Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization.

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.

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.

IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity.

Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8+ T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.

Changes in Smoking Behavior Since the Declaration of the COVID-19 State of Emergency in Japan: A Cross-sectional Study From the Osaka Health App.

BACKGROUND: In April 2020, the Japanese government declared a state of emergency due to the COVID-19 pandemic, and infection control measures, including requests to work from home and stay-at-home restrictions, were introduced. This study examined changes in smoking behavior during the COVID-19 state of emergency. METHODS: An online cross-sectional survey was conducted in Osaka, Japan. To assess differences in smoking behavior among 5,120 current smokers before and after the declaration of a state of emergency, prevalence ratios (PRs) for two outcomes, increased smoking and quitting smoking, were calculated using multivariable Poisson regression, adjusting for potential covariates. RESULTS: We found 32.1% increased the number of cigarettes smoked and 11.9% quit smoking. After adjustment for all variables, we found risk factors for COVID-19 (men and older age group) had both significantly higher PR for quitting smoking (men: PR 1.38; 95% confidence interval [CI], 1.17-1.62) and participants aged ≥65 years: PR 2.45; 95% CI, 1.92-3.12) and significantly lower PR of increased smoking (men: PR 0.85; 95% CI, 0.78-0.93 and participants ≥65 years: PR 0.38; 95% CI, 0.29-0.49). Additionally, respondents working from home or living alone had significantly higher PR for increased smoking (working from home: PR 1.29; 95% CI, 1.17-1.41 and living alone: PR 1.23; 95% CI, 1.10-1.38) and respondents who changed from cigarettes to heated tobacco products (HTPs) had significantly lower PR for quitting smoking (PR 0.150; 95% CI, 0.039-0.582). CONCLUSIONS: We suggest people who have high-risk factors for COVID-19 might change their smoking behavior for the better, while people who work from home or live alone might change their smoking behavior for the worse, during the COVID-19 state of emergency. Additionally, changing from smoking cigarettes to using HTPs makes smokers less likely to quit.

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.

Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis (CRS) that is characterized by intractable nasal polyp formation. Eosinophil-derived neurotoxin (EDN) is an eosinophil granule protein that is closely related to allergic inflammation, but the pathological implications of EDN in ECRS remain unknown. In this study, we evaluated the function of EDN in ECRS pathogenesis and assessed its potential as a disease activity marker. Serum EDN levels were significantly higher in patients with ECRS than in those with other nasal and paranasal diseases, and were positively correlated with clinical disease activity. Production of EDN from isolated human eosinophils was induced by stimulation with IL-5 in vitro. Human nasal epithelial cells were stimulated with EDN, and the resultant changes in gene expression were detected by RNA sequencing. Pathway analysis revealed that the major canonical pathway affected by EDN stimulation was 'regulation of the epithelial-mesenchymal transition pathway'; the only gene in this pathway to be up-regulated was matrix metalloproteinase 9 (MMP-9). Consistent with this, immunostaining analysis revealed intense staining of both EDN and MMP-9 in nasal polyps from patients with ECRS. In conclusion, our data demonstrate that serum EDN level is a useful marker for the evaluation of ECRS severity. Furthermore, EDN induces production of MMP-9 from the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Effect of Therapeutic Modification on Outcomes in Heart Transplantation Over the Past Two Decades　- A Single-Center Experience in Japan.

BACKGROUND: During these 2 decades (1999-2019), many therapeutic strategies have been developed in the field of heart transplant (HTx) to improve post-HTx outcomes. In the present study, 116 consecutive HTx adults between 1999 and 2019 were retrospectively reviewed to evaluate the influences of a therapeutic modification on post HTx outcomes.Methods and Results:Patient survival, functional status and hemodynamics after HTx and modification of therapeutic strategies were reviewed. The overall cumulative survival rate at 10 and 20 years post-HTx was 96.4 and 76.7%, respectively. There were no significant differences in survival rate or exercise tolerance after HTx between extracorporeal and implantable continuous flow-LVAD. Post-HTx patient survival in patients, irrespective of the donor risk factors such as donor age, low LVEF, history of cardiac arrest, was equivalent across cohorts, while longer TIT and higher inotrope dosage prior to procurement surgery were significant risk factors for survival. In 21 patients given everolimus (EVL) due to renal dysfunction, serum creatinine significantly decreased 1 year after initiation. In 22 patients given EVL due to transplant coronary vasculopathy (TCAV), maximum intimal thickness significantly decreased 3 years after initiation. CONCLUSIONS: The analysis of a 20-year single-center experience with HTx in Japan shows encouraging improved results when several therapeutic modifications were made; for example, proactive use of donor hearts declined by other centers and the use of EVL in patients with renal dysfunction and TCAV.

Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB.

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid-sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.

Long-Term Results of Intracardiac Mesenchymal Stem Cell Transplantation in Patients With Cardiomyopathy.

BACKGROUND: Mesenchymal stem cells (MSCs), which have the potential to differentiate into cardiomyocytes or vascular endothelial cells, have been used clinically as therapy for cardiomyopathy. In this study, we aimed to evaluate the long-term follow-up results.Methods and Results:We studied 8 patients with symptomatic heart failure (HF) on guideline-directed therapy (ischemic cardiomyopathy, n=3; nonischemic cardiomyopathy, n=5) who underwent intracardiac MSC transplantation using a catheter-based injection method between May 2004 and April 2006. Major adverse events and hospitalizations were investigated up to 10 years afterward. Compared with baseline, there were no significant differences in B-type natriuretic peptide (BNP) (from 211 to 173 pg/mL), left ventricular ejection fraction (LVEF) (from 24% to 26%), and peak oxygen uptake (from 16.5 to 19.2 mL/min/kg) at 2 months. During the follow-up period, no patients experienced serious adverse events such as arrhythmias. Three patients died of pneumonia in the 1st year, liver cancer in the 6th year, and HF in the 7th year. Of the remaining 5 patients, 3 patients were hospitalized for exacerbated HF, 1 of whom required heart transplantation in the 2nd year; 2 patients survived for 10 years without worsening HF. CONCLUSIONS: The results of this exploratory study of intracardiac MSCs administration suggest further research regarding the feasibility and efficacy is warranted.

Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function.

Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4+ T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4+ T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes. Polarization of Th17 cells, but not Th1 and Th2 cells, diminished following the loss of Lamtor1. Accordingly, CD4-Cre-driven Lamtor1-knockout mice exhibited reduced numbers of CD4+ and CD8+ T cells at rest, and they were completely resistant to experimental autoimmune encephalomyelitis. In contrast, genetic ablation of Lamtor1 in Foxp3+ T cells resulted in severe autoimmunity and premature death. Lamtor1-deficient regulatory T cells survived ex vivo as long as wild-type regulatory T cells; however, they exhibited a marked loss of suppressive function and expression of signature molecules, such as CTLA-4. These results indicate that Lamtor1 plays essential roles in CD4+ T cells. Our data suggest that Lamtor1 should be considered a novel therapeutic target in immune systems.

Clinical Results, Adverse Events, and Change in End-Organ Function in Elderly Patients With HeartMateII Left Ventricular Assist Device　- Japanese Multicenter Study.

BACKGROUND: Advanced age has an adverse impact on clinical results in left ventricular assist device (LVAD) patients. We compared the clinical results of patients aged >60 years with younger patients using a national Japanese database.Methods and Results:Between April 2013 and December 2016, 300 patients underwent HeartMateII implantation. Of these, 37 patients were ≥60 years at LVAD implantation, and the clinical results of these patients were compared with the other younger 263 patients. At 1 and 3 years the on-device survival was 95%, 91% in younger patients, and 85%, 75% in older patients, respectively (P=0.016), although age was not a risk factor on the multivariate analysis. There was no significant difference between the groups in incidence of various adverse events except stroke. In the propensity-matching cohort, the incidence of stroke was significantly higher in patients aged >60 years (P=0.047). In patients aged >60 years, improvement of renal function was transient and there was no improvement later than 3 months, and recovery of serum albumin level to preoperative value was delayed. CONCLUSIONS: There were significant differences in the stroke incidence and recovery of end-organ functions after LVAD implantation. This may have important implications for patient selection in future destination therapy in Japan, where quality of life is an important issue in LVAD support.

Role of percutaneous veno-arterial extracorporeal membrane oxygenation as bridge to left ventricular assist device.

Percutaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides emergency circulatory support for cardiogenic shock patients and is used as a bridge to a left ventricular assist device (LVAD). The purpose of this study was to determine risk factors for LVAD implantation in patients who required percutaneous VA-ECMO as a bridge to long-term LVAD. We retrospectively investigated 32 consecutive LVAD patients who required percutaneous VA-ECMO as a bridge to long-term LVAD. Twenty-nine patients (91%) were intubated, and their serum creatinine and total bilirubin levels before LVAD implantation were 2.1 ± 2.0 and 3.7 ± 3.7 mg/dl, respectively. Patients were supported by LVAD for 495 ± 393 days, during which 15 died, 6 recovered native cardiac functions and LVAD was explanted, and 11 underwent heart transplantation. Multivariate logistic regression analysis revealed that a preoperative left ventricular end-diastolic diameter (LVDd) ≤54 mm was a significant predictor of 90-day mortality after LVAD implantation (OR 13.64; 95% CI 1.081-172.0; p = 0.0433) and freedom from death during LVAD support was significantly worse in patients with an LVDd ≤54 mm. Furthermore, preoperative LVDd was positively correlated with postoperative right ventricular stroke work index (r = 0.739, p < 0.0001) and patients with an LVDd ≤54 mm had significantly worse postoperative right ventricular, renal, and hepatic functions. We demonstrated that percutaneous VA-ECMO could be utilized as a bridge to long-term LVAD in selected patients. Our results suggest that preoperative LVDd is a useful predictor of mortality and right ventricular function after LVAD implantation in patients requiring VA-ECMO, in whom assessment of right ventricular function is challenging.

Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.

OBJECTIVES: Inappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis. METHODS: Serum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and SEMA4D-/- mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays. RESULTS: Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D's intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation. CONCLUSIONS: Neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.

Circadian pharmacokinetics and limited sampling strategy of everolimus in heart transplant patients
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OBJECTIVE: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration-time curve (AUC) of EVL in heart transplant patients. METHODS: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). RESULTS: AUC0-4h, peak concentration (Cmax), Cmax/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Half-life and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC0-12h in the active period was similar (p = 0.154) and correlated with that in the resting period (r2 = 0.93). Two-point blood samplings, C0 and C2, correlated more strongly with AUC0-12h for EVL, compared with C0 alone (0.92 vs. 0.79, respectively, for r2 in the active period). CONCLUSIONS: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC0-12h. A 2-time-point model that included C0 and C2 was more accurate for predicting the AUC0-12h of EVL than C0 alone in heart transplant patients.
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Temporary biventricular support with extracorporeal membrane oxygenation: a feasible therapeutic approach for cardiogenic shock with multiple organ failure.

Various strategies using a ventricular assist device (VAD) are applied to rescue Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (Profile-1) patients. However, the optimal use of VAD in Profile-1 patients has not been completely elucidated. We retrospectively reviewed 23 Profile-1 patients [mean age 36.9 ± 16.6 years, 14 males; 11 with non-ischemic cardiomyopathy (NICM), 9 with fulminant myocarditis (FM), 2 with ischemic cardiomyopathy (ICM), and 1 with peripartum cardiomyopathy (PPCM); 18 with pre-operative percutaneous extracorporeal membrane oxygenation (p-ECMO) support] who underwent VAD implantation from 2011 to 2015 at our institution. Nine initially received left VAD (LVAD) alone (NICM in 9, ICM in 2 with ICM, and FM in 1), one with NICM received biventricular VAD (BiVAD; n = 1), and 10 received LVAD combined with right ventricular support using an ECMO circuit (BiVAD-ECMO) (FM in 8, NICM in 1, and PPCM in 1). Paracorporeal VAD was used in all patients. ECMO was used for the patients with severe pulmonary edema, inflammation, anemia, and thrombopenia. The BiVAD patient died 1.4 months after VAD implantation. The overall survival was comparable between patients with BiVAD-ECMO and LVAD (2-year survival, 80.0 and 75.0%, respectively). Three VAD strategies were initially applied in Profile-1 patients. Among them, the BiVAD-ECMO strategy is a promising therapeutic option to rescue Profile-1 patients with multiple organ failure.

Japanese Multicenter Outcomes With the HeartMate II Left Ventricular Assist Device in Patients With Small Body Surface Area.

BACKGROUND: The HeartMate II (HMII) continuous-flow LVAD was approved for Japanese health insurance coverage in April 2013 as a bridge to transplantation (BTT). We report on post-approval Japanese multicenter outcomes, and a comparison between patients with low and high body surface area (BSA). METHODS AND RESULTS: HMII LVAD was implanted in 104 consecutive patients at 15 Japanese centers between April 2013 and July 2014. Perioperative data were submitted to the Japanese Registry for Mechanically Assisted Circulatory Support. Patients were divided into 2 groups on the basis of BSA less or greater than 1.5 m(2). Survival outcomes, New York Heart Association functional class, and adverse event rates were compared between the 2 groups. Preoperative hemodynamics and INTERMACS profiles were similar between groups. There were more females and younger patients in the low BSA group. The respective 6-month and 1-year death- or pump exchange-free survival rates were excellent: 90% and 90% in the BSA <1.5 group vs. 90% and 85% in the BSA ≥1.5 group. In the BSA <1.5 group, occurrence of hemorrhagic stroke was 10% and occurrence of embolic stroke was 0%, vs. 12% and 8% in BSA ≥1.5 group. Driveline infection was encountered more frequently in the BSA <1.5 group. CONCLUSIONS: Results for HMII LVAD as BTT in the post-approval era showed excellent survival and functional capacity improvement. Of particular interest to the Japanese patient population are the excellent results in patients with small BSA. (Circ J 2016; 80: 1931-1936).

Risk Stratification for Cardiac Allograft Vasculopathy in Heart Transplant Recipients - Annual Intravascular Ultrasound Evaluation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term success after heart transplant. We assessed the post-transplant risk factors for CAV development. METHODS AND RESULTS: Patients who underwent heart transplant between May 1999 and December 2013 were included in this study. Patients (n=54) were divided into 2 groups according to the presence or absence of CAV progression after transplant. Coronary angiogram and intravascular ultrasound were conducted within 5-11 weeks after transplant, at 12 months, and annually thereafter. Scheduled endomyocardial biopsies were performed after transplant or whenever acute cellular rejection (ACR) or antibody-mediated rejection was suspected. Twenty-five of 54 patients (46.2%) had CAV progression. ACR ≥ International Society for Heart and Lung Transplantation grade 2 (ACR ≥ 2) and donor age >50 years were significantly associated with CAV development compared with ACR <2 and donor age <50 years. Patients with no history of ACR ≥ 2 and donor age ≤50 years had a significantly low risk of developing CAV compared with the other groups. CONCLUSIONS: Donor age and history of ACR ≥ 2 are independent risk factors for CAV development. Identifying patients at risk of developing CAV is important for appropriate direction of resources and intensity of follow-up.

Incidence, etiology, and outcome of primary graft dysfunction in adult heart transplant recipients: a single-center experience in Japan.

Donor and recipient characteristics, as well as donor-recipient matching, affect clinical outcomes after heart transplantation (HTx). This study aimed to clarify how donor and recipient characteristics affect the clinical course after HTx. The medical records of all the patients who underwent HTx at the National Cerebral and Cardiovascular Center from 1999 to 2014 were retrospectively reviewed. Sixty-one patients (48 males) underwent HTx. Six recipients (9.8 %) developed primary graft dysfunction (PGD) determined by criteria recently established at a consensus conference. Development of PGD was associated with high-dose inotropic support for the donor heart and a history of stroke in the recipient (p = 0.04 and p = 0.002, respectively). Recipients with PGD had higher right atrial pressure (RAP) and lower cardiac output (CO) compared with those without PGD at 6 months after HTx (RAP, 6.8 ± 3.6 vs. 2.8 ± 2.2 mmHg, p < 0.001; CO, 4.6 ± 0.8 l vs. 5.8 ± 1.2 l/min, p = 0.02). With respect to survival, patients with PGD had a 5-year survival rate equivalent to those without PGD (83.3 vs. 93.3 %, p = 0.23). High-dose inotropic support for the donor heart and a history of stroke in the recipient are significant predictive factors for the development of PGD. However, recipients with PGD demonstrate mid-term survival comparable to those without PGD.

Successful treatment of near-fatal fulminant myocarditis using bi-ventricular assist device support.

Fulminant myocarditis is a rare but fatal serious disease that may cause prolonged native cardiac dysfunction with multiorgan failure despite temporary mechanical circulatory support with percutaneous venoatrial extracorporeal membrane oxygenation (VA-ECMO) or intraaortic balloon pumping (IABP). A 26-year-old man with fulminant myocarditis developed life-threatening multiorgan failure after 8 days support by VA-ECMO and IABP. He was transferred to our institution with prolonged cardiac dysfunction on hospital day 8; massive pulmonary edema developed into severe pulmonary dysfunction. Immediately after admission, VA-ECMO and IABP were switched to a paracorporeal pneumatic left ventricular assist device (LVAD) and right centrifugal ventricular assist device with an ECMO circuit shunting from the right ventricle to the pulmonary artery (RVAD-ECMO). After intensive care focusing on respiratory dysfunction, ECMO was successfully weaned, and the right ventricular assist device was switched to a durable paracorporeal pneumatic right ventricular assist device. The paracorporeal bi-ventricular assist devices were finally replaced with an implantable non-pulsatile LVAD on hospital day 181. Currently, 1 year after discharge, the patient is at home awaiting heart transplantation. Combined LVAD and RVAD-ECMO appear to be useful for resolving severe pulmonary edema due to unnecessarily long VA-ECMO support as well as kidney or liver dysfunction caused by circulatory collapse.