Regional and systemic hemodynamic responses following the creation of a murine arteriovenous fistula

Abstract

The study of hemodynamic alterations following the creation of an arteriovenous fistula (AVF) is relevant to vascular adaptive responses and hemodialysis access dysfunction. This study examined such alterations in a murine AVF created by anastomosing the carotid artery to the jugular vein. AVF blood flow was markedly increased due to reduced AVF vascular resistance. Despite such markedly increased basal blood flow, AVF blood flow further increased in response to acetylcholine. This AVF model exhibited increased cardiac output and decreased systemic vascular resistance; the kidney, in contrast, exhibited decreased blood flow and increased vascular resistance. Augmentation in AVF blood flow was attended by increased arterial heme oxygenase-1 (HO-1) mRNA and protein expression, the latter localized to smooth muscle cells of the AVF artery; AVF blood flow was substantially reduced in HO-1(-/-) mice compared with HO-1(+/+) mice. Finally, in a murine model of a representative disease known to exhibit impaired hemodynamic responses (sickle cell disease), the creation of an AVF was attended by decreased AVF flow and impaired AVF function. We conclude that this AVF model exhibits markedly increased AVF blood flow, a vasodilatory reserve capacity, increased cardiac output, decreased renal blood flow, and a dependency on intact hemodynamic responses, in general, and HO-1 expression, in particular, in achieving and maintaining AVF blood flow. We suggest that these findings support the utility of this model in investigating the basis for and the consequences of hemodynamic stress, including shear stress, and the pathobiology of hemodialysis AVF dysfunction.

Carotid-Jugular Fistula Model to Study Systemic Effects and Fistula-Related Microcirculatory Changes

“…Studies have shown that the mean arterial blood pressure is significantly decreased immediately after the construction of an AVF [3, 9, 28, 29], and after 4 weeks, significant cardiac hypertrophy develops, with near-normal function at 4 weeks [9, 29]. In the current study, only SBP was measured at baseline and at the 1-week follow-up, because noninvasive pressure measurement systems are more sensitive when measuring SBP.…”

“…Arteriovenous fistulae (AVF) are known for their immediate and late systemic effects which contribute to morbidity and mortality, especially in the presence of high-flow fistulae, prosthetic grafts, or other comorbidities [1-3]. These effects are mediated by significant pathophysiological changes in the cardiovascular system, such as altering the systemic hemodynamic status, the cardiac loads, and the level of some vasodilators and vasoconstrictors [4, 5].…”

Novel Therapies for Hemodialysis Vascular Access Dysfunction

“…Because of the small size of mouse vessels, creation of an AVF requires substantial surgical skill, and wall shear stress and blood velocities can be orders of magnitude greater than in human AV accesses. These hemodynamic characteristics likely contribute to the accelerated pace of neointimal hyperplasia in this model (8). It is less technically challenging to create an AVF in a rat compared with a mouse, but as with the mouse, the AV access blood flow parameters differ from those parameters in humans (14)(15)(16).…”

“…Although creating an AVF with this configuration is more technically challenging, the resulting hemodynamics more closely approximate the hemodynamics of AVFs used for dialysis. Advantages of using mouse models include low cost compared with large animals, the availability of assay reagents, and the ability to study the influence of gene expression on access function through the use of available or relatively easily-created transgenic animals (7)(8)(9)(10)(11). Additionally, because mouse models of kidney failure are well established, mouse AVFs provide the important opportunity to study AV access treatments in the presence of uremia.…”

Novel Therapeutic Paradigms to Treat Hemodialysis Access Dysfunction

“…Markers of endothelial dysfunction such as increased thickening of arterial intima, media and medial hypertrophy that result from these processes are found to affect the outcome of AVF [18][19][20]. With these known and possibly many unknown factors (Hemoxygenase 1, Nitrotyrosine) in play, a better understanding of the interaction between the flow dynamic and vascular adaptations are essential for developing successful therapy [21]. …”