Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands e.paalberends@vumc.nl a.guclu@vumc.nl.
E Rosalie
ER
Witjas-Paalberends
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.
Ahmet
A
Güçlü
Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Tjeerd
T
Germans
Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Paul
P
Knaapen
Department of Radiology and Nuclear Medicine, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
Hendrik J
HJ
Harms
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Alexa M C
AM
Vermeer
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Imke
I
Christiaans
Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Arthur A M
AA
Wilde
Institute for Biomedical Research, Muscle Research Unit, University of Sydney, Sydney, Australia.
Cris
C
Dos Remedios
Department of Radiology and Nuclear Medicine, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
Adriaan A
AA
Lammertsma
Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Albert C
AC
van Rossum
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.
Ger J M
GJ
Stienen
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Marjon
M
van Slegtenhorst
Thorax Center, Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Arend F
AF
Schinkel
Thorax Center, Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Michelle
M
Michels
Brigham and Women's Hospital, Cardiology, Boston, MA, USA.
Carolyn Y
CY
Ho
Department of Physiology, University of Florence, Florence, Italy.
Corrado
C
Poggesi
Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands ICIN Netherlands Heart Institute, Utrecht, The Netherlands.
Jolanda
J
van der Velden
D008841:Actin Cytoskeleton / Q000235:genetics; D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009200:Myocardial Contraction / Q000235:genetics* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics*; D012518:Sarcomeres / Q000235:genetics / Q000473:pathology; D000099163:Myosin Binding Protein C
D024722:Cardiac Myosins; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human
Hypertrophic cardiomyopathy; Mutation carriers; Myocardial efficiency; Sarcomere function; Sarcomere mutations