Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. Mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe(III)-citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion exaggerated cell death in these conditions. 2',7'-Dichlorodihydrofluorescein diacetate measurement of reactive oxygen species (ROS) production showed that erastin-induced ROS production was significantly lower in mTOR transgenic versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part, by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis.

Background: Inability to adhere to nutritional recommendations is common and linked to worse outcomes in patients with nutrition-sensitive conditions. Objectives: The purpose of this study is to evaluate whether medically tailored meals (MTMs) improve outcomes in recently discharged adults with nutrition-sensitive conditions compared with usual care. Research Design: Remote pragmatic randomized trial. Subjects: Adults with heart failure, diabetes, or chronic kidney disease being discharged home between April 27, 2020, and June 9, 2021, from 5 hospitals within an integrated health care delivery system. Measures: Participants were prerandomized to 10 weeks of MTMs (with or without virtual nutritional counseling) compared with usual care. The primary outcome was all-cause hospitalization within 90 days after discharge. Exploratory outcomes included all-cause and cause-specific health care utilization and all-cause death within 90 days after discharge. Results: A total of 1977 participants (MTMs: n=993, with 497 assigned to also receive virtual nutritional counseling; usual care: n=984) were enrolled. Compared with usual care, MTMs did not reduce all-cause hospitalization at 90 days after discharge [adjusted hazard ratio, aHR: 1.02, 95% confidence interval (CI), 0.86–1.21]. In exploratory analyses, MTMs were associated with lower mortality (aHR: 0.65, 95% CI, 0.43–0.98) and fewer hospitalizations for heart failure (aHR: 0.53, 95% CI, 0.33–0.88), but not for any emergency department visits (aHR: 0.95, 95% CI, 0.78–1.15) or diabetes-related hospitalizations (aHR: 0.75, 95% CI, 0.31–1.82). No additional benefit was observed with virtual nutritional counseling. Conclusions: Provision of MTMs after discharge did not reduce risk of all-cause hospitalization in adults with nutrition-sensitive conditions. Additional large-scale randomized controlled trials are needed to definitively determine the impact of MTMs on survival and cause-specific health care utilization in at-risk individuals.

BACKGROUND: Osteoporosis is traditionally associated with post-menopausal women, but up to up to one-third of osteoporosis-related fractures occur in elderly men. The International Society for Clinical Densitometry (ISCD), the World Health Organization, and the Fracture Risk Assessment Tool (FRAX) all recommend using a white female reference for BMD T-score for men. However, in clinical practice and previous clinical trials, a sex-specific white male reference T-score is used. This report examines the implications of using a female versus male reference for T-score calculation in men. METHODS: We reviewed BMD findings in 703 men (age 70-85y) who experienced a proximal femur, humerus, or distal radius/ulna fracture. For this cohort, femoral neck BMD was used to calculate a BMD T-score using either the young adult male and young adult female peak values (mean BMD 0.930 ± 0.136 and 0.849 ± 0.111 g/cm2, respectively). Osteoporosis was defined by BMD T-score ≤ -2.5, and osteopenia by BMD T-score < -1.0 and > -2.5. We also calculated FRAX-estimated fracture risk for hypothetical men ages 60-85y, with and without prior fracture. We used the National Osteoporosis Foundation (NOF) recommendations for treatment based on BMD (osteoporosis by BMD, or osteopenia by BMD with a 10-year risk of hip fracture ≥ 3% or 10-year risk of major osteoporotic fracture ≥ 20%). RESULTS: The mean BMD for this cohort was 0.670 g/cm2 and the median T scores were -2.0 (male reference) and -1.7 (female reference). Using the male T-score, 29% of men were classified as having osteoporosis, while using the female T-score, only 21% were so classified. 36% of men age 70-79y and 19% of men age 80-85y with osteoporosis (using the male T-score) would be reclassified from osteoporosis to osteopenia when a female T-score is used. Hypothetical cases of men age 60-85y (height 170 cm, weight 70 kg, BMD 0.590 g/cm2 equivalent to a male T -2.5 or female T -2.2) were used to calculate 10-year hip fracture risk using FRAX. For these hypothetical cases, the calculated 10-year risk of hip fracture exceeded the NOF treatment threshold of 3% (10-year hip fracture risk) for all cases, with or without prior fracture. CONCLUSION: For elderly men with fracture with male-T osteoporosis and female-T osteopenia, the T-score reference population used does not alter treatment recommendations because the calculated hip fracture risk is already above the treatment threshold of 3%. This is also true for men age ≥70 without a prior fracture. Hence the debate pertaining to the appropriate T-score reference population for men has limited relevance for men age ≥ 70 years who are being screened for osteoporosis.