Hemodynamic Influences on Abdominal Aortic Aneurysm Disease

Katsuyuki Hoshina, MD
Ronald L. Dalman, MD

The term "hemodynamic forces" refers to the kinetic energy generated by the flow of blood through arteries and veins. Vascular endothelial and smooth muscle cells are constantly exposed to a variety of physical stimuli generated by flowing blood. Two parameters relevant to abdominal aortic aneurysm (AAA) pathogenesis include the tangential force exerted by moving blood along the axis of flow (wall shear stress (WSS) and the motion exerted by cyclic luminal pressure changes on aortic diameter (relative wall strain (RWS). Under normal homeostatic conditions arteries regulate diameter in part due to WSS sensed and transduced via endothelial cells1-4. Growing experimental evidence indicates that low antegrade or oscillatory shear conditions promote proliferative, thrombotic, adhesive and inflammation-mediated degenerative conditions throughout the vascular system5. Although aneurysm enlargement and rupture are a function of both aortic structural integrity and hemodynamic forces, most AAA research to date has focused on degenerative mechanisms within the aortic wall6-7 and epidemiological risk factors8 rather than on the influence of intraluminal physical forces on disease progression9.

Several clinical situations highlight the potential influence of hemodynamic forces on AAA pathogenesis. Post-traumatic above knee amputees were found to be 5 times more likely to develop AAA > 40 years following injury than non-amputee subjects matched for traditional AAA risk factors such as cigarette smoking. Aneurysm morphology in the amputee patients was strongly influenced by amputation laterality, prompting the original observation that chronically diminished or asymmetric distal aortic blood flow promotes and mediates aneurysmal aortic degeneration (Figure 1)10.

	Figure 1. (Vollmar et. al., ref 10)

Spinal cord injury (SCI) patients also appear to be at > 2 fold risk for AAA formation more than two decades following injury as compared to age and risk-factor matched ambulatory control subjects. In SCI patients high resting peripheral resistance greatly diminishes distal aortic and iliac blood flow, generating chronically low antegrade and oscillatory shear stress conditions in the infrarenal abdominal aorta11. The presence of small or diseased distal arteries may also predispose ambulatory, bipedal patients to develop AAA disease. Excluding patient with popliteal or femoral aneurysms, distal arterial diameters are smaller than average in AAA patients12. This finding 1) discounts the likelihood of a general arterial dilating diathesis as a predisposing condition in most AAA patients and 2) provides further support for a putative etiologic connection between sedentary existence (as evidenced by diminished distal arterial diameter) and increased AAA risk. A recent report of the SMART study group confirmed multiple previous observations noting increased AAA risk in patients with symptomatic peripheral vascular disease13. While this predilection for AAA in PVD patients may be due in part to the common influence of shared risk factors (such as cigarette smoking) for both diseases, it is also likely that symptomatic PVD results in reduced lower extremity exercise, promoting low antegrade and oscillatory shear forces in the infrarenal aorta and eventual aneurysmal degeneration.

Turbulence, vibratory forces and transmural pressure gradients (hypertension) are also hemodynamic influences relevant to AAA pathogenesis and progression. Turbulence and vibratory forces are difficult to measure in-vivo and hence less well described. The presence of hypertension, although previously associated with increased risk for AAA rupture14-15 is not so clearly associated with increased risk for developing AAA disease. The largest and most comprehensive prevalence and association study completed to date did not identify hypertension as an independent risk factor for AAA disease8. In experimental animal models selective inducible nitric oxide synthase (iNOS) inhibition induces hypertension while paradoxically limiting AAA progression16. While pressure clearly influences rupture risk, hypertension may not predispose patients to aneurysmal degeneration at earlier timepoints in the course of their disease.

Animal AAA models provide unique opportunities for examining the influence of hemodynamic forces such as WSS and RWS on aneurysm pathogenesis. Quantifying wall shear and strain forces requires the simultaneous measurement of blood pressure, blood flow, and cyclical wall motion. These three parameters are measured in rodent models using intraluminal pressure transducer catheters (Millar Micro-tip; Millar Instruments, Houston, TX), ultrasonic flow probes (Transonic Systems Inc, Ithaca, NY), and ultrasound microcrystals for diameter measurement via triangulation (Sonometrics Sonosystem® London, Ontario). Wall motion or cyclic wall deformation may also be measured accurately using high-speed video microscopy (> 30 frames/second). WSS is calculated as 4x0.035xQ/r3 (Poiseuille's law) where 0.035 is blood viscosity in poise, Q = mean blood flow, and r = aortic radius. Relative wall strain is calculated as (max diameter-minimum diameter)/minimum diameter.

Intra-aortic elastase infusion reliably produces AAA in mice and rats. This is the best-described and most widely used method of experimental aneurysm formation17. Immediately following a two-hour infusion period, histological analysis demonstrates fragmented and disorganized elastic lamellae. Within 12 hours no stainable elastic lamellae remain. Collagen remains present and apparently unaffected in the immediate post-infusion interval. Within the first 48 hours, only minimal (<25%) aortic diameter enlargement is noted. Beginning on the second post-infusion day, infiltrative mono- and polynuclear inflammatory cells are noted in the media and adventitia. Both the degree of elastin degradation and the intensity of the ensuing inflammatory infiltrate correlate with the rapidity and extent of aneurysmal aortic enlargement. Within 14 days AAA develop and aortic diameter increases > 4 fold. Elastin degradation and the formation of elastin degradation peptides (EDPs) promote strong chemotactic responses from macrophages, and may represent the initial pro-inflammatory stimulus in human aortic aneurysms6. AAA pathogenesis in the elastase infusion models has been partially defined through a series of inhibition experiments using hydroxamic acid compounds (for selective and non-selective matrix metalloproteinase (MMP) inhibition), indomethacin, selective iNOS inhibitors, anti-CD 18 monoclonal antibodies and genetically deficient mice18-22.

We have created distal femoral arteriovenous fistulae (AVF) or employed distal iliac ligation to modify aortic blood flow, WSS and RWS in rodent models23-24. Small distal AVF do not measurably influence arterial pressure, but do increase flow, shear and strain forces as noted below (Table I, AVF = <3mm femoral avf, Sham = sham femoral exposure, *= significantly different from sham at the 0.05 level)

	GROUPS Flow (ml/min) Wall Shear Stress (dynes/cm2) Diameter (mm) Wall Strain (%) 3 day AVF 34 ± 13* 4.0 ± 1.3* 1.7 ± 1.0* 9.0 ± 2.8* 3 day SHAM 16 ± 6 2.9 ± 0.7 1.5 ± 1.1 5.4 ± 1.0 7 day AVF 40 ± 10* 3.3 ± 1.7 2.0 ± 0.3 8.7 ± 4.0 7 day SHAM 15 ± 6 2.7 ± 1.6 1.5 ± 0.2 6.71 ±2.3 21 day AVF 49 ± 21* 2.7 ± 1.2 2.2 ± 0.4* 11.9 ±5.6 21 day SHAM 10 ± 5 1.2 ± 0.5 1.6 ± 0.4 8.7 ± 3.6

Flow mediated arterial enlargement is dependant upon vascular smooth-muscle cell mediated extracellular matrix remodeling (MMP-2 and possibly MMP-9 activity)24-25, disruption and reformation of the internal elastic lamina26 as well as endothelial cell migration and proliferation27.

We have employed both distal arteriovenous fistula creation and iliac ligation to examine the influences of WSS and RWS on AAA pathogenesis in the rodent elastase infusion model28-29. AVF creation before or after elastase infusion increases WSS, RWS and limits AAA progression (Figure 2). Figure 3 demonstrates typical post-elastase AAA.

Figure 2. Femoral AVF or sham created 7 days prior to aortic elastase infusion (0 POD). Ordinate represents aortic diameter in mm. 7POD-pre and post diameters obtained during elastase infusion procedure. At final measurement (14 POD), AVF limits AAA diameter vs. AVF sham (p<0.01). Reversing the order of procedures (infusion prior to AVF) produces similar results (data not shown).		Figure 3. Infrarenal rodent AAA. Ruler demarcation in mm.

Unilateral common iliac artery ligation decreases rodent aortic wall shear stress in proportion to diminished aortic flow, again without affecting pressure (Table II). Seven days later, ligation produces larger AAA than elastase infusion alone (Figures 4 and 5).

	Measurement Baseline condition Following iliac ligation Flow (ml/mm) 19.7 ± 2.9 13.0± 3.9* WSS (dynes/cm2) 21.6± 4.6 14.2± 4.8* Pressure (s/d (mean) torr) 168/126 (140) 168/127 (141)

* = p<0.05 vs. baseline conditions

Figure 4: Aortic diameter prior to elastase infusion (Before AD) and 7 days following elastase infusion (AD 7POD), with and without unilateral common iliac ligation. Ligation augments AAA diameter (p<0.01).

Figure 5: Rodent aortic prep immediately prior to elastase infusion. Note flow probe (white clip), sono crystals (green wires), and left iliac ligation clip (stainless)

Data obtained from these rodents models, as well as computational human aortic models30 and MR-derived in-vivo human aortic flow data31 support the contention that increased AAA risk in amputees or paraplegic patients may well be due to diminished or asymmetric infrarenal aortic blood flow and associated low antegrade or oscillatory shear conditions in the infrarenal aorta. The rodent data also suggests that elevated antegrade shear stress present during sustained high flow conditions (following AVF creation in these experiments, or increased lower extremity activity in human subjects) may limit aneurysmal progression. The mechanisms responsible for modulation of AAA progression via hemodynamic influences are the current focus of our laboratory investigations.

The possibility that hemodynamic conditions may modify the natural history of AAA disease has broad public health implications for both chronically disabled patients as well as ambulatory but relatively sedentary individuals. In addition to myriad broad health benefits, a program of regular lower extremity exercise may prove useful in reducing aneurysm risk or rate of progression in AAA patients.

References

1. Glagov S, Weisenberg E, Zarins CK et al. Compensatory enlargement of human atherosclerotic coronary arteries. NEJM 1987;316:1371-5.
2. Guyton JR, Hartley CJ: Flow restriction of one carotid artery in juvenile rats inhibits growth of arterial diameter. Am J Physiol 1985;248:H540-546.
3. Langille BL, Bendeck MP, Keeley FW: Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Phisiol 1989;256:H931-939.
4. Sho E, Sho M, Singh T, et al: Blood flow decrease induces apoptosis of endothelial cells in previously dilated arteries resulting from chronic high blood flow. Art Thomb Vasc Biol 2001, 21: 1139-45.
5. Topper JN, Gimbrone MA. Hemodynamics and endothelial phenotype: New insights into the modulation of vascular gene expression by fluid mechanical stimuli. Mechanical Forces and the Endothelium, (Ed. Lelkes, PI), Harwood Academic Publishers, Amsterdam 1999.
6. Hance KA, Tataria M, Ziporin SJ, et al: Monocyte chemotactic activity in human abdominal aortic aneurysms: Role of elastin degeneration peptides and the 67-kD cell surface elastin receptor. J Vasc Surg 2002;35:254-61.
7. Huffman MD, Curci JA, Moore G, et al: Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms. Surgery 2000; 158:429-38.
8. Lederle FA, Johnson GR, Wilson SE, et al: Prevalence and associations of abdominal aortic aneurysm detected through screening. Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Group. Ann Intern Med 1997,15:441-9.
9. Wassef M, Baxter BT, Chisholm RL, et al: Pathogenesis of abdominal aortic aneurysms: A multidisciplinary research program supported by the National Heart, Lung, and Blood Institute. J Vasc Surg 2001;34:730-8.
10. Vollmar JF, Paes E, Pauschinger P, et al: Aortic aneurysms as late sequelae of above-knee amputation. Lancet 1989;ii:834-5.
11. Dalman RL, Abbruzzese TA, Karwowski JK, Yeung KK, Society for Vascular Surgery/AAVS 2001 Joint Annual Meeting, "Chronic Spinal Cord Injury Increases Risk for Abdominal Aortic Aneurysm Disease". Poster presentation. 6/10/01, Baltimore, MD.
12. Sandgren T, Sonesson B, Ryden-Ahlgren A, et al: Arterial dimensions in the lower extremities of patients with abdominal aortic aneurysms- no indications of a generalized dilating diathesis. J Vasc Surg 2001;34:1079-84.
13. van den Bosch MA, van der Graaf Y, Eikelboom BC, et al; Distal aortic diameter and peripheral arterial occlusive disease. J Vasc Surg 2001;34:1085-9.
14. Cronenwett JL, Sargent SK, Wall MH, et al: Variables that affect the expansion rate and outcome of small abdominal aortic aneurysms. J Vasc Surg 1990;11:260-9.
15. Sterpetti AV, Hunter WJ, Feldhaus RJ, et al: Inflammatory aneurysms of the abdominal aorta: Incidence, pathologic, and etiologic considerations. J Vasc Surg 1989;9:643-650
16. Armstrong PJ, Franklin DP, Carey DJ, Elmore JR. Prevention of experimental aortic aneurysms: Selective inhibition of inducible nitric oxide synthase is superior to cyclooxygenase inhibition. Submitted for the Lifeline Foundation Resident Research Prize 2002.
17. Anidjar S, Salzmann JL, Gentric D et al. Elastase-induced experimental aneurysms in rats. Circulation 1990;82:973-81.
18. Moore G, Liao S, Curci JA, et al: Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS132908). J Vasc Surg 1999,29;522-32.
19. Miralles M, Wester W, Sicard GA, et al: Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase. J Vasc Surg 1999, 29;884-93.
20. Ricci MA, Strindberg G, Slaiby JM, et al: Anti-CD 18 monoclonal antibody slows experimental aortic aneurysm expansion. J Vasc Surg 1996,23;301-7.
21. Pyo R, Lee JK, Shipley M, et al: Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 2000;105:1641-49.
22. Lee JK, Borhani M, Ennis TL, et al: Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase. Art Thromb Vasc Biol 2001;21:1393-1401.
23. Abbruzzese TA, Guzman RJ, Martin RL et al. Matrix metalloproteinase inhibition limits arterial enlargement in a rodent arteriovenous fistula model. Surgery 1998;124:328-34.
24. Karwowski JK, Markezich A, Whitson J, et al: Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113456. J Surg Res 1999;87:122-129.
25. Tronc F, Mallat Z, Lehoux S, et al: Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Art Thromb Vasc Biol 2000;20:E120-6.
26. Masuda H, Zhuang YJ, Singh TM et al. Adaptive remodeling of the internal elastic lamina and endothelial lining during flow-induced arterial enlargement. Art Thromb Vasc Biol 1999;19:2298-307.
27. Sho E, Sho M, Singh T, et al: Blood flow decrease induces apoptosis of endothelial cells in previously dilated arteries resulting from chronic high blood flow. Arterioscler Thromb Vasc Biol 2001, 21: 1139-45.
28. Mendoza AC, Karwowski JK, Zarins CK, Dalman RL. Increased flow limits enlargement of experimental aneurysms. ACS Surgical Forum 1999;Vol L:425-428.
29. Nakahashi TK, Hoshina K, Yeh C et al. High blood flow limits experimental aneurysm enlargement: the role of hemeoxygenase 1. Art Thromb Vasc Biol, submitted 2002.
30. Taylor CA, Hughes TJ, and Zarins CK. Finite element modeling of three-dimensional pulsatile flow in the abdominal aorta. Ann Biomed Eng 1998, 26;6:975-987.
31. Taylor CA, Hughes TJ, Zarins CK: Effect of exercise on hemodynamic conditions in the abdominal aorta. J Vasc Surg 1999, 29;6:1077-1089.