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PM396 Impact of Fetal Growth and Preterm Birth on the Microvasculature in Mid Adulthood
POSTER ABSTRACTS
suppressed due to augmented generation of ‘cardioprotective’ P-CaMKIIdB possibly limiting deleterious actions associated with ox-CaMKIIdC. Disclosure of Interest: None Declared PM396 Impact of Fetal Growth and Preterm Birth on the Microvasculature in Mid Adulthood Monira Hussain*1,2, Mika Kähönen3, Olli Raitakari4, Michael Skilton5, Nicholas Witt6, Nishi Chaturvedi6, Alun Hughes6, Simon McG Thom6, Andrew Metha1, Robyn Tapp1 1 Department of Optometry and Vision Sciences, The University of Melbourne, 2 Department of Epidemiology and Preventive Medicine, Monash University, Victoria, Australia, 3 Department of Clinical Physiology, Tampere University Hospital and the University of Tampere, Tampere, 4Research Centre of Applied and Preventive Cardiovascular Medicine and Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland, 5Boden Institute of Obesity Nutrition Exercise and Eating Disorders, University of Sydney, New South Walse, Australia, 6International Centre for Circulatory Health, St Mary’s Hospital and Imperial College, London, United Kingdom Introduction: Microvascular dysfunction may be critical to our understanding of the mechanisms linking early life events with the later development of cardiovascular disease. Objectives: We hypothesised that preterm birth and being born small for gestational age would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We predicted that these changes would correlate with early markers of cardiovascular disease in midadulthood. Methods: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm (<37 weeks gestation, n¼122), born at term and small for gestational age (n¼122) and a control group born at term and appropriate for gestational age (n¼495) were compared. Retinal microvascular measures were evaluated, including tortuosity, retinal diameters, bifurcation angles and length/diameter ratios. Results: The mean age of the participants was 40 years (range 34 – 49 years) at the time of retinal photography. In participants born preterm, simple arteriolar tortuosity was higher (means (standard error), 0.06 (0.01) versus 0.04 (0.01), p¼0.001), arteriolar length increased (644.9 (35.9) versus 591.7 (33.5), p¼0.007) and arteriolar diameters narrowed (19.9 (0.4) versus 20.3 (0.3), p¼0.034) compared to participants born appropriate for gestational age. All the analysis were adjusted for age, sex, marital status, employment status and smoking. In participants born small for gestational age, only simple arteriolar tortuosity was higher (0.05 (0.01) versus 0.04 (0.01), p¼0.074) compared to participants born appropriate for gestational age. A difference in birth weight of 500g independently influenced arteriolar tortuosity by the same amount as 23mmHg systolic blood pressure, 0.3mm intima media thickness and had three times the effect of daily smoking. Conclusion: This study demonstrated that being born small for gestational age and in particular preterm birth are associated with changes in retinal microvascular architecture and may be related to early markers of cardiovascular disease. The immediate postnatal environment may provide vital information on the mechanisms of early vascular changes. Disclosure of Interest: None Declared
PM397 Nerve Growth Factor promotes mammalian cardiomyocytes to proliferate Nicholas T. Lam1, David M. Kaye*1 1 Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia Introduction: Significant cardiomyocyte loss and insufficient endogenous cardiac regeneration in adult mammals lead to heart failure. In contrast, fetal and neonatal hearts are capable of compensatory proliferation of cardiomyocytes following cardiac injury. We have previously shown that Nerve growth factor (NGF) is decreased in failing hearts and recently it was demonstrated in zebrafish that NGF enhanced cardiac regeneration by increasing cardiomyocyte proliferation in vivo. It is not yet known whether NGF can also increase cardiomyocyte proliferation in mammals. Objectives: We aim to validate the effect of NGF on cardiomyocyte proliferation in a mammalian system by studying the effect of NGF on mouse embryonic heart organ culture. Methods: E13.5 mouse hearts were cultured for 2 and 24 hours in vitro and the effect of NGF was tested. Confocal micrographs generated from transverse sections of E13.5 heart immunohistochemistry were manually counted for cTnT+ and pH3+ cells. Results: Of the total cTnT+ cells in random transverse sections from E13.5 mouse hearts cultured in DMEM and DMEM supplemented with NGF for 24 hours, approximately 2.20.2% and 5.10.1% of cardiomyocytes respectively were also positive for pH3. E13.5 mouse hearts exposed to NGF for 24 hours induced a 2.30.2 fold increase in pH3+ cTnT+ cells (p<0.001, n¼3) compared to DMEM controls. Taken together, these data would suggest that NGF increased mitosis of cardiomyocytes in E13.5 mouse heart explant cultures. E13.5 mouse hearts cultured in DMEM supplemented with NGF for 2 hours increased Nrg1 and ErbB4 mRNA transcript levels by 2.260.48 fold (p<0.05, n¼3) and 3.270.76 fold (p<0.05, n¼3) respectively compared to hearts cultured in DMEM controls. This
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suggests that NGF mediates this effect through the NRG1/ErbB4 cardiomyocyte proliferation pathway. Conclusion: In summary, this study validated that NGF promotes cardiomyocyte proliferation in mammals, which may be mediated through the Neuregulin1/ErbB4 pathway. Further studies are required to determine if NGF can increase adult mammalian cardiomyocytes to proliferate. Disclosure of Interest: None Declared
PM398 Mechanisms Underlying High Temperature-Induced Arrhythmogenesis In An Experimental Model Of Brugada Syndrome Rocio Picon*1, Jose Di Diego2, Charles Antzelevitch3 1 Cardiology, Hospital Universitario Virgen De Valme, Seville, Spain, 2Experimental Cardiology, 3 Director of Research, Masonic Medical Research Laboratory, Utica, United States Introduction: It well known that in some cases of Brugada syndrome (BrS) a febrile state can unmask or exacerbate the electrocardiographic and arrhythmic manifestations of BrS Objectives: In this study, we examine the effect of high temperature in a coronary-perfused right ventricular wedge preparations treated with and sodium channel current (INa) blocker and transient outward current (Ito) agonist to pharmacologically model BrS. Methods: Canine right ventricular wedge preparations (2x1x1 cm; n¼ 18) were coronary perfused with Tyrode’s solution and bubbled with O2/CO2 (95%/5%) at 370.5oC. Ajmaline (5-10 mM), an INa blocker and the Ito activator NS5806 (5-10 mM) were used to pharmacologically model BrS-related SCN5A and KCND3 mutations. Pacing was applied to the endocardial surface at basic cycle lengths of 500 and 2000 ms. Floating glass microelectrodes were used to simultaneously record intracellular action potentials from subendocardium and subepicardium (Epi) together with a transmural ECG recorded across the bath. Coronary perfusate temperature was varied over a range of 37 to 40 C. Results: Elevating temperature to 40 C resulted in abbreviation of repolarization and reduction of the Epi AP notch, under control conditions as well as under conditions that mimic the ECG phenotype of BrS, suggesting reduced arrhythmic risk at 40 C. Conclusion: Our results suggest that reduction of peak INa and augmentation of peak Ito alone are not sufficient to recapitulate the response to high temperatures in the setting of BrS. Our data support the notion that other factors including temperature-mediated effects on already defective ion channel gating (e.g., accelerated inactivation of INa), further reduction of already impaired trafficking, and possibly release of endogenous cytokines, may underlie the higher arrhythmia risk of BrS patients during fever. Disclosure of Interest: None Declared PM399 Chronic High Salt Intake Induces Myocardial Autophagic Vacuolization and Accelerates Left Ventricular Dysfunction in Spontaneously Hypertensive Rats Ying Bi1, Xin Zhou1, Wen-Jie Ji1, Shan Zeng1, Guo-Hong Yang1, Tie-Min Jiang1, Yu-Ming Li1, Zhao-Zeng Guo*1 1 Institute of Cardiovascular Disease and Heart Center, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital, Logistics University of Cpapf, Tianjin, China Introduction: Chronic high salt (HS) intake is associated with left ventricular (LV) hypertrophy and progression to systolic and diastolic dysfunction. Autophagy is an essential, life-sustaining renewal process that involves the degradation of cell constituents, when subjected to cellular stress or during certain stages of development. The involvement of autophagy in HS intake-accelerated LV remodeling progression remains unclear. Objectives: To investigate the dynamic of autophagic activation and its association with the functional and structural transition from compensated left ventricular (LV) hypertrophy to decompensation during chronic HS challenge in spontaneously hypertensive rats (SHR) Methods: SHR and Wistar Kyoto (WKY) rats were fed low-salt (LS, 0.5% NaCl) and HS (8.0% NaCl) diets and were subject to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Results: A global activation of autophagy-associated key components, as well as increased cardiomyocyte autophagic vacuolization by transmission electron microscopy, was observed after 12 weeks of HS challenge, along with a transition from compensated to decompensated LV hypertrophy during this period, as shown by a progressive impairment of the SHR LV function. Myocardial tonicity-responsive enhancer binding protein, a transcription factor induced by osmotic stress, was significantly upregulated in HS fed rats, thus providing evidence that supports myocardial interstitial hypertonicity by chronic HS intake. The global activation of autophagy and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. An in vitro study using rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species (ROS)-dependent enhancement of the autophagic response when exposed to an increased extracellular [Na+]. Conclusion: This work depicts the kinetics of myocardial autophagy during the transition from compensated LV hypertrophy to decompensated heart failure after HS challenge in SHR and reveals a novel mechanism by which interstitial hypertonicity-induced cytosolic [Na+] elevation triggers an ROS-dependent autophagy activation. Disclosure of Interest: None Declared
GHEART Vol 9/1S/2014
j
March, 2014
j
POSTER/2014 WCC Posters
suppressed due to augmented generation of ‘cardioprotective’ P-CaMKIIdB possibly limiting deleterious actions associated with ox-CaMKIIdC. Disclosure of Interest: None Declared PM396 Impact of Fetal Growth and Preterm Birth on the Microvasculature in Mid Adulthood Monira Hussain*1,2, Mika Kähönen3, Olli Raitakari4, Michael Skilton5, Nicholas Witt6, Nishi Chaturvedi6, Alun Hughes6, Simon McG Thom6, Andrew Metha1, Robyn Tapp1 1 Department of Optometry and Vision Sciences, The University of Melbourne, 2 Department of Epidemiology and Preventive Medicine, Monash University, Victoria, Australia, 3 Department of Clinical Physiology, Tampere University Hospital and the University of Tampere, Tampere, 4Research Centre of Applied and Preventive Cardiovascular Medicine and Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland, 5Boden Institute of Obesity Nutrition Exercise and Eating Disorders, University of Sydney, New South Walse, Australia, 6International Centre for Circulatory Health, St Mary’s Hospital and Imperial College, London, United Kingdom Introduction: Microvascular dysfunction may be critical to our understanding of the mechanisms linking early life events with the later development of cardiovascular disease. Objectives: We hypothesised that preterm birth and being born small for gestational age would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We predicted that these changes would correlate with early markers of cardiovascular disease in midadulthood. Methods: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm (<37 weeks gestation, n¼122), born at term and small for gestational age (n¼122) and a control group born at term and appropriate for gestational age (n¼495) were compared. Retinal microvascular measures were evaluated, including tortuosity, retinal diameters, bifurcation angles and length/diameter ratios. Results: The mean age of the participants was 40 years (range 34 – 49 years) at the time of retinal photography. In participants born preterm, simple arteriolar tortuosity was higher (means (standard error), 0.06 (0.01) versus 0.04 (0.01), p¼0.001), arteriolar length increased (644.9 (35.9) versus 591.7 (33.5), p¼0.007) and arteriolar diameters narrowed (19.9 (0.4) versus 20.3 (0.3), p¼0.034) compared to participants born appropriate for gestational age. All the analysis were adjusted for age, sex, marital status, employment status and smoking. In participants born small for gestational age, only simple arteriolar tortuosity was higher (0.05 (0.01) versus 0.04 (0.01), p¼0.074) compared to participants born appropriate for gestational age. A difference in birth weight of 500g independently influenced arteriolar tortuosity by the same amount as 23mmHg systolic blood pressure, 0.3mm intima media thickness and had three times the effect of daily smoking. Conclusion: This study demonstrated that being born small for gestational age and in particular preterm birth are associated with changes in retinal microvascular architecture and may be related to early markers of cardiovascular disease. The immediate postnatal environment may provide vital information on the mechanisms of early vascular changes. Disclosure of Interest: None Declared
PM397 Nerve Growth Factor promotes mammalian cardiomyocytes to proliferate Nicholas T. Lam1, David M. Kaye*1 1 Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia Introduction: Significant cardiomyocyte loss and insufficient endogenous cardiac regeneration in adult mammals lead to heart failure. In contrast, fetal and neonatal hearts are capable of compensatory proliferation of cardiomyocytes following cardiac injury. We have previously shown that Nerve growth factor (NGF) is decreased in failing hearts and recently it was demonstrated in zebrafish that NGF enhanced cardiac regeneration by increasing cardiomyocyte proliferation in vivo. It is not yet known whether NGF can also increase cardiomyocyte proliferation in mammals. Objectives: We aim to validate the effect of NGF on cardiomyocyte proliferation in a mammalian system by studying the effect of NGF on mouse embryonic heart organ culture. Methods: E13.5 mouse hearts were cultured for 2 and 24 hours in vitro and the effect of NGF was tested. Confocal micrographs generated from transverse sections of E13.5 heart immunohistochemistry were manually counted for cTnT+ and pH3+ cells. Results: Of the total cTnT+ cells in random transverse sections from E13.5 mouse hearts cultured in DMEM and DMEM supplemented with NGF for 24 hours, approximately 2.20.2% and 5.10.1% of cardiomyocytes respectively were also positive for pH3. E13.5 mouse hearts exposed to NGF for 24 hours induced a 2.30.2 fold increase in pH3+ cTnT+ cells (p<0.001, n¼3) compared to DMEM controls. Taken together, these data would suggest that NGF increased mitosis of cardiomyocytes in E13.5 mouse heart explant cultures. E13.5 mouse hearts cultured in DMEM supplemented with NGF for 2 hours increased Nrg1 and ErbB4 mRNA transcript levels by 2.260.48 fold (p<0.05, n¼3) and 3.270.76 fold (p<0.05, n¼3) respectively compared to hearts cultured in DMEM controls. This
e142
suggests that NGF mediates this effect through the NRG1/ErbB4 cardiomyocyte proliferation pathway. Conclusion: In summary, this study validated that NGF promotes cardiomyocyte proliferation in mammals, which may be mediated through the Neuregulin1/ErbB4 pathway. Further studies are required to determine if NGF can increase adult mammalian cardiomyocytes to proliferate. Disclosure of Interest: None Declared
PM398 Mechanisms Underlying High Temperature-Induced Arrhythmogenesis In An Experimental Model Of Brugada Syndrome Rocio Picon*1, Jose Di Diego2, Charles Antzelevitch3 1 Cardiology, Hospital Universitario Virgen De Valme, Seville, Spain, 2Experimental Cardiology, 3 Director of Research, Masonic Medical Research Laboratory, Utica, United States Introduction: It well known that in some cases of Brugada syndrome (BrS) a febrile state can unmask or exacerbate the electrocardiographic and arrhythmic manifestations of BrS Objectives: In this study, we examine the effect of high temperature in a coronary-perfused right ventricular wedge preparations treated with and sodium channel current (INa) blocker and transient outward current (Ito) agonist to pharmacologically model BrS. Methods: Canine right ventricular wedge preparations (2x1x1 cm; n¼ 18) were coronary perfused with Tyrode’s solution and bubbled with O2/CO2 (95%/5%) at 370.5oC. Ajmaline (5-10 mM), an INa blocker and the Ito activator NS5806 (5-10 mM) were used to pharmacologically model BrS-related SCN5A and KCND3 mutations. Pacing was applied to the endocardial surface at basic cycle lengths of 500 and 2000 ms. Floating glass microelectrodes were used to simultaneously record intracellular action potentials from subendocardium and subepicardium (Epi) together with a transmural ECG recorded across the bath. Coronary perfusate temperature was varied over a range of 37 to 40 C. Results: Elevating temperature to 40 C resulted in abbreviation of repolarization and reduction of the Epi AP notch, under control conditions as well as under conditions that mimic the ECG phenotype of BrS, suggesting reduced arrhythmic risk at 40 C. Conclusion: Our results suggest that reduction of peak INa and augmentation of peak Ito alone are not sufficient to recapitulate the response to high temperatures in the setting of BrS. Our data support the notion that other factors including temperature-mediated effects on already defective ion channel gating (e.g., accelerated inactivation of INa), further reduction of already impaired trafficking, and possibly release of endogenous cytokines, may underlie the higher arrhythmia risk of BrS patients during fever. Disclosure of Interest: None Declared PM399 Chronic High Salt Intake Induces Myocardial Autophagic Vacuolization and Accelerates Left Ventricular Dysfunction in Spontaneously Hypertensive Rats Ying Bi1, Xin Zhou1, Wen-Jie Ji1, Shan Zeng1, Guo-Hong Yang1, Tie-Min Jiang1, Yu-Ming Li1, Zhao-Zeng Guo*1 1 Institute of Cardiovascular Disease and Heart Center, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Pingjin Hospital, Logistics University of Cpapf, Tianjin, China Introduction: Chronic high salt (HS) intake is associated with left ventricular (LV) hypertrophy and progression to systolic and diastolic dysfunction. Autophagy is an essential, life-sustaining renewal process that involves the degradation of cell constituents, when subjected to cellular stress or during certain stages of development. The involvement of autophagy in HS intake-accelerated LV remodeling progression remains unclear. Objectives: To investigate the dynamic of autophagic activation and its association with the functional and structural transition from compensated left ventricular (LV) hypertrophy to decompensation during chronic HS challenge in spontaneously hypertensive rats (SHR) Methods: SHR and Wistar Kyoto (WKY) rats were fed low-salt (LS, 0.5% NaCl) and HS (8.0% NaCl) diets and were subject to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Results: A global activation of autophagy-associated key components, as well as increased cardiomyocyte autophagic vacuolization by transmission electron microscopy, was observed after 12 weeks of HS challenge, along with a transition from compensated to decompensated LV hypertrophy during this period, as shown by a progressive impairment of the SHR LV function. Myocardial tonicity-responsive enhancer binding protein, a transcription factor induced by osmotic stress, was significantly upregulated in HS fed rats, thus providing evidence that supports myocardial interstitial hypertonicity by chronic HS intake. The global activation of autophagy and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. An in vitro study using rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species (ROS)-dependent enhancement of the autophagic response when exposed to an increased extracellular [Na+]. Conclusion: This work depicts the kinetics of myocardial autophagy during the transition from compensated LV hypertrophy to decompensated heart failure after HS challenge in SHR and reveals a novel mechanism by which interstitial hypertonicity-induced cytosolic [Na+] elevation triggers an ROS-dependent autophagy activation. Disclosure of Interest: None Declared
GHEART Vol 9/1S/2014
j
March, 2014
j
POSTER/2014 WCC Posters