Publications by authors named "Joseph Cleveland"

188 Publications

Primary Results of Long-Term Outcomes in the MOMENTUM 3 Pivotal Trial and Continued Access Protocol Study Phase: A Study of 2200 HeartMate 3 Left Ventricular Assist Device Implants.

Eur J Heart Fail 2021 May 1. Epub 2021 May 1.

Montefiore Einstein Center for Heart and Vascular Care, New York, NY.

Aim: The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal-flow pump, over the HeartMate II axial-flow pump. We now evaluate HM3 LVAD outcomes in a single-arm prospective continuous access protocol (CAP) post-pivotal trial study.

Methods And Results: We enrolled 2200 HM3 implanted patients (515 pivotal trial and 1685 CAP patients) and compared outcomes including survival free of disabling stroke or reoperation to replace or remove a malfunctioning device (primary composite endpoint), overall survival and major adverse events at 2-years. The 2-year primary endpoint (76.7% vs 74.8%; adjusted hazard ratio (HR)=0.87 [95% confidence intervals (CI): 0.71-1.08], P=0.21) and overall survival (81.2% vs 79.0%) were similar among CAP and Pivotal cohorts despite sicker patients (more intra-aortic balloon pump use and INTERMACS profile 1) in CAP who were more often intended for destination therapy. Survival was similar between the CAP and pivotal trial in transplant ineligible patients (79.1% vs 76.7%; adjusted HR=0.89 [95% CI: 0.68-1.16], P=0.38). In a pooled analysis, the 2-year primary endpoint was similar between INTERMACS profiles 1-2 ("unstable" advanced heart failure), profile 3 ("stable" on inotropic therapy), and profiles 4-7 ("stable" ambulatory advanced heart failure) (75.7% vs 77.6% vs 72.9% respectively). The net-burden of adverse events was lower in CAP (adjusted rate ratio=0.93 [95% CI: 0.88-0.98], P=0.006), with consequent decrease in hospitalization.

Conclusions: The primary results of accumulating HM3 LVAD experience suggest a lower adverse event burden and similar survival compared to the pivotal MOMENTUM 3 trial. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ejhf.2211DOI Listing
May 2021

Reactive Oxygen Species Mediate Nicorandil-induced Metabolic Tolerance to Spinal Cord Injury.

Ann Thorac Surg 2020 Oct 22. Epub 2020 Oct 22.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado. Electronic address:

Background: Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species.

Methods: Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n = 19); nicorandil 1.0 mg/kg (n = 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n = 18)]) 150 mg/kg; NAC 150 mg/kg (n = 13); and sham (n = 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated.

Results: Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P = .024) and nicorandil plus NAC group (14 ± 8.3, P = .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P = 0.768).

Conclusions: Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.038DOI Listing
October 2020

Commentary: This heart will travel.

J Thorac Cardiovasc Surg 2021 Mar 24. Epub 2021 Mar 24.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Anschutz Medical Center, Aurora, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.03.066DOI Listing
March 2021

Society of Thoracic Surgeons 2021 Adult Cardiac Surgery Risk Models for Multiple Valve Operations.

Ann Thorac Surg 2021 Apr 9. Epub 2021 Apr 9.

Duke University, Durham, North Carolina.

Background: The STS Quality Measurement Task Force has developed risk models and composite performance measures for isolated coronary artery bypass grafting surgery (CABG), isolated aortic valve replacement (AVR), isolated mitral valve replacement or repair (MVRR), AVR+CABG, and MVRR+CABG. To further enhance its portfolio of risk-adjusted performance metrics, STS has developed new risk models for multiple valve operations +/- CABG procedures.

Methods: Using July 2011 to June 2019 STS Adult Cardiac Surgery Database (ACSD) data, risk models for AVR+MVRR (n=31,968) and AVR+MVRR+CABG (n=12,650) were developed with the following endpoints: operative mortality, major morbidity (any one or more of the following: cardiac reoperation; deep sternal wound infection/mediastinitis; stroke; prolonged ventilation; and renal failure), and combined mortality and/or major morbidity. Data were divided into development (July 2011 - June 2017, n=35,109) and validation (July 2017 - June 2019, n=9,509) samples. Predictors were selected by assessing model performance and clinical face validity of full and progressively more parsimonious models. Performance of the resulting models was evaluated by assessing discrimination and calibration.

Results: C-statistics for the overall population of multiple valve +/- CABG procedures were 0.7086, 0.6734, and 0.6840 for mortality, morbidity, and combined mortality and/or morbidity in the development sample, and 0.6953, 0.6561, and 0.6634 for the same outcomes, respectively, in the validation sample.

Conclusions: New STS-ACSD risk models have been developed for multiple valve +/- CABG operations, and these models will be used in subsequent STS performance metrics.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.089DOI Listing
April 2021

Commentary: Physician payment under the Centers for Medicare and Medicaid Services: A global storm looms on the horizon.

J Thorac Cardiovasc Surg 2021 Mar 10. Epub 2021 Mar 10.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Anschutz Medical Center, Aurora, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.03.018DOI Listing
March 2021

Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.

J Heart Lung Transplant 2021 May 22;40(5):323-333. Epub 2021 Feb 22.

Division of Cardiology, Duke University School of Medicine, Durham, North Carolina.

Background: Several distinctly engineered left ventricular assist devices (LVADs) are in clinical use. However, contemporaneous real world comparisons have not been conducted, and clinical trials were not powered to evaluate differential survival outcomes across devices.

Objectives: Determine real world survival outcomes and healthcare expenditures for commercially available durable LVADs.

Methods: Using a retrospective observational cohort design, Medicare claims files were linked to manufacturer device registration data to identify de-novo, durable LVAD implants performed between January 2014 and December 2018, with follow-up through December 2019. Survival outcomes were compared using a Cox proportional hazards model stratified by LVAD type and validated using propensity score matching. Healthcare resource utilization was analyzed across device types by using nonparametric bootstrap analysis methodology. Primary outcome was survival at 1-year and total Part A Medicare payments.

Results: A total of 4,195 de-novo LVAD implants were identified in fee-for-service Medicare beneficiaries (821 HeartMate 3; 1,840 HeartMate II; and 1,534 Other-VADs). The adjusted hazard ratio for mortality at 1-year (confirmed in a propensity score matched analysis) for the HeartMate 3 vs HeartMate II was 0.64 (95% CI; 0.52-0.79, p< 0.001) and for the HeartMate 3 vs Other-VADs was 0.51 (95% CI; 0.42-0.63, p < 0.001). The HeartMate 3 cohort experienced fewer hospitalizations per patient-year vs Other-VADs (respectively, 2.8 vs 3.2 EPPY hospitalizations, p < 0.01) and 6.1 fewer hospital days on average (respectively, 25.2 vs 31.3 days, p < 0.01). The difference in Medicare expenditures, conditional on survival, for HeartMate 3 vs HeartMate II was -$10,722, p < 0.001 (17.4% reduction) and for HeartMate 3 vs Other-VADs was -$17,947, p < 0.001 (26.1% reduction).

Conclusions: In this analysis of a large, real world, United States. administrative dataset of durable LVADs, we observed that the HeartMate 3 had superior survival, reduced healthcare resource use, and lower healthcare expenditure compared to other contemporary commercially available LVADs.
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http://dx.doi.org/10.1016/j.healun.2021.02.010DOI Listing
May 2021

Maturation of Pluripotent Stem Cell-Derived Cardiomyocytes Enables Modeling of Human Hypertrophic Cardiomyopathy.

Stem Cell Reports 2021 Mar 25;16(3):519-533. Epub 2021 Feb 25.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940251PMC
March 2021

Tumor Metabolism and Neurocognition in CNS Lymphoma.

Neuro Oncol 2021 Feb 24. Epub 2021 Feb 24.

Helen Diller Family Comprehensive Cancer Center, UCSF.

Background: The mechanistic basis for neurocognitive deficits in CNS lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.

Methods: We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examinations (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (gee) models were also established, adjusting for within-subject repeated measures.

Results: Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (p<8E-8, rho=-0.67). High lactate was associated with lower GABA, higher glutamate/GABA ratio and dopamine. Conversely, high succinate correlated with higher MMSE score. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.

Conclusions: We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance and neurocognition may promote interventions that preserve cognitive function.
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http://dx.doi.org/10.1093/neuonc/noab045DOI Listing
February 2021

Optimizing Nicorandil for Spinal Cord Protection in a Murine Model of Complex Aortic Intervention.

Semin Thorac Cardiovasc Surg 2021 Jan 12. Epub 2021 Jan 12.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado. Electronic address:

There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 minutes before ischemia showed no neuroprotection. All nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.
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http://dx.doi.org/10.1053/j.semtcvs.2021.01.003DOI Listing
January 2021

Commentary: Selecting the right cardiac donor.

J Thorac Cardiovasc Surg 2021 03 4;161(3):1061-1062. Epub 2020 Dec 4.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Anschutz Medical Center, Aurora, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.11.140DOI Listing
March 2021

2019 STS/Intermacs Annual Report Writing Committee's Response: Reply.

Ann Thorac Surg 2021 02 2;111(2):734. Epub 2020 Nov 2.

The Society of Thoracic Surgeons Research Center, The Society of Thoracic Surgeons, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.athoracsur.2020.07.102DOI Listing
February 2021

Training for Multiple Arterial Grafting: A Thoracic Surgery Resident Survey.

Ann Thorac Surg 2020 Oct 14. Epub 2020 Oct 14.

Division of Cardiothoracic Surgery, Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, Colorado. Electronic address:

Background: Utilization of multiple arterial grafting (MAG) in the United States is less than 10%. Trainee experience with MAG has not previously been examined.

Methods: A total of 497 thoracic surgery residents in accredited training programs in March 2019 and 115 who completed residency in 2018 were electronically surveyed regarding their experience with MAG using a radial artery (RA) graft or bilateral internal mammary artery (BIMA) grafts with a skeletonized mammary (SM).

Results: Eighty-four (14%) trainees responded: 54% had completed 2+ years of training and 87% declared their focus as cardiac, undecided, or both cardiac and thoracic (CUB). Of all 84 respondents, 76% (n = 64 of 84) had no experience with RA harvest. A total of 35% (n = 29 of 84) had no experience with SM harvest. The majority, 68% (n = 57 of 84), used BIMA grafting in 0% to 5% of cases. A total of 61% (n = 51 of 84) used RA conduit in 0% to 5% of cases. Among trainees with 2+ years of experience, 56% (n = 25 of 45) had performed more than 6 SM takedowns, 18% (n = 8 of 45) had no experience. In trainees with 2+ years, 20% (n = 9 of 45) performed more than 5 RA harvests, while 80% (n = 36 of 45) had no experience. Examining integrated 6-year residents with greater than 3 years of experience, only 33% (n = 5 of 15) performed more than 5% RA grafting. A total of 90% of CUB trainees wanted to perform MAG in practice and 75% felt prepared to do so.

Conclusions: Despite substantial variation in MAG training, respondents expressed an overwhelming interest in performing MAG. These data and the reality of MAG utilization in the United States indicate that a more rigorous, standardized approach to MAG training may be required.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.017DOI Listing
October 2020

Clinical predictors of in-hospital mortality in venoarterial extracorporeal membrane oxygenation.

J Card Surg 2020 Oct 13;35(10):2512-2521. Epub 2020 Aug 13.

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado.

Introduction: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is utilized as a life-saving procedure and bridge to myocardial recovery for patients in refractory cardiogenic shock. Despite technical advancements, VA-ECMO retains high mortality. This study aims to identify the clinical predictors of in-hospital mortality after VA-ECMO to improve risk stratification for this tenuous patient population.

Methods: The REgistry for Cardiogenic Shock: Utility and Efficacy of Device Therapy database is a multicenter, observational registry of ECMO patients. From 2013 to 2018, 789 patients underwent VA-ECMO. Bivariate analysis was performed on more than 300 variables regarding their association with in-hospital mortality. Logistic regression analyses were performed with variables chosen based upon clinical and statistical significance in the bivariate analysis. Tests were considered significant at a two-sided P < .05.

Results: Although 63.5% patients were successfully weaned from VA-ECMO, in-hospital mortality was 57.9%. Nonsurvivors were older (P < .0001), had higher body mass index (P = .01), higher rates of hypertension (P = .02), coronary artery disease (P = .02), chronic obstructive pulmonary disease (P = .02), chronic liver disease (P = .008), percutaneous coronary intervention (P = .02), and surgical revascularization (P = .02). Multivariate predictors for in-hospital mortality include older age (odds ratio [OR], 1.019; P = .007), cardiac arrest (OR, 2.76; P = .006), chronic liver disease (OR, 8.87; P = .04), elevated total bilirubin (OR, 1.093; P < .0001), and the presence of a left ventricular vent (OR, 2.018; P = .03). Pre-ECMO sinus rhythm was protective (OR, 0.374; P = .006).

Conclusions: In a large study of recent VA-ECMO patients, in-hospital mortality remains significant, but acceptable given the severe pathology manifested in this population. Identification of pre-ECMO predictors of mortality helps stratify high-risk patients when deciding on ECMO placement, prolonged support, and prognosis.
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http://dx.doi.org/10.1111/jocs.14758DOI Listing
October 2020

Creatinine elevations from baseline at the time of cardiac surgery are associated with postoperative complications.

J Thorac Cardiovasc Surg 2020 Jun 26. Epub 2020 Jun 26.

Division of Cardiothoracic Surgery, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colo; Rocky Mountain Regional VA Medical Center, Aurora, Colo. Electronic address:

Objectives: Baseline kidney function is a key predictor of postoperative morbidity and mortality. Whether an increased creatinine at the time of surgery, compared with the lowest creatinine in the 3 months before surgery, is associated with poor outcomes has not been evaluated. We examined whether creatinine elevations from "baseline" were associated with adverse postoperative outcomes.

Methods: A total of 1486 patients who underwent cardiac surgery at the University of Colorado Hospital between January 2011 and May 2016 met inclusion criteria. "Change in creatinine from baseline" was defined as the difference between the immediate presurgical creatinine value and the lowest creatinine value within 3 months preceding surgery. Outcomes evaluated were in-hospital mortality, postoperative infection, postoperative stroke, development of stage 3 acute kidney injury, intensive care unit length of stay, and hospital length of stay. Outcomes were adjusted using a balancing score to account for differences in patient characteristics.

Results: There were significant increases in the odds of postoperative infection (odds ratio, 1.17; confidence interval, 1.02-1.34; per 0.1 mg/dL increase in creatinine), stage 3 acute kidney injury (odds ratio, 1.44; confidence interval; 1.18-1.75), intensive care unit length of stay (odds ratio, 1.13; confidence interval, 1.01-1.26), and hospital length of stay (odds ratio, 1.09; confidence interval, 1.05-1.13). There was a significant increase in mortality in the unadjusted analysis, although not after adjustment using a balancing score. There was no association with postoperative stroke.

Conclusions: Elevations in creatinine at the time of surgery above the "baseline" level are associated with increased postoperative morbidity. Baseline creatinine should be established before surgery, and small changes in creatinine should trigger heightened vigilance in the postoperative period.
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http://dx.doi.org/10.1016/j.jtcvs.2020.03.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762739PMC
June 2020

Photo-SNAP-tag, a Light-Regulated Chemical Labeling System.

ACS Chem Biol 2020 08 16;15(8):2212-2220. Epub 2020 Jul 16.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, United States.

Methods that allow labeling and tracking of proteins have been instrumental for understanding their function. Traditional methods for labeling proteins include fusion to fluorescent proteins or self-labeling chemical tagging systems such as SNAP-tag or Halo-tag. These latter approaches allow bright fluorophores or other chemical moieties to be attached to a protein of interest through a small fusion tag. In this work, we sought to improve the versatility of self-labeling chemical-tagging systems by regulating their activity with light. We used light-inducible dimerizers to reconstitute a split SNAP-tag (modified human O-alkylguanine-DNA-alkyltransferase, hAGT) protein, allowing tight light-dependent control of chemical labeling. In addition, we generated a small split SNAP-tag fragment that can efficiently self-assemble with its complement fragment, allowing high labeling efficacy with a small tag. We envision these tools will extend the versatility and utility of the SNAP-tag chemical system for protein labeling applications.
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http://dx.doi.org/10.1021/acschembio.0c00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596905PMC
August 2020

On point in primary CNS lymphoma.

Hematol Oncol 2020 Dec 3;38(5):640-647. Epub 2020 Jul 3.

Division of Hematology/Oncology, University of California, San Francisco, California, USA.

Primary CNS lymphoma (PCNSL) is an aggressive brain tumor that represents a significant challenge both to elucidate its biological pathogenesis as well as to develop definitive precision medicines with minimal collateral toxicity. We highlight the key issues in diagnosis and treatment and focus on emerging technologies, current options among consolidation strategies, and biological agents. We anticipate that further development of molecular diagnostics and molecular imaging approaches that elucidate minimal residual disease in brain parenchyma, leptomeninges, intraocular compartments and even bone marrow will greatly impact the delivery and timing of cytotoxic and biological therapies. Implementation of these approaches is likely essential to clarify ongoing discrepancies in the interpretation of clinical trial results that currently are based on relatively unrefined definitions of response. While the results of early phase investigations involving ibrutinib and the IMiD agents, lenalidomide, pomalidomide, as well as avadomide, strongly support the hypothesis that the B-cell receptor (BCR) pathway, involving MYD88 and CD79B and NF-kB activation, is critical to the pathogenesis of PCNSL, much work is needed to elucidate mechanisms of resistance. Similarly, development of strategies to overcome immunosuppressive mechanisms that are upregulated in the tumor microenvironment is a high priority. Finally, ongoing evidence supports the hypothesis that the blood-brain barrier represents a significant impediment to efficient brain tumor penetration of novel therapeutic agents and innovative strategies of drug delivery remain essential to further improve outcomes.
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http://dx.doi.org/10.1002/hon.2761DOI Listing
December 2020

Cardiac Emergencies in Patients with Left Ventricular Assist Devices.

Heart Fail Clin 2020 Jul;16(3):295-303

Department of Medicine-Cardiology, University of Colorado Anschutz Medical Campus, 12631 East 17th Avenue, B130, Office 7107, Aurora, CO 80045, USA. Electronic address:

Continuous-flow left ventricular assist devices are frequently used for management of patients with advanced heart failure with reduced ejection fraction. Although technologic advancements have contributed to improved outcomes, several complications arise over time. These complications result from several factors, including medication effects, physiologic responses to chronic exposure to circulatory support that is minimally/entirely nonpulsatile, and dysfunction of the device itself. Clinical presentation can range from chronic and indolent to acute, life-threatening emergencies. Several areas of uncertainty exist regarding best practices for managing complications; however, growing awareness has led to development of new guidelines to reduce risk and improve outcomes.
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http://dx.doi.org/10.1016/j.hfc.2020.02.003DOI Listing
July 2020

Noteworthy Cardiac Literature 2019: Cerebral Protection, Zone 2 Arch, Intravascular Ultrasonography in Dissection, Heart Allocation, and Mitral Durability.

Semin Cardiothorac Vasc Anesth 2020 Jun 28;24(2):187-191. Epub 2020 Apr 28.

University of Colorado, Aurora, CO, USA.

The year of 2019 continues to have notable literature advancing the practice of cardiac surgery. In this article, topics of discussion will include the evolution of cerebral protection, the advancement of arch surgical techniques, the heart transplant allocation system, and mitral repair approach and durability.
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http://dx.doi.org/10.1177/1089253220920146DOI Listing
June 2020

Effect of aspirin dose on hemocompatibility-related outcomes with a magnetically levitated left ventricular assist device: An analysis from the MOMENTUM 3 study.

J Heart Lung Transplant 2020 06 20;39(6):518-525. Epub 2020 Mar 20.

Department of Medicine and Department of Cardiothoracic and Vascular Surgery, Montefiore-Einstein Center for Heart and Vascular Care, Bronx, New York. Electronic address:

Background: Aspirin (ASA) anti-platelet therapy is mandated with left ventricular assist devices (LVADs) to prevent hemocompatibility-related adverse events (HRAEs). However, the optimal dose of ASA with HeartMate 3 (HM3) LVAD is unknown.

Methods: In an exploratory analysis of HM3-supported patients in the MOMENTUM 3 study (NCT02224755), 2 groups were analyzed: usual-dose (325 mg) and low-dose (81 mg) ASA with anti-coagulation targeted to an international normalized ratio of 2.0 to 3.0. Exclusion criteria included patients not receiving either ASA 81 mg or 325 mg, those with HRAEs ≤7 days after device implantation, and those receiving >1 anti-platelet agent. The primary end-point was survival free from HRAEs (non-surgical bleeding, pump thrombosis, stroke, and peripheral arterial thromboembolic events) at 2 years.

Results: Overall, 321 HM3 patients (usual-dose: n = 141, low-dose: n = 180) were included in this analysis. Usual-dose group patients were younger (57 ± 13 vs 60 ± 12 years, p = 0.035) and less often assigned destination therapy (55% vs 67%, p = 0.029) than low-dose ASA. At 2 years, a similar proportion of patients in the usual- and low-dose groups (43.4% vs 45.3%, p = 0.94) met the primary end-point. There were no differences in survival free from hemorrhagic (usual-dose: 54.4% vs low-dose: 51.7%, p = 0.42) or thrombotic (usual-dose: 76.8% vs low-dose: 75.7%, p = 0.92) events.

Conclusions: Usual- and low-dose ASA revealed similar rates of bleeding and thrombotic events in HM3 LVAD-supported patients within the MOMENTUM 3 trial. Whether ASA therapy provides any meaningful therapeutic effect in patients treated by the HM3 LVAD remains to be determined.
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http://dx.doi.org/10.1016/j.healun.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650304PMC
June 2020

Impact of left ventricular assist device implantation on mitral regurgitation: An analysis from the MOMENTUM 3 trial.

J Heart Lung Transplant 2020 06 20;39(6):529-537. Epub 2020 Mar 20.

Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Mitral regurgitation (MR) determines pathophysiology and outcome in advanced heart failure. The impact of left ventricular assist device (LVAD) placement on clinically significant MR and its contribution to long-term outcomes has been sparsely evaluated.

Methods: We evaluated the effect of clinically significant MR on patients implanted in the MOMENTUM 3 trial with either the HeartMate II (HMII) or the HeartMate 3 (HM3) at 2 years. Clinical significance was defined as moderate or severe grade MR determined by site-based echocardiograms.

Results: Of 927 patients with LVAD implants without a prior or concomitant mitral valve procedure, 403 (43.5%) had clinically significant MR at baseline. At 1-month of support, residual MR was present in 6.2% of patients with HM3 and 14.3% of patients with HMII (relative risk = 0.43; 95% CI, 0.22-0.84; p = 0.01) with a low rate of worsening at 2 years. Residual MR at 1-month post-implant did not impact 2-year mortality for either the HM3 (hazard ratio [HR],1.41; 95% CI, 0.52-3.89; p = 0.50) or HMII (HR, 0.91; 95% CI, 0.37-2.26; p = 0.84) LVAD. The presence or absence of baseline MR did not influence mortality (HM3 HR, 0.86; 95% CI, 0.56-1.33; p = 0.50; HMII HR, 0.81; 95% CI, 0.54-1.22; p = 0.32), major adverse events or functional capacity. In multivariate analysis, severe baseline MR (p = 0.001), larger left ventricular dimension (p = 0.002), and implantation with the HMII instead of the HM3 LVAD (p = 0.05) were independently associated with an increased likelihood of persistent MR post-implant.

Conclusions: Hemodynamic unloading after LVAD implantation improves clinically significant MR early, sustainably, and to a greater extent with the HM3 LVAD. Neither baseline nor residual MR influence outcomes after LVAD implantation.
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http://dx.doi.org/10.1016/j.healun.2020.03.003DOI Listing
June 2020

Left ventricular assist systems and infection-related outcomes: A comprehensive analysis of the MOMENTUM 3 trial.

J Heart Lung Transplant 2020 08 20;39(8):774-781. Epub 2020 Mar 20.

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: In a randomized controlled trial (MOMENTUM 3), the HeartMate 3 (HM3) fully magnetically levitated centrifugal-flow left ventricular assist device (LVAD) demonstrated superiority over the HeartMate II (HMII) axial-flow LVAD. These findings were driven by hemocompatibility-related outcomes, but infection-related outcomes were not altered by device choice. In this trial-level analysis, we analyzed the clinical patterns of infection-related outcomes over 2 years of support.

Methods: In MOMENTUM 3, 1,020 patients were implanted with either the HM3 (n = 515) or HMII (n = 505) pump. Clinical characteristics and morbidity- and mortality-related outcomes were evaluated to identify predictors associated with major infectious complications, using univariable and multivariable models.

Results: The cumulative number of infections at 2 years was 1,213 (634 HM3 and 579 HMII), and major infection occurred in 58% of patients with the HM3 and 56% of patients with the HMII (p = 0.57). Infections of a local nature unrelated to pump components were most common (n = 681/1,213; 56%), followed by driveline-associated infection (n = 329/1,213; 27%), sepsis (n = 194/1,213; 16%), and other events (n = 9/1,213; 0.7%). Bacterial pathogens were implicated in 806 of 1,213 events (66%); significant predictors of infection included sex (women vs men; hazard ratio [HR]: 1.38, p = 0.003), pre-implant use of intra-aortic balloon pump (HR: 1.33, p = 0.02), pre-implant history of cardiac surgery (HR: 1.28, p = 0.01), and body mass index ≥ 30 (HR: 1.40, p < 0.0001). Most deaths in those with infection occurred owing to non-infectious causes.

Conclusion: Infection is the most common adverse effect in patients implanted with contemporary continuous-flow LVADs, with most such events unrelated to the pump or its peripheral components. Whether chronic mechanical circulatory devices confer an immunomodulatory effect pre-disposing to infection warrants closer scrutiny to understand and ameliorate this morbidity.
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http://dx.doi.org/10.1016/j.healun.2020.03.002DOI Listing
August 2020

Evaluation for Heart Transplantation and LVAD Implantation: JACC Council Perspectives.

J Am Coll Cardiol 2020 03;75(12):1471-1487

Michael E. DeBakey VA Medical Center and Section of Cardiology, Winters Center for Heart Failure, Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas.

Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?
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http://dx.doi.org/10.1016/j.jacc.2020.01.034DOI Listing
March 2020

The Society of Thoracic Surgeons Intermacs 2019 Annual Report: The Changing Landscape of Devices and Indications.

Ann Thorac Surg 2020 03;109(3):649-660

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: The field of mechanical circulatory support has been impacted by the approval of new continuous-flow left ventricular assist devices (LVADs) and changes to the United States heart allocation system.

Methods: Primary isolated continuous-flow LVAD implants in The Society of Thoracic Surgeons Intermacs registry from January 2014 through September 2019 were evaluated. Survival and freedom from major adverse events were compared between axial-flow, centrifugal-flow with hybrid levitation (CF-HL), and centrifugal-flow with full magnetic levitation (CF-FML) devices.

Results: Of 2603 devices implanted in 2014, 1824 (70.1%) were axial flow and 1213 (46.6%) were destination therapy (DT); through September 2019, 1752 devices were implanted, but only 37 (2.1%) were axial flow and 1230 (70.2%) were DT. Implants were performed in 13,016 patients between 2014 and 2018. Patients receiving implants in 2017-2018 compared with 2014-2016 were more likely to be at Intermacs profile 1 (17.1% vs 14.3%, P < .001) and to have preimplant temporary mechanical circulatory support (34.8% vs 29.3%, P < .001). Overall survival and freedom from major adverse events were higher with CF-FML devices. In multivariable analysis of survival between CF-HL and CF-FML, device type was not a significant early hazard, but the use of CF-HL devices had a late hazard ratio for death of 3.01 (P < .001).

Conclusions: Over the past 5 years, centrifugal-flow LVADs have become the dominant technology and DT the most common implant strategy. While outcomes with CF-FML devices are promising, comparisons with other devices from nonrandomized registry studies should be made with caution.
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http://dx.doi.org/10.1016/j.athoracsur.2019.12.005DOI Listing
March 2020

Stage 1 acute kidney injury is independently associated with infection following cardiac surgery.

J Thorac Cardiovasc Surg 2021 04 25;161(4):1346-1355.e3. Epub 2019 Nov 25.

Division of Cardiothoracic Surgery, Department of Surgery, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colo; Rocky Mountain Regional VA Medical Center, Aurora, Colo. Electronic address:

Objectives: Severe acute kidney injury (AKI) is a known risk factor for infection and mortality. However, whether stage 1 AKI is a risk factor for infection has not been evaluated in adults. We hypothesized that stage 1 AKI following cardiac surgery would independently associate with infection and mortality.

Methods: In this retrospective propensity score-matched study, we evaluated 1620 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital from 2011 to 2017. Patients who developed stage 1 AKI by Kidney Disease Improving Global Outcomes creatinine criteria within 72 hours of surgery were matched to patients who did not develop AKI. The primary outcome was an infection, defined as a new surgical-site infection, positive blood or urine culture, or development of pneumonia. Secondary outcomes included in-hospital mortality, stroke, and intensive care unit (ICU) and hospital length of stay (LOS).

Results: Stage 1 AKI occurred in 293 patients (18.3%). Infection occurred in 20.9% of patients with stage 1 AKI compared with 8.1% in the no-AKI group (P < .001). In propensity-score matched analysis, stage 1 AKI independently associated with increased infection (odds ratio [OR]; 2.24, 95% confidence interval [CI], 1.37-3.17), ICU LOS (OR, 2.38; 95% CI, 1.71-3.31), and hospital LOS (OR, 1.30; 95% CI, 1.17-1.45).

Conclusions: Stage 1 AKI is independently associated with postoperative infection, ICU LOS, and hospital LOS. Treatment strategies focused on prevention, early recognition, and optimal medical management of AKI may decrease significant postoperative morbidity.
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http://dx.doi.org/10.1016/j.jtcvs.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285820PMC
April 2021

Association of Clinical Outcomes With Left Ventricular Assist Device Use by Bridge to Transplant or Destination Therapy Intent: The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) Randomized Clinical Trial.

JAMA Cardiol 2020 04;5(4):411-419

Heart and Vascular Center, Center for Advanced Heart Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Left ventricular assist devices (LVADs) are well established in the treatment of advanced heart failure, but it is unclear whether outcomes are different based on the intended goal of therapy in patients who are eligible vs ineligible for heart transplant.

Objective: To determine whether clinical outcomes in the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) trial differed by preoperative categories of bridge to transplant (BTT) or bridge to transplant candidacy (BTC) vs destination therapy (DT).

Design, Setting, And Participants: This study was a prespecified secondary analysis of the MOMENTUM 3 trial, a multicenter randomized clinical trial comparing the magnetically levitated centrifugal-flow HeartMate 3 (HM3) LVAD to the axial-flow HeartMate II (HMII) pump. It was conducted in 69 centers with expertise in managing patients with advanced heart failure in the United States. Patients with advanced heart failure were randomized to an LVAD, irrespective of the intended goal of therapy (BTT/BTC or DT).

Main Outcomes And Measures: The primary end point was survival free of disabling stroke or reoperation to remove or replace a malfunctioning device at 2 years. Secondary end points included adverse events, functional status, and quality of life.

Results: Of the 1020 patients with implants (515 with HM3 devices [50.5%] and 505 with HMII devices [49.5%]), 396 (38.8%) were in the BTT/BTC group (mean [SD] age, 55 [12] years; 310 men [78.3%]) and 624 (61.2%) in the DT group (mean [SD] age, 63 [12] years; 513 men [82.2%]). Of the patients initially deemed as transplant ineligible, 84 of 624 patients (13.5%) underwent heart transplant within 2 years of LVAD implant. In the primary end point analysis, HM3 use was superior to HMII use in patients in the BTT/BTC group (76.8% vs 67.3% for survival free of disabling stroke and reoperation; hazard ratio, 0.62 [95% CI, 0.40-0.94]; log-rank P = .02) and patients in the DT group (73.2% vs 58.7%; hazard ratio, 0.61 [95% CI, 0.46-0.81]; log-rank P < .001). For patients in both BTT/BTC and DT groups, there were not significantly different reductions in rates of pump thrombosis, stroke, and gastrointestinal bleeding with HM3 use relative to HMII use. Improvements in quality of life and functional capacity for either pump were not significantly different regardless of preimplant strategy.

Conclusions And Relevance: In this trial, the superior treatment effect of HM3 over HMII was similar for patients in the BTT/BTC or DT groups. It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure.

Trial Registration: ClinicalTrials.gov identifier: NCT02224755.
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http://dx.doi.org/10.1001/jamacardio.2019.5323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990746PMC
April 2020

Defining decreased protein succinylation of failing human cardiac myofibrils in ischemic cardiomyopathy.

J Mol Cell Cardiol 2020 01 10;138:304-317. Epub 2019 Dec 10.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

Succinylation is a post-translational modification of protein lysine residues with succinyl groups derived from succinyl CoA. Succinylation is considered a significant post-translational modification with the potential to impact protein function which is highly conserved across numerous species. The role of succinylation in the heart, especially in heart failure and myofibril mechanics, remains largely unexplored. Mechanical parameters were measured in myofibrils isolated from failing hearts of ischemic cardiomyopathy patients and non-failing donor controls. We employed mass spectrometry to quantify differential protein expression in myofibrils from failing ischemic cardiomyopathy hearts compared to non-failing hearts. In addition, we combined peptide enrichment by immunoprecipitation with liquid chromatography tandem mass spectrometry to quantitatively analyze succinylated lysine residues in these myofibrils. Several key parameters of sarcomeric mechanical interactions were altered in myofibrils isolated from failing ischemic cardiomyopathy hearts, including lower resting tension and a faster rate of activation. Of the 100 differentially expressed proteins, 46 showed increased expression in ischemic heart failure, while 54 demonstrated decreased expression in ischemic heart failure. Our quantitative succinylome analysis identified a total of 572 unique succinylated lysine sites located on 181 proteins, with 307 significantly changed succinylation events. We found that 297 succinyl-Lys demonstrated decreased succinylation on 104 proteins, while 10 residues demonstrated increased succinylation on 4 proteins. Investigating succinyl CoA generation, enzyme activity assays demonstrated that α-ketoglutarate dehydrogenase and succinate dehydrogenase activities were significantly decreased in ischemic heart failure. An activity assay for succinyl CoA synthetase demonstrated a significant increase in ischemic heart failure. Taken together, our findings support the hypothesis that succinyl CoA production is decreased and succinyl CoA turnover is increased in ischemic heart failure, potentially resulting in an overall decrease in the mitochondrial succinyl CoA pool, which may contribute to decreased myofibril protein succinylation in heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2019.11.159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058372PMC
January 2020

Thrombocytopenia After Cardiopulmonary Bypass Is Associated With Increased Morbidity and Mortality.

Ann Thorac Surg 2020 07 6;110(1):50-57. Epub 2019 Dec 6.

Division of Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Medicine, Rocky Mountain Regional VA Medical Center, Denver, Colorado. Electronic address:

Background: Thrombocytopenia is a risk factor for morbidity and mortality in critically ill patients, and is common after cardiopulmonary bypass (CPB). In this study, we evaluate whether thrombocytopenia after CPB is an independent risk factor for postoperative morbidity and mortality.

Methods: We retrospectively evaluated 1364 patients requiring CPB at the University of Colorado Hospital between January 2011 and May 2016. Platelet nadir, absolute change in platelets, and percent change in platelets were modeled as continuous variables. Patients with postoperative thrombocytopenia (defined a nadir <75 × 10/μL within 72 hours) were also compared with patients without thrombocytopenia in a propensity-matched model. The primary outcome was in-hospital mortality, and secondary outcomes included postoperative infection, postoperative acute kidney injury (AKI), postoperative stroke, and prolonged intensive care unit (ICU) and hospital lengths of stay (LOS).

Results: Postoperative thrombocytopenia occurred in 356 (26.0%) patients. In multivariable analysis, platelet nadir was significantly inversely associated with mortality (odds ratio [OR], 0.955; 95% confidence interval [CI], 0.934-0.975; P < .001), postoperative infection (OR, 0.992; 95% CI, 0.986-0.999; P = .03), AKI (all stage) (OR, 0.993; 95% CI, 0.988-0.998; P = .01), AKI (stage 3) (OR, 0.966; 95% CI, 0.951-0.982; P < .001), postoperative stroke (OR, 0.974; 95% CI, 0.956-0.992; P = .006), prolonged ICU stay (OR, 0.986; 95% CI, 0.981-0.991; P < .001), and hospital LOS (OR, 0.998; 95% CI, 0.997-0.999; P = .001). Percent change in platelets from baseline was also significantly associated with all primary and secondary outcomes.

Conclusions: Postoperative thrombocytopenia is independently associated with postoperative mortality, AKI, infection, stroke, and prolonged ICU and hospital LOS. Serial platelet monitoring may help identify patients at higher risk of postoperative complications. Further studies investigating strategies to reduce postoperative thrombocytopenia, including reducing CPB time, are needed.
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http://dx.doi.org/10.1016/j.athoracsur.2019.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279614PMC
July 2020

Postoperative Complications Are Not Elevated in Well-Compensated ESRD Patients Undergoing Cardiac Surgery: End-Stage Renal Disease Cardiac Surgery Outcomes.

J Surg Res 2020 03 27;247:136-143. Epub 2019 Nov 27.

Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Aurora, Colorado. Electronic address:

Background: Patients with end-stage renal disease (ESRD) are at high risk for cardiac disease requiring surgery, and have been shown to have increased surgical risks. There have been significant improvements in ESRD management, surgical techniques, and patient selection over the past 10 y. We evaluated rates of serious postoperative outcomes in stable, well-dialyzed patients with ESRD undergoing nonemergent cardiac surgery compared to the general cardiac surgery population.

Methods: In this propensity-score matched study, we evaluated 1451 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital (UCH) between 2011 and 2016. Patients with ESRD were compared to nonESRD patients. The primary outcome was a composite endpoint, including 30-d mortality, stroke, postoperative infection, and prolonged intensive care unit (ICU) length of stay (LOS).

Results: A total of 35 patients with ESRD met inclusion criteria. These select patients were younger with few comorbidities than the nonESRD population. There were no statistically significant differences in the composite outcome between ESRD and nonESRD patients in the propensity-matched analysis (OR 0.70, CI 0.29-1.72, P = 0.44). There were no significant differences or trends for in-hospital mortality, postoperative stroke, infection, ICU LOS, or hospital LOS between the patients with and without ESRD.

Conclusions: Stable ESRD patients undergoing nonemergent surgery are not at increased risk of major postoperative complications when compared to those without ESRD. Well-compensated ESRD patients should not be excluded from surgical consideration.
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http://dx.doi.org/10.1016/j.jss.2019.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192065PMC
March 2020