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Periodic Report Summary 2 - OPTIMEX (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure)

Project Context and Objectives:
Heart Failure with Preserved Ejection Fraction (HFpEF) currently affects more than 7 million Europeans and is the only cardiovascular disease with increasing prevalence and incidence. A cardinal feature of the disease is substantially reduced exercise-tolerance associated with pathophysiological disturbances both centrally (myocardium, hemodynamics) and peripherally (blood vessel- and skeletal muscle function). No pharmacological agent has yet shown to improve symptoms or prognosis. The most promising way to improve pathophysiology and deprived exercise-tolerance in HFpEF patients seems to be exercise training, but the optimal dose of exercise to improve and maximize clinical and mechanistic data are very limited.

OptimEx focus on the cardiovascular effects of exercise training in primary and secondary prevention of HFpEF. We direct our research to find the optimal dose of exercise to improve pathophysiology, prevent disease development and reverse the disease state in HFpEF. Therefore, we combine in vivo and in vitro studies in rats and humans in serial experiments with similar exercise protocols that will advance our understanding of fundamental cellular and molecular mechanisms underpinning dose-dependent exercise-induced changes in heart, blood vessels and skeletal muscles in HFpEF. In addition, we perform a clinical European multicentre trial introducing exercise training in addition to best practice therapy (traditional risk factor management, mainly blood pressure lowering medication) that enable us to determine the additional effect of exercise training beyond current treatment and guidelines.
The major objectives of OptimEx are:
a) to understand the effect of the volume (frequency x intensity x duration) of exercise interventions on structural and functional outcome parameters in animal models at risk for or with HFpEF
b) to gain mechanistic insight into pathophysiological pathways affected by exercise training in HFpEF
c) to establish the optimal volume of exercise training on structural and functional outcome in patients with established HFpEF in a prospective European multicenter trial
d) to introduce and investigate a novel telemedicine approach, in the context of exercise training in HFpEF in order to optimize adherence, supervision, and economic aspects of the intervention
e) to identify potential novel therapeutic targets for future pharmacotherapies for this syndrome

Project Results:
Through a series of experiments, we compared two clinically relevant training regimens to prevent development of HFpEF and to evaluate its effects on pathophysiological mechanisms as well as on potential novel biomarkers. Female Dahl salt-sensitive rats fed a high-salt diet were used as HFpEF model. Cardiac function and structure were assessed by echocardiographic and invasive hemodynamic measurements, while molecular signalling was investigated with Western immunoblotting, microRNA array and RT-qPCR. Exercise training was performed as intensity-controlled running (MCT: moderate-intensity continuous training; HIIT-LV: high-intensity interval training in low volume; and HIIT-HV: high-intensity interval training in high volume). All three exercise regimens improved exercise capacity in HFpEF, with superior results found in HIIT-HV and MCT, as compared to HIIT-LV. HIIT-HV and MCT prevented diastolic dysfunction in vivo and reduced incidence of HFpEF, without major effects on cardiac structure. HIIT-HV also prevented HFpEF-induced imbalance of circulating microRNA levels, which may support diagnostic strategies in HFpEF. Most importantly, this is the first study to show that exercise training delays development of HFpEF and HIIT-HV, but not MCT, reduces mortality rates. Together, these findings show HIIT-HV is the most time-efficient protocol for preventing development of HFpEF and improving survival rates in an animal model. Through a series of in vivo and in vitro studies we have demonstrated that the obese ZSF1 rat model (ZSF-1 HFpEF) is a more relevant model than the Dahl salt-sensitive model when it comes to studying the effect of exercise as secondary prevention in HFpEF. Our data shows that exercise training, as a secondary prevention of HFpEF improved exercise capacity with no clear benefits on diastolic function in the ZSF1 obese rat. Interestingly, when studying cardiomyocyte characteristics and function we observed that ZSF-1 HFpEF was associated with reduced cardiomyocyte Ca2+ transient amplitude and SR Ca2+ content but unchanged Ca2+ transient kinetics. Preliminary analysis suggests that MCT but not HIIT worsened cellular Ca2+ handling in this HFpEF model. Furthermore, endothelial function (endothelial-dependent and endothelial-independent) was significantly impaired in ZSF-1 HFpEF. Both training intervention, HIIT and MCT, improved endothelial dysfunction possibly due to modulation of NO bioavailability. Our findings also demonstrate that ZSF-1 HFpEF was associated with significant impairment in absolute force generation in the soleus and EDL muscles. Moderate continuous and HIIT had no impact on force generation and fatigue.

Potential Impact:
Expected final results and their potential impact: Ageing of populations explains in part why HFpEF is the only cardiovascular disease with increasing prevalence and incidence, affecting 10-20% of the elderly and contributing substantially to hospitalizations of elderly HF patients. Although the prognosis of HFpEF patients is slightly better than for those with HF with Reduced EF (HFrEF), the 3-year fatality rate approaches 25%. As a result, the economic, social and personal burden of HFpEF is enormous. Therefore, this disease constitutes one of the most pressing unmet clinical needs in Europe. OptimEx addresses central objectives set by the last work program of the FP7 in view of the new orientations given by the Europe 2020 strategy and the European Innovation Partnership for “active and healthy ageing”. This research aims to tackle one of the major health problems the developed world faces with increasing sedentarism, obesity and ageing, all of which are known to increase the prevalence of HFpEF and will support sustainable health systems in EU member states through improvements in the clinical management of a common and disabling disease. The project is therefore highly relevant to improve the health of European citizens in every country and important to promote healthy ageing and preventing disease.

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