Similar to primary prevention (WP1), the benefit of exercise training and the related physiological and molecular mechanisms are also not understood in clinically manifest HFPEF. In addition, there is still controversy regarding the level and format of exercise that can yield the most benefit in treating HFPEF, and whether this may delay the severity of disease or even mortality.

To analyze the impact of different training regimes on different molecular alterations, as identified by another ongoing EU project (MEDIA, PI: Walter J. Paulus), we will analyze Dahl-salt-sensitive rats with established HFPEF before and after a training intervention. We will also compare the effects of the different exercise programs on physiological and molecular markers obtained from another ongoing EU project where we contribute with biological material, aimed to understand biological networks which influence health (META-PREDICT, PI: James Timmons, external link). The focus of our analyses will be the myocardium, the skeletal muscle as well as the vascular system. In addition, we will include follow-up data on separate animals randomized to the different exercise protocols, investigating development of clinical symptoms and mortality.

Objectives
1. To optimize the dose-response relationship of exercise as a therapeutic strategy on left ventricular diastolic dysfunction and exercise capacity (peakVO2) in a rat model with established HFPEF
2. To optimize the dose-response relationship of exercise as a therapeutic strategy on:
a. Heart (Determinants of myocardial stiffness: Extracellular matrix environment, cardiomyocyte Ca2+ handling and excitation-contraction coupling, energy production, PKG/NO dependency)
b. Blood vessels (Molecular determinants of endothelial dysfunction in arteries, vascular stiffness)
c. Skeletal muscle (Determinants of exercise intolerance: energy production, anabolic and catabolic pathways, expression and secondary modification of contractile proteins)
3. To identify and test potential novel targets (mRNAs/miRs) through which exercise training elicits therapeutic efficacy in the setting of established HFPEF.
4. To analyze the effect of exercise on morbidity and mortality in established HFPEF.

Work description
All the tasks in WP2 will compare the effect of three clinically relevant endurance protocols as treatment strategy for HFPEF. The impact of the three training protocols on left ventricular diastolic dysfunction, exercise capacity (peakVO2) and molecular alterations in heart, vessels and skeletal muscle will be analyzed. In addition the impact on morbidity and mortality will be studied.

WP2 leader is Ulrik Wisløff, The Norwegian University of Science and Technology (NTNU).