Cardiac dysfunction and pulmonary systolic hypertension among patients with homozygous VHLR200W mutation (Chuvash polycythemia)

Abstract

Pulmonary hypertension occurs with chronic high-altitude hypoxia and is exacerbated by iron deficiency. Chuvash polycythemia, due to homozygosity for the R200W mutation in the von Hippel Lindau gene ( VHL ), is characterized in normoxia by elevated levels of hypoxia inducible factors HIF-1 and HIF-2, transcription factors regulating many hypoxia-inducible genes. Three cross-sectional clinical and echocardiography study in Chuvashia, Russian Federation among 120 child and adult VHL R200W homozygotes and 31 VHL- wildtype controls under basal conditions. VHL R200W homozygotes had frequently been treated by phlebotomy and were often iron-deficient based on low ferritin. After adjustment for age, sex, and hemoglobin concentration, the mean ± SD systolic blood pressure tended to be lower in VHL R200W homozygotes compared to controls (112 ± 15.1 vs. 119 ± 17.2 mm Hg; P = .045). In contrast, the echo-determined tricuspid regurgitation velocity (TRV), which reflects right ventricular systolic pressure, was significantly higher in the VHL R200W homozygotes (2.5 ± 0.3 vs. 2.3 ± 0.4 m/s, P = .007). The left ventricular diastolic dimension (4.8 ± 0.5 vs. 4.5 ± 0.6 cm; P = .039) and left atrial diameter (3.4 ± 0.5 vs. 3.2 ± 0.5; P = .045) tended to be larger in the VHL R200W homozygotes, but this was not the case for the mitral valve E/Etdi ratio. Among VHL R200W homozygotes, phlebotomy therapy was associated with lower ferritin, and low ferritin independently predicted higher TRV (standardized beta = −0.29; P = .009). Children and adults with congenital upregulation of HIF-1 and 2 tend to have higher right ventricular systolic pressure as estimated by echocardiography than control subjects. Similar to high-altitude pulmonary hypertension, iron deficiency may contribute to elevated right ventricular systolic pressure in Chuvash polycythemia.