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PROGNOSTIC VALUE OF NON-INDUCIBILITY ON OUTCOMES OF VENTRICULAR TACHYCARDIA ABLATION: A VENTRICULAR TACHYCARDIA ABLATION VS. ENHANCED DRUG THERAPY IN STRUCTURAL HEART DISEASE (VANISH) SUBSTUDY
Abstracts
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greater QALYs (1.48 vs 1.26, difference: 0.22 (95% CI -0.16 to 0.62)) and lower costs ($67,307 vs $68,959, difference: -$1,652 (95% CI -$33,230 to $22,268)). For patients not on amiodarone at baseline, ablation resulted in similar QALYs (1.90 vs 1.90, difference: -0.00 (95% CI -0.62 to 0.60)) and higher costs ($59,883 vs $45,874, difference: $14 009 (95% CI -$9,948 to $43,412)). CONCLUSION: For the total trial population, ablation was cost effective compared with escalation of drug therapy. This result was manifest for the subgroup of patients who were receiving amiodarone at baseline but not for those not receiving amiodarone. Canadian Institutes of Health Research (CIHR)
029 THE VANISH STUDY IN CONTEXT - A NETWORK META-ANALYSIS OF TREATMENTS TO PREVENT VENTRICULAR TACHYCARDIA IN PATIENTS WITH ISCHEMIC CARDIOMYOPATHY P Leong-Sit, S Kelly, J Peterson, A Tang, G Wells, J Sapp London, Ontario BACKGROUND:
Recurrent ventricular tachycardia (VT) is associated with high morbidity in patients with ischemic heart disease. Treatment strategies include antiarrhythmic drugs (AADs) and catheter ablation (CA). A 2016 meta-analysis found significant reduction in the risk of VT with CA, but direct comparisons of AADs to CA were not available. OBJECTIVE: To assess the comparative effectiveness of CA, non-amiodarone AADs, amiodarone, and standard medical care in patients with ischemic cardiomyopathy and ICDs. METHODS: A recent, high-quality systematic review was updated with a systematic review of MEDLINE, Embase, Cochrane CENTRAL, the Cochrane Library and PubMed to include randomized controlled trials (RCTs) published since the date of the prior review (Oct 2015) and Sept 1, 2016. A study level network meta-analysis (NMA) was performed by using a Bayesian evidence network. Treatments were pooled into 4 treatment nodes: 1) standard medical care, 2) nonamiodarone AADs, 3) amiodarone, and 4) CA. RESULTS: Fourteen RCTs from the prior review (Santangeli) met inclusion criteria. The search update identified 105 further titles/abstracts of which one RCT (Sapp et al. VANISH 2016) met inclusion criteria. Treatment networks and risk ratio estimates for appropriate shocks are reported in Figure 1. Comparison of CA to non-amiodarone AADs became statistically significant with the addition of the VANISH study to the NMA. CONCLUSION: With the addition of the VANISH study and using Bayesian NMA, amiodarone was found to be superior to control for reduction of appropriate ICD shocks and CA was superior to non-amiodarone AADs, a comparison that has not been directly studied in a RCT.
030 PROGNOSTIC VALUE OF NON-INDUCIBILITY ON OUTCOMES OF VENTRICULAR TACHYCARDIA ABLATION: A VENTRICULAR TACHYCARDIA ABLATION VS. ENHANCED DRUG THERAPY IN STRUCTURAL HEART DISEASE (VANISH) SUBSTUDY V Essebag, J Joza, S Doucette, J Raymond, J Sapp, L Rivard Montréal, Québec BACKGROUND:
The traditional endpoint of VT ablation is non-inducibility of VT by programmed electrical stimulation (PES); however, the definition of inducibility remains variable and its prognostic value has been muddied by alterations in peri-ablation antiarrhythmic drug (AAD) therapy or nonstandardized ICD programming in prior observational studies. The VANISH trial randomized ischemic VT patients to VT ablation (with endpoint of non-inducibility of VT >¼300ms after ablation) vs. AAD escalation. We proposed to determine the predictive value of non-inducibility on long-term clinical outcomes, adjusting for other clinical and procedural characteristics. METHODS AND RESULTS: The relationship of inducibility on the primary composite endpoint of death, VT storm > 30 days, or appropriate ICD shock > 30 days, was assessed using a time-to-event analysis. Survival rates were summarized between inducibility groups using Kaplan-Meier product-limit estimates. Results were analyzed according to presence of inducible VT (defined as inducibility post ablation of any VT e including those < 300ms) vs. non-inducible or inducibility not performed. Polymorphic VT or VF were not considered to be inducible. 129 patients from the ablation arm were included in the primary analysis of which 51 were non-inducible post ablation as compared to 78 who were inducible or where inducibility was not performed. At baseline, there was no significant characteristic or procedural differences between the noninducible vs inducible/not performed cohorts except for an increased number of ICD shocks within 3 months observed in the latter group. There were no baseline characteristics that were shown to be significantly predictive of inducibility. In multivariate analysis, inducibility was associated with an increase in the primary endpoint of death, appropriate shock or
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VT storm after 30 days (HR 1.87, 95% CI 1.12, 3.11, P ¼ 0.017). CONCLUSION: Inducibility of any VT post ablation was associated with an increased risk of the composite outcome in the VANISH Trial. No patient or procedural characteristics were shown to be significantly predictive of inducibility. A randomized trial targeting faster induced VTs may determine whether a more aggressive strategy can improve outcomes.
Canadian Journal of Cardiology Volume 33 2017
S Der Sarkissian, J Sauvé, E Larose, H Aceros, S Mansour, L Stevens, I Prieto, F Basile, D Roy, N Noiseux
pre-treatments from our drug discovery platform that could activate cellular phenotypes replicating those of patients responding to cell therapy. METHODS: In this exploratory study, expression of 20,800 human genes (Ion AmpliSeq) are analyzed in high-throughput format using CD133+ stem cells from 13 patients classified as responders (5% LVEF and/or 10% left ventricular volumes) vs non-responders according to cardiac fMRI comparing pre- and 6-month post-treatment changes. Differential expression and pathway analysis are performed using computational tools including DESeq2, GAGE (Generally Applicable GeneSet Enrichment for Pathways Analysis), PathView and R. RESULTS: Pathway analyses show significant association in responders with genes related to cytokine production, activity and receptor interaction, cell adhesion molecules, regulation of kinase cascades (p < 0.05). Several other comparisons were performed to characterize gene expression vs patient demographics. The general pattern of activity was replicated in human mesenchymal stem cells (hMSC) by short ex vivo pharmacological conditioning with Celastrol, an HSP90 targeting compound. Celastrol activates kinases PI3K/Akt and ERK1/2 within 5min, upregulates HSP70 and HO-1 mRNAs (>30-fold) as well as VEGF in cells maintained in normoxic (2.7-fold) or hypoxic condition (1.3-fold, p < 0.05). Celastrol improves hMSC viability during hypoxic or oxidative challenges. Proteomic analysis of culture conditioned-media shows upregulation (>2-fold) of over 100 proteins, including HSPs, growth factors, antioxidants, cytokines indicating improved paracrine potential. CONCLUSION: IMPACT-CABG responder’s stem cells express gene sets associated with paracrine potential, cell engraftment and survival that can be mimicked by an ex vivo pharmacological pre-conditioning to improve stem cell therapeutic potential. Information gathered will be used in IMPACTCABG II trial involving a first of its kind precision pharmacooptimization strategy (USPTO62/350,258 patent pending) to harness the full potential of cellular cardiomyoplasty using CD133+ cells.
Montréal, Québec
Heart and Stroke Foundation of Canada, TheCell
Canadian Cardiovascular Society (CCS) Moderated Presentations THE “OMICS” OF HEART FAILURE: GENOMIC & PROTEOMIC SCIENCE Saturday, October 21, 2017 031 RNA-SEQ DATA ANALYSIS IDENTIFIES STEM CELL TRANSCRIPTOMIC SIGNATURES UNDERPINNING THE THERAPEUTIC EFFECTIVENESS OF PATIENT CELLS IN THE IMPACT-CABG TRIAL
BACKGROUND:
Therapeutic benefits of cell therapy remain mitigated due to factors including cell phenotypes and their poor survival and function in pathologic heart. Whereas first generation of advances focused on cell selection, delivery and a broad understanding of mechanisms involved in therapy success, the next advances will come from decoding complex biological pathways underpinning regenerative potential of cells from different patients. IMPACT-CABG trial represents the first North American phase II multicenter randomized study of intra-myocardial delivery of autologous CD133+ cells in chronic cardiomyopathy patients undergoing CABG. With banked stem cells from this trial, we have the opportunity to correlate the patient’s clinical outcome with cellular gene expression profiles. Our goal is to identify genomic signatures responsible for therapeutic effectiveness and identify
032 OVER-EXPRESSION OF MYBL2 REJUVENATES EXPLANT DERIVED CARDIAC STEM CELLS FROM AGED DONORS WITH ISCHEMIC CARDIOMYOPATHY G Rafatian, E Suuronen, D Davis Ottawa, Ontario BACKGROUND:
Aged explant derived cardiac stem cells (EDCs) sourced from donors suffering from ischemic-cardiomyopathy (ICM) demonstrate increased production of the pro-inflammatory cytokine IL-6, shorter telomere lengths, higher levels of oxidative stress and impaired therapeutic repair of ischemic myocardium compared to EDCs sourced from
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greater QALYs (1.48 vs 1.26, difference: 0.22 (95% CI -0.16 to 0.62)) and lower costs ($67,307 vs $68,959, difference: -$1,652 (95% CI -$33,230 to $22,268)). For patients not on amiodarone at baseline, ablation resulted in similar QALYs (1.90 vs 1.90, difference: -0.00 (95% CI -0.62 to 0.60)) and higher costs ($59,883 vs $45,874, difference: $14 009 (95% CI -$9,948 to $43,412)). CONCLUSION: For the total trial population, ablation was cost effective compared with escalation of drug therapy. This result was manifest for the subgroup of patients who were receiving amiodarone at baseline but not for those not receiving amiodarone. Canadian Institutes of Health Research (CIHR)
029 THE VANISH STUDY IN CONTEXT - A NETWORK META-ANALYSIS OF TREATMENTS TO PREVENT VENTRICULAR TACHYCARDIA IN PATIENTS WITH ISCHEMIC CARDIOMYOPATHY P Leong-Sit, S Kelly, J Peterson, A Tang, G Wells, J Sapp London, Ontario BACKGROUND:
Recurrent ventricular tachycardia (VT) is associated with high morbidity in patients with ischemic heart disease. Treatment strategies include antiarrhythmic drugs (AADs) and catheter ablation (CA). A 2016 meta-analysis found significant reduction in the risk of VT with CA, but direct comparisons of AADs to CA were not available. OBJECTIVE: To assess the comparative effectiveness of CA, non-amiodarone AADs, amiodarone, and standard medical care in patients with ischemic cardiomyopathy and ICDs. METHODS: A recent, high-quality systematic review was updated with a systematic review of MEDLINE, Embase, Cochrane CENTRAL, the Cochrane Library and PubMed to include randomized controlled trials (RCTs) published since the date of the prior review (Oct 2015) and Sept 1, 2016. A study level network meta-analysis (NMA) was performed by using a Bayesian evidence network. Treatments were pooled into 4 treatment nodes: 1) standard medical care, 2) nonamiodarone AADs, 3) amiodarone, and 4) CA. RESULTS: Fourteen RCTs from the prior review (Santangeli) met inclusion criteria. The search update identified 105 further titles/abstracts of which one RCT (Sapp et al. VANISH 2016) met inclusion criteria. Treatment networks and risk ratio estimates for appropriate shocks are reported in Figure 1. Comparison of CA to non-amiodarone AADs became statistically significant with the addition of the VANISH study to the NMA. CONCLUSION: With the addition of the VANISH study and using Bayesian NMA, amiodarone was found to be superior to control for reduction of appropriate ICD shocks and CA was superior to non-amiodarone AADs, a comparison that has not been directly studied in a RCT.
030 PROGNOSTIC VALUE OF NON-INDUCIBILITY ON OUTCOMES OF VENTRICULAR TACHYCARDIA ABLATION: A VENTRICULAR TACHYCARDIA ABLATION VS. ENHANCED DRUG THERAPY IN STRUCTURAL HEART DISEASE (VANISH) SUBSTUDY V Essebag, J Joza, S Doucette, J Raymond, J Sapp, L Rivard Montréal, Québec BACKGROUND:
The traditional endpoint of VT ablation is non-inducibility of VT by programmed electrical stimulation (PES); however, the definition of inducibility remains variable and its prognostic value has been muddied by alterations in peri-ablation antiarrhythmic drug (AAD) therapy or nonstandardized ICD programming in prior observational studies. The VANISH trial randomized ischemic VT patients to VT ablation (with endpoint of non-inducibility of VT >¼300ms after ablation) vs. AAD escalation. We proposed to determine the predictive value of non-inducibility on long-term clinical outcomes, adjusting for other clinical and procedural characteristics. METHODS AND RESULTS: The relationship of inducibility on the primary composite endpoint of death, VT storm > 30 days, or appropriate ICD shock > 30 days, was assessed using a time-to-event analysis. Survival rates were summarized between inducibility groups using Kaplan-Meier product-limit estimates. Results were analyzed according to presence of inducible VT (defined as inducibility post ablation of any VT e including those < 300ms) vs. non-inducible or inducibility not performed. Polymorphic VT or VF were not considered to be inducible. 129 patients from the ablation arm were included in the primary analysis of which 51 were non-inducible post ablation as compared to 78 who were inducible or where inducibility was not performed. At baseline, there was no significant characteristic or procedural differences between the noninducible vs inducible/not performed cohorts except for an increased number of ICD shocks within 3 months observed in the latter group. There were no baseline characteristics that were shown to be significantly predictive of inducibility. In multivariate analysis, inducibility was associated with an increase in the primary endpoint of death, appropriate shock or
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VT storm after 30 days (HR 1.87, 95% CI 1.12, 3.11, P ¼ 0.017). CONCLUSION: Inducibility of any VT post ablation was associated with an increased risk of the composite outcome in the VANISH Trial. No patient or procedural characteristics were shown to be significantly predictive of inducibility. A randomized trial targeting faster induced VTs may determine whether a more aggressive strategy can improve outcomes.
Canadian Journal of Cardiology Volume 33 2017
S Der Sarkissian, J Sauvé, E Larose, H Aceros, S Mansour, L Stevens, I Prieto, F Basile, D Roy, N Noiseux
pre-treatments from our drug discovery platform that could activate cellular phenotypes replicating those of patients responding to cell therapy. METHODS: In this exploratory study, expression of 20,800 human genes (Ion AmpliSeq) are analyzed in high-throughput format using CD133+ stem cells from 13 patients classified as responders (5% LVEF and/or 10% left ventricular volumes) vs non-responders according to cardiac fMRI comparing pre- and 6-month post-treatment changes. Differential expression and pathway analysis are performed using computational tools including DESeq2, GAGE (Generally Applicable GeneSet Enrichment for Pathways Analysis), PathView and R. RESULTS: Pathway analyses show significant association in responders with genes related to cytokine production, activity and receptor interaction, cell adhesion molecules, regulation of kinase cascades (p < 0.05). Several other comparisons were performed to characterize gene expression vs patient demographics. The general pattern of activity was replicated in human mesenchymal stem cells (hMSC) by short ex vivo pharmacological conditioning with Celastrol, an HSP90 targeting compound. Celastrol activates kinases PI3K/Akt and ERK1/2 within 5min, upregulates HSP70 and HO-1 mRNAs (>30-fold) as well as VEGF in cells maintained in normoxic (2.7-fold) or hypoxic condition (1.3-fold, p < 0.05). Celastrol improves hMSC viability during hypoxic or oxidative challenges. Proteomic analysis of culture conditioned-media shows upregulation (>2-fold) of over 100 proteins, including HSPs, growth factors, antioxidants, cytokines indicating improved paracrine potential. CONCLUSION: IMPACT-CABG responder’s stem cells express gene sets associated with paracrine potential, cell engraftment and survival that can be mimicked by an ex vivo pharmacological pre-conditioning to improve stem cell therapeutic potential. Information gathered will be used in IMPACTCABG II trial involving a first of its kind precision pharmacooptimization strategy (USPTO62/350,258 patent pending) to harness the full potential of cellular cardiomyoplasty using CD133+ cells.
Montréal, Québec
Heart and Stroke Foundation of Canada, TheCell
Canadian Cardiovascular Society (CCS) Moderated Presentations THE “OMICS” OF HEART FAILURE: GENOMIC & PROTEOMIC SCIENCE Saturday, October 21, 2017 031 RNA-SEQ DATA ANALYSIS IDENTIFIES STEM CELL TRANSCRIPTOMIC SIGNATURES UNDERPINNING THE THERAPEUTIC EFFECTIVENESS OF PATIENT CELLS IN THE IMPACT-CABG TRIAL
BACKGROUND:
Therapeutic benefits of cell therapy remain mitigated due to factors including cell phenotypes and their poor survival and function in pathologic heart. Whereas first generation of advances focused on cell selection, delivery and a broad understanding of mechanisms involved in therapy success, the next advances will come from decoding complex biological pathways underpinning regenerative potential of cells from different patients. IMPACT-CABG trial represents the first North American phase II multicenter randomized study of intra-myocardial delivery of autologous CD133+ cells in chronic cardiomyopathy patients undergoing CABG. With banked stem cells from this trial, we have the opportunity to correlate the patient’s clinical outcome with cellular gene expression profiles. Our goal is to identify genomic signatures responsible for therapeutic effectiveness and identify
032 OVER-EXPRESSION OF MYBL2 REJUVENATES EXPLANT DERIVED CARDIAC STEM CELLS FROM AGED DONORS WITH ISCHEMIC CARDIOMYOPATHY G Rafatian, E Suuronen, D Davis Ottawa, Ontario BACKGROUND:
Aged explant derived cardiac stem cells (EDCs) sourced from donors suffering from ischemic-cardiomyopathy (ICM) demonstrate increased production of the pro-inflammatory cytokine IL-6, shorter telomere lengths, higher levels of oxidative stress and impaired therapeutic repair of ischemic myocardium compared to EDCs sourced from