Year of grant:
2020

Research Area:
Heilsa

Project type:
Ph.d.-verkætlan

Project title:
Týdningur av angiotensin converting enzyme virkisstigi fyri tillaging til kropsliga venjing.

Grant number:
0352

Project manager:
Tórur Sjúrðarson

Institution/company:
Deildini fyri Heilsu og Sjúkrarøkt, Fróðskaparsetrið

Other participants:
Nikolai Baastrup Nordsborg, Magni Mohr, Pál Weihe, Kasper Kyhl, Noomi Gregersen, Guðrið Andorsdóttir, Anne-Mette Hvas, Erik Lerkevang Grove, Jakobina Kristiansen

Project period:
Planned: 01.09.2020- 31.08.2022
Actual: 01.09.2020- 21.12.2022

Total budget:
kr. 2.194.297

Grant from the FRC in DKK:
kr. 1.100.000

Project description:
Original
The present ACE follow-up͟ project lasts two years and will result in a ph.d. within ‘personalized exercise prescription͛ originating from the University of Faroe Islands and University of Copenhagen. The first year of the project has been completed in 2019, where 51 participants successfully completed an 8-week exercise training intervention in Torshavn.

Scientific background
Cardiorespiratory fitness or maximal oxygen uptake (VO2max) is a robust index of all-cause mortality. Human VO2max differs more than four fold in an age and gender-specific comparison and is generally improved by exercise training.
However, exercise training causes a highly individual increase of VO2max ranging from 0-50%. It is of obvious importance to determine the underlying mechanisms for the individual response to exercise training, since these directly influence health. Additionally, a deep phenotypic investigation is required, because VO2max is only a crude measure of cardio-respiratory capacity.
A potential decisive factor for the individual exercise training adaptation in humans is the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene. Thus, the present study utilizes a high number of obtained physiological measurements and samples from an exercise-training study including carriers of ACE II, ID and DD genotypes who were randomly allocated to treatment with the ACE inhibitor Enalapril ® in order to manipulate the resulting phenotype.
Project content
The primary tasks of the remaining 2 year ph.d. project is completion of the deep phenotype analyses. This will consist of muscle tissue analysis at the University of Copenhagen (7 months) as well as analyses of obtained echocardiography recordings (6 months) and cardiac magnetic resonance imaging (5 months) on the National hospital of the Faroe Islands.
Subsequently, the ph.d. candidate will be responsible for the publication process (3 months) and completing a thesis based on the large and demanding project (3 months).
Project outcome
The project will have several important outcomes: It will establish to which degree an individual variation exists in a high number of physiological variables in response to physical exercise. It will establish if the ACE genotype can predict the degree of adaptation to exercise and whether manipulation of the ACE phenotype impacts the exercise training response. All of these findings will greatly improve our understanding of personalized exercise prescription for health.

Final
Human exercise capacity is a strong prognostic marker of cardiac events and all-cause mortality in healthy and diseased individuals. Regular endurance training improves exercise capacity, but the extent of improvement varies between individuals. Thus, it is highly important to investigate why humans differ in their adaptability to exercise training. It has been suggested that the well-described angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism affects the adaptation to exercise training by determining the ACE activity phenotype. Importantly, the ACE phenotype can be manipulated pharmacologically by ACE inhibitors. The present thesis aimed to investigate the importance of ACE activity for exercise training adaptability in healthy individuals and patients with coronary artery disease.

Through exercise training interventions in healthy individuals and patients with coronary artery disease, and by obtaining a high number of physiological measurements before and after the interventions, the impact of the ACE I/D genotype for adaptation to exercise training was evaluated by determining the ACE genotype in all participants. In addition, by randomizing the healthy individuals to exercise training combined with ACE inhibitor treatment or exercise training combined with placebo, the impact of pharmacological ACE inhibition on multiple training-sensitive variables was established.

The results from the present thesis demonstrated that the magnitude of exercise-training-induced improvements in exercise capacity was independent of the ACE genotype in healthy individuals and patients with coronary artery disease. However, augmented lean body mass and left atrial volume expansion induced by exercise training in healthy individuals were abolished by concomitant ACE inhibition. Furthermore, ACE inhibitors appeared to reduce red blood cell volume but not exercise capacity gains in healthy individuals. Future studies should establish whether these findings can be replicated in relevant patient groups and whether treatment periodization can augment the outcome of exercise training in patient groups commonly treated with ACE inhibitors.

Project status:
Liðug

Project output:
PhD-project successfully defended on 31 March 2023

Scientific articles, books, thesis etc.

I. Sjúrðarson T, Bejder J, Breenfeldt Andersen A, Bonne T, Kyhl K, Róin T, Patursson P, Oddmarsdóttir Gregersen N, Skoradal MB, Schliemann M, Lindegaard M, Weihe P, Mohr M, Nordsborg NB. Effect of angiotensin-converting enzyme inhibition on cardiovascular adaptation to exercise training. Physiol Rep. 2022 Jul;10(13):e15382. doi: 10.14814/phy2.15382.

II. Sjúrðarson T, Bejder J, Breenfeldt Andersen A, Bonne TC, Kyhl K, Thomassen M, Prats J, Oddmarsdóttir Gregersen N, Skoradal MB, Weihe P, Nordsborg NB, Mohr M. Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial. Eur J Appl Physiol. 2022 Oct 22. doi: 10.1007/s00421-022-05072-5.

III. Kristiansen J, Sjúrðarson T, Grove EL, Rasmussen J, Kristensen SD, Hvas AM, Mohr M. Feasibility and impact of whole-body high-intensity interval training in patients with stable coronary artery disease: a randomised controlled trial. Sci Rep. 2022 Oct 14;12(1):17295. doi: 10.1038/s41598-022-21655-w. (shared co-first authorship)

IV. Sjúrðarson T, Kristiansen J, Nordsborg NB, Gregersen NO, Lydersen LN, Grove EL, Kristensen SD, Hvas AM, Mohr M. The angiotensin-converting enzyme I/D polymorphism does not impact training-induced adaptations in exercise capacity in patients with stable coronary artery disease. Sci Rep. 2023 Oct 25;13(1):18300. doi: 10.1038/s41598-023-45542-0. PMID: 37880303; PMCID: PMC10600103.

Publications outside the scientific community, i.e. lectures, periodicals, articles in newspapers, television and radio
Articles in newspapers
https://www.in.fo/news-detail/heilivagur-fyri-hoegt-blodtryst-tykist-minka-um-gagnid-av-venjing
https://www.setur.fo/fo/setrid/tidindi/heilivagur-fyri-hoegt-blodtryst-tykist-minka-um-gagnid-av-venjing
https://dagur.fo/fyrstu-kanningarurslitini-fra-ace-verkaetlan-kunngjord
https://www.gransking.fo/fo/tilfeingi/tidindi/heilivagur-tarnar-gagnligari-avirkan-av-venjing/
https://www.vp.fo/news/heilivagur-fyri-hoegt-blodtryst-tykist-minka-um-gagnid-av-venjing

Radio
https://kvf.fo/gmf?sid=146901&page=1



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