Complement Membrane Attack Complexes Disrupt Proteostasis to Function as Intracellular Alarmins.

Internalized pools of membrane attack complexes (MACs) promote NF-kB and dysregulated tissue inflammation. Here, we show that C9, a MAC-associated protein, promotes loss of proteostasis to become intrinsically immunogenic. Surface-bound C9 is internalized into Rab5 + endosomes whose intraluminal acidification promotes C9 aggregates. A region within the MACPF/CDC domain of C9 stimulates aggrephagy to induce NF-kB, inflammatory genes, and EC activation. This process requires ZFYVE21, a Rab5 effector, which links LC3A/B on aggresome membranes to RNF34-P62 complexes to mediate C9 aggrephagy. C9 aggregates form in human tissues, C9-associated signaling responses occur in three mouse models, and ZFYVE21 stabilizes RNF34 to promote C9 aggrephagy in vivo. Gene-deficient mice lacking ZFYVE21 in ECs showed reduced MAC-induced tissue injury in a skin model of chronic rejection. While classically defined as cytotoxic effectors, MACs may impair proteostasis, forming aggregates that behave as intracellular alarmins.

Circulating T cell specific extracellular vesicle profiles in cardiac allograft acute cellular rejection.

There is a critical need for biomarkers of acute cellular rejection (ACR) in organ transplantation. We hypothesized that ACR leads to changes in donor-reactive T cell small extracellular vesicle (sEV) profiles in transplant recipient circulation that match the kinetics of alloreactive T cell activation. In rodent heart transplantation, circulating T cell sEV quantities (P < .0001) and their protein and mRNA cargoes showed time-specific expression of alloreactive and regulatory markers heralding early ACR in allogeneic transplant recipients but not in syngeneic transplant recipients. Next generation sequencing of their microRNA cargoes identified novel candidate biomarkers of ACR, which were validated by stem loop quantitative reverse transcription polymerase chain reaction (n = 10). Circulating T cell sEVs enriched from allogeneic transplant recipients mediated targeted cytotoxicity of donor cardiomyocytes by apoptosis assay (P < .0001). Translation of the concept and EV methodologies to clinical heart transplantation demonstrated similar upregulation of circulating T cell sEV profiles at time points of grade 2 ACR (n = 3 patients). Furthermore, T cell receptor sequencing of T cell sEV mRNA cargo demonstrated expression of T cell clones with intact complementarity determining region 3 signals. These data support the diagnostic potential of T cell sEVs as noninvasive biomarker of ACR and suggest their potential functional roles.

Clinical implications of Type 2 diabetes on outcomes after cardiac transplantation.

BACKGROUND: T2D is an increasingly common disease that is associated with worse outcomes in patients with heart failure. Despite this, no contemporary study has assessed its impact on heart transplantation outcomes. This paper examines the demographics and outcomes of patients with type 2 diabetes (T2D) undergoing heart transplantation. METHODS: Using the United Network for Organ Sharing (UNOS) database, patients listed for transplant were separated into cohorts based on history of T2D. Demographics and comorbidities were compared, and cox regressions were used to examine outcomes. RESULTS: Between January 1st, 2011 and June 12th, 2020, we identified 9,086 patients with T2D and 23,676 without T2D listed for transplant. The proportion of patients with T2D increased from 25.2% to 27.9% between 2011 and 2020. Patients with T2D were older, more likely to be male, less likely to be White, and more likely to pay with public insurance (p<0.001, all). After adjustment, T2D patients had a lower likelihood of transplantation (Hazard Ratio [HR]: 0.93, CI: 0.90-0.96, p<0.001) and a higher likelihood of post-transplant mortality (HR: 1.30, CI: 1.20-1.40, p<0.001). Patients with T2D were more likely to be transplanted in the new allocation system compared to the old allocation system (all, p<0.001). CONCLUSIONS: Over the last ten years, the proportion of heart transplant recipients with T2D has increased. These patients are more likely to be from traditionally underserved populations. Patients with T2D have a lower likelihood of transplantation and a higher likelihood of post-transplant mortality. After the allocation system change, likelihood of transplantation has improved for patients with T2D.

Redo mitral valve surgery: A totally endoscopic, robotic-assisted approach for adhesiolysis and complex repair.

We describe our technique for totally endoscopic, robotic-assisted thoracic and pericardial adhesiolysis and redo complex mitral valve repair.

Membrane attack complexes, endothelial cell activation, and direct allorecognition.

Endothelial cells (ECs) form a critical immune interface regulating both the activation and trafficking of alloreactive T cells. In the setting of solid organ transplantation, donor-derived ECs represent sites where alloreactive T cells encounter major and minor tissue-derived alloantigens. During this initial encounter, ECs may formatively modulate effector responses of these T cells through expression of inflammatory mediators. Direct allorecognition is a process whereby recipient T cells recognize alloantigen in the context of donor EC-derived HLA molecules. Direct alloresponses are strongly modulated by human ECs and are galvanized by EC-derived inflammatory mediators. Complement are immune proteins that mark damaged or foreign surfaces for immune cell activation. Following labeling by natural IgM during ischemia reperfusion injury (IRI) or IgG during antibody-mediated rejection (ABMR), the complement cascade is terminally activated in the vicinity of donor-derived ECs to locally generate the solid-phase inflammatory mediator, the membrane attack complex (MAC). Via upregulation of leukocyte adhesion molecules, costimulatory molecules, and cytokine trans-presentation, MAC strengthen EC:T cell direct alloresponses and qualitatively shape the alloimmune T cell response. These processes together promote T cell-mediated inflammation during solid organ transplant rejection. In this review we describe molecular pathways downstream of IgM- and IgG-mediated MAC assembly on ECs in the setting of IRI and ABMR of tissue allografts, respectively. We describe work demonstrating that MAC deposition on ECs generates 'signaling endosomes' that sequester and post-translationally enhance the stability of inflammatory signaling molecules to promote EC activation, a process potentiating EC-mediated direct allorecognition. Additionally, with consideration to first-in-human xenotransplantation procedures, we describe clinical therapeutics based on inhibition of the complement pathway. The complement cascade critically mediates EC activation and improved understanding of relevant effector pathways will uncover druggable targets to obviate dysregulated alloimmune T cell infiltration into tissue allografts.

Double Papillary Muscle Relocation: A Totally Endoscopic, Robotic-Assisted Approach.

We detail our technique for totally endoscopic, robotic-assisted mitral valve repair with the reimplantation of a ruptured papillary muscle head supported by double papillary muscle relocation and mitral annuloplasty for the treatment of nonacute ischemic mitral regurgitation.

Totally endoscopic, robotic-assisted tricuspid valve repair with neochords.

We describe our technique for totally endoscopic, robotic-assisted tricuspid valve repair with neochords and annuloplasty in a high-risk, obese patient.

Institution representation in publications reporting mitral valve repair durability: A scoping review.

BACKGROUND: Mitral valve repair durability currently plays a key role in operative decision making and in defining optimal surgical practice. However, mitral valve durability outcomes measures are not captured by national registries and limited to centers that publish their outcomes. In this study, we aim to describe the scope of institutions represented by reports describing durability outcomes after mitral valve repair within the contemporary literature. METHODS AND RESULTS: A scoping review of the literature was performed to extract abstracts potentially reporting mitral valve operation outcomes published between 2000-2019. 370 full text articles reporting mitral valve durability outcomes by either reoperation rate or rate of recurrent mitral regurgitation met criteria for analysis. Study characteristics including case volume, country and institution of origin, and surgeon volume were extracted and used to calculate the proportion of total cases in the top 3, 5, and 10 represented countries and institutions by the sum of reported mitral valve repairs described. The top 5 of 21 countries represented 78.9% of the mitral valve repair cases described. The top 3 most represented institutions described 20,120 (37.3%) of all mitral valve repairs in 58 (33.9%) single-center studies. CONCLUSION: Published mitral valve repair durability data must be interpreted with caution when used to derive policies and practice recommendations that govern the cardiovascular community at large.

Trends in transcatheter and surgical aortic valve replacement in the United States, 2008-2018.

We conducted a retrospective study using the NIS database from 2008 to 2018 to examine the most contemporary national hospitalization trends of transcatheter (TAVR) and surgical (SAVR) aortic valve replacement regarding volume, patient and hospital demographics and economics, resource utilization, total cost of stay, and in-hospital mortality. We demonstrate that TAVR procedures have been performed on a slow by steadily diversifying patient population while volume has grown significantly, while in-hospital mortality, length of stay, discharge home, and costs have improved, whereas these metrics have generally remained stable for SAVR. These trends will likely drive continued TAVR adoption, greatly expanding the overall aortic stenosis patient population eligible for AVR.

Impact of Obesity on Heart Transplantation Outcomes.

Background Patients with obesity and advanced heart failure face unique challenges on the path to heart transplantation. There are limited data on waitlist and transplantation outcomes in this population. We aimed to evaluate the impact of obesity on heart transplantation outcomes, and to investigate the effects of the new organ procurement and transplantation network allocation system in this population. Methods and Results This cohort study of adult patients listed for heart transplant used the United Network for Organ Sharing database from January 2006 to June 2020. Patients were stratified by body mass index (BMI) (18.5-24.9, 25-29.9, 30-34.9, 35-39.9, and 40-55 kg/m2). Recipient characteristics and donor characteristics were analyzed. Outcomes analyzed included transplantation, waitlist death, and posttransplant death. BMI 18.5 to 24.9 kg/m2 was used as the reference compared with progressive BMI categories. There were 46 645 patients listed for transplantation. Patients in higher BMI categories were less likely to be transplanted. The lowest likelihood of transplantation was in the highest BMI category, 40 to 55 kg/m2 (hazard ratio [HR], 0.19 [0.05-0.76]; P=0.02). Patients within the 2 highest BMI categories had higher risk of posttransplantation death (HR, 1.29; P<0.001 and HR, 1.65; P<0.001, respectively). Left ventricular assist devices among patients in obese BMI categories decreased after the allocation system change (P<0.001, all). After the change, patients with obesity were more likely to undergo transplantation (BMI 30-35 kg/m2: HR, 1.31 [1.18-1.46], P<0.001; BMI 35-55 kg/m2: HR, 1.29 [1.06-1.58]; P=0.01). Conclusions There was an inverse relationship between BMI and likelihood of heart transplantation. Higher BMI was associated with increased risk of posttransplant mortality. Patients with obesity were more likely to undergo transplantation under the revised allocation system.

Trends and Outcomes of Cardiac Transplantation in the Lowest Urgency Candidates.

Background Because of discrepancies between donor supply and recipient demand, the cardiac transplantation process aims to prioritize the most medically urgent patients. It remains unknown how recipients with the lowest medical urgency compare to others in the allocation process. We aimed to examine differences in clinical characteristics, organ allocation patterns, and outcomes between cardiac transplantation candidates with the lowest and highest medical urgency. Methods and Results We performed a retrospective analysis of the United Network for Organ Sharing database. Patients listed for cardiac transplantation between January 2011 and May 2020 were stratified according to status at time of transplantation. Baseline recipient and donor characteristics, waitlist survival, and posttransplantation outcomes were compared in the years before and after the 2018 allocation system change. Lower urgency patients in the old system were older (58.5 versus 56 years) and more likely female (54.4% versus 23.8%) compared with the highest urgency patients, and these trends persisted in the new system (P<0.001, all). Donors for the lowest urgency patients were more likely older, female, or have a history of cytomegalovirus, hepatitis C, or diabetes (P<0.01, all). The lowest urgency patients had longer waitlist times and under the new allocation system received organs from shorter distances with decreased ischemic times (178 miles versus 269 miles, 3.1 versus 3.5 hours; P<0.001, all). There was no difference in posttransplantation survival (P<0.01, all). Conclusions Patients transplanted as lower urgency receive hearts from donors with additional comorbidities compared with higher urgency patients, but outcomes are similar at 1 year.

The impact of trainees' working hour regulations on outcome in CABG and valve surgery in the State of New York.

BACKGROUND AND AIM: In 2011, the Accreditation Council for Graduate Medical Education (ACGME) restricted the first-year residents' duty-hour to less than 16-hour shifts, decreased the maximum shift duration for senior residents, and increased minimum time off after on-call duties. Whether these changes may have impacted the outcomes in cardiac surgery remains unclear. METHODS: We performed a difference-in-difference analysis of the New York State Cardiac Surgery Reporting System data in 2004-2006 (before the duty-hour policies change) and 2014-2016 (after the change). We evaluated differences in 30-day risk-adjusted mortality rates (RAMR) in coronary artery bypass grafting (CABG) and valve surgeries, stratifying data by hospital type: teaching hospitals (TH) versus nonteaching hospitals (NTH). NTH served as the control not affected by the duty-hour policies. RESULTS: (1) The overall surgical volume for CABG surgery has decreased over time (37,645-24,991), while the volume for valve surgery remained similar (20,969-21,532); (2) TH had better short-term outcomes for CABG procedures during 2014-2016 (median RAMR: 1.01% vs. 1.55% in TH vs. NTH, respectively; p = .025) as well as for valve procedures during both 2004-2006 (5.16% vs. 7.49%, p = .020) and 2014-2016 (2.59% vs. 4.09%, p = .033); (3) at difference-in-difference analysis, trainees' duty-hour regulations were not associated with worsening short-term outcomes in both CABG (p = .296) and valve (p = .651) procedures performed in TH. CONCLUSION: The introduction of the 2011 trainees' duty-hour regulations was not associated with worse short-term outcomes for CABG and valve surgery performed in the State of NY by TH.

Brief report: Cannabis and opioid use disorder among heart failure admissions, 2008-2018.

BACKGROUND: In the United States, both cannabis use disorder (CUD) and opioid use disorder (OUD) have increased in prevalence. The prevalence, demographics, and costs of CUD and OUD are not well known in heart failure (HF) admissions. This study aimed to use a national database to examine the prevalence, demographics, and costs associated with CUD and OUD in HF. METHODS: This study used the National Inpatient Sample from 2008 to 2018 to identify all primary HF admissions with and without the co-diagnosis of OUD or CUD using International Classification for Diagnosis, diagnosis codes. Demographics, costs, and trends were examined. RESULTS: Between 2008 and 2018, we identified 11,692,995 admissions for HF of which 84,796 (0.8%) had a co-diagnosis of CUD only, and 67,137 (0.6%) had a co-diagnosis of OUD only. The proportion of HF admissions with CUD significantly increased from 0.3% in 2008 to 1.3% in 2018 (p<0.001). The proportion of HF admissions with OUD significantly increased from 0.2% in 2008 to 1.1% in 2018 (p<0.001). Patients admitted with HF and either CUD or OUD were younger, more likely to be Black, and from lower socioeconomic backgrounds (p<0.001, all). HF admissions with OUD or CUD had higher median costs compared to HF admissions without associated substance abuse diagnoses ($8,611 vs. $8,337 for CUD HF and $10,019 vs. $8,337 for OUD HF, p<0.001 for both). CONCLUSIONS: Among discharge records for HF, CUD and OUD are increasing in prevalence, significantly affect underserved populations and are associated with higher costs of stay. Future research is essential to better delineate the cause of these increased costs and create interventions, particularly in underserved populations.

Mechanical ventilation at the time of heart transplantation and associations with clinical outcomes.

AIMS: The impact of mechanical ventilation (MV) at the time of heart transplantation is not well understood. In addition, MV was recently removed as a criterion from the new US heart transplantation allocation system. We sought to assess for the association between MV at transplantation and 1-year mortality. METHODS AND RESULTS: We utilized the United Network for Organ Sharing database and included all adult, single organ heart transplantations from 1990 to 2019. We utilized multivariable logistic regression adjusting for demographics, comorbidities, and markers of clinical acuity. We identified 60 980 patients who underwent heart transplantation, 2.4% (n = 1431) of which required MV at transplantation. Ventilated patients were more likely to require temporary mechanical support, previous dialysis, and had a shorter median waitlist time (21 vs. 95 days, P < 0.001). At 1 year, the mortality was 33.7% (n = 484) for ventilated patients and 11.7% (n = 6967) for those not ventilated at the time of transplantation (log-rank P < 0.001). After multivariable adjustment, patients requiring MV continued to have a substantially higher 90-day [odds ratio (OR) 3.20, 95% confidence interval (CI): 2.79-3.66, P < 0.001] and 1-year mortality (OR 2.67, 95% CI: 2.36-3.03, P < 0.001). For those that survived to 90 days, the adjusted mortality at 1 year continued to be higher (OR 1.48, 95% CI: 1.16-1.89, P = 0.002). CONCLUSION: We found a strong association between the presence of MV at heart transplantation and 90-day and 1-year mortality. Future studies are needed to identify which patients requiring MV have reasonable outcomes, and which are associated with substantially poorer outcomes.

Evaluation of Racial and Ethnic Disparities in Cardiac Transplantation.

Background Racial and ethnic disparities contribute to differences in access and outcomes for patients undergoing heart transplantation. We evaluated contemporary outcomes for heart transplantation stratified by race and ethnicity as well as the new 2018 allocation system. Methods and Results Adult heart recipients from 2011 to 2020 were identified in the United Network for Organ Sharing database and stratified into 3 groups: Black, Hispanic, and White. We analyzed recipient and donor characteristics, and outcomes. Among 32 353 patients (25% Black, 9% Hispanic, 66% White), Black and Hispanic patients were younger, more likely to be women and have diabetes mellitus or renal disease (all, P<0.05). Over the study period, the proportion of Black and Hispanic patients listed for transplant increased: 21.7% to 28.2% (P=0.003) and 7.7% to 9.0% (P=0.002), respectively. Compared with White patients, Black patients were less likely to undergo transplantation (adjusted hazard ratio [aHR], 0.87; CI, 0.84-0.90; P<0.001), but had a higher risk of post-transplant death (aHR, 1.14; CI, 1.04-1.24; P=0.004). There were no differences in transplantation likelihood or post-transplant mortality between Hispanic and White patients. Following the allocation system change, transplantation rates increased for all groups (P<0.05). However, Black patients still had a lower likelihood of transplantation than White patients (aHR, 0.90; CI, 0.79-0.99; P=0.024). Conclusions Although the proportion of Black and Hispanic patients listed for cardiac transplantation have increased, significant disparities remain. Compared with White patients, Black patients were less likely to be transplanted, even with the new allocation system, and had a higher risk of post-transplantation death.