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Background: Recovery of hearts from donation after circulatory death donors has been performed either with direct procurement and perfusion (DPP) using the TransMedics Organ Care System or with normothermic regional perfusion (NRP) with subsequent cold storage. It remains unclear which of these 2 strategies yields optimal posttransplant outcomes., Methods: All heart transplant recipients from donors after circulatory death donors at the Vanderbilt University Medical Center (Nashville, TN) were reviewed (February 2020 to January 2023). Recipients were stratified into an NRP or DPP cohort. All DPP recoveries were performed using the TransMedics Organ Care System. The key outcome was severe primary graft dysfunction at 24 hours, defined by the need for postoperative extracorporeal membrane oxygenation., Results: A total of 118 hearts were transplanted (NRP, 87; DPP, 31). Donors recovered using NRP were younger (25 years [interquartile range {IQR}, 21-31 years] vs 31 years [IQR, 24-37 years]; P = .008) and had shorter distance traveled (292 miles [158-516 miles] vs 449 miles [IQR, 248-635 miles]; P = .02). Recipient preoperative risk factors were similar between the groups. There was no difference in the incidence of severe primary graft dysfunction at 24 hours (NRP, 5.8%; and DPP, 12.9%; P = .24). However, ejection fraction at 7 days after transplantation was higher in the NRP group (65% [IQR, 60%-65%] vs 60% [IQR, 60%-68%]; P = .005). There was no difference in inotrope scores at 24 hours (P = 1.00) or 72 hours (P = .87) or in 30-day (NRP, 95% vs DPP, 97%; P = .75) and 1-year (NRP, 94% vs DPP, 86%; P = .19) survival., Conclusions: NRP and DPP strategies for recovery of cardiac allografts yield comparable early allograft outcomes. Future studies are needed to confirm these findings in larger prospective cohorts., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Background: Utilization of temporary mechanical circulatory support, including veno-arterial extra-corporeal membrane oxygenation as a bridge to heart transplantation (HT) has increased significantly under the revised United Network for Organ Sharing (UNOS) donor heart allocation system. The revised heart allocation system aimed to lower waitlist times and mortality for the most critically ill patients requiring biventricular, nondischargeable, mechanical circulatory support. While previous reports have shown improved 1-year post-HT survival in the current era, 3-year survival and factors associated with mortality among bridge-to-transplant (BTT) extra-corporeal membrane oxygenation (ECMO) patients are not well described., Methods: We queried the UNOS database for all adult (age ≥ 18 years) heart-only transplants performed between 2010 and 2019. Patients were stratified as either pre- (January 2010-September 2018; era 1) or post-allocation change (November 2018-December 2019; era 2) cohort based on their HT date. Baseline recipient characteristics and post-transplant outcomes were compared. A Cox regression analysis was performed to explore risk factors for 3-year mortality among BTT-ECMO patients in era 2. For each era, 3-year mortality was also compared between BTT ECMO patients and those transplanted without ECMO support., Results: During the study period, 116 patients were BTT ECMO during era 1 and 154 patients during era 2. Baseline recipient characteristics were similar in both groups. Median age was 48 (36-58 interquartile range (IQR)) years in era 2, while it was 51 (27-58 IQR) years in era 1. The majority of BTT-ECMO patients were males in both era 2 and era 1 (77.7% vs 71.5%, p = 0.28). Median ECMO run times while listed for HT were significantly shorter (4 days vs 7 days, p < 0.001) in era 2. Waitlist mortality among BTT ECMO patients was also significantly lower in era 2 (6.3% vs 19.3%, p < 0.001). Post-HT survival at 6 months (94.2% vs 75.9%, p < 0.001), 1 year (90.3% vs 74.2%, p < 0.001), and 3 years (87% vs 66.4%, p < 0.001) was significantly improved in era 2 as compared to era 1. Graft failure at 1 year (10.3% vs 25.8%, p = 0.0006) and 3 years (13.6% vs 33.6%, p = 0.0001) was also significantly lower in era 2 compared to era 1. Three-year survival among BTT ECMO patients in era 2 was similar to that of patients transplanted in era 2 without ECMO support (87% vs 85.7%, p = 0.75). In multivariable analysis of BTT-ECMO patients in era 2, every 1 kg/m 2 increase in body mass index was associated with higher mortality at 3 years (hazard ratio (HR) 1.09, 95% CI 1.02-1.15, p = 0.006). Similarly, both post-HT stroke (HR 5.58, 95% CI 2.57-12.14, p < 0.001) and post-HT renal failure requiring hemodialysis (HR 4.36, 95% CI 2.43-7.82, p < 0.001) were also associated with 3-year mortality., Conclusions: Three years post-HT survival in patients bridged with ECMO has significantly improved under the revised donor heart allocation system compared to prior system. BTT ECMO recipients under the revised system have significantly shorter ECMO waitlist run times, lower waitlist mortality and 3-year survival similar to those not bridged with ECMO. Overall, the revised allocation system has allowed more rapid transplantation of the sickest patients without a higher post-HT mortality., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies., (© 2024. The Author(s).)

Background: Transplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre-direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test-positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear., Methods and Results: We performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT- donors. Additionally, in a subsample of 149 patients (including 55 in the NAT+ cohort and 94 in the NAT- cohort) who had serial adjunctive intravascular ultrasound examination performed, we compared development of rapidly progressive CAV, defined as an increase in maximal intimal thickening of ≥0.5 mm in matched vessel segments during the first year post-transplant. In an unadjusted analysis, recipients of HCV NAT+ hearts had reduced survival free of CAV ≥1 over the first year after heart transplant compared with recipients of HCV NAT- hearts. After adjustment for known CAV risk factors, however, there was no significant difference between cohorts in the likelihood of the primary outcome, nor was there a difference in development of rapidly progressive CAV., Conclusions: These findings support larger, longer-term follow-up studies to better elucidate CAV outcomes in recipients of HCV NAT+ hearts and to inform post-transplant management strategies., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Diabetes medications place significant financial burden on patients but less is known about factors affecting cost variation., Objective: To examine pharmacy and neighborhood factors associated with cost variation for diabetes drugs in the US., Research Design, Subjects and Measures: We used all-payer US pharmacy data from 45,874 chain and independent pharmacies reflecting 7,073,909 deidentified claims. We divided diabetes drugs into insulins, non-insulin generic medications, and brand name medications. Generalized linear models, stratified by pharmacy type, identified pharmacy and neighborhood factors associated with higher or lower cash price-per-unit (PPU) for each set of drugs., Results: Cash PPU was highest for brand name therapies ($149.4±203.2), followed by insulins ($42.4±25.0), and generic therapies ($1.3±4.4). Pharmacy-level price variation was greater for non-insulin generic therapies than insulins or brand name therapies. Chain pharmacies had both lower prices and lesser variation compared with independent pharmacies., Conclusions: Cash prices for diabetes medications in the US can vary considerably and that the greatest degree of price variation occurs in non-insulin generic therapies., Competing Interests: HW is a member of the GoodRx medical advisory board. DL and JvM are employees of GoodRx. MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Occlutech, and Impulse Dynamics. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919., Competing Interests: Disclosures ZC receives research funding from AstraZeneca and Cumberland Pharmaceuticals and consulting fees from Roche and Translational Catalyst. JHH receives research funding from the NIA, Boehringer Ingelheim and Merck. JL receives research funding from AstraZeneca, Volumetrix, Sensible Medical, NIH and consulting fees from AstraZeneca, Abbott, Alleviant, Boehringer Ingelheim, Boston Scienrific, CVRx, Edwards Lifesciences, Medtronic, Merck, Vascular Dynamics, VWave, WHiteswell. CJL reports research grants and contracts to institution from NIH, CDC, DoD, AbbVie, Entegrion, Endpoint Health, bioMerieux, and patents for risk stratification in septic shock unrelated to the current work. JOW receives research funding from Bristol Myers Squibb. EDS receives personal fees as an Associate Editor for the Clinical Journal of the American Society of Nephrology and royalties as an author for UptoDate. JT 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, JMT has a patent 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. SPC reports consulting with Boehringer Ingelheim, Reprieve Cardiovascular, Aboott and research support from PCORI, NIH, DOD, and Beckman Coulter., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Heart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes., Objectives: We sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts., Methods: We conducted a single-center retrospective observational study of all adult heart-only transplants from January 2020 to January 2023. Recipient and donor data were abstracted from medical records and the United Network for Organ Sharing registry, respectively. Survival analysis and Cox regression were used to compare the groups., Results: During the study period, 385 adults (median age 57.4 years [IQR: 48.0-63.7 years]) underwent heart-only transplantation, including 122 (32%) from DCD donors, 83% of which were recovered with the use of NRP. DCD donors were younger and had fewer comorbidities than DBD donors. DCD recipients were less often hospitalized before transplantation and less likely to require pretransplantation temporary mechanical circulatory support compared with DBD recipients. There were no significant differences between groups in 1-year survival, incidence of severe primary graft dysfunction, treated rejection during the first year, or likelihood of cardiac allograft vasculopathy at 1 year after transplantation., Conclusions: In the largest single-center comparison of DCD and DBD heart transplantations to date, outcomes among DCD recipients are noninferior to those of DBD recipients. This study adds to the published data supporting DCD donors as a safe means to expand the heart donor pool., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Allosensitization is prevalent in heart transplant candidates and is associated with prolonged waiting times and poor outcomes following transplantation. We analyzed the efficacy of a desensitization regimen consisting of plasma exchange, intravenous immunoglobulin, and bortezomib among 25 consecutive sensitized waitlisted candidates at our center from 2016 to 2021. Following desensitization therapies, all C1q negative antibodies were removed from a candidate's unacceptable antigen list. There was a significant decrease in the median number of human leukocyte antigen (HLA) class I (21-15, p = .001) but not class II antibodies (7-6.5, p = .07). There was a significant corresponding decrease in median calculated panel reactive antibodies for class I (90%-74%, p = .004) but not class II (74.5%-75.5%, p = .30). Following desensitization, 76% of patients were transplanted at a median of 91 days. One-year survival following transplant was 89% with a 33% rate of antibody-mediated rejection (AMR). In conclusion, a bortezomib desensitization protocol was modestly effective for class I antibodies and allowed successful transplant in most cases when combined with selective crossing of C1q negative antigens., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Disclosure: T.D.B., G.S., J.L.V., and H.K.S. do not have any conflict of interest to disclose with respect to this work. M.R.M. has received consulting fees from Abbott Medtronic, Janssen (a division of Johnson and Johnson), Natera, Baim Institute for Clinical Research, and Paragonix, participation on a data safety monitoring board or advisory board for Mesoblast, and reports holding stock or stock options in NupulseCV, Leviticus, and Fineheart.

Objectives: To investigate risk factors and outcomes of cardiogenic shock complicating acute myocardial infarction (AMI-CS) in young patients with AMI., Background: AMI-CS is associated with high morbidity and mortality rates. Data regarding AMI-CS in younger individuals are limited., Methods and Results: Consecutive patients with type 1 AMI aged 18-50 years admitted to 2 large tertiary-care academic centers were included, and they were adjudicated as having cardiogenic shock (CS) by physician review of electronic medical records using the Society for Cardiovascular Angiography and Interventions CS classification system. Outcomes included all-cause mortality (ACM), cardiovascular mortality (CVM) and 1-year hospitalization for heart failure (HHF). In addition to using the full population, matching was also used to define a comparator group in the non-CS cohort. Among 2097 patients (mean age 44 ± 5.1 years, 74% white, 19% female), AMI-CS was present in 148 (7%). Independent risk factors of AMI-CS included ST-segment elevation myocardial infarction, left main disease, out-of-hospital cardiac arrest, female sex, peripheral vascular disease, and diabetes. Over median follow-up of 11.2 years, young patients with AMI-CS had a significantly higher risk of ACM (adjusted HR 2.84, 95% CI 1.68-4.81; P < 0.001), CVM (adjusted HR 4.01, 95% CI 2.17-7.71; P < 0.001), and 1-year HHF (adjusted HR 5.99, 95% CI 2.04-17.61; P = 0.001) compared with matched non-AMI-CS patients. Over the course of the study, there was an increase in the incidence of AMI-CS among young patients with MI as well as rising mortality rates for patients with both AMI-CS and non-AMI-CS., Conclusions: Of young patients with AMI, 7% developed AMI-CS, which was associated with a significantly elevated risk of mortality and HHF., Competing Interests: Disclosures Sanjay Divakaran: Grant funding: Joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10). James Januzzi: Trustee, American College of Cardiology; Research Support/Funding, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; Consulting: Abbott, Janssen, Novartis, and Roche Diagnostics; Clinical Endpoint Committees/Data Safety Monitoring Boards: Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Garrick Stewart: Consulting: Abbott Laboratories, Procyrion. Deepak L. Bhatt: Advisory Board: Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: Boston VA Research Institute, DRS.LINQ (stock options), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Novartis, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, Svelte; Trustee, American College of Cardiology; Unfunded Research: FlowCo, Merck, Takeda. Ron Blankstein: Research support: Amgen, Novartis; Consulting: Roivant Sciences, Caristo Diagnostics, Silence Therapeutics. All other authors have no disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Women have a lower incidence of atrial fibrillation (AF) compared with men in several studies, but it is unclear whether this sex difference is independent of sex differences in prevalent cardiovascular disease (CVD), body size, and other risk factors., Objective: To examine sex differences in AF incidence and whether AF risk factors differ by sex in a contemporary cohort of men and women without prevalent CVD., Design, Setting, and Participants: This was a prospective cohort analysis within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, a randomized trial that examined the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among men 50 years or older and women 55 years or older without a prior history of prevalent AF, CVD, or cancer at baseline. Data were analyzed from September 29, 2020, to June 29, 2021., Exposures: Sex, height, weight, body mass index (BMI), body surface area (BSA), and other AF risk factors at study enrollment., Main Outcomes and Measures: Incident AF confirmed by medical record review., Results: A total of 25 119 individuals (mean [SD] age, 67.0 [7.1] years; 12 757 women [51%]) were included in this study. Over a median (IQR) follow-up of 5.3 (5.1-5.7) years, 900 confirmed incident AF events occurred among 12 362 men (495 events, 4.0%) and 12 757 women (405 events, 3.2%). After adjustment for age and treatment assignment, women were at lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P < .001). The inverse association between female sex and AF persisted after adjustment for race and ethnicity, smoking, alcohol intake, hypertension, diabetes (type 1, type 2, gestational), thyroid disease, exercise, and BMI (HR, 0.73; 95% CI, 0.63-0.85; P <.001). However, female sex was positively associated with AF when height (HR, 1.39; 95% CI, 1.14-1.72; P = .001), height and weight (HR 1.49, 95% CI, 1.21-1.82; P <.001), or BSA (HR, 1.25; 95% CI, 1.06-1.49; P = .009) were substituted for BMI in the multivariate model. In stratified models, risk factor associations with incident AF were similar for women and men., Conclusions and Relevance: In this cohort study, findings suggest that after controlling for height and/or body size, women without CVD at baseline were at higher risk for AF than men, suggesting that sex differences in body size account for much of the protective association between female sex and AF. These data underscore the importance of AF prevention in women.

Background: Patients with coronavirus disease 2019 (COVID-19) have a high prevalence of detectable troponin and myocardial injury. In addition, a subset of patients with COVID-19 has detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral loads. The objective of this study was to understand the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in hospitalized patients with COVID-19., Methods: SARS-CoV-2 plasma viral load was measured in plasma samples drawn from patients hospitalized for COVID-19 at 2 academic medical centers. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin T (hs-cTnT) values were abstracted from the medical record. The main outcome was detectable hs-cTnT (≥6 ng/mL) and  myocardial injury (hs-cTnT ≥14 ng/mL; >99th percentile for assay)., Results: A total of 70 hospitalized patients with COVID-19 were included in this study, with 39% females and median age 58 ± 17 years; 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. All of the patients with viremia (100%) had detectable troponin during hospitalization compared with 59% of patients without viremia (P = 0.0003). Myocardial injury was seen in 76% of patients with viremia and 38% of those patients without viremia (P = 0.004)., Conclusions: Hospitalized patients with COVID-19 with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization compared with patients who did not. This first report of the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in patients with COVID-19 points to additional mechanistic pathways that require deeper study to understand the complex interplay among these unique findings, cardiovascular outcomes, and mortality in COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking., Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF., Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017., Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed)., Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review., Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39)., Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF., Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.

Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described., Methods: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries., Results: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41)., Conclusions: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: To summarize outcomes to date, as well as important considerations and unanswered questions related to the use of hepatitis C virus (HCV) positive donors for heart transplantation., Recent Findings: Outcomes from single-center studies and registry data to date suggest that among patients who develop donor-transmitted HCV after heart transplantation, direct-acting antiviral therapies (DAAT) are effective and well-tolerated, and that short-term survival is similar to that of patients transplanted with HCV - donors., Summary: In an era marked by increasing numbers of HCV positive deceased donors and a growing imbalance between the demand and supply of donor hearts, utilization of HCV + donors is a feasible strategy to expand the donor pool and reduce waitlist times. Ongoing work is needed to clarify longer-term outcomes with the use of this strategy., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to multi-system dysfunction with emerging evidence suggesting that SARS-CoV-2-mediated endothelial injury is an important effector of the virus. Potential therapies that address vascular system dysfunction and its sequelae may have an important role in treating SARS-CoV-2 infection and its long-lasting effects., Competing Interests: Declaration of Competing Interest Hasan Siddiqi: No disclosures Peter Libby: Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion, Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer, Sanofi-Regeneron. Dr. Libby is a member of scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr. Libby receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892), the American Heart Association (18CSA34080399), and the RRM Charitable Fund. Paul Ridker: Dr Ridker has received research grant support from Kowa, Novartis, NHLBI, NCI, and Amarin (unrelated to this manuscript) and served as a consultant to Novartis, Jansen, CiviBiopharm, Corvidia, Flame, Agepha, and Inflazome, (unrelated to this manuscript). Dr. Ridker is also part of the National Institutes of Health Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) collaborative steering committee., (Copyright © 2020. Published by Elsevier Inc.)

Although coronavirus disease 2019 (COVID-19) predominantly disrupts the respiratory system, there is accumulating experience that the disease, particularly in its more severe manifestations, also affects the cardiovascular system. Cardiovascular risk factors and chronic cardiovascular conditions are prevalent among patients affected by COVID-19 and associated with adverse outcomes. However, whether pre-existing cardiovascular disease is an independent determinant of higher mortality risk with COVID-19 remains uncertain. Acute cardiac injury, manifest by increased blood levels of cardiac troponin, electrocardiographic abnormalities, or myocardial dysfunction, occurs in up to ~60% of hospitalized patients with severe COVID-19. Potential contributors to acute cardiac injury in the setting of COVID-19 include (1) acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction; (2) acute coronary syndrome due to acute atherothrombosis in a virally induced thrombotic and inflammatory milieu; (3) microvascular dysfunction due to diffuse microthrombi or vascular injury; (4) stress-related cardiomyopathy (Takotsubo syndrome); (5) nonischemic myocardial injury due to a hyperinflammatory cytokine storm; or (6) direct viral cardiomyocyte toxicity and myocarditis. Diffuse thrombosis is emerging as an important contributor to adverse outcomes in patients with COVID-19. Practitioners should be vigilant for cardiovascular complications of COVID-19. Monitoring may include serial cardiac troponin and natriuretic peptides, along with fibrinogen, D-dimer, and inflammatory biomarkers. Management decisions should rely on the clinical assessment for the probability of ongoing myocardial ischemia, as well as alternative nonischemic causes of injury, integrating the level of suspicion for COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has reached pandemic status. As it spreads across the world, it has overwhelmed health care systems, strangled the global economy, and led to a devastating loss of life. Widespread efforts from regulators, clinicians, and scientists are driving a rapid expansion of knowledge of the SARS-CoV-2 virus and COVID-19. The authors review the most current data, with a focus on the basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. The authors discuss the basic virology, epidemiology, clinical manifestation, multiorgan consequences, and outcomes. With a focus on cardiovascular complications, they propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies., (© 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Acute aortic syndromes are highly morbid conditions that require prompt diagnosis and management. Aortic dissections have rhythmic patterns, with notable peaks at certain points in every 24 hours as well as weekly and seasonal variations. Several retrospective studies have assessed the chronobiology of acute aortic dissections and there seems to be a winter seasonal peak and morning daily peak in incidence. Although the pathophysiology of this chronobiology is unclear, there are several environmental and physiologic possibilities. This article reviews the major studies examining the chronobiology of acute aortic dissection, and summarizes some theories on the pathophysiology of this phenomenon., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Marfan syndrome (MFS) is an autosomal dominant connective tissue disease associated with acute aortic dissection (AAD). We used 2 large registries that include patients with MFS to investigate possible trends in the chronobiology of AAD in MFS. We queried the International Registry of Acute Aortic Dissection (IRAD) and the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry to extract data on all patients with MFS who had suffered an AAD. The group included 257 patients with MFS who suffered an AAD from 1980 to 2012. The chi-square tests were used for statistical testing. Mean subject age at time of AAD was 38 years, and 61% of subjects were men. AAD was more likely in the winter/spring season (November to April) than the other half of the year (57% vs 43%, p = 0.05). Dissections were significantly more likely to occur during the daytime hours, with 65% of dissections occurring from 6 a.m. to 6 p.m. (p = 0.001). Men were more likely to dissect during the daytime hours (6 a.m. to 6 p.m.) than women (74% vs 51%, p = 0.01). These insights offer a glimpse of the times of greatest vulnerability for patients with MFS who suffer from this catastrophic event. In conclusion, the chronobiology of AAD in MFS reflects that of AAD in the general population., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: A low level of plasma high density lipoprotein cholesterol (HDL-C) is a strong and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, several large studies recently revealed that pharmacologic interventions that increase HDL-C concentration have not improved cardiovascular outcomes when added to standard therapy. In addition, specific genetic variants that raise HDL-C levels are not clearly associated with reduced risk of coronary heart disease. These observations have challenged the 'HDL hypothesis' that HDL-C is causally related to ASCVD and that intervention to raise HDL-C will reduce ASCVD events. This article will present the current data on the HDL hypothesis and provide a revised paradigm of considering HDL in the atherosclerotic pathway., Recent Findings: Recent evidence has shed light on the complex nature of HDL-C metabolism and function. There are compelling data that the ability of HDL to promote cholesterol efflux from macrophages, the first step in the 'reverse cholesterol transport' (RCT) pathway, is inversely associated with risk for ASCVD even after controlling for HDL-C. This has led to the 'HDL flux hypothesis' that therapeutic intervention that targets macrophage cholesterol efflux and RCT may reduce risk. Preclinical studies of such interventions show promise and early phase clinical studies, though small, are encouraging., Summary: The role of HDL-C in modulating atherosclerotic disease is as yet uncertain. However, new findings and therapies targeting HDL-C show early promise and may provide an important intervention in attenuating the burden of ASCVD in the future.

Acute aortic dissection (AAD) is a severe and potentially fatal disease which requires rapid diagnosis and appropriate treatment in order to improve survival. The variable and sometimes non-specific presentation of this rare condition makes it a continued diagnostic challenge for even the best of clinicians. Multiple clinical factors have been studied for their role in increasing the risk of AAD. While the complete pathophysiology of the condition is not known, contemporary research has shed light on many important factors that might lead to the development of aortic aneurysms and AAD. Despite continued research in this area, there is scant research looking at gender-related differences in the epidemiology, presentation, treatment and outcomes of patients with AAD. This review first revisits lessons about gender-related differences seen in various cardiovascular diseases, and then critically examines the data on gender-related differences in AAD diagnosis, management and outcomes. A summary of the pathophysiology and possible reasons for gender-specific differences in the development of aneurysms and dissections is also provided.

Background: Calcium channel blockade with nicardipine (NC) is an alternative to phenoxybenzamine (PB) preparation for resection of a pheochromocytoma. Intraoperative magnesium sulfate infusion (+MgSO(4)) is often used for its cardiovascular stabilizing properties. We hypothesized that preparation with NC would be similar clinically to PB for resection of a pheochromocytoma, and MgSO(4) infusion would not affect intraoperative stability., Methods: This retrospective review included 64 patients undergoing resections of a pheochromocytoma from 2003 to 2011. PB or NC was used preoperatively, with MgSO(4) use distributed equally in the population. Pre-, intra-, and postoperative hemodynamics and outcomes were compared., Results: There was no difference in NC (n = 7) versus PB (n = 57) or +MgSO(4) (n = 33) versus -MgSO(4) (n = 31) groups for demographics with the exception of age. The NC group had smaller median tumor size and lesser plasma baseline levels of normetanephrine than the PB group, but subgroup analysis of all neoplasms <3.0 cm revealed no differences. Pre-, intra- and postoperative hemodynamic stability and outcomes were similar for NC versus PB analyses as well as the +MgSO(4) versus -MgSO(4) groups., Conclusion: NC use may be an equivalent alternative to PB in preoperative preparation, especially for smaller pheochromocytomas. Intraoperative MgSO(4) use does not seem to have a substantive effect on hemodynamic stability., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Object: Identifying risk factors for surgical morbidity and mortality might improve the safety and efficacy of neurosurgical intervention. Cigarette smoking is a relatively common practice and is associated with several adverse health outcomes. The authors examined the relationship between smoking and intraoperative blood loss, postoperative outcomes, and survival following craniotomy for tumor resection., Methods: A consecutive population of patients undergoing craniotomy for tumor resection between 2006 and 2009 was identified. Using multivariable models and Cox proportional hazard regression analysis, the authors assessed the relation between smoking and operative outcomes including blood loss, complication rates, hospital length of stay, 30-day mortality, and 1-year survival among patients who underwent craniotomy for tumor resection., Results: A total of 453 patients were included in this study: 237 patients never smoked, 54 quit smoking for at least 1 year, and 162 were current smokers. Current smoking status was an independent risk factor for higher intraoperative blood loss, complication risk, and lower 1-year survival following intervention relative to patients who never smoked. Patients who quit smoking had significantly higher mean blood loss, but did not carry a higher risk for other outcomes such as postoperative complications and 1-year mortality compared with patients who never smoked., Conclusions: Current cigarette smoking is associated with poor surgical outcome and lower 1-year survival after undergoing craniotomy for tumor resection. However, quitting smoking and implementing strict smoking cessation programs may help mitigate these risks. Future research might investigate mechanisms underlying these associations.

Objective: Little is known about socioeconomic differences in postoperative outcomes after neurosurgery. We assessed the relation between insurance status and postoperative complication risk, neurosurgical intensive care unit stay, and hospital stay after neurosurgery., Methods: We collected data on 918 consecutive craniotomy or spine-related neurosurgical cases in patients at least 18 years of age at the University of Michigan Hospitals after April 2006. Bivariate χ(2) tests and analysis of variance were used to assess bivariate relations, and multivariable logistic regression models and analysis of covariance were used to adjust for potential confounders., Results: A total of 11.2% of privately insured patients, 23.6% of Medicare patients, 25.8% of Medicaid patients, and 27.3% of uninsured patients suffered complications within 30 days of surgery (P < 0.001). In adjusted models, odds of postoperative complications among Medicare (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.3-3.3), Medicaid (OR = 3.1, 95% CI 1.5-6.1), and uninsured patients (OR = 3.6. 95% CI 1.3-10.3) were higher than among privately insured patients. By analysis of covariance, only Medicaid patients had significantly longer intensive care unit (P = 0.040) and hospital stays (P = 0.028) than privately insured patients., Conclusions: Our findings suggest important socioeconomic disparities in outcomes after neurosurgical intervention. Access to postoperative outpatient care may mediate our findings., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestations appearing in old age, however, the initial stages of this disease may begin early in life. AD is characterized by the presence of excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are derived from the beta-amyloid precursor protein (APP) following processing by beta-secretase and gamma-secretase. Recently, we have reported that developmental exposure of rats to Pb resulted in latent elevation of APP mRNA, APP, and Abeta in old age. Here we examined whether latent up-regulation in APP expression and Abeta levels is exacerbated by concurrent disturbances in APP processing or Abeta aggregation. Among the environmental metals tested, only Abeta solutions containing Pb promoted the formation of Abeta aggregates at nanomolar concentrations. The lifetime profiles of alpha-, beta-, and gamma-secretases remained constant in adult and aging animals, and developmental exposure to Pb did not alter them. Furthermore, the addition of various concentrations of Pb (0.1 to 50 microM) to cerebral cortical extracts derived from control animals also did not affect the proteolytic activities of these enzymes. Therefore, we propose that amyloidogenesis is promoted by a latent response to developmental reprogramming of the expression of the APP gene by early exposure to Pb, as well as enhancement of Abeta aggregation in old age. In rodents, these events occur without Pb-induced disturbances to the enzymatic processing of APP. The aforementioned results provide further evidence for the developmental basis of amyloidogenesis and late-life disturbances in AD-associated proteins by environmental agents.

The fetal basis of adult disease (FeBAD) hypothesis states that many adult diseases have a fetal origin. According to FeBAD, injury or environmental influences occurring at critical periods of organ development could result in "programmatic" changes via alterations in gene expression or gene imprinting that may result in functional deficits that become apparent later in life. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are snippets of the beta-amyloid precursor protein (APP). The predominantly sporadic nature of AD suggests that the environment must play a role in neurodegeneration. To examine latent responses to an environmental agent, we exposed rodents to lead and monitored the lifetime expression of the APP gene. We observed that APP mRNA expression was transiently induced in neonates, but exhibited a delayed overexpression 20 months after exposure to Pb had ceased. This upregulation in APP mRNA expression was commensurate with a rise in activity of the transcription factor Sp1, one of the regulators of the APP gene. Furthermore, the increase in APP gene expression in old age was accompanied by an elevation in APP and its amyloidogenic Abeta product. In contrast, APP expression, Sp1 activity, as well as APP and Abeta protein levels were unresponsive to Pb exposure during old age. These data suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis.