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Weighted Gene Co-expression Network Analysis Reveals Distinct Interaction Patterns in Failing and Recovering Human Myocardium
S142
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
Conclusion: PFT for patients with pulmonary disease prior to heart transplant can be a good indicator of outcome after heart transplantation. Specifically, FEV1/FVC < 70% and DLCO < 60% may contraindicate proceeding with heart transplant in these patients.
Intubation Time (hours) Post-transplant ICU Stay (days) 1-year freedom from Pulmonary Infection 3-year Survival 3-year freedom from CAV 3-year freedom from NF-MACE 1-year freedom from Any Treated Rejection
FEV1/FVC < FEV1/FVC ³ DLCO < 60% 70% (n= 144) 70% (n= 485) (n= 211)
DLCO ³ 60% (n= 224)
60.2 ± 45.61
45.6 ± 37.6
57.4 ± 48.53
43.3 ± 37.2
8.4 ± 4.6
7.6 ± 5.0
7.9 ± 4.2
7.8 ± 5.7
74.5%
84.5%
80.0%
84.0%
75.7%2 78.5%
84.9% 84.9%
78.2%4 78.7%
86.6% 84.8%
87.5%
90.9%
89.6%
88.8%
79.9%
82.1%
84.2%
84.3%
compared to FEV1/FVC > 70% group; 2p< 0.01 compared to FEV1/FVC > 70% group; 3p< 0.05 compared to DLCO > 60% group; 4p< 0.05 compared to DLCO > 60% group
1p< 0.05
3( 75) Weighted Gene Co-expression Network Analysis Reveals Distinct Interaction Patterns in Failing and Recovering Human Myocardium V.K. Topkara . Cardiology, Columbia University, New York, NY. Purpose: Previous microarray studies in LVAD myocardial samples using standard statistical methods provided inconsistent results and failed to identify a common pathway for myocardial recovery process. We sought to investigate gene-gene interaction patterns in failing and post-LVAD samples to identify novel regulators of reverse remodeling. Methods: Gene expression dataset for human failing and postLVAD paired myocardial samples (n= 3 8) were obtained from Gene Expression Omnibus Database (series GSE974). Expression data file was log-transformed and normalized in PARTEK GS, and transferred to R for weighted gene co-expression network analysis using package WGCNA. WGCNA uses network terminology to describe co-expression patterns between genes of a network and identifies clusters of highly correlated genes (modules), which can be related to sample traits. Results: Hierarchical clustering using TOM dissimilarity measure with dynamic tree cut algorithm yielded 9 distinct HF and 7 Recovery gene modules. Recovery modules were poorly preserved in HF network suggesting distinct signaling mechanisms for the two process (Figure 1A). Module-trait relationship analysis identified a unique LVAD module which correlated with duration of support. Cellular component analysis of the “myocardial plasticity” module showed genes that were significantly mapped to extracellular region including 9 different collagen genes. Hub genes of this module included lysyl oxidase (LOX) and CD44, both of which have been implicated in the myocardial remodeling process (Figure 1B). Conclusion: Our findings suggest that alterations in extracellular matrix occur in a time-dependent fashion following LVAD support and may contribute to reverse remodeling process. Analysis of gene-gene interaction patterns rather than traditional differential gene expression analysis may provide valuable mechanistic insights into myocardial recovery.
3( 76) Myocardial Regeneration and Recovery with Extracellular Matrix and LVAD Support M.S. Slaughter ,1 G.D. Rokosh,2 R.G. Matheny,3 M.A. Sobieski,1 M. Wysoczynski,4 M. Solanki,2 G.A. Giridharan,1 K.G. Soucy,1 P.L. Linsky,1 G. Monreal,1 S.C. Koenig.1 1Surgery, University of Louisville, Louisville, KY; 2University of Louisville, Louisville, KY; 3CorMatrix, Roswell, GA; 4Institute of Molecular Cardiology, University of Louisville, Louisville, KY. Purpose: Myocardial recovery with LVAD support is uncommon and unpredictable. We tested the hypothesis that injectable extracellular matrix (ECM) with left ventricular assist device (LVAD) support promotes cell proliferation, improves cardiac function and possible myocardial recovery. Methods: LVAD, ECM, and LVAD+ECM therapies were investigated in 60-day (n= 6) and 90-day (n= 5) chronic ischemic heart failure (HF) calves (5080 kg) induced using coronary embolization (90μ m spheres). Treatment was initiated 30 days after HF induction. ECM emulsion was injected intramyocardially using a 7-needle (25 ga) pneumatic delivery tool. LVAD were implanted in an LV apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified using fluorescent labeled microspheres. At necropsy, tissues were obtained for histopathology and BrdU quantification. Results: Prior to treatment, HF calves had an LVEF of 32±7.6% and LVEDV of 203±73 mL with cardiac cachexia (reduced weight gain of 0.69±0.20 kg/ day). Healthy weight gain was restored in all groups. EF increased with
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
Conclusion: PFT for patients with pulmonary disease prior to heart transplant can be a good indicator of outcome after heart transplantation. Specifically, FEV1/FVC < 70% and DLCO < 60% may contraindicate proceeding with heart transplant in these patients.
Intubation Time (hours) Post-transplant ICU Stay (days) 1-year freedom from Pulmonary Infection 3-year Survival 3-year freedom from CAV 3-year freedom from NF-MACE 1-year freedom from Any Treated Rejection
FEV1/FVC < FEV1/FVC ³ DLCO < 60% 70% (n= 144) 70% (n= 485) (n= 211)
DLCO ³ 60% (n= 224)
60.2 ± 45.61
45.6 ± 37.6
57.4 ± 48.53
43.3 ± 37.2
8.4 ± 4.6
7.6 ± 5.0
7.9 ± 4.2
7.8 ± 5.7
74.5%
84.5%
80.0%
84.0%
75.7%2 78.5%
84.9% 84.9%
78.2%4 78.7%
86.6% 84.8%
87.5%
90.9%
89.6%
88.8%
79.9%
82.1%
84.2%
84.3%
compared to FEV1/FVC > 70% group; 2p< 0.01 compared to FEV1/FVC > 70% group; 3p< 0.05 compared to DLCO > 60% group; 4p< 0.05 compared to DLCO > 60% group
1p< 0.05
3( 75) Weighted Gene Co-expression Network Analysis Reveals Distinct Interaction Patterns in Failing and Recovering Human Myocardium V.K. Topkara . Cardiology, Columbia University, New York, NY. Purpose: Previous microarray studies in LVAD myocardial samples using standard statistical methods provided inconsistent results and failed to identify a common pathway for myocardial recovery process. We sought to investigate gene-gene interaction patterns in failing and post-LVAD samples to identify novel regulators of reverse remodeling. Methods: Gene expression dataset for human failing and postLVAD paired myocardial samples (n= 3 8) were obtained from Gene Expression Omnibus Database (series GSE974). Expression data file was log-transformed and normalized in PARTEK GS, and transferred to R for weighted gene co-expression network analysis using package WGCNA. WGCNA uses network terminology to describe co-expression patterns between genes of a network and identifies clusters of highly correlated genes (modules), which can be related to sample traits. Results: Hierarchical clustering using TOM dissimilarity measure with dynamic tree cut algorithm yielded 9 distinct HF and 7 Recovery gene modules. Recovery modules were poorly preserved in HF network suggesting distinct signaling mechanisms for the two process (Figure 1A). Module-trait relationship analysis identified a unique LVAD module which correlated with duration of support. Cellular component analysis of the “myocardial plasticity” module showed genes that were significantly mapped to extracellular region including 9 different collagen genes. Hub genes of this module included lysyl oxidase (LOX) and CD44, both of which have been implicated in the myocardial remodeling process (Figure 1B). Conclusion: Our findings suggest that alterations in extracellular matrix occur in a time-dependent fashion following LVAD support and may contribute to reverse remodeling process. Analysis of gene-gene interaction patterns rather than traditional differential gene expression analysis may provide valuable mechanistic insights into myocardial recovery.
3( 76) Myocardial Regeneration and Recovery with Extracellular Matrix and LVAD Support M.S. Slaughter ,1 G.D. Rokosh,2 R.G. Matheny,3 M.A. Sobieski,1 M. Wysoczynski,4 M. Solanki,2 G.A. Giridharan,1 K.G. Soucy,1 P.L. Linsky,1 G. Monreal,1 S.C. Koenig.1 1Surgery, University of Louisville, Louisville, KY; 2University of Louisville, Louisville, KY; 3CorMatrix, Roswell, GA; 4Institute of Molecular Cardiology, University of Louisville, Louisville, KY. Purpose: Myocardial recovery with LVAD support is uncommon and unpredictable. We tested the hypothesis that injectable extracellular matrix (ECM) with left ventricular assist device (LVAD) support promotes cell proliferation, improves cardiac function and possible myocardial recovery. Methods: LVAD, ECM, and LVAD+ECM therapies were investigated in 60-day (n= 6) and 90-day (n= 5) chronic ischemic heart failure (HF) calves (5080 kg) induced using coronary embolization (90μ m spheres). Treatment was initiated 30 days after HF induction. ECM emulsion was injected intramyocardially using a 7-needle (25 ga) pneumatic delivery tool. LVAD were implanted in an LV apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified using fluorescent labeled microspheres. At necropsy, tissues were obtained for histopathology and BrdU quantification. Results: Prior to treatment, HF calves had an LVEF of 32±7.6% and LVEDV of 203±73 mL with cardiac cachexia (reduced weight gain of 0.69±0.20 kg/ day). Healthy weight gain was restored in all groups. EF increased with