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P26
Combined Treatment with Exercise Training and Losartan Ameliorates Metabolic
Dysfunction in the Failing Heart
Morten André Høydal1, Ole Johan Kemi3, Per Magnus Haram1, Anne Garnier4, Renee VenturaClapier4, Øyvind Ellingsen1,2
1
Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of
Science and Technology, Trondheim, Norway
2 Department of Cardiology, St Olavs Hospital, Trondheim, Norway
3 Institute of Biomedical and Life, University of Glasgow, UK.
4 Université Paris Sud, Faculté de Pharmacie, Paris, France
Aim: Current clinical approaches for post-myocardial infarction heart failure include exercise training
and pharmacological strategies. However, few studies have investigated how combined treatment with
those two separates from exercise training or medication alone.
Method and results: We established cardiac metabolic dysfunction in post-myocardial infarction heart
failure, before starting combined or separate treatment interventions with exercise training and
losartan, and Angiotensin II type I (AT1) receptor antagonist. Following left coronary artery ligation in
Sprague-Dawley rats, losartan was distributed after 1 week, whereas aerobic interval exercise training
at 85-90% of maximal oxygen uptake was initiated 4 weeks post-infarction. Overall, combined
treatment yielded best outcome for ventricular pressure characteristics and exercise capacity.
Metabolic dysfunction was indicated in myocardial tissue in heart failure, as observed by reduced
enzyme activities of creatine and adenylate kinase systems, citrate synthase, cytochrome c oxidase,
and, to a lesser degree, lactate dehydrogenase. Gene expression levels of cytochrome c oxidase and
peroxisome proliferator-activated receptor gamma coactivator 1  (PGC1), a key regulator of
mitochondrial biogenesis and homeostasis tended to decrease in heart failure. Combinatorial
treatment with exercise training and losartan partly or fully restored metabolic enzymes and PGC1
gene expression towards healthy levels, whereas exercise training or losartan alone had less order of
magnitude effects; in fact, losartan alone appeared to further reduce activity in enzymes involved in
energy shuttling and ATP production.
Conclusion: Cardiac metabolic dysfunction in heart failure is ameliorated when losartan is given jointly
with a controlled, rigorous exercise training program.