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Aims Prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implant remains a challenge. The EUROMACS right-sided heart failure (EUROMACS-RHF) risk score was proposed as a prediction tool for post-LVAD RHF but lacks from large external validation. The aim of our study was to externally validate the score. Methods and results From January 2007 to December 2017, 878 continuous-flow LVADs were implanted at three tertiary centres. We calculated the EUROMACS-RHF score in 662 patients with complete data. We evaluated its predictive performance for early RHF defined as either (i) need for short- or long-term right-sided circulatory support, (ii) continuous inotropic support for ≥14 days, or (iii) nitric oxide for ≥48 h post-operatively. Right heart failure occurred in 211 patients (32%). When compared with non-RHF patients, pre-operatively they had higher creatinine, bilirubin, right atrial pressure, and lower INTERMACS class (P Conclusion In an external cohort, the EUROMACS-RHF had limited discrimination predicting RHF. The clinical utility of this score remains to be determined.

Introduction: The utilization of beta blockers (BB) post LVAD implantation is controversial, especially in the setting of right ventricular failure. There is limited evidence-based data regarding the survival benefits of BB post LVAD implantation Hypothesis: We hypothesized that BB use would not be associated with increased mortality Methods: We performed a dual-center retrospective study of 487 patients from Ohio State University & Montefiore Medical Center who received a continuous-flow durable LVAD bet. Jan 2006 through Dec 2016. A survival analysis was done to determine if patients had increased 1 year mortality depending on whether they received BB within 30 days post LVAD, after 30 days & up to 1 year post LVAD, or did not receive BB. Multivariate analysis of predictors of post LVAD mortality was conducted. Results: Overall the baseline characteristics bet. the 3 groups were similar (Table 1). BB utilization within 30 days post LVAD was associated with a drastic decrease in 1 year mortality (p Conclusions: The early use of BB significantly improves 1 year survival post LVAD. Notably these results are from Midwest and East Coast Medical Centers to improve generalizability.

Purpose Prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implant is a crucial step to improve outcomes. The EUROMACS Right-Sided Heart Failure (EUROMACS-RHF) risk score is one of the most recent derived scores for RHF prediction after LVAD but it lacks external validation. The aim of our study was to validate the EUROMACS-RHF risk score. Methods From 01/2007 to 12/2017, 878 continuous-flow LVADs were implanted at three tertiary care centers. We calculated the EUROMACS-RHF score in 662 patients with complete data. We evaluated the predictive performance of the score for early RHF defined as need for short- or long-term right-sided circulatory support, continuous inotropic support for ≥14 days or nitric oxide ventilation for ≥48 hours post-operatively. Results RHF occurred in 211 patients (32%). RHF patients had higher creatinine, bilirubin and right atrial pressure, more echocardiographic RV dysfunction and were more critically ill reflected in lower INTERMACS class (p Conclusion In an external validation, the EUROMACS-RHF had similar discrimination predicting RHF compared to the original derivation cohort, which was better than other published scores. The clinical utility of these scores in the decision to implant LVAD in prospective studies remains to be determined.

Background The vasoactive inotrope score (VIS) has been used as a model to predict mortality and adverse events following left ventricular assist device (LVAD) implantation. We attempt to validate the previously reported association between elevated VIS and increased long-term mortality and assess if elevated VIS and other hemodynamic parameters increase the odds of right ventricular failure (RVF) within 30 days of LVAD implantation. Hypothesis Increased VIS following LVAD implantation will increase mortality and odds of developing RVF. Methods A single-center retrospective chart review was conducted for 235 patients with LVAD implantation and complete post-operative management from 2006-2016. The VIS was calculated as 100 x epinephrine + 100 x norepinephrine + 10 x milrinone + dopamine + dobutamine (μg/kg/min) + 1000 x vasopressin (U/kg/min) and was collected at 6, 24, and 48-hour intervals post-implantation. Patients were stratified by a maximum VIS score of 20 and compared via baseline demographics and comorbidities. Results The average maximum VIS for all patients was 15.38 (± 8.77). Those with a VIS ≥20 had a greater proportion of males (p = 0.046) and a history of obstructive sleep apnea (p = 0.002), MI (p = 0.005), CABG (p = 0.001), PCI (p = 0.007), and ICD placement (p = 0.003). (Table 1). Survival analysis found that VIS ≥ 20 was associated with increased 1-year mortality (HR 2.08, 95% CI [1.20- 3.31], p = 0.009) (Figure 1). In our multivariable logistic regression model a VIS ≥ 20 (OR 2.79, 95% CI [1.34- 5.79], p = 0.006) and a CVP/ PCWP >0.6 (OR 2.26, 95% CI [1.08- 4.73], p = 0.030) significantly increased the odds of early RVF. Conclusion Elevated VIS score in the first 48 hours following LVAD implantation is associated with an increased risk of mortality. Elevated VIS and CVP/PCWP >0.6 also increase the odds of early RVF. Further research with larger cohorts is needed to validate these findings as they could have significant implications on perioperative LVAD management.

Background Venous congestion in heart failure (HF) may lead to worsening renal failure (WRF). We hypothesised that WRF in patients hospitalised for left ventricular assist device (LVAD) implantation is associated with increased 1-year mortality. There is limited data regarding WRF in HF patients with mechanical support. The objective of this paper is to determine whether WRF in HF patients hospitalised for LVAD implantation is associated with increased 1-year mortality and to identify risk factors for WRF. Methods We performed a single centre retrospective chart analysis of 162 patients who received an LVAD between August 2006 and December 2014 with pre-LVAD right heart catheterisation data. We stratified patients to those who demonstrated WRF and the use of haemodialysis (HD) or ultrafiltration (UF). Results Patients with a higher central venous pressure (CVP) >16 mmHg (17–24 mmHg range) developed WRF (29.7% vs. 14.1%, p=0.019). A CVP ≥16 and glomerular filtration rate (GFR) 16 increased the odds of requiring HD/UF. Conclusions Worsening renal failure is associated with a higher CVP at the time of LVAD implantation and increases the risk of 1-year mortality and the odds of requiring HD/UF. Careful evaluation of renal function and comorbid conditions during LVAD implantation is critical to reduce mortality and for risk stratification.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Background βII spectrin is an actin associated protein which regulates the localization of cytoskeletal and plasma membrane protein complexes necessary for normal cellular function. In cardiac myocytes βII spectrin recruits ankyrin-B to the cardiac dyad and modulates the functions of Na+/Ca2+ exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Disruption of the βII spectrin/ankyrin-B complex due to genetic mutation results in the onset of fatal arrhythmias. This was associated to the dysregulation of Ca2+ channels via ryanodine receptor 2 which forms the cardiac dyad. We hypothesize that loss of spectrin leads to acceleration of heart failure (HF), and plays a critical role in the SMAD pathway in the heart, and spectrin based arrhythmias are caused by abnormalities with the cardiac dyad. Methods Transgenic βII conditional knockout (cKO) mice were regenerated with a cleaner genetic profile (C57BL/6J) via Cre/LoxP system. Cardiac function of flox and cKO confirmed mice is assessed every 4 weeks via transthoracic echocardiogram (TTE) and electrocardiogram. We used the following antibodies: βII-spectrin (lab created), Ankryin B (lab created), βI (Novos), Nav (Abcam), Cav1.2 (Abcam), RyR receptor 2 (Abcam), Girk1 (alomone), Girk4 (alomone). A 2-tailed Student's t-test was performed on all data obtained from immunoblots. A p value of Results βII spectrin cKO mice display HF phenotypes as early as 4 weeks, verified by TTE. The observed ejection fraction is notably lower in the βII spectrin cKO mice compared to control (Flox) mice (LVEF 46.2% vs 57.8%, p=0.046). Expression of ankyrin-B was lower in the conditional knockout mice cardio myocytes relative to flox control (55.6 % vs 76.5%, n=3, p=0.38). Consistent with our previous work, expression of Ryanodine receptor 2 is significantly decreased in cKO relative to flox control (0.78 % vs 2.02, n=3, p=0.036). Conclusions The regeneration of cardiac specific βII-spectrin knockout mice model using the genetically homogenous C57BL/6J mice has been successful and confirmed to have decreased βII spectrin expression. Of note, these cKO mice do not require an external stressor for the development of heart failure phenotypes and exhibit this phenotype quite early on. Future studies we will explore other spectrin based regulatory pathways (SMADs) and assess the role of spectrins in organizing the cardiac dyad.

Spectrins are large, flexible proteins comprised of α-β dimers that are connected head-to-head to form the canonical heterotetrameric spectrin structure. Spectrins were initially believed to be exclusively found in human erythrocytic membrane and are highly conserved among different species. βII spectrin, the most common isoform of non-erythrocytic spectrin, is found in all nucleated cells and forms larger macromolecular complexes with ankyrins and actins. Not only is βII spectrin a central cytoskeletal scaffolding protein involved in preserving cell structure but it has also emerged as a critical protein required for distinct physiologic functions such as posttranslational localization of crucial membrane proteins and signal transduction. In the heart, βII spectrin plays a vital role in maintaining normal cardiac membrane excitability and proper cardiac development during embryogenesis. Mutations in βII spectrin genes have been strongly linked with the development of serious cardiac disorders such as congenital arrhythmias, heart failure, and possibly sudden cardiac death. This review focuses on our current knowledge of the role βII spectrin plays in the cardiovascular system in health and disease and the potential future clinical implications.

Ibrutinib is a new Bruton’s tyrosine kinase inhibitor associated with improvements in the outcomes of various B-cell hematologic malignancies and is now standard lifelong therapy in those without intolerance or disease progression [(1)][1]. However, there is a >4-fold increased risk of incident

Background Based on current literature, the impact of atrial fibrillation (AF) on patients undergoing left ventricular assist device (LVAD) placement is unclear. Therefore, we sought to investigate the effect of AF on mortality, as well as right ventricle (RV) failure and stroke. Hypothesis AF will increase mortality and stroke risk after LVAD placement. Methods 296 patients who received a HeartMate II or HeartWare LVAD between 6/29/2006 and 12/29/2016 and care at The Ohio State University Medical Center were included in this study. Patients were stratified based on presence of AF before and after LVAD placement and compared via t-test based on demographics, major comorbidities and other post-LVAD complications. Additionally, a survival analysis was performed to assess for mortality associated with AF. Results Comparing patients who developed AF after LVAD placement and those who did not, there were no significant differences in baseline demographics, including age, sex or BMI, regardless of prior AF history. Survival analysis found that a history of AF prior to LVAD placement increased the hazard of mortality nearly 2-fold (HR 1.9, 95% CI [1.2-3.1], p=0.006) (Figure 1). However, new AF following LVAD placement did not demonstrate a significant difference in survival at one year (p=0.41) (Figure 2). In addition, patients with new AF after LVAD placement did not demonstrate a significant difference in the incidence of RV failure (p=0.27) or ischemic stroke (p=1) compared to those who did not. Similarly, there was no significant difference in incidence of RV failure (p=1) and ischemic stroke (p=0.34) after LVAD placement in patients with pre-existing AF. Conclusions Our study found that a history of AF is associated with increased mortality at one year following LVAD placement. However, onset of AF after LVAD placement was not associated with increased one-year mortality, and was not associated with increased RV failure or stroke risk. While these findings could impact management and risk stratification of LVAD patients, further research is required for validation in larger cohorts.

Introduction The pulmonary artery pulsatility index (PAPi) is an emerging hemodynamic marker correlated with severe post-LVAD RVF in single-center cohort studies. We set out to examine if this is generalizable in a multi-institutional analysis. Hypothesis The preoperative PAPi correlates with RVF as defined by new INTERMACS criteria (INTERMACS-RVF), severe RVF, and death at 1-year. Methods We performed a dual-center retrospective study of 404 patients from Ohio and New York who received a continuous-flow durable LVAD and had a pre-operative PAPi measurement. The PAPi was defined as: [(PA systolic - PA diastolic) ÷ RA pressure]. Severe RVF was defined as meeting criteria for clinical RVF and having inotropes > 14 days after implant, inotropes re-started 14 days after implant, RVAD placement during implant admission, and death from RVF during implant admission. A multivariate analysis of predictors of post-LVAD severe RVF was conducted. A survival analysis was performed to examine pre-operative PAPi as a predictor of 1-year mortality. Results In our cohort of 404 patients, 84 (21%) had severe RVF. Multivariable logistic regression for severe RVF (controlling for age, INTERMACS level, creatinine, and gender) showed that creatinine > 1.5 (OR 2.24, p=0.002, 95% CI [1.43-4.42]) and total bilirubin > 2.5 (OR 2.87, p=0.004, 95% CI [1.39-5.93]) significantly increased the odds of severe RVF, and a PAPi Figure 1 ) and INTERMACS-RVF (c-statistic=0.63) were similar. With respect to survival, the final multivariable model (controlling for age, gender, and ethnicity) showed a PAPi Conclusion PAPi

Introduction Early RVF after LVAD implant has been studied using varying definitions. We set out to compare the new INTERMACS post-LVAD RVF criteria and traditional severe RVF definitions in our multi-institutional cohort. Hypothesis The INTERMACS RVF and severe RVF definition will both show increased mortality at 1-year. Methods We performed a dual-center retrospective study of 471 patients who received a continuous-flow durable LVAD and data available to assess RVF severity. The new INTERMACS RVF definition stratifies RVF into mild, moderate, severe, and acute-severe. Severe RVF was defined as meeting criteria for clinical RVF and having inotropes > 14 days after implant, inotropes re-started after 14 days of implant, RVAD placement during implant admission, and death from RVF during implant admission. A survival analysis of the INTERMACS RVF and severe RVF definitions was performed. A multivariate analysis using clinical markers associated with post-LVAD mortality was then completed to assess the independent effect of the RVF definitions. Results Of the 471 patients, 100 (21%) had severe RVF. Stratified by INTERMACS-RVF, 279 (59%) had no RVF, 37 (8%) had mild RVF, 53 (11%) had moderate RVF, 57 (12%) had severe RVF, and 47 (17%) had acute-severe RVF. Our multivariate model (adjusted for age, gender, and ethnicity) for predictors of 1-year mortality showed that PAPi Conclusion Our multi-institutional cohort shows that severe RVF and INTERMACS RVF severe and acute-severe predict mortality at 1-year, and notably shows that mild and moderate INTERMACS RVF do not predict mortality. The new INTERMACS classification of RVF provides more granularity in stratifying RVF and may be more clinically applicable.

Ibrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor associated with dramatic improvements in outcomes of various B-cell hematologic malignancies and is now standard therapy. However, Ibrutinib is associated with a >4-fold increased risk of incident atrial arrhythmias. Recently, an alarming

Background Left ventricular assist devices (LVADs) have revolutionized and improved the care of the sickest heart failure (HF) patients, and it is imperative that they receive appropriate ventricular unloading. Assessing this critical parameter with current methodologies (labs, imaging) is usually suboptimal in this patient population. Hence it is imperative to elucidate the molecular underpinnings involved in ventricular unloading. We have previously identified the cytoskeletal protein βII spectrin as an essential nodal protein involved in post-translational targeting and βII spectrin protein levels are significantly altered in multiple forms of human and animal HF. We therefore hypothesized that the βII spectrin pathway would play a critical role in LVAD remodeling. Methods Human heart failure samples were obtained from patients undergoing heart transplantation. Wild type (WT) mice and our previously validated βII spectrin conditional knock out (βII cKO) mice were used for animal experiments. Transaortic constriction (TAC) was performed on WT mice. Protein expression was assessed via immunoblots, and protein interactions were assessed with co-immunoprecipitation. Transcriptome analysis was performed using isolated whole hearts from control adult WT mice (n = 3) compared to βII cKO spectrin mice (n = 3). Results We report that hearts from mice selectively lacking βII spectrin expression in cardiomyocytes displayed altered transcriptional regulation of cardiac ankyrin repeat protein (CARP). Notably, CARP protein expression is increased after TAC. Additionally, our findings illustrate that prior to LVAD support, CARP levels are elevated in HF patients compared to normal healthy controls. Further, for the first time in a LVAD population, we show that elevated CARP levels in HF patients return to normal following LVAD support. Conclusion Our findings illustrate that CARP is a dynamic molecule that responds to reduced afterload and stress, and has the potential to serve as a prognostic biomarker to assess for an adequate response to LVAD therapy.