Efficacy of exercise training in patients with HFpEF

ABSTRACT
Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by exercise intolerance
and premature fatigue during physical activity. An abnormal exercise pressor reflex mediated by neural feedback
from mechano- and/or metabosensitive group III and IV muscle afferents may contribute to these debilitating
symptoms. However, little is known about the role and relative contribution of group III/IV afferents in circulatory
control and fatigue development in patients with HFpEF. By studying both patients with HFpEF and well-matched
controls, we will evaluate the contribution of these muscle afferents to circulatory control and fatigue
development, factors recognized to be major contributors to exercise intolerance. We will use lumbar intrathecal
fentanyl to block the central projection of group III/IV muscle afferents during voluntary and passive exercise (no
concomitant effect on feedforward drive). This proven approach will enable us to evaluate, and distinguish
between, the effects of group III and IV muscle afferents on central and peripheral hemodynamics during
exercise, the exercise-induced development of central and peripheral fatigue (femoral nerve stimulation
techniques), and on exercise tolerance. We will also study muscle morphometry, baroreflex and chemoreflex
sensitivity, and investigate intramuscular metabolic changes of the quadriceps during exercise using
31phosphorus magnetic resonance spectroscopy to evaluate disease-related alterations in cardiovascular reflex
sensitivity and intrinsic muscle characteristics as a potential factor determining alterations in circulatory control
and fatigue resistance in patients with HFpEF. Finally, we will repeat these studies after a supervised 12-week
knee-extension exercise training program, allowing us to investigate the effect of chronic exercise on the role of
group III/IV muscle afferents in the hemodynamic response to exercise, the development of fatigue, and,
ultimately, exercise tolerance. If this project confirms a significant contribution of group III/IV muscle afferents to
the exercise intolerance exhibited by patients with HFpEF, and that chronic exercise can alleviate these
impairments, the proposed work will provide the scientific basis for a paradigm shift in the treatment of this
growing population.

Grant Number: 5I01RX003343-05
NIH Institute/Center: VA
Principal Investigator: MARKUS AMANN