Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.

Hospitalized patients who meet specific criteria at discharge are referred to the transitional care clinic team consisting of a nurse practitioner and/or physician and a clinical pharmacist. In collaboration with the providers, the pharmacist reviews medications for appropriateness, assesses adherence, recommends medication changes and provides education. The purpose of this study was to measure the effect of an outpatient transitional care clinical pharmacist on 30-day re-admissions in an urban setting serving a population of low socioeconomic status. After receiving IRB approval, this single-center retrospective study analyzed records of 573 patient visits of which nearly 75% included a clinical pharmacist interaction. Rates of 30-day re-admissions were not statistically different among the two groups, however, it was found that each added co-morbidity significantly increased the patients' 30-day re-admission rate by 26%.

A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient’s rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.

Rapamycin (Rap), an inhibitor of mTORC1, reduces obesity and improves lifespan in mice. However, hyperglycemia and lipid disorders are adverse side effects in patients receiving Rap treatment. We previously reported that diabetes induces pansuppression of cardiac cytokines in Zucker obese rats (ZO-C). Rap treatment (750 μg/kg/day for 12 weeks) reduced their obesity and cardiac fibrosis significantly; however, it increased their hyperglycemia and did not improve their cardiac diastolic parameters. Moreover, Rap treatment of healthy Zucker lean rats (ZL-C) induced cardiac fibrosis. Rap-induced changes in ZL-C's cardiac cytokine profile shared similarities with that of diabetes-induced ZO-C. Therefore, we hypothesized that the cardiac microRNA transcriptome induced by diabetes and Rap treatment could share similarities. Here, we compared the cardiac miRNA transcriptome of ZL-C to ZO-C, Rap-treated ZL (ZL-Rap), and ZO (ZO-Rap). We report that 80% of diabetes-induced miRNA transcriptome (40 differentially expressed miRNAs by minimum 1.5-fold in ZO-C versus ZL-C; p ≤ 0.05) is similar to 47% of Rap-induced miRNA transcriptome in ZL (68 differentially expressed miRNAs by minimum 1.5-fold in ZL-Rap versus ZL-C; p ≤ 0.05). This remarkable similarity between diabetes-induced and Rap-induced cardiac microRNA transcriptome underscores the role of miRNAs in Rap-induced insulin resistance. We also show that Rap treatment altered the expression of the same 17 miRNAs in ZL and ZO hearts indicating that these 17 miRNAs comprise a unique Rap-induced cardiac miRNA signature. Interestingly, only four miRNAs were significantly differentially expressed between ZO-C and ZO-Rap, indicating that, unlike the nondiabetic heart, Rap did not substantially change the miRNA transcriptome in the diabetic heart. In silico analyses showed that (a) mRNA-miRNA interactions exist between differentially expressed cardiac cytokines and miRNAs, (b) human orthologs of rat miRNAs that are strongly correlated with cardiac fibrosis may modulate profibrotic TGF-β signaling, and (c) changes in miRNA transcriptome caused by diabetes or Rap treatment include cardioprotective miRNAs indicating a concurrent activation of an adaptive mechanism to protect the heart in conditions that exacerbate diabetes.