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Introduction: The COVID-19 pandemic led to temporary restrictions on in-person cardiac rehabilitation (CR) services to mitigate high-risk exposure. Hypothesis: In order to better understand the impact of COVID-19 restrictions on CR services, we evaluated changes in the frequency and characteristics of CR visits in 2020 compared with 2019 in a commercially-insured population. Methods: We queried the Michigan Value Collaborative statewide claims data registry for outpatient CR visits between 01/01/2019 and 12/31/2020 using CPT codes (93797, 93798) among patients with diagnoses of ischemic heart disease, heart failure, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or heart valve procedure. We described monthly trends in CR visits, and used bivariate analyses to compare changes in the demographics and medical diagnoses for CR visits in 2020 compared with 2019. Results: We identified a total of 45,553 CR visits in 2019 and 30,236 visits in 2020, representing a 33.6% relative decline. Monthly CR visits reached a nadir of 138 visits in April 2020 (96.5% reduction compared with April 2019), recovered to 3072 visits in September (-17.9%), and fell again to 2434 visits in December (-34.7%) (Figure). Relative changes in CR visits from 2019 to 2020 varied by diagnosis (p Conclusions: Total cardiac rehabilitation visits in 2020 were 33.6% lower compared with 2019, with heterogeneity in declines by underlying eligible diagnosis. Continued monitoring is needed to understand the public health impact of reduced CR use due to the COVID-19 pandemic.

Purpose: Caregivers (CGs) provide essential support to older (60-80 years) patients with advanced heart failure (HF), yet caregiving may be burdensome. Understanding the caregivers time spent and difficulty in caring for patients may inform CG support needs before and after cardiac surgery. We compared CG burden before and 24 months after heart transplantation (HT), with or without baseline mechanical circulatory support (MCS), and long-term MCS as destination therapy (DT). Methods: Between 10/1/15-12/31/18, we enrolled 301 CGs of HF patients from 13 U.S. hospitals: 193 awaiting HT (92 with and 101 without MCS), and 108 scheduled for long-term MCS. At baseline (pre-surgery) and 24 months post-surgery, CGs completed the Oberst Caregiving Burden Scale (OCBS), which has 15 items with 2 subscales: (1) time: range=1-5, higher score=more time spent on task and (2) difficulty: range=1-5, higher score=higher task difficulty. Statistical analyses included t-tests and baseline-adjusted linear regression models. Results: CGs’ average age was 60.9±10 years, 83% were spouses, 85% female, and 85% white. Across all groups and both time points, time spent on caregiving tasks was moderate and task difficulty was rated low. Time spent on caregiving decreased significantly from baseline to 24-months for all groups (p-value Conclusions: CG time on tasks decreased from baseline to 24-months post-surgery in all groups, and both time and difficulty scores were persistently higher for CGs of DT patients. These results may inform identification of support options to reduce time and difficulty of CG tasks, particularly for those who care for destination therapy HF patients.

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: 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.

Left ventricular assist devices (LVADs) are an increasingly used strategy for the management of patients with advanced heart failure with reduced ejection fraction. Although these devices effectively improve survival, atrial and ventricular arrhythmias are common, predispose these patients to additional risk, and complicate patient management. However, there is no consensus on best practices for the medical management of these arrhythmias or on the optimal timing for procedural interventions in patients with refractory arrhythmias. Although the vast majority of these patients have preexisting cardiovascular implantable electronic devices or cardiac resynchronization therapy, given the natural history of heart failure, it is common practice to maintain cardiovascular implantable electronic device detection and therapies after LVAD implantation. Available data, however, are conflicting on the efficacy of and optimal device programming after LVAD implantation. Therefore, the primary objective of this scientific statement is to review the available evidence and to provide guidance on the management of atrial and ventricular arrhythmias in this unique patient population, as well as procedural interventions and cardiovascular implantable electronic device and cardiac resynchronization therapy programming strategies, on the basis of a comprehensive literature review by electrophysiologists, heart failure cardiologists, cardiac surgeons, and cardiovascular nurse specialists with expertise in managing these patients. The structure and design of commercially available LVADs are briefly reviewed, as well as clinical indications for device implantation. The relevant physiological effects of long-term exposure to continuous-flow circulatory support are highlighted, as well as the mechanisms and clinical significance of arrhythmias in the setting of LVAD support.

Introduction: Although wait times vary widely across geographic regions and blood type under the current allocation system, it is unclear if minority patients have longer waitlist times. Hypothesis: We hypothesized that racial/ethnic minority patients experience longer wait times to transplant, even after accounting for age, gender, blood type, heart failure severity defined by UNOS status, and region. Methods: Patients listed for first transplant from 2005-2016 in the UNOS database were analyzed by racial/ethnic groups: African-American (AA), Hispanic, White (Non-Hispanic) and Other. We estimated median time to transplant for each group by year of listing using cumulative incidence functions and accounted for competing risks of waitlist mortality and delisting. For 2015-2016, we performed multivariable cause-specific Cox regression modeling accounting for age, gender, UNOS status urgency (status 1A, 1B, 2, 7) ABO blood type, and region by organ procurement organization. The reference population was Whites. Results: A total of 36,801 patients (21.5% AA, 7.8% Hispanic, 4.0% Other and 66.6% White) were available for analysis. Since 2005, the proportion of AAs on the waitlist has increased slightly, while the proportion of Whites has decreased. Wait times increased to a peak in 2014 for all ethnic/racial groups, but were disproportionally increased for AAs. In 2015-2016 this disparity persisted but was less pronounced compared to prior years. ( Figure ) After multivariable adjustment, the Hazard Ratio for time to transplant in AAs was 0.90 (95% CI 0.83 – 0.96) compared to Whites, with no prolonged time to transplant for other minorities. Conclusions: AAs experience disproportionally long wait times for heart transplant, which could not be explained by traditional determinants of time to transplant. How the new allocation system implemented in 2018 will impact this disparity should be a focus for ongoing population health research.

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.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.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%; P0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; 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, P0.001) and similar in either bridge to transplant or destination therapy intent.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.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.

Background and Purpose:The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF.Methods:The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through September 2017. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or reference to contemporary clinical practice recommendations.Results:Chronic RHF is associated with decreased exercise tolerance, poor functional capacity, decreased cardiac output and progressive end-organ damage (caused by a combination of end-organ venous congestion and underperfusion), and cachexia resulting from poor absorption of nutrients, as well as a systemic proinflammatory state. It is the principal cause of death in patients with pulmonary arterial hypertension. Similarly, acute RHF is associated with hemodynamic instability and is the primary cause of death in patients presenting with massive pulmonary embolism, RV myocardial infarction, and postcardiotomy shock associated with cardiac surgery. Functional assessment of the right side of the heart can be hindered by its complex geometry. Multiple hemodynamic and biochemical markers are associated with worsening RHF and can serve to guide clinical assessment and therapeutic decision making. Pharmacological and mechanical interventions targeting isolated acute and chronic RHF have not been well investigated. Specific therapies promoting stabilization and recovery of RV function are lacking.Conclusions:RHF is a complex syndrome including diverse causes, pathways, and pathological processes. In this scientific statement, we review the causes and epidemiology of RV dysfunction and the pathophysiology of acute and chronic RHF and provide guidance for the management of the associated conditions leading to and caused by RHF.

Mechanical circulatory support (MCS) offers a surgical option for advanced heart failure when optimal medical therapy is inadequate. MCS therapy improves prognosis, functional status, and quality of life.1,2 The INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) tracks patient selection and outcomes for all implanted US Food and Drug Administration–approved MCS devices. From June 2006 until December 2014, >15 000 patients received MCS, and >2000 implantations are performed annually. One-year survival with current continuous-flow devices is reported to be 80%, and 2-year survival, 70%.3 In patients awaiting heart transplantation, MCS provides a bridge to transplantation, and for others who are ineligible for heart transplantation, MCS provides permanent support or destination therapy. Indications and absolute and relative contraindications to durable MCS are listed in Table 1. View this table: Table 1. Indications and Contraindications to Durable Mechanical Support As of July 2014, 158 centers in the United States offer long-term MCS.3 Patients often live a substantial distance from the implanting center, necessitating active involvement of local first responders (emergency medical technicians, police, and fire department personnel), emergency department staff, primary care, and referring cardiologists. Because patients with MCS are becoming increasingly mobile, basic knowledge of equipment is necessary for personnel in public areas such as schools, public transportation, and airplanes/airports. Ambulatory patients with MCS can span the entire age spectrum from pediatrics to geriatrics. The aim of this document is to provide guidance for nonexperts in MCS and to facilitate the informed assessment, stabilization, and transport of the patient with MCS back to the MCS center for definitive therapy. In addition, the principles herein provide a foundation for emergency management and a framework to address the management of known MCS-associated complications and expected comorbid medical problems. Currently in the United States, the most frequently used durable devices are continuous-flow devices with …

Background— Ventricular assist devices (VADs) improve survival and quality of life in patients with advanced heart failure, but their use is frequently complicated by infection. There are limited data on the microbiology and epidemiology of these infections. Methods and Results— One hundred fifty patients scheduled for VAD implantation were enrolled (2006–2008) at 11 US cardiac centers and followed prospectively until transplantation, explantation for recovery, death, or for 1 year. Eighty-six patients (57%) received HeartMate II devices. Data were collected on potential preoperative, intraoperative, and postoperative risk factors for infection. Clinical, laboratory, and microbiological data were collected for suspected infections and evaluated by an infectious diseases specialist. Thirty-three patients (22%) developed 34 VAD-related infections with an incidence rate of 0.10 per 100 person-days (95% confidence interval, 0.073–0.142). The median time to infection was 68 days. The driveline was the most commonly infected site (n=28); 18 (64%) were associated with invasive disease. Staphylococci were the most common pathogen (47%), but pseudomonas or other Gram-negative bacteria caused 32% of infections. A history of depression and elevated baseline serum creatinine were independent predictors of VAD infection (adjusted hazard ratio=2.8 [ P =0.007] and 1.7 [ P =0.023], respectively). The HeartMate II was not associated with a decreased risk of infection. VAD infection increased 1-year mortality (adjusted hazard ratio=5.6; P Conclusions— This prospective, multicenter study demonstrates that infection frequently complicates VAD placement and is a continuing problem despite the use of newer, smaller devices. Depression and renal dysfunction may increase the risk of VAD infection. VAD infection is a serious consequence because it adversely affects patient survival. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01471795.

Background— The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail. Methods and Results— We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time. Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37±14 to 23±10 mg/dL ( P P P P Conclusions— The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121472.

Introduction: Various risk models have been used to predict mortality after implantation of continuous-flow ventricular assist devices (CF-VADs). Discriminatory power and predictive accuracy vary, and there is a need to develop and validate a contemporary risk score in a large multicenter patient cohort. Hypothesis: We sought to develop an early mortality risk score utilizing a large voluntary research registry of patients implanted with CF-VADs, with the focus on increased discriminatory power. Methods: From May 2004 to May 2015, 1150 patients in the Mechanical Circulatory Support Research Network (MCSRN) registry were randomly divided into equal-sized derivation and validation samples (n=575, each group). Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified for predicting 90-day mortality. A risk score was developed based on the variables and their respective regression coefficients in the final model. Discriminatory power of the risk score was evaluated using receiver operating characteristic analysis, and calibration was assessed using Hosmer-Lemeshow goodness of fit test. Results: Overall 90-day mortality was 9.4% (n=99). The final logistic regression model consisted of 9 predictors: Age at implant, preoperative mechanical ventilation, serum total bilirubin, hemoglobin, tricuspid valve regurgitation severity, left ventricular end-diastolic diameter, cardiac index, pulmonary capillary wedge pressure, and destination therapy (DT) as an indication for pump placement. The area under the curve was 0.86 in the derivation sample (95% CI, 0.75-0.97) and 0.75 in the validation sample (95% CI, 0.63-0.86). Hosmer-Lemeshow goodness of fit test yielded insignificant values in both samples (p=0.75, p=0.58) consistent with good calibration. Conclusions: The proposed 90-day mortality MCSRN risk score provides highest-to-date discriminatory power when compared to already published models. The risk score is applicable to a contemporary large cohort of patients implanted with CF-VADs for either indication (bridge or DT).

Introduction: Axial and centrifugal-flow left ventricular assist devices (LVAD) have varied response to changes in loading conditions. Whether ventricular size modulates the response to LVAD therapy between the axial flow Heartmate II (HMII) and centrifugal flow Heartware (HVAD) is unknown. Hypothesis: Adverse event and survival rates between devices are affected by recipient pre-op left ventricular end-diastolic diameter (LVEDD). Methods: Data on 1,149 continuous-flow LVAD recipients from May 2004 to May 2015 was pooled from the Mechanical Circulatory Support Research Network (MCSRN). The effect of pre-op LVEDD on the instantaneous hazard of death and adverse events was evaluated between HMII (n=864) and HVAD (n=283). Results: The average LVEDD was 7.0cm and did not differ between the device recipients. Patients with a smaller LVEDD (≤ 6.3cm) were more likely female 39% v. 24% (p < 0.0001) and to have an ischemic cardiomyopathy (30% v. 24%, p = 0.045). For every 1cm increase in pre-op LVEDD, the adjusted hazard ratio (HR) for mortality increased with HVAD (HR 1.31, 95% CI 0.94-1.82, p = 0.005) and decreased with HMII (HR 0.78, 95% CI 0.67-0.92, p = 0.005), Figure 1a. Other predictors of mortality included age (HR 1.31, 95% CI 1.12 - 1.53 per 10y, p < 0.001) and bilirubin (HR 1.15, 95% CI 0.94-1.42 per mg/dL, p = 0.027). LVEDD by device type interaction was not a significant predictor of gastrointestinal bleeding or pump thrombosis. The risk of stroke increased with LVEDD for HVAD and decreased for HMII, but this did not reach statistical significance, Figure 1b. Ischemic etiology of heart failure (HR 1.7 95% CI 1.14 - 2.55, p = 0.01) and HVAD device use (HR 1.47 95% CI 1.00 - 2.17, p = 0.03) were significant predictors of stroke. Conclusions: Our data suggest important differences exist in patient outcomes between HMII and HVAD based on pre-op ventricular size. Studies are needed to determine if these differences in outcome are due to device or flow-specific differences in patient support.

Background: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. Methods: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). Results: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls. CaMKII protein abundance was increased only in sarcomere-mutation HCM ( P P =0.01), as was autophosphorylated CaMKII ( P PPP3CB ) mRNA was not increased, nor was RCAN1 mRNA level, indicating a lack of calcineurin activation. Furthermore, myocyte enhancer factor 2 and nuclear factor of activated T cell transcription factor activity was not increased in HCM, suggesting that calcineurin pathway activation is not an upstream cause of increased CAMKII protein abundance or activation. SERCA2A mRNA transcript levels were reduced in HCM regardless of genotype, as was sarcoplasmic endoplasmic reticular calcium ATPase 2/phospholamban protein ratio (45% reduced; P =0.03). 45 Ca sarcoplasmic endoplasmic reticular calcium ATPaseuptake assay showed reduced uptake velocity in HCM regardless of genotype ( P =0.01). The cardiac ryanodine receptor was not altered in transcript, protein, or phosphorylated (pS2808, pS2814) protein abundance, and [ 3 H]ryanodine binding was not different in HCM, consistent with no major modification of the ryanodine receptor. Conclusions: Human HCM demonstrates calcium mishandling through both genotype-specific and common pathways. Posttranslational activation of the CaMKII pathway is specific to sarcomere mutation–positive HCM, whereas sarcoplasmic endoplasmic reticular calcium ATPase 2 abundance and sarcoplasmic reticulum Ca uptake are depressed in both sarcomere mutation–positive and –negative HCM.

Background— Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. Methods and Results— Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction Conclusions— These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

Background— In an animal model, stretch was shown to induce myocardial tumor necrosis factor-α (TNF-α) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF-α expression and whether there is a relationship between TNF-α expression and LV remodeling. Methods and Results— Plasma TNF-α and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23±12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF-α were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF-α (3.59±1.81 versus 2.03±1.02 pg/mL, P 6 and 0.88±0.75×10 6 , respectively ( P =0.01). After MV surgery, there was a decrease in the plasma levels of TNF-α (2.79±1.14 versus 3.51±1.34 pg/mL, P =0.02) and its receptors. There was a correlation between myocardial TNF-α expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF-α expression and regression in LV end-diastolic ( r =−0.76, P =0.007) and end-systolic ( r =−0.73, P =0.01) volumes after MV surgery. Conclusions— TNF-α is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF-α expression. There is a relationship between TNF-α expression and parameters of LV remodeling, suggesting that TNF-α may play a role in the pathogenesis of the LV remodeling that occurs in MR.

Background— Subjects in the upper-normal range of arterial pressure have an excess cardiovascular risk, which suggests that other factors, such as impaired autonomic regulation, might be implicated. This study was designed to assess whether noninvasive markers of cardiac and vascular autonomic regulation might already be altered in subjects with high-normal arterial pressure levels. Methods and Results— We performed an observational study on a population comprising 300 subjects of both sexes with arterial pressure ranging from 90/60 to 210/120 mm Hg, who were divided into 3 groups (each n=100) with average systolic pressures of 103, 133, and 163 mm Hg. Autonomic regulation was inferred from spectral analysis of RR interval and systolic arterial pressure variability, considering rest and stand-induced changes, to account for sympathetic excitatory components. Significant alterations in markers of sinoatrial regulation (increased low-frequency normalized units, reduced high-frequency normalized units, and α-index) were already apparent in subjects in the second tertile, ie, those with arterial pressure within normal limits. Markers of vascular regulation instead showed significant alterations in the third (hypertensive) tertile. In response to standing, changes in markers of sinoatrial modulations were gradually reduced, whereas those of vascular regulation were increased. A tight link between progression of arterial pressure and the continuum of changes in autonomic markers as shown by simple correlation analysis appeared strongly affected by age and was spread across many spectral analysis–derived variables. Hypertensive autonomic dysregulation was particularly apparent in the youngest group. Conclusions— RR-variability parameters might prove useful to assess, with longitudinal studies, the mechanistic role of autonomic impairment in the increased risk of prehypertensive conditions.

Background — Benefits of moderate endurance training include increases in parasympathetic activity and baroreflex sensitivity (BRS) and a relative decrease in sympathetic tone. However, the effect of very intensive training load on neural cardiovascular regulation is not known. We tested the hypothesis that strenuous endurance training, like in high-performance athletes, would enhance sympathetic activation and reduce vagal inhibition. Methods and Results — We studied the entire Italian junior national team of rowing (n=7) at increasing training loads up to 75% and 100% of maximum, the latter ∼20 days before the Rowing World Championship. Autoregressive power spectral analysis was used to investigate RR interval and blood pressure (BP) variabilities. BRS was assessed by the sequences method. Increasing training load up to 75% of maximum was associated with a progressive resting bradycardia and increased indexes of cardiac vagal modulation and BRS. However, at 100% training load these effects were reversed, with increases in resting heart rate, diastolic BP, low-frequency RR interval, and BP variabilities and decreases in high-frequency RR variability and BRS. Three athletes later won medals in the World Championship. Conclusions — This study indicates that very intensive endurance training shifted the cardiovascular autonomic modulation from a parasympathetic toward a sympathetic predominance. This finding should be interpreted within the context of the substantial role played by the sympathetic nervous system in increasing cardiovascular performance at peak training. Whether the altered BP and autonomic function shown in this study might be in time hazardous to human cardiovascular system remains to be established.

Introduction: Recent reports have documented an abrupt increase in 3-month confirmed HeartMate II left ventricular assist device (LVAD) thrombosis beginning in 2011 without a plateau observed to date. Because very little data exist from multi-institutional efforts, we report our experience. Methods: From January 2004 to December 2013, 516 pt underwent HeartMate II LVAD implant at three institutions (University of Michigan (n=254), Mayo Clinic Rochester (n=205), and Vanderbilt Heart and Vascular Institute (n=57)). Median age at implant was 60 yr (range, 18-82) and 428 (83%) were male. Confirmed pump thrombosis at 3 months was defined as thrombus found in the blood-contacting surfaces of the pump at the time of urgent transplant, device exchange or autopsy. Pt without at least 3 months of follow-up were excluded. Results: Confirmed pump thrombosis occurred in 9 pt within 3 months post implant. The incidence was greatest in the year 2012 (5.3%). Following this peak, the incidence of 3-month confirmed pump thrombosis decreased significantly to 2.9% (Figure). Significant differences in preoperative characteristics between patients with pump thrombosis and without thrombosis included female sex (36% vs. 16%, p=0.01), bridge to transplant (77% vs. 54%, p=0.03), atrial fibrillation (55% vs. 32%, p=0.04), and preop platelet count (231,000 vs. 172,000, p Conclusions: We report a recent decrease in early, confirmed HeartMate II LVAD thrombosis to historically observed levels, which is disparate to recent reports. While we identified several differences in clinical characteristics between patient groups, the issue of pump thrombosis is complex and multifactorial. Most importantly, our findings demonstrate the need for more granular analyses from collaborative efforts.

Background— Cardiac valve procedures are commonly performed concurrently during implantation of left ventricular assist devices, but the added procedural risk has not been studied in detail. Methods and Results— Data from patients receiving the HeartWare Ventricular Assist Device in the ADVANCE bridge to transplant (BTT) trial and continued access protocol were reviewed. Of 382 consecutive patients who completed follow-up between August 2008 and June 2013 (mean time on support 389 days, median 271 days), 262 (68.6%) underwent isolated HeartWare Ventricular Assist Device implantation, 75 (19.6%) a concurrent valve procedure, and 45 (11.8%) concurrent nonvalvular procedures. Of the concurrent valve procedures, 56 were tricuspid, 13 aortic, and 6 mitral. Survival was similar between groups (79% for concurrent valve procedures and 85% for HeartWare Ventricular Assist Device only at 1 year; P =0.33). Concurrent valve procedures were also associated with increased unadjusted early right heart failure (RHF). A multivariable analysis for death and RHF (121 total events) identified female sex (odds ratio=2.0 [95% confidence interval, 1.2–3.3; P =0.0053]) and preimplant tricuspid regurgitation severity (odds ratio=2.9 [95% confidence interval, 1.8–4.8, P P =0.024). Conclusions— Compared with HeartWare Ventricular Assist Device alone, survival was equivalent for the concurrent valve procedure group. Tricuspid regurgitation severity was the most important predictor of increased postoperative RHF, and concurrent TVP was not an independent predictor of RHF overall. Concurrent TVP may reduce the rate of late RHF for patients with significant preimplant tricuspid insufficiency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.

Background In normal humans, variability of blood pressure, RR interval, and sympathetic activity occurs predominantly at a low frequency (LF; 0.04 to 0.14 Hz) and a high frequency (HF; ±0.25 Hz). In conditions that increase sympathetic activation in normal humans, the LF component is increased relative to the HF component. Patients with heart failure have high levels of sympathetic activity. We tested the hypothesis that the LF component of sympathetic nerve activity variability is increased in heart failure. Methods and Results. We performed spectral analysis of simultaneous recordings of resting muscle sympathetic nerve activity (MSNA) and RR interval in 21 patients with chronic heart failure and 12 age-matched control subjects. MSNA was higher in patients with heart failure (62±4 bursts per minute) than in the normal subjects (39±4 bursts per minute; P P P Conclusions The LF variability of sympathetic nerve activity is absent in patients with severe heart failure. This disturbed pattern of variability is closely coherent with the abnormal variability of RR interval. These disturbances of rhythmic oscillations of autonomic outflow, evident in both RR interval and MSNA, suggest a central autonomic regulatory impairment in heart failure and may have important prognostic implications.