E Rosalie Witjas-Paalberends1, Ahmet Güçlü2, Tjeerd Germans3, Paul Knaapen3, Hendrik J Harms4, Alexa M C Vermeer5, Imke Christiaans5, Arthur A M Wilde6, Cris Dos Remedios7, Adriaan A Lammertsma4, Albert C van Rossum3, Ger J M Stienen8, Marjon van Slegtenhorst9, Arend F Schinkel10, Michelle Michels10, Carolyn Y Ho11, Corrado Poggesi12, Jolanda van der Velden13. 1. Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands e.paalberends@vumc.nl a.guclu@vumc.nl. 2. Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands ICIN Netherlands Heart Institute, Utrecht, The Netherlands e.paalberends@vumc.nl a.guclu@vumc.nl. 3. Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. 4. Department of Radiology and Nuclear Medicine, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands. 5. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 6. Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands. 7. Institute for Biomedical Research, Muscle Research Unit, University of Sydney, Sydney, Australia. 8. Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands Department of Physics and Astronomy, VU University, Amsterdam, The Netherlands. 9. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. 10. Thorax Center, Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. 11. Brigham and Women's Hospital, Cardiology, Boston, MA, USA. 12. Department of Physiology, University of Florence, Florence, Italy. 13. Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands ICIN Netherlands Heart Institute, Utrecht, The Netherlands.
Abstract
AIMS: Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. METHODS AND RESULTS: Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. CONCLUSION: We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of humanHCM disease. METHODS AND RESULTS: Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. CONCLUSION: We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Jolanda van der Velden; Carolyn Y Ho; Jil C Tardiff; Iacopo Olivotto; Bjorn C Knollmann; Lucie Carrier Journal: Cardiovasc Res Date: 2015-01-28 Impact factor: 10.787
Authors: Paul J M Wijnker; Vasco Sequeira; Diederik W D Kuster; Jolanda van der Velden Journal: Antioxid Redox Signal Date: 2018-04-11 Impact factor: 8.401