Low‐intensity exercise improves cardiac antioxidants in young animals irrespective of metabolic changes in type 2 diabetes (T2D). As diabetes and aging synergistically can decrease antioxidants, if exercises can increase antioxidants in mature T2D hearts, is unknown. 8‐month old db/db and wild‐type (WT) mice were moderately exercised for 3 weeks, and cardiac redox regulation was evaluated. Without altering metabolic status, exercise increased cardiac antioxidants and attenuated stress in mature WT mice. In contrast, exercise in db/db mice worsened oxidative damage, which was not explained by superoxide dismutase or catalase activities. Instead, loss of the antioxidant, glutathione (GSH) was noted. Further, GSH biosynthesis [γ‐glutamylcysteine synthase] and recycling [NADPH/NADP, glutathione reductase] were impaired while GSH‐dependent stress (GPX, 4‐hydroxynonenal, TGF‐β) was increased in these hearts. To validate the causal role for GSH, exercising db/db mice were administered exogenous GSH, which attenuated cardiac damage. This study shows that unlike younger animals, short‐term exercise may induce oxidative stress in mature animals and GSH supplementation can inhibit such stress in these hearts. Therefore, recent assertions of detrimental impact of antioxidants during exercise in healthy individuals should be extrapolated with caution in mature T2D patients undergoing exercise.

Primary hyperparathyroidism (PHPT) is an excessive parathyroid hormone (PTH) production disorder, causing increased calcium levels. Commonly, these cases are asymptomatic and detected incidentally on routine labs. These patients are usually conservatively managed and monitored periodically, including bone and kidney health evaluation. Medical management of severe hypercalcemia secondary to PHPT includes IV fluids, cinacalcet, bisphosphonates, and dialysis, while the surgical treatment is parathyroidectomy. Patients suffering from heart failure with reduced ejection fraction (HFrEF) on diuretics and PHPT require a delicate balance of their volume status to prevent exacerbation of either condition. In patients with these two comorbidities on the opposite ends of the volume spectrum, it can lead to challenges in managing these patients. We present a case of a woman with repeated hospitalizations due to poor volume status control. An 82-year-old female with primary hyperparathyroidism (diagnosed 17 years ago), HFrEF due to non-ischemic cardiomyopathy, sick sinus syndrome with a pacemaker, and persistent atrial fibrillation presented to the emergency department with worsening bilateral lower limb swelling for several months. The remaining review of systems was largely negative. Her home medication regimen included carvedilol, losartan, and furosemide. Vitals were stable, and the physical exam revealed bilateral lower extremity pitting edema. Chest x-ray revealed cardiomegaly with mild pulmonary vascular congestion. Relevant labs were NT pro-BNP at 2190 pg/mL, calcium at 11.2 mg/dL, creatinine at 1.0 mg/dL, PTH at 143 pg/mL, and Vitamin D, 25-hydroxy at 48.6 ng/mL. The echocardiogram showed an ejection fraction (EF) of 39%, grade III diastolic dysfunction, severe pulmonary hypertension, and mitral and tricuspid regurgitation. The patient received IV diuretics and guideline-directed treatment for congestive heart failure exacerbation. She was managed conservatively for her hypercalcemia and advised to maintain hydration at home. Spironolactone and Dapagliflozin were added to her regimen, and the Furosemide dose was increased at discharge. The patient was re-admitted three weeks later with fatigue and decreased fluid intake. Vitals were stable; however, the physical exam revealed dehydration. Pertinent labs were calcium at 13.4 mg/dL, potassium at 5.7 mmol/L, creatinine at 1.7 mg/dL (baseline 1.0), PTH at 204 pg/mL, and Vitamin D, 25-hydroxy at 54.1 ng/mL. Repeat ECHO showed an ejection fraction (EF) of 15%. She was started on gentle IV fluids to correct the hypercalcemia while preventing volume overload. Hypercalcemia and acute kidney injury improved with hydration. She was put on Cinacalcet 30 mg, and home medications were adjusted for better volume control at discharge. This case highlights the complications of balancing the volume status with primary hyperparathyroidism and CHF. Worsening HFrEF resulted in a higher diuretic requirement, thereby worsening her hypercalcemia. With ...

Pathways by which excess n‐6 PUFAs promotes cardiac inflammation and apoptosis is unclear. We predicted a role for ER stress in inducing such cardiotoxicity. Female C57/Bl6 mice were fed normal chow or high‐fat (40%) diets rich either in n‐6 PUFA or monounsaturated fatty acids (MUFA) for 5 weeks. Immunoblotting revealed upregulation of proteins like IRE‐1α, BiP, PERK and calnexin in the heart of n‐6 PUFA but not in MUFA fed hearts. Further, upregulation of CHOP‐1, caspase‐12, TUNEL and ubiquitinated protein expressions confirmed elevated apoptosis in n‐6 PUFA fed hearts. Interestingly, MCPIP [monocyte chemotactic protein‐1 (MCP‐1) induced protein], a nuclear transcription factor was also induced with n‐6 PUFA. As MCP‐1 is key in cardiac inflammation we hypothesized that n‐6 PUFA triggers cardiac ER stress in an MCP‐1 dependent manner. MCP‐1−/− mice hearts demonstrated significantly less ER stress and undetectable MCPIP levels in response to high n‐6 PUFA than MCP‐1+/+ hearts. Deletion of MCP‐1 also attenuated CHOP‐1, caspase‐12 and ubiquitinated proteins in response to n‐6 PUFA. These results indicate that dietary excess of n‐6 PUFA may lead to cardiac ER stress and apoptosis during diet induced obesity via MCP‐1 signaling. These data may provide an insight into possible mechanisms for cardiotoxicity of dietary oils like corn and sunflower oils in the western diet.