Prediction of cardiac allograft vasculopathy using splenic switch-off on myocardial PET.

BACKGROUND: Heart transplantation (HTx) is a definitive therapy for refractory heart failure. Cardiac allograft vasculopathy (CAV), characterized by diffuse arteriopathy involving the epicardial coronary arteries and microvasculature, is the major cause of death for patients with HTx. 13N-ammonia positron emission tomography (NH3-PET) can offer diagnostic and prognostic utility for CAV. The splenic switch-off (SSO) detected in NH3-PET is a hemodynamic indicator of favorable response to adenosine. We hypothesized that both CAV and SSO reflected a pathology that progresses in parallel with systemic vascular endothelial dysfunction. Therefore, we quantitatively evaluated splenic adenosine reactivity measured using NH3-PET as an index of endothelial function, and examined its predictability for CAV. METHODS: Forty-eight patients who underwent NH3-PET after HTx were analyzed. The spleen ratio was calculated as the mean standardized uptake value, measured by placing an ROI on the spleen, at stress divided by that at rest. SSO was defined by a cutoff determined using receiver operating characteristic (ROC) analysis for the spleen ratio. The endpoint was appearance or progression of CAV. Predictability of SSO was analyzed using Kaplan-Meier analysis. RESULTS: The endpoint occurred in 9 patients during a mean follow-up of 45 ±â€¯17 months. ROC curve analysis demonstrated a cutoff of 0.94 for spleen ratio. Patients without SSO displayed a significantly higher CAV rate than those with SSO (p = 0.022). CONCLUSIONS: SSO reflects the endothelial function of systemic blood vessels and was a predictor of CAV in patients with HTx.

Novel Scoring System to Risk Stratify Patients Receiving Durable Left Ventricular Assist Device From J-MACS Registry Data.

BACKGROUND: Recently, destination therapy (DT) was approved in Japan, and patients ineligible for heart transplantation may now receive durable left ventricular assist devices (LVADs). Several conventional risk scores are available, but a risk score that is best to select optimal candidates for DT in the Japanese population remains unestablished.Methods and Results: A total of 1,287 patients who underwent durable LVAD implantation and were listed for the Japanese registry for Mechanically Assisted Circulatory Support (J-MACS) were eligible for inclusion. Finally, 494 patients were assigned to the derivation cohort and 487 patients were assigned to the validation cohort. According to the time-to-event analyses, J-MACS risk scores were newly constructed to predict 3-year mortality rate, consisting of age, history of cardiac surgery, serum creatinine level, and central venous pressure to pulmonary artery wedge pressure ratio >0.71. The J-MACS risk score had the highest predictability of 3-year death compared with other conventional scores in the validation cohort, including HeartMate II risk score and HeartMate 3 risk score. CONCLUSIONS: We constructed the J-MACS risk score to estimate 3-year mortality rate after durable LVAD implantation using large-scale multicenter Japanese data. The clinical utility of this scoring to guide the indication of DT should be validated in the next study.

Clinical Validation of a Neointima-Inducing Inflow Cannula in a Continuous Flow Left Ventricular Assist Device.

Wedge thrombus formation around the inflow cannula of a continuous left ventricular assist device (LVAD) is a source of systemic thromboemboli. We previously reported the potential advantages of a new inflow cannula wrapped with titanium mesh (GU30) over the standard smooth surface oblique cut cannula (GU10). The objective of the present study was to clinically validate this new cannula. A retrospective cohort analysis of patients with implanted LVAD (EVAHEART) comparing the GU10 to the GU30 was conducted. Clinical outcomes, including survival, the incidence of thromboembolism, and bleeding events, were compared. Gross and histopathological analyses of explanted GU30 cannula were conducted following transplant or patient death. No significant differences in the survival rate, severe emboli, or cerebral bleeding were observed during the LVAD implantation. However, severe emboli occurred earlier after LVAD implantation when using the GU30 cannula compared with the GU10. In cases of long LVAD support, the neointima fully covered the inflow of the GU30 cannulae without wedge thrombus formation. The titanium mesh-wrapped inflow cannulae did not reduce the overall incidence of neurological events significantly. However, the titanium mesh-wrapped inflow cannula induced autologous neointimal growth over the cannula and prevented wedge thrombus formation in late-phase LVAD implantation.

Stratification of Destination Therapy Candidates by J-HeartMate Risk Score Among Elderly Non-Responders to Cardiac Resynchronization Therapy.

Background: For elderly patients with refractory heart failure (HF), destination therapy (DT) with a continuous-flow left ventricular assist device (LVAD) is a possible treatment. The aim of DT is for long-term, satisfying quality of life on LVAD support. Previously, elderly non-responders to cardiac resynchronization therapy (CRT) were primarily destined for palliative care, but DT has been available in Japan since April 30, 2021. This study investigated the prognosis of elderly CRT non-responders and assessed the feasibility of DT in these patients based on the J-HeartMate Risk Score (J-HMRS). Methods and Results: Of the 559 patients who underwent CRT at Tokyo Women's Medical University between 2000 and 2018, 198 were aged 65-75 years. Among these, 76 were identified as non-responders based on echocardiographic data, and were included in this study. We calculated patients' J-HMRS and investigated associations between the J-HMRS and cardiac events after CRT. Patients were divided into 3 groups according to the J-HMRS: low (n=23), medium (n=29), and high (n=24) risk. Patients in the low-risk group experienced as many HF rehospitalizations and ventricular arrhythmia events as those in the other groups. However, survival analysis revealed that, after CRT, survival was higher for patients in the low- compared with high-risk group (P=0.04). Conclusions: The J-HMRS classified 30% of elderly CRT non-responders as low risk and as suitable candidates for DT in Japan.

Acute myocardial infarction and sudden cardiac arrest caused by anomalous left coronary artery arising from the noncoronary cusp.

Anomalous left coronary artery arising from the noncoronary cusp (LCANCC) is a rare congenital disorder. We herein describe a 17-year-old female patient with sudden cardiac arrest followed by refractory cardiogenic shock. LCANCC-induced acute myocardial infarction with left main coronary artery involvement was subsequently diagnosed, and the patient required a durable left ventricular assist device. .

[Proposal to Development of the Heart Transplant in Our Country in the Future].

Although the first heart transplantation in Japan by Dr. Wada had influenced the establishment of heart transplantation in Japan for many years, many efforts for re-starting and establishing heart transplantation in Japan have also occurred in the past 40 years. The Japanese Society for Heart Transplantation was established in 1983, which was two years after the establishment of the International Society for Heart Transplantation. Much effort had been made to pass the Act on Organ Transplantation in 1997 and revise it in 2010. However, very few heart transplantations are performed in our country because there have been very few deceased donors according to a 2015 report. Currently, more than 10 times the number of donors are awaiting heart transplantation in Japan. Compared to countries using an opt-in system for organ donation such as the United States and South Korea, earlier referral of possible donors to transplant coordination teams should be incorporated in Japan to increase the possibility of organ donation. The medical consultant system developed in Japan is a unique partnership between transplant consultant physicians and local physicians that should put more effort into increasing the number of organs for donation. The current number of transplant physicians is very low. This number should be increased for pre- and post-transplant management as well as medical consultation for donation in the emergency room. Another reason for the shortage of donors is that there are two judgement standards of death in Japan. One standard is brain death only at the time of donation for transplantation. This definition should be re-considered in various fields in Japan.

Impact of anatomical position of the inflow cannula on stroke in patients with left ventricular assist devices.

OBJECTIVES: Stroke is a substantial complication of left ventricular assist device (LVAD) implantation. The relationship between stroke and the anatomical position of the inflow cannula of patients who underwent LVAD implantation was investigated. METHODS: We enrolled 15 patients with advanced-stage heart failure who underwent implantation of continuous-flow-LVAD. Data of patients who suffered a stroke within 6 months after LVAD implantation were retrospectively compared to those who remained free of stroke. The distance between the inflow duct and left ventricular (LV) septum (duct-sep distance) and its ratio to LV diastolic diameter (LVDd) were measured from echocardiography at 1 month after LVAD implantation. Receiver operating characteristic curves for the endpoint of stroke using the duct-sep distance to LVDd ratio was created and the cut-off value was calculated. The incidence of stroke during the 6 months after LVAD implantation according to this ratio was estimated using the Kaplan-Meier method. RESULTS: At 1 month after LVAD implantation, there were no significant differences in baseline characteristics and echocardiography parameters between the stroke and stroke-free groups. Receiver operating characteristic curve analysis for the endpoint of stroke using the duct-sep distance to LVDd ratio revealed 0.217 as a cut-off value (sensitivity: 80%, specificity: 80%, area under the curve: 0.72). Stroke was more frequent in patients with a duct-sep distance to LVDd ratio ⩾0.217 at 1 month than in those with a lower ratio. CONCLUSION: The duct-sep distance to LVDd ratio was associated with the occurrence of stroke, suggesting that inflow cannula position influences the incidence of stroke.

13N-ammonia positron emission tomography-derived left-ventricular strain in patients after heart transplantation validated using cardiovascular magnetic resonance feature tracking as reference.

OBJECTIVE: Heart transplant rejection leads to cardiac allograft vasculopathy (CAV). 13N-ammonia positron emission tomography (PET) can be useful in detecting CAV, as it can evaluate both epicardial vessels and microvasculature. In this study, we evaluated the regional wall motion in heart transplant patients using our PET-specific feature-tracking (FT) algorithm for myocardial strain calculation and validated it using a cardiovascular magnetic resonance (CMR) FT strain as a reference. METHODS: A total of 15 heart transplant patients who underwent both 13N-ammonia PET and CMR within 3 months were retrospectively enrolled. The same slice position of short-axis cine images of the middle slice of left ventricle (LV) and the same slice position of horizontal long-axis cine images were selected for the two modalities to measure the circumferential strain (CS) and longitudinal strain (LS), respectively. Based on the FT technique, time-strain curves were calculated by semi-automatic tracking of the endocardial contour on cine images throughout a cardiac cycle. The peak value in the time-strain curve was defined as the representative value. Correlations of CS and LS between PET and CMR were analyzed using Pearson correlation coefficients. The inter-modality error of strain measurements was evaluated using intraclass correlation coefficients (ICCs) with two-way random single measures. RESULTS: Excellent correlations of CS and LS between PET and CMR were observed (CS: r = 0.80; p < 0.01; LS: r = 0.87; p < 0.01). Excellent ICCs were observed (0.89 and 0.85) in CS and LS derived from PET. CONCLUSIONS: We propose the first PET strain showing an excellent agreement with the CMR strain and high reproducibility in measurement.

Complete remission from post-heart transplant lymphoproliferative disorder: A case report.

We report a case of Burkitt's lymphoma, post-transplant lymphoproliferative disorder (BL-PTLD) that was treated with intensive chemotherapy. The patient was a 4-year-old boy who underwent heart transplantation at 7 months of age for refractory heart failure due to dilated cardiomyopathy. He was admitted to our hospital with a chief complaint of abdominal pain associated with an abdominal mass. Computed tomography was notable for a bulky mass arising from the terminal ileum. Fluorodeoxyglucose-positron emission tomography revealed multiple lesions in brain, bone, and lymph nodes. He was diagnosed with BL-PTLD stage III by pathological and clinical scoring. He was Epstein-Barr virus (EBV)-seronegative with a low EBV viral DNA load. No EBV-encoded small RNAs were in his intra-abdominal lymph nodes by in situ hybridization. On cytogenetic examination, the intra-abdominal lymph nodes revealed both a MYC rearrangement and a t(8;14)(q24;32), t(16;19)(q24;q13.1) translocation. Administration of tacrolimus and mycophenolate mofetil was discontinued; immunosuppression was maintained with everolimus. Intensive chemotherapy based on the modified LMB 96 protocol for BL was initiated, resulting in complete remission achieved. During the intensive chemotherapy and immunosuppressive switching period, cardiac dysfunction and allograft rejection had not been shown. The patient has remained well for two years after the treatment with no evidence of relapse. .

Consensus Report on Destination Therapy in Japan　- From the DT Committee of the Council for Clinical Use of Ventricular Assist Device Related Academic Societies.

Destination therapy (DT) is the indication to implant a left ventricular assist device (LVAD) in a patient with stage D heart failure who is not a candidate for heart transplantation. The implantable LVAD has been utilized in Japan since 2011 under the indication of bridge to transplant (BTT). After almost 10 year lag, DT has finally been approved and reimbursed in May 2021 in Japan. To initiate the DT program in Japan, revision of the LVAD indication from BTT is necessary. Also, in-depth discussion of caregiver issues as well as end-of-life care is indispensable. For that purpose, we assembled a DT committee of multidisciplinary members in August 2020, and started monthly discussions via web-based communication during the COVID-19 pandemic. This is a summary of the consensus reached after 6 months' discussion, and we have included as many relevant topics as possible. Clinical application of DT has just started, and we are willing to revise this consensus to meet the forthcoming issues raised during real-world clinical experience.

Heart transplant candidate with medical complexity in the era of prolonged left ventricular assist device support - A case report.

Heart transplantation improves quality of life and survival in patients with advanced heart failure. However, the shortage of available heart donors and technological advances for left ventricular assist devices (LVAD) have led to longer waiting times for transplantation, and long-term use of LVAD may increase the medical complexity of subsequent transplantation. We present the case of a 35-year-old man who underwent heart transplantation after being supported by an LVAD for 1490 days (∼4 years). He was sensitized with kidney dysfunction and recurrent infections, including candidemia, at the time of transplantation. He underwent a successful heart transplantation with pretransplant plasma exchange, intravenous immunoglobulin administration, early initiation of everolimus, and prompt management of infections. .

The second official report from Japanese registry for mechanical assisted circulatory support (J-MACS): first results of bridge to bridge strategy.

BACKGROUND: The Japanese registry for mechanical assisted circulatory support (J-MACS) is a prospective registry to collect all data of implantable left ventricular assist device (LVAD) (and part of paracorporeal VAD) established in 2010. The first analytical report was published in 2017. The organization running J-MACS was used to be the pharmaceuticals and medical devices agency (PMDA), but has been changed to the council for clinical use of ventricular assist device related academic societies in 2017. METHODS: Since 2018, we changed the analytical methods as follows: first, we eliminated paracorporeal VAD from the analysis. Second, we included not only primary implantation but bridge to bridge (BTB) implantation of LVAD. Third, we added the analyses of adverse events that were not included in the previous analysis. RESULTS: As of Oct 2018, 711 primary LVAD implants and 168 BTB implants were enrolled. Survival rate of primary LVAD was 93% at 360 days and 91% at 720 days, and that of BTB was 86% at 360 days and 82% at 720 days. CONCLUSION: We first reported the results of BTB in the second official report of J-MACS. The prognosis after LVAD implantation has been kept good in Japanese circumstances.

Impact of pretransplant antibodies on outcomes after heart transplantation.

PURPOSE OF REVIEW: Since the discovery of human leukocyte antigen (HLA) in the 1950s, there has been great interest in the role of antibodies in posttransplant rejection. The development of the lymphocyte toxicity test by Terasaki et al. in the 1960s was the first step toward understanding the role of antibodies in posttransplant rejection. RECENT FINDINGS: Subsequently, various organs have been transplanted and improving posttransplant outcomes have become a focus of research. In particular, methods to measure antibodies that affect posttransplant outcomes, including anti-HLA antibodies, and methods to desensitize patients from specific antibodies have been explored. One recent method for measuring antibodies is called the solid-phase assay, which uses purified HLA fixed to microbeads. This assay does not use donor lymphocytes and allows clinicians to test the reactivity of patient serum against a panel of antibodies. It has also enabled the identification of specific anti-HLA antibodies using a single HLA. SUMMARY: In addition to advances in methods to measure and analyze anti-HLA antibodies, the clinical impact of non-HLA antibodies has also received much attention recently.

Survival of Heart Transplant Candidates in Japan.

BACKGROUND: In Japan, there are more patients waiting for heart transplants (HTXs) than available organs. Methods and Results: Since July 2010, 68 pediatric and 366 adult patients aged <60 years applied for HTX candidacy with the Japanese Circulation Society's HTX Committee. No significant differences in freedom from death or HTX were observed between pediatric Status 1 and Status 2 patients. More adult Status 1 patients reached the endpoint of death or HTX than adult Status 2 patients. Pediatric patients (Status 1 and 2) did not have better survival than adult Status 1 or Status 2 patients. CONCLUSIONS: Pediatric patients should be prioritized over adult patients for HTX.

Impact of Recurrent Ventricular Tachyarrhythmia on Outcome in Japanese Heart Transplant Candidates With a Left Ventricular Assist Device.

BACKGROUND: Recurrent ventricular tachyarrhythmias (VTA) are "A factor" modifiers in the Interagency Registry for Mechanically Assisted Circulatory Support profile. The effect of recurrent VTA on clinical outcome, however, is controversial. We evaluated the impact of recurrent VTA on outcome in Japanese heart transplant candidates with a left ventricular assist device (LVAD). Methods and Results: Sixty-six adult patients with advanced heart failure who were listed for heart transplantation between January 2005 and October 2017 were enrolled in the study. Recurrent VTA (modifier A status) was defined as a sustained ventricular tachycardia or fibrillation that required implantable cardioverter defibrillator shocks or an external defibrillator more than twice weekly. The primary outcome was death from any cause. The secondary outcomes were the first occurrence of VTA and recurrent VTA after LVAD implantation. Sixteen patients (24%) met the criteria for modifier A status, and 15 patients had an LVAD implanted. During a median follow-up of 1,124 days, 21 of 60 patients with an LVAD died. There was a significantly higher mortality rate in LVAD patients with modifier A status than in those who did not meet the modifier A criteria. On multivariate analysis, patients with modifier A status had an increased risk of mortality (HR, 3.43; 95% CI: 1.30-8.61, P=0.001). CONCLUSIONS: Recurrent VTA might be a marker for worse outcome in Japanese heart transplant candidates with an LVAD.

Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) present a high risk for sudden cardiac death in pediatric patients. The aim of this study was to identify disease-associated genetic variants in Japanese patients with pediatric HCM and RCM. We analyzed 67 cardiomyopathy-associated genes in 46 HCM and 7 RCM patients diagnosed before 16 years of age using a next-generation sequencing system. We found that 78% of HCM and 71% of RCM patients carried disease-associated genetic variants. Disease-associated genetic variants were identified in 80% of HCM patients with a family history and in 77% of HCM patients with no apparent family history (NFH). MYH7 and/or MYBPC3 variants comprised 76% of HCM-associated variants, whereas troponin complex-encoding genes comprised 75% of the RCM-associated variants. In addition, 91% of HCM patients with implantable cardioverter-defibrillators and infant cases had NFH, and the 88% of HCM patients carrying disease-associated genetic variants were males who carried MYH7 or MYBPC3 variants. Moreover, two disease-associated LAMP2, one DES and one FHOD3 variants, were identified in HCM patients. In this study, pediatric HCM and RCM patients were found to carry disease-associated genetic variants at a high rate. Most of the variants were in MYH7 or MYPBC3 for HCM and TNNT2 or TNNI3 for RCM.

Donor bone marrow cells are essential for iNKT cell-mediated Foxp3+ Treg cell expansion in a murine model of transplantation tolerance.

Mixed chimerism induction is the most reliable method for establishing transplantation tolerance. We previously described a novel treatment using a suboptimal dose of anti-CD40 ligand (anti-CD40L) and liposomal formulation of a ligand for invariant natural killer T cells administered to sub-lethally irradiated recipient mice after donor bone marrow cell (BMC) transfer. Recipient mice treated with this regimen showed expansion of a Foxp3-positive regulatory T(Treg) cell phenotype, and formation of mixed chimera. However, the mechanism of expansion and bioactivity of Treg cells remains unclear. Here, we examine the role of donor BMCs in the expansion of bioactive Treg cells. The mouse model was transplanted with a heart allograft the day after treatment. The results showed that transfer of spleen cells in place of BMCs failed to deplete host interferon (IFN)-γ-producing CD8+ T cells, expand host Ki67+ CD4+ CD25+ Foxp3+ Treg cells, and prolong graft survival. Severe combined immunodeficiency mice who received Treg cells obtained from BMC-recipients accepted skin grafts in an allo-specific manner. Myeloid-derived suppressor cells, which were a copious cell subset in BMCs, enhanced the Ki67 expression of Treg cells. This suggests that donor BMCs are indispensable for the expansion of host bioactive Treg cells in our novel treatment for transplant tolerance induction.