ABSTRACT
RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.
Subject(s)
Cardiomegaly/metabolism , Gene Knockdown Techniques/methods , Glucose/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Signal Transduction/genetics , Animals , Cardiomegaly/diet therapy , Cardiomegaly/genetics , Cardiomegaly/prevention & control , Cells, Cultured , Diet/methods , Disease Models, Animal , Enzyme Activation/genetics , Glucose-6-Phosphatase/metabolism , Isomerases/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocytes, Cardiac/metabolism , Oxidation-Reduction , Phosphorylation/genetics , Sirolimus/administration & dosage , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/metabolismABSTRACT
BACKGROUND: Phase of care mortality analysis (POCMA) is a quality improvement tool categorizing triggers for mortality into phases of patient care. However, the relationship between a patient's risk profile and the triggers for mortality is incompletely understood. METHODS: POCMA was implemented for cases with available Society of Thoracic Surgeons (STS) risk models. Risk-adjusted rates were obtained from the STS database. Mortality triggers were categorized by the phase of occurrence (preoperative, intraoperative, intensive care unit [ICU], postoperative floor, and discharge). Patients were then stratified by STS risk score: low risk (<4%), intermediate (4% to 8%), and high risk (>8%). RESULTS: A total of 3,919 isolated coronary artery bypass grafting (CABG), 901 isolated valve, and 321 CABG plus single-valve procedures were performed from 2012 to 2018, with 4.6% crude mortality and a median STS risk score of 5.8%. POCMA was performed on 67 patient mortalities, with triggers occurring in the following phases of care: 49.3% preoperative, 13.4% intraoperative, 23.9% ICU, 3.0% postoperative floor, and 10.4% discharge phase. Mortality distribution was bimodal, occurring mostly in low-risk (37.3%) and high-risk (38.8%) patients. For low-risk patients, the trigger for mortality most frequently occurred during the postoperative ICU phase, while for high-risk patients, the trigger for mortality most frequently occurred during the preoperative phase. CONCLUSIONS: Mortality had a bimodal distribution with respect to patient risk profile. Phase-of-care triggers for mortality differed according to patient risk profile: low-risk triggers during the postoperative ICU phase versus high-risk triggers typically during the preoperative phase. Specific focus on phases according to the patient's risk profile represents an opportunity to improve quality and outcomes.