Role of Exercise and Low-Dose Rapamycin on Age-Associated Impairments in Older Adults With Coronary Artery Disease: Cardiac Rehabilitation And Rapamycin in Elderly (CARE) Trial

Participants:

Pilot study: Patients, 60 years or older, selected for this single-center open label pilot study will be consented for participation at initiation of CR following PCI or CABG. We will enroll up to 18 patients; no more than 6 patients will receive a dose at one of the three proposed levels:0.5mg, 1.0mg, and 2mg daily oral rapamycin for the duration of CR (typically 12 weeks). We will perform physical performance tests for frailty assessment, short-form 12 for quality of life, and tests for SASP [(IL-6), matrix metalloproteinase (MMP) 3, and monocyte chemotactic protein (MCP) 1], and abdominal/thigh subcutaneous adipose biopsy for measurement of adipocyte mitochondrial DNA copy number and to quantitate the number of senescent preadipocytes. at baseline and at the conclusion of CR. Fasting lipid panel will be performed at baseline and at the completion of CR. Baseline complete blood count, liver, and kidney functions will be performed. These tests will be repeated at 14 days, 30 days, 8 weeks, and at the completion of CR. Serum rapamycin levels will be measured at 7, 14, 30 days, and at the completion of CR. The serum levels of the drug will be kept below 6ng/ml. If the drug levels were found to be higher, next low dose of the medication will be prescribed. Participants with serious side effects (appendix) from the medications will be withdrawn from the study.

Patients will be enrolled in sets of three. Thirty days of monitoring must pass on all three subjects before three more may be enrolled. The first three patients will be assigned to the 0.5 mg dose level. If two patients of those three have serious adverse events, the pilot study will be terminated. If 1 of 3 patients has an serious adverse event, we will enroll three more subjects at the 0.5 mg level. If those three have no serious events or if there were no events in the first three subjects, then we will proceed to enroll three subjects at the 1.0mg level. Otherwise, if there are 2 or more serious events in the 6 patients assigned to 0.5mg, we will terminate the study. We will proceed similarly with the 1.0 mg level before enrolling patients to the 2.0 mg level. If we observe 2 serious events at the 1.0 mg level and only 3 patients have been enrolled at the 0.5mg level, we will finish the pilot by enrolling 3 more at the 0.5 mg level. Similarly, if we observe 2 serious events at the 2.0 mg level and only have 3 subjects (with 0 events) at the 1.0 level, we will enroll 3 more at the 1.0 level.

Randomized Trial: The Cardiac rehabilitation And Rapamycin in Elderly (CARE) study is a prospective, randomized, phase 2 clinical trial that will be done at Mayo Clinic, Rochester, MN. The pool of potential study participants will consist of all patients 60 years or older with CAD who are referred to the CR following PCI or CABG. To minimize the drop out rate, we will obtain consent at the end of first week of CR participation, since most patients who quit CR do so in the first week. Consent will be obtained by the study coordinator.

Baseline Assessment: