Patients with chronic heart failure (HF) are characterized by disability and exercise intolerance which impair their quality of life and depict major source of morbidity in this population. Cardinal determinants of these characteristics include excessive exercise pressor reflex, premature fatigue, and exertional dyspnea. Abnormally elevated neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents might play a key role in these abnormalities. However, even in healthy humans, our understanding of the exact role/relative contribution of group III/IV afferents to the circulatory and ventilatory control during exercise and the development of fatigue is incomplete. By studying both HF patients and age- and activity-matched healthy controls (CTRLs), we will evaluate the impact of HF on the relative contribution of these muscle afferents to a) the circulatory/ventilatory control, and b) the development of central and peripheral fatigue during exercise. Additionally, the proposed research will examine whether HF affects the expression of genes linked to metabosensitive receptors on muscle afferents and the functional impact of these changes in terms of central fatigue. Specifically, we will use lumbar intrathecal fentanyl to block the central projection of group III/IV muscle afferents during exercise (no concomitant effect on feedforward drive). This unique, previously proven approach will enable us to evaluate the effects of group III/IV muscle afferents on leg blood flow, heart rate, blood pressure and ventilation during large and small muscle mass rhythmic exercise (bicycle and single leg knee-extension), and the development of central and peripheral fatigue (using magnetic femoral nerve stimulation techniques). Furthermore, we will take baseline and post-exercise blood samples from HF patients and CTRLs to determine the expression (mRNA) of ASIC3, P2X, and TRPV1 metaboreceptors on leukocytes in each population. Finally, to determine the specific contribution of these metabosensitive molecular receptors to the development of central fatigue in HF patients and CTRLs, we will perform an intramuscular infusion of a "metabolite soup" into the unfatigued quadriceps muscle. We have designed the "soup" to exclusively activate ASIC3, P2X, and TRPV1 metaboreceptors and have previously verified its specificity in published animal and human studies. Based on recent findings suggesting blunted metaboreceptor sensitivity in HF patients vs. CTRLs, we expect, following the specific stimulation of metaboreceptors due to the intramuscular soup infusion, greater central fatigue in CTRLs vs HF patients. The results from this analysis will contribute to a better understanding of the role of metaboreceptors as a potential mechanism underlying central fatigue and reflex abnormalities characterizing exercising HF patients. Combined, this research will provide new insight into the impact of HF on neural feedback and its role in the control of circulation and ventilation and the development of fatigue during physical activity. Furthermore, our experiments will identify potential molecular targets for therapeutic interventions with the overall purpose to improve the quality of life in patients with HF.

Public Health Relevance

This research in humans with heart failure will provide new information on the mechanisms accounting for the altered blood flow, excessive blood pressure, severe breathlessness and high fatigability/ premature fatigue characterizing these patients during physical activity. These limitations not only cause disability, but also account for the hig mortality in this population. We will focus on the role of nerves originating in working limb muscles in determining these abnormalities. The results from our research will identify potential targets for therapeutic interventions, with the overall purpose of improving the quality of life of patients with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116579-02
Application #
8617297
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Keleti, Julianna
Project Start
2013-04-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$365,050
Indirect Cost
$120,050
Name
University of Utah
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Dempsey, Jerome A; Blain, Gregory M; Amann, Markus (2014) Are type III-IV muscle afferents required for a normal steady-state exercise hyperpnoea in humans? J Physiol 592:463-74
Sidhu, Simranjit K; Weavil, Joshua C; Venturelli, Massimo et al. (2014) Spinal ?-opioid receptor-sensitive lower limb muscle afferents determine corticospinal responsiveness and promote central fatigue in upper limb muscle. J Physiol 592:5011-24
Pollak, Kelly A; Swenson, Jeffrey D; Vanhaitsma, Timothy A et al. (2014) Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects. Exp Physiol 99:368-80
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