Objectives To evaluate the association between early mechanical circulatory support (MCS) use and mortality in patients with cardiogenic shock (CS). Patients and Methods We identified adults aged 18 years or older hospitalized from October 1, 2015, to June 30, 2023, with a diagnosis of CS. Patients receiving MCS within the first 2 days of admission were included in the study. Using inverse probability of treatment weighting, we assessed the association between receiving MCS on day 1 vs day 2 and in-hospital mortality. Results Among 69,085 patients, 75.7% (n=52,307) and 24.3% (n=16,778) received MCS on day 1 and day 2, respectively. Devices included the intra-aortic balloon pump (62.9% [n=43,467]), percutaneous left ventricular assist device (25.0% [n=17,236]), and extracorporeal membrane oxygenation (22.0% [n=14,920]). The unadjusted mortality was 38.7% (n= 20,225 of 52,307) and 37.9% (n= 6,353 of 16,778) for MCS use on day 1 vs day 2, respectively (P=.06). After inverse probability of treatment weighting, MCS on day 1 was associated with a 7.4% (weighted mean; 95% CI, −8.4% to −6.4%; P<.001) reduction in mortality. Results persisted when each device was assessed separately and among patients presenting with acute myocardial infarction or heart failure as the shock etiology (all P<.001). When assessed by admission Society for Cardiovascular Angiography and Interventions shock stage, MCS on day 1 remained associated with lower mortality for each stage (stage C, −11.1%; 95% CI, −12.4 to −9.8%; stage D, −9.1%; 95% CI, −10.8% to −7.3%; stage E, −2.7%; 95% CI, −5.0% to −0.4%). Conclusion For patients with CS, MCS on the first compared with the second day of admission was associated with a lower in-hospital mortality.

Chronic rejection of allografts appears mechanistically distinct from acute antibody-mediated and or acute cell-mediated rejection. Histological features point to roles for alloantibody and lymphocytic infiltrates, and allograft vasculopathy is a common feature in chronic rejection of several different solid organs. Vasculopathy, in turn, can cause late graft failure due to chronic ischemia, parenchymal cell loss, and replacement fibrosis. Molecular analyses implicate graft vascular endothelial cells in this process. Here, we review evidence favoring a hypothesis linking alloantibody and complement to induction of endothelial cell surface expression and trans-presentation of IL-15 as a critical signal that enhances lymphocyte activation during antigen-mediated recruitment of alloreactive T cells. These T cells trans-migrate into the intima and secrete interferon-γ, which acts both on vascular smooth muscle cells within the arterial wall to stimulate their proliferation, resulting in vasculopathy, and back on the endothelial cells to provide positive feedback for this sequence of events.

Expression of IL-15 on the surface of human graft endothelial cells (ECs) bound to the IL-15Rα subunit can increase the activation of CTLs, potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1β synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-κB. In this article, we report that cultured human ECs express eight differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-κB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p anti-miR can induce EC surface expression of IL-15/IL-15Rα in the absence of complement activation or of IL-1, enabling IL-15 transpresentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for transpresentation.

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.

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.

Mitral regurgitation is a common disorder with serious consequences for patient morbidity, including arrhythmias, heart failure, and stroke, as well as mortality.1 For acceptable-risk patients with severe, symptomatic disease or evidence of left ventricular (LV) dysfunction, surgical repair at a center of excellence is widely accepted as the gold standard therapy2; however, no formal recommendations for optimal repair strategies exist, likely due to the multiple and complex phenotyping of primary mitral valve disease.

Purpose Thoracic organ recovery has historically been conducted by individual center specific procurement surgeons. The recent rise in direct procurement and machine perfusion of cardiac allografts following donation after cardiac death has added complexity, cost and challenges associated with human resource allocation. Here, we report on the successful utilization of an independent procurement team for the recovery of cardiac allografts following circulatory death. Methods This was a single-center review of all patients who underwent DCD heart transplantation following recovery by our individual center specific team (CST) vs. an independent national procurement service (NPS) from August 1st 2020, to October 15th 2022. This cohort includes all DCD heart transplantations done at this institution. Data was obtained through manual chart review. A total of 20 patients were identified. All cardiac allografts underwent direct procurement and machine perfusion using the TransMedics® OCSTM. Results Median recipient age was 49 ± 14 years in the CST group and in the NPS group 52 ± 12, p=0.64 (see Table). The CST group had 7 males (78%) compared to 9 males (82%) in the NPS group, p=1.0. In the CST group, 1 patient (11%) had a previously implanted HeartMate 3 compared to 4 patients (36%) in the NPS group, p=0.32. The mean donor age was similar in both groups and all donors were male. Median warm ischemia time was 19 minutes (IQR 18-24) in the CST group compared to 23 minutes (IQR 24-28) in the NPS group. In the CST group, 4 patients (44%) required postoperative mechanical support compared to 3 patients (27%) in the NPS group, p=0.35. There were no deaths within 30 days from transplantation. The overall estimated 180-day survival was 95% (number at risk 10). Conclusion The early experience with DCD heart transplantation and utilization of an independent procurement team at our center has been very successful with excellent short-term survival.

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.

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.

Since its discovery in the 1940s, warfarin has served as the principal vitamin K antagonist and anticoagulant.1Ziakas P.D. Kourbeti I.S. Poulou L.S. et al.Medicare Part D prescribing for direct oral anticoagulants in the United States: cost, use and the “rubber effect.”.PloS One. 2018; 13e0198674Google Scholar Warfarin administration has well-known challenges, including frequent monitoring and food and medication interactions, and consequences, including gastrointestinal and neurologic bleeds. Increasingly clinical and mechanistic evidence supports an association with warfarin use and calcific valve disease.2Palaniswamy C. Sekhri A. Aronow W.S. et al.Association of warfarin use with valvular and vascular calcification: a review.Clin Cardiol. 2011; 34: 74-81Google Scholar In this issue of The Annals of Thoracic Surgery, Venardos and colleagues3Venardos N. Gergen A.K. Jarrett M. et al.Warfarin induces calcification of the aortic valve through extracellular signal-regulated kinase 1/2 and β-catenin signaling.Ann Thorac Surg. 2022; 113: 824-836Google Scholar describe a mechanism by which osteogenic changes of the aortic valve interstitial cells are induced. They demonstrate that in vitro exposure to warfarin induces calcific nodule formation in diseased aortic valve interstitial cells, that this is specific to warfarin exposure, and that this is mediated by extracellular signal-regulated kinase 1/2 and β-catenin signaling, leading to runt-related transcription factor 2 expression. With millions of individuals taking warfarin, even a small risk of long-term cardiovascular effects translates to potentially tens of thousands of individuals suffering the consequences. The novel description of long-term cardiovascular consequences of common medications is increasingly part of the modern pharmacologic and regulatory zeitgeist; however, delays in translating findings to regulatory warnings remain. For instance, despite convincing evidence of an association with aortopathies and fluoroquinolones dating to 2015,4Lee C.-C. Lee M-tG. Chen Y.-S. et al.Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone.JAMA Intern Med. 2015; 175: 1839-1847Google Scholar it was not until years later that the US Food and Drug Administration added a black box warning to fluoroquinolones. Although perhaps not as dramatic as acute aortic pathologies, the risk of induced aortic valve calcification to human life cannot be understated; even with mild (stage A or “at-risk” states) aortic valve disease patients have a 50% increase in risk of myocardial infarction or cardiovascular death at 5 years.5Kanwar A. Thaden J.J. Nkomo V.T. Management of patients with aortic valve stenosis.Mayo Clin Proc. 2018; 93: 488-508Google Scholar With the number of individuals on warfarin therapy, one wonders how many otherwise healthy persons have been committed to a lifetime of increased cardiovascular risk or had that risk escalated from merely at risk to progressive or even end-stage disease? As demonstrated by Venardos and colleagues, there is a clear underlying mechanistic explanation for the clinical observations of other groups who have associated warfarin administration with calcific changes of the aortic valve. Despite the comfort of managing familiar medications, the findings described offer support for continued vigilance of even the oldest members of the modern pharmacopeia. Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and β-catenin SignalingThe Annals of Thoracic SurgeryVol. 113Issue 3PreviewRecent clinical evidence suggests an association between warfarin use and calcification of the aortic valve. We sought to determine the effect of warfarin on aortic valve interstitial cell (AVIC) osteogenic protein expression and the signaling pathways by which this effect is mediated. Full-Text PDF Editor’s Choice: Landmark in XenotransplantationThe Annals of Thoracic SurgeryVol. 113Issue 3PreviewOn Friday January 7, 2022, David Bennett, a 57-year-old man, received a heart transplant from a genetically modified pig. The extensive media coverage that ensued, starting with a full-length article in The New York Times the following Monday, reveals that Mr Bennet had been supported with extracorporeal membrane oxygenation for several weeks, disqualifying him from heart transplant at major centers his team approached, and that he was doing well after a technically straightforward operation, with extracorporeal membrane oxygenation successfully weaned a few days postoperatively. Full-Text PDF

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.

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

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

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.

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.

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.

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.