Triglyceride levels are an established marker for an increased risk of pancreatitis in patients with hypertriglyceridemia. However, the heterogeneous risk of pancreatitis among individual patients suggests that a more complex physiology is involved. Accumulating evidence from animal and human studies suggests that microvascular compromise and hemodynamic dysfunction play a role in the onset and progression of severe pancreatitis [1-4]. Severe hypertriglyceridemia in lipoprotein deficient mice reduces the cholesterol and phospholipid content of erythrocyte membranes, which increases membrane microviscosity [5]. In these same experiments, hypertriglyceridemia impaired erythrocyte deformability and increased erythrocyte osmotic fragility [5]. These rheological abnormalities would be expected to contribute to the reduced tissue perfusion, pancreatic oxygen tension, oxygen saturation of hemoglobin, and reduced pancreatic oxygen consumption reported in experimental models of hypertriglyceridemia-induced acute pancreatitis and microthrombi observed in pancreatic tissue of patients with severe hypertriglyceridemia.

Blood viscosity is a hemodynamic parameter which directly affects microcirculatory perfusion. Numerous studies have examined the relationship between viscosity and triglyceride levels. The West of Scotland Coronary Prevention Study followed 6,595 hypercholesterolemic adult males prospectively for an average of 4.9 years and reported that plasma viscosity and whole blood viscosity were both significantly associated with triglycerides and VLDL concentration [6]. In a study of 126 healthy nonsmoking adults, blood viscosity was shown to correlate with triglyceride concentration (r=0.41, p=0.0007) [7]. Using hematocrit-adjusted blood viscosity levels at high-shear and low-shear rates, blood viscosity was shown to be significantly associated with triglycerides in a cross-sectional study of 257 adults who were being assessed for cardiovascular risk factors (high-shear viscosity r=0.35, low-shear viscosity r=0.22, both p values < 0.0005) [8].

Hyperlipoproteinemia patients with type IV or type IIb phenotypes were reported to have higher plasma and blood viscosity than type IIa hyperlipidemia patients or controls. For patients with type IV or type IIb hyperlipoproteinemia, a positive correlation was shown between VLDL concentrations and plasma viscosity (p<0.01) [9]. In a previous controlled mechanistic study of 70 patients with hyperlipidemia or hypertriglyceridemia, plasma viscosity was correlated with plasma triglyceride concentration (r=0.56, p<0.01). In this study, isolated chylomicrons, VLDL, and LDL particles were separately added to plasma or serum in vitro and demonstrated dose-dependent and exponential increases in viscosity. A strong linear relationship was observed between plasma viscosity and chylomicron concentration in vitro (r=0.98, p<0.001), and a significant correlation was also shown between plasma viscosity and VLDL concentration (r=0.70, p<0.001). The study authors extrapolated their findings to suggest increases in viscosity and subsequent reductions in pancreatic blood flow may be a factor in acute pancreatitis in patients with severe hypertriglyceridemia [10].

As a primary objective of triglyceride lowering therapies in hypertriglyceridemia is avoidance of pancreatitis, investigation of associations between reductions in hypertriglyceridemia -induced hyperviscosity on one hand and incident pancreatitis on the other could yield insights and research benefits including improved stratification of patients, increased diagnostic sensitivity and a prognostic role for blood viscosity changes on incident pancreatitis, and new options for monitoring therapy.

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