Background of the study - why exercise as medicine?

Research has shown that the poor clinical outcome in patients with HFPEF is not explained by age, gender, nor the high prevalence of cardiovascular risk factors and co-morbidities. The underlying mechanisms and therefore treatment options are thus incompletely understood.

Photo: NTNU/Geir MogenThe pharmacological therapy of HFPEF to improve outcome and symptoms has been particularly disappointing. Several large trials using established pharmacological strategies in HFPEF have failed to convincingly demonstrate substantially improved symptoms, morbidity or mortality in HFPEF. Clinical heart failure trials have also been conducted by members of our research group, either as principal investigator or member of the steering committee. Som examples of pharmaceutical approaches are neprilysin inhibition (the PARAMOUNT trial, n=301)1, and mineralocorticoid receptor blockade (Aldo-DHF trial, n= 422)2.

On the other hand, exercise is emerging as a promising way to improve exercise intolerance in patients with low exercise capacity and cardiovascular risk factors. In addition, exercise training may exert beneficial effects on a number of pathophysiological components in patients with HFPEF. From a pathophysiological point of view, exercise could by far outweigh any pharmacological intervention in this heterogeneous syndrome, since lifestyle dependent risk factors, physical inactivity, and physical deconditioning largely contribute to the progressive development of HFPEF.

Diastolic heart failure and exercise, photo: NTNU/Geir MogenSmall randomized trials involving exercise in HFPEF patients3,4,5 showed improvements in peakVO2 of about 20%. Our own group conducted the largest proof-of concept exercise training study in HFPEF published so far. In this prospective, randomized controlled multi-center study3, we observed beneficial effects of exercise training on cardiac structure and diastolic function that directly translated into improved exercise capacity. However, our pilot study did neither address mechanistic aspects, long-term effects, nor the optimum mode and dose of exercise interventions in this common disease.

In addition, our overall interest in the topic of exercise intervention has been the assessment of different exercise regimens particularly focusing on dose of endurance training. In this context, we and others have shown uniform and superior effects of endurance exercise regimes at higher intensities vs. low to moderate intensities on maximal exercise capacity, metabolism and even myocardial function in patients with metabolic syndrome, hypertension, coronary artery disease and heart failure. So far, however, the role of exercise dose in HFPEF has not been investigated. Since metabolic syndrome and hypertension, which are successfully influenced by high intensity interval training (HIT), are prevalent in the HFPEF population, we expect to find an optimized exercise protocol in these patients as well.

1 Solomon SD, et al. The angiotensin rceptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. Lancet. 2012 Oct 20;380(9851):1387-95.
2 Edelmann F, et al. Rationale and design of the 'aldosterone receptor blockade in diastolic heart failure' trial: a double-blind, randomized, placebo-controlled, parallel group study to determine the effects of spironolactone on exercise capacity and diastolic function in patients with symptomatic diastolic heart failure (Aldo-DHF). Eur J Heart Fail. 2010 Aug;12(8):874-82.
3 Edelmann F, et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. Am J Coll Cardiol 2011, 58; 1780-1791.
4 Kitzman DW, et al. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail. 2010 Nov;3(6):659-67.
5 Smart NA, et al. Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. Congest Heart Fail. 2012 Nov-Dec;18(6):295-301.