Abstract MP26: Endothelial-derived Microvesicles From Andean Highlanders With Excessive Erythrocytosis Induce A Deleterious Cardiomyocyte Phenotype

Abstract

Background: Excessive erythrocytosis (EE), defined as Hb ≥21 g/dL in men and ≥19 g/dL in women, is a pathologic consequence of residing at high altitude (>2500 m) and is common in Andean highlanders. EE is associated with increased cardiovascular risk and cardiac dysfunction. Specifically, EE has been linked to congestive heart failure as well as right ventricular hypertrophy in high altitude dwellers. The mechanisms responsible for diminished cardiac function in adults with EE remain unclear. Endothelial microvesicles (EMVs) play an important role in mediating interaction between the vascular endothelium and cardiac function. The experimental aim of this study was to determine the effects of EMVs isolated from adults with EE on markers of cardiomyocyte fibrosis, hypertrophy and autophagy as well as endothelial nitric oxide synthase (eNOS). Methods: Twenty-four male residents of Cerro de Pasco, Peru (4,340 m) were studied: 12 highlanders without EE (Healthy; age: 40±4 yr; BMI: 26.4±1.7; Hb: 17.4±0.5 g/dL) and 12 highlanders with EE (EE: 45±5 yr; 26.7±1.0; 24.4±0.4 g/dL). All subjects were non-obese, normotensive, normolipidemic and non-diabetic. EMVs (CD31+/CD42b-) were identified, enumerated, and isolated from plasma by flow cytometry. Human induced pluripotent stem cell cardiomyocytes were cultured and treated with EMVs from either healthy or EE men. Results: EMVs from EE men induced significantly greater expression of specific markers of fibrosis: TGF-β (91.1±4.0 vs 52.7±3.8 AU) and alpha-1 type I collagen (85.6±5.6 vs 59.7±4.8 AU) and hypertrophy: troponin T (41.4±2.0 vs 16.9±1.4 AU) and α-actinin (95.3±6.7 vs 62.4±5.0 AU) than EMVs from healthy men. Cell autophagy was not significantly affected by EE EMVs. Intercellular expression of phosphorylated eNOS at the primary activation site, Ser1177 (13.3±1.1 vs 18.9±1.2 AU), and inhibitory site, Thr495 (56.7±3.4 vs 40.8±2.7 AU), were ~35% lower and ~30% higher (both P<0.05), respectively, in cells treated with EMVs from EE compared with healthy men. Conclusions: These data indicate that EMVs from Andean highlanders with EE negatively affect cardiomyocyte function and, therefore, may contribute to the increased risk of heart failure and cardiac dysfunction associated with EE.