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Endurance Exercise Training in Patients With Small Abdominal Aortic Aneurysm: A Randomized Controlled Pilot Study

      Abstract

      Tew GA, Moss J, Crank H, Mitchell PA, Nawaz S. Endurance exercise training in patients with small abdominal aortic aneurysm: a randomized controlled pilot study.

      Objective

      To investigate the feasibility of endurance exercise training in patients with small abdominal aortic aneurysm (AAA), and to obtain preliminary data of its impact on important health outcomes.

      Design

      Randomized controlled pilot study.

      Setting

      University rehabilitation facility.

      Participants

      Patients with small AAA (N=28; mean age ± SD, 72±7y).

      Intervention

      Participants were randomized to a 12-week program of moderate-intensity endurance exercise or standard care control (encouragement to exercise only).

      Main Outcome Measures

      Safety was assessed in terms of the frequency of adverse events and changes in maximum AAA diameter. Outcomes were assessed at baseline and 12 weeks including cardiopulmonary fitness (ventilatory threshold), health-related quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [version 2]), and markers of vascular risk (eg, blood pressure and high-sensitivity C-reactive protein).

      Results

      Of 545 patients contacted, 28 (5%) entered the trial. There were 3 (11%) dropouts. Adherence to the exercise program was 94%. There were no paradoxical increases in AAA size or adverse clinical events. Ventilatory threshold increased in the exercise group, but not the control group (adjusted mean difference, 2.5mL·kg−1·min−1; 95% confidence interval, 0.5–4.5; d=.82). Systolic blood pressure and high-sensitivity C-reactive protein decreased in the exercise group compared with the control group (d=.34 and d=.58, respectively). There were no substantial changes in anthropometric variables or quality of life.

      Conclusions

      Despite a low recruitment rate, the findings suggest that moderate-intensity endurance exercise training is feasible in patients with small AAA, and can evoke improvements in important health outcomes.

      Key Words

      List of Abbreviations:

      AAA (abdominal aortic aneurysm), hs-CRP (high-sensitivity C-reactive protein), MMP-9 (matrix metalloproteinase-9), Vo2peak (peak oxygen consumption)
      ABDOMINAL AORTIC aneurysm (AAA) is a frequently lethal age-related disease affecting 5% to 7.5% of men and 1.5% to 3% of women aged >65 years.
      • Lederle F.A.
      • Johnson G.R.
      • Wilson S.E.
      • et al.
      Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators
      The aneurysm detection and management study screening program: validation cohort and final results.
      Rupture of an AAA and its associated catastrophic physiologic insult carries overall mortality in excess of 80%,
      • Nordon I.M.
      • Hinchliffe R.J.
      • Loftus I.M.
      • Thompson M.M.
      Pathophysiology and epidemiology of abdominal aortic aneurysms.
      and 2% of all deaths are AAA-related in men aged 65 to 74 years.
      • Thompson S.G.
      • Ashton H.A.
      • Gao L.
      • Scott R.A.
      Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study.
      Mechanical intervention (open surgical or endovascular repair) is currently the only treatment shown to be effective in preventing AAA rupture and aneurysm-related death; it is reserved for AAAs ≥55mm in diameter for men and ≥50mm in women.
      • Baxter B.T.
      • Terrin M.C.
      • Dalman R.L.
      Medical management of small abdominal aortic aneurysms.
      Fortunately, 90% of AAAs detected during screening fall below these thresholds
      • Brewster D.C.
      • Cronenwett J.L.
      • Hallett Jr, J.W.
      • Johnston K.W.
      • Krupski W.C.
      • Matsumura J.S.
      Guidelines for the treatment of abdominal aortic aneurysms Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery.
      and expansion rates are gradual, with mean growth rates for small AAAs (30–49mm) of 2 to 3mm per year.
      • Moll F.L.
      • Powell J.T.
      • Fraedrich G.
      • et al.
      Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery.
      There are currently few treatment options available for people with small AAAs
      • Baxter B.T.
      • Terrin M.C.
      • Dalman R.L.
      Medical management of small abdominal aortic aneurysms.
      • Moll F.L.
      • Powell J.T.
      • Fraedrich G.
      • et al.
      Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery.
      ; most patients simply enter a surveillance program to monitor the progression of their aneurysm.
      Endurance exercise training might be a useful intervention for patients with early AAA disease for several reasons. First, exercise might reduce the excessive risk of all-cause mortality and cardiovascular disease events that characterizes this population.
      • Freiberg M.S.
      • Arnold A.M.
      • Newman A.B.
      • Edwards M.S.
      • Kraemer K.L.
      • Kuller L.H.
      Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study.
      For example, epidemiologic data indicate that a 3.5mL·kg−1·min−1 increase in maximum oxygen consumption is associated with 13% and 15% decrements in risk of all-cause mortality and cardiovascular disease events, respectively.
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis.
      Second, indirect evidence suggests that exercise might inhibit AAA enlargement through mechanisms including improved aortic hemodynamics and reduced inflammation. For example, a study in a rat experimental model demonstrated that increased aortic flow inhibited AAA expansion.
      • Nakahashi T.K.
      • Hoshina K.
      • Tsao P.S.
      • et al.
      Flow loading induces macrophage antioxidative gene expression in experimental aneurysms.
      Finally, exercise might reduce the risk of perioperative morbidity and mortality in patients progressing to elective aneurysm repair via enhanced cardiopulmonary fitness.
      • Jack S.
      • West M.
      • Grocott M.P.
      Perioperative exercise training in elderly subjects.
      Indeed, preoperative fitness levels have been associated with higher survival rates in individuals undergoing open surgical AAA repair
      • Carlisle J.
      • Swart M.
      Mid-term survival after abdominal aortic aneurysm surgery predicted by cardiopulmonary exercise testing.
      and other major intra-abdominal surgery.
      • Older P.
      • Hall A.
      • Hader R.
      Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly.
      At present, little is known about the effects of exercise training in patients with AAA disease, most likely because this condition was not as widely recognized in the past as it is today, and perhaps because of concerns about excessive rises in double product (systolic blood pressure × heart rate) causing aneurysm rupture. However, such concerns about the risks of exercise, particularly that of moderate intensity, appear unfounded. For example, Myers et al
      • Myers J.
      • Powell A.
      • Smith K.
      • Fonda H.
      • Dalman R.L.
      Cardiopulmonary exercise testing in small abdominal aortic aneurysm: profile, safety, and mortality estimates.
      recently assessed the safety of maximal treadmill exercise testing in 306 patients with small AAAs ranging from 30 to 50mm in diameter. Despite the incidence of exercise-induced hypotension and hypertension being higher in AAA patients than in age-matched adults referred for clinical reasons (2.9% and 3.6% vs <1.0%, respectively; P<.001), there were no serious adverse events (eg, ventricular tachycardia, aneurysm rupture). Of note, the American College of Cardiology/American Heart Association Practice Guidelines for the Management of Patients with Peripheral Vascular Disease 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.
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • et al.
      ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
      To date there have only been 2 published reports of exercise training in patients with AAA.
      • Myers J.N.
      • White J.J.
      • Narasimhan B.
      • Dalman R.L.
      Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial.
      • Kothmann E.
      • Batterham A.M.
      • Owen S.J.
      • et al.
      Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: a pilot study.
      In the first of these, Kothmann et al
      • Kothmann E.
      • Batterham A.M.
      • Owen S.J.
      • et al.
      Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: a pilot study.
      randomized 30 patients with small AAAs (30–51mm) to either a 6-week endurance exercise program (30min continuous moderate-intensity cycle ergometry, twice weekly) or usual care control. Twenty-five of the participants completed this pilot study, and ventilatory threshold increased by 10% in the intervention group compared with the controls (P=.007). This modest change is probably largely because of the low overall training volume. No other health outcomes were reported. In the other report, which described preliminary data from the AAA Simple Treatment or Prevention trial,
      • Myers J.N.
      • White J.J.
      • Narasimhan B.
      • Dalman R.L.
      Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial.
      57 patients with small AAA (30–50mm) were randomized to either exercise or usual care control. The exercise regimen involved a combination of moderate-intensity endurance and resistance exercises performed in-house and/or at home over the period of 1 year. Thus, the exact training stimulus likely varied somewhat between patients. Nevertheless, no participants in training experienced AAA-related symptoms, exercise-related clinical events, or excessive aneurysm growth rates. Although the increases in peak oxygen consumption (Vo2peak) did not reach statistical significance (P=.29), the increase in treadmill test duration was considerable (42% vs 2%, respectively; P=.01), and the mean recreational energy expenditure equated to over 1 hour of moderate-intensity exercise per day.
      Although these previous reports have provided some insight into the safety, acceptability, and efficacy of exercise training in patients with small AAAs, further research is needed to assess its feasibility and impact on a broad range of important health outcomes. Furthermore, we believe it is important to assess the effects of different training regimes. Therefore, the aim of this study was to investigate the feasibility of a 12-week program of supervised endurance exercise training in patients with small AAAs, as well as its impact on cardiopulmonary fitness, health-related quality of life, and several disease-specific and cardiovascular risk markers by comparison with patients receiving standard care only.

      Methods

      Participants

      Based on the pilot study guidelines of Lancaster et al,
      • Lancaster G.A.
      • Dodd S.
      • Williamson P.R.
      Design and analysis of pilot studies: recommendations for good practice.
      we aimed to recruit 60 patients with early AAA disease between January 2010 and September 2011. Only 28 patients were recruited during this period (fig 1). Potential participants were identified from vascular clinics and aneurysm surveillance lists at the Northern General Hospital, Sheffield and Rotherham Hospital, Rotherham, UK. Inclusion criteria were men and women patients aged 50 to 85 years with an asymptomatic, infrarenal AAA 30 to 50mm in diameter. Exclusion criteria were any contraindications to exercise testing and training (eg, severe hypertension, unstable angina, and uncontrolled cardiac arrhythmias), an inability or unwillingness to undertake the commitments of the study, and current participation in regular purposeful exercise (≥30min, ≥3 times per wk). This research was carried out in accordance with the Declaration of Helsinki of the World Medical Association, and was approved by the South Yorkshire Research Ethics Committee. Participants provided written informed consent before being included in the study. The study was registered in ClinicalTrials.gov under reference no. NCT01234610.
      Figure thumbnail gr1
      Fig 1Consolidated Standards of Reporting Trials flow diagram.

      Design

      This was a randomized controlled pilot trial. After completion of baseline assessments, participants were randomly assigned 1:1 either to exercise training or standard care control. Both groups had access to standard care, which consisted of a basic recommendation to be physically active, but to avoid strenuous lifting. Allocation to exercise or control was done using a randomization sequence created by an independent researcher before study commencement.a The study researchers were made aware of this sequence on a case-by-case basis after baseline assessments were completed.
      Study methods for all participants included extraction of medical history and drug information from medical records and patient questioning, and assessment of the following outcomes at baseline and after 12 weeks of follow-up: health-related quality of life using the Medical Outcomes Study 36-Item Short-Form Health Survey (version 2) questionnaire,
      • Ware Jr, J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36) I. Conceptual framework and item selection.
      maximum AAA diameter via transabdominal ultrasound,b and ventilatory threshold via cardiopulmonary exercise testing. Fasting venous blood samples were collected for analysis of lipid profiles, high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase-9 (MMP-9),c and glucose (all serum).

      Cardiopulmonary Exercise Testing

      The assessment of cardiopulmonary fitness was achieved by measuring ventilatory threshold. Participants underwent cardiopulmonary exercise testing using an incremental protocol on an electronically braked cycle ergometer.d After 2 minutes of unloaded cycling, the intensity of exercise was increased by 15 W/min. The target cadence was 60 to 80 rev/min. Participants were encouraged to continue cycling to volitional exhaustion. Capillary blood lactate concentrations were assessed before and after exercise using a portable lactate analyzer.e Twelve-lead electrocardiogram monitoring with ST segment analysis was performed continuously.f The test was terminated if there was participant distress or development of ≥2mm ST depression in any lead. The volume of oxygen consumed during exercise was calculated from minute ventilation, measured using a pneumotachometer, and simultaneous breath-by-breath analysis of expired gas fractions.g Gas analyzers and flow probes were calibrated before each test. Oxygen consumption was expressed relative to body mass (mL/kg/min). Ventilatory threshold was determined by an independent exercise physiologist blinded to group allocation using the v-slope and ventilatory equivalents methods.
      • Beaver W.L.
      • Wasserman K.
      • Whipp B.J.
      A new method for detecting anaerobic threshold by gas exchange.
      Peak Vo2 was also calculated as the highest consecutive 20-second period of gas exchange data in the last minute before volitional exhaustion, which generally occurred because of leg fatigue and/or breathlessness.

      Exercise Training

      Participants randomized to exercise were invited to undertake training 3 times per week for 12 consecutive weeks at a dedicated exercise suite at Sheffield Hallam University. Each session involved a mixture of treadmill walking and cycle ergometry for 35 to 45 minutes, supervised by an experienced exercise physiologist. Perceived exertion was targeted to fall within the range of 12 to 14 (ie, somewhat hard) on the Borg 6 to 20 scale.
      • Borg G.A.
      Psychophysical bases of perceived exertion.
      This intensity of training was chosen because of its coincidence with the ventilatory threshold,
      • Purvis J.W.
      • Cureton K.J.
      Ratings of perceived exertion at the anaerobic threshold.
      and because it has been shown to be an adequate training stimulus for improving ventilatory threshold in sedentary adults.
      • Londeree B.R.
      Effect of training on lactate/ventilatory thresholds: a meta-analysis.
      Perceived exertion and heart rate were recorded at 5-minute intervals during each session.

      Statistical Analysis

      Mean and SD values were used to describe baseline characteristics and within-group changes. Changes were calculated by subtracting the baseline measurement from the 12-week follow-up measurement. Comparisons between study groups were performed using analysis of covariance procedures, with baseline values used as the covariate.
      • Vickers A.J.
      • Altman D.G.
      Statistics notes: analysing controlled trials with baseline and follow up measurements.
      Data were log-transformed prior to analysis when 2 or more of the following test assumptions were violated: normality (Shapiro-Wilk test), homogeneity of regression slopes, and homogeneity of variances (Levene test). Statistical significance was set at P≤.05. Effect sizes (Cohen d) were calculated using the methods of Morris,
      • Morris S.B.
      Estimating effect sizes from pretest-posttest-control group designs.
      and the minimum clinically important difference was defined as one-third of the pooled SD at baseline. Patients who withdrew before follow-up were not included in the analysis, and there was no adjustment for multiple comparisons. Data were analyzed using the PASW statistical package.h

      Results

      Of 545 patients contacted, 28 (5%) were allocated to exercise (n=14) or standard care control (n=14) (see fig 1). Three participants did not complete the exercise intervention: 1 withdrew because of being diagnosed with cancer, 1 underwent pacemaker implantation, and 1 suffered a back injury at home. Baseline characteristics of patients who completed the study are presented in table 1. Compliance to the exercise program was excellent, with 371 of 396 sessions attended (94%). Mean ratings of perceived exertion and percentage of age-predicted maximum heart rate (based on the formula 220 – age in years) during the exercise sessions were 11.8±0.8 and 72%±8%, respectively. No adverse clinical events occurred during the 53 maximal exercise tests and 371 training sessions, and there was no paradoxical increase in aneurysm diameter (adjusted mean difference, –0.1mm [favoring exercise]; 95% confidence interval, –1.5 to 1.2; P=.836).
      Table 1Demographic and Descriptive Variables at Baseline
      VariableExercise (n=11)Standard Care (n=14)
      Characteristics
       Age (y)71±874±6
       Sex (male/female)10 / 111 / 3
       Aneurysm size (mm)40.9±7.039.3±6.4
       Body mass (kg)83.1±9.782.6±12.9
       Stature (cm)172.7±7.3170.6±7.2
       Body mass index (kg/m2)27.9±3.228.3±3.2
       Systolic blood pressure (mmHg)149±25152±26
       Diastolic blood pressure (mmHg)81±974±11
      Comorbidities
       Coronary artery disease43
       Peripheral artery disease06
       Hypertension612
       Diabetes22
       Current smoker12
      Medication
       Beta-blocker43
       Angiotensin converting enzyme inhibitor47
       Calcium channel antagonist24
       Diuretic45
       Statin912
       Aspirin77
      NOTE. Data are presented as mean ± SD or frequencies.
      The exercise test data are presented in table 2. Ventilatory threshold increased in the exercise group compared with the controls (2.5mL·kg−1·min−1; 0.5–4.5; P=.016). The adjusted means also tended to be higher in exercise versus controls for Vo2peak (1.5mL·kg−1·min−1; –0.8 to 3.8; P=.183) and exercise test duration (62s; –2 to 126; P=.057). Effect sizes were large for ventilatory threshold (d=.82), and small-to-moderate for Vo2peak (d=.33) and exercise test duration (d=.36). There were no substantial changes in either group for peak values of heart rate, blood lactate, perceived exertion, and respiratory exchange ratio (P>.05).
      Table 2Cardiopulmonary Exercise Test Results at Baseline and 12 Weeks
      VariableExerciseControlCI ΔPd
      Baseline12wkChangeBaseline12wkChange
      Ventilatory threshold (mL/kg/min)12.8±2.415.3±3.92.5±2.912.2±3.312.2±3.10.0±1.30.5 to 4.5.0160.82
      Vo2peak (mL/kg/min)19.3±4.521.1±6.71.8±3.517.9±5.418.0±5.70.1±1.5−0.8 to 3.8.1830.33
      Exercise test duration (s)744.0±165.0807.0±200.063.0±65.0689.0±193.0685.0±218.0−4.0±77.0−2 to 126.0570.36
      Peak heart rate (beats/min)139.0±23.0129.0±27.0−10.0±14.0135.0±20.0132.0±21.0−3.0±10.0−16 to 4.2280.32
      Peak blood lactate (mmol/L)4.8±1.84.9±2.10.0±0.94.5±1.24.3±1.0−0.2±0.9−0.5 to 1.0.5060.13
      Peak perceived exertion16.0±2.015.0±2.0−1.0±2.016.0±2.017.0±2.00.0±3.0−3 to 0.0590.48
      Peak respiratory exchange ratio1.2±0.11.2±0.10.0±0.11.2±0.11.2±0.10.0±0.1−0.1 to 0.1.9790.00
      NOTE. Data are mean ± SD or as otherwise indicated.
      Abbreviation: CI Δ, 95% confidence interval for the adjusted mean difference.
      Changes in risk markers are presented in table 3. Serum hs-CRP decreased by 114% in the exercise group compared with the controls (26%–201%; P=.014; d=.58). There was also a trend for a small-to-moderate decrease in systolic blood pressure (–10mmHg; –21 to 2; P=.099; d=.34). There were no substantial changes in body mass index, diastolic blood pressure, lipid profiles, MMP-9, and glucose (see table 3), or any of the 8 quality of life domains (P>.05; data not presented).
      Table 3Risk Marker Results at Baseline and 12 Weeks
      VariableExerciseControlCI ΔPd
      Baseline12wkChangeBaseline12wkChange
      Body mass index (kg/m2)27.9±3.227.7±3.3−0.1±0.628.3±3.228.1±3.4−0.2±0.7−0.5 to 0.6.7850.03
      Systolic BP (mm Hg)149.0±25.0138.0±20.0−12.0±12.0152.0±26.0148.0±15.0−3.0±25.0−21 to 2.0990.34
      Diastolic BP (mm Hg)81.0±9.078.0±11.0−3.0±9.074.0±11.076.0±1.02.0±12.0−10 to 7.6990.47
      Total cholesterol (mmol/L)3.7±0.43.8±0.40.0±0.34.2±1.14.2±1.30.0±0.6−0.4 to 0.4.9930.00
      HDL cholesterol (mmol/L)1.1±0.31.1±0.20.0±0.11.3±0.31.2±0.4−0.1±0.2−0.2 to 0.1.7750.32
      LDL cholesterol (mmol/L)1.9±0.41.9±0.30.0±0.52.0±0.52.0±0.70.0±0.5−0.5 to 0.3.7020.00
      Triglycerides (mmol/L)1.8±0.81.7±0.6−0.1±0.71.8±1.11.9±1.10.1±0.6−0.6 to 0.5.8330.20
      hs-CRP (mg/L)1.4±1.10.9±0.9−0.5±0.72.3±1.52.6±1.60.3±1.7−2.5 to −0.2.014
      P log-transformed hs-CRP data (raw data units [mg/L] are presented in the table; these equate to a 114% decrease in intervention vs control [CI Δ = 26%–201%].
      0.58
      MMP-9 (ng/mL)359.0±168.0456.0±211.097.0±129.0393.0±230.0487.0±323.094.0±203.0−152 to 163.9420.01
      Glucose (mmol/L)5.3±1.05.2±1.3−0.2±1.55.8±1.75.3±0.8−0.5±1.7−0.9 to 0.9.9560.20
      Aneurysm diameter (mm)40.9±7.041.4±7.00.5±1.539.3±6.440.0±5.70.7±1.6−1.5 to 1.2.8360.03
      NOTE. Data are mean ± SD or as otherwise indicated.
      Abbreviations: BP, blood pressure; CI Δ, 95% confidence interval for the adjusted mean difference; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
      low asterisk P log-transformed hs-CRP data (raw data units [mg/L] are presented in the table; these equate to a 114% decrease in intervention vs control [CI Δ = 26%–201%].

      Discussion

      The findings suggest that moderate-intensity endurance exercise training is feasible in patients with small AAAs. Indeed, despite a low recruitment rate, there were no intervention-related dropouts, compliance to the exercise program was excellent, and no participants experienced aneurysm-related symptoms, exercise-related clinical events, or excessive AAA enlargement. Exercise training also evoked improvements in cardiopulmonary fitness, systemic inflammation, and systolic blood pressure, which might be important for reducing cardiovascular risk and AAA disease progression.
      Compliance to the exercise program was excellent (94%), and only 3 patients withdrew from the study, all for medical reasons. We attribute these findings to the flexible approach taken when arranging exercise training sessions and the regular contact maintained with all patients. In contrast, the recruitment rate was unexpectedly low, with only 28 patients recruited from 545 initially identified as potentially eligible (5%). This compares unfavorably with previous exercise trials in small AAAs (15%),
      • Myers J.N.
      • White J.J.
      • Narasimhan B.
      • Dalman R.L.
      Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial.
      peripheral arterial disease (9%),
      • Greenhalgh R.M.
      • Belch J.J.
      • Brown L.C.
      • et al.
      The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease.
      and healthy older adults (17%).
      • Finucane F.M.
      • Sharp S.J.
      • Purslow L.R.
      • et al.
      The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial.
      Although the low recruitment rate could mean that only a small minority of highly motivated (perhaps atypical) patients volunteered for this study, the baseline characteristics were similar to those of patients in a large trial of surveillance versus aortic endografting for small AAAs,
      • Cao P.
      • De Rango P.
      • Verzini F.
      • et al.
      Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial.
      suggesting that this was unlikely to be the case. To improve recruitment rates, future studies could include monetary incentives or an education session aimed at increasing awareness of the health problem being studied and the potential benefits of exercise training.
      • Caldwell P.H.
      • Hamilton S.
      • Tan A.
      • Craig J.C.
      Strategies for increasing recruitment to randomised controlled trials: systematic review.
      Although limited by a small sample size, our results indicate that patients with small AAAs can safely participate in endurance exercise training that is supervised and of moderate intensity. Indeed, there were no adverse events from a total of 53 maximal exercise tests and 371 training sessions, and no excessive increase in maximum AAA diameter. This is consistent with the AAA Simple Treatment or Prevention trial that also reported no adverse events in 26 small AAA patients completing moderate-intensity endurance and resistance exercise training for 1 year.
      • Myers J.N.
      • White J.J.
      • Narasimhan B.
      • Dalman R.L.
      Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial.
      However, in the only other exercise trial in AAA disease to date, Kothmann et al
      • Kothmann E.
      • Batterham A.M.
      • Owen S.J.
      • et al.
      Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: a pilot study.
      reported a nonfatal cardiac arrest in a patient undertaking moderate-intensity cycling exercise. Together these findings suggest that, although exercise is generally safe, this high-risk group should initially undertake training in a center where appropriately trained staff and resuscitation equipment are immediately available.
      In this study, we used ventilatory threshold as the primary measure of cardiopulmonary fitness because, unlike Vo2peak, it is independent of patient motivation and has been shown to be a good predictor of midterm survival in patients undergoing AAA surgery.
      • Carlisle J.
      • Swart M.
      Mid-term survival after abdominal aortic aneurysm surgery predicted by cardiopulmonary exercise testing.
      Ventilatory threshold improved in the exercise group with a mean benefit of 2.5mL·kg−1·min−1 compared with controls. This change is similar to that observed for healthy older adults completing comparable programs of exercise,
      • Fabre C.
      • Masse-Biron J.
      • Ahmaidi S.
      • Adam B.
      • Prefaut C.
      Effectiveness of individualized aerobic training at the ventilatory threshold in the elderly.
      • Takeshima N.
      • Tanaka K.
      • Kobayashi F.
      • Watanabe T.
      • Kato T.
      Effects of aerobic exercise conditioning at intensities corresponding to lactate threshold in the elderly.
      suggesting that the presence of AAA disease did not limit the trainability of our patients. It is also above the minimum clinically important difference of 2mL·kg−1·min−1 proposed by Kothmann et al.
      • Kothmann E.
      • Batterham A.M.
      • Owen S.J.
      • et al.
      Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: a pilot study.
      Such a change in fitness could, if extrapolated to patients awaiting elective AAA repair, improve an individual's preoperative risk stratification, potentially leading to enhanced postoperative outcomes such as reduced hospital length of stay and risk of death. An important consideration here is the length of our exercise program. In the UK, it is recommended that all large AAAs, in patients safe for intervention, are repaired within 8 weeks from referral.
      The Vascular Society
      National Abdominal Aortic Aneurysm Quality Improvement Programme Interim Report 2011.
      Therefore, when balanced against the risk of aneurysm rupture and current guidelines, our 12-week program appears inappropriately long for the presurgical setting, except perhaps for patients who are physically unfit for open surgical repair, because endovascular repair does not reduce all-cause mortality compared with no repair in these patients.
      • Greenhalgh R.M.
      • Brown L.C.
      • Powell J.T.
      • Thompson S.G.
      • Epstein D.
      Endovascular repair of aortic aneurysm in patients physically ineligible for open repair.
      Therefore, can meaningful improvements in fitness be achieved with shorter-term exercise training? In the only relevant study to date, Kothmann et al
      • Kothmann E.
      • Batterham A.M.
      • Owen S.J.
      • et al.
      Effect of short-term exercise training on aerobic fitness in patients with abdominal aortic aneurysms: a pilot study.
      reported a mean improvement in ventilatory threshold of 10% (1.1mL·kg−1·min−1) relative to controls after a 6-week supervised exercise program in AAA surveillance patients (30min continuous moderate-intensity cycle ergometry, twice weekly). Despite the small mean benefit, the marked variability in the individual patient responses revealed that a proportion of patients did benefit clinically (improvement >2mL·kg−1·min−1), with an estimated number needed to treat of 5. Further research is needed to identify the optimal exercise prescription for patients awaiting AAA repair, and to clarify if improvements in fitness before surgery translate to reductions in morbidity and mortality. Aerobic interval training appears worthy of inclusion in such work, because evidence suggests that it is safe and superior to moderate continuous training for improving cardiopulmonary fitness in heart failure patients.
      • Wisloff U.
      • Stoylen A.
      • Loennechen J.P.
      • et al.
      Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.
      In the current study, exercise-related gains in cardiopulmonary fitness were accompanied by moderate reductions in hs-CRP and systolic blood pressure. The former is particularly intriguing given that CRP is considered one of the most important markers of inflammation and subsequent cardiovascular disease.
      • Ridker P.M.
      • Bassuk S.S.
      • Toth P.P.
      C-reactive protein and risk of cardiovascular disease: evidence and clinical application.
      Currently, values of <1.0, 1.0 to 3.0, and >3.0 mg/L correspond to the relative risk categories of low, moderate, and high, respectively.
      • Ridker P.M.
      • Bassuk S.S.
      • Toth P.P.
      C-reactive protein and risk of cardiovascular disease: evidence and clinical application.
      The observed decrease in hs-CRP might be considered clinically important given that the exercise group's risk stratification changed from moderate to low. Indices of blood pressure relate positively to coronary artery disease risk in young and older adults, with systolic blood pressure being a stronger predictor than diastolic blood pressure in older adults.
      • Franklin S.S.
      • Larson M.G.
      • Khan S.A.
      • et al.
      The Framingham Heart Study
      Does the relation of blood pressure to coronary heart disease risk change with aging?.
      The change in systolic blood pressure (–10mmHg) is consistent with the 7mmHg reduction reported in a meta-analysis of endurance training studies in hypertensive patients.
      • Fagard R.H.
      Exercise is good for your blood pressure: effects of endurance training and resistance training.
      The fact that diastolic blood pressure did not change substantially might be because of the fact that the hypertensive patients in our study mostly had isolated systolic hypertension. Hence, our findings underscore the idea that regular exercise training could reduce cardiovascular events in patients with small AAA. The observed reductions in hs-CRP and systolic blood pressure also support the development of definitive trials addressing if endurance exercise training can limit aneurysm progression, given that these are risk factors (albeit weak) for AAA development.
      • Lederle F.A.
      • Johnson G.R.
      • Wilson S.E.
      • et al.
      Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators
      The aneurysm detection and management study screening program: validation cohort and final results.
      • Vainas T.
      • Lubbers T.
      • Stassen F.R.
      • et al.
      Serum C-reactive protein level is associated with abdominal aortic aneurysm size and may be produced by aneurysmal tissue.

      Study Limitations

      This study is limited by the small sample size, resulting in a lack of statistical power to detect changes in some of the outcomes. Indeed, all results must be treated as preliminary and interpreted with caution. This limitation can be explained by the exploratory nature of the study and the finite number of AAA patients under surveillance at our institutions. Clearly, it is vital to perform such exploratory phase research in a bid to inform a definitive, multicenter trial, without the risk of major resource allocation wastage. A second limitation was that there were not any longer-term follow-up measures, which prevents an evaluation of whether the observed changes in outcomes were maintained subsequent to the program.

      Conclusions

      Our findings suggest that moderate-intensity endurance exercise training is feasible and has the potential to evoke improvements in important health outcomes in patients with small AAAs, including cardiopulmonary fitness, systolic blood pressure, and systemic inflammation. We believe that our results justify further trials that are specifically designed to clarify the role of exercise training in improving outcomes from aneurysm repair procedures, inhibiting AAA expansion, and reducing the high incidence of cardiovascular events in these patients.
      • a
        nQuery Advisor 6.01; nQuery Statistical Solution, Stonehill Corporate Center, Suite 104, 777 Broadway, Saugus, MA 01906.
      • b
        Terason t3000; Terason Ultrasound, Division of Teratech Corporation, 77 Terrace Hall Ave, Burlington, MA 01803.
      • c
        Quantikine Human MMP-9 Immunoassay; R&D Systems Inc, 614 McKinley Place NE, Minneapolis, MN 55413.
      • d
        Excalibur Sport; Lode, Cranlea & Co, The Sandpits, Acacia Rd, Bournville, Birmingham, B30 2AH, UK.
      • e
        1500 Sport; YSI (UK) Ltd, 119 Fleet Rd, Fleet, Hampshire, GU51 3PD, UK.
      • f
        Cardioperfect; Welch Allyn, Welch Allyn Corporate Headquarters, 4341 State Street Rd, PO Box 220, Skaneateles Falls, NY 13153-0220.
      • g
        ultima CardiO2; Medical Graphics UK Ltd, Unit 9 Clifton Centre, Bamel Way, Gloucester Business Park, Gloucester, GL3 4BH, UK.
      • h
        SPSS UK Ltd, 2 New Square (B3 Fl 2), Bedfont Lakes, Feltham, Middlesex, TW14 8HB, UK.

      Acknowledgments

      We thank the technical team at Sheffield Hallam University for their support during the assessment sessions.

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