Hypercholesterolemia magnitude increases sympathetic modulation and coagulation in LDLr knockout mice

We investigated the effects of low lipoprotein receptor deficiency in cholesterol blood concentrations, blood pressure, hemostatic factors, and the autonomic nervous system in three groups: control mice fed standard diet (CO, n=9), lipoprotein receptor-deficient mice (LDLr(-/-), n=9) fed standard diet (LDLr-S) or hypercholesterolemic diet (LDLr-H, n=8). Frequency domain analysis of heart rate and blood pressure variability was performed with an autoregressive algorithm. The spectral components were expressed in absolute (s(2) or mmHg(2)) and normalized units. Spontaneous baroreflex sensitivity (BRS) was estimated by alpha index, defined as square root ratio between low frequency power in blood pressure variability and heart rate variability. LDLr/- mice presented a significant increase in the cholesterol blood concentration (mean±SD; mg/dl; LDLr-S=202.01±34.38 and LDLr-H=530.7±75.17) compared to CO (79.2±13.6), p=0.001. The receptor deletion was associated with a heart rate variability reduction (p=0.013). The BRS was reduced (p<0.05) in LDLr-S and LDL-H (mean±SD: 0.96±0.39 and 0.59±0.34, respectively) compared to CO (4.02±1.92). Moreover, hypercholesterolemic diet significantly increased the cardiac sympathetic modulation (0V pattern of symbolic analysis: mean±SD, CO=8.04±4.53; LDLr-S=16.49±4.52 and LDLr-H=21.80±8.24, p=0.006). The 0V pattern was statically correlated to coagulation factor VII (r=0.555, p=0.0208). In LDLr-H, the concentration (interquartile range) of plasmatic fibrinogen and hemostatic factors VII (2.8-3.3) and XII (1.1-1.3) were increased compared to CO (0.9-1.1and 0.9-1.0, respectively) and LDLr-S (0.7-1.0 and 0.8-0.9, respectively) (p<0.004 for FVII and p<0.006 for FXII). Taken together, the results indicate that plasmatic cholesterol magnitude is determinant to increase the coagulation and the sympathetic modulation.