A Novel, Highly Discriminatory Risk Model Predicting Acute Severe Right Ventricular Failure in Patients Undergoing Continuous-Flow Left Ventricular Assist Device Implant

Abstracts S93 Results: Both treatments with PI resulted in improved graft survival (logrank 17.1, p< 0.001): 7.0±0.0 days in controls, 11.5 ± 2.9 days in bortezomib group (64% relative increase, effect size dCohen=  2.19, 95% CI 0.63 - 3.42), and 12.2 ± 2.2 days in ONX0914 group (74 % relative increase, effect size dCohen=  3.34, 95% CI 1.41 - 4.76). (Immuno)histological analyses on explanted hearts at postoperative day four as well as blood analyses exposed a reduction of leukocytes (infiltration), particularly (T) lymphocytes, and pancytopenia was less in ONX0914 group. No difference in C4d staining was found. PI decreased the secretion of pro-inflammatory cytokines, but even the anti-inflammatory cytokines were affected. A study of side effects showed macroscopic and histological toxic alterations of liver, lymph nodes, thymus, and atrophy of the hematopoietic and lymphatic tissue in bortezomib treated animals, whereas autopsies of ONX0914 or saline treated animals revealed no abnormalities. Conclusion: PI increased perioperative mortality if given pre-transplantation. Starting on day one after transplantation, both PI prolonged graft survival. ONX0914 was less toxic; however, its circulating half-life is too short to sustain possibly longer-term graft survival. New immunoproteasome inhibitors with more selectivity and capacity, and a better bioavailability, could offer a promising therapy in clinical transplantation. 2( 31) Ibrutinib Suppresses De Novo Alloantibodies and Recall Antibody Responses in a Mouse Model of Allosensitization: A Preliminary Report G.D. Wu , I. Kim, N. Chai, A.S. Klein, S. Jordan.  Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA. Purpose: Ibrutinib is a Bruton tyrosine kinase (BTK) antagonist that can inhibit B cell receptor (BCR) signaling, therefore blocking B cell activation. Ibrutinib has been approved by FDA for treatment of B-cell malignancies. In considering its anti B cell property, we recently carried out studies to evaluate whether ibrutinib has suppressive effect on alloantibody responses to transplant. Methods: A mouse model of allosensitization using a C57BL/6 mouse as the recipient of a HLA.A2+ skin allograft was employed to examine the effects of ibrutinib (20 mg/kg/day IP injection for 14 days) on de novo alloantibody responses. For the study of recall antibody suppression by ibrutinib, mice received primary SG were re-immunized with a second HLA.A2+ SG at Day 90 Ptx. Donor-specific antibody (DSA) levels were measured in a flowcytometric antibody binding assay. Splenic T and B cell subsets and bone marrow B/plasma cells were analyzed in flow cytometry. Results: Control mice (n= 6) developed peak levels of DSA IgM at day 14 PTx while the ibrutinib treated mice (n= 6) had significantly lower levels of DSA IgM (p= 0.0047). Control mice developed HLA.A2-specific IgG antibodies at day 14 (230+-60 MFI) and reached peak levels at day 21 (426+61 MFI). In contrast, mice in the treatment group had low levels of HLA. A2-specific IgG at day 14 (109+-59 MFI, p= 0.004) and day 21 (241+-86 MFI, p= 0.003). FACS analysis of lymphocytic cells showed a reduction of B220+/CD19+ B cell population (p< 0.05) and reduction of CD38+CD138+ plasma cells (p< 0.05). In addition, ibrutinib treatment reduced recall DSA IgG levels (281+-119 vs. control 455+-147 MFI, p= 0.05) in responses to 2nd SG. Conclusion: Ibrutinib is effective in suppressing de novo alloantibody responses through blocking BTK mediated BCR signaling, leading to reduction of B cells. Use of ibrutinib may provide benefits to HLA-sensitized transplant patients for B cell suppression. 2( 32) Risk Factors Associated with Right Ventricular Assist Device Implantation: Insights from INTERMACS M.S. Kiernan ,1 D. DeNofrio,1 D.T. Pham,2 N.K. Kapur,1 R. Ruthazer,3 E. W,4 J.E. Rame,4 P. Alturi,4 E.Y. Birati,4 S.L. Myers,5 G.H. Oliveira,6 J.K. Kirklin,5 R.L. Kormos,7 F.D. Pagani,8 J. Teuteberg.7  1Cardiology, Tufts Medical Center, Boston, MA; 2Cardiology, Northwestern University Medical Center, Chicago, IL; 3Tufts Clinical and Translational Science Institute, Boston, MA; 4University of Pennsylvania, Philadelphia, PA; 5University of Alabama, Birmingham, Birmingham, AL; 6Case Western Reserve University, Cleveland, OH; 7University of Pittsburg Medical Center, Pittsburg, PA; 8University of Michigan, Ann Arbor, MI.

Purpose: To investigate pre-implant variables associated with RVAD use in pts undergoing CF-LVAD surgery. Methods: Pts in INTERMACS registry from 6/06 to 3/14 who underwent CF-LVAD surgery (n= 9978) were examined for concurrent or subsequent RVAD use within 14d of LVAD. Risk factors for RVAD were assessed with stepwise logistic regression using univariate p-value <  0.05. Model performance was assessed with ROC analysis for the outcomes of 1) early RVAD and 2) combined RVAD or death within 14d. Log-rank test and Cox-PH models were used to compare survival between pts with and without RVAD. Results: 386 pts (3.9%) required an RVAD within 14d of LVAD. Characteristics associated with RVAD use are listed in the Table. INTERMACS pt profiles 1 & 2 as well as need for preoperative ECMO or dialysis/UF were independently associated with RVAD. Hemodynamic determinants included elevated right atrial and reduced pulmonary artery pulse pressure (systolic - diastolic). Other notable predictors included severe pre-implant tricuspid (TV) regurgitation and history of prior cardiac surgery. Concomitant procedures other than TV repair at time of LVAD were also associated with RVAD. The final model demonstrated good performance for RVAD implant (AUC 0.78) and the combined end-point of RVAD or death within 14d (AUC 0.73). Patients requiring RVAD had decreased survival: 1and 6-mo 78.1% and 63.6% vs. 95.8% and 87.9% for pts receiving isolated LVAD (p< 0.0001). Adjusting for baseline risk, RVAD remained associated with increased risk of death: HR 2.76 (95% CI 2.34-3.24). Conclusion: Correlates of overall severity of illness, including markers of end-organ dysfunction and profiles of hemodynamic instability, are associated with RVAD implantation.

Risk factors for RVAD use in CF-LVAD recipients Variable

Odds Ratio*

95% CI

p-value

INTERMACS Profile 1 (vs other) INTERMACS Profile 2 (vs other) Creatinine (mg/dL) Total Bilirubin (mg/dL) INR WBC (K/UL) Prior CABG/valve surgery Tricuspid valve repair at time   of LVAD Other concomitant surgery at LVAD Severe Tricuspid Regurgitation LV end diastolic diameter (mm) Right atrial pressure (mmHg) Pulmonary artery pulse pressure  (mmHg) Stroke volume (per 10ml increase) Dialysis or ultrafiltration prior   to LVAD ECMO preoperative (yes vs. no)

2.79 1.98 1.25 1.13 1.50 1.04 1.70 1.06

(2.00, 3.89) (1.49, 2.64) (1.07, 1.46) (1.04, 1.23) (1.02, 2.22) (1.01, 1.07) (1.34, 2.14) (0.78, 1.45)

< 0.0001 < 0.0001    0.005    0.003    0.04    0.008 < 0.0001    0.70

1.47 1.61 0.80 1.05 0.96

(1.14, 1.88) (0.78, 1.45) (0.67, 0.95) (1.03, 1.08) (0.94, 0.98)

   0.003    0.002    0.01    0.0001    0.0002

0.89 1.67

(0.80, 0.99) (1.08, 2.57)

   0.03    0.02

2.71

(1.82, 4.05)

< 0.0001

*OR per unit increase for continuous variables

2( 33) A Novel, Highly Discriminatory Risk Model Predicting Acute Severe Right Ventricular Failure in Patients Undergoing Continuous-Flow Left Ventricular Assist Device Implant V. Tchantchaleishvili ,1 S. Maltais,2 N.A. Haglund,3 M.E. Davis,3 J. Cowger,4 P. Shah,5 K.D. Aaronson,6 F.D. Pagani,6 S.M. Dunlay,2 J.M. Stulak.2  1University of Rochester, Rochester, NY; 2Mayo Clinic, Rochester, MN; 3Vanderbilt University, Nashville, TN; 4St.Vincent Medical Group, Indianapolis, IN; 5Inova Fairfax Hospital, Falls Church, VA; 6University of Michigan, Ann Arbor, MI. Purpose: Commonly used risk scores for predicting right ventricular failure (RVF) after continuous-flow left ventricular assist device (CF-LVAD) placement have poor discriminatory power, while Bayesian models are not practical for very high number of predictor variables. We sought to develop a simple, yet highly discriminatory RVF risk score that is applicable to patients in the modern era undergoing placement of two commonly used CF-LVADs.

S94

The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016

Methods: Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF-LVAD implantation, were randomly divided into equal-sized derivation and validation samples. The need for a right ventricular assist device (RVAD) was used as a hard primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified for predicting the need for RVAD, a surrogate for severe RVF. A risk score was developed based on the identified variables and their respective regression coefficients. Results: Between May 2004 and September 2014, 734 patients underwent implantation of CF-LVADs at three institutions [HeartMate II LVAD, 76% (n= 560), HeartWare HVAD, 24% (n= 174)]. 19.5% of the patients (n= 143) were female, median age at implant was 59 (IQR, 49.4 - 65.3), and median baseline INTERMACS profile was 3 (IQR, 2-3). Both derivation and validation groups consisted of 367 patients. Overall, RVAD was required in 4.5% (n= 33) patients. The final model consisted of six preoperative predictor variables: heart rate, white blood cell count, albumin level, blood urea nitrogen level, cardiac index, and severity of tricuspid valve regurgitation. Receiver operating characteristic analysis showed that the area under the curve was 0.86 in the derivation sample (95% CI, 0.74-0.99) and 0.92 in the validation sample (95% CI, 0.85-0.99). Hosmer-Lemeshow goodness of fit test yielded insignificant values in both samples (p= 0.45, p= 0.57) consistent with good calibration. Conclusion: The proposed RVF risks score is applicable to patients undergoing placement of both commonly used CF-LVADs and provides highestto-date discriminatory power when compared to the risks scores used for this purpose. 2( 34) Chemokine Receptor Down Regulation in Mechanical Circulatory Support Patients with Right Ventricular Failure A. Nayak ,1 T.N. Bachman,2 K. Hanley-Yanez,3 C. McTiernan,2 D. McNamara,3 R.L. Kormos,3 O. Hunter,4 A. Inashvili,1 L. Lagazzi,3 J. Teuteberg,3 M.A. Simon.3  1Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA; 3Heart and Vascular Institute at UPMC Presbyterian, University of Pittsburgh Medical Center, Pittsburgh, PA; 4University of Pittsburgh Medical School, University of Pittsburgh, Pittsburgh, PA. Purpose: RV failure complicates about 9-44% of LVAD implants. The complex pathophysiology- myocardial dysfunction, septal mechanics and increased RV preload with consequent demand for increased RV outputmakes prediction difficult. Chemokines play a key role in cardiac self regulation, with down regulation associated with progression of heart failure in vivo. Our aim was to determine if chemokine levels could predict RV failure requiring RVAD in MCS patients. Methods: Expression of common inflammatory genes were examined in patient’s peripheral blood collected 24 hours prior to MCS and in healthy controls. RNA was isolated using a PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR array, Qiagen). Results were expressed as PCR cycles to threshold (CT); more highly expressed genes having a lower CT and normalized to GAPDH. Results are reported as log-fold differences in expression. Results: Compared to normal controls (n= 8), chemokines tested were down regulated in MCS patients (n= 20): CCR3 (3.48 fold decrease, p= 0.02), CCR4 (2.64 fold decrease, p= 0.001), CCR5 (3.25 fold decrease, p= 0.001), CCR6 (5.5 fold decrease, p< 0.001), CCR7 (4.29 fold decrease, p= < 0.001), CCR8 (2 fold decrease, p= 0.058), IL5a (2.64 fold decrease, p= 0.049). The following chemokines were further down regulated in MCS patients requiring RVAD (n= 7, vs n= 13 not requiring RVAD): CCR3 (4.59 fold decrease, p= 0.013), CCR4 (1.74 fold decrease, p= 0.044), CCR8 (2.46 fold decrease, p= 0.017), IL5a (3.25 fold decrease, p= 0.045). Conclusion: Chemokines are down regulated in severe HF patients requiring MCS with further down regulation of CCR3, CCR4, CCR8, and IL5a in those patients with severe RV failure requiring additional mechanical RV support. Further studies are needed to elucidate the role of these chemokines in the pathogenesis of RV failure post LVAD, however these results raise the potentiality of this novel chemokine expression profile as predictive biomarkers in this setting.

2( 35) Biventricular Bridge to Transplant: Total Artificial Heart (TAH) vs Thoratec Paracorporeal VADs (PVADs) Outcomes Post Heart Transplant (HT) E.C. DePasquale , A. Salimbangon, E. Howell, A. Chang, A. Nsair, A. Ardehali.  David Geffen Sch Med, Los Angeles, CA. Purpose: Post-transplant outcomes in those bridged with biventricular mechanical support have not been well described by device. We sought to examine post-HT outcomes in this population in a large national registry. Methods: 682 pts bridged to transplant with either TAH (120) or PVADs (562) were identified from UNOS (1987-2013), of which 498 underwent HT at end of study period (420 PVADs vs 78 TAH). Exclusions include age <  18y, follow-up loss, multiorgan transplant & re-HT. Survival was censored at 12y & multivariate Cox proportional hazard regression analysis (adjusted for age, sex, diabetes, race, ischemic time, dialysis, life support, waiting time & HLA mismatch) was performed. Results: 498 underwent successful HT with either TAH or PVADs. Predominant etiologies included ischemic (44%) & dilated cardiomyopathy (43%) (p= NS between groups). During study period, 153 pts died post HT (130 PVAD vs 23 TAH). Crude 1 month, 1y, 5y post-HT survival was: PVADs [94, 84, 72%] vs TAH [94, 80, 54%] (log-rank, p <  0.064). TAH recipients were less likely to be female (p =  0.010), more likely to have diabetes (p= 0.009), more likely to wait longer for HT (p <  0.001). Multivariate analysis yielded a hazard ratio of 1.55 (CI 0.97 - 2.45) comparing TAH to PVADs. Conclusion: While overall short-term survival was comparable between those bridged with TAH and PVAD biventricular support, there was a trend towards worse survival with the TAH group. Further study is warranted to refine patient selection as both choices present unique challenges.