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Cardiac troponin I Ser44 is a downstream target for protein kinase C. The current studies show heightened phosphorylation develops during contractile dysfunction in failing human myocardium and in rat models of pressure overload and aging with contractile dysfunction., Increases in protein kinase C (PKC) are associated with diminished cardiac function, but the contribution of downstream myofilament phosphorylation is debated in human and animal models of heart failure. The current experiments evaluated PKC isoform expression, downstream cardiac troponin I (cTnI) S44 phosphorylation (p-S44), and contractile function in failing (F) human myocardium, and in rat models of cardiac dysfunction caused by pressure overload and aging. In F human myocardium, elevated PKCα expression and cTnI p-S44 developed before ventricular assist device implantation. Circulatory support partially reduced PKCα expression and cTnI p-S44 levels and improved cellular contractile function. Gene transfer of dominant negative PKCα (PKCαDN) into F human myocytes also improved contractile function and reduced cTnI p-S44. Heightened cTnI phosphorylation of the analogous residue accompanied reduced myocyte contractile function in a rat model of pressure overload and in aged Fischer 344 × Brown Norway F1 rats (≥26 mo). Together, these results indicate PKC-targeted cTnI p-S44 accompanies cardiac cellular dysfunction in human and animal models. Interfering with PKCα activity reduces downstream cTnI p-S44 levels and partially restores function, suggesting cTnI p-S44 may be a useful target to improve contractile function in the future.

In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device.We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years.This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group.Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)-LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF-LVAD implantation, were randomly divided into equal-sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF-LVADs [HeartMate II LVAD, 76% (n = 560), HeartWare HVAD, 24% (n = 174)]. A RVAD was required in 4.5% (n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients (n = 143) were female, median age at implant was 59 years (IQR, 49.4-65.3), and median INTERMACS profile was 3 (IQR, 2-3). RVAD was required in 4.5% (n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.

Background Infections are the most common complication in recipients of durable left ventricular assist devices (LVAD) and are associated with increased morbidity, mortality, and expenditures. The existing literature examining factors associated with infection in LVAD recipients is limited and principally comprises single-center studies. This scoping review synthesizes all available evidence related to identifying modifiable, non-patient factors associated with infections among LVAD recipients. Methods Published studies were identified through searching 5 bibliographic databases: PubMed, Scopus, EMBASE, CINAHL, and Web of Science Core Collection. Inclusion criteria required examination of factors associated with infections among recipients of contemporary, implantable, continuous flow LVADs. Key study characteristics were extracted by 4 independent reviewers and current literature described narratively. The Systems Engineering Initiative for Patient Safety (SEIPS) model was used to develop a taxonomy for non-patient related factors (e.g., tasks, tools, technologies, organization, and environment) associated with infections following LVAD implantation. All analyses took place between February 2019 and May 2021. Findings A total of 43 studies met inclusion criteria. The majority of included studies were observational (n = 37), single-center (n = 29), from the U.S. (n = 38), and focused on driveline infections (n = 40). Among the 22 evaluated sub-domains of non-patient related factors, only two: increasing center experience and establishing a silicone-skin interface at the driveline exit site, were identified as consistently being associated with a lower risk of infection. Conclusion This review identified 43 studies that described non-patient related factors associated with infection in LVAD recipients. Only two factors were consistently associated with lower infection risk in LVAD recipients: increasing experience and establishing a silicone-skin interface at driveline exit site. The large variability in reporting across multiple studied interventions limited the ability to discern their effectiveness.

Left ventricular assist devices (LVADs) improve quality of life (QoL) and functional capacity (FC) for patients with advanced heart failure. The association between adverse events (AEs) and changes in QoL and FC are unknown. Patients treated with the HeartWare ventricular assist device (HVAD) with paired 6-minute walk distance (6MWD, n = 263) and Kansas City Cardiomyopathy Questionnaires (KCCQ, n = 272) at baseline and 24 months in the ENDURANCE and ENDURANCE Supplemental Trial databases were included. Patients were stratified based upon occurrence of clinically significant AEs during the first 24 months of support and analyzed for the mean change in 6MWD and KCCQ. The impact of AE frequency on change in 6MWD and KCCQ from baseline to 24 months was evaluated. Of the AEs examined, only sepsis was associated with an improvement in 6MWD (109 m vs. 16 m, p = 0.002). Patients without improvement in 6MWD test from baseline to 24 months had significantly more AEs than those with FC improvement (p = 0.0002). Adverse events did not affect the KCCQ overall summary score. In this analysis, patients with fewer AEs had greater improvement in FC during the 24-month follow up. The frequency of AEs did not have a significant impact on QoL after LVAD implantation.

Although the current wide-scale adoption of the HeartMate 3 left ventricular assist device can be attributed to favorable clinical trial outcomes, restrictive clinical trial eligibility criteria may result in lack of generalizability to real-world populations. We assessed the generalizability of left ventricular assist device clinical trial outcomes and evaluated the prognostic value of specific inclusion and exclusion criteria.The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Therapy With HeartMate 3 (MOMENTUM 3) eligibility criteria were applied to patients identified in The Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) who underwent HeartMate 3 implantation (n = 4610) between August 2017 and March 2020. Patients were categorized as trial-eligible or trial-ineligible and by number of ineligibility criteria. The effect of trial eligibility on mortality was estimated using Cox models.Indications for HeartMate 3 implant included destination therapy (n = 2827, 61%), bridge to candidacy (n = 969, 21%), and bridge to transplant (n = 702, 15%). A total of 1941 recipients (42%) were trial-ineligible, with 1245 (27%) meeting one ineligibility criterion, 470 (10%) meeting two, and 226 (5%) meeting three or more. Estimated 1-year mortality for trial-ineligible recipients was higher than for trial-eligible recipients (17% ± 1% vs 10% ± 1%, P.001). Compared with trial-eligible patients, 1-year mortality was incrementally higher for patients meeting one ineligibility criterion (15% ± 1%), two criteria (16% ± 2%), and three or more criteria (30% ± 3%). Thrombocytopenia and elevated creatinine, bilirubin, and international normalized ratio in trial-ineligible patients were independently associated with increased mortality.Despite differences in mortality, both trial-eligible and trial-ineligible HeartMate 3 recipients had excellent outcomes in real-world practice, suggesting future trial eligibility criteria could be expanded.

Severe mitral annular calcification (MAC) increases surgical complexity and is independently associated with increased operative mortality for mitral valve replacement (MVR). Recently we adopted ultrasonic emulsification/aspiration for annular decalcification to address these risks and describe our early experience with this new technology.Excluding previous mitral valve surgery or endocarditis, 179 patients with MAC underwent MVR at a single institution between January 2015 and March 2020. Of these, 15 consecutive patients with severe MAC (≥50% of the annulus) underwent annular decalcification with ultrasonic emulsification/aspiration as an adjunct treatment during MVR from April 2019 to March 2020.Mean patient age was 68 ± 12 years, and 72% (n = 128) were female. Mean preoperative left ventricular ejection fraction was 60% ± 11%, and mean mitral valve gradient was 9.1 ± 4.4 mm Hg. Concomitant procedures included antiarrhythmia (n = 52), aortic valve replacement (n = 32), and coronary artery bypass grafting (n = 20). There were no operative deaths or strokes in the group undergoing ultrasonic emulsification and aspiration.The use of ultrasonic emulsification and aspiration in severe MAC patients may help mitigate the risks of MVR and facilitate operative success in this challenging, high-risk population.

BackgroundOf the 150,000 patients annually undergoing coronary artery bypass grafting, 35% develop complications that increase mortality 5 fold and expenditure by 50%. Differences in patient risk and operative approach explain only 2% of hospital variations in some complications. The intraoperative phase remains understudied as a source of variation, despite its complexity and amenability to improvement.ObjectiveThe objectives of this study are to (1) investigate the relationship between peer assessments of intraoperative technical skills and nontechnical practices with risk-adjusted complication rates and (2) evaluate the feasibility of using computer-based metrics to automate the assessment of important intraoperative technical skills and nontechnical practices.MethodsThis multicenter study will use video recording, established peer assessment tools, electronic health record data, registry data, and a high-dimensional computer vision approach to (1) investigate the relationship between peer assessments of surgeon technical skills and variability in risk-adjusted patient adverse events; (2) investigate the relationship between peer assessments of intraoperative team-based nontechnical practices and variability in risk-adjusted patient adverse events; and (3) use quantitative and qualitative methods to explore the feasibility of using objective, data-driven, computer-based assessments to automate the measurement of important intraoperative determinants of risk-adjusted patient adverse events.ResultsThe project has been funded by the National Heart, Lung and Blood Institute in 2019 (R01HL146619). Preliminary Institutional Review Board review has been completed at the University of Michigan by the Institutional Review Boards of the University of Michigan Medical School.ConclusionsWe anticipate that this project will substantially increase our ability to assess determinants of variation in complication rates by specifically studying a surgeon’s technical skills and operating room team member nontechnical practices. These findings may provide effective targets for future trials or quality improvement initiatives to enhance the quality and safety of cardiac surgical patient care.International Registered Report Identifier (IRRID)PRR1-10.2196/22536

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.

Introduction: Caregivers (CGs) of heart failure (HF) patients (PTs) who undergo heart transplantation (HT) or Destination Therapy Mechanical Circulatory Support (DT MCS) provide support to PTs before and after surgery, which may affect their own health-related quality of life (HRQOL). In SUSTAIN-IT, we previously reported that CG HRQOL was good at baseline (i.e., before HT and DT MCS surgery) and was impacted by CG comorbidities and CG anxiety. This report explores change in CG overall HRQOL, depression, and anxiety from baseline to 12 months after HT or DT MCS surgery. Methods: From 10/1/15-12/31/18, 13 U.S. centers enrolled 301 CGs of HF PTs: 193 awaiting HT (92 HT with MCS as a bridge to transplant [HT BTT] and 101 HT without MCS [HT non-BTT]), and 108 awaiting DT MCS. At baseline, 3, 6, and 12 months post HT or DT MCS surgery, CGs completed the following instruments: EQ-5D-3L (Visual Analog Scale [VAS]: 0 [worst] to 100 [best] imaginable health state), PHQ-8 (range=0-24; score ≥10=depressive symptoms requiring evaluation), and STAI-State (range=20-80, higher score=more anxiety). Analyses included unadjusted and baseline-adjusted linear regression models. Results: CGs were age 61.0±10.3 years; the majority were Caucasian (86%), female (86%), spouses (85%) of enrolled HF PTs. At baseline, CG EQ-5D-3L VAS and PHQ-8 average scores were 83.8 ± 13.99 (high) and 2.6 ± 2.85 (low), respectively, for the entire cohort. No significant interval changes in CG HRQOL and depressive symptoms were found within or between groups. DT MCS and HT non-BTT CG anxiety significantly decreased over time (baseline to 12 months) (Figure). Levels of CG anxiety were similar among all groups at 12 months after HT or DT MCS surgery. Conclusions: The demonstrated reduction in anxiety among CGs in the post-operative period provides clinicians with important information to share with CGs when PTs are considering surgical treatment options for HF.

Background: Tolerance of donor hearts of different ABO blood types to allograft ischemic time has not been previously examined. Objectives: We determined the impact of allograft ischemic time on heart transplant outcomes with differing ABO donor organ types. Methods: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous variables were analyzed with t-test and categorical variables were compared with Chi-squared test. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. Results: Comparing allograft ischemic times 0.150). Conclusions: Compared with non-O hearts, transplantation with O donor hearts stored for ≥4hrs leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when extended cold preservation times are anticipated.

Introduction: Health systems with more robust provider teamwork have lower mortality rates for coronary artery bypass grafting. Patients undergoing durable ventricular assist device (VAD) therapy have complex comorbidities and develop adverse events requiring multidisciplinary provider teamwork. Hypothesis: Provider teamwork is associated with 180-day mortality following durable VAD implantation. Methods: Data (linked Medicare claims+INTERMACS) were analyzed from primary durable VADs implanted across 119 hospitals over a five-year period. Claims were used to identify provider interactions (cardiac surgeons, cardiologists, anesthesiologists, intensivists, nurse practitioners, physician assistants) for previously shared VAD patients during the 1-year period ending 6-months before each patient’s VAD implant admission. Provider teamwork was assessed at the hospital level using a clustering coefficient (range: 0-1; higher values = greater teamwork), an established and validated measure capturing the prevalence of tightly connected groups in a network. Provider teamwork level was associated with a patient’s 180-day mortality rate using multivariable regression adjusting for baseline characteristics reported to INTERMACS. Results: The study cohort included 2,807 VAD patients (mean age 63 years, 53% for destination therapy, 19% female, 74% white) with 10.8% identified as INTERMACS Profile 1. There were 468 deaths (16.7%) within 180 days of implantation. Provider teamwork (clustering coefficient) was inversely associated with 180-day mortality (beta=-0.79; 95%CI: -1.26, -0.11). A 1SD increase in provider teamwork was associated with a 13.4% decrease in the predicted probability of 180-day mortality, Figure. Conclusions: Social networks characterized by greater provider teamwork are important determinants of mortality following VAD implantation and may serve as targets for optimizing outcomes and greater adoption for this therapy.

Introduction: In heart transplantation, the supply of donor hearts is contributed by the short tolerable preservation period with risk for primary graft dysfunction. Understanding the differential biological responses to preservation between the left ventricle (LV) and right ventricle (RV) may provide critical insights. Methods: Murine donor hearts were infused with cold HTK solution and stored on ice for 0h, 4h and 8h followed by 90minutes perfusion with Krebs Buffer. The LV and RV were collected at the end of reperfusion for gene expression and protein analysis by RNA-sequencing and western blot. Results: Differential gene expression analysis showed that RV has 1092 upregulated genes and 291 downregulated genes compared to LV after cold storage followed by perfusion. GO analysis show that gene sets related to immune response (padj=7e-27), cell responses to interferon-beta (padj=8.90e-19) were enriched in RV upregulated genes (figure). We also confirmed the upregulation of immune response genes such IL1-β, Myd88 by qPCR and western blot. Moreover, we found that active β-catenin, a potential upstream regulator of IL1- β, also upregulated in RV. Wnt/β-catenin downstream target genes were also enriched in human donor RVs during prolonged preservation. Importantly, donor hearts from murine Myd88-/- showed reduced differences in the transcriptome of the LV vs RV (figure) and demonstrated improved heart function after prolonged cold storage with reperfusion. Conclusions: The RV demonstrates more extensive inflammatory response to storage compared to the LV. Selective upregulation of Wnt/β-catenin signaling in the RV may be important for enhancing this inflammatory response to preservation. Deficiency of MyD88 mediated innate immune signaling improved cardiac contractility after prolonged preservation and likely have important clinical implications for transplantation.

Purpose: Caregivers (CGs) for patients with advanced heart failure (HF) assist in HF-specific disease management. In the SUSTAIN-IT study, we reported CG perception of difficulty and time needed to perform tasks for patients awaiting surgery in 3 groups: HF patients awaiting heart transplant (HT) without mechanical support (HT-non-MCS), HF patients awaiting HT bridged with mechanical support (HT-MCS), and HF patient awaiting left ventricular device implantation as destination therapy (DT-MCS). In this report, we compare CG perceived burden from baseline to 1 year after surgery. Methods: We enrolled 301 CGs of HF patients between 10/1/15-12/31/18 from 12 U.S. hospitals: 193 awaiting HT (92 with and 101 without MCS), and 108 scheduled for DT-MCS. Prior to surgery and 3, 6, and 12 months after surgery, CGs completed the Oberst Caregiver Burden Scale (OCBS) which has 15 items with 2 subscales: (1) time and (2) difficulty: range=1-5, higher score=more time required for tasks and more task difficulty. Analyses included t-tests, chi-square tests, and baseline-adjusted linear regression models. Results: CGs were age 61.0±10.3 years, the majority were spouses (85%), female (86%), and white (86%). Average time spent on caregiving was moderate and decreased significantly from baseline to 12 months after surgery for all groups (Figure). DT-MCS CGs spent significantly more time than HT CGs on tasks 12 months after surgery. There were no significant differences in perceived difficulty (which was low) in performing CG tasks in all groups from baseline to 12 months. DT-MCS CGs did perceive tasks to be more difficult than HT CGs at 12 months. Conclusion: CGs of advanced HF patients adapted well to assisting with care, without increased burden, 1 year after HT and DT-MCS surgery. CGs of DT-MCS patients required more time and reported CG tasks to be more difficult than HT CGs. Understanding differences in CG burden will aid in pre surgical risk discussions and post-surgical follow-up.

Background: Postacute care is a major driver of cardiac surgical episode spending, but the sources of variation in spending have not been explored. The objective of this study was to identify sources of variation in postacute care spending within 90-days of discharge following coronary artery bypass grafting (CABG) and aortic valve replacement (AVR) and the relationship between postacute care spending and other postdischarge utilization. Methods and Results: A retrospective analysis was conducted of public and private administrative claims for Michigan residents insured by Medicare fee-for-service and Blue Cross Blue Shield of Michigan/Blue Care Network commercial and Medicare Advantage plans undergoing CABG (n=11 208) or AVR (n=6122) in 33 nonfederal acute care Michigan hospitals between January 1, 2015 and December 31, 2018. Postacute care use was present in 9662 (86.2%) CABG episodes and 4242 (69.3%) AVR episodes, with respective mean (SD) 90-day spending of $4398±$6124 and $3465±$5759. Across hospitals, mean postacute care spending ranged from $3280 to $8186 for CABG and $2246 to $7710 for AVR. Inpatient rehabilitation and skilled nursing facility care accounted for over 80% of the variation spending between low and high postacute care spending hospitals. At the hospital-level, postacute care spending was modestly correlated across procedures and payers. Spending associated with readmissions, emergency department visits, and outpatient facility care was significantly different between low and high postacute care spending hospitals in CABG and AVR episodes. Conclusions: There was wide hospital variation in postacute care spending after cardiac surgery, which was primarily driven by differential use and intensity in facility-based postacute care. Optimizing facility-based postacute care after cardiac surgery offers unique opportunities to reduce potentially unwarranted care variation.

BACKGROUND Of the 150,000 patients annually undergoing coronary artery bypass grafting, 35% develop complications that increase mortality 5 fold and expenditure by 50%. Differences in patient risk and operative approach explain only 2% of hospital variations in some complications. The intraoperative phase remains understudied as a source of variation, despite its complexity and amenability to improvement. OBJECTIVE The objectives of this study are to (1) investigate the relationship between peer assessments of intraoperative technical skills and nontechnical practices with risk-adjusted complication rates and (2) evaluate the feasibility of using computer-based metrics to automate the assessment of important intraoperative technical skills and nontechnical practices. METHODS This multicenter study will use video recording, established peer assessment tools, electronic health record data, registry data, and a high-dimensional computer vision approach to (1) investigate the relationship between peer assessments of surgeon technical skills and variability in risk-adjusted patient adverse events; (2) investigate the relationship between peer assessments of intraoperative team-based nontechnical practices and variability in risk-adjusted patient adverse events; and (3) use quantitative and qualitative methods to explore the feasibility of using objective, data-driven, computer-based assessments to automate the measurement of important intraoperative determinants of risk-adjusted patient adverse events. RESULTS The project has been funded by the National Heart, Lung and Blood Institute in 2019 (R01HL146619). Preliminary Institutional Review Board review has been completed at the University of Michigan by the Institutional Review Boards of the University of Michigan Medical School. CONCLUSIONS We anticipate that this project will substantially increase our ability to assess determinants of variation in complication rates by specifically studying a surgeon’s technical skills and operating room team member nontechnical practices. These findings may provide effective targets for future trials or quality improvement initiatives to enhance the quality and safety of cardiac surgical patient care. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/22536

Intracardiac blood flow is driven by differences in relative pressure, and assessing these is critical in understanding cardiac disease. Non-invasive image-based methods exist to assess relative pressure, however, the complex flow and dynamically moving fluid domain of the intracardiac space limits assessment. Recently, we proposed a method, ?WERP, utilizing an auxiliary virtual field to probe relative pressure through complex, and previously inaccessible flow domains. Here we present an extension of ?WERP for intracardiac flow assessments, solving the virtual field over sub-domains to effectively handle the dynamically shifting flow domain. The extended ?WERP is validated in an in-silico benchmark problem, as well as in a patient-specific simulation model of the left heart, proving accurate over ranges of realistic image resolutions and noise levels, as well as superior to alternative approaches. Lastly, the extended ?WERP is applied on clinically acquired 4D Flow MRI data, exhibiting realistic ventricular relative pressure patterns, as well as indicating signs of diastolic dysfunction in an exemplifying patient case. Summarized, the extended ?WERP approach represents a directly applicable implementation for intracardiac flow assessments. Funding agencies: D.M. holds a Knut and Alice Wallenberg Foundation scholar-ship for postdoctoral studies at Massachusetts Institute of Technology. M.B. acknowledges funding from King’s College London and Imperical College London ESPRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1). D.N. would like to acknowledge funding from Engineering and Physical Sciences Research Council (EP/N011554/1 and EP/R003866/1). P.L. holds a Wellcome Trust Senior Research Fellowship (g.a. 209450/Z/17/Z). T.E. would like to acknowledge funding from the Swedish Research Council (2018–04454) and the Swedish Heart-Lung Foundation (2018-0657). This work was also supported by the Wellcome ESPRC Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z) and the British Heart Foundation (TG/17/3/33406). E.R.E. was funded in part by NIH R01 49039.

IMPORTANCE: Given the shortage of donor hearts and improvement in outcomes with left ventricular assist device (LVAD) therapy, a relevant but, to date, unanswered question is whether select patients with advanced heart failure should receive LVAD destination therapy as an alternative to heart transplant. OBJECTIVE: To determine whether a strategy of LVAD destination therapy is associated with similar survival benefit as wait-listing for heart transplant with or without LVAD therapy among patients with advanced heart failure. DESIGN, SETTING, AND PARTICIPANTS: This retrospective propensity-matched cohort analysis used data on heart transplants from the United Network for Organ Sharing registry and LVAD implants from the Interagency Registry for Mechanically Assisted Circulatory Support from January 1, 2010, to December 31, 2014. The matched LVAD destination therapy cohort included 3411 patients. Data analysis for this study was conducted from December 22, 2017, to May 24, 2019. MAIN OUTCOMES AND MEASURES: Survival at 5 years was analyzed using Cox proportional hazards models. RESULTS: In total, 8281 patients had albumin level, creatinine level, and BMI data recorded and were included in the analysis. Despite propensity score matching, the 3411 patients receiving LVAD destination therapy still tended to be slightly older than the 3411 patients wait-listed for heart transplant (64.0 years [interquartile range, 55.0-70.0 years] vs 60.0 [interquartile range, 54.0-65.0 years]; P

Background This study evaluated the impact of adverse events (AEs) on the development of subsequent AEs after left ventricular assist device (LVAD) surgery. Methods and Results The INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) was used to identify primary durable LVADs implanted between 2006 and 2016. The temporal relationships between AEs occurring during the index hospitalization were evaluated using separate risk‐adjusted Cox proportional hazard models. LVADs were implanted in 18 763 patients. The strongest positive relationships were renal failure leading to hepatic dysfunction (hazard ratio [HR], 6.62; 95% CI, 5.12–8.54; P P P P P P Conclusions Most in‐hospital AEs after LVAD implantation have a significant association with the development of subsequent AEs, with the most profound impact associated with primary renal or respiratory failure, which are also associated with the lowest 1‐year survival. Targeting the reduction of renal or respiratory failure as the primary AE after LVAD surgery would likely yield the greatest reductions in overall AE burden and subsequent mortality.

Background: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. Methods: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. Results: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. Conclusions: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.

Computational fluid dynamics has become a dynamic tool in the development of ventricular assist devices (VADs) and as a predictor of thrombosis within these pumps. The genesis of thrombi could be in loco, due to deposition within the VAD, or upstream such as the left atrial appendage or inside the left ventricle. To calibrate our group's computational model, a retrospective analysis of 29 explanted HeartMate II (HMII) VADs due to suspected pump thrombosis (PT) from the University of Michigan was conducted. Thrombi in these pumps were characterized by their frequency, composition, severity, and physical distribution in five regions of the blood flow pathway. The outlet bearing/stator region had the highest frequency of deposition (≈72%), and the preponderance of thrombi appeared white and unlaminated in their microstructure. Conversely, 41.3% of VADs showed thrombus on the fore bearing of the HMII, and these formations tended to be red and laminated, indicating they formed in layers over time. Furthermore, the majority of clots observed in the fore bearing and outlet bearing/stator regions were partially occlusive in nature. Fourteen VADs presented PT in multiple regions and analysis of the data showed a statistically significant correlation (p < 0.01) between deposition in the fore bearing and subsequent thrombosis in the outlet bearing/stator; however, no other regions exhibited statistically significant correlations. This gives credence to the hypothesis that thrombi do not occur independently in multiple regions of the blood flow pathway in the HMII but may propagate downstream.

Mechanical circulatory support (MCS) with durable ventricular assist devices (VADs) has become an accepted therapy for advanced heart failure that is refractory to medical management. There have been many advances in the landscape of VAD technology over the past two decades. This chapter outlines clinically available solutions, clinical trials and experimental treatments, and preclinical technologies that are in development. These notable advancements in device designs have been associated with significant improvements in patient outcomes. In order for the field of MCS to evolve and become accessible to a population of patients with less-advanced heart failure, continued progress is needed to reduce the current burden of major adverse events. It is likely that in the next decade a majority of these hurdles can be overcome and that VAD therapy can expand to a broader population of patients with advanced heart failure.

Mechanical circulatory support with durable, left ventricular assist devices has become a mainstay therapy for treatment of advanced heart failure refractory to optimal medical management and has now surpassed cardiac transplantation as the most frequently utilized surgical therapy for the treatment of end-stage heart failure. Important progress in the field has occurred with the introduction of continuous-flow rotary pump technology that has supplanted older pulsatile displacement pumps. Continuous-flow rotary pump technology has afforded patients improved survival and reduced occurrence of major adverse events owing to the smaller size of these pumps, quieter operation, improved power efficiency, and greater reliability and durability. Continuous-flow rotary pumps have significantly different flow characteristics compared to pulsatile pumps, and continuous-flow rotary pumps in clinical use have differing device designs that influence the flow properties of the pump and its interaction with the native heart. There are several important features of the continuous-flow rotary pump technology that permit characterization of the pumps based on axial versus centrifugal design, bearing design, hydrodynamic properties, and mode of pump speed operation. Despite the marked advantages of this technology, this technology raises numerous challenges in the management of patients related, in part, on limitations in the ability of continuous-flow rotary pumps to adapt to marked changes in preload and afterload conditions, reduced pulsatility, and lack of algorithms that provide physiologic input into pump speed control. A thorough understanding of the theory of operation and design features of the pumps is necessary to provide care for patients supported with this technology.

Highly specialized left ventricular assist device care is not readily available in many areas, potentially limiting access to therapy. This retrospective analysis examines the relationship of outcomes by patient distance from implanting left ventricular assist device center within the Mechanical Circulatory Support Research Network. Zip codes were used to calculate patient distance, with the primary outcome of interest being 3-year survival by distance from the surgical center. Secondary outcomes included 90-day survival and incident event rates for the following: gastrointestinal bleeding, infection, cerebral event, and pump thrombosis. Across the four centers, there were 1184 patients supported for a median of 486 days. Overall survival was 91 ± 0.8% at 90 days and 61 ± 1.9% at 3 years, with worse 3-year survival in those living >90 vs. ≤90 miles from the ventricular assist device implant center (55 ± 3.0% vs. 64 ± 2.5, p = 0.019). Patients living >90 miles from an implant center were older, more likely to be implanted for destination therapy support, had a prior sternotomy, and had worse renal function than those living closer (p

This article on continuous-flow device technology engages in an in-depth discussion on the engineering aspects of continuous-flow devices. The authors examine the energy transfer mechanics of centrifugal versus axial devices, and the impact of novel noncontact pump bearings. Furthermore, this article reviews the relationship between continuous-flow pump speed, flow, and pressure gradients across the device. Potential future advances in pump design with greater algorithmic responses to changes in patient physiology are also considered.

Background: The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial’s 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. Methods: We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non–device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. Results: In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P =0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P =0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P P =0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P Conclusions: In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.

Objectives The aim of this study was to prospectively evaluate the impact of blood pressure management on stroke rates in patients receiving the HeartWare HVAD System. Background The ENDURANCE trial demonstrated noninferiority of the HeartWare HVAD System versus control (HeartMate II) in patients with advanced heart failure ineligible for heart transplantation. However, stroke was more common in HVAD subjects. Post hoc analyses demonstrated increased mean arterial blood pressure as a significant independent risk factor for stroke. Methods The ENDURANCE Supplemental Trial was a prospective, multicenter evaluation of 465 patients with advanced heart failure ineligible for transplantation, randomized 2:1 to HVAD (n = 308) or control (n = 157). The primary endpoint was the 12-month incidence of transient ischemic attack or stroke with residual deficit 24 weeks post-event. Secondary endpoints included the composite of freedom from death, disabling stroke, and need for device replacement or urgent transplantation, as well as comparisons of stroke or transient ischemic attack rates in HVAD cohorts in ENDURANCE Supplemental and ENDURANCE. Results The enhanced blood pressure protocol significantly reduced mean arterial blood pressure. The primary endpoint was not achieved (14.7% with HVAD vs. 12.1% with control, noninferiority [margin 6%] p = 0.14). However, the secondary composite endpoint demonstrated superiority of HVAD (76.1%) versus control (66.9%) (p = 0.04). The incidence of stroke in HVAD subjects was reduced 24.2% in ENDURANCE Supplemental compared with ENDURANCE (p = 0.10), and hemorrhagic cerebrovascular accident was reduced by 50.5% (p = 0.02). Conclusions The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of HVAD versus control regarding the pre-specified primary endpoint. However, the trial confirmed that BP management is associated with reduced stroke rates in HVAD subjects. HVAD subjects, relative to control subjects, more commonly achieved the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation). (A Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System [ENDURANCE SUPPLEMENTAL TRIAL] [DT2]; NCT01966458)

This study tested the applicability of the individual and family self-management theory (IFSMT) to self-management (SM) in patients with left ventricular assist devices (LVADs). From an existing data set, we extracted the following variables that correspond to IFSMT's conceptual dimensions: anxiety, depression, and cognition (context dimension); self-efficacy (SM process dimension); adherence and quality of life (QOL; outcome dimensions). Descriptive statistics and partial least squares path modeling procedures were used for data analyses. A total of 100 patients (mean age 52 ± 13.4 years) with continuous flow LVAD designs comprised the present study. Most patients were White (78%), married (69%), college-educated (72%), and on disability (53%). Their mean anxiety and depression scores were slightly above normal, while their cognitive function scores were slightly lower than normal. LVAD care self-efficacy, adherence, and QOL were within normal ranges. Factor loadings ranged from 0.50 to 1.0, and there were significant forward path relationships among the context, process, and outcome dimensions (β ranges from 0.02 to 0.60, all P values < 0.05). In conclusion, the IFSMT provides a good fit for SM in LVAD. Further research is needed to clarify how best to improve LVAD SM practice and treatment outcomes.

Despite major advancements in mechanical circulatory support, the self-management (SM) for patients with a left-ventricular assist device (LVAD) remains complex and challenging for patients and their caregivers. We have developed a mobile phone application (VAD Care App) to organize and simplify the LVAD SM process. This article describes the development and feasibility study of the app as an SM tool for LVAD patients and caregivers requiring support from ventricular assist device (VAD) coordinators. The specific aim was to evaluate the app's acceptability and usability and the users' competency. App features included an automated alert, data collection/reporting, and dynamic real-time interaction systems embedded in the LVAD SM process. Beta-testing of the prototype was completed by five adults. For the feasibility study, we employed a mixed-method descriptive research design involving nine patients and nine caregivers from two VAD centers in the Midwest. We asked them to use the app daily for more than 30 days and complete an app Evaluation Questionnaire and an interview. The questionnaire uses a five-point rating scale (1 = strongly disagree to 5 = strongly agree) evaluating usability, acceptability, and competency domains. Data generated from the questionnaires and interviews were analyzed with descriptive statistics and content analytic procedures. A total of 16 users (eight patients [all male] and eight caregivers [seven female]) aged 22 to 68 years completed the 30 day study. Median acceptability, usability, and competency scores were 4.6, 4.5, and 4.7, respectively. Based on the data, it is feasible for patients and caregivers to use an app as an LVAD SM tool warranting further research.

Background Tricuspid regurgitation after cardiac transplantation is associated with worse clinical outcomes. This study sought to determine the association of donor tricuspid valve repair (dTVR) with outcomes after cardiac transplantation. Methods Patients who underwent cardiac transplantation between January 20, 2002, and December 31, 2016, were included. Multivariable Cox regression modeling was performed to determine the association between dTVR and the composite outcome of death, posttransplant TVR, kidney transplant after cardiac transplant, or chronic dialysis, and included propensity scoring to control for baseline differences in likelihood of undergoing dTVR. Results The analysis included 330 patients, with 173 (52.4%) undergoing dTVR. dTVR performance varied by surgeon and also increased over time, with 71 (83.5%) performed during January 1, 2011, to November 30, 2013. Transplant year and surgeon were significantly associated with the baseline likelihood of undergoing dTVR. Although fewer composite outcomes occurred in the dTVR vs no dTVR group (39 [22.5%] vs 56 [36.4%], p = 0.006), dTVR was not significantly associated with the composite outcome in multivariable modeling. Lower risk for the composite outcome was associated with greater number of biopsies during the first posttransplant year, whereas higher risk was associated with more high-grade biopsy specimens and higher creatinine. Conclusions There was no significant benefit or harm with regards to the composite of death, posttransplant TVR, or dialysis associated with dTVR.

Background: Mechanical circulatory support (MCS) of a failing Fontan circulation remains challenging. We hypothesized that MCS can be provided by converting the Fontan circulation into a mechanically assisted single ventricle parallel circulation (MASVC). Methods: A porcine model of functionally univentricular circulation was created under cardiopulmonary bypass (CPB) by performing an atrial septectomy, tricuspid valvectomy, and interrupting antegrade pulmonary blood flow. A centrifugal flow pump was placed with inflow from the common atrium. Eight millimeter Dacron grafts anastomosed to the ascending aorta and main pulmonary artery supplied systemic (Qs) and pulmonary (Qp) blood flow. Ultrasonic flow probes were used to measure Qs and Qp after weaning from CPB. The Qp/Qs ratio was regulated using an adjustable clamp. Hemodynamic and laboratory data were recorded. Results: All four animals were successfully weaned from CPB onto the MASVC for a duration of two hours. Mechanically assisted single ventricle parallel circulation achieved satisfactory hemodynamics. As anticipated, the arterial oxygen saturation and partial pressure of oxygen in arterial blood were lower in the MASVC compared to baseline biventricular circulation. At the conclusion of the study, there was a trend towards a decrease in the mixed venous saturation with increasing oxygen extraction compared to the baseline. Serum lactate levels increased after weaning from CPB and did not return to baseline after two hours of support. Conclusion: Mechanically assisted single ventricle parallel circulation can be established in a single ventricle animal model. This strategy could potentially provide MCS of a single ventricle circulation. Studies with longer duration of support are required to assess adequacy of support and long-term sustainability.

Background Primary outcomes analysis of the Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3 (MOMENTUM 3) trial short-term cohort demonstrated a higher survival rate free of debilitating stroke and reoperation to replace/remove the device (primary end-point) in patients receiving the HeartMate 3 (HM3) compared with the HeartMate (HMII). In this study we sought to evaluate the individual and interactive effects of pre-specified patient subgroups (age, sex, race, therapeutic intent [bridge to transplant/bridge to candidacy/destination therapy] and severity of illness) on primary end-point outcomes in MOMENTUM 3 patients implanted with HM3 and HMII devices. Methods Cox proportional hazard models were used to analyze patients enrolled in the “as-treated cohort” ( n = 289) of the MOMENTUM 3 trial to: (1) determine interaction of various subgroups on primary end-point outcomes; and (2) identify independent variables associated with primary end-point success. Results Baseline characteristics were well balanced among HM3 ( n = 151) and HMII ( n = 138) cohorts. No significant interaction between the sub-groups on primary end-point outcomes was observed. Cox multivariable modeling identified age (≤65 years vs >65 years, hazard ratio 0.42 [95% confidence interval 0.22 to 0.78], p = 0.006]) and pump type (HM3 vs HMII, hazard ratio 0.53 [95% confidence interval 0.30 to 0.96], p = 0.034) to be independent predictors of primary outcomes success. After adjusting for age, no significant impact of sex, race, therapeutic intent and INTERMACS profiles on primary outcomes were observed. Conclusions This analysis of MOMENTUM 3 suggests that younger age (≤65 years) at implant and pump choice are associated with a greater likelihood of primary end-point success. These findings further suggest that characterization of therapeutic intent into discrete bridge-to-transplant and destination therapy categories offers no clear clinical advantage, and should ideally be abandoned.

Device indications have changed for placement of continuous-flow left ventricular assist devices (CF-LVADs). We performed a multicenter analysis evaluating temporal variations in outcomes after CF-LVAD implantation.We retrospectively defined 3 time intervals to reflect changes in CF-LVAD technology (period 1, 2004-2009; period 2, 2010-2012; and period 3, 2012-2014). A total of 1,064 patients (Heartmate II [HMII] = 835; Heartware [HVAD] = 229) underwent CF-LVAD implantation from May 2004 to October 2014. Device utilization was different between periods: period 1: HMII = 134 (100%); period 2: HMII = 480 (88%) and HW = 63 (12%); and period 3: HMII = 221 (57%) and HW = 166 (43%); P .001. Despite few baseline group differences, adjusted survivals were similar among the time periods (P = .96). Adjusted multivariable analysis revealed age (per 10-year increase) and Interagency Registry for Mechanically Assisted Circulatory Support category (1 vs all others) as the only independent predictors of mortality: P .001 and P = .008, respectively. Furthermore, it also showed the later periods to be at an increased risk of adverse events: 1) pump thrombosis (periods 2 and 3); and 2) gastrointestinal bleeding (period 3).Despite significant differences in device types, indications, and patient characteristics, post-implantation survivals were similar across time intervals. The most recent cohort seems to be at an increased risk of gastrointestinal bleeding and pump thrombosis.