Department of Cardiology,Stavanger University Hospital, Norway. State of the Art on Heart Failure in memory of Professor Helmut Drexler

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1 Myocardial Connective Tissue Growth Factor (CCN2/CTGF) attenuates Left Ventricular Remodeling after Myocardial Infarction and Prevents Ischemic Heart Failure 1,2 Jørgen Gravning, 3 Stein Ørn, 1,2 Thor Edvardsen, 1 Vladimir N. Martinov, 3 Cord Manhenke, 3 Kenneth Dickstein, 1,2 Håvard Attramadal and 1 Mohammed S. Ahmed 1 Inst. for Surgical Research and 2 Department of Cardiology, Oslo University Hospital, 3 Department of Cardiology,Stavanger University Hospital, Norway State of the Art on Heart Failure in memory of Professor Helmut Drexler ESC Congress 2010, Stockholm

2 Disclosures J. Gravning, V.N. Martinov, H. Attramadal and M.S. Ahmed are partners in a patent application filed by the University of Oslo regarding the use of CCN2/CTGF as a cardioprotective agent.

3 Background Myocardial connective tissue growth factor (CTGF/CCN2) is: highly expressed during embryogenesis repressed in the postnatal heart dramatically induced in heart failure (HF) CTGF may be synthesized in several cells of myocardial tissue, i.e; cardiac fibroblasts endothelial cells cardiac myocytes The pathophysiological role of myocardial CTGF remain unresolved. Ahmed et al. Acta Physiol Scand 2005; CTGF in pacing induced heart failure in pigs Chen et al. JMCC 2000; Regulation of CTGF in human heart failure

4 Aims To elucidate the role of myocardial CTGF in left ventricular remodeling and ischemic heart failure Experimental model: transgenic mice with cardiac-restricted overexpressing of CTGF ligation of the left coronary artery Clinical model: serial analyses of serum CTGF levels STEMI patients treated with primary PCI assesed by serial MRI

5 Experimental study Generation of transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) * P<0.05

6 Assessment of cardiac function in Tg-CTGF mice vs. NLC mice by left ventricular pressure-volume analysis Parameter NLC ( n=8) Tg-CTGF (n=7) HR (bpm) 517 ± ± 14 LVSP (mmhg) ± ± 3.2 LVEDP (mmhg) 1.1 ± ± 1.5 LVESV (µl) 12.3 ± ± 0.4 LVEDV (µl) 21.8 ± ± 1.3 * SV (µl) 13.9 ± ± 1.0 SW (mmhg/µl) 1167 ± ± 126 EF % 58.0 ± ± 3.4 LV +dp/dt (mmhg/s) ± ± 738 LV -dp/dt (mmhg/s) 8879 ± ± 949 Cardiac output (µl/min) 7211 ± ± 555 * P<0.05

7 Comperative analysis of myocardial transcriptome: Myocardial mrna levels upregulated more than 2-fold in Tg-CTGF mice vs. NLC mice Gene name Fold change vs. NLC mice Signal Transduction Cyclin D2 2.3 Cyclin-dependent kinase inhibitor 1A (P21) 2.1 G protein-coupled receptor kinase Growth differentiation factor Transcription Factor Activating transcription factor Neuronal PAS domain protein Metabolism Aldehyde dehydrogenase 18 family, member A1 3.4 Asparagine synthetase 20.0 BAI1-associated protein 2-like Methylenetetrahydrofolate dehydrogenase phosphoglycerate dehydrogenase 9.0 Phosphoserine aminotransferase Pyrroline-5-carboxylate reductase 1 2.2

8 Left ventricular remodeling after induction myocardial infarction in Tg-CTGF vs. NLC mice MI Echo Echo Echo N=43 Baseline Sham 14 days 28 days N=12 Terminal Experiments Area at risk after ligation of the left coronary artery was estimated using Evans blue dye in a separate group of mice, and was similar among Tg-CTGF and NLC mice (42.7 ± 1.6%, n=8 vs 40.4 ± 2.1%, n=8, p=0.39)

9 Serial echocardiographic measurements and survival curves after myocardial infarction in Tg-CTGF and NLC mice * P<0.05

10 Analysis of cardiac mass, collagen and myocardial gene expression markers of heart failure after myocardial infarction in Tg-CTGF mice vs. NLC mice * P<0.05 vs. NLC CHF, ** P<0.05 vs. NLC sham, P<0.05 vs. corresponding sham

11 Clinical study 42 patients with first-time ST-elevation myocardial infarction Single vessel disease Successful revascularization with primary PCI Infarct size and left ventricular volumes determined by cardiac MRI 2 days, 1 week, 2 months and 1 year after PCI Serum CTGF levels measured at the same timepoints as above

12 Serum CTGF levels and stratification of patients depending on relative changes in CTGF levels during follow-up * P<0.05

13 Baseline characteristics of patient groups after stratification -1-

14 Baseline characteristics of patient groups after stratification -2-

15 Left ventricular volumes and infarct size determined by cardiac MRI in the stratified patient cohorts * P<0.05

16 Potential mechanisms for CTGF-mediated cardioprotective effects Gene name Fold change vs. NLC mice Signal Transduction Cyclin D2 2.3 Cyclin-dependent kinase inhibitor 1A (P21) 2.1 G protein-coupled receptor kinase Growth differentiation factor G protein-coupled receptor kinase Transcription Factor Activating transcription factor Neuronal PAS domain protein Metabolism Aldehyde dehydrogenase 18 family, member A1 3.4 Asparagine synthetase 20.0 BAI1-associated protein 2-like Methylenetetrahydrofolate dehydrogenase phosphoglycerate dehydrogenase 9.0 Phosphoserine aminotransferase Pyrroline-5-carboxylate reductase 1 2.2

17 G Protein-Coupled Receptor Kinases (GRKs) Freedman NJ et al. JBC 1995

18 CTGF-mediated induction of myocardial GRK5 * P<0.05

19 CTGF-mediated increase of cardiac myocyte GRK5 attenuates β-adrenergic receptor responsiveness * P<0.05

20 Enhanced ERK-activation in cardiac myocytes from Tg-CTGF vs. NLC mice upon isoproterenol stimulation * P<0.05 vs. NLC CHF, P<0.05 vs. corresponding sham

21 CTGF enhances β-arrestin binding to the β 2 -adrenergic receptor upon agonist-stimulation in CHO cells * * * P<0.05

22 Conclusion: CTGF prevents development of experimental ischemic heart failure in mice Increase in s-ctgf levels in patients after MI is associated with attenuated LV remodeling and improved cardiac function CTGF causes induction of GRK5 with subsequent desensitization of β-adrenergic receptors and activation of G- protein independent signaling Thus, these data demonstrate that CTGF exerts cardioprotective effects that may be clinically relevant in ischemic heart failure