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.

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.

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.

The Impact of Depression on Outcomes in Patients With Heart Failure and Reduced Ejection Fraction Treated in the GUIDE-IT Trial.

BACKGROUND: It remains unclear why depression is associated with adverse outcomes in patients with heart failure (HF). We examine the relationship between depression and clinical outcomes among patients with HF with reduced ejection fraction managed with guideline-directed medical therapy (GDMT). METHODS AND RESULTS: Using the GUIDE-IT trial, 894 patients with HF with reduced ejection fraction were stratified according to a history of depression, and Cox proportional hazards regression modeling was used to examine the association with outcomes. There were 140 patients (16%) in the overall cohort who had depression. They tended to be female (29% vs 46%, P < .001) and White (67% vs 53%, P = .002). There were no differences in GDMT rates at baseline or at 90 days; nor were there differences in target doses of these therapies achieved at 90 days (NS, all). amino-terminal pro-B-type natriuretic peptide levels at all time points were similar between the cohorts (P > .05, all). After adjustment, depression was associated with all-cause hospitalizations (hazard ratio, 1.42, 95% confidence interval 1.11-1.81, P < .01), cardiovascular death (hazard ratio, 1.69, 95% confidence interval 1.07-2.68, P = .025), and all-cause mortality (hazard ratio, 1.54, 95% confidence interval 1.03-2.32, P = .039). CONCLUSIONS: Depression impacts clinical outcomes in HF regardless of GDMT intensity and amino-terminal pro-B-type natriuretic peptide levels. This finding underscores the need for a focus on mental health in parallel to achievement of optimal GDMT in these patients. TRIAL REGISTRATION: NCT01685840, https://clinicaltrials.gov/ct2/show/NCT01685840.

Impact of chronic lung disease on quality-of-life outcomes in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: As the symptoms for both chronic lung disease (CLD) and aortic stenosis (AS) frequently overlap, it may be challenging to determine the degree of symptomatic improvement expected for a patient with CLD after correction of AS. Our aim was to determine if patients with CLD have the same degree of quality-of-life improvement following transcatheter aortic valve replacement (TAVR) as patients without CLD. METHODS: A retrospective review of 238 TAVR patients from January 2017 to November 2018 who underwent preoperative pulmonary function tests and completed 30-day follow-up was performed. Patients were identified as having CLD with FEV1 more than 75% predicted. Postoperative outcomes and changes in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) were compared between groups. RESULTS: Of the 238 patients identified, 143 (60.0%) had CLD, 50 (35.0%) of whom had an obstructive disease pattern. Patients with CLD were more likely to be male, had higher rates of peripheral artery disease, and had lower baseline ejection fraction. There was no difference in STS Predicted Risk of Mortality, but patients with CLD were more likely to be designated as high-risk by surgeon evaluation. While initial and follow-up KCCQ-12 was lower for patients with CLD, there was no significant difference in degree of improvement (p = .900). When comparing patients with obstructive lung disease (FEV1/FVC < 0.70) to those without CLD, there was also no significant difference in the change of quality of life (p = .720). CONCLUSION: Although patients with concomitant severe AS and CLD have reduced baseline quality of life compared to patients without CLD, they experience a comparable degree of improvement following TAVR.

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.

Relationship of surgeon experience and outcomes of surgery for degenerative mitral valve disease.

OBJECTIVE: To assess the impact of surgeon experience on the outcomes of degenerative mitral valve disease. METHODS: We reviewed all patients who had surgery for degenerative mitral valve disease between 2011 and 2016. Experienced surgeon was defined as performing ≥ 25 mitral valve operations/year. Patient characteristics and outcomes were compared. Competing risk analysis was performed to identify factors associated with mitral regurgitation (MR) recurrence. Survival analysis for mortality was done using Kaplan Meier curve and Cox proportional hazard method. RESULTS: There were 575 patients treated by 9 surgeons for severe MR caused by degenerative mitral valve disease between 2011 and 2016. Three experienced surgeons performed 77.2% of the operations. Patients treated by less experienced surgeons had worse comorbidity profile and were more likely to have an urgent or emergent operation (p = .001). Experienced surgeons were more likely to attempt repair (p = .024), to succeed in repair (94.7% vs. 87%; p = .001), had shorter cross-clamp times (p = .001), and achieved higher repair rate (81.3% vs. 69.7%; p = .005). Experienced surgeons were more likely to use neochordae (p = .001) and less likely to use chordae transfer (p = .001). Surgeon experience was not associated with recurrence of moderate or higher degree of MR after repair but was an independent risk factor for mortality (HR = 2.64; p = .002). CONCLUSIONS: Techniques of degenerative mitral valve surgery differ with surgeon experience, with higher rates of repair and better outcomes associated with more experienced surgeons.

Variants of the aortic arch in adult general population and their association with thoracic aortic aneurysm disease.

BACKGROUND: Query a single institution computed tomography (CT) database to assess the prevalence of aortic arch anomalies in general adult population and their potential association with thoracic aortopathies. METHODS: CT chest scan reports of patients aged 50-85 years old performed for any indication at a single health system between 2013 and 2016 were included in the analysis. Characteristics of patients with and without aortic arch anomalies were compared by t test and Fisher exact tests. Logistic regression analysis was performed to assess for independent risk factors of thoracic aortic aneurysm (TAA). RESULTS: Of 21,336 CT scans, 603 (2.8%) described arch anomalies. Bovine arch (n = 354, 58.7%) was the most common diagnosis. Patients with arch anomalies were more likely to be female (p < .001), non-Caucasian(p < .001), and hypertensive (p < .001). Prevalence of TAA in arch anomalies group was 10.8% (n = 65) compared to 4.1% (n = 844) in the nonarch anomaly cohort (p < .001). The highest prevalence of thoracic aneurysm was associated with right-sided arch combined with aberrant left subclavian configuration (33%), followed by bovine arch (13%), and aberrant right subclavian artery (8.2%). On binary logistic regression, arch anomaly (OR = 2.85 [2.16-3.75]), aortic valve pathology (OR 2.93 [2.31-3.73]), male sex (OR 2.38 [2.01-2.80]), and hypertension (OR 1.47 [1.25-1.73]) were significantly associated with increased risk of thoracic aneurysm disease. CONCLUSIONS: Reported prevalence of aortic arch anomalies by CT imaging in the older adult population is approximately 3%, with high association of TAA (OR = 2.85) incidence in this subgroup. This may warrant a more tailored surveillance strategy for aneurysm disease in this subpopulation.

Transition to Advanced Therapies in Elderly Patients Supported by Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: Although the use of extracorporeal membrane oxygenation (ECMO) continues to increase, very little is known about how age influences the transition to definitive advanced therapies. METHODS: Using the National Inpatient Sample database from 2008 to 2017, we analyzed patients supported by ECMO for cardiogenic shock and separated patients into 2 age cohorts: < 65 years and ≥ 65 years. Primary outcomes of interest included the proportion of patients undergoing orthotopic cardiac transplantation (OHT) and left ventricular assist device (LVAD) implantation. RESULTS: Over the study period, we identified 16,132 hospitalizations of people with cardiogenic shock requiring ECMO support. Significantly fewer patients in the older group underwent OHT compared to the younger group (0.4% vs 1.2%, P < 0.001). Compared to the younger group, a lower proportion of those ≥ 65 years received an LVAD (3.7% vs 5.8%, P < 0.001). LVAD implantation increased over the study period in both age cohorts, whereas OHT increased only in the < 65 group (P < 0.05, all). After multivariable adjustment, patients in the oldest age group were still less likely to receive an LVAD (odds ratio 0.54; confidence interval: 0.43-0.69, P < 0.001) and continued to have the highest odds of in-hospital mortality (odds ratio 1.53; confidence interval : 1.39-1.69, P < 0.001). CONCLUSIONS: Survival of patients ≥ 65 years requiring ECMO for cardiogenic shock is poor and less commonly includes transition to definitive advanced therapies. Although we must stress that no patient should be denied ECMO based solely on age, we believe our results may be helpful for providers when counseling patients and their families.

United States national trends in comorbidity and outcomes of adult cardiac surgery patients.

BACKGROUND: Comorbidity profiles of cardiac surgery patients are known to have changed over time, but modern national trends in these comorbidities and outcomes are not described. This study describes comorbidity trends over time for common adult cardiac surgery procedures. METHODS: A retrospective, cross-sectional analysis of the National Inpatient Sample was conducted for years 2005-2014. Hospitalizations with coronary artery bypass grafting (CABG), aortic valve replacement (AVR), and mitral valve repair/replacement (MVRR), as well as combined CABG/valve operations, were identified by ICD-9 procedure codes. Comorbidities were defined based on ICD-9 codes to discriminate between comorbidities and complications. Surgical volume, patient age, in-hospital mortality, and length of stay trends over time were evaluated by linear regression. RESULTS: Incidence increased for AVR, MVRR, and CABG + AVR and declined for CABG and CABG + MVRR (P < .001). The mean number of comorbidities across all surgeries increased from 1.4 to 1.9 (P < .001). Length of stay declined for AVR, CABG + AVR, and CABG + MVRR (P < .001) with an overall decline from 10.1 to 9.7 days (P = .003). In-hospital mortality decreased in all categories over time (P < .001). Overall, in-hospital mortality decreased from 2.9% to 2.3% (P < .001). CONCLUSIONS: Despite increasing comorbidity in cardiac surgery, operations are being conducted with fewer in-hospital mortalities across all types of surgery and decreasing length of stay for most types of surgery, which should inform the frequency of risk model updates and raise questions of the applicability of earlier studies in cardiac surgery to the modern population.

Drug use associated tricuspid valve infective endocarditis in pregnancy.

BACKGROUND AND AIM: We report a case of intravenous drug use associated tricuspid valve endocarditis in a 28-year-old pregnant female at 26-week gestation. METHODS: Patient management required a multidisciplinary collaboration between cardiac surgery, obstetrics and gynecology, and neonatal critical care. RESULTS: Despite appropriate intravenous antibiotics, the patient developed life-threatening complications and underwent planned cesarean delivery at 28 weeks 6 days gestation followed by interval tricuspid valve replacement 1 week later. CONCLUSIONS: Both the patient and her infant were successfully managed through the perioperative period.

Pediatric thymectomy: a study of national trends in demographics, short-term outcomes, and cost.

BACKGROUND: Thymectomy in pediatric patients is an effective treatment for myasthenia gravis (MG), thymic neoplasms, and other rarer pathologies. It is an uncommon procedure in children and studies have focused on small, single-institution cohorts. We sought to better characterize its use by utilizing a national database. METHODS: The Kids' Inpatient Database was used to identify hospital discharge records of patients ≤ 20 years old who underwent thymectomy. A retrospective cross-sectional analysis for 2003, 2006, 2009, and 2012 was performed. Trends in patient characteristics, diagnosis, surgical approach, and short-term outcomes were analyzed. Risk factors were identified using univariate and multivariate analyses. RESULTS: There were 600 thymectomies identified. MG was the most common indication. Thoracoscopy is being used increasingly for all diagnoses except malignancy. The overall morbidity rate was 14.0%, with respiratory complications representing the largest group. No in-hospital deaths were identified. Private insurance was associated with shorter hospital stays and lower costs. Hispanic race was associated with more complications, longer stays, and higher costs. Thoracoscopic thymectomies had shorter stays than open procedures. CONCLUSION: Thymectomy in the pediatric population is being performed safely, with low morbidity and no identified mortalities. Thoracoscopy results in reduced length of stay and is being used increasingly. Of note, socioeconomic and racial factors impact outcomes.

Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial.

BACKGROUND: Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers. METHODS AND FINDINGS: Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. CONCLUSIONS: Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01168401.

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.

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.

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.