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 eld...