PROJECT SUMMARY Clinical events and hospitalization can be physically disabling, especially for older adults because of their reduced physiological reserve. Cardiovascular disease (CVD) is the leading cause of hospital-acquired disability in older adults, and many patients fail to remediate losses in physical functional capacity. To correct these disabling effects, cardiac rehabilitation (CR) was established with exercise training as its foundation. Moderate intensity continuous aerobic training (MICT) and moderate intensity resistance training (MIRT) are core components of CR designed to improve functional capacity, with peak oxygen uptake (VO2peak) the primary metric used to gauge its effectiveness. Despite clear functional and survival benefits of MICT+MIRT training, some groups of patients who enroll in CR receive less functional benefit. Attention has focused on high intensity interval aerobic training (HIIT) as an alternative intervention because it yields greater improvements in VO2peak compared to MICT. However, neither of these aerobic training protocols address skeletal muscle size and weakness that occur with aging, are exacerbated by hospitalization and limit exercise- induced physical functional gains in older adults. While guidelines include MIRT in standard CR exercise programs, it has minimal effects to remediate fundamental deficits in muscle size and contractility in older adults. Thus, there is an unmet clinical need for innovative, multi-modal exercise interventions to optimize gains in VO2peak and physical function with CR exercise that address specific limitations found in older adult patients. Building on our strong published and preliminary data, the current proposal addresses this need by testing the efficacy of combined HIIT+ high intensity resistance training (HIRT) to improve VO2peak and physical function in patients eligible for CR compared to standard of care MICT+MIRT. We hypothesize that HIIT+HIRT will promote greater functional improvements due to greater gains in skeletal muscle fiber size and function. To test this hypothesis, we will evaluate patients eligible for CR using a rigorous, RCT design, with a sub-set of patients undergoing assessments to examine the effects of each training program at the organ, tissue, and cellular levels to define mediators of the benefits of exercise on functional capacity. Successful completion of the proposed studies would challenge current clinical practice and advance a novel multi-modal CR exercise paradigm to optimize improvement in VO2peak, physical function and clinical outcomes in older adults and generate foundational knowledge of the mechanisms whereby these exercise modalities modulate function capacity. Demonstration of the efficacy of HIIT+HIRT within CR, the largest, structured clinical rehabilitation program that serves older adults, would provide a strong impetus to broaden the use of high intensity exercise paradigms among healthy, older adults and patient popul...