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Intra-aortic balloon pump (IABP) utilization has significantly outpaced other Status 2 eligibility criteria for heart transplant. The risk of waitlist mortality of IABP-supported patients relative to other Status 2 listed patients has not been described.We performed a retrospective analysis of all adult patients listed Status 2 for heart transplantation under the current U.S. allocation policy, using data from the United Network for Organ Sharing. Patients listed status 1 and status 3 for high-dose inotropes were included for reference. Mortality and waitlist decompensation were modeled as a function of time-varying status in cause-specific Cox survival models.We identified 3638 Status 2 listings, of whom 1676 (46%) were Status 2 due to IABP. Relative to patients supported with IABP, status 2 patients with ventricular tachycardia/fibrillation [VT/VF] (HR 4.0, p.001), right-or-biventricular assist device configurations (HR 2.3, p = .002), or temporary surgical left ventricular assist devices [LVAD] (HR 2.6, p = .003) had greater risk of waitlist mortality and decompensation. Other Status 2 subgroups had mortality comparable to IABP Status 2. Risk of waitlist mortality and decompensation for IABP Status 2 was similar to Status 3 patients listed for high-dose inotropes (HR 1.2, p = .27) and lower than Status 1 patients (HR 0.7, p = .002).Waitlist mortality varies significantly by Status 2 eligibility criteria and is highest among patients listed for VT/VF, right-or-biVAD configurations, or temporary surgical LVADs. IABP-supported patients were among those with the lowest Status 2 waitlist mortality risk and comparable to Status 3 inotrope-supported patients.

Donor heart scarcity remains the fundamental barrier to increased transplant access. We examined whether 2018 United Network for Organ Sharing (UNOS) policy changes have had an impact on donor heart acceptance rates.We performed an interrupted time series analysis in UNOS to evaluate for abrupt changes in donor heart-acceptance rates associated with the new policy. All adult donor offers were evaluated between 2015 and 2021 (n = 66,654 donors). Donor volumes and transplants increased during this period, but the donor acceptance rate declined significantly from 31% in quarter 3 of 2018 to 26% acceptance in quarter 3 of 2021 (slope change -0.4% per quarter; P0.001). We identified 2 trends associated with this decline: (1) a growing number of donors with high-risk features, and (2) decreased acceptance of donors with certain high-risk features in the new allocation system.Heart transplant volumes have increased in recent years as a result of increased donor volumes, but donor heart acceptance rates began decreasing under the current allocation system. Changes in the donor pool and acceptance patterns for certain donor-risk features may explain this shift and warrant further evaluation to maximize donor heart use.

Continuous-flow left ventricular assist devices (CF-LVAD) have been shown to enhance reverse remodeling and myocardial recovery in certain patients allowing for device removal. We sought to analyze the characteristics and describe outcomes of patients who underwent CF-LVAD explantation at a large academic center. We retrospectively identified all patients who underwent CF-LVAD explants due to recovery from 2006 to 2019. Patient baseline characteristics and data on pre- and postexplant evaluation were collected and analyzed. Of 421 patients who underwent CF-LVAD implantation, 13 underwent explantation (3.1%). Twelve HeartMate II and one HeartWare LVAD were explanted. All patients had nonischemic cardiomyopathy. Median time from heart failure diagnosis to LVAD implant was 12 months (interquartile range [IQR], 2-44) and the median time supported on LVAD was 22 months (IQR, 11-28). Two patients died within 30 days of explant. Three additional patients died during the follow-up period and all were noted to be nonadherent to medical therapy. After a mean follow-up duration of 5 years, overall survival was 52%. Mean pre-explant ejection fraction was 49%, which decreased at most recent follow-up to 32%. Mean pre-explant left ventricular internal diameter in diastole (LVIDD) was 4.37 cm and increased to 5.52 cm at most recent follow-up. Continuous-flow left ventricular assist device explantation is feasible and safe in select patients.

The mechanisms of coronavirus disease-2019 (COVID-19)-related myocardial injury comprise both direct viral invasion and indirect (hypercoagulability and immune-mediated) cellular injuries. Some patients with COVID-19 cardiac involvement have poor clinical outcomes, with preliminary data suggesting long-term structural and functional changes. These include persistent myocardial fibrosis, edema, and intraventricular thrombi with embolic events, while functionally, the left ventricle is enlarged, with a reduced ejection fraction and new-onset arrhythmias reported in a number of patients. Myocarditis post-COVID-19 vaccination is rare but more common among young male patients. Larger studies, including prospective data from biobanks, will be useful in expanding these early findings and determining their validity.

Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed “responders”). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown. Methods: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders. Results: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions. Conclusions: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.

Background: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. Methods: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). Results: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03–1.76]; P =0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08–1.48]; P =0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00–1.35]; P =0.049). Conclusions: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

Aims Perioperative blood transfusions are common among patients undergoing left ventricular assist device (LVAD) implantation. The association between blood product transfusion at the time of LVAD implantation and mortality has not been described. Methods and results This was a retrospective cohort study of all patients who underwent continuous flow LVAD implantation at a single, large, tertiary care, academic centre, from 2008 to 2014. We assessed used of packed red blood cells (pRBCs), platelets, and fresh frozen plasma (FFP). Outcomes of interest included all‐cause mortality and acute right ventricular (RV) failure. Standard regression techniques were used to examine the association between blood product exposure and outcomes of interest. A total of 170 patients were included in this study (mean age: 56.5 ± 15.5 years, 79.4% men). Over a median follow‐up period of 11.2 months, for every unit of pRBC transfused, the hazard for mortality increased by 4% [hazard ratio (HR) 1.04; 95% CI 1.02–1.07] and odds for acute RV failure increased by 10% (odds ratio 1.10; 95% CI 1.05–1.16). This association persisted for other blood products including platelets (HR for mortality per unit 1.20; 95% CI 1.08–1.32) and FFP (HR for mortality per unit 1.08; 95% CI 1.04–1.12). The most significant predictor of perioperative blood product exposure was a lower pre‐implant haemoglobin. Conclusions Perioperative blood transfusions among patients undergoing LVAD implantation were associated with a higher risk for all‐cause mortality and acute RV failure. Of all blood products, FFP use was associated with worst outcomes. Future studies are needed to evaluate whether pre‐implant interventions, such as intravenous iron supplementation, will improve the outcomes of LVAD candidates by decreasing need for transfusions.

Thrombotic complications are frequent in COVID-19 and contribute significantly to mortality and morbidity. We review several mechanisms of hypercoagulability in sepsis that may be upregulated in COVID-19. These include immune-mediated thrombotic mechanisms, complement activation, macrophage activation syndrome, antiphospholipid antibody syndrome, hyperferritinemia, and renin-angiotensin system dysregulation. We highlight biomarkers within each pathway with potential prognostic value in COVID-19. Lastly, recent observational studies have evaluated a role for the expanded use of therapeutic anticoagulation in COVID-19. We review strengths and weaknesses of these studies, and we also discuss the hypothetical benefit and anticipated challenges of fibrinolytic therapy in COVID-19.

Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.

Background: Due to the high cost of left ventricular assist device (LVAD) therapy, payer type may be an important factor in determining eligibility. How payer type influences outcomes after LVAD implantation is unclear. We, therefore, aimed to study the association of health insurance payer type with outcomes after durable LVAD implantation. Methods: Using STS-INTERMACS (Society of Thoracic Surgeons-Interagency Registry for Mechanically Assisted Circulatory Support), we studied nonelderly adults receiving a durable LVAD from 2016 to 2018 and compared all-cause mortality and postindex hospitalization adverse event episode rate by payer type. Multivariable Fine-Gray and generalized linear models were used to compare the outcomes. Results: Of the 3251 patients included, 26.0% had Medicaid, 24.9% had Medicare alone, and 49.1% had commercial insurance. Compared with commercially insured patients, mortality did not differ for patients with Medicaid (subdistribution hazard ratio, 1.00 [95% CI, 0.75–1.34], P =0.99) or Medicare (subdistribution hazard ratio, 1.09 [95% CI, 0.84–1.41], P =0.52). Medicaid was associated with a significantly lower adjusted incidence rate (incidence rate ratio, 0.88 [95% CI, 0.78–0.99], P =0.041), and Medicare was associated with a significantly higher adjusted incidence rate (incidence rate ratio, 1.16 [95% CI, 1.03–1.30], P =0.011) of adverse event episodes compared with commercially insured patients. Conclusions: All-cause mortality after durable LVAD implantation did not differ significantly by payer type. Payer type was associated with the rate of adverse events, with Medicaid associated with a significantly lower rate, and Medicare with a significantly higher rate of adverse event episodes compared with commercially insured patients.

Background COVID-19 continues to inflict significant morbidity and mortality, particularly on patients with preexisting health conditions. The clinical course, outcomes, and significance of immunosuppression regimen in heart transplant recipients with COVID-19 remains unclear. Methods We included the first 99 heart transplant recipients at participating centers with COVID-19 and followed patients until resolution. We collected baseline information, symptoms, laboratory studies, vital signs, and outcomes for included patients. The association of immunosuppression regimens at baseline with severe disease were compared using logistic regression , adjusting for age and time since transplant. Results The median age was 60 years, 25% were female, and 44% were white. The median time post-transplant to infection was 5.6 years. Overall, 15% died, 64% required hospital admission, and 7% remained asymptomatic. During the course of illness, only 57% of patients had a fever, and gastrointestinal symptoms were common. Tachypnea , oxygen requirement, elevated creatinine and inflammatory markers were predictive of severe course. Age ≥ 60 was associated with higher risk of death and the use of the combination of calcineurin inhibitor , antimetabolite , and prednisone was associated with more severe disease compared to the combination of calcineurin inhibitor and antimetabolite alone (adjusted OR = 7.3, 95% CI 1.8-36.2). Among hospitalized patients, 30% were treated for secondary infection, acute kidney injury was common and 17% required new renal replacement therapy . Conclusions We present the largest study to date of heart transplant patients with COVID-19 showing common atypical presentations and a high case fatality rate of 24% among hospitalized patients and 16% among symptomatic patients.

Background: Biological considerations suggest that renin–angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin–angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. Methods: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin–angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin–angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin–angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. Findings: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin–angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin–angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40–110] for continuation vs 81 [38–117] for discontinuation; β-coefficient 8 [95% CI −13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. Interpretation: Consistent with international society recommendations, renin–angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. Funding: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants. Fil: Cohen, Jordana B.. State University of Pennsylvania; Estados Unidos Fil: Hanff, Thomas C.. State University of Pennsylvania; Estados Unidos Fil: William, Preethi. University of Arizona; Estados Unidos Fil: Sweitzer, Nancy. University of Arizona; Estados Unidos Fil: Rosado Santander, Nelson R.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Medina, Carola. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Rodriguez-Mori, Juan E. Hospital Nacional Alberto Sabogal Sologuren; Perú Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo; Argentina Fil: Chang, Tara I.. University of Stanford; Estados Unidos Fil: Corrales Medina, Vicente. Ottawa Hospital Research Institute; Canadá Fil: Andrade Villanueva, Jaime F.. Hospital Civil de Guadalajara; México Fil: Barbagelata, Alejandro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires"; Argentina. University of Duke; Estados Unidos Fil: Cristodulo Cortez, Roberto. No especifíca; Fil: Díaz-Cucho, Omar A. Hospital Alberto Leopoldo Barton Thompson; Perú Fil: Spaak, Jonas. Danderyd University Hospital; Suecia Fil: Alfonso, Carlos E.. University of Miami; Estados Unidos Fil: Valdivia Vega, Renzo. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Villavicencio Carranza, Mirko. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Ayala García, Ricardo J.. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: Castro Callirgos, Carlos A.. Hospital Nacional Edgardo Rebagliati Martins; Perú Fil: González Hernández, Luz A.. Hospital Civil de Guadalajara; México Fil: Bernales Salas, Eduardo F.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Coacalla Guerra, Johanna C.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Salinas Herrera, Cynthia D.. Hospital Nacional Carlos Alberto Seguin Escobedo; Perú Fil: Nicolosi, Liliana. Hospital Espanol; Argentina Fil: Basconcel, Mauro. Hospital Espanol; Argentina Fil: Byrd, James B.. University of Michigan; Estados Unidos Fil: Sharkoski, Tiffany. University of Pennsylvania; Estados Unidos Fil: Bendezú Huasasquiche, Luis E.. Hospital Alberto Leopoldo Barton Thompson; Perú Fil: Chittams, Jesse. University of Pennsylvania; Estados Unidos Fil: Edmonston, Daniel L.. University of Duke; Estados Unidos Fil: Vasquez, Charles R.. University of Pennsylvania; Estados Unidos Fil: Chirinos, Julio A.. University of Pennsylvania; Estados Unidos

Aims Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants. Methods and results Fifty‐nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal‐effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical‐Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half‐time of Cr recovery (t1/2, Cr) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak, VT, and VO2 efficiency than either control group (all P

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.

Background With a growing population of patients supported by ventricular assist devices (VADs) and the improvement in survival of this patient population, understanding the healthcare system burden is critical to improving outcomes. Thus, we sought to examine national estimates of VAD‐related emergency department (ED) visits and characterize their demographic, clinical, and outcomes profile. Additionally, we tested the hypotheses that resource use increased and mortality improved over time. Methods and Results This retrospective database analysis uses encounter‐level data from the 2010 to 2017 Nationwide Emergency Department Sample. The primary outcome was mortality. From 2010 to 2017, >880 million ED visits were evaluated, with 44 042 VAD‐related ED visits identified. The annual mean visits were 5505 (SD 4258), but increased 16‐fold from 2010 to 2017 (824 versus 13 155). VAD‐related ED visits frequently resulted in admission (72%) and/or death (3.0%). Median inflation‐adjusted charges were $25 679 (interquartile range, $7450, $63 119) per encounter. The most common primary diagnoses were cardiac (22%), and almost 30% of encounters were because of bleeding, stroke, or device complications. From 2010 to 2017, admission and mortality decreased from 82% to 71% and 3.4% to 2.4%, respectively ( P for trends Conclusions We present the first study using national‐level data to characterize the growing ED resource use and financial burden of patients supported by VAD. During the past decade, admission and mortality rates decreased but remain substantial; in 2017 ≈1 in every 40 VAD ED encounters resulted in death, making it critical that clinical decision–making be optimized for patients with VAD to maximize good outcomes.

Visual Abstract, Highlights • DM is a significant risk factor for major adverse cardiovascular events in patients with HFpEF. • Patients with diabetes with HFpEF have a distinct proteome compared with patients without diabetes with HFpEF. • Proteomics analysis identified higher levels of alpha-1-microglobulin/bikunin precursor protein in patients with diabetes with HFpEF and lower levels of CILP2 and Apo M. • Lower Apo M levels mediate most of the association between diabetes and major adverse cardiovascular events in HFpEF., Summary Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p

Background: Non-citizens of the United States face complex social and economic issues, which may impact their post-transplant outcomes compared to US citizens. To this end, we utilized the United Network for Organ Sharing (UNOS) database to examine post-heart transplant (OHT) outcomes, stratified by citizenship status. Methods: UNOS was queried to identify OHT recipients from 03/01/12 (start of new schema for citizenship categorization) through 10/18/18 (start of new heart allocation algorithm). Groups for analysis, were as follows: US Citizen, Non-US Citizen/Resident (NC-R) and Non-US Citizen/Non-US Resident (NC-NR). Post-transplant survival and rate of post-transplant rejection were assessed via Kaplan-Meier analysis and tests of proportions. Results: Of the 16,211 OHT recipients identified, 15,677 (96.7%) were US citizens and 534 (3.3%) were Non-Citizens. Among Non-Citizens, 430 were NC-R and 104 were NC-NR, representing 2.7% and 0.6% of the total transplants. Notably, NC-NR were younger than either Citizens or NC-R, and had the shortest median time from listing to transplant (NC-R 80 days vs. Citizens 107 days vs. NC-NR 76 days, p=0.001). The proportion of transplants received by non-citizens varied widely by region, ranging from 0.59% in region 8 (6/1018) to 8.31% (84/1011) in region 9. There was no significant difference in post-transplant survival estimates in citizens vs. non-citizens (logrank p = 0.542), nor in the proportion of patients treated for rejection by one year (15.0% vs. 16.1%, p= 0.504) Conclusion: Non-US Citizens receive three percent of heart transplants performed in the US each year. Post-heart transplant survival and rate of rejection are similar in US citizens and non-citizens. These data may be relevant in the context of evolving UNOS policies. Additional studies are needed are to further inform organ allocation policy.

Introduction: The past decade has seen tremendous growth in ambulatory ventricular assist device (VAD) patients. We sought to identify patients that present to the emergency department (ED) who are at the highest risk of death. Methods: We performed a retrospective analysis of ED encounters of VAD patients using data from the Nationwide Emergency Department Sample (NEDS) from 2010-2017. Demographic and clinical variables significantly associated with mortality (p < 0.2) in a univariate analysis were evaluated in a multivariate model. Using a random sampling of patient encounters, 80% were assigned to development and 20% to validation cohorts. A risk model was derived from independent predictors of mortality, which were weighted using integer-normalized beta coefficients. Each patient encounter was assigned to one of three groups based on risk score. Results: A total of 44,042 ED encounters of VAD patients were included in the study. The majority of patients were male (73.6%), Conclusions: We present a novel risk score and its validation for predicting mortality of VAD patients who present to the ED, which can serve as useful tool for clinicians caring for this high-risk, and growing, population.

Introduction: There are minimal data describing the prevalence of mental health disorders (MHDO) in VAD-supported patients, or the association between MHDO and resource use or outcomes. Methods: This retrospective analysis utilizes all emergency department (ED) encounter-level data from the 2010-2017 Nationwide Emergency Department Sample (NEDS). Patients with VADs were identified using ICD-9/10 codes, as were associated MHDO diagnoses, which were categorized as depression/anxiety, suicide/self harm, bipolar/psychoses, and substance abuse. Outcomes and characteristics were compared for patients with and without a MHDO via descriptive statistics. Hospital admission and mortality occurring in ED or inpatient was investigated with logistic multivariable regression models adjusted for demographic and clinical characteristics. Results: Of the 47,543 encounters with VADs during the study period, 23% (n=11,103) had at least one MHDO. Depression/anxiety (82%) and substance abuse (22%) were the most prevalent MHDOs. Suicide attempt or self harm was the primary diagnosis for 20 (0.2%) encounters. Patients with MHDOs were more likely to be female (31% vs. 26%), younger (median age 59 vs. 61 years), and to have a non-MHDO chronic condition (77% vs 70%, P Discussion: 1 in 5 VAD-supported ED patient encounters also have a MHDO diagnosis. VAD-supported patients with a MHDO had higher resource use but lower mortality. These data underscore the need for greater attention to how MHDO may impact outcomes in VAD-supported patients.

ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.

Purpose of the Review Angiotensin-converting enzyme 2 (ACE2) is a key counter-regulatory component of the renin-angiotensin system. Here, we briefly review the mechanistic and target organ effects related to ACE2 activity, and the importance of ACE2 in SARS-CoV-2 infection. Recent Findings ACE2 converts angiotensin (Ang) II to Ang-(1–7), which directly opposes the vasoconstrictive, proinflammatory, and prothrombotic effects of Ang II. ACE2 also facilitates SARS-CoV-2 viral entry into host cells. Drugs that interact with the renin-angiotensin system may impact ACE2 expression and COVID-19 pathogenesis; however, the magnitude and direction of these effects are unknown at this time. Summary High quality research is needed to improve our understanding of how agents that act on the renin-angiotensin system impact ACE2 and COVID-19-related disease outcomes.

This study investigates trends in mechanical support use after implementation of the Organ Procurement and Transplantation Network’s new heart transplant allocation rules.

LVAD therapy has traditionally been viewed as a bridge to transplant or destination therapy strategy. However, an exciting new area of research has reopened the door to using these devices as a bridge to recovery. The RESTAGE-HF trial was designed to evaluate the potential for a recovery protocol to achieve successful explantation of the device. The early results from this trial suggest that a protocol including optimal medical therapy in the setting of LVAD therapy may allow for explantation in many cases with durable recovery. This chapter outlines the concepts and data surrounding this important area of study.

The purpose of this review is to synthesize and summarize recent developments in the care of patients with end-stage heart failure being managed with a left ventricular assist device (LVAD) as destination therapy. Although the survival of patients treated with LVAD continues to improve, the rates of LVAD-associated complication, such as right ventricular failure, bleeding complications, and major infection, remain high, and management of these patients remains challenging. The durability and hemocompatibility of LVAD support have greatly increased in recent years as a result of new technologies and novel management strategies. Challenges remain in the comprehensive care of patients with destination therapy LVADs, including management of comorbidities and optimizing patient function and quality of life.

Mechanical assist devices have emerged as an established therapeutic option for patients with end-stage heart failure. Because preimplant hypoalbuminemia is a known risk factor for adverse outcomes, we hypothesized that change in albumin may be a prognostic indicator in patients with continuous-flow left ventricular assist devices (cfLVADs). This is a retrospective single-center study of patients who underwent cfLVAD implantation (HeartMate II and HeartWare HVAD) at an academic center from 2008 to 2014. After excluding those who died, were transplanted, or hospitalized during the first 3 months post-implant, albumin values were obtained and stratified by an increase or a decrease from pre-implant to 3 months post-implant on 171 (81% male, mean age 57 ± 16 years) patients (139 for the survival analysis and 90 for the hospitalization analysis). Decrease in albumin from pre-implant to 3 months after implant correlated with increased mortality (hazard ratio 2.93, confidence interval 1.57 to 5.44, p 0.01) and reduced time to next hospitalization (hazard ratio 1.70, confidence interval 1.03 to 2.81, p = 0.04). The Kaplan-Meier survival curve estimated a 49.43% 2-year survival rate in those whose albumin decreased versus 83.62% in those whose albumin increased over 3 months (p 0.01). Improved outcomes were seen in patients whose albumin normalized versus patients whose albumin remained normal over 3 months. In conclusion, our study is the first to demonstrate the importance of change in albumin from pre- to postimplant on the prognosis of cfLVAD patients. Future studies are needed to determine whether therapeutic intervention to improve albumin post-implant will prevent hospitalizations and improve outcomes.

Background Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses. Methods and findings In this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73–0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86–0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30–5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93–1.38, median follow-up 30 days). Conclusions This observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials.

Purpose Despite significant improvements in survival with continuous flow left ventricular assist devices (LVADs), outflow graft obstruction remains a rare, but serious complication. We report the clinical course and management of patients supported with LVADs who were diagnosed with outflow graft obstruction at a large academic center. Methods We performed a retrospective review of patients receiving LVAD support from January 2012 through September 2020. Patients who developed outflow graft obstruction diagnosed by computed tomography angiography (CTA) or angiogram were identified, and patient characteristics and outcomes were reported. Results Of 324 patients supported by LVAD at our institution between January 2012 and February 2020, 10 patients (3.2%) were diagnosed with outflow graft obstruction. The most common presentation was low flow alarms, which was present in 8/10 patients. The other two patients had lightheadedness and/or dyspnea. Patients had minimal LDH elevation with 7/10 presenting with less than 2-fold the upper limit of normal. Transthoracic echocardiograms were not diagnostic, but CTA enabled non-invasive diagnoses in 8/10 of the patients. Three patients were treated with endovascular stent placement, while one received heart transplant, one had an increase in INR goal, and one had an LVAD outflow revision; all of whom are still living. Three patients were treated with supportive care with two expiring away shortly after. The last patient was treated with tPA and also expired. Conclusion Outflow graft obstructions remain a rare, but serious complication. The true prevalence of this entity is likely underestimated due to the non-specific clinical presentation and the fact that CTA is not a part of routine standard of care.

Purpose Patients supported by VA-ECMO are prioritized for heart transplantation under the new United States donor allocation system, which is intended to decrease their waitlist mortality. The use of VA-ECMO as a bridge to transplant (BTT) has increased under the new system, which may lead to shifts in the characteristics of the VA-ECMO BTT population. We hypothesize that 1) the rate of waitlist death or delisting for VA-ECMO BTT is lower under the new allocation system and 2) this improvement is mediated by a shorter waitlist duration. Methods Using the United Network for Organ Sharing database, we analyzed all adult patients listed for heart transplant between 1/1/2014 and 6/12/2020 who were on VA-ECMO at listing. Waitlist entry after October 18, 2018 defined the new allocation system. We used Fine-Gray competing risk models to analyze the subdistribution relative hazard (sdRH) of death or delisting while accounting for the competing risk of successful transplant, with adjustment for baseline characteristics. Risk of death may increase with additional waitlist duration, so we compared separate models conditional on survival (without transplant) to days 7 and 14. Results VA-ECMO was present at listing in 238 patients in the old system and 163 in the new system, with comparable baseline characteristics. Under the old system, waitlist death or delisting occurred in 125 patients (53%), with 108 (45%) transplanted and median time to transplant 51 days (IQR 11 to 228). In the new system, death or delisting occurred in 29 patients (18%), with 125 (77%) transplants and median time to transplant 4 days (IQR 2 to 7). The adjusted risk of death or delisting decreased by 73% in the new system (sdRH 0.27, 95%CI 0.17-0.42, P Conclusion For patients bridged to heart transplant with VA-ECMO, the risk of waitlist death or delisting is significantly lower in the new allocation system. This improvement is mediated by a shorter time to transplant.