ReviewHemodynamic Influences on abdominal aortic aneurysm disease: Application of biomechanics to aneurysm pathophysiology
Graphical abstract
Introduction
AAA is a common and frequently lethal age-related disease process that affects 6% of men and 1% of women over the age of 60 (Ashton et al., 2002, Lawrence-Brown et al., 2001, Lederle et al., 2000, Lindholt et al., 2002). Although aneurysms may develop throughout the length of the aorta, abdominal aneurysms are at least 5 times more prevalent than thoracic or thoracoabdominal aneurysms. This review introduces the concept of “regional pathogenic risk” in aortic disease, describing how the unique hemodynamic conditions present in the infrarenal aorta may modulate biologic mechanisms predisposing to aortic degeneration. We examine the relationship between aortic flow conditions and aortic aneurysmal degeneration in both experimental models and in patients, and examine how exercise may favorably influence hemodynamic conditions to reduce risk for or progression of AAA disease. Current imaging modalities allow for evaluation of patient-specific hemodynamic patterns; derivation of AAA growth and rupture risks through computational modeling techniques are also discussed.
Risks of rupture and sudden death are most closely related to aneurysm diameter. Infrarenal aortae ≥ 3 cm in diameter are generally considered aneurysmal; AAAs > 6 cm have a 10 to 20% chance of rupture within 12 months, and one third of all AAAs eventually rupture if left untreated (Darling et al., 1977). Surgical intervention is currently the only treatment shown to be effective in preventing AAA rupture and aneurysm-related death. Elective repair is reserved for aneurysms considered at risk for rupture or clinical evolution (≥ 5.5 cm in diameter) based on the likelihood of aneurysm-related death exceeding the surgical risk. AAA rupture or complications following surgical treatment are responsible for an estimated 30,000 deaths per year (Kent et al., 2004); AAA is the 13th leading cause of adult mortality, and the 3rd leading cause of sudden death in men > 65 years of age (Cowan et al., 2006). Current management of early AAA disease (4.0 cm to 5.5 cm in diameter) calls for serial imaging and clinical surveillance, coupled with medical management of traditional atherosclerotic risk factors. Approximately 70% of small AAA will require surgical repair within 10 years of initial diagnosis (Brady et al., 2002). The modest efficacy of current medical interventions to prevent AAA progression has recently been reviewed (Baxter et al., 2008).
The increasing use of endovascular approaches to exclude, rather than resect, AAAs, has been accompanied by a nationwide decline in procedure-related morbidity and mortality (Dillavou et al., 2006). Despite improved perioperative outcomes, however, endovascular aneurysm repair (EVAR) has limitations of its own, including blood flow developing outside of the graft either early or late following placement, termed “endoleaks”, requiring lifelong imaging surveillance and occasional reintervention (Brewster et al., 2003). The overall value of EVAR vs. traditional open surgical repair has been difficult to assess in the last decade, due to almost continuous improvement in device and imaging technology. The results of a national prospective randomized trial comparing the two were recently published (Lederle et al., 2009). Two prospective trials have considered the potential benefits of EVAR management in AAA ≤ 5.5 cm in diameter; the PIVOTAL trial (USA) recently ended enrollment (Ouriel, 2009), unable to demonstrate improved outcomes or reduced costs with early procedural intervention. The CAESAR trial (Europe) is ongoing.
Prior screening studies have identified advanced age, male gender, cigarette smoking, family history, hypertension, obesity, hypercholesterolemia and concomitant coronary or cerebrovascular arterial occlusive disease as distinct AAA risk factors (Blanchard et al., 2000, Lederle et al., 1997a, Lederle et al., 1997b, Lederle et al., 2000, Singh et al., 2001). Although epidemiologic associations are well recognized, the mechanisms promoting AAA disease development in each case are less well understood. Cigarette smoking is the most significant acquired risk; smokers have up to a 7-fold increased risk for AAA disease; AAA has the closest association to cigarette smoking than any other save lung cancer, and 90% of all AAA patients have been regular smokers at sometime during their lifetimes (Baxter et al., 2008, Lederle et al., 2003). Obesity represents another significant acquired risk; waist circumference and waist-to-hip ratio have been independently associated with AAA after adjustment for other known risk factors and serum levels of the pro-inflammatory adipokine, resistin, correlate strongly with aortic diameter (Golledge et al., 2007). Female gender, African American race, regular aerobic exercise and diabetes mellitus are protective against AAA disease. The disproportionate influence of environmental and behavioral risks in disease pathogenesis is highlighted by the fact that, excluding individuals with congenital aneurysm syndromes such as Marfan Syndrome or Ehlers–Danlos Syndrome, positive family histories can be obtained from only 15% of patients with AAA disease (Kuivaniemi et al., 2008, Verloes et al., 1995).
Research efforts in AAA disease remain focused on understanding the patho-biological mechanisms underlying aneurysm development. Although circulating biomarkers are being investigated for their utility in assessment of AAA status (Dalman et al., 2006, Golledge et al., 2008), aneurysm diameter remains the principle clinical determinant of disease progression and rupture risk. Expansion rates average 2–3 mm/year, influenced by baseline diameter and the above mentioned systemic risk factors. On the basis of a systematic review from population-based, randomized, controlled screening trials, the United States Preventative Services Task Force concluded that AAA screening may reduce AAA-related mortality by 43% in men aged 65–75 years (Fleming et al., 2005). Supported by this evidence, the 2007 Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) (Lee et al., 2009) amendment included ultrasound screening to the Initial Preventative Physical Examination (IPPE) as a new federally-funded benefit provided by Medicare in response to the high prevalence and lethality of AAA disease.
In comparison to the well-recognized systemic AAA risk factors detailed in the preceding section, few studies have measured or defined regional pathogenic risks. The marked predilection for aneurysmal dilatation in the abdominal as compared to thoracic segments draws attention to physiologic and anatomic features unique to the distal aorta. The infrarenal aorta is the most common site of extracranial aortic aneurysm formation. Differential hemodynamic influences present along the length of the aorta may work in concert with other regional factors to explain this preferential distribution. Region-specific structural differences are well recognized along the aorta; the elastin–collagen ratio declines along the length of the aorta, reducing elasticity and wall motion (Ailawadi et al., 2003a). Reduced distal aortic elasticity, in combination with augmented pressure due to pulse wave reflections from the aortic bifurcation and other downstream arteries, may increase wall strain and aneurysm susceptibility (Humphrey and Taylor, 2008). Extracellular matrix integrity and proteolysis may also vary regionally; increased expression and activity of matrix metalloproteinase-9 (MMP-9) is present in the native infrarenal murine aorta compared to thoracic and aortic arch specimens. However, when the thoracic and abdominal segments are transposed, thoracic segments increased MMP-9 expression when transplanted to the abdomen, while abdominal segment demonstrated reduced MMP-9 expression when transplanted to the thoracic segment (Ailawadi et al., 2003b).
The term “hemodynamic forces” refer to the kinetic energy generated by the flow of blood through arteries and veins. Vascular endothelial and smooth muscle cells are constantly exposed to the dynamic influences of flowing blood. Cellular responses to these physical stimuli influence vessel wall homeostasis (Hsiai, 2008). Hemodynamic forces relevant to AAA pathogenesis can be resolved into three components: 1) wall shear stress (WSS), the tangential force exerted by moving blood along the axis of flow; 2) hydrostatic pressure, the perpendicular force acting on the vascular wall; and 3) relative wall strain (RWS), the circumferential stretch of the vessel wall exerted by cyclic luminal pressure changes and the resulting tensile stress (Fig. 1).
Hemodynamic conditions vary markedly along the aorta, from high Reynolds numbers at the aortic root to low and oscillatory shear conditions at the aortic bifurcation (Greve et al., 2006). Most relevant to AAA disease pathophysiology, and its predilection for the distal-most aortic segment, is the marked difference between resting aortic WSS in the thoracic and abdominal aorta. In suprarenal aortic segments, flow is antegrade throughout the cardiac cycle, providing continuous antegrade laminar WSS. In the infrarenal aorta, WSS values are lower, and reverse flow is present in late systole and diastole. In response to reduced distal arterial resistance and increased flow, such as is demonstrated in the response to even modest lower extremity exercise, WSS becomes antegrade and laminar throughout the cardiac cycle, mimicking those characteristic of more proximal aortic segments. These distinct regional differences in hemodynamic influences may account for some component of the differential aneurysm risk noted between the thoracic and abdominal aortic segments.
At the interface between blood and the vessel wall, vascular endothelial cells sense and respond to differential hemodynamic forces (Hsiai, 2008). Complementary in vitro data from human umbilical vein and bovine aortic endothelial cultures suggest several potential mechanisms by which exposure to steady physiologic shear stress may suppress pro-inflammatory gene expression (De Keulenaer et al., 1998). Following acute application of laminar SS to cultured endothelial cells, ion channel activation activates downstream signaling cascades such as the c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) pathways (Resnick et al., 2000), leading to shear-responsive gene transcription. In rodent models, increased antegrade shear stress stimulates anti-oxidant, anti-inflammatory, and anti-apoptotic aortic gene expression (Dalman, 2003). Known shear-responsive genes include ICAM-1, cycloxygenase-2, eNOS, Smad6, TGFβ1, copper zinc superoxide dismutase (SOD2), thrombomodulin and heme-oxygenase-1 (HO-1) (Wasserman et al., 2002). These shear-responses may ultimately mitigate inflammation (Gimbrone et al., 1999) and proteolysis in the infrarenal aorta, suggesting mechanisms by which regional differences in aortic hemodynamic conditions may account for differential aneurysm risk.
Section snippets
Resistive aortic hemodynamics
Several clinical associations highlight the pathogenic significance of resistive hemodynamic conditions on AAA progression. Patients with major limb amputation were found to be five times more likely to have AAAs > 40 years following injury than non-amputee patients matched for traditional AAA risk factors (Vollmar et al., 1989). Spinal cord injury (SCI) is also independently associated with increased prevalence of AAA disease. SCI greatly diminishes distal aortic blood flow and promotes
Consequences of flow variability on experimental AAA diameter
Since human AAA specimens obtained at the time of operative repair are typically acellular and atretic (representing end-stage disease), biologically relevant murine AAA models have been developed to better characterize the inciting events of aneurysm formation. To investigate the mechanisms linking hemodynamic forces and aneurysm pathogenesis, we incorporated variable flow conditions into the well-described rodent porcine pancreatic elastase (PPE) infusion AAA model (Anidjar et al., 1990).
Predicting AAA growth and rupture
While aortic diameter has generally proven to be an effective determinant of risk for aneurysm rupture and aneurysm-related mortality, some small AAAs continue to rupture prior to reaching surgical size thresholds, while other larger AAAs never require surgery. Increased precision in assessing risk for aneurysm rupture and clinical progression would improve current treatment outcomes while reducing the expense and risk of unnecessary reconstructive procedures performed for patients at low risk
Concluding remarks
Local aortic hemodynamic conditions may influence the risk for and progression of aneurysm disease. Compared with the suprarenal aorta, the infrarenal environment in resting subjects is characterized by increased peripheral resistance, increased oscillatory wall shear stress and stagnant flow. Several lines of investigations, both clinical and experimental, provide increasing evidence that sedentary hemodynamic conditions contribute to disease susceptibility through underlying influences on
Acknowledgement
Portions of this review were supported by NIH grants 2 R01 HL064338‐08 and 1 P50 HL083800‐03.
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