PRIME HRrEF: Novel Exercise for Older Patients with Heart Failure with Reduced Ejection Fraction

Abstract.
Heart failure (HF) is the leading cause of hospitalization among Americans ≥65 years old with 5.7 million
sufferers and an annual of ~$39.2 billion. Patients with HF suffer from shortness of breath, fatigue and exercise
intolerance. Improving VO2peak is an important clinical goal in HF as it is correlated with reduced mortality rate
and increased quality of life. Exercise rehabilitation is considered class IA recommendation for people with HF,
with guidelines recommending moderate-intensity aerobic modalities, often in conjunction with resistance
training (AT+RT). A key limitation of these guidelines is that they arise largely from data involving a patient
cohort sometimes two decades younger (range 51-81 yrs) than the median age of diagnosis for HF (77 yrs).
Considering that older adults with HF experience a high prevalence of co-morbidities, impaired functional
capacity, reduced muscle mass and strength, and a 5-year survival of 25%, it is unclear whether the current
exercise guidelines can be tolerated by and generate functional benefits by a majority real-world HF patients.
It is well accepted that impairments in peripheral tissues including; decreased muscle blood flow, decreased
muscle mass, and abnormal muscle metabolism have a significant contribution to the reduced exercise capacity
in patients with HF. In fact, many older patients with HF exhibit the sequelae of sarcopenia, which independently
carries an ominous prognosis. Accordingly, we have developed and pilot tested the “Peripheral Remodelling
via Intermitted Muscular Exercise” (PRIME) approach. PRIME offers a low mass, high repetition, localised
stimulus to peripheral muscles and tissues, without imposing central cardiorespiratory strain. In an exploratory
study which informed the current proposal, 19 subjects with HFrEF (>65yr, VO2peak=13.5ml/kg/min) increased
VO2peak, anaerobic threshold and maximal strength with 4 weeks of PRIME followed by 4 weeks of AT+RT. The
“control” group performed AT+RT for the whole 8 weeks and only increased maximal strength.
We propose to expand on this promising data to definitively determine in an intent-to-treat trial enrolling 92
patients with HFrEF randomized to either: (A) 4 weeks of PRIME followed by 8 weeks of AT+RT, or: (B) 12
weeks of AT+RT. Data at baseline and following the 12-week interventions will be used to determine; (Aim1)
group changes in VO2peak during maximal cycle exercise (secondary clinical outcomes of muscle strength and
activities of daily living); (Aim2) group changes in central and peripheral hemodynamics and tissue perfusion.
Exploratory aims will examine blood markers of CHF severity, questionnaires for quality of life and skeletal
muscle mediators of VO2peak (opt-in biopsy). We will perform a 6-month post training assessment for durability
of any changes in fitness and function.
This study represents an important step in closing the age-bias seen in clinical exercise studies. If PRIME is
shown to benefit elderly patients with HFrEF it may better inform exercise rehabilitation guidelines for these
individuals.

Grant Number: 5R01AG075556-04
NIH Institute/Center: NIH
Principal Investigator: Jason Allen