Long-term post-transplantation outcomes in patients with hypertrophic cardiomyopathy: Single-center 35-year experience.

BACKGROUND: Heart transplantation (HT) is the only option for most patients with end-stage heart failure and hypertrophic cardiomyopathy (HCM) who fail medical therapy. Data on the long-term outcomes post-transplant in HCM individuals remain scarce. METHODS: We analyzed data of 319 adult patients who underwent HT between 1984 and 2019. Patients were followed for cardiac allograft rejection, cardiac allograft vasculopathy (CAV), death, or re-transplantation. RESULTS: Outcomes of 24 patients with HCM, 160 with ischemic, and 135 with dilated cardiomyopathy were compared. During a mean follow-up of 11.6 ± 7.2 (max 27.8), 16.7 ± 8.2 (max 32.7), and 16.1 ± 9.7 (max 34.6) years after HT in hypertrophic, ischemic, and dilated cardiomyopathy groups, respectively: 10-year survival rate was 67%, 62%, 69%, respectively (p = .04). Post-transplantation, HCM individuals more often than the other two studied groups required prolonged inotropic support (37%, 12%, 17%, respectively, p = .02), temporary mechanical circulatory support (45%, 13%, 14%, respectively, p < .01), and renal replacement therapy immediately post-HT (55%, 19%, 24%, respectively, p < .01). No significant inter-group differences were noted in the 10-year freedom from acute allograft rejection (38%, 46%, 43%, respectively, p = .38) or 10-year freedom from CAV (88%, 78%, 81%, respectively, p = .57). CONCLUSIONS: The long-term post-transplant prognosis of adult patients with hypertrophic cardiomyopathy is favorable despite more challenging immediate post-HT course.

Heart Transplant Donor Selection Guidelines: Review and Recommendations.

PURPOSE OF REVIEW: The rate of heart transplants, while steadily increasing, is insufficient to meet the growing list of transplant candidates. Marginal donors expand the donor pool. However, criteria used to identify donors greatly vary by institution. RECENT FINDINGS: The International Society of Heart and Lung Transplant (ISHLT) heart transplant report of 2020 reinforced the importance of donor selection criteria on heart transplant outcomes. Existing literature challenges and reinforces the report's findings. Newer methods, such as donation after circulatory death (DCD), also recontextualize existing donor selection criteria. Transplant prediction models from international databases are poor predictors of individual centers' outcome. Further study is needed to understand associations among donor risk factors, and update the methods used for donor heart selection. In this review, we examine the current literature on extended donor criteria and recommend a model for donor selection.

Frailty in heart transplantation: Report from the heart workgroup of a consensus conference on frailty.

A consensus conference on frailty in solid organ transplantation took place on February 11, 2018, to discuss the latest developments in frailty, adopt a standardized approach to assessment, and generate ideas for future research. The findings and consensus of the Frailty Heart Workgroup (American Society of Transplantation's Thoracic and Critical Care Community of Practice) are presented here. Frailty is defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with every day or acute stressors is compromised. Frailty is increasingly recognized as a distinct biologic entity that can adversely affect outcomes before and after heart transplantation. A greater proportion of patients referred for heart transplantation are older and have more complex comorbidities. However, outcomes data in the pretransplant setting, particularly for younger patients, are limited. Therefore, there is a need to develop objective frailty assessment tools for risk stratification in patients with advanced heart disease. These tools will help to determine appropriate recipient selection for advanced heart disease therapies including heart transplantation and mechanical circulatory support, improve overall outcomes, and help distinguish frailty phenotypes amenable to intervention.

Vasoplegia from Continuous Flow Left Ventricular Assist Devices.

PURPOSE OF REVIEW: The contribution of continuous flow left ventricular assist devices (c-LVAD) to vasoplegic syndrome and postoperative outcomes after orthotopic heart transplant (OHT) is contested in the literature. A standardized definition of vasoplegic syndrome (VS) is needed to better recognize and manage vasoplegic shock. RECENT FINDINGS: Vasoplegic syndrome occurs after orthotopic heart transplant more frequently than after other surgeries requiring cardiopulmonary bypass. c-LVADs lead to small vessel endothelial dysfunction and desensitized adrenal receptors; however, their contribution to the development of vasoplegia is debated in clinical studies. Pulsatility may mitigate vascular dysfunction resulting from long-term continuous flow, and should be further explored in the clinical setting when considering risk factors for vasoplegic syndrome. The incidence of vasoplegic syndrome after orthotopic heart transplant is rising with the increasing use of c-LVAD bridge to therapy. Robust clinical studies are needed to advance our understanding and approach to mitigating VS after OHT.

Intrapericardial Left Ventricular Assist Device for Advanced Heart Failure.

BACKGROUND: Mechanical circulatory support with a left ventricular assist device (LVAD) is an established treatment for patients with advanced heart failure. We compared a newer LVAD design (a small intrapericardial centrifugal-flow device) against existing technology (a commercially available axial-flow device) in patients with advanced heart failure who were ineligible for heart transplantation. METHODS: We conducted a multicenter randomized trial involving 446 patients who were assigned, in a 2:1 ratio, to the study (centrifugal-flow) device or the control (axial-flow) device. Adults who met contemporary criteria for LVAD implantation for permanent use were eligible to participate in the trial. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The trial was powered to show noninferiority with a margin of 15 percentage points. RESULTS: The intention-to treat-population included 297 participants assigned to the study device and 148 participants assigned to the control device. The primary end point was achieved in 164 patients in the study group and 85 patients in the control group. The analysis of the primary end point showed noninferiority of the study device relative to the control device (estimated success rates, 55.4% and 59.1%, respectively, calculated by the Weibull model; absolute difference, 3.7 percentage points; 95% upper confidence limit, 12.56 percentage points; P=0.01 for noninferiority). More patients in the control group than in the study group had device malfunction or device failure requiring replacement (16.2% vs. 8.8%), and more patients in the study group had strokes (29.7% vs. 12.1%). Quality of life and functional capacity improved to a similar degree in the two groups. CONCLUSIONS: In this trial involving patients with advanced heart failure who were ineligible for heart transplantation, a small, intrapericardial, centrifugal-flow LVAD was found to be noninferior to an axial-flow LVAD with respect to survival free from disabling stroke or device removal for malfunction or failure. (Funded by HeartWare; ENDURANCE ClinicalTrials.gov number, NCT01166347 .).

Report from the American Society of Transplantation on frailty in solid organ transplantation.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Impact of QRS Duration and Ventricular Pacing on Clinical and Arrhythmic Outcomes in Continuous Flow Left Ventricular Assist Device Recipients: A Multicenter Study.

OBJECTIVES: Wide QRS duration and ventricular pacing are common in recipients of continuous-flow left ventricular assist devices (CF-LVADs) but their impact on outcomes remains unclear. We assessed the clinical and arrhythmic outcomes of CF-LVAD patients with wide QRS or right ventricular (RV) pacing at baseline, compared with those with narrow QRS and those with continued cardiac resynchronization therapy (CRT). METHODS AND RESULTS: A total of 520 patients (57 ± 13 years) with an implantable cardioverter-defibrillator (ICD) (n = 240) or CRT-defibrillator (n = 280) who underwent CF-LVAD implantation at 5 centers in 2007-2015 were studied. Patients were divided into 3 groups: ICD-N (QRS ≤120 ms; n = 134), ICD-W (QRS >120 ms; n = 106), and CRT (n = 280). Mortality, hospitalization, and ventricular arrhythmia (VA) incidence were compared among the groups. Baseline QRS duration was different among the groups (100 ± 13 [ICD-N] vs 155 ± 26 [ICD-W] vs 159 ± 29 ms [CRT]; P < .0001). In the ICD-W group, 37 (35%) had >80% RV pacing at baseline. Median biventricular pacing in the CRT group was 96%. Over 523 days of CF-LVAD support, Kaplan-Meier analysis showed no difference in survival among groups (log rank P = .9). According to multivariate Cox regression, wide QRS duration and RV pacing were not associated with survival. QRS narrowed during CF-LVAD support in the ICD-W and CRT groups but was not associated with improved survival (P = .9). No differences were noted among the groups in hospitalizations (P = .9), VA (P = .2), or ICD shocks (P = .06). CONCLUSIONS: In this large CF-LVAD cohort, a wide QRS duration, high percentage of RV pacing at baseline, and changes in QRS duration after LVAD implantation were not associated with survival. Continued CRT after CF-LVAD implantation also was not associated with improved survival or HF hospitalizations.

Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice.

ICOS, a member of the CD28 family, represents a key molecule that regulates adaptive responses to foreign Ags. ICOS is prominently expressed on T follicular helper (TFH) cells, a specialized CD4(+) T cell subset that orchestrates B cell differentiation within the germinal centers and humoral response. However, the contribution of ICOS and TFH cells to autoantibody profiles under pathological conditions has not been thoroughly investigated. We used the Sle1 lupus-prone mouse model to examine the role of ICOS in the expansion and function of pathogenic TFH cells. Genetic deletion of ICOS impacted the expansion of TFH cells in B6.Sle1 mice and inhibited the differentiation of B lymphocytes into plasma cells. The phenotypic changes observed in B6.Sle1-ICOS-knockout mice were also associated with a significant reduction in class-switched IgG, and anti-nucleosomal IgG-secreting B cells compared with B6.Sle1 animals. The level of vascular cell adhesion protein 1, a molecule that was shown to be elevated in patients with SLE and in lupus models, was also increased in an ICOS-dependent manner in Sle1 mice and correlated with autoantibody levels. The elimination of ICOS-expressing CD4(+) T cells in B6.Sle1 mice, using a glyco-engineered anti-ICOS-depleting Ab, resulted in a significant reduction in anti-nucleosomal autoantibodies. Our results indicate that ICOS regulates the ontogeny and homeostasis of B6.Sle1 TFH cells and influences the function of TFH cells during aberrant germinal center B cell responses. Therapies targeting the ICOS signaling pathway may offer new opportunities for the treatment of lupus and other autoimmune diseases.

The Sodium Paradox: Dysnatremia and Mortality in Patients Implanted With Extracorporeal Mechanical Circulatory Support Devices.

INTRODUCTION: Dysnatremia, abnormal serum sodium levels, has long been used as a marker for disease progression in heart failure patients. Classically, hyponatremia is associated with increased fluid volume in heart failure and is often a result of neuroendocrine dysfunction and poor cardiac output. Recent studies have noted that dysnatremia and hypernatremia are predictive of worsened outcomes in critical care and renal disease populations. We investigated the relationship between dysnatremia and postoperative outcomes in patients implanted with extracorporeal mechanical circulatory devices. METHODS: A total of 97 patients who underwent implantation with the CentriMag mechanical circulatory assist system were included in this retrospective study. Patients were divided into 2 groups based on preoperative serum sodium level cutoff of 135 mEq/L. Outcomes and mortality were compared between groups. RESULTS: The mean age for the study population was 56.21 ± 15.13 years, and 57 patients (58.8%) were male. The mean time on CentriMag support was 22.7 days. Patients with serum sodium levels ≤135 mEq/L were noted to have significantly worsened indicators of preoperative cardiac function. However, patients with serum sodium levels >135 mEq/L had significantly shorter postoperative survival ( P = .006). When entered into a multivariate Cox proportional hazards model, sodium was an independent predictor for increased risk of mortality (hazard ratio: 1.224; 95% confidence interval: 1.009-1.485; P = .040). CONCLUSION: Our results indicate that elevated preoperative sodium in patients undergoing implantation of a temporary mechanical circulatory support system is predictive of worsened postoperative survival.

The neutrophil to lymphocyte ratio in patients supported with extracorporeal membrane oxygenation.

INTRODUCTION: The neutrophil to lymphocyte ratio (NLR) has proven to be a robust predictor of mortality in a wide range of cardiovascular diseases. This study investigated the predictive value of the NLR in patients supported by extracorporeal membrane oxygenation (ECMO) systems. METHODS: This study included 107 patients who underwent ECMO implantation for cardiogenic shock. Median preoperative NLR was used to divide the cohort, with Group 1 NLR <14.2 and Group 2 with NLR ≥14.2. Survival, the primary outcome, was compared between groups. RESULTS: The study cohort was composed of 64 (60%) males with an average age 53.1 ± 14.9 years. Patients in Group 1 had an average NLR of 7.5 ± 3.5 compared to 27.1 ± 19.9 in Group 2. Additionally, those in Group 2 had significantly higher preoperative blood urea nitrogen (BUN) and age. Survival analysis indicated a thirty-day survival of 56.2%, with significantly worsened mortality in patients with NLR greater than 14.2, p=0.047. DISCUSSION: Our study shows the NLR has prognostic value in patients undergoing ECMO implantation. Leukocytes are known contributors to myocardial damage and neutrophil infiltration is associated with damage caused by myocardial ischemia.

Mean Arterial Pressure to Central Venous Pressure Ratio: A Novel Marker for Right Ventricular Failure After Left Ventricular Assist Device Placement.

BACKGROUND: Early right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and often leads to increased morbidity and mortality. It is difficult to predict early RVF on the basis of clinical and hemodynamic parameters. We investigated the utility of mean arterial pressure (MAP) to central venous pressure (CVP) ratio in predicting early RVF. METHODS AND RESULTS: We analyzed a retrospective cohort of 212 consecutive patients who underwent hemodynamic assessment before destination-therapy LVAD implantation. Patients were followed for early RVF and mortality. Receiver operating characteristic (ROC) analysis was used to determine discriminative capacity of MAP/CVP and tested the diagnostic and prognostic value of median MAP/CVP threshold. The ROC analysis demonstrated that pre-LVAD MAP/CVP was associated with an area under the ROC curve of 0.65 (95% confidence interval 0.58-0.73; P < .001). MAP/CVP threshold <7.5 (simple nearest-to-median value) was associated with 70% sensitivity and 56% specificity for early RV failure. Patients with MAP/CVP <7.5 had a higher incidence of post-LVAD RVF than those with a ratio ≥7.5 (44% vs 23%, respectively; P = .001). Right ventricular assist device requirement was higher in the MAP/CVP <7.5 group (11% vs 2%; P = .01). All-cause mortality was higher in the MAP/CVP <7.5 group (annualized mortality 26% vs 16%; log-rank P = .017). MAP-CVP ratio provided incremental prognostic value for RVF and all-cause mortality beyond established Heartmate II and RVF risk scores. CONCLUSIONS: Our findings suggest that pre-LVAD MAP/CVP <7.5 is associated with early RVF and increased mortality risk. This novel parameter can be used in risk stratification of LVAD candidates. Prospective validation of our findings is needed.

Reduced Anxiety and Depression in Patients With Advanced Heart Failure After Left Ventricular Assist Device Implantation.

BACKGROUND: Despite the high prevalence of depression and anxiety in patients with advanced heart failure, the effects of left ventricular assist device (LVAD) implantation on these critically important aspects of mental health are not well understood. OBJECTIVE: We sought to assess changes in depression and anxiety following LVAD implantation. METHODS: The Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) were administered to 54 patients by a clinical psychologist at a mean of 12 days before LVAD implantation and 251 days after implantation. Patient demographics and clinical data were collected concurrently to psychologic testing. Changes in BDI-II, BAI, and clinical markers of heart failure were assessed using paired t-tests. A p < 0.05 was considered significant. RESULTS: The average age of the group was 56.63 years with a mean ejection fraction 20.8%. Before implantation, mean BAI and BDI scores indicated mild depression and anxiety. Following LVAD implantation, average scores for both BDI-II and BAI decreased significantly, indicating minimal depression and anxiety (12.6-8.54, p = 0.001 and 12.06-6.6, p < 0.001, respectively). Mean scores were significantly lowered in 11 and 8 of the 21 subdomains tested by the BAI and BDI, respectively. Significant improvements were noted in post-LVAD B-type natriuretic peptide, serum sodium, and blood urea nitrogen. CONCLUSION: Depression and anxiety scores improved significantly after LVAD implantation. Factors contributing to changes in depression and anxiety after LVAD could be related to the improvement in acute heart failure symptoms, functional capacity, and quality of life. Prospective studies with larger sample sizes are warranted.

The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes.

BACKGROUND: Chronic kidney disease (CKD) is a known predictor for adverse outcomes in patients with advanced heart failure requiring left ventricular assist devices (LVADs). The effect of pre-LVAD glomerular filtration rate (GFR) on post-LVAD outcomes in CKD patients is not completely understood. Additionally, a subset of patients improve their GFR after LVAD placement. In this study we sought to determine the effects of pre-LVAD GFR on post-LVAD outcomes. METHODS: Two hundred and seventy consecutive patients with LVADs were enrolled. Patients were stratified based on a GFR cut-off of 60mL/min/1.73m2. Patients with preoperative GFR <60 were further divided into two subgroups based post-LVAD discharge GFR of 60. Post-LVAD major adverse effects were analysed. RESULTS: Patients with pre-implant GFR <60 had higher all cause mortality than patients with pre-implant GFR ≥60 (45% vs. 27%, p=0.006). These patients also had higher incidence of early right ventricular failure and congestive heart failure hospitalisations. Kaplan-Meier survival analysis confirmed poor survival in this group. When the subgroup analysis of patients in the GFR <60 cohort was performed, the above findings were heavily weighted towards patients who did not improve their GFR to ≥60 post-LVAD. CONCLUSION: Pre-implant GFR is an important prognostic marker in LVAD patients. Patients with pre-implant GFR <60 are at higher risk of cardiovascular morbidity and mortality. Our findings suggest that the patients who do not improve their GFR post-LVAD are at the highest risk.

Psychosocial Evaluation in Patients Undergoing Left Ventricular Assist Device Implantation Using the Transplant Evaluation Rating Scale.

BACKGROUND: It has been recommended that all candidates for left ventricular assist device (LVAD) implantation undergo preoperative psychologic evaluation for risk assessment. OBJECTIVE: We used the transplant evaluation rating scale (TERS) that was established for pretransplant evaluation to investigate the psychosocial assessment of patients undergoing LVAD implantation. METHODS: This study retrospectively analyzed data from 125 patients with advanced heart failure who were evaluated by the TERS before LVAD implantation. Postoperative follow-up included survival, total length of hospital stay, readmissions, and post-LVAD out-of-hospital days after discharge. The cohort was stratified according to the TERS scores into low-, moderate-, and high-risk groups. The outcomes were analyzed to evaluate whether the TERS score was associated with post-LVAD adverse events. RESULTS: The TERS, when stratified into 3 risk groups showed significant difference in 8 of the 10 psychosocial domains (p < 0.001). The mean number of outpatient days after discharge was significantly different between the low-, moderate-, and high-risk groups (p < 0.001). All other outcomes were not significantly different. CONCLUSIONS: This study showed that the TERS is successful in stratifying our patients with an LVAD into 3 risk groups, indicating the internal validity of this test. The number of out-of-hospital (outpatient) days after discharge was significantly shorter in the TERS high-risk group, which may affect the quality of life and cost of post-LVAD care.

Model for end-stage liver disease predicts right ventricular failure in patients with left ventricular assist devices.

High rates of right ventricular failure continue to affect postoperative outcomes in patients implanted with left ventricular assist devices (LVADs). Development of right ventricular failure and implantation with right ventricular assist devices is known to be associated with significantly increased mortality. The model for end-stage liver disease (MELD) score is an effective means of evaluating liver dysfunction. We investigated the prognostic utility of postoperative MELD on post-LVAD implantation outcomes. MELD scores, demographic data, and outcomes including length of stay, survival, and postoperative right ventricular failure were collected for 256 patients implanted with continuous flow LVADs. Regression and Kaplan-Meier analyses were used to investigate the relationship between MELD and all outcomes. Increased MELD score was found to be an independent predictor of both right heart failure and necessity for RVAD implantation (OR 1.097, CI 1.040-1.158, p = 0.001; OR 1.121, CI 1.015, p = 0.024, respectively). Patients with RV failure and who underwent RVAD implantation had reduced postoperative survival compared to patients with RV dysfunction (no RV failure = 651.4 ± 609.8 days, RV failure = 392.6 ± 444.8 days, RVAD = 89.3 ± 72.8 days; p < 0.001). In conclusion, MELD can be used to reliably predict postoperative right heart failure and the necessity for RVAD implantation. Those patients with RV failure and RVADs experience significantly increased postoperative mortality compared to those without RV dysfunction.

Intraoperative bronchoscopic visualization of left ventricular assist device thrombus.

Despite advancements in left ventricular assist device (LVAD) design and clinical management, device thrombosis remains a pertinent complication. Limited imaging makes precise visualization of clot location and shape very challenging. We report the usage of videobronchoscopic exploration of explanted LVADs for direct visualization of clot in two patients. This technique is a rapid and inexpensive means of improving our understanding of LVAD clot formation and may be useful in surgical exploration of inflow and outflow tracts during LVAD exchange.

Obesity as a Risk Factor for Consideration for Left Ventricular Assist Devices.

BACKGROUND: Obesity is a major risk factor for cardiovascular outcomes and is prevalent in patients with advanced heart failure requiring left ventricular assist devices (LVADs). The understanding of high body mass index (BMI) and outcomes after LVAD implantation continues to evolve. In this study we investigated the effects of obesity on post-LVAD implantation outcomes. METHODS AND RESULTS: In this retrospective study, 288 patients with both Heartmate II and Heartware HVADs, implanted as bridge to transplantation (BTT) and destination therapy (DT), were enrolled. Patients were stratified according to BMI ≥30 kg/m(2). Baseline demographics were obtained. Post-LVAD implantation incidence of readmissions and major adverse events were tabulated. The cohort comprised of 95 (33%) obese and 193 (67%) nonobese patients, as well as, 63 (25%) female and 225 (75%) male patients; 48 (20%) were implanted as BTT and 240 (80%) as DT. The mean BMI in the obese group was 35.2 kg/m(2) compared with 24.3 kg/m(2) (P < .001) in the control group. There was no difference in survival between the two groups. Incidence of post-LVAD implantation heart failure readmissions was higher in the obese cohort. (29% vs 16% P = .009). Multivariate analysis confirmed that BMI was an independent predictor for post-LVAD heart failure readmissions (odds ratio 2.47, 95% confidence interval 1.15-5.32; P = .02) Obese patients had a higher mean total number of hospitalizations compared with nonobese patients, (4.2 vs 3.4; P = .03) as well as higher median total length of stay after LVAD implantation (28 vs 14 days; P = .05), but these were not significant when adjusted for covariates. CONCLUSIONS: Obese patients had higher incidence of post-LVAD implantation heart failure readmissions. There was no difference in overall survival or outcomes between the 2 groups. There was no difference in total rehospitalizations or length of stay between obese and nonobese patients. Our analysis suggests that obesity should not preclude LVAD candidacy.

Clinical outcomes in sensitized heart transplant patients bridged with ventricular assist devices.

BACKGROUND: Left ventricular assist devices (LVADs) as a bridge to transplant (BTT) have been known to cause allosensitization, as measured by panel-reactive antibody (PRA) levels. The goal of this study was to measure the impact of this allosensitization on outcomes. METHODS: Panel-reactive antibodies were analyzed in BTT patients, with sensitization defined as peak PRAs ≥ 10%. Baseline characteristics and outcomes in the two patient groups were evaluated using descriptive statistics, Kaplan-Meier, and regression analysis. RESULTS: Thirty-eight patients were included in the study (17 sensitized vs. 21 non-sensitized). There were more women in the sensitized group (47% vs. 10%, p = 0.023). There was no difference in mean times to high-grade acute cellular rejection (ACR; 18.3 months in sensitized vs. 36.9 months in non-sensitized). Five patients in the sensitized groups developed antibody-mediated rejection (AMR) vs. 0 in the non-sensitized, and all five patients died (Kaplan-Meier log-rank p = 0.024). There was also a significant difference in the incidence of infection at the one- to six-month stage (52.9% vs. 19.0%, p = 0.03). CONCLUSION: Sensitization appears to have a negative effect on mortality. This mortality appears to be concentrated in patients with AMR, and we postulate that the development of AMR in a sensitized patient may be a predictor of mortality.

Changes in Spirometry After Left Ventricular Assist Device Implantation.

Left ventricular assist devices (LVADs) are increasingly being used as life-saving therapy in patients with end-stage heart failure. The changes in spirometry following LVAD implantation and subsequent unloading of the left ventricle and pulmonary circulation are unknown. In this study, we explored long-term changes in spirometry after LVAD placement. In this retrospective study, we compared baseline preoperative pulmonary function test (PFT) results to post-LVAD spirometric measurements. Our results indicated that pulmonary function tests were significantly reduced after LVAD placement (forced expiratory volume in one second [FEV1 ]: 1.9 vs.1.7, P = 0.016; forced vital capacity [FVC]: 2.61 vs. 2.38, P = 0.03; diffusing capacity of the lungs for carbon monoxide [DLCO]: 14.75 vs. 11.01, P = 0.01). Subgroup analysis revealed greater impairment in lung function in patients receiving HeartMate II (Thoratec, Pleasanton, CA, USA) LVADs compared with those receiving HeartWare (HeartWare, Framingham, MA, USA) devices. These unexpected findings may result from restriction of left anterior hemi-diaphragm; however, further prospective studies to validate our findings are warranted.

Kynurenine 3-monooxygenase mediates inhibition of Th17 differentiation via catabolism of endogenous aryl hydrocarbon receptor ligands.

The aryl hydrocarbon receptor (AhR) is a key transcriptional regulator of Th17-cell differentiation. Although endogenous ligands have yet to be identified, evidence suggests that tryptophan metabolites can act as agonists for the AhR. Tryptophan metabolites are abundant in circulation, so we hypothesized that cell intrinsic factors might exist to regulate the exposure of Th17 cells to AhR-dependent activities. Here, we find that Th17 cells preferentially express kynurenine 3-monooxygenase (KMO), which is an enzyme involved in catabolism of the tryptophan metabolite kynurenine. KMO inhibition, either with a specific inhibitor or via siRNA-mediated silencing, markedly increased IL-17 production in vitro, whereas IFN-γ production by Th1 cells was unaffected. Inhibition of KMO significantly exacerbated disease in a Th17-driven model of autoimmune gastritis, suggesting that expression of KMO by Th17 cells serves to limit their continuous exposure to physiological levels of endogenous AhR ligands in vivo.