Comprehensive Cardiac Rehabilitation as a Therapeutic Strategy for Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysms (AAA) are referred to as “time bombs”. The only way to prevent AAA rupture is elective repair beforehand using surgical replacement or an endovascular procedure. Non-surgical strategies to prevent AAA expansion are under intense investigation. At each AAA stage, that is, occurrence, expansion, and rupture, the mechanisms and risk factors are different, as discussed in this review. Based on the mechanism and risk factors for AAA expansion, the most effective strategy against AAA expansion need to be identified, but so far none has. Exercise is known to be essential for preventing atherosclerosis related to the coexistence of AAA and CAD, but some doctors are hesitant to prescribe exercise programs to AAA patients given that BP elevation during exercise can cause AAA expansion or rupture. In our retrospective study and prospective study on the safety and effectiveness of exercise for AAA patients, the protective role of mild-moderate exercise against expansion of small AAA was clearly shown. The stability of AAA on exercise might be related to reduced inflammatory activity in the aortic wall, stabilized elevation in BP during exercise, increased aortic blood flow, upregulation of transforming growth factor-β1, moderated BMI and/or fat, or improved endothelial function. Until a revolutionary drug emerges that can regress AAA, cardiac rehabilitation remains the best strategy for preventing AAA expansion and rupture.

Abdominal aortic aneurysms (AAA) are referred to as the “silent killer” or “time bomb”¹ because they grow asymptomatically until they rupture suddenly. The associated mortality rate after AAA rupture is as high as 80%,^2,3 with some patients surviving after successful emergency surgical repair. The only method to prevent AAA rupture is elective repair beforehand using surgical replacement or endovascular procedure. Some medications, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, and statins, have been shown to suppress AAA expansion in mouse AAA models.^4–9 Moreover, an inhibitor of c-jun N-terminal kinase led to the successful regression of AAA in animal models.¹⁰ These medications, however, could not suppress AAA expansion in humans. Hence, at present, we have no choice but to observe AAA expansion carefully until the AAA reaches the point where it meets the elective repair criteria. Accordingly, our urgent task is to elucidate the key mechanisms for AAA expansion and identify the potential therapeutic strategies for suppressing AAA expansion.

Mechanisms of AAA Occurrence and Expansion

The expansion of AAA is mediated by multiple factors, which partly differ from those related to the occurrence of AAA and other vascular diseases such as coronary artery disease (CAD), peripheral artery disease (PAD), and carotid stenosis.¹¹ Among them, inflammatory cells and cytokines play an important role in AAA occurrence and expansion.^12–14 Consistently, inhibition of tumor necrosis factor (TNF)-α, the complement system and peroxisome proliferator-activated receptor γ successfully prevented AAA formation and expansion in mouse AAA models.¹⁵ In contrast, anti-transforming growth factor-β (anti-TGF-β) antibody injection induced AAA rupture in an angiotensin II-stimulated AAA model,¹⁶ indicating that upregulated TGF-β plays a protective role against AAA progression and rupture.^16,17 Taken together, at least in animal models, the mechanism underlying AAA expansion is not similar to that underlying the occurrence of AAA.

Risk Factors for AAA Occurrence, Expansion, and Rupture in Humans

Consistent with the aforedescribed experimental findings, the risk profiles of occurrence, expansion, and rupture of AAA are different from one another in humans.

Except for AAA caused by infection, trauma, or Marfan syndrome, AAA occurrence is more prevalent in aged patients, male subjects, smokers, and those who have chronic obstructive pulmonary disease, hypertension, and low high-density lipoprotein cholesterol.¹⁸ Many cohort studies identified smoking as the strongest risk factor for AAA formation.¹⁹ A cohort study in Sweden suggested that a low anti-inflammatory dietary index is a risk factor for AAA occurrence.²⁰

Several studies indicated that atherosclerotic conditions do not contribute to the risk of AAA expansion.^21–26 The major risk factors for AAA expansion were the diameter of AAA and smoking, whereas atherosclerosis per se played a minor role in AAA expansion.²¹ Diabetes, a strong promoter of atherosclerosis, and PAD, representing the end stage of atherosclerosis, were inversely correlated with AAA expansion rate.²² We analyzed the clinical characteristics related to AAA expansion in 665 patients, and found an inverse correlation between accelerated AAA expansion rate and the existence of CAD,²³ and subsequent meta-analysis indicated an inverse association of CAD with AAA expansion, although that association did not reach statistical significance.²⁴ We also identified that high calcification index of the AAA wall, reflecting atherosclerosis stage, is inversely correlated with AAA expansion rate.^25,26 A recent biomechanical analysis showed that elevated peak wall stress (PWS) and peak wall shear stress accelerated AAA expansion, resulting in rupture.²⁷ Indeed, recent meta-analyses did not identify hypertension as a risk factor for AAA expansion.²⁸ Large AAA diameter, rapid expansion, smoking, hypertension, female sex, saccular morphology, and elevated PWS are risk factors for AAA rupture.^27,29,30 Here, it is important to be aware that hypertension is a risk factor for AAA rupture,^29,30 but it is not a significant risk factor for AAA expansion.^21–23,28 Therefore, it is understandable that antihypertensive therapy cannot prevent AAA expansion in humans.

Management of Small AAA

The guidelines for small AAA management recommend avoidance of smoking and competitive sports.^31,32 The guidelines do not recommend anaerobic exercise to AAA patients due to a lack of evidence supporting its benefit. Some doctors are hesitant to prescribe the exercise program to AAA patients for fear that blood pressure (BP) elevation during exercise may cause AAA expansion or rupture. Indeed, in the case report of a 71-year-old man with a 7-cm AAA, high-intensity exercise induced AAA rupture when BP increased from 160/94 mmHg to 200/100 mmHg on an exercise nuclear ventriculogram.³³ Exercise activates the sympathetic nervous system and elevates BP, possibly functioning as a trigger for AAA rupture. Also, an old report indicated that 17% of ruptures occurred while patients were lying in bed, 15% in the sitting position, 54% during mild or moderate load activity, and 13% during high load activity.³⁴ As for the AAA rupture, the safety margin of exercise intensity is unknown, therefore, it is natural that some doctors are hesitant to prescribe the exercise program to AAA patients for fear of AAA rupture during exercise.

High Frequency of CAD in AAA Patients

In a clinical setting, AAA frequently co-exists with CAD. A recent cohort study reported that 65.3% of AAA patients who underwent elective AAA repair had significant coronary artery stenosis,³⁵ whereas 51% of AAA patients were found to have CAD in a previous study.²³ Also, 5.4% of CAD patients had AAA in a large cohort study.³⁶

CAD patients require cardiac rehabilitation (CR) to improve life expectancy,³⁷ but when CAD patients have AAA, doctors are hesitant to prescribe CR for fear that BP elevation during exercise may cause AAA expansion or rupture. Here, we should identify the safety zone of exercise intensity for AAA patients, and examine whether CAD patients with AAA could obtain benefit from CR.

Small AAA and Exercise

In 2009, Kothmann et al first studied exercise in AAA patients,³⁸ but they could not sufficiently analyze the safety or effectiveness of exercise due to the small sample size. Myers et al performed a randomized controlled trial involving AAA patients, showing that peak exercise load in cardiopulmonary exercise test was safe for AAA patients.³⁹ The sample size, however, was still insufficient to enable generalization of the safety of exercise to all AAA patients. Therefore, the same group conducted a follow-up study in a larger population of AAA patients, and observed that moderate exercise with a target heart rate (HR) 60–80% of the HR reserve was safe.⁴⁰ In that study, moderate exercise did not enhance the AAA expansion as compared with AAA patients without exercise (Figure 1). Exercise improved peak V̇O₂ also in AAA patients.⁴¹ These studies, however, were performed in small groups for short follow-up periods.

Figure 1.

Change in exercise capacity vs. change in abdominal aortic aneurysm (AAA) diameter between baseline and 1-year evaluations. The change in AAA diameter tended to be slightly lower as exercise capacity improved at 1 year. Reproduced with permission from Myers J, et al.⁴⁰

We conducted a retrospective study in 1,515 AAA patients in 2 high-volume hospitals from April 2004 to September 2015, using propensity matching analysis.⁴² We compared patients with small AAA who underwent CR with those with small AAA who did not undergo CR, and 88 patients remained after propensity score matching. The typical exercise intensity with regular anaerobic threshold (AT) level for cardiovascular patients corresponds to 60–80% of maximum HR (%HR), or 0.4–0.6 of the exercise factor using the Karvonen formula.⁴³ Considering that elevated BP during exercise could be a risk factor for AAA rupture,^29,30 the exercise intensity corresponded to 0.2 of the exercise factor for the HR reserve using the Karvonen formula, which was designated as exercise with a “modified AT level” in that study (Figure 2).⁴² This exercise with modified AT level was prescribed to patients with resting BP <130/90 mmHg, and was discontinued when BP during exercise was >150/100 mmHg.

Figure 2.

Degree of exercise stress. Exercise at a modified anaerobic threshold (AT) level corresponds to systolic blood pressure (SBP) <150 mmHg. AAA, abdominal aortic aneurysm. Reproduced with permission from Nakayama A, et al.⁴²

That study confirmed the apparent positive effects of CR in patients with small AAA.⁴² The risk for AAA repair was significantly lower in the CR group (before matching: hazard ratio, 0.43; 95% CI: 0.25–0.72; P=0.001; after matching: hazard ratio, 0.19; 95% CI: 0.07–0.50; P<0.001; Figure 3). The AAA expansion rate was slower in the CR group (before matching: CR group vs. non-CR group, 2.3±3.7 vs. 3.8±3.4 mm/year, P=0.008; after matching: CR vs. non-CR group, 2.1±3.0 vs. 4.5±4.0 mm/year, P<0.001). The risks for major adverse cardiovascular events or death were similar between groups. Based on that retrospective study, we concluded that CR with a modified AT level was safe and effective for slowing AAA expansion.⁴²

Figure 3.

Kaplan-Meier analysis of the risks of abdominal aortic aneurysm (AAA) repair, all-cause death, and major adverse cardiovascular events (MACE) in small AAA patients (A) before propensity score matching between the cardiac rehabilitation (CR) group (n=49) and the non-CR group (n=163), and (B) after matching, between the CR group (n=44) and the non-CR group (n=44). Reproduced with permission from Nakayama A, et al.⁴²

Prevention of AAA Expansion by CR: Possible Mechanisms

The mechanisms by which CR prevents AAA expansion remain to be investigated. We assessed the potential for CR to prevent AAA expansion in a prospective study of 40 patients with small AAA (maximum diameter >30 mm and <50 mm).⁴⁴ The risk of AAA repair was significantly lower in the CR group than in the non-CR group (P=0.026; Figure 4). The AAA diameter expansion rate was higher in the non-CR group than in the CR group (CR, −1.3±2.4 mm/year; non-CR, 2.0±3.6 mm/year, P<0.01; Figure 5).

Figure 4.

Kaplan-Meier freedom from the risk of abdominal aortic aneurysm (AAA) repair according to the presence of cardiac rehabilitation (CR) in patients with small AAA.

Figure 5.

Change in maximum abdominal aortic aneurysm (AAA) size after registration, according to the presence of cardiac rehabilitation (CR). The reason for AAA repair is based on the criteria of diameter and expansion rate. Ope, operation. Reproduced with permission from Nakayama A, et al.⁴⁴

There are several hypotheses regarding the preventive role of CR against AAA expansion (Figure 6).⁴⁵ Briefly, the stability of AAA could be related to reduced inflammatory activity in the aortic wall, stabilized elevation of BP during exercise, increased aortic blood flow, upregulation of TGF-β1, moderated body mass index (BMI) and/or fat, or improved endothelial function.

Figure 6.

Schematic diagram of the effect of cardiac rehabilitation on the formation, expansion, and rupture of abdominal aortic aneurysms (AAA). BP, blood pressure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DM, diabetes mellitus; HDL, high-density lipoprotein cholesterol; IL-6, interleukin-6; PAD, peripheral artery disease; PWS, peak wall stress; TGF-β1, transforming growth factor-β1; VSMC, vascular smooth muscle cell. Reproduced with permission from Carino D, et al.⁴⁵

Inhibition of Aortic Wall Inflammation

Inflammatory activity in the aortic wall is thought to be a trigger for AAA formation and expansion.^12–14 Atherosclerosis-driven changes in the aortic wall underlie the pathogenesis of AAA, and inflammatory mechanisms contribute to aortic wall weakening. The inflammatory cytokine TNF-α plays a role in the pathogenic mechanisms of AAA, and oral intake of a TNF-α antagonist, infliximab, inhibited AAA formation in mice.¹³ Treatment with an anti-interleukin-1β (anti-IL-1β) antibody also suppressed angiotensin II-induced aortic inflammation and AAA formation in mice.¹⁴ In our analysis, however, the inflammatory cytokines high-sensitivity C-reactive protein and IL-6 were not suppressed by CR, and they were not related to the AAA expansion rate.⁴⁴ Additional research on inflammatory cytokines, including interferon-γ, TNF-α, IL-1, and IL-8, is needed to confirm the anti-inflammatory effect on the relationship between CR and AAA expansion.

Stabilization of BP Elevation During Exercise

By exercise training, both systolic and diastolic BP were lowered,⁴⁶ and BP elevation during exercise was stabilized.⁴⁷ The BP-lowering effects of CR can be explained by a reduction in total peripheral resistance⁴⁸ or improvement in autonomic function⁴⁹ following exercise training. Both our studies suggested that stabilization of changes in BP from rest to modified AT level after the CR program were correlated with the lower AAA expansion rate.^42,44 Although hypertension per se was not a risk factor for AAA expansion, daily BP fluctuations may contribute to the risk of AAA expansion and CR could limit this BP fluctuation.

Increased Aortic Blood Flow

Increased aortic blood flow is reported to attenuate AAA expansion via wall shear or strain-related reductions in oxidative stress.⁵⁰ Moderate exercise can increase aortic blood flow,⁵¹ but it is unknown whether this increased blood flow could slow AAA expansion in humans.

Upregulation of TGF-β1

Activated TGF-β1 is well-reported in patients and in animal models of AAA. Several studies reported TGF-β1 activity as the cause of AAA formation, but downregulation of TGF-β induced AAA rupture in an angiotensin II-stimulated AAA model,¹⁶ and TGF-β1 upregulation slowed AAA expansion.¹⁷ TGF-β1 might be activated by inflammation or atherosclerosis, exerting a protective effect against AAA expansion. In our prospective study, TGF-β1 activation was higher in the CR group, but the change in TGF-β1 level was not related to AAA expansion rate.⁴⁴ There are few reports regarding TGF-β1 after exercise training in humans, and our prospective study first reported elevation in serum TGF-β1 after CR.⁴⁴ We expect that the activation of TGF-β1 might be a key mechanism for suppressed AAA expansion by CR. The role of activated TGF-β1 signaling after CR remains to be investigated, and more studies with larger populations are needed to clarify its protective role in AAA expansion.

Lowering BMI and/or Body Fat

One of the causes of AAA formation is atherosclerosis. In that sense, a high BMI or excess fat were thought to be a trigger of AAA formation. A recent meta-analysis demonstrated a trend toward a positive, although not statistically significant, association between BMI and AAA formation.⁵² In contrast, a meta-analysis on the association between BMI and AAA rupture demonstrated that a lower BMI was related to AAA rupture.⁵³ In our study, the changes in BMI or body fat mass during 6 months were not correlated with AAA expansion rate.⁴⁴ Therefore, we cannot regard BMI and body fat mass as target modification factors to protect against AAA expansion.

Improved Endothelial Function

Endothelial cells have been reported to play an important role in AAA expansion through increased oxidative stress.⁵⁴ A meta-analysis showed that physical exercise has beneficial effects on endothelial function, measured as flow-mediated dilation, which could regulate vascular tone and circulatory homeostasis.⁵⁵ Additional research is needed to understand the relationship between CR, endothelial function and AAA expansion.

Conclusions

Considering the hypotheses discussed here, stabilization of the elevation of BP during exercise plays an important role in protecting against rapid AAA expansion. Our goal is to regress the small AAA to avoid surgical repair, but medication for small AAA lacks sufficient evidence in humans. Anti-TNF-α and TGF-β1 activation are expected to be good candidates for treatment to protect against AAA expansion. Until a revolutionary drug has been developed that can regress AAA, CR remains the best therapeutic strategy for preventing AAA expansion and rupture (Figure 6).

Funding

This study was supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

Disclosure

I.K. is a member of Circulation Reports ’ Editorial Team. The other authors declare no conflicts of interest.

References

• 1.   Aoki H. Taking control of the time bomb in abdominal aortic aneurysm. Circ J 2016; 80: 314–315.
• 2.   Schermerhorn ML, Bensley RP, Giles KA, Hurks R, O’Malley AJ, Cotterill P, et al. Changes in abdominal aortic aneurysm rupture and short-term mortality, 1995–2008: A retrospective observational study. Ann Surg 2012; 256: 651–658.
• 3.   Nelissen BG, Herwaarden JA, Pasterkamp G, Moll FL, Vaartjes I. Shifting abdominal aortic aneurysm mortality trends in The Netherlands. J Vasc Surg 2015; 61: 642–627.e2.
• 4.   Liao S, Miralles M, Kelley BJ, Curci JA, Borhani M, Thompson RW. Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors. J Vasc Surg 2001; 33: 1057–1064.
• 5.   Kaschina E, Schrader F, Sommerfeld M, Kemnitz UR, Grzesiak A, Krikov M, et al. Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation. J Hypertens 2008; 26: 2361–2373.
• 6.   Slaiby JM, Ricci MA, Gadowski GR, Hendley ED, Pilcher DB. Expansion of aortic aneurysms is reduced by propranolol in a hypertensive rat model. J Vasc Surg 1994; 20: 178–183.
• 7.   Kalyanasundaram A, Elmore JR, Manazer JR, Golden A, Franklin DP, Galt SW, et al. Simvastatin suppresses experimental aortic aneurysm expansion. J Vasc Surg 2006; 43: 117–124.
• 8.   Shiraya S, Miyake T, Aoki M, Yoshikazu F, Ohgi S, Nishimura M, et al. Inhibition of development of experimental aortic abdominal aneurysm in rat model by atorvastatin through inhibition of macrophage migration. Atherosclerosis 2009; 202: 34–40.
• 9.   Golledge J, Cullen B, Moran C, Rush C. Efficacy of simvastatin in reducing aortic dilatation in mouse models of abdominal aortic aneurysm. Cardiovasc Drugs Ther 2010; 24: 373–378.
• 10.   Yoshimura K, Aoki H, Ikeda Y, Fujii K, Akiyama N, Furutani A, et al. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 2005; 11: 1330–1338.
• 11.   Takagi H, Umemoto T. Associations of coronary and peripheral artery disease with presence, expansion, and rupture of abdominal aortic aneurysm: A grin without a cat! Vasa 2017; 46: 151–158.
• 12.   Peshkova IO, Schaefer G, Koltsova EK. Atherosclerosis and aortic aneurysm: Is inflammation a common denominator? FEBS J 2016; 283: 1636–1652.
• 13.   Xiong W, MacTaggart J, Knispel R, Worth J, Persidsky Y, Baxter BT. Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol 2009; 183: 2741–2746.
• 14.   Isoda K, Akita K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Isobe S, et al. Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. Int J Cardiol 2018; 270: 221–227.
• 15.   Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A. Novel mechanisms of abdominal aortic aneurysms. Curr Atheroscler Rep 2012; 14: 402–412.
• 16.   Wang Y, Ait-Oufella H, Herbin O, Bonnin P, Ramkhelawon B, Taleb S, et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 2010; 120: 422–432.
• 17.   Dai J, Losy F, Guinault AM, Pages C, Anegon I, Desgranges P, et al. Overexpression of transforming growth factor-beta1 stabilizes already-formed aortic aneurysms: A first approach to induction of functional healing by endovascular gene therapy. Circulation 2005; 112: 1008–1015.
• 18.   Forsdahl SH, Singh K, Solberg S, Jacobsen BK. Risk factors for abdominal aortic aneurysms: A 7-year prospective study Circulation 2009; 119: 2202–2208.
• 19.   Jahangir E, Lipworth L, Edwards TL, Kabagambe EK, Mumma MT, Mensah GA, et al. Smoking, sex, risk factors and abdominal aortic aneurysms: A prospective study of 18 782 persons aged above 65 years in the Southern Community Cohort Study. J Epidemiol Community Health 2015; 69: 481–488.
• 20.   Kaluza J, Stackelberg O, Harris HR, Björck M, Wolk A. Anti-inflammatory diet and risk of abdominal aortic aneurysm in two Swedish cohorts. Heart, doi:10.1136/heartjnl-2019-315031.
• 21.   Brady AR, Thompson SG, Fowkes FG, Greenhalgh RM, Powell JT; UK Small Aneurysm Trial Participants. Abdominal aortic aneurysm expansion: Risk factors and time intervals for surveillance. Circulation 2004; 110: 16–21.
• 22.   Shantikumar S, Ajjan R, Porter KE, Scott DJ. Diabetes and the abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2010; 39: 200–207.
• 23.   Nakayama A, Morita H, Miyata T, Ando J, Fujita H, Ohtsu H, et al. Inverse association between the existence of coronary artery disease and progression of abdominal aortic aneurysm. Atherosclerosis 2012; 222: 278–283.
• 24.   Takagi H, Umemoto T; ALICE (All-Literature Investigation of Cardiovascular Evidence) Group. Coronary artery disease and abdominal aortic aneurysm growth. Vasc Med 2016; 21: 199–208.
• 25.   Nakayama A, Morita H, Hayashi N, Nomura Y, Hoshina K, Shigematsu K, et al. Inverse correlation between calcium accumulation and the expansion rate of abdominal aortic aneurysms. Circ J 2016; 80: 332–339.
• 26.   Nakayama A, Morita H, Hoshina K, Komuro I. Quantification of abdominal aortic aneurysm calcification using the Agatston method can predict accelerated expansion rate. Circ J 2019; 83: 689.
• 27.   Leemans EL, Willems TP, van der Laan MJ, Slump CH, Zeebregts CJ. Biomechanical indices for rupture risk estimation in abdominal aortic aneurysms. J Endovasc Ther 2017; 24: 254–261.
• 28.   Takagi H, Umemoto T; ALICE (All-Literature Investigation of Cardiovascular Evidence) Group. Association of hypertension with abdominal aortic aneurysm expansion. Ann Vasc Surg 2017; 39: 74–89.
• 29.   Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance: UK Small Aneurysm Trial Participants. Ann Surg 1999; 230: 289–296.
• 30.   Gokani VJ, Sidloff D, Bath MF, Bown MJ, Sayers RD, Choke E. A retrospective study: Factors associated with the risk of abdominal aortic aneurysm rupture. Vascul Pharmacol, doi:10.1016/j.vph.2014.11.006.
• 31.   Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 58: 2020–2045.
• 32.   Erbel R, Aboyans V, Boileau C, Bossone E, Di Bartolomeo R, Eggebrecht H, et al. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014; 35: 2873–2926.
• 33.   Puls A, Thadani U. Rupture of abdominal aortic aneurysm during exercise. Gated blood pool studies. Am J Med 1986; 81: 887–889.
• 34.   Cherry CB, Cherry KT. Dissecting aneurysm of the aorta; evaluation of the role of exertion in its production. Industrial Med 1941; 10: 525–528.
• 35.   Hołda MK, Iwaszczuk P, Wszołek K, Chmiel J, Brzychczy A, Trystuła M, et al. Coexistence and management of abdominal aortic aneurysm and coronary artery disease. Cardiol J, doi:10.5603/CJ.a2018.0101.
• 36.   Koshty A, Bork M, Böning A, Gündüz D, Pleger SP. Coronary artery disease as a relevant risk factor in screening of abdominal aortic ectasia and aneurysm. Thorac Cardiovasc Surg, doi:10.1055/s-0038-1676336.
• 37.   Dorn J, Naughton J, Imamura D, Trevisan M. Results of a multicenter randomized clinical trial of exercise and long-term survival in myocardial infarction patients: The National Exercise and Heart Disease Project (NEHDP). Circulation 1999; 100: 1764–1769.
• 38.   Kothmann E, Batterham AM, Owen SJ, Turley AJ, Cheesman M, Parry A, et al. Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: A pilot study. Br J Anaesth 2009; 103: 505–510.
• 39.   Myers JN, White JJ, Narasimhan B, Dalman RL. Effects of exercise training in patients with abdominal aortic aneurysm: Preliminary results from a randomized trial. J Cardiopulm Rehabil Prev 2010; 30: 374–383.
• 40.   Myers J, McElrath M, Jaffe A, Smith K, Fonda H, Vu A, et al. A randomized trial of exercise training in abdominal aortic aneurysm disease. Med Sci Sports Exerc 2014; 46: 2–9.
• 41.   Barakat HM, Shahin Y, Barnes R, Gohil R, Souroullas P, Khan J, et al. Supervised exercise program improves aerobic fitness in patients awaiting abdominal aortic aneurysm repair. Ann Vasc Surg 2014; 28: 74–79.
• 42.   Nakayama A, Morita H, Nagayama M, Hoshina K, Uemura Y, Tomoike H, et al. Cardiac rehabilitation protects against the expansion of abdominal aortic aneurysm. J Am Heart Assoc 2018; 7: e007959.
• 43.   JCS Joint Working Group. Guidelines for rehabilitation in patients with cardiovascular disease (JCS 2012): Digest version. Circ J 2014; 78: 2022–2093.
• 44.   Nakayama A, Amiya E, Morita H, Hyodo K, Takayama N, Konishi Y, et al. The potential of cardiac rehabilitation as a method of suppressing abdominal aortic aneurysm expansion: A pilot study. Heart Vessels, doi:10.1007/s00380-019-01441-x.
• 45.   Carino D, Sarac TP, Ziganshin BA, Elefteriades JA. Abdominal aortic aneurysm: Evolving controversies and uncertainties. Int J Angiol 2018; 27: 58–80.
• 46.   Cornelissen VA, Smart NA. Exercise training for blood pressure: A systematic review and meta-analysis. J Am Heart Assoc 2013; 2: e004473.
• 47.   Cornelissen VA, Buys R, Smart NA. Endurance exercise beneficially affects ambulatory blood pressure: A systematic review and meta-analysis. J Hypertens 2013; 31: 639–648.
• 48.   Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: A randomized trial. JAMA 2000; 283: 3095–3101.
• 49.   Iellamo F, Legramante JM, Massaro M, Raimondi G, Galante A. Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: A randomized, controlled study. Circulation 2000; 102: 2588–2592.
• 50.   Nakahashi TK, Hoshina K, Tsao PS, Sho E, Sho M, Karwowski JK, et al. Flow loading induces macrophage antioxidative gene expression in experimental aneurysms. Arterioscler Thromb Vasc Biol 2002; 22: 2017–2022.
• 51.   Tenforde AS, Cheng CP, Suh GY, Herfkens RJ, Dalman RL, Taylor CA. Quantifying in vivo hemodynamic response to exercise in patients with intermittent claudication and abdominal aortic aneurysms using cine phase-contrast MRI. J Magn Reson Imaging 2010; 31: 425–429.
• 52.   Takagi H, Umemoto T. A meta-analysis of the association of obesity with abdominal aortic aneurysm presence. Int Angiol 2015; 34: 383–391.
• 53.   Sweeting MJ, Thompson SG, Brown LC, Powell JT; RESCAN collaborators. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012; 99: 655–665.
• 54.   Siasos G, Mourouzis K, Oikonomou E, Tsalamandris S, Tsigkou V, Vlasis K, et al. The role of endothelial dysfunction in aortic aneurysms. Curr Pharm Des 2015; 21: 4016–4034.
• 55.   Pearson MJ, Smart NA. Effect of exercise training on endothelial function in heart failure patients: A systematic review meta-analysis. Int J Cardiol 2017; 231: 234–243.