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There is significant center-dependent variation in duration of steroid use post-heart transplant (HT). This analysis aims to evaluate the impact of steroid withdrawal on gene expression profiling (GEP), donor derived cell free DNA (dd-cfDNA), rejection, de novo donor specific antibodies (dnDSA), graft dysfunction [LVEF ≤30% and/or a ≥25% decline in LVEF], ISHLT Grade 2/3 cardiac allograft vasculopathy (CAV), and all-cause mortality. Patients from the multi-center Surveillance HeartCare Outcomes Registry (SHORE) were evaluated for steroid withdrawal, as defined by complete discontinuation of steroids for at least 3 months. Resumption of steroids was defined as resumption of any steroid dose after a minimum of 3 months of stopping steroids. Multi-organ transplant recipients were excluded. 2563 patients with a median follow-up of 24 months were included. 1552 patients had steroids discontinued, 327 of whom ultimately resumed steroids. Steroids were withdrawn for at least 3 months in 1384. dd-cfDNA levels remained stable from 6 months prior to steroid withdrawal to 6 months after withdrawal. There was a non-statistically significant rise in GEP score during steroid withdrawal which, once complete, remained stable for 6 months (Figure 1). Patients in the steroid withdrawal group were less likely to experience rejection, graft dysfunction, dnDSA, and death. These outcomes were unchanged with propensity matching. Steroid resumption was associated with more rejection (22% vs. 9%, p<0.001), dnDSA (35% vs. 24%, p<0.001), graft dysfunction (9.5% vs. 5.1%, p=0.006), and higher dd-cfDNA levels (p=0.047) compared to patients who remained off of steroids indefinitely. dd-cfDNA levels and GEP scores remained stable following complete withdrawal of steroids. Rejection, de-novo DSA, and graft dysfunction were associated with resumption of steroid treatment. [ABSTRACT FROM AUTHOR]

Background: Right ventricular dysfunction (RVD) is an important prognostic factor in several cardiac conditions, including acute and chronic heart failure. The impact of baseline RVD on clinical outcomes of patients undergoing high-risk percutaneous coronary intervention (HRPCI) supported by Impella is unknown., Methods: Patients from the single-arm, multicenter PROTECT III study of Impella-supported HRPCI were stratified based on the presence or absence of RVD. RVD was quantitatively assessed by an echocardiography core laboratory and was defined as fractional area change < 35%, tricuspid annular plane systolic excursion < 17 mm or pulsed-wave Doppler S-wave of the lateral tricuspid annulus < 9.5 cm/s. Procedural outcomes, 90-day major adverse cardiac and cerebrovascular events (MACCE: the composite of all-cause mortality, myocardial infarction, stroke/TIA, and repeat revascularization), and 1-year mortality were assessed., Results: Of the 239 patients who underwent RV function assessment, 124 were found to have RVD. Lower left ventricular ejection fraction, higher blood urea nitrogen levels, and more severe RV dilation were independently associated with RVD. The incidence of hypotensive episodes during PCI, the proportion of patients requiring prolonged Impella support, the completeness of revascularization, and the rate of in-hospital mortality did not differ significantly between patients with vs without RVD. However, 90-day MACCE rates were higher in those with RVD, and RVD was a robust predictor of 1-year mortality in multivariable Cox-regression analyses., Conclusion: In patients undergoing HRPCI with Impella, RVD was associated with more advanced biventricular failure. The use of Impella support during HRPCI facilitated effective revascularization, even in those with concomitant RVD. Nevertheless, RVD was associated with unfavorable long-term prognoses., Competing Interests: Disclosures AJL has received speaker fees from Keystone Heart. BR has received consultant fees from Pfizer and Boehringer Ingelheim. JFG is the cofounder of Cephea Valve Technologies (Abbott) and is the president and CEO of Cardiovascular Research Foundation. ASB reports consulting and speaker fees from Abiomed, Shockwave Medical, and Cardiovascular Systems. MBB has been a consultant/speaker for Abiomed, Boston Scientific, Chiesi, Saranas, and Zoll. WWO reports grant/research support from St. Jude Medical, Edwards Life Sciences and Biomed, consulting fees/honoraria from Medtronic and Abiomed, and major stock shareholder/equity in Synecor, Accumed, Neovasc, Tendyne, and Mitralign. DB has received institutional grants from Abiomed, Ancora Heart, and Fire-1, and consulting fees from PVLoops and Axon Therapeutics. All other authors report no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated., Methods: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed., Results: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction., Conclusions: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Mitral valve regurgitation (MR) is associated with worse outcomes in patients undergoing percutaneous coronary intervention (PCI). We sought to evaluate outcomes of Impella-supported high-risk PCI (HRPCI) patients according to MR severity., Methods: Patients from the PROTECT III study undergoing Impella-supported HRPCI were stratified into 4 groups according to MR severity: No or trace MR, mild MR, moderate MR, and severe MR. Immediate PCI-related complications, major adverse cardiovascular and cerebrovascular events (MACCE: all-cause death, myocardial infarction, stroke/transient ischemic attack, and repeat revascularization) at 90 days and death at 1-year were assessed., Results: From March 2017 to March 2020, 631 patients who underwent Impella-supported HRPCI in the PROTECT III study had evaluable MR severity at baseline. Patients with severe MR had lower body mass indices, lower left ventricular ejection fractions (LVEFs), and were more frequently diagnosed with heart failure. The incidence of immediate PCI-related complications was similar between groups. Unadjusted 90-day MACCE and 1-year mortality rates were numerically higher in patients with severe MR compared to the other study groups yet without reaching statistical significance. In multivariable analyses, there was no significant association between the presence of severe MR for 90-day MACCE or 1-year mortality compared with other degrees of MR (adj. HR = 1.71, 95% CI [0.73, 3.98], p = 0.21; adj. HR = 1.79, 95% CI [0.86, 3.74], p = 0.12, respectively)., Conclusions: Impella-supported HRPCI patients with moderate or severe MR exhibited a higher prevalence of heart failure, lower LVEF, and longer hospital stays. Patients with severe MR showed numerically higher unadjusted rates of 90-day MACCE and 1-year mortality compared to other groups, however these differences did not reach statistical significance even after adjustment for potential confounders., Clinical Trial Information: Trial Name: The Global cVAD Study (cVAD) ClinicalTrial.govIdentifier:NCT04136392 URL: https://clinicaltrials.gov/ct2/show/NCT04136392?term=cvad&draw=2&rank=2., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Accurate assessment of aortic valve (AV) stenosis (AS) on transthoracic echocardiogram is crucial for appropriate clinical management. However, discordance between aortic valve area (AVA) and Doppler can complicate the diagnosis of severe AS in low-gradient (LG) AS phenotypes., Methods: We reviewed 220 consecutive patients with suspected severe AS and AVA ≤1.0 cm 2 on transthoracic echocardiogram who were evaluated for transcatheter AV replacement (TAVR) within a large health system from 2015 to 2019. We compared AV calcium score and aorto-mitral angle (AMA) on 3-chamber views from ECG-gated cardiovascular CT among patients with high-gradient (HG) AS (N = 19), paradoxical low-flow low-gradient (PLFLG) AS (N = 24) and normal-flow low-gradient (NFLG) AS (N = 14)., Results: All groups had comparable age, comorbidities, and AV calcium scores. Compared to patients with HG AS (mean AMA 120 ± 10°), those with PLFLG AS (104 ± 12°; p < 0.001) and NFLG AS (106 ± 13°; p = 0.008) had narrower mean AMA values on cardiovascular CT., Conclusion: LG AS patients have significantly narrower AMA than HG AS patients on cardiovascular CT. Due to difficulty obtaining parallel Doppler alignment, narrower AMA may contribute to AVA-Doppler discordance on echocardiogram. These findings emphasize the need for additional information in the setting of LG AS., Competing Interests: Declaration of competing interest Dr. Kamil Faridi receives research funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL161424), outside the scope of the current work. Dr. David Hur receives research support from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL168473), outside the scope of the current work. The remaining authors have no conflicts of interest relevant to this manuscript., (Published by Elsevier B.V.)

Aims: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance., Methods and Results: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved., Conclusions: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS., Clinical Trial Registration: RED DESERT (NCT04116034), SAHARA (NCT04882358)., (© 2024 European Society of Cardiology.)

Competing Interests: Conflicts of Interest None.

Background: Left ventricular (LV) systolic dysfunction worsens outcomes in patients undergoing percutaneous coronary intervention (PCI). The objective of this study, therefore, was to evaluate outcomes of pLVAD-supported high-risk PCI (HRPCI) patients according to LV ejection fraction (LVEF)., Methods: Patients from the PROTECT III study undergoing pLVAD-supported HRPCI were stratified according to baseline LVEF: severe LV dysfunction (LVEF <30%), mild and moderate LV dysfunction (LVEF ≥30% to <50%), or preserved LV function (LVEF ≥50%). Major adverse cardiovascular and cerebrovascular events (MACCE: composite of all-cause death, myocardial infarction, stroke/transient ischemic attack, and repeat revascularization), and PCI-related complications were assessed at 90 days and mortality was assessed at 1-year., Results: From March 2017 to March 2020, 940 patients had evaluable baseline LVEF recorded in the study database. Patients with preserved LV function were older, more frequently presented with myocardial infarction, and underwent more left main PCI and atherectomy. Immediate PCI-related coronary complications were infrequent (2.7%, overall), similar between groups (P = 0.98), and not associated with LVEF. Unadjusted 90-day MACCE rates were similar among LVEF groups; however, as a continuous variable, LVEF was associated with both 90-day MACCE (adj.HR per 5% 0.89, 95% CI [0.80, 0.98], P = 0.018) and 1-year mortality (adj.HR per 5% 0.84 [0.78, 0.90], P <0.0001)., Conclusions: Patients who underwent pLVAD-supported HRPCI exhibited low incidence of PCI-related complications, regardless of baseline LVEF. However, LVEF was associated with 90-day MACCE and 1-year mortality., Competing Interests: Disclosures C.L. Grines reports participation on the advisory boards for Philips and Abiomed. W.B. Batchelor reports consulting for Abbott, Medtronic, Abiomed, and Boston Scientific. A.S. Bharadwaj has received consultant and speaker fees from Abiomed Inc, Cardiovascular Systems Inc and Shockwave Medical. J.W. Moses reports holding equity in Orchestra Biomed. A.G. Truesdell has received consultant and speaker fees from Abiomed, Inc. and Shockwave Medical Inc. S.J. Baron reports receiving consulting fees from Abbott, Abiomed, Edwards LifeSciences, and MitraLabs outside the submitted work as well as speaker fees from and advisory board membership with Boston Scientific. A.J. Lansky received speaker fees from Keystone Heart. M.B. Basir reports consultant fees from Abbott Vascular, Abiomed, Cardiovascular Systems, Chiesi, and Zoll. D.J. Cohen reports grant funding and consulting income from Edwards LifeSciences, Medtronic, Abbott, Boston Scientific, Philips, and CathWorks. W.W. O'Neill reports grant/research support from St. Jude Medical, Edwards Life Sciences, and Biomed; consulting fees/honoraria from Medtronic and Abiomed; and major stock shareholder/equity in Synecor, Accumed, Neovasc, Tendyne, and Mitral Align. The remaining authors report no relevant conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Significance Statement: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling., Background: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits., Methods: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide., Results: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT., Conclusions: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile., Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov ( NCT03027960 )., (Copyright © 2023 by the American Society of Nephrology.)

Purpose of the Review: Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care., Recent Data: Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial., Summary: CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: The number of dual organ transplantations (DOT) are steadily increasing over the past few years. This is both a reflection of increasing complexity and advanced disease process in the patients and greater transplant center experience with performing dual organ transplants. Due to lack of standardization of the process, there remains significant center-based variability in patient selection, perioperative and long-term management of these patients., Recent Findings: Overall posttransplant outcomes for DOT have been acceptable with some immunological advantages because of partial tolerance offered by the second organ. These achievements should, however, be balanced with the ethical implications of bypassing the patients who are listed for single organ transplantation because of the preferential allocation of organs for DOT., Summary: The field of DOT is expanding rapidly, with good long-term outcomes. There is an urgent need for guidelines to standardize the process of patient selection and listing dual organ transplantation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Aims: Previous studies have suggested venous congestion as a stronger mediator of negative cardio-renal interactions than low cardiac output, with neither factor having a dominant role. While the influence of these parameters on glomerular filtration have been described, the impact on diuretic responsiveness is unclear. The goal of this analysis was to understand the hemodynamic correlates of diuretic response in hospitalized patients with heart failure., Methods and Results: We analyzed patients from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) dataset. Diuretic efficiency (DE) was defined as the average daily net fluid output per doubling of the peak loop diuretic dose. We evaluated a pulmonary artery catheter hemodynamic-guided cohort (n = 190) and a transthoracic echocardiogram (TTE) cohort (n = 324) where DE was evaluated with hemodynamic and TTE parameters. Metrics of "forward flow" such as cardiac index, mean arterial pressure and left ventricular ejection fraction were not associated with DE (p > 0.2 for all). Worse baseline venous congestion was paradoxically associated with better DE as assessed by right atrial pressure (RAP), right atrial area (RAA), and right ventricular systolic and diastolic area (p < 0.05 for all). Renal perfusion pressure (capturing both congestion and forward flow) was not associated with diuretic response (p = 0.84)., Conclusions: Worse venous congestion was weakly associated with better loop diuretic response. Metrics of "forward flow" did not demonstrate any correlation with diuretic response. These observations raise questions about the concept of central hemodynamic perturbations as the primary drivers of diuretic resistance on a population level in HF., Competing Interests: Conflicts of interest J.M.T. reports grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Astra Zeneca, Novartis, Cardionomic, MagentaMed, Reprieve inc., FIRE1,W.L. Gore, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards life sciences, and Lilly. In addition, J.M.T. has a patent for Treatment of diuretic resistance issued to Yale and Corvidia Therapeutics Inc., a patent methods for measuring renalase issued to Yale, and a patent Treatment of diuretic resistance pending with Reprieve inc. V.S.R. has a patent for Treatment of diuretic resistance US20200079846A1 issued to Yale and Corvidia Therapeutics Inc. with royalties paid to Yale University, V.S.R. and J.M.T. and a patent Methods for measuring renalase WO2019133665A2 issued to Yale. V.S.R. reports personal fees from Translational Catalyst. Z.L.C. reports grants from AstraZeneca. J.B.I.M. reports personal fees from Astra-Zeneca, Boehringer Inglheim, Novartis, Merck, Moksha8, and Translational Catalyst. J.B serves as a consultant for Abbott, Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, FIRE1, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, and Vifor. The rest of the authors report no disclosures relevant to the content of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures Angela Velleca None Michael A Shullo Consulting- Natera Kumud Dhital None Estela Azeka MD None Monica Colvin MD Grants- Natera-Grant funding; Advisory board- Natera; Consulting- Mescape Eugene DePasquale Grants- CareDX; Advisory Board- Yale Marta Farrero Speakers bureaus- Novatris, AstraZeneca, Boehringer, Chiesi; Meeting support- Novartis, Chiesi; Material support/ Other Services- AstraZeneca Luis García-Guereta None Gina Jamero None Kiran Khush Grants- National Institutes of Health, Enduring Hearts; Royalties- Stanford; Consulting, speakers bureaus- CareDx Jacob Lavee None Stephanie Pouch None Jignesh Patel Grants- Alexion; Consulting- CareDx, Natera; Advisory Board- CareDx, Natera; CJ Michaud None Stephan Schubert Consulting- Medtronic, Edwards; Speakers Bureaus- Abbott, Lifetech, Medtronic; Meeting support- Medtronic, Edwards Annalisa Angelini None Lilibeth Carlos None Sonia Mirabet None Michael Pham Grants- CareDx, Royalties-Up to Date Simon Urschel Grants- Canadian Institute for Health Research, Enduring Hearts, Heart and Stroke foundation; Speaker/Educational- University of Alabama; Meeting support- Lange Symposium; Advisory Board- SMB of the Canadian Donation and Transplantation Research Program Kyung-Hee Kim None Shelly Miyamoto None Sharon Chih Grants- Heart and Stroke Foundation Ontario, Canadian Institutes of Health Research Kevin Daly Grants- US Department of Defense, Novartis, AHA/Enduring Hearts, Consulting- AstraZeneca; Advisory Board- CareDx Paolo Grossi Consulting- Merck, Sharp & Dohme Allovir, Takeda; Speakers Bureaus- Atara, Gilead, Shionogi; Advisory Board- Reithera Doug Jennings None In-cheol Kim None Hoong Sern Lim Speakers bureaus- Abiomed Tara Miller None Luciano Potena Consulting- Biotest, Novartis; Speakers bureaus- Biotest, Takada, Paragonix, Boeringher Ingheleim, AstraZeneca Howard Eisen None Lavanya Bellumkonda Grants- Natera, CareDx; Meeting support- Conformal Medical; Advisory Board- CareDx Lara Danziger-Isakov Grants- NIH, Ansun BioPharma, Astellas, Merck, Pfizer, Takada, AiCuris; Consulting- Takeda; Speakers Bureaus- RMEI; Meeting support- ID SAFE: Swiss Infectious Disease; Advisory Board/DSMB- Merck Fabienne Dobbels None Michelle Harkess None Daniel Kim None Haifa Lyster None Yael Peled None Zdenka Reinhardt None

Background: Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions., Methods: In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider's decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD., Results: Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other ( r =0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period ( P >0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated ( r =0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93-1.05]; P =0.51)., Conclusions: In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02546583.

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined., Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation-Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers., Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m 2 ; worsening renal function, 43 [35 to 55] mL/min per 1.73 m 2 ; and SRF, 43 [32 to 55] mL/min per 1.73 m 2 ; P trend =0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend =0.024) and weight loss (IRF, -9.0 [-12.4 to -5.3] lb; worsening renal function, -5.1 [-8.1 to -1.3] lb; and SRF, -7.1 [-11.9 to -3.2] lb; P trend <0.001) despite similar diuretic doses ( P trend =0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups ( P trend >0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10-3.58]; P =0.024)., Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

Objectives: Extracorporeal membrane oxygenation (ECMO) is used to support patients in severe cardiogenic shock. In the absence of recovery, these patients may need to be listed for heart transplant (HT), which offers the best long-term prognosis. However, posttransplantation mortality is significantly elevated in patients who receive ECMO. The objective of the present study was to describe and risk-stratify different profiles of patients listed for HT supported by ECMO., Methods: Patients listed for HT in the United Network for Organ Sharing database were analyzed. The primary outcome was 1-year survival and was assessed in patients bridged to transplant with ECMO (ECMO BTT ) and patients who were previously supported on ECMO but had it removed before HT (ECMO REMOVED )., Results: Among 65,636 adult candidates listed for HT (between 2001 and 2017), 712 were supported on ECMO, 292 of whom (41%) underwent HT (ECMO BTT , n = 202; ECMO REMOVED , n = 90). Most of the patients with ECMO REMOVED were transplanted with a ventricular assist device. In ECMO BTT , recipient age (each 10-year increase), time on the waitlist (both defined as minor risk factors), need for dialysis, and need for mechanical ventilation (both defined as major risk factors) were independent predictors of mortality. ECMO REMOVED and ECMO BTT with no risk factors showed 1-year survival comparable to that in patients who were never supported on ECMO. Compared with patients who were never on ECMO, patients in ECMO BTT group with minor risk factors, 1 major risk factor, and 2 major risk factors had ~2-, ~5-, and >10-fold greater 1-year mortality, respectively (P < .05)., Conclusions: The HT recipients in the ECMO REMOVED and ECMO BTT groups with no risk factors showed similar survival as the HT recipients who were never supported on ECMO. In the ECMO BTT group, posttransplantation mortality increased significantly with increasing risk factors., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the predictive value of cardiac magnetic resonance (CMR) and echocardiographic parameters on left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients without cardiogenic shock and treated with mechanical LV unloading followed by immediate or delayed percutaneous coronary intervention (PCI)-mediated reperfusion., Background: In STEMI, infarct size (IS) directly correlates with major cardiovascular outcomes. Preclinical models demonstrate mechanical LV unloading before reperfusion reduces IS. The door-to-unload (DTU)-STEMI pilot trial evaluated the safety and feasibility of LV unloading and delayed reperfusion in patients with STEMI., Methods: This multicenter, prospective, randomized, safety and feasibility trial evaluated patients with anterior STEMI randomized 1:1 to LV unloading with the Impella CP (Abiomed) followed by immediate reperfusion vs delayed reperfusion after 30 minutes of unloading. Patients were assessed by CMR at 3-5 days and 30 days post PCI. Echocardiographic evaluations were performed at 3-5 and 90 days post PCI. At 3-5 days post PCI, patients were compared based on IS as percentage of LV mass (group 1 ≤25%, group 2 >25%). Selection of IS threshold was performed post hoc., Results: Fifty patients were enrolled from April 2017 to May 2018. At 90 days, group 1 (IS ≤25%) exhibited improved LV ejection fraction (from 53.1% to 58.9%; P=.001) and group 2 (IS >25%) demonstrated no improvement (from 37.6% to 39.1%; P=.55). LV end-diastolic volume and end-systolic volume were unchanged in group 1 and worsened in group 2. There was correlation between 3-5 day and 30-day CMR measurements of IS and 90-day echocardiography-derived LV ejection fraction., Conclusions: Immediate 3-5 day post-therapy IS by CMR correlates with 90-day echocardiographic LVEF and indices of remodeling. Patients with post-therapy IS >25% demonstrated evidence of adverse remodeling. Larger studies are needed to corroborate these findings with implications on patient management and prognosis.

Background: Inferior vena cava (IVC) measurements correlate only modestly with right atrial pressure (RAP). Part of this inaccuracy is due to the high compliance of the venous system, where a large change in blood volume may result in only a small change in pressure. As such, the information provided by the IVC may be different rather than redundant., Methods and Results: We analyzed patients in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial who had both pulmonary artery catheter and IVC measurements at baseline (n = 108). There was only a modest correlation between baseline RAP and IVC diameter (r = 0.41; P < 0.001). Hemoconcentration, defined as an increase in hemoglobin levels between admission and discharge, was correlated with decrease in IVC diameter (r = 0.35; P = 0.02) but not with a decrease in RAP (r = 0.01; P = 0.95). When patients had both IVC and RAP measurements that were below the median, survival rates were superior to the rates of those who had only 1 measurement below the median, and when both rates were above the median, patients fared the worst (P = 0.002)., Conclusion: IVC and RAP have limited correlation with each another, and changes in intravascular volume appear to correlate better with IVC diameter rather than with RAP. Furthermore, complementary information is provided by pressure and volume assessments in acute decompensated heart failure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Evidence regarding the utility of routine induction therapy on outcomes is not clear. This study aims to evaluate whether induction therapy is associated with a reduced risk of treated rejection and improved overall survival., Methods: We retrospectively analyzed all adult patients (age ≥ 18 years) that are included in the UNOS database who underwent heart transplantation between 2000 and 2017. Patients with prior transplants and dual organ transplants were excluded. 34,361 patients were included in the final analysis. We assessed the impact of induction therapy with T cell depleting agents (TC-DA), IL2 receptor antagonists (IL2R antagonist) and compared that to no induction therapy using Cox regression models adjusted for propensity scores. The primary outcome measure was all-cause mortality, whereas treated rejection at one year was analyzed as a secondary outcome measure (available in 77% of patients)., Results: A total of 52% of the cohort did not receive any induction therapy. A total of 27% received IL2R antagonist and the rest received TC-DA. Median age of the recipients was 55 (IQR: 46-62) years. A total of 25% of the population were women and 39% were supported on left ventricular assist device therapy at the time of transplantation. Median follow-up was 4.2 (IQR: 1.1-8.5) years with 32% reported mortality. Multivariate analysis with propensity score adjustment showed that TC-DA induction did not have any effect on mortality (HR = 0.98, 95% CI 0.93-1.03, p = 0.48). However, IL2R antagonist was associated with a modestly increased risk of all-cause mortality compared to no induction (HR = 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). A total of 25% of patients were found to have treated rejection at one year, TC-DA induction was associated with reduced odds of rejection at one year (OR = 0.82, 95% CI 0.76-0.88, p < 0.001). However, induction with IL2R antagonist was not found to have a significant impact (OR = 1.03, 95% CI 0.96-1.11, p = 0.36)., Conclusions: Compared to no induction therapy, induction with TC-DA was associated with reduction in risk of treated rejection at 1 year with no effect on mortality and IL2R antagonist was associated with a small but statistically significant increase in mortality without any impact on risk of rejection., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Implantable cardioverter-defibrillators (ICDs) are recommended for patients with cardiac sarcoidosis (CS) with an indication for pacing, prior ventricular arrhythmias, cardiac arrest, or left ventricular ejection fraction <35%, but data on outcomes are limited., Methods: Using data from the National Cardiovascular Data Registry ICD Registry between April 1, 2010 and December 31, 2015, we evaluated a propensity matched cohort of CS patients implanted with ICDs versus non-ischemic cardiomyopathies (NICM). We compared mortality using Kaplan-Meier survival curves and Cox proportional hazards models., Results: We identified 1,638 patients with CS and 8,190 propensity matched patients with NICM. The rate of death at 1 and 2 years was similar in patients with CS and patients with NICM (5.2% vs 5.4%, P = 0.75 and 9.0% vs 9.3%, P = 0.72, respectively). After adjusting for other covariates, patients with CS had similar mortality at 2 years after ICD implantations compared with NICM patients (RR 1.03, 95% CI 0.87-1.23). Among patients with CS, multivariable logistic regression identified 6 factors significantly associated with increased 2-year mortality: presence of heart failure (HR 1.92, 95% CI 1.44-3.22), New York Heart Association (NYHA) Class III heart failure (HR 1.68, 95% CI 1.16-2.45), NYHA Class IV heart failure (HR 3.08, 95% CI 1.49-6.39), atrial fibrillation/flutter (HR 1.66, 95% CI 1.17-2.35), chronic lung disease (HR 1.64, 95% CI 1.17-2.29), creatinine >2.0 mg/dL (HR 4.07, 95% CI 2.63-6.30), and paced rhythm (HR 2.66, 95% CI 1.07-6.59)., Conclusion: Mortality following ICD implantation was similar in CS patients compared with propensity matched NICM patients. Presence of heart failure, NYHA class, atrial fibrillation/flutter, chronic lung disease, renal dysfunction, and paced rhythm at time of implantation were all predictors of increased 2-year mortality among CS patients with ICDs., Competing Interests: Declaration of interest Dr Minges and Yongfei Wang receive salary support for analytic services provided to the American College of Cardiology. Dr Lampert reports research grants from Medtronic and Abbott Laboratories/St. Jude Medical and serves on Medtronic advisory board and receives moderate honoraria. Dr Rosenfeld reports fellowship support and stock ownership for Abbott Laboratories and fellowship support from Boston Scientific and Medtronic. Dr Jacoby reports being on the speaker's bureau and an advisory board for Alnylam and participating in ongoing funded research with Alnylam; receiving research grant from Myokardia; serving on an advisory board and steering committee for Myokardia; and receiving consulting fees from Abbott. Dr Curtis has a contract with the American College of Cardiology for his role as Senior Medical Officer, NCDR; receives salary support from the American College of Cardiology, NCDR; receives funding from the Centers for Medicare & Medicaid Services to develop and maintain performance measures that are used for public reporting; and holds equity interest in Medtronic. Dr Miller reports grants from Bracco and Eidos, grants and consulting for Alnylam and Pfizer, outside the submitted work. Dr Freeman reports Consulting/Advisory Board fees from Janssen Pharmaceuticals, Medtronic, Boston Scientific and Biosense Webster. He receives salary/research support from the American College of Cardiology, NCDR and the National Heart Lung and Blood Institute. The remaining authors have no disclosures to report., (Copyright © 2021. Published by Elsevier Inc.)

Aims: In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown., Methods and Results: Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47)., Conclusion: On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Lymphopenia has been implicated in poor outcomes in the heart failure population. However, the prognostic implication of lymphopenia in left ventricular assist device (LVAD) patients is unknown. We examine the impact of lymphopenia on all-cause mortality in this population over a 24-month period post-implantation. A total of 170 patients between June 2011 and July 2018 receiving permanent durable LVAD at a single center formed the study population. Criteria for lymphopenia on admission, defined as an absolute lymphocyte count (ALC) <1500 cells/μl, was met in 99 patients. A total of 11 patients were excluded: two with ALC >4800/μl and nine with incomplete data. Survival across groups was compared with a Kaplan-Meier plot and log-rank statistics. The Cox proportional hazard model was used to examine the association between lymphopenia and 24-month all-cause mortality. In the lymphopenia group, mean ALC was 909.6 ± 331.9 versus 2073.6 ± 501.1 in the non-lymphopenic group. Twenty-four-month all-cause mortality was significantly higher in the lymphopenia group (p = 0.009). The lymphopenic patients had worse unadjusted (hazard ratio [HR] = 2.14, confidence interval [CI] = 1.19-3.82; p = 0.01) and adjusted survival (HR = 2.07, CI = 1.13-3.79; p = 0.02). Further clinical investigations are required to assess the utility of continued clinical monitoring of ALC levels beyond LVAD placement., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)