Evaluating threshold for donor fraction cell-free DNA using clinically available assay for rejection in pediatric and adult heart transplantation.

BACKGROUND: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection. METHODS: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance. RESULTS: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection. CONCLUSION: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance.

Increase in nuclear cell-free DNA is associated with major adverse events in adult and pediatric heart transplant recipients.

BACKGROUND: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. OBJECTIVE: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. METHODS: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints. RESULTS: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection. CONCLUSIONS: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant.

Heparin Monitoring with an Anti-Xa Protocol Compared to Activated Clotting Time in Patients on Temporary Mechanical Circulatory Support.

BACKGROUND: Temporary mechanical circulatory support (tMCS) devices are used for patients with severe cardiac or respiratory failure; however, these patients are at high risk for clotting and bleeding. The best method to monitor heparin in these patients has not been established. OBJECTIVE: To determine the risks for bleeding and clotting while monitoring heparin with either anti-Xa or activated clotting time (ACT) in tMCS patients. METHODS: A retrospective cohort study was conducted on tMCS patients who received heparin adjusted according to an anti-Xa or ACT protocol. The primary outcome was incidence of major bleeding. Pertinent secondary outcomes were individual components of the primary outcome, clotting events, and time to therapeutic range. RESULTS: There were 103 patients included in the study: 53 in the ACT group and 50 in the anti-Xa group. Overall, there were 30 (56.6%) patients with major bleeding in the ACT group, compared with 16 (32%) patients in the anti-Xa group (P = 0.017). An anti-Xa-based protocol was associated with a decreased hazard of major bleeding (hazard ratio = 0.388 [0.215-0.701]; P = 0.002) in the univariate analysis. In the multivariable analysis, an anti-Xa protocol remained associated with a significantly lower hazard of bleeding. Findings were similar when broken down into more discrete subgroups of the entire cohort, extracorporeal membrane oxygenation life support (ECMO), and non-ECMO groups. CONCLUSION AND RELEVANCE: Anti-Xa monitoring was associated with a lower hazard of bleeding during tMCS compared to an ACT-based protocol. Further studies should evaluate if anti-Xa monitoring should be preferentially used in tMCS.

Relationship between donor fraction cell-free DNA and clinical rejection in heart transplantation.

BACKGROUND: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. METHODS: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. RESULTS: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001). CONCLUSION: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.

Protocolized screening effectively identifies myocardial recovery following destination therapy left ventricular assist device implantation.

BACKGROUND: Myocardial recovery following left ventricular assist device (LVAD) implantation has been of interest in transplant candidates with non-ischemic cardiomyopathy but is rare. Evidence suggests that a combination of left ventricular unloading and pharmacologic reverse remodeling is beneficial. Recovery in non-transplant candidates (i.e., destination therapy [DT]) patients is believed to be even rarer. METHODS: All DT LVADs between January 1, 2017 and November 23, 2020 were reviewed. All patients were subjected to an institutional protocol consisting of combined pharmacologic remodeling and mechanical unloading with proactive screening for recovery. The primary outcome of interest was the cumulative incidence of myocardial recovery. Baseline characteristics and operative outcomes were compared between recovered and non-recovered DT patients using non-parametric tests to identify predictive factors. RESULTS: A total of 49 patients received DT LVADs. Nine patients were identified as myocardial recovery candidates using the protocol screening criteria. Overall, 11 patients underwent formal confirmatory testing for recovery, of which 10 were deemed recovered and underwent LVAD explant, defunctionalization, or transplantation. 37.5% of patients that had a concomitant coronary artery bypass during LVAD implantation achieved recovery. An equal proportion of ischemic and non-ischemic cardiomyopathy patients achieved recovery. The cumulative incidence of myocardial recovery was 25.1% at 36 months. No factors were identified as being predictive of recovery. CONCLUSION: Myocardial recovery in DT LVAD patients can be achieved at a higher rate than previously reported. Revascularization at the time of LVAD is safe and may be beneficial. LVAD therapy may not be the final destination in these patients.

Heart Failure Trial Update-Analysis of Recent Data.

The prevalence of heart failure (HF) continues to increase, and its economic effect is significant in the United States and globally. During the past 2 years, a number of high-quality clinical trials were published with the aim of addressing different stages of the disease process and improving outcomes for patients with preserved and depressed ejection fraction (EF). In this review, data from these trials are summarized and critically appraised. There are several important findings from these studies, including, but not limited to, the benefit of dapagliflozin in HF with reduced EF, sacubitril-valsartan in acute decompensated HF, thoracotomy in left ventricular assist device implantation, and the overall risk-benefit ratios of centrifugal pumps as opposed to continuous flow pumps. Effective therapies for HF with preserved EF continue to evolve for this varied group of high morbidity and mortality conditions.

Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults.

OBJECTIVES: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients. METHODS: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated. RESULTS: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively). CONCLUSIONS: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value.

Move more and sit less pilot intervention for individuals with heart failure.

BACKGROUND: Higher physical activity (PA) and lower sedentary behavior (SB) have been independently associated with lower risk of Heart Failure (HF). However, few individuals with HF engage in sufficient PA to confer benefits and many engage in high amounts of SB. This this feasibility study was conducted to examine changes in steps/day and SB in response to a tailored move more and sit less intervention. METHODS: This study used a single group, pre-post study design to assess changes in steps/day, inactive time, and time in moderate- to vigorous-intensity physical activity in individuals with HF stage C and D. Participants completed 1-week baseline assessment and an 11-week intervention. GEE Poisson model was used to evaluate the effect of intervention on change in PA and SB. RESULTS AND TRANSLATIONAL CONCLUSIONS: Thirteen participants with an average age of 69 ± 13 years that had been living with heart failure for 5.5 ± 4.2 years completed this intervention study. Average steps per day increased significantly over the intervention from 4778 steps/day at baseline to 5518 steps/day post-intervention. Time spent sedentary did not change. Move more and sit less interventions that include behavioral change techniques such as immediate feedback on steps can result in changes in walking behavior. Further strategies for reducing SB in this population should be explored.

Bariatric surgery in patients with advanced heart failure: A proposed multi-disciplinary pathway for surgical care in medically complex patients.

BACKGROUND: The objective of this study was to develop a multi-disciplinary care pathway to minimize perioperative complications in patients with advanced heart failure undergoing bariatric surgery. Patients with severe obesity and heart failure carry increased perioperative surgical risk compared to patients with no heart failure due to the severity of their cardiac disease state and associated comorbidities. Our bariatric program routinely excluded patients with advanced heart failure from undergoing bariatric surgery due to the high reported perioperative risk. However, knowing the potential beneficial impact of bariatric surgery for advanced heart failure, our program hoped that the thoughtful development of a perioperative pathway before inclusion of patients with advanced heart failure in the bariatric surgery program could minimize the morbidity of these high-risk patients in comparison to prior publications in the literature. METHODS: Two multi-disciplinary care pathways were developed, including advanced heart failure, anticoagulation specialists, and transplant cardiologists, to optimize bariatric care for severely obese patients with advanced heart failure with or without mechanical circulatory support and implementation was evaluated for short-term 30-day complications and 6 month cardiac and weight-loss outcomes. RESULTS: Two multi-disciplinary care pathways were developed and implemented on 5 patients with heart failure with reduced ejection fraction (pathway 1) and 3 patients requiring mechanical circulatory support (pathway 2). There were no in-hospital complications or mortality following either pathway, and there was only 1 emergency room visit and 1 re-admission. The average length of stay for patients with heart failure with reduced ejection fraction without mechanical circulatory support was 2.4 days and for heart failure with reduced ejection fraction with mechanical circulatory support was 4.3 days. Three patients met body mass index criteria for transplant listing at 6 months. Ejection fraction increased an average of 9% at 6 months postoperatively for patients with heart failure with reduced ejection fraction not requiring mechanical circulatory support. CONCLUSION: With multi-disciplinary care pathway development designed to maximize safety by intensely supporting preoperative cardiac optimization and medication titration postoperatively, bariatric surgery can be performed in patients with advanced heart failure with or without mechanical circulatory support, allowing patients the opportunity for weight loss as a bridge to transplant or potentially meaningful cardiac recovery.

A Dual-Lumen Percutaneous Cannula for Managing Refractory Right Ventricular Failure.

A right ventricular assist device (RVAD) using a dual-lumen percutaneous cannula inserted through the right internal jugular vein (IJV) might improve weaning in patients with refractory right ventricular (RV) failure. However, the reported experience with this cannula is limited. We reviewed the records of all patients receiving RVAD support with this new dual-lumen cannula at our institution between April 2017 and February 2019. We recorded data on weaning, mortality, and device-specific complications. We compared outcomes among three subgroups based on the indications for RVAD support (postcardiotomy, cardiogenic shock, and primary respiratory failure) and against similar results in the literature. Mean (standard deviation [SD]) age of the 40 patients (29 men) was 53 (15.5) years. Indications for implantation were postcardiotomy support in 18 patients, cardiogenic shock in 12, and respiratory failure in 10. In all, 17 (94%) patients in the postcardiotomy group were weaned from RVAD support, five (42%) in the cardiogenic shock group, and seven (70%) in the respiratory failure group, overall higher than those reported in the literature (49% to 59%) for surgically placed RVADs. Whereas published in-hospital mortality rates range from 42% to 50% for surgically placed RVADs and from 41% to 50% for RVADs with percutaneous cannulas implanted through the right IJV, mortality was 11%, 58%, and 40% in our subgroups, respectively. There were no major device-related complications. This percutaneous dual-lumen cannula appears to be safe and effective for managing refractory RV failure, with improved weaning and mortality profile, and with limited device-specific adverse events.

Association of preoperative duration of inotropy on prevalence of right ventricular failure following LVAD implantation.

AIMS: 20% to 40% of left ventricular assist device (LVAD) device implantations are complicated by right ventricular (RV) failure that results in significant morbidity and mortality. We hypothesized that the duration on milrinone infusion is an independent risk factor for RV failure following LVAD implantation. METHODS AND RESULTS: Retrospective demographic, clinical and hemodynamic data were collected on all adults with ACC/AHA stage D heart failure on intravenous milrinone who underwent LVAD implantation between 2012 and 2019. Patients (n = 104) were divided into two groups, those on milrinone <30 days (STM, n = 55) vs. ≥30 (LTM, n = 49). The primary endpoint was the prevalence of RV failure (need for inotropic support for more than 14 days or RV assist device) within 30 days post-LVAD implantation. There were no significant differences between STM and LTM patients with respect to demographic, echocardiographic, right heart catheterization data, or baseline medications. The mean age of patients was 55.6 ± 12 years (70% male patients). Mean duration on milrinone was 13.7 vs. 81.0 days in STM and LTM, respectively. Forty-five (43.3%) patients developed RV failure. LTM had higher prevalence of RV failure with odds ratio (OR) = 5.04 (95% CI 2.18-11.68, P = 0.0002). After adjusting for age, gender, and co-morbidity count, the OR was 6.33 (95% CI 2.51-15.93), P < 0.0001. CONCLUSIONS: In this retrospective study of ACC/AHA stage D HF patients, longer duration of milrinone infusion was associated with higher prevalence of RV failure after LVAD implantation.

Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

A Rare Complication of HVAD Outflow Thrombosis and the Importance of HVAD Waveform Analysis.

We present a case of a 64-year-old female who was supported with an HVAD as bridge-to-transplant (BTT) who presented with a gastrointestinal (GI) bleeding and underwent esophagogastroduodenoscopy (EGD) and colonoscopy. Her waveforms changed abruptly following the procedure, and she decompensated. With various imaging modalities and hemodynamic monitoring, we felt that she had thrombus in her outflow graft, which improved following systemic heparinization. She was listed for cardiac transplantation and remained hospitalized. At the time of surgery, her outflow graft was noted to be compressed externally and pathology was consistent with platelet-fibrin thrombus deposition.

Octreotide for the Management of Gastrointestinal Bleeding in a Patient with a HeartWare Left Ventricular Assist Device.

HeartWare is a third generation left ventricular assist device (LVAD), widely used for the management of advanced heart failure patients. These devices are frequently associated with a significant risk of gastrointestinal (GI) bleeding. The data for the management of patients with LVAD presenting with GI bleeding is limited. We describe a 56-year-old lady, recipient of a HeartWare device, who experienced recurrent GI bleeding and was successfully managed with subcutaneous (SC) formulations of octreotide.