Myocardial recovery with left ventricular assist device (LVAD) therapy is highly variable and difficult to predict. Next generation ribonucleic acid (RNA) sequencing is an innovative, rapid, and quantitative approach to gene expression profiling in small amounts of tissue. Our primary goal was to identify baseline transcriptional profiles in non-ischemic cardiomyopathies that predict myocardial recovery in response to LVAD therapy. We also sought to verify transcriptional differences between failing and non-failing human hearts.

The efficacy of optimal medical therapy (OMT) with systolic heart failure is well established. Recent data has demonstrated myocardial recovery in patients with end-stage cardiomyopathy via the use of mechanical as well as pharmacological support. Despite having evidence that a similar regimen (beta-blockade, ACEi/ARBs, diuretics and aldosterone antagonist) may benefit myocardial recovery, their use in this population varies. This study evaluates the proportion of patients with LVADs in our institution that received what is considered OMT as it pertains to systolic heart failure. We performed a retrospective analysis of 146 patients following implantation of the HeartMate II Left Ventricular Assist Device between 2009 and 2014 at our institution. Their medication regimen was evaluated at 3 months post implant. Patients included were over the age of 18 and we excluded patients who failed to have their device for 3 months following implant due to device explant, transplant or death as well as those with missing information. Bridge to transplant as well as destination LVAD patients were included. We then evaluated the percentage of patients on beta-blockers, ACEi or ARBs, aldosterone antagonists and diuretics. We also compared LVEF at 3 months post implant. Of the 146 patients evaluated, 110 patients met inclusion criteria. Of those 110 patients, 49.1% were DT LVAD patients and 78.2% were male. With regard to medical therapy, 20.9% were on Beta-Blockade, 57.2% ACEi, 10% ARB, 50% aldosterone antagonists and 70.9% on diuretic therapy. In our patient population only 9 (8%) were on what is considered OMT (Beta-blocker, ACEi/ARB and Aldosterone antagonists). The average change in left ventricular ejection fraction over the 3 month period was 6.97%. The change in LVEF for patients on OMT compared to those not on OMT was 16.88% versus 5.29%. In this single center, retrospective analysis, 92% of patients were not maintained on OMT with regard to systolic heart failure. Furthermore, there was a more significant increase in LVEF in patients on OMT compared to those not receiving OMT.

Left ventricular assist devices are routinely placed for end stage non-ischemic cardiomyopathy patients. Myocardial recovery on therapy is highly variable. Next Generation Sequencing gives us the ability to test for a wide range of damaging mutations. Our objective was to determine the association

Abstract Background: Next generation sequencing technology, coupled with population genetic databases, have made broad genetic evaluation relatively inexpensive and widely available. Our objective was to assess the prevalence of potentially damaging cancer and cardiac gene variants in advanced non-ischemic cardiomyopathy patients. Methods: Explanted human heart tissue procured at LVAD placement was obtained from the University of Nebraska Medical Center Heart Tissue Bank. Genomic DNA was isolated from tissues and amplified by PCR using targeted ampliseq primer pools from an inherited disease panel. Individual libraries were amplified by emulsion PCR on Ion Sphere particles and sequencing was performed on a PGM sequencer (Ion torrent) using the Ion 316 chip. The Ion Torrent browser suite was used to map the reads and call the variants. The identified single nucleotide polymorphisms, insertions, and deletions were then annotated and characterized with ANNOVAR. Non-synonymous mutations with a population frequency of less than or equal to 1% were identified and analyzed utilizing an open source integrative genomics viewer. Amino acid substitution effects on protein function were determined by a bioinformatics algorithm. Myocardial recovery was defined as an improvement in EF to greater than 45% at three months post implant. Results: Our sample population included 12 males and 2 females with an average age of 49 and an average EF at presentation of 17%. Damaging cardiac gene variants were present in 11/14 patients. Only 1 of the 11 patients with damaging cardiac gene variants improved their ejection fraction to greater than 45% post LVAD. Two of the 2 patients without mutations improved their ejection fraction to greater than 45%, p-value=.04. Nine of the 14 patients in this population had damaging oncogene mutations. Conclusions: Damaging variants in cancer and cardiac genes are common in end-stage non-ischemic cardiomyopathy patients undergoing LVAD placement. Genetic variation likely contributes to disease progression and cancer risk.

Explanted human heart tissue procured at LVAD placement was obtained from the University of Nebraska Medical Center Heart Tissue Bank. Genomic DNA was isolated from tissues and amplified by PCR using targeted ampliseq primer pools from an inherited disease panel. Individual libraries were amplified by emulsion PCR on Ion Sphere particles and sequencing was performed on a PGM sequencer (Ion torrent) using the Ion 316 chip. The Ion Torrent browser suite was used to map the reads and call the variants. The identified single nucleotide polymorphisms, insertions, and deletions were then annotated and characterized with ANNOVAR. Non-synonymous mutations with a population frequency of less than or equal to 1% were identified and analyzed utilizing an open source integrative genomics viewer. Amino acid substitution effects on protein function were determined by a bioinformatics algorithm. Myocardial recovery was defined as an improvement in EF to greater than 45% at three months post implant. Citation: Lowes,B. et al. (2015). Damaging Cardiac and Cancer Genetic Variants in the LVAD Population, The VAD Journal, 1. doi: http://dx.doi.org/10.13023/VAD.2 015.19

Heart failure patients are at increased risk for developing newly diagnosed cancer. The epidemiology of this increased risk is poorly understood. Treatment strategies, chronic inflammation and shared genetic triggers are potential mechanisms. Our objective was to assess the prevalence of damaging oncogene mutations in non-ischemic cardiomyopathy patients undergoing LVAD placement. Explanted human heart tissue procured at the time of LVAD placement was obtained from the heart tissue bank at the University of Nebraska. Cancer associated genes were sequenced utilizing an inherited disease panel (Ion Torrent). Genomic DNA was isolated from tissues using the All DNA/RNA mini kit (Qiagen). 10 ng of DNA was amplified by PCR using inherited diseases panel primer pools. The amplicons were then ligated to adapters and additional library amplification was done by emulsion PCR on Ion Sphere particles (ISPs). Sequencing was performed on PGM sequencer (Ion torrent) using the Ion 316 chip. The Ion Torrent browser suite was used to map the reads and call the variants. The identified single nucleotide polymorphisms, insertions, and deletions were then annotated and characterized with ANNOVAR. Variants with a population frequency of less than or equal to 1% were identified and analyzed utilizing an open source integrative genomics viewer. Amino acid substitution effects on protein function were determined by a bioinformatics algorithm (MutationTaster program). Our sample population included 6 males and 2 females with an average age of 57 and an average EF at presentation of 18%. All of our samples contained oncogene variants. Notably, all samples had the same ATM variant. Rare oncogenes variants are highly prevalent in the advanced heart failure population. The higher frequency of cancer in heart failure populations may be attributable to a higher frequency of variant cancer genes. These results also suggest that altered DNA repair mechanisms may be essential to the progression and worsening of advanced heart failure.Tabled 1Cancer GenePrevalenceSample – MutationATM8/88 NNSD11/8NMLH11/8DFANCG1/8FMYH111/8DRET1/8N, DAPC1/8DFANCA1/8NAbbreviations: N = Polymorphism; D = Disease causing; F = Frameshift; S = Splice; NA = No prediction Open table in a new tab

Objectives:Doxorubicin is associated with a cumulative dose-dependent nonischemic cardiomyopathy. Cardiac magnetic resonance imaging (cMRI) is able to examine both structural and functional components of the myocardium. Our aim was to assess the myocardial changes in non-Hodgkin lymphoma patients undergoing doxorubicin-based chemotherapy using cMRI.Materials and Methods:cMRI examination was performed before and 3 months after chemotherapy. Experienced investigators interpreted each cMRI, and were blinded to all data. Left ventricular ejection fractions (LVEF), cardiac deformation, and delayed gadolinium enhancement (GD-DE) were quantified for each cMRI. The change between LVEF, GD-GE, and cardiac deformation parameters were compared between the 2 cMRI studies. A LVEF10% was considered clinically relevant. The findings of GD-GE or changes in myocardial strain were analyzed as independent variables.Results:All 10 patients enrolled received a cumulative dose of doxorubicin of 300 mg/m(2). A comparison of pretreatment and posttreatment cMRI demonstrated 5 (50%) patients with a 10% decrease in LVEF (median, -8.4%; range, 1% to -17%; P=0.004). Three patients had at least 1 new or progressive segment of GD-DE. The global circumferential strain was significantly lower in patients after treatment, as compared with values before treatment (P=0.018) and to normal controls (P=0.046). Patients after treatment also had significantly lower global longitudinal strain than controls (P=0.035), and longitudinal strain values that tended to decrease compared with pretreatment values (P=0.073).Discussion:Our data suggests that cMRI has the ability to assess both early structural and functional myocardial changes in association with doxorubicin-based chemotherapy.

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents. (C) 2013 The Authors. Published by Elsevier Inc.

The recent trial on dabigatran versus warfarin in Atrial Fibrillation (RELY) demonstrated dabigatran 150 mg twice daily was associated with small but statistically significant increased number of Myocardial Infarction (MI) as compared to warfarin. The purpose of this study was to investigate whether