Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Which advanced heart failure therapy strategy is optimal for patients over 60 years old?

BACKGROUND: The optimal advanced heart failure (HF) therapy strategy for patients aged 60 or older with end-stage HF refractory to optimal medical therapy remains uncertain. This study compares outcomes of three advanced HF therapy strategies in this patient population. METHODS: A single-center retrospective study was conducted in 95 patients aged 60-73 years who had undergone isolated heart transplantation (HTx) or continuous flow left ventricular assist device (LVAD) implantation from 2010 to 2017. Patients were stratified into three cohorts by strategy; HTx-only (N.=25), LVAD-to-HTx (N.=29), and LVAD-only (N.=41). Primary end point was 2-year overall survival. Secondary end points included incidence of post-operative adverse events, freedom from first readmission at 1 year, and percentage of days spent in hospital following advanced HF therapy. RESULTS: Two-year survival was 91% in HTx-only patients, 88% in LVAD-to-HTx patients, and 49% in LVAD-only patients (P=0.0008). No significant difference in post-transplant survival was found between patients with or without LVAD-related adverse events preceding transplantation (P=0.42). One-year freedom from first readmission was 38.3% in HTx-only patients, 17.2% in LVAD-to-HTx patients and 7.3% in LVAD-only patients (P=0.0028). Patients in LVAD-to-HTx cohort had higher incidences of gastrointestinal bleeding (38% vs. 3%; P<0.01), major bleeding (28% vs. 3%; P=0.02), and right heart failure (69% vs. 31%; P<0.01) during post-LVAD period compared with post-HTx period. Their percentage of days spent in hospital during post-LVAD period was significantly higher than post-HTx period (7.9% vs. 1.2%; P<0.001). CONCLUSIONS: Our experience with patients over 60 years old undergoing advanced therapy suggests that HTx-only and LVAD-to-HTx strategies had superior medium-term survival than LVAD-only strategy. LVAD-to-HTx strategy is effective in reducing incidence of adverse events and percentage of hospitalized days in this specific patient population.

Mechanical Circulatory Support: Current Status and Future Directions.

Advance heart failure (AHF) is a growing epidemic with high morbidity and mortality. Left ventricular assist device (LVAD) has come to offer an opportunity to improve survival and quality of life. This form of therapy however, is not free of complications and poses a challenge to apply to a broader population. Adjunct therapies in combination with LVAD therapy and advances in device technology are in the near future, which may lessen the number of adverse events. This review summarizes the history, clinical outcomes and current challenges facing LVAD therapy. Finally, future directions of LVADs in the treatment of AHF are discussed.

Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme.

Angiotensin-converting enzyme 2 (ACE2) is a newly identified regulator of the renin-angiotensin system. This type I membrane-anchored protein has a catalytically active ectodomain that undergoes shedding. Tumor necrosis factor alpha-converting enzyme (TACE) has been shown to be involved in ACE2 shedding. Although pathophysiological significance of ACE2 shedding has been suggested, regulation of this process by TACE is not clearly defined. We characterized TACE-mediated constitutive ectodomain shedding of ACE2 using wild-type Chinese Hamster Ovary (WT-CHO), the TACE-mutant M2 (M2-CHO) cells, and EC-4 and EC-2 cells that are fibroblasts from wild-type and TACE-null mice, respectively. ACE2 was constitutively cleaved to release two distinct major soluble forms. The deglycosylated molecular masses of the larger (LSF) and smaller soluble form (SSF) were approximately 80 and 70 kDa, respectively. These forms had equivalent enzyme activities. Reduced shedding for the LSF from M2-CHO and EC-2 cells when compared with WT-CHO and EC-4 cells, respectively, was noted. TACE reconstitution in EC-2 cells expressing ACE2 resulted in increase in LSF but not SSF release, demonstrating a main role of TACE in LSF release and distinct regulations of release of the two soluble forms. Deletions of the juxtamembrane region of ACE2 reduced LSF release in CHO cell lines, whereas it abolished TACE-induced shedding in EC-2 cells. Analysis of TACE structural domains confirmed that the active site in the catalytic domain is essential for ACE2 shedding but that noncatalytic domains also play additional roles. These results demonstrate selective and specific regulation of constitutive shedding of ACE2 by TACE.