- Email: [email protected]
Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling after Myocardial Infarction
The 13th Annual Scientific Meeting
HFSA
S41
protein is significantly lower (w35%) in failing LV from both adults and children. In the normal adult and pediatric LV the b1:b2AR ratio is w80:20. In contrast, the b1:b2 ratio is 59 6 4:41 6 4 (P!0.05) in the failing adult LV while no significant difference is found in the failing pediatric LV (81 6 2:19 6 2). The expression of b1AR mRNA is significantly lower in the adult failing LV (0.8 6 0.1 vs control: 1.4 6 0.2; P!0.05) with no difference between IDC and NF pediatric expression. In contrast, b2AR mRNA is significantly lower in the pediatric failing LV (0.6 6 0.1 vs control: 1.0 6 0.2; P!0.05) while expression is unchanged between adult groups. Age-related differences in the expression of several other pathologic markers in response to HF were also demonstrated when compared to age-matched controls (Cx43: \ w50% PedHF, Z w40% AdHF; BNP: 5 PedHF, O9-fold \ AdHF). Numerous differences are apparent at a molecular level between the AdHF and PedHF populations. The discordant regulation of the bAR may play a mechanistic role in the lack of clinical response to bAR blocking therapy in PedHF. It is fundamental to improve our understanding of age-specific pathophysiologic changes in response to HF to develop proper therapy for the PedHF population.
127 Adiponectin Protects Doxorubicin-Induced Cardiomyopathy in Mice Masanori Konishi, Go Haraguchi, Takashi Ishihara, Hirokazu Ohigashi, Mitsuaki Isobe; Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Background: Adiponectin has been reported to protect cardiac dysfunction such as ischemia reperfusion injury and hypertrophy. However, there are few reports about its cardioprotective effects in doxorubicin (DOX) -induced cardiomyopathy. We investigated whether adiponectin is effective for DOX-induced cardiomyopathy or not in vivo using adiponectin transgenic mice. Methods and Results: We quantified cardiac pathology in C57BL/6mice (WT mice) and adiponectin transgenic mouse (Tg mice) (K Saito et al: Biochimica et Biophysica Acta 2006) after the administration of DOX. Heart rate was similar in both groups (583 6 47 vs. 588 6 23bpm, n55 vs. 5, p 5 NA), but systolic blood pressure was preserved in Tg mice compare to WT mice (83 6 3 vs.73 6 4mmHg, p!0.005) . Echocardiographic evaluation revealed that cardiac function in Tg mice was significantly improved compare to WT mice (%FS 5 48.5 6 2.8% vs. 31.2 6 4.0%, p!0.005). Tg mice had significantly smaller increased in LV chamber size and smaller decreased in wall thickness than WT mice. We also assessed myocardial pathological changes, and observed that fibrosis and scattered cardiomyocytes were significantly decreased in Tg mice compare to WT mice. Conclusion: In this study, we observed adiponectin improves cardiac function in DOX-induced cardiomyopathy. Adiponectin could be associated with protection of heart failure in this model.
128 Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling after Myocardial Infarction Mark S. Moon1,2, HongLiang Li2, Min Nian2, Manyin Chen2, Chen Liu2, Peter P. Liu1,2,3; 1University of Toronto, Toronto, ON, Canada; 2Division of Cardiology, University Health Network, Toronto, ON, Canada; 3Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto, ON, Canada Background: The role of cellular FLICE-inhibitory protein (cFLIP), a member of the tumor necrosis factor (TNF) signaling pathway and regulator of apoptosis, in cardiac remodeling following myocardial infarction (MI) remains largely unknown. The objective of this study was to determine the function of cFLIP as a potential mediator of cardiac remodeling with loss- and gain-of-function genetic manipulations in an experimental model. Methods and Results: Myocardial infarction was created in cFLIP heterozygous (cFLIP6, HET) mice and littermate wild-type (WT) mice by the permanent ligation of the left anterior descending (LAD) artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Levels of apoptosis, inflammation, angiogenesis, and fibrosis were assessed in the myocardium. HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and myocyte hypertrophy compared with WT mice 42 days after MI surgery. Impaired LV function in HET mice was associated with increased infarct size, apoptosis, inflammation, interstitial fibrosis, and reduced capillary density. Administration of adenovirus-mediated cFLIP in HET and WT mice resulted in decreased LV dilatation and improved LV function. This was associated with increased capillary density, decreased cardiac hypertrophy, fibrosis, and diminished apoptosis. In addition, we also found decreased Akt signaling and increased JNK1/2 and NF-kB signaling in the hearts of HET mice compared to control animals, all of which were reversed after infection with Ad-cFLIP. Conclusions: Cellular FLIP protects against the development of cardiac remodeling after myocardial infarction. Improvement in remodeling by cFLIP was associated with decreased myocyte and capillary loss, cardiac hypertrophy, inflammation, and interstitial fibrosis.
129 Myocardial Upregulation of hnRNP-C Predicts Short Term Recovery in Patients with Acute Systolic Heart Failure Kimberly A. Parks, Marc J. Semigran, James R. Stone; Massachusetts General Hospital, Harvard Medical School, Boston, MA Purpose: Acute nonischemic systolic heart failure (NISHF) is a major cause of morbidity and mortality. Predicting which patients will recover from cardiomyopathy and
which need advanced therapies presents a great challenge to the clinician. We hypothesized that the level of expression of heterogeneous nuclear ribonucleoprotein C (hnRNP-C) in cardiac myocytes would predict short term recovery in patients presenting with new-onset systolic heart failure. Materials & Methods: 8 consecutive patients who underwent endomyocardial biopsy because of suspicion for myocarditis were retrospectively reviewed. Coronary artery disease was excluded by angiography and biopsy showed no evidence of myocarditis. Biopsy samples were stained for hnRNP-C and the percentage of positively staining myocytes was correlated with myocardial recovery. Results: By 17 months follow-up, 5 patients demonstrated ‘‘recovery’’ defined as an improved LVEF (baseline 0.20 6 0.03 mean6SD follow-up 0.43 6 0.12, P!0.01) and 3 patients did not have significant improvement ‘‘no recovery’’ in left ventricular ejection fraction (baseline 0.17 6 0.07, follow-up 0.26 6 0.01). The mean age of the recovery group was 44 6 14, in the no recovery group was 41 6 16 and in controls 51 6 8. There was no significant difference in initial LVEF between the heart failure groups (0.20 6 0.03 vs 0.17 6 0.07 p50.4). All patients were on an optimal heart failure medical regimen consisting of a beta blocker (n58), ACE inhibitors (n57) or angiotensin receptor blocker (n51). None received cardiac resynchronization therapy. Patients in the recovery group had significant upregulation of hnRNP-C on initial biopsy compared with the no recovery group and compared with control hearts from autopsies (Figure 1).Conclusions: Our preliminary study suggests that the level of expression of hnRNP-C in cardiac myocytes in patients with acute NISHF is predictive of short term recovery of LVEF. This may have clinical implications in the decision to offer advanced therapies to NISHF patients. Further evaluation of the utility of hnRNP-C as a prognostic marker in a larger population of patients with heart failure is necessary.
130 Sarcomeric Dilated Cardiomyopathy: Onset from Infancy to Late Adulthood Neal K. Lakdawala1, Samantha Baxter2, Elizabeth Duffy2, Raju Kucherlapati2, J.G. Seidman3, Christine E. Seidman1,3, Carolyn Y. Ho1, Birgit Funke2; 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA; 2Pathology, Laboratory for Molecular Medicine, Cambridge, MA; 3Department of Genetics, Harvard Medical School, Boston, MA Introduction: Dilated Cardiomyopathy (DCM) is an important cause of heart failure and leading indication for heart transplantation in children and adults. Genetic causes have been identified and include mutations in sarcomere genes. The age of presentation in sarcomeric DCM remains incompletely defined, but preliminary reports suggest marked, age-dependent variability in clinical disease onset and manifestations. Methods and Results: Results of genetic testing performed by a CLIA certified lab were retrospectively reviewed. Patients referred with diagnosis of DCM who underwent DNA sequencing of 5 sarcomere genes (MYH7, TNNT2, TNNI3, TPM1, MYBPC3) and LMNA (Lamin A/C) were included for study (n5173). Newly discovered genetic variants were classified as either presumed pathogenic or of uncertain significance based on internal or published data on segregation and frequency in controls. Patients were excluded from analysis if underlying hypertrophic cardiomyopathy was suspected based on reported family history. Demographic characteristics were compared between patients with and without sarcomere mutations. There was a broad age-range in tested individuals which was skewed towards infancy and early childhood. Sarcomere mutations were commonly identified across all ages and at particularly high frequency in early childhood (Figure 1). In contrast to sarcomere mutations, mutations in LMNA were not seen in probands younger than 15 years.
HFSA
S41
protein is significantly lower (w35%) in failing LV from both adults and children. In the normal adult and pediatric LV the b1:b2AR ratio is w80:20. In contrast, the b1:b2 ratio is 59 6 4:41 6 4 (P!0.05) in the failing adult LV while no significant difference is found in the failing pediatric LV (81 6 2:19 6 2). The expression of b1AR mRNA is significantly lower in the adult failing LV (0.8 6 0.1 vs control: 1.4 6 0.2; P!0.05) with no difference between IDC and NF pediatric expression. In contrast, b2AR mRNA is significantly lower in the pediatric failing LV (0.6 6 0.1 vs control: 1.0 6 0.2; P!0.05) while expression is unchanged between adult groups. Age-related differences in the expression of several other pathologic markers in response to HF were also demonstrated when compared to age-matched controls (Cx43: \ w50% PedHF, Z w40% AdHF; BNP: 5 PedHF, O9-fold \ AdHF). Numerous differences are apparent at a molecular level between the AdHF and PedHF populations. The discordant regulation of the bAR may play a mechanistic role in the lack of clinical response to bAR blocking therapy in PedHF. It is fundamental to improve our understanding of age-specific pathophysiologic changes in response to HF to develop proper therapy for the PedHF population.
127 Adiponectin Protects Doxorubicin-Induced Cardiomyopathy in Mice Masanori Konishi, Go Haraguchi, Takashi Ishihara, Hirokazu Ohigashi, Mitsuaki Isobe; Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Background: Adiponectin has been reported to protect cardiac dysfunction such as ischemia reperfusion injury and hypertrophy. However, there are few reports about its cardioprotective effects in doxorubicin (DOX) -induced cardiomyopathy. We investigated whether adiponectin is effective for DOX-induced cardiomyopathy or not in vivo using adiponectin transgenic mice. Methods and Results: We quantified cardiac pathology in C57BL/6mice (WT mice) and adiponectin transgenic mouse (Tg mice) (K Saito et al: Biochimica et Biophysica Acta 2006) after the administration of DOX. Heart rate was similar in both groups (583 6 47 vs. 588 6 23bpm, n55 vs. 5, p 5 NA), but systolic blood pressure was preserved in Tg mice compare to WT mice (83 6 3 vs.73 6 4mmHg, p!0.005) . Echocardiographic evaluation revealed that cardiac function in Tg mice was significantly improved compare to WT mice (%FS 5 48.5 6 2.8% vs. 31.2 6 4.0%, p!0.005). Tg mice had significantly smaller increased in LV chamber size and smaller decreased in wall thickness than WT mice. We also assessed myocardial pathological changes, and observed that fibrosis and scattered cardiomyocytes were significantly decreased in Tg mice compare to WT mice. Conclusion: In this study, we observed adiponectin improves cardiac function in DOX-induced cardiomyopathy. Adiponectin could be associated with protection of heart failure in this model.
128 Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling after Myocardial Infarction Mark S. Moon1,2, HongLiang Li2, Min Nian2, Manyin Chen2, Chen Liu2, Peter P. Liu1,2,3; 1University of Toronto, Toronto, ON, Canada; 2Division of Cardiology, University Health Network, Toronto, ON, Canada; 3Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto, ON, Canada Background: The role of cellular FLICE-inhibitory protein (cFLIP), a member of the tumor necrosis factor (TNF) signaling pathway and regulator of apoptosis, in cardiac remodeling following myocardial infarction (MI) remains largely unknown. The objective of this study was to determine the function of cFLIP as a potential mediator of cardiac remodeling with loss- and gain-of-function genetic manipulations in an experimental model. Methods and Results: Myocardial infarction was created in cFLIP heterozygous (cFLIP6, HET) mice and littermate wild-type (WT) mice by the permanent ligation of the left anterior descending (LAD) artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Levels of apoptosis, inflammation, angiogenesis, and fibrosis were assessed in the myocardium. HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and myocyte hypertrophy compared with WT mice 42 days after MI surgery. Impaired LV function in HET mice was associated with increased infarct size, apoptosis, inflammation, interstitial fibrosis, and reduced capillary density. Administration of adenovirus-mediated cFLIP in HET and WT mice resulted in decreased LV dilatation and improved LV function. This was associated with increased capillary density, decreased cardiac hypertrophy, fibrosis, and diminished apoptosis. In addition, we also found decreased Akt signaling and increased JNK1/2 and NF-kB signaling in the hearts of HET mice compared to control animals, all of which were reversed after infection with Ad-cFLIP. Conclusions: Cellular FLIP protects against the development of cardiac remodeling after myocardial infarction. Improvement in remodeling by cFLIP was associated with decreased myocyte and capillary loss, cardiac hypertrophy, inflammation, and interstitial fibrosis.
129 Myocardial Upregulation of hnRNP-C Predicts Short Term Recovery in Patients with Acute Systolic Heart Failure Kimberly A. Parks, Marc J. Semigran, James R. Stone; Massachusetts General Hospital, Harvard Medical School, Boston, MA Purpose: Acute nonischemic systolic heart failure (NISHF) is a major cause of morbidity and mortality. Predicting which patients will recover from cardiomyopathy and
which need advanced therapies presents a great challenge to the clinician. We hypothesized that the level of expression of heterogeneous nuclear ribonucleoprotein C (hnRNP-C) in cardiac myocytes would predict short term recovery in patients presenting with new-onset systolic heart failure. Materials & Methods: 8 consecutive patients who underwent endomyocardial biopsy because of suspicion for myocarditis were retrospectively reviewed. Coronary artery disease was excluded by angiography and biopsy showed no evidence of myocarditis. Biopsy samples were stained for hnRNP-C and the percentage of positively staining myocytes was correlated with myocardial recovery. Results: By 17 months follow-up, 5 patients demonstrated ‘‘recovery’’ defined as an improved LVEF (baseline 0.20 6 0.03 mean6SD follow-up 0.43 6 0.12, P!0.01) and 3 patients did not have significant improvement ‘‘no recovery’’ in left ventricular ejection fraction (baseline 0.17 6 0.07, follow-up 0.26 6 0.01). The mean age of the recovery group was 44 6 14, in the no recovery group was 41 6 16 and in controls 51 6 8. There was no significant difference in initial LVEF between the heart failure groups (0.20 6 0.03 vs 0.17 6 0.07 p50.4). All patients were on an optimal heart failure medical regimen consisting of a beta blocker (n58), ACE inhibitors (n57) or angiotensin receptor blocker (n51). None received cardiac resynchronization therapy. Patients in the recovery group had significant upregulation of hnRNP-C on initial biopsy compared with the no recovery group and compared with control hearts from autopsies (Figure 1).Conclusions: Our preliminary study suggests that the level of expression of hnRNP-C in cardiac myocytes in patients with acute NISHF is predictive of short term recovery of LVEF. This may have clinical implications in the decision to offer advanced therapies to NISHF patients. Further evaluation of the utility of hnRNP-C as a prognostic marker in a larger population of patients with heart failure is necessary.
130 Sarcomeric Dilated Cardiomyopathy: Onset from Infancy to Late Adulthood Neal K. Lakdawala1, Samantha Baxter2, Elizabeth Duffy2, Raju Kucherlapati2, J.G. Seidman3, Christine E. Seidman1,3, Carolyn Y. Ho1, Birgit Funke2; 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA; 2Pathology, Laboratory for Molecular Medicine, Cambridge, MA; 3Department of Genetics, Harvard Medical School, Boston, MA Introduction: Dilated Cardiomyopathy (DCM) is an important cause of heart failure and leading indication for heart transplantation in children and adults. Genetic causes have been identified and include mutations in sarcomere genes. The age of presentation in sarcomeric DCM remains incompletely defined, but preliminary reports suggest marked, age-dependent variability in clinical disease onset and manifestations. Methods and Results: Results of genetic testing performed by a CLIA certified lab were retrospectively reviewed. Patients referred with diagnosis of DCM who underwent DNA sequencing of 5 sarcomere genes (MYH7, TNNT2, TNNI3, TPM1, MYBPC3) and LMNA (Lamin A/C) were included for study (n5173). Newly discovered genetic variants were classified as either presumed pathogenic or of uncertain significance based on internal or published data on segregation and frequency in controls. Patients were excluded from analysis if underlying hypertrophic cardiomyopathy was suspected based on reported family history. Demographic characteristics were compared between patients with and without sarcomere mutations. There was a broad age-range in tested individuals which was skewed towards infancy and early childhood. Sarcomere mutations were commonly identified across all ages and at particularly high frequency in early childhood (Figure 1). In contrast to sarcomere mutations, mutations in LMNA were not seen in probands younger than 15 years.