The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure.

BACKGROUND: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. METHODS: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. RESULTS: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. CONCLUSIONS: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading.

Risk score-guided multidisciplinary team-based Care for Heart Failure Inpatients is associated with lower 30-day readmission and lower 30-day mortality.

OBJECTIVE: Using augmented intelligence clinical decision tools and a risk score-guided multidisciplinary team-based care process (MTCP), this study evaluated the MTCP for heart failure (HF) patients' 30-day readmission and 30-day mortality across 20 Intermountain Healthcare hospitals. BACKGROUND: HF inpatient care and 30-day post-discharge management require quality improvement to impact patient health, optimize utilization, and avoid readmissions. METHODS: HF inpatients (N = 6182) were studied from January 2013 to November 2016. In February 2014, patients began receiving care via the MTCP based on a phased implementation in which the 8 largest Intermountain hospitals (accounting for 89.8% of HF inpatients) were crossed over sequentially in a stepped manner from control to MTCP over 2.5 years. After implementation, patient risk scores were calculated within 24 hours of admission and delivered electronically to clinicians. High-risk patients received MTCP care (n = 1221), while lower-risk patients received standard HF care (n = 1220). Controls had their readmission and mortality scores calculated retrospectively (high risk: n = 1791; lower risk: n = 1950). RESULTS: High-risk MTCP recipients had 21% lower 30-day readmission compared to high-risk controls (adjusted P = .013, HR = 0.79, CI = 0.66, 0.95) and 52% lower 30-day mortality (adjusted P < .001, HR = 0.48, CI = 0.33, 0.69). Lower-risk patients did not experience increased readmission (adjusted HR = 0.88, P = .19) or mortality (adjusted HR = 0.88, P = .61). Some utilization was higher, such as prescription of home health, for MTCP recipients, with no changes in length of stay or overall costs. CONCLUSIONS: A risk score-guided MTCP was associated with lower 30-day readmission and 30-day mortality in high-risk HF inpatients. Further evaluation of this clinical management approach is required.

Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18.

Clinical Trials in Organ Transplantation-18 (CTOT-18) is a follow-up analysis of the 200-subject multicenter heart transplant CTOT-05 cohort. CTOT-18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity. The composite endpoint (CE) included death, retransplantation, coronary stent, myocardial infarction, and cardiac allograft vasculopathy. The mean follow-up was 4.5 ± SD 1.1 years. Subjects with serum anti-cardiac myosin (CM) antibody detected at transplantation and at 12 months had a higher risk of meeting the CE compared to those without anti-CM antibody (hazard ratio [HR] = 2.9, P = .046). Plasma VEGF-A and VEGF-C levels pretransplant were associated with CE (odds ratio [OR] = 13.24, P = .029; and OR = 0.13, P = .037, respectively). Early intravascular ultrasound findings or other candidate biomarkers were not associated with the study outcomes. In conclusion, anti-CM antibody and plasma levels of VEGF-A and VEGF-C were associated with an increased risk of adverse events. Although this multicenter report supports further evaluation of the mechanisms through which anti-CM antibody and plasma angiogenesis proteins lead to allograft injury, we could not identify additional markers of adverse events or potential novel therapeutic targets.

The impact of asymptomatic antibody-mediated rejection on outcome after heart transplantation.

PURPOSE OF REVIEW: Defining criteria for antibody-mediated rejection (AMR) in heart transplantation were standardized a few years ago, but very little is known about asymptomatic cardiac AMR. We will start the review with a background summarizing the timeline of cardiac AMR. Then we will cover past and current knowledge about asymptomatic cardiac AMR and its impact on outcome after transplantation, with added insight from experience with other solid-organ transplants. RECENT FINDINGS: The incidence of asymptomatic cardiac AMR had likely been under-estimated because biopsy surveillance for it in the absence of clinical manifestation was not the norm. Recent data indicate that it may be more common especially when counting concomitant acute cellular rejection (mixed rejection). Also a higher risk of cardiac allograft vasculopathy (CAV) and cardiovascular mortality have been linked to it. The primary implication of these findings is whether therapeutic intervention is warranted, but the appropriate target patient population likely to benefit from treatment is yet to be determined. SUMMARY: Asymptomatic cardiac AMR is not uncommon and it negatively impacts outcome after heart transplantation.

Early inpatient calculation of laboratory-based 30-day readmission risk scores empowers clinical risk modification during index hospitalization.

Improving 30-day readmission continues to be problematic for most hospitals. This study reports the creation and validation of sex-specific inpatient (i) heart failure (HF) risk scores using electronic data from the beginning of inpatient care for effective and efficient prediction of 30-day readmission risk. METHODS: HF patients hospitalized at Intermountain Healthcare from 2005 to 2012 (derivation: n=6079; validation: n=2663) and Baylor Scott & White Health (North Region) from 2005 to 2013 (validation: n=5162) were studied. Sex-specific iHF scores were derived to predict post-hospitalization 30-day readmission using common HF laboratory measures and age. Risk scores adding social, morbidity, and treatment factors were also evaluated. RESULTS: The iHF model for females utilized potassium, bicarbonate, blood urea nitrogen, red blood cell count, white blood cell count, and mean corpuscular hemoglobin concentration; for males, components were B-type natriuretic peptide, sodium, creatinine, hematocrit, red cell distribution width, and mean platelet volume. Among females, odds ratios (OR) were OR=1.99 for iHF tertile 3 vs. 1 (95% confidence interval [CI]=1.28, 3.08) for Intermountain validation (P-trend across tertiles=0.002) and OR=1.29 (CI=1.01, 1.66) for Baylor patients (P-trend=0.049). Among males, iHF had OR=1.95 (CI=1.33, 2.85) for tertile 3 vs. 1 in Intermountain (P-trend <0.001) and OR=2.03 (CI=1.52, 2.71) in Baylor (P-trend < 0.001). Expanded models using 182-183 variables had predictive abilities similar to iHF. CONCLUSIONS: Sex-specific laboratory-based electronic health record-delivered iHF risk scores effectively predicted 30-day readmission among HF patients. Efficient to calculate and deliver to clinicians, recent clinical implementation of iHF scores suggest they are useful and useable for more precise clinical HF treatment.

Clinical Decision Support to Efficiently Identify Patients Eligible for Advanced Heart Failure Therapies.

BACKGROUND: Patients who need and receive timely advanced heart failure (HF) therapies have better long-term survival. However, many of these patients are not identified and referred as soon as they should be. METHODS: A clinical decision support (CDS) application sent secure email notifications to HF patients' providers when they transitioned to advanced disease. Patients identified with CDS in 2015 were compared with control patients from 2013 to 2014. Kaplan-Meier methods and Cox regression were used in this intention-to-treat analysis to compare differences between visits to specialized and survival. RESULTS: Intervention patients were referred to specialized heart facilities significantly more often within 30 days (57% vs 34%; P < .001), 60 days (69% vs 44%; P < .0001), 90 days (73% vs 49%; P < .0001), and 180 days (79% vs 58%; P < .0001). Age and sex did not predict heart facility visits, but renal disease did and patients of nonwhite race were less likely to visit specialized heart facilities. Significantly more intervention patients were found to be alive at 30 (95% vs 92%; P = .036), 60 (95% vs 90%; P = .0013), 90 (94% vs 87%; P = .0002), and 180 days (92% vs 84%; P = .0001). Age, sex, and some comorbid diseases were also predictors of mortality, but race was not. CONCLUSIONS: We found that CDS can facilitate the early identification of patients needing advanced HF therapy and that its use was associated with significantly more patients visiting specialized heart facilities and longer survival.

Implementation of Real-Time Assessment of Patient-Reported Outcomes in a Heart Failure Clinic: A Feasibility Study.

BACKGROUND: Patient-reported outcomes (PROs) quantify, from patients' perspectives, their symptoms, function, and quality of life. Our aim was to determine the feasibility of integrating PRO capture into routine clinical practice at a large heart failure (HF) clinic. METHODS: We examined the practicality of PRO completion at the time of clinic visit, the time required to complete the selected instruments, the completion rate, and the feasibility of immediate PRO scoring and integration of the results into the electronic health record (EHR). We deployed a computer program to capture PROs (Kansas City Cardiomyopathy Questionnaire, Patient-Reported Outcomes Measurement Information System) on a portable computer platform at the time of a clinic visit. An automated algorithm identified patients scheduled for appointments at the HF clinic at registration, provided a portable tablet computer with which to complete the appropriate PRO instruments and then scored and immediately integrated the results in the patient's EHR. RESULTS: In a 12-month period, 862 unique patients completed 1,320 PRO assessments. The mean age of this cohort was 60.1 ± 16.3 years and 66% were male. The average time for PRO assessment was 6.7 minutes and the completion rate among eligible patients was 58%, with 91% of started assessments completed in full. CONCLUSIONS: These preliminary data support the feasibility of serial PRO assessment with real-time integration into the EHR in a large outpatient population of patients with HF. We identified critical steps that should enhance adoption of this approach by clinicians and render PRO results meaningful and actionable in routine clinical care.

Antibody-mediated rejection in the cardiac allograft: diagnosis, treatment and future considerations.

PURPOSE OF REVIEW: This review summarizes the latest publications dealing with antibody-mediated rejection (AMR) and defines areas of controversy and future steps that may improve the outcome for patients with this virulent form of rejection. RECENT FINDINGS: Recent progress includes publication of standardized pathologic criteria for acute AMR by the International Society for Heart and Lung Transplantation (ISHLT) and guidelines for treatment of acute AMR by the American Heart Association, endorsed by ISHLT as well. Recently published review articles emphasize the important role of innate immune mechanisms, clarify the role of viral infection and provide insights into vascular biology and the role of innate effector populations, macrophages and dendritic cells. SUMMARY: Strategies for future studies are discussed in the context of these new findings and similar efforts undertaken by renal and liver allograft investigators.

Health characteristics of heart transplant recipients surviving into their 80s.

BACKGROUND: Heart transplantation (HTx) is the preferred treatment for patients with end-stage heart failure and has been successful for >30 y. The clinical course of recipients at the extreme of age is unknown. We reviewed our experience to determine the overall health and prevalence of Tx-related medical problems for recipients in their ninth decade. METHODS: We reviewed the UCTP experience from 1985 to present to identify patients who survived into their 80s and matched (1:1) with other recipients for gender and age at HTx, but did not survive to ≥80 y. The end point was the prevalence of medical problems. RESULTS: Since 1985, 1129 adult HTx have been performed and 14 patients (1.2%) survived to ≥80 y old. The mean age at HTx was 63 ± 4 y. Of octogenarians, the majority were males with ischemic cardiomyopathy. The average survival after transplant was 19 ± 5 y in the octogenarians and 5 ± 5 y in the controls (P < 0.01). Over time, the prevalence of comorbidities increased. Compared with nonoctogenarians, we observed higher prevalence of dyslipidemia (P = 0.02), and chronic renal insufficiency (P = 0.02) during follow-up. Cardiac function was normal (ejection fraction > 55%) for all octogenarians at age 80 y. CONCLUSIONS: Despite improvements in posttransplant care, survival of HTx patients into the ninth decade is rare (1%). For those surviving into their 80s, cardiac function is preserved but dyslipidemia, renal insufficiency, and skin cancers are common. As the age of Htx patients continues to increase, posttransplant care should be tailored to minimize post-HTx complications and further extend survival.

Reasons for, and outcomes of patients who were referred for a ventricular assist device but were declined: the recent era forgotten ones.

BACKGROUND: Ventricular assist devices (VADs) have a proven survival benefit in select patients with advanced heart failure, yet many patients considered for implantation are declined for various reasons. The outcome of these patients is obscure owing to their exclusion from recent VAD studies. We aim to compare the outcomes of patients who received a VAD to those who did not. METHODS: For this study, the Artificial Heart Program's database at Intermountain Medical Center was queried from 2006 to 2012 for patients referred for a VAD. Kaplan-Meier survival analysis was performed with log-rank test determining significance. RESULTS: Of 232 patients included, 118 patients received a VAD and 114 patients did not. The prevailing reason for VAD decline in eligible and willing patients was due to pre-existing illness (39%). Mortality was higher in non-VAD vs. VAD patients (58.8% vs. 35.6%, p < 0.001) with a median time-to-death of 67 (IQR:12-314) and 301 (IQR:136-694) d, respectively (p = 0.007). CONCLUSIONS: In the current era of non-pulsatile VADs, mortality of patients who are considered but not implanted remains high. Additionally, mortality of these patients occurred much sooner. Educational efforts ensuring timely referral for VAD therapy are important to maximize the number of patients who may benefit.

Elevated resting heart rate in heart transplant recipients: innocent bystander or adverse prognostic indicator?

BACKGROUND: The elevated baseline heart rate (HR) of a heart transplant recipient has previously been considered inconsequential. However, we hypothesized that a resting HR above 100 beats per minute (bpm) may be associated with morbidity and mortality. METHODS: The U.T.A.H. Cardiac Transplant Program studied patients who received a heart transplant between 2000 and 2011. Outpatient HR values for each patient were averaged during the first year post-transplant. The study cohort was divided into two groups: the tachycardic (TC) (HR > 100 bpm) and the non-TC group (HR ≤ 100 bpm) in which mortality, incidence of rejection, and cardiac allograft vasculopathy were compared. RESULTS: Three hundred and ten patients were included as follows: 73 in the TC and 237 in the non-TC group. The TC group had a higher risk of a 10-yr all-cause mortality (p = 0.004) and cardiovascular mortality (p = 0.044). After adjustment for donor and recipient characteristics in multivariable logistic regression analysis, the hazard ratio was 3.9, (p = 0.03, CI: 1.2-13.2) and 2.6 (p = 0.02, CI: 1.2-5.5) for cardiovascular mortality and all-cause mortality, respectively. CONCLUSION: Heart transplant recipients with elevated resting HR appear to have higher mortality than those with lower resting HR. Whether pharmacologically lowering the HR would result in better outcomes warrants further investigation.

Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified?

BACKGROUND: Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. METHODS AND RESULTS: We analyzed mortality and morbidity in 33,073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001). CONCLUSIONS: Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.

Diuretic strategies in patients with acute decompensated heart failure.

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 µmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 µmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 µmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 µmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation.

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy (n = 14) and from normal donors (n = 5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1 ), secondary (D2 ) and tertiary (D3 ) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (P < 0.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were -0.51, 0.59, 0.56 and 0.62 (P < 0.05), respectively. The correlation between D1 and collagen content was not significant (r = 0.46, P = 0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts.

Gene-expression profiling for rejection surveillance after cardiac transplantation.

BACKGROUND: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS: We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS: During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS: Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Interleukin receptor family member ST2 concentrations in patients following heart transplantation.

OBJECTIVE: To evaluate soluble (s) ST2 as a biomarker of rejection, allograft vasculopathy and mortality after orthotopic heart transplantation (OHT). METHODS: sST2 concentrations were measured in 241 patients following OHT. RESULTS: Elevated sST2 was associated with cellular rejection (CR) ≥ 1R, with highest rates of CR in the 4th sST2 quartile (p = 0.003). No significant association between sST2 and antibody-mediated rejection or allograft vasculopathy was found. sST2 ≥ 30 ng/mL independently predicted death over 7-year follow-up (HR = 2.01; 95% CI 1.15-3.51; p = 0.01). CONCLUSION: Concentrations of sST2 are associated with the presence of CR and predict long-term mortality following OHT.

The detection and role of circulating antibodies in rejection.

PURPOSE OF REVIEW: In this review, we first discuss the evolution and current controversies in antibody detection methodology for transplant candidates. Then, we summarize how immunologists and transplant clinicians integrate new evidence with their understanding of how recipient alloantibodies influence patient management and posttransplant outcomes. RECENT FINDINGS: New advances in solid-phase assays have allowed a more accurate and discriminate appraisal of preformed antibodies. As a result, sensitized patients who are awaiting suitable heart donors can now be better risk-stratified and screened by virtual crossmatch. Yet, the progress in the field also brings to light some new contentious issues in need of further exploration and consideration. Some of these issues are explored in this review: are the new solid-phase assays too sensitive? What are the reasons for and the clinical implications of inconsistencies in results between the different techniques? Which antibodies from a growing list are clinically pertinent? What is the role of the virtual crossmatch? And how do antibodies impact posttransplant outcomes? SUMMARY: Serologic detection of preformed or de-novo donor anti-human leukocyte antigen (HLA) antibodies has been closely linked to allograft rejection and poor outcomes. Although welcome, new histocompatibility testing methods also pose new challenges in clinical decision-making. Increased interaction between the clinicians and the histocompatibility laboratory is paramount to better understand the significance of antibodies, to maximize safe donor organ use, and to improve the overall posttransplant outcomes.

Donor Age, Sex, and Cause of Death and Their Relationship to Heart Transplant Recipient Cardiac Death.

BACKGROUND: Recent studies indicate that donor innate immune responses participate in initiating and accelerating innate responses and allorecognition in the recipient. These immune responses negatively affect recipient outcomes and predispose recipients to cardiovascular death (CV death). We hypothesized that a donor cause of death (COD) associated with higher levels of innate immune response would predispose recipients to more adverse outcomes post-transplant, including CV death. METHODS: We performed a single-institution retrospective analysis comparing donor characteristics and COD to recipient adverse cardiovascular outcomes. We analyzed the medical records of local adult donors (age 18-64) in a database of donors where adequate data was available. Donor age was available on 706 donors; donor sex was available on 730 donors. We linked donor characteristics (age and sex) and COD to recipient CV death. The data were analyzed using logistic regression, the log-rank test of differences, and Tukey contrast. RESULTS: Donor age, female sex, and COD of intracranial hemorrhage were significantly associated with a higher incidence of recipient CV death. CONCLUSIONS: In this single institution study, we found that recipients with hearts from donors over 40 years, donors who were female, or donors who died with a COD of intracranial hemorrhage had a higher frequency of CV death. Donor monitoring and potential treatment of innate immune activation may decrease subsequent recipient innate responses and allorecognition stimulated by donor-derived inflammatory signaling, which leads to adverse outcomes.

Impact of high-dose inotropic donor support on early myocardial necrosis and outcomes in cardiac transplantation.

BACKGROUND: Cardiac donors routinely require vasoactive agents for circulatory stability after brain death. Nevertheless, inotropes have been associated with direct cardiac toxicity. Our study evaluated whether the use of high-dose inotropic support in potential donors was associated with increased early myocardial necrosis (MN) and worse clinical outcomes after cardiac transplantation. METHODS: The UTAH Cardiac Transplant Program (UCTP) and Intermountain Donor Services databases were queried for records between 1996 and 2009. The high-dose donor inotropic support (HDIS) group was defined as patients on dopamine >10 µg/kg/min. The incidence of early MN, intensive care unit (ICU) length of stay, length of ventilator support, and mortality was evaluated. RESULTS: Two hundred and forty-four recipients undergoing transplant met study criteria. The average donor age was 27 yr. The incidence of MN in the HDIS (n=29) and non-HDIS (n=204) groups was 14.8% and 6.7%, respectively, OR 2.67. Total ischemic time, ventilator support time, ICU stay, and actuarial survival were similar between both groups. CONCLUSION: The use of high-dose inotropic support to maintain donor stability appears to have a higher trend for early post-transplant MN without an impact on clinical outcomes. With the current growing shortage of organ donors, it appears reasonable to use donors on high-dose inotropic support.

Right Heart Failure Following Left Ventricular Device Implantation: Natural History, Risk Factors, and Outcomes: An Analysis of the STS INTERMACS Database.

BACKGROUND: Our current understanding of right heart failure (RHF) post-left ventricular assist device (LVAD) is lacking. Recently, a new Interagency Registry for Mechanically Assisted Circulatory Support definition of RHF was introduced. Based on this definition, we investigated natural history, risk factors, and outcomes of post-LVAD RHF. METHODS: Patients implanted with continuous flow LVAD between June 2, 2014, and June 30, 2016 and registered in the Interagency Registry for Mechanically Assisted Circulatory Support/Society of Thoracic Surgeons Database were included. RHF incidence and predictors, and survival after RHF were assessed. The manifestations of RHF which were separately analyzed were elevated central venous pressure, peripheral edema, ascites, and use of inotropes. RESULTS: Among 5537 LVAD recipients (mean 57±13 years, 49% destination therapy, support 18.9 months) prevalence of 1-month RHF was 24%. Of these, RHF persisted at 12 months in 5.3%. In contrast, de novo RHF, first identified at 3 months, occurred in 5.1% and persisted at 12 months in 17% of these, and at 6 months occurred in 4.8% and persisted at 12 months in 25%. Higher preimplant blood urea nitrogen (ORs,1.03-1.09 per 5 mg/dL increase; P<0.0001), previous tricuspid valve repair/replacement (ORs, 2.01-10.09; P<0.001), severely depressed right ventricular systolic function (ORs,1.17-2.20; P=0.004); and centrifugal versus axial LVAD (ORs,1.15-1.78; P=0.001) represented risk factors for RHC incidence at 3 months. Patients with persistent RHF at 3 months had the lowest 2-year survival (57%) while patients with de novo RHF or RHF which resolved by 3 months had more favorable survival outcomes (75% and 78% at 2 years, respectively; P<0.001). CONCLUSIONS: RHF at 1 or 3 months post-LVAD was a common and frequently transient condition, which, if resolved, was associated with relatively favorable prognosis. Conversely, de novo, late RHF post-LVAD (>6 months) was more frequently a persistent disorder and associated with increased mortality. The 1-, 3-, and 6-month time points may be used for RHF assessment and risk stratification in LVAD recipients.