolic (e') velocities, longitudinal strain and systolic strain rate, and early diastolic strain rate data at rest and at peak exercise were obtained for the systemic ventricle. The myocardial reserve of functional parameters was calculated as the difference between peak exercise and rest. RESULTS: Inter- and intra-observer reliability were both high for exercise stress echocardiography measurements. Compared with controls, Fontan patients had significantly lower s', e', longitudinal systolic strain and strain rate, and early diastolic longitudinal strain rate at rest and at peak exercise as well as reduced myocardial reserve. CONCLUSIONS: Fontan patients have markedly reduced myocardial reserve during exercise. The use of exercise stress echocardiography assessment may improve the clinical management of Fontan patients.

Pediatric Medical Devices　- Survey of Pediatric Cardiologists and Cardiovascular Surgeons in Japan.

Background: In Japan, the choice of pediatric medical devices is limited because of 2 "device lag" problems: Japan lags behind the USA and Europe in device development, and development of pediatric devices lags behind that of adult devices. We aimed to identify the problems with and impediments to pediatric medical device development as recognized by pediatric physicians in Japan. Methods and Results: A voluntary survey of pediatric medical devices for all council members of the Japanese Society of Pediatric Cardiology and Cardiac Surgery was conducted in 2019. The response rate was 47.1% (154/327). The respondents were 115 pediatric cardiologists (74.7%) and 39 cardiovascular surgeons (25.3%). Approximately 90% believed that difficulties in development existed. Approximately 70% were dissatisfied with the pediatric medical devices currently available in Japan, which was a result of the unavailability of medical devices approved overseas, few types and sizes, and off-label use. Factors that hindered the development of pediatric medical devices included anatomical issues specific to children with congenital heart disease, as well as system issues such as lack of corporate profitability, development cost, and amount of time for development. Conclusions: Pediatric cardiologists and cardiovascular surgeons regard "device lag" and "off-label use" in Japan as important hindrances to the delivery of better medical care for pediatric patients with congenital heart disease.

Partnership Between Japan and the United States for Early Development of Pediatric Medical Devices　- Harmonization By Doing for Children.

BACKGROUND: The Harmonization By Doing (HBD) program was established in 2003 as a partnership among stakeholders of academia, industry and regulatory agencies in Japan and the United States, with a primary focus on streamlining processes of global medical device development for cardiovascular medical devices. While HBD has traditionally focused on development of devices intended to treat conditions prevalent in adults, in 2016, HBD established the "HBD-for-Children" program, which focuses on the development of pediatric devices as the development of medical devices for pediatric use lags behind that of medical devices for adults in both countries.Methods and Results:Activities of the program have included: (1) conducting a survey with industry to better understand the challenges that constrain the development of pediatric medical devices; (2) categorizing pediatric medical devices into five categories based on global availability and exploring concrete solutions for the early application and regulatory approval in both geographies; and (3) facilitating global clinical trials of pediatric medical devices in both countries. CONCLUSIONS: The establishment of the HBD-for-Children program is significant because it represents a global initiative for the introduction of pediatric medical devices for patients in a timely manner. Through the program, academia, industry and regulatory agencies can work together to facilitate innovative pediatric device development from a multi-stakeholder perspective. This activity could also encourage industry partners to pursue the development of pediatric medical devices.

Antenatal Therapy for Fetal Supraventricular Tachyarrhythmias: Multicenter Trial.

BACKGROUND: Standardized treatment of fetal tachyarrhythmia has not been established. OBJECTIVES: This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL). METHODS: In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or AFL ≥180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed. RESULTS: A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth. CONCLUSIONS: Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth.

Neo-aortic insufficiency late after staged reconstruction for hypoplastic left heart syndrome: impact of differences in initial palliative procedures.

The neo-aortic insufficiency in patients with hypoplastic left heart syndrome is an important sequela. We assessed the risks of the neo-aortic valve deterioration by the difference of initial palliations: Group I underwent primary Norwood (Nw) with systemic-to-pulmonary artery shunt (SPS), Group II underwent bilateral pulmonary artery banding (bPAB) and subsequent Nw with SPS (bPAB-Nw/SPS), Group III underwent bPAB and subsequent Nw with bidirectional Glenn (BDG) procedure (bPAB-Nw/BDG). The neo-aortic valve z score changes over time did not reach statistical significance in all groups (p = 0.43 for Group I, 0.20 for Group II, and 0.30 for Group III). The degree of neo-aortic valve insufficiency did not change significantly over time during this period except for Group III (p = 0.34 for Group I, 0.20 for Group II, and 0.02 for Group III). On the other hand, dimensions of the neo-aortic annulus and degrees of neo-aortic insufficiency did not differ significantly among the 3 groups at any pre-determined time. The presence or absence of incision into the sino-tubular junction at Nw did not affect the late neo-aortic valve z score or insufficiency. These data indicate that the difference of initial palliative procedures does not affect late neo-aortic valve insufficiency in Nw survivors. Because valve failure may develop in longer follow-up, further observation should be conducted.

Establishment of a Healthcare System for Patients With Adult Congenital Heart Disease in Collaboration With Children's Hospital　- The Nagano Model.

BACKGROUND: Despite the best efforts of pediatricians, healthcare for adult patients with congenital heart disease (ACHD) has proven challenging because of the increased numbers. This study presents the process of establishing an ACHD care system as a collaborative effort between Shinshu University Hospital and Nagano Children's Hospital. Methods and Results: Establishing an outpatient clinic for transition, a cooperation agreement for in-patient care between the 2 hospitals, and quality management of diagnostic imaging and educational meetings for adult cardiologists were the 3 major challenges. Of the 99 patients who visited the transition clinic in the children's hospital between May 2014 and December 2016, 3 returned to the pediatrician's clinic. Between June 2013 and December 2017, 273 patients visited the ACHD center in Shinshu University Hospital. Until December 2017, mortality and fatal arrhythmia were noted in 3 and 2 cases, respectively. Catheter ablation for arrhythmia was performed in 12 cases, and 4 cases of pregnancy with moderate/severe ACHD or estimated as high risk were managed with healthy livebirths. Surgical interventions for moderate/severe ACHD were performed in collaboration with the children's hospital or Sakakibara Heart Institute. CONCLUSIONS: Patients were successfully transferred to adult cardiology departments. Surgical and nonsurgical interventions for ACHD were provided. Collaboration between adult and pediatric cardiologists assists in the establishment of healthcare systems for ACHD.

The impact of intrauterine treatment on fetal tachycardia: a nationwide survey in Japan.

OBJECTIVES: To investigate the clinical course of fetal tachycardia and analyze the impact of intrauterine treatment on the postnatal treatment and patient outcomes. STUDY DESIGN: This was a retrospective review of cases of fetal tachycardia that occurred from 2004 to 2006. Data were collected from questionnaires that were sent to all 750 secondary or tertiary perinatal care centers in Japan. RESULTS: Eighty-two cases (14 with fetal hydrops) were analyzed (supraventricular tachycardia [SVT], n = 52; atrial flutter [AFL], n = 23; and ventricular tachycardia, n = 7). The overall mortality was 3.7%. Intrauterine treatment was performed for 41 fetuses (50.0%). Digoxin, flecainide and sotalol were mainly used for SVT and AFL. Fetal tachycardia resolved in 90.0% (27/30) of the cases without fetal hydrops and 90.9% (10/11) of the cases with fetal hydrops. Intrauterine treatment significantly reduced the incidence of cesarean delivery (29.3 vs. 70.7%, p < .01), preterm birth (12.2 vs. 41.5%, p = .02) and neonatal arrhythmias (48.8 vs. 78.0%, p = .01) in comparison to untreated fetuses. CONCLUSIONS: This nationwide survey revealed that intrauterine treatment was performed for approximately half of the cases of fetal tachycardia and was associated with lower rates of cesarean delivery, premature birth and neonatal arrhythmias in comparison to untreated fetuses.