Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators.

BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

Right Atrial Compression From Biodebris Associated With Long-Term Left Ventricular Assist Device Support.

Biodebris surrounding HVAD (Medtronic) intrapericardial centrifugal-flow left ventricular assist device outflow cannulas is common and appears to accumulate over time. We recently encountered 2 patients on long-term HVAD support with right atrial compression from such biodebris, prompting a review of our institution's HVAD cohort to better understand this phenomenon. (Level of Difficulty: Intermediate.).

Combined Heart-Liver and Domino Liver Transplantation in Familial Amyloidosis.

BACKGROUND: Combined heart-liver transplantation (CHLT) is the only curative option for patients with concomitant pathology affecting the heart and liver. In some cases, the native livers of familial amyloidosis (FA) patients may be suitable for domino transplantation into other recipients. METHODS: Retrospective analysis (2013 to 2019) of all CHLT at our center was performed. Continuous data were presented as mean with standard deviation and discrete variables as percentages. RESULTS: Familial amyloidosis was the indication for CHLT in 5 out of 6 patients. The mean recipient age was 55 ± 5.62 years. Two patients were bridged with total artificial heart. The mean model for end-stage liver disease score at transplant was 17.17 ± 3.7. Two explanted livers were used for transplantation in a domino fashion. The median intensive care and hospital stays were 5.5 and 19 days, respectively. Complications included renal failure (1), groin abscess (1), pulmonary embolism (1), and cardiac rejection (1). Patient and graft survival for both organs was 100% at a median follow-up of 59 (range 20-76) months. DISCUSSION: Combined heart-liver transplantation for FA achieves excellent outcomes. The possible use of livers explanted from patients with FA for domino liver transplantation can contribute to the liver donor pool.

Predictors of Renal Failure in Patients Treated With the Total Artificial Heart.

BACKGROUND: The incidence of hemodialysis (HD)-dependent renal failure after total artificial heart (TAH) implantation is high. We sought to determine the preoperative predictors of HD after TAH implantation. METHODS AND RESULTS: We studied 87 patients after TAH implantation at our institution between April 2006 and March 2017. Baseline clinical data were obtained from the medical records, and patients were followed until death or heart transplantation. We performed logistic regression analysis to identify predictors of HD after TAH implantation. Of the patients, 24 (28%) required postimplantation HD. Those requiring HD were more likely to have histories of coronary artery disease (58% vs 29%; P = 0.01), required preoperative membrane oxygenation (33% vs 4.8%; P = 0.001) and had lower baseline estimated glomerular filtration rates (54 ± 29 vs 67 ± 24 mL/min/1.73m2; P = 0.04). Patients requiring HD were at a higher risk of death on device at 1 year (33% vs 5%, P = 0.001; log rank test: P =0.001, hazard ratio 6.6 [95% CI:1.8-23], P = 0.003). CONCLUSIONS: The incidence of postimplantation HD is high and is associated with increased likelihood of mortality. Lower baseline estimated glomerular filtration rates, histories of coronary artery disease and preoperative membrane oxygenation support are predictors of postimplantation requirement of HD. These data may help to identify patients at risk for adverse outcomes after TAH implantation.

Peak Oxygen Uptake Recovery Delay After Maximal Exercise in Patients With Heart Failure.

PURPOSE: Peak oxygen uptake recovery delay (V˙o2peakRD), measured as the time until post-exercise oxygen uptake (V˙o2) decreases below V˙o2peak following maximal cardiopulmonary exercise testing (CPX), has been recognized as an abnormal response, associated with reduced cardiac output reserve during exercise in patients with heart failure (HF). In the current study we examined the association of V˙o2peakRD during routine CPX testing of patients with symptomatic HF across a wide range of left ventricular ejection fraction (LVEF) values with clinical biomarkers. METHODS: In this retrospective study, 80 clinically stable symptomatic HF patients across a wide range of LVEF at our institution were evaluated that put forth a minimally acceptable effort during CPX testing (respiratory exchange ratio ≥ 1.00). The V˙o2peakRD was measured in 10-sec intervals following maximal CPX testing. Markers of elevated cardiac filling pressures (N-terminal pro-brain natriuretic peptide [NTproBNP] and echocardio-Doppler E/e') and other key CPX parameters were explored for their association with V˙o2peakRD. RESULTS: The mean V˙o2peakRD and V˙o2peak were 10 (interquartile range 10, 40) sec and 13.9 (11.6, 16.4) mL· kg · min, respectively. V˙o2peakRD demonstrated a positive linear trend with serum NTproBNP levels and E/e' (TJT = 1239.500, z = 2.634, P < .01; TJT = 1081.000, z = 2.046, P = .04, respectively). CONCLUSION: Prolonged V˙o2peakRD following exercise is associated with markers of greater disease severity in patients with HF.

Chryseobacterium bacteraemia in a patient with heart failure: case report and literature review.

BACKGROUND: A 29-year-old male with recently diagnosed biventricular failure from myopericarditis and subsequent constrictive pericarditis on home milrinone presented to the Emergency Department with fevers/chills. CASE SUMMARY: On arrival to the Emergency Department, he was found to have septic shock and required vasopressor therapy. Chryseobacterium indologenes grew on his admission blood cultures, and he was treated with ciprofloxacin and piperacillin/tazobactam. He quickly improved, allowing for a successful pericardiectomy, was weaned off inotropes and discharged from the hospital. DISCUSSION: Chryseobacterium indologenes is an environmental Gram-negative rod found in groundwater. It is rarely associated with human infection, but is associated with indwelling lines and has been documented in immunocompromised patients. Treatment typically involves line removal and a fluoroquinolone or piperacillin/tazobactam; the most optimal antimicrobial regimen and duration of treatment are unknown.

Impact of Socioeconomic Factors on Patient Desire for Early LVAD Therapy Prior to Inotrope Dependence.

BACKGROUND: Worsening heart failure (HF) and health-related quality of life (HRQOL) have been shown to impact the decision to proceed with left ventricular assist device (LVAD) implantation, but little is known about how socioeconomic factors influence expressed patient preference for LVAD. METHODS AND RESULTS: Ambulatory patients with advanced systolic HF (n=353) reviewed written information about LVAD therapy and completed a brief survey to indicate whether they would want an LVAD to treat their current level of HF. Ordinal logistic regression analyses identified clinical and demographic predictors of LVAD preference. Higher New York Heart Association (NYHA) class, worse HRQOL measured by Kansas City Cardiomyopathy Questionnaire, lower education level, and lower income were significant univariable predictors of patients wanting an LVAD. In the multivariable model, higher NYHA class (OR [odds ratio]: 1.43, CI [confidence interval]: 1.08-1.90, P = .013) and lower income level (OR: 2.10, CI: 1.18 - 3.76, P = .012 for <$40,000 vs >$80,000) remained significantly associated with wanting an LVAD. CONCLUSION: Among ambulatory patients with advanced systolic HF, treatment preference for LVAD was influenced by level of income independent of HF severity. Understanding the impact of socioeconomic factors on willingness to consider LVAD therapy may help tailor counseling towards individual needs.

Determinants of Cardiorespiratory Fitness in Patients with Heart Failure Across a Wide Range of Ejection Fractions.

Impaired cardiorespiratory fitness (CRF) in heart failure (HF) is influenced by a complex array of cardiac and extracardiac factors. The study aimed to identify clinical determinants of CRF measured as peak oxygen consumption (peak VO2) in HF patients, and to determine a peak VO2 prediction model using regression equations. Retrospective analysis of 200 HF patients who completed treadmill cardiopulmonary exercise testing and underwent Doppler echocardiography and/or biomarker analysis on the same day was performed. After univariate linear regression analysis, a multivariate peak VO2 prediction model was developed using significant variables in a stepwise linear regression analysis. In subjects with repeated testing, Pearson's correlation was used to assess correlations between measured and predicted change in peak VO2 (Δpeak VO2) over time. Mean age was 57 years, with 55% being male. Stepwise linear regression was used to generate a weighted model for peak VO2: 30.895 + (-0.112•age[years]) + (0.296•hemoglobin [g/dl]) + (-0.101•E/e'[unit change]) + (-0.202• body mass index [kg/m2]) + (-0.593• N-terminal pro-brain natriuretic peptide [logN pg/ml])) + (-1.349•CRP [log mg/L]). Predicted peak VO2 correlated strongly with measured peak VO2 in HF with reduced ejection fraction and HF with preserved ejection fraction patients (r = +0.63, p <0.001; r = +0.64, p <0.001, respectively). Predicted Δpeak VO2 correlated with measured Δpeak VO2 (r = +0.23, p <0.001). In conclusion, in patients with HF across a wide range of left ventricular ejection fraction, age, systemic inflammation, oxygen carrying capacity, obesity, and elevated filling pressures are the strongest predictors of impaired CRF. The proposed CRF model allows prediction of peak VO2 in HF patients and may be used to estimate peak VO2 changes over time.

Device Management and Flow Optimization on Left Ventricular Assist Device Support.

The authors discuss principles of continuous flow left ventricular assist device (LVAD) operation, basic differences between the axial and centrifugal flow designs and hemodynamic performance, normal LVAD physiology, and device interaction with the heart. Systematic interpretation of LVAD parameters and recognition of abnormal patterns of flow and pulsatility on the device interrogation are necessary for clinical assessment of the patient. Optimization of pump flow using LVAD parameters and echocardiographic and hemodynamics guidance are reviewed.

Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart.

BACKGROUND: Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). METHODS: We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. RESULTS: Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). CONCLUSIONS: Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation.

Renal Function Recovery with Total Artificial Heart Support.

Heart failure patients requiring total artificial heart (TAH) support often have concomitant renal insufficiency (RI). We sought to quantify renal function recovery in patients supported with TAH at our institution. Renal function data at 30, 90, and 180 days after TAH implantation were analyzed for patients with RI, defined as hemodialysis supported or an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m. Between January 2008 and December 2013, 20 of the 46 (43.5%) TAH recipients (age 51 ± 9 years, 85% men) had RI, mean preoperative eGFR of 48 ± 7 ml/min/1.73 m. Renal function recovery was noted at each follow-up interval: increment in eGFR (ml/min/1.73 m) at 30, 90, and 180 days was 21 ± 35 (p = 0.1), 16.5 ± 18 (p = 0.05), and 10 ± 9 (p = 0.1), respectively. Six patients (30%) required preoperative dialysis. Of these, four recovered renal function, one remained on dialysis, and one died. Six patients (30%) required new-onset dialysis. Of these, three recovered renal function and three died. Overall, 75% (15 of 20) of patients' renal function improved with TAH support. Total artificial heart support improved renal function in 75% of patients with pre-existing significant RI, including those who required preoperative dialysis.

The total artificial heart.

The total artificial heart (TAH) is a form of mechanical circulatory support in which the patient's native ventricles and valves are explanted and replaced by a pneumatically powered artificial heart. Currently, the TAH is approved for use in end-stage biventricular heart failure as a bridge to heart transplantation. However, with an increasing global burden of cardiovascular disease and congestive heart failure, the number of patients with end-stage heart failure awaiting heart transplantation now far exceeds the number of available hearts. As a result, the use of mechanical circulatory support, including the TAH and left ventricular assist device (LVAD), is growing exponentially. The LVAD is already widely used as destination therapy, and destination therapy for the TAH is under investigation. While most patients requiring mechanical circulatory support are effectively treated with LVADs, there is a subset of patients with concurrent right ventricular failure or major structural barriers to LVAD placement in whom TAH may be more appropriate. The history, indications, surgical implantation, post device management, outcomes, complications, and future direction of the TAH are discussed in this review.

Leptin as a common link to obesity and hypertension.

Leptin is a recently isolated circulating peptide hormone that is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. While the relevance of endogenous leptin needs further clarification, it appears to be a potential pressure- and volume-regulating factor, and may function pathophysiologically as a common link to obesity and hypertension.

Leptin blockade attenuates sodium excretion in saline-loaded normotensive rats.

Previous investigations in normotensive animals have demonstrated a marked natriuretic and diuretic response following the acute administration of supraphysiologic doses of synthetic leptin. However, the importance of endogenous leptin in the regulation of renal sodium and water balance is not yet defined. This study examined the hemodynamic and renal excretory effects of circulating leptin blockade with a specific polyclonal antibody in groups of normotensive, chronically saline-loaded Sprague-Dawley rats. In the experimental group (n = 10), leptin antibody significantly decreased urinary sodium excretion and urinary flow by approximately 30% compared to the control rats (n = 10). Mean arterial pressure remained unchanged. Collectively, these results are interpreted to suggest that leptin is an important renal sodium-regulating factor under conditions of mild sodium and volume expansion.

Leptin as a common link to obesity and hypertension.

Leptin is a recently isolated circulating peptide hormone that is primarily synthesized and secreted by adipocytes. One of the major functions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake, elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect actions, may play an important role in cardiovascular and renal functions. While the relevance of endogenous leptin needs further clarification, it appears to be a potential pressure- and volume-regulating factor, and may function pathophysiologically as a common link to obesity and hypertension.