Exercise, Vascular Health, and Abdominal Aortic Aneurysms

Abstract

Abdominal aortic aneurysms (AAA) account for an increasing burden on health care costs in the United States. AAA are the 13th-leading cause of death in the United States and are the 3rd-leading cause of sudden death in men >60 yr of age, accounting for roughly 4% to 5% of sudden deaths (12,46). AAA are directly related to age, with a prevalence of approximately 6% in men >60 yr, increasing to roughly 11% in men >80 yr (62). However, prevalence varies considerably depending on the presence of other risk factors. The most important modifiable risk factor is cigarette smoking; smokers are 2 to 9 times more likely to develop an AAA than nonsmokers (6,14,28,32,60). Other risk factors for AAA include hypertension, obesity, markers of inflammation, and white race (6,14,22,28,32,36, 60). The recognition of AAA has increased significantly over the last decade due in part to improvements in detection, greater media attention (63), public outreach programs (3) and the recent addition of ultrasound screenings for AAA to the Medicare program (48). Thus, many otherwise healthy individuals are becoming aware of their early AAA disease at relatively younger ages. This has resulted in a large population of patients who have small AAA, are not surgical candidates, and fall into the category of “watchful waiting” with limited treatment options.Physical inactivity is a major risk factor for cardiovascular disease (41) and is associated with microvascular dysfunction, inflammation, and other factors related to increased AAA risk, including obesity (13, 24,39). Low fitness, caused in part by physical inactivity, is a powerful marker of adverse outcomes in asymptomatic populations (33,41,44) and those with known cardiovascular disease (13,33,39,44,63). Chronic physical inactivity and poor fitness are potential contributors to AAA. Regular exercise favorably alters epicardial and peripheral flow dynamics, resulting in improved blood flow to ischemic areas in patients with vascular disease (29,39,41). The last two decades have brought an awareness that the luminal diameter of epicardial vessels change rapidly in response to mechanical (flow related) and endogenous or pharmacological stimuli and that endothelial health can be enhanced by exercise training (21,39). In patients with AAA, recent studies show that acute exercise favorably alters adverse hemodynamic conditions in the abdominal aorta, including lessening peripheral resistance and oscillatory sheer stress, which may attenuate AAA growth (35,54,56). However, little is known about the duration of the favorable exercise effects, particularly in the postexercise period. Therefore, patients with AAA represent a population that could potentially benefit from exercise therapy and secondary prevention. However, because broad recognition of AAA is relatively recent, little is known regarding the safety and efficacy of formal exercise-based rehabilitation programs in patients with AAA.The purpose of this article is to review the available data on exercise testing and training in AAA and to discuss the potential for exercise therapy to reduce AAA risk and limit AAA progression. We are currently completing a randomized trial—funded by the National Heart, Lung, and Blood Institute (NHLBI)—on the effectiveness of exercise training to improve functional status and limit small aneurysm growth in this population (termed AAA: Simple Treatment or Prevention [AAA STOP]). While the major outcomes of the trial are still being assessed, some preliminary results recently published from the study have provided relevant insights into the effects of exercise in AAA and are discussed herein.An AAA is a localized dilation caused by a weakening of the vessel wall, most often in the infrarenal area (Figure 1). An AAA is usually defined as an outer aortic diameter >3.0 cm (normal diameter of the aorta is <2.5 cm). If the outer diameter exceeds 5.5 cm, the aneurysm is considered to be large and such patients are considered candidates for surgical repair (7). Individuals with AAA are usually asymptomatic and are often not discovered until they rupture or cause symptoms due to localized pressure on adjacent tissues. The major complication is rupture of the aneurysm; this is a life-threatening event, as large amounts of blood spill into the abdominal cavity, and can lead to death within minutes. Many factors can contribute to an AAA. They occur most commonly among individuals between ages 65 and 75 yr and are more common among men (4–5 times higher incidence) and among smokers (2–13 times higher incidence) (14,23,28,60). Those with AAA tend to be asymptomatic, although they can have pain in the abdomen and back (due to pressure on surrounding tissues) or in the lower limbs (claudication due to impaired blood flow).In 2005, a U.S. Preventive Services Task Force (USPSTF) report recommended that men 65–75 yr who had ever smoked be screened for AAA on one occasion by abdominal ultrasound (61). The USPSTF found little benefit to repeat screening in men who have a negative ultrasound and that men over 75 yr are unlikely to benefit from screening. While the USPSTF recommended against screening for women, a 2006 budget amendment termed Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) authorized the Centers for Medicare & Medicaid Services to cover screening for men in the 65–75 yr range who had smoked more than 100 cigarettes in their lifetime, in addition to men and women in this age range with a family history of AAA disease (48). Abdominal ultrasonography has been used as the screening modality in the large randomized trials of screening for an AAA because of its high sensitivity and specificity and low cost. With a sensitivity >95% and a specificity nearly 100%, ultrasonography has excellent test characteristics for diagnosing and following patients with an AAA (61).Guidelines on exercise testing and training have generally not addressed patients with AAA, likely due to AAA not being as widely recognized in the past as it is today and the fact that little is known about exercise testing and physical activity in this population. A 1997 recommendation suggested that individuals with AAA should not undergo maximal exercise testing, that heart rate should not exceed 100 beats·min−1, and that excessive rises in double-product (systolic blood pressure × heart rate) be avoided due to concerns about the potential for rupture (50). Pre-operative risk assessments in patients with AAA have largely employed pharmacologic stress with dobutamine, ostensibly to avoid an excessive rise in systolic blood pressure (30). However, these limitations have been based on intuition rather than known risks associated with exercise. The ACC/AHA Practice Guidelines for the Management of Patients With Peripheral Vascular Disease (27) suggest that AAA patients should not be fearful of vigorous activity and that efforts should be made to improve fitness in the event that surgery is required. Although a small number of recent reports used pharmacologic stress to risk-stratify patients with AAA (15,25,26), none, to our knowledge, have reported on adverse events. It should be noted that while few of these studies specified an AAA's size, most patients presumably had larger aneurysms because they were undergoing evaluation for surgery.Limited data are available regarding maximal exercise test responses in patients with AAA. Undoubtedly, this is because many AAA were undiagnosed, in addition to limited awareness of AAA among clinicians and the public until recent years. A tendency to refer these patients to pharmacologic stress testing because of concerns about safety has also occurred. For example, while the American Heart Association (AHA) Guidelines for Exercise Testing reviewed the applications of the test in a wide variety of cardiovascular and related conditions, AAA is not mentioned (19). Likewise, exercise testing is not mentioned in the AHA/American College of Cardiology (ACC) Practice Guidelines on Vascular Disease (27). Two recent studies have assessed the safety of maximal exercise testing in patients with AAA. Best and colleagues (5) retrospectively evaluated 262 patients with AAA with a diameter >4.0 cm who had undergone exercise testing at the Mayo Clinic. One patient with a large (6.1 cm diameter) aneurysm was reported to have a rupture 12 hours after the exercise test. While this event may or may not have been related to the exercise test, this yielded a rupture rate of 0.4%. No other negative outcomes were associated with the maximal exercise tests in this report. In a case report from 1986, Puls and Thadani described a patient with a 7.0 cm aneurysm who underwent supine exercise nuclear ventriculography (49). Six minutes into the test, at a work rate of 450 kpm (approximately 65 watts) and a blood pressure of 200/100 mmHg, the patient complained of excruciating low back pain. The test was stopped, an ultrasound was performed, revealing a rupture, and the patient underwent surgical repair. Two days following surgery, the patient died of myocardial infarction.Out of more than 500 maximal exercise tests conducted in patients with small AAA as part of the AAA STOP trial, no exercise test responses occurred that were serious enough to be considered an “event” by conventional definitions. A comparison of exercise test responses between patients with AAA and subjects of similar age referred for exercise testing for clinical reasons is presented in Table 1; these results reflect preliminary findings at roughly the halfway point of the trial (43). While the occurrence of hyper- and hypotensive responses were slightly higher in AAA subjects than those among age-matched VA referrals, the incidence of these responses was similar to other studies in subjects referred for exercise testing for clinical reasons (18). Notably, no instances of sustained or nonsustained ventricular tachycardia existed in the AAA subjects; this contrasts the incidence rate of 1.5% in age-matched subjects referred for exercise testing for clinical reasons; an incidence rate of 1.0% previously reported by our lab (40); and rates ranging from 0.08% to 1.1% reported elsewhere (4). It is also noteworthy that at the close of the trial in April 2011, no exercise-related hemodynamic or arrhythmic or other events related to in-house or home exercise training in the AAA STOP trial were reported (45).Little doubt exists that many post-MI, post PCI, or heart failure patients with occult small AAA have participated in rehabilitation programs in the years prior to the wider screening programs and awareness of the condition that exists today. Numerous studies report event rates associated with rehabilitation programs, and these studies are summarized in various sources, including national guidelines (57). No specific incidences of an AAA rupture are reported in these studies, although the possibility that an AAA event was attributed to acute MI or another cause cannot be discounted. It is notable that the two exercise test–related events in the literature described earlier occurred in patients with very large aneurysms (6.1 and 7.0 cm), which represent obvious contraindications to exercise.Limited data exist in the literature regarding the applications of fitness and physical activity patterns in the context of risk for an AAA. Peak V˙O2 has been used to estimate pre- and postoperative risk among patients undergoing vascular surgery in recent years, and AAA subjects with preserved exercise capacity have better postsurgical outcomes (10,34,52). In the United Kingdom Small Aneurysm Trial (UKSAT) (9), patients with a small AAA and who were poorly fit (based on a global preoperative score) benefitted from early surgery, with a 44% higher survival when expressed as aneurysm-related mortality. In a Swedish cohort of >33,000 men and women, physically inactive subjects classified crudely as “not walking or cycling to work” had a nearly threefold higher risk of developing an AAA (36). In a 6 yr follow-up of Finnish smokers, subjects categorized as “no exercise in leisure time” had a 29% higher risk of developing an AAA (60). In a cross-sectional study of 6,386 subjects in Norway, the odds ratios for AAA presence among active versus inactive men and women (defined as < or > 3 h·wk−1 low intensity activity in the last year) were 0.80 and 0.79, respectively (51). Finally, one of the major conclusions of the Endovascular Aneurysm Repair II (EVAR II) trial was that improving patient fitness, particularly cardiovascular, pulmonary, and renal function, should be the focus of treatment prior to considering repair (17). In a follow-up analysis in which EVAR I and EVAR II data were combined, the benefit of endovascular repair was demonstrated to be most convincing in the fittest patients (8). These studies suggest that in addition to modifying conventional risk markers for vascular disease, efforts to improve fitness by increasing activity should be included in the prevention and treatment paradigm for an AAA.In a recent pilot study, Kothmann and colleagues (31) studied 30 small AAA patients randomized to either a 7 wk exercise intervention program or usual care. Twenty-five of the subjects completed the program. Baseline and posttraining exercise tests were only performed up to the ventilatory threshold (VT) due to safety concerns. The exercise group participated in two supervised sessions weekly at a hospital-based facility, using moderate intensity training based on a rating of 12–14 on the Borg perceived exertion scale. Following the 7 wk period, a 10% improvement in V˙O2 at the VT was observed in the exercise group, whereas control subjects remained unchanged (p = 0.007 between groups). While this represented a statistically significant increase, it did not reach the level of improvement the investigators defined a priori as clinically significant (≥2.0 mL·kg·−1min−1). The effect of the program on maximal exercise capacity is unknown because the subjects were tested only to the VT. The investigators' conservative approach using exercise testing only to the level of the VT underscores the fact that little is known about exercise in this population and highlights the perception that a high level of exertion may adversely affect the aneurysm or lead to rupture.AAA STOP included subjects aged 50 to 85 yr with aortic diameters ≥3.0 and <5.0 cm. They followed a standard regimen by using a combination of in-house and home exercise training (45). Initially, subjects participated in at least 1 mo of in-house training under supervision, and this was followed by continued training at the VA rehabilitation facility, at home, or a combination of both depending on travel requirements and related issues. Exercise intensity was targeted between 60% and 80% of heart rate reserve depending on progression in the program and exercise training tolerance. Regardless of where training occurred, subjects were interviewed weekly by telephone to obtain estimates of recreational energy expenditure by using a 7 d activity recall tool. Results were recorded as calories (kcals) and MET-hours per week. These weekly interviews served the purposes of recognizing study-related complications, quantifying energy expenditure, and encouraging subjects to comply with their exercise prescription. The overall goal of training was to achieve a relatively ambitious mean energy expenditure of 2,000 kcal·wk−1 or the equivalent of roughly 1 h of moderate exercise per day.Preliminary results following 1 yr of exercise training in AAA STOP are presented in Table 2. No participants in training experienced AAA-related symptoms, exercise-related clinical events, or excessive growth rates. Notably, although the increases in estimated and measured peak V˙O2 did not reach statistical significance in this interim analysis, the increase in treadmill time was considerable (42%, p = 0.01), and participants readily incorporated walking, biking, or other activities into their daily routine and increased their energy expenditure well beyond that reported in population surveys in the United States (18) and elsewhere, including among veterans (42). The mean recreational energy expenditure of 2,269 kcal·wk−1 (Figure 2) is roughly double the minimum amount widely recommended in guidelines on physical activity and health (2). This amount of activity is associated with improved vascular function and marked reductions in cardiovascular morbidity and mortality (41,42,48). In the AAA subjects, this volume of training was sufficient to show trends for reductions in waist circumference and waist-to-hip ratio for participants completing 1 yr. Further analyses are being undertaken to assess safety and efficacy of participation for up to 3 yr, in addition to the potential role of training in limiting small AAA progression.Hemodynamic factors, including shear stress, cyclic strain, and various other pressure forces, play an important role in the normal adaptive response of the vasculature to changes in physiologic demands as well as maladaptive responses that lead to cardiovascular disease. The abdominal aorta is suggested to be particularly prone to unfavorable hemodynamic conditions due to low mean shear wall stress, high retrograde flow, and other factors (13,35,53,54,55,56). Exercise training is known to favorably modify the systemic inflammatory state, and the vascular shear stress caused by moderate exercise has been demonstrated to improve endothelial function in radial, femoral, and coronary arteries (20). It is therefore suggested that regular exercise may also provide localized benefits to the abdominal aortic vasculature by triggering biologic processes that lead to protection from the progression of atherosclerosis. These processes include hemodynamic conditions that inhibit atherosclerosis, such as unidirectional laminar flow, increased wall shear stress, the upregulation of endothelial vasodilator mechanisms, and the downregulation of vasoconstrictor properties, inflammatory molecules, and adhesion proteins (13,37,47,56,58,59).Recent studies using magnetic resonance imaging (MRI) and computational fluid dynamics have characterized abdominal aortic flow conditions in patients with an AAA. Acute bouts of submaximal exercise counteract these abnormal hemodynamic conditions by attenuating retrograde flow and increasing wall shear stress in the abdominal aorta (35,41,53,54,55,56). These studies have consistently observed that unfavorable hemodynamic conditions at rest are improved with even modest levels of acute exercise. While the association between regular exercise and an AAA progression has yet to be fully explored, these studies suggest that regular exercise may modify disease progression by altering local hemodynamic conditions.Although data are limited on the physiologic effects of exercise training in patients with an AAA, it seems reasonable to expect that moderate exercise typical of standard outpatient rehabilitation programs is safe for and beneficial to these patients. The ACC/AHA Practice Guidelines for the Management of Patients with Peripheral Vascular Disease (27) recommend modest activity in AAA patients, in part to counteract the reductions in fitness that are associated with poor outcomes among patients who eventually require surgery (8,10,17,34,52). The Society for Vascular Surgery Practice Guidelines for AAA recommend that during surveillance for patients with a small AAA, management should include counseling that moderate activity does not precipitate rupture and may limit AAA growth rate (11). For patients with aneurysms in general, the American College of Sports Medicine (ACSM) recommends moderate aerobic exercise, 20–40 min per session, 3–4 d·wk−1, with an emphasis on exercise duration over intensity (40). The recommendations for a small AAA also include low resistance strength training as a complement to the aerobic component. It would be appropriate to perform a treadmill test, particularly for patients wishing to engage in more vigorous activities (e.g., running or biking), to assess the physiologic response to exercise and to ascertain that the patient does not have a hypertensive response (29,40). The test should be performed while on beta-blockers and/or other antihypertensive medications, and recommendations for activity should be targeted below a systolic blood pressure rise of 180 mmHg on the treadmill test (29).Rehabilitation programs have been broadening their referral base in recent years to include nontraditional patients, such as postcardiac transplant, implantable cardioverter-defibrillators (ICDs), heart failure, and post-PCI patients, and stable patients with a small AAA would also appear to be good candidates for rehabilitation programs. In addition, given that cardiac rehabilitation has evolved from traditional exercise-based programs to comprehensive secondary prevention and chronic disease management centers (1), AAA patients would be ideal candidates for intervention because an AAA is strongly associated with cardiometabolic risk (13,22,23,28,36). Concerns about risks associated with moderate levels of exercise appear to be unfounded (11,27,43,45). However, available data remain limited on the effects of training in AAA, and more studies are needed to explore the role of rehabilitation in the prevention and treatment of an AAA. Further analyses from AAA STOP and a recently initiated trial in the United Kingdom (16) will no doubt provide additional insights into the role of exercise therapy as a treatment option for AAA.