Title: Exercise Capacity in Patients With Severe Symptomatic Aortic Stenosis Before and Six Months After Transcatheter Aortic Valve Implantation
Abstract: Few data exist on the use of the 6-minute walk test (6MWT) to measure the exercise capacity of patients with severe symptomatic aortic stenosis considered at very high surgical risk. The objectives of the present prospective study were (1) to determine the feasibility and safety of the 6MWT as a measure of exercise capacity before and after transcatheter aortic valve implantation (TAVI), and (2) to determine the clinical and hemodynamic parameters associated with the exercise capacity changes in such patients. A total of 64 patients (age 80 ± 8 years, logistic European System for Cardiac Operative Risk Evaluation score 21 ± 15%, Society of Thoracic Surgeons' score 7.5 ± 3.9%) who had undergone successful TAVI were included. The 6MWT was performed within the month before TAVI and at the 6-month follow-up visit. The mean distance walked increased from 165.3 ± 79.7 to 231.7 ± 88.9 m (p <0.0001); however, up to 25% of the patients did not improve or even decreased their exercise capacity. After adjustment for the baseline distance walked, multilinear regression analysis showed that a greater degree of renal dysfunction, as evaluated by the serum creatinine levels (r2 = 0.05, p = 0.03), lower postprocedural hemoglobin values (r2 = 0.13, p = 0.0012), and a longer hospitalization length (r2 = 0.08, p = 0.007) were associated with lower improvement in exercise capacity. In conclusion, exercise capacity, as evaluated by the 6MWT, was very poor in patients with severe symptomatic aortic stenosis considered at very high surgical risk. TAVI was associated with a significant increase in exercise capacity, although no improvement was observed in 1/4 of the patients. A greater degree in renal dysfunction, lower postprocedural hemoglobin values, and longer hospitalization stay were predictors of lower improvement in exercise capacity after TAVI. These results suggest that the 6MWT might become an important tool as a part of the evaluation process for TAVI candidates. Few data exist on the use of the 6-minute walk test (6MWT) to measure the exercise capacity of patients with severe symptomatic aortic stenosis considered at very high surgical risk. The objectives of the present prospective study were (1) to determine the feasibility and safety of the 6MWT as a measure of exercise capacity before and after transcatheter aortic valve implantation (TAVI), and (2) to determine the clinical and hemodynamic parameters associated with the exercise capacity changes in such patients. A total of 64 patients (age 80 ± 8 years, logistic European System for Cardiac Operative Risk Evaluation score 21 ± 15%, Society of Thoracic Surgeons' score 7.5 ± 3.9%) who had undergone successful TAVI were included. The 6MWT was performed within the month before TAVI and at the 6-month follow-up visit. The mean distance walked increased from 165.3 ± 79.7 to 231.7 ± 88.9 m (p <0.0001); however, up to 25% of the patients did not improve or even decreased their exercise capacity. After adjustment for the baseline distance walked, multilinear regression analysis showed that a greater degree of renal dysfunction, as evaluated by the serum creatinine levels (r2 = 0.05, p = 0.03), lower postprocedural hemoglobin values (r2 = 0.13, p = 0.0012), and a longer hospitalization length (r2 = 0.08, p = 0.007) were associated with lower improvement in exercise capacity. In conclusion, exercise capacity, as evaluated by the 6MWT, was very poor in patients with severe symptomatic aortic stenosis considered at very high surgical risk. TAVI was associated with a significant increase in exercise capacity, although no improvement was observed in 1/4 of the patients. A greater degree in renal dysfunction, lower postprocedural hemoglobin values, and longer hospitalization stay were predictors of lower improvement in exercise capacity after TAVI. These results suggest that the 6MWT might become an important tool as a part of the evaluation process for TAVI candidates. During the past 2 decades, the 6-minute walk test (6MWT) has become one of the most popular clinical and research tools used to evaluate the functional exercise capacity, the effects of therapy, and their predictive value for morbidity and mortality in a broad spectrum of patients with cardiopulmonary diseases.1American Thoracic SocietyATS Statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med. 2002; 166: 111-117Crossref PubMed Scopus (8582) Google Scholar The 6MWT is a simple, practical, and inexpensive test that does not require training or complex equipment and reflects the capacity to perform the activities of daily life.1American Thoracic SocietyATS Statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med. 2002; 166: 111-117Crossref PubMed Scopus (8582) Google Scholar The test has also shown its feasibility in elderly patients who are not able to perform standard, maximum, symptom-limited exercise tests,2Tolep K. Kelsen S.G. Effect of aging on respiratory skeletal muscles.Clin Chest Med. 1993; 14: 363-378PubMed Google Scholar, 3Bootsma-van der Wiel A. Gussekloo J. De Craen A.J. Van Exel E. Bloem B.R. Westendorp R.G. Common chronic diseases and general impairments as determinants of walking disability in the oldest-old population.J Am Geriatr Soc. 2002; 50: 1405-1410Crossref PubMed Scopus (95) Google Scholar as well as in the evaluation of patients diagnosed with severe symptomatic aortic stenosis (AS).4Clavel M.A. Fuchs C. Burwash I.G. Mundigler G. Dumesnil J.G. Baumgartner H. Bergler-Klein J. Beanlands R.S. Mathieu P. Magne J. Pibarot P. Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study.Circulation. 2008; 118: S234-S242Crossref PubMed Scopus (190) Google Scholar, 5de Arenaza D.P. Pepper J. Lees B. Rubinstein F. Nugara F. Roughton M. Jasinski M. Bazzino O. Flather M. Preoperative 6-minute walk test adds prognostic information to Euroscore in patients undergoing aortic valve replacement.Heart. 2010; 96: 113-117Crossref PubMed Scopus (75) Google Scholar Few data exist on the use of the 6MWT for the evaluation of the exercise capacity of elderly patients with severe symptomatic AS considered at very high surgical risk and the effect of transcatheter aortic valve implantation (TAVI) on the exercise capacity of such patients. Thus, the aims of the present prospective study were: (1) to determine the feasibility and safety of the 6MWT in a high-risk population of elderly patients with symptomatic severe AS as a measure of functional exercise capacity before and after TAVI, and (2) to evaluate the baseline, procedural, and hemodynamic variables determining the exercise capacity changes in this high-risk group of patients. Of the 119 patients diagnosed with severe symptomatic AS who had undergone TAVI at our center, 64 patients, who had performed a 6MWT before and 6 months after the procedure, were included in the present study. Of the remaining 55 patients, 20 were unable to perform the 6MWT at baseline because of New York Heart Association (NYHA) class IV in 7, severely limited mobility in 3, oxygen dependency in 3, and logistical reasons in 7. Another 28 patients did not perform the 6MWT at follow-up because of death (n = 10), hospitalization from pneumonia (n = 1), or logistical reasons (n = 17). Finally, 5 patients were excluded from the present study because they had participated in the Placement of AoRTic traNscatheter valve (PARTNER) trial, and 2 patients were excluded because of unsuccessful TAVI. The Edwards-SAPIEN valve (Edwards Lifesciences, Irvine, California) was used in all cases and was implanted using either a transfemoral (n = 14, 22%) or a transapical (n = 50, 78%) approach. TAVI was performed under a compassionate clinical program approved by the Canadian Department of Health and Welfare (Ottawa, Ontario, Canada), and all patients provided informed consent for the procedures. The TAVI procedures have been described in detail in previous reports.6Rodés-Cabau J. Dumont E. De Larochellière Robert Doyle D. Lemieux J. Bergeron S. Clavel M.A. Villeneuve J. Raby K. Bertrand O.F. Pibarot P. Feasibility and initial results of percutaneous aortic valve implantation including selection of the transfemoral or transapical approach in patients with severe aortic stenosis.Am J Cardiol. 2008; 102: 1240-1246Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar All clinical, echocardiographic, procedural, and postprocedural data were prospectively collected. The 6MWT was performed within the month before TAVI and at 6 months of follow-up according to the American Thoracic Society standardized protocol.1American Thoracic SocietyATS Statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med. 2002; 166: 111-117Crossref PubMed Scopus (8582) Google Scholar Briefly, using an internal flat corridor of a 30-m distance, marked by 2 orange traffic cones, the participants received the following instructions: "walk from end to end of the corridor, around the cones, at your own pace, in order to cover as much ground as possible for 6 minutes, but don't run or jog." Each minute, a nurse encouraged the participants only with the standardized statements "you're doing well" or "keep up the good work"; no other phrases were used. The participants were allowed to stop and rest during the test but were instructed to resume walking as soon as they were able to do so. The patient used a mechanical lap counter, and the distance covered during the test was recorded in meters. The distance that each patient was expected to walk in the 6MWT on the basis of age, gender, height, and weight was calculated using Enright's formula.7Enright P.L. McBurnie M.A. Bittner V. Tracy R.P. McNamara R. Arnold A. Newman A.B. The 6-min walk test: a quick measure of functional status in elderly adults.Chest. 2003; 123: 387-398Crossref PubMed Scopus (601) Google Scholar Just before starting and at the end of the test, the patients were asked to qualify their feelings of breathlessness as a feeling of an uncomfortable need to breath rather than any other sensation associated with exercise, such as fatigue or pain. They were asked to estimate the level of breathlessness using the visual analog scale (VAS)8Aitken R.C. Measurement of feelings using visual analogue scales.Proc R Soc Med. 1969; 62: 989-993PubMed Google Scholar and the modified Borg scale.9Mahler D.A. Rosiello R.A. Harver A. Lentine T. McGovern J.F. Daubenspeck J.A. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease.Am Rev Respir Dis. 1987; 135: 1229-1233PubMed Google Scholar The VAS is a 100-mm horizontal line with the boundaries clearly defined as the extremes of breathlessness, with the left side corresponding to "not at all breathless" and the right side to "maximum imaginable breathless." The resolution of the measurement of the 100-mm line to the nearest millimeter is both convenient and appropriate because 1 part of 100 is sufficiently sensitive and can be transformed easily from a multinomial to near-normal distribution.8Aitken R.C. Measurement of feelings using visual analogue scales.Proc R Soc Med. 1969; 62: 989-993PubMed Google Scholar The Borg scale was the modified version for measuring dyspnea.9Mahler D.A. Rosiello R.A. Harver A. Lentine T. McGovern J.F. Daubenspeck J.A. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease.Am Rev Respir Dis. 1987; 135: 1229-1233PubMed Google Scholar This consists of a vertical scale labeled from 0 to 10, representing the progressive dyspnea-trigger sensation.9Mahler D.A. Rosiello R.A. Harver A. Lentine T. McGovern J.F. Daubenspeck J.A. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease.Am Rev Respir Dis. 1987; 135: 1229-1233PubMed Google Scholar It has been shown that both scales have the potential to provide sensitive, reliable, and reproducible estimations of breathlessness during exercise.10Wilson R.C. Jones P.W. A comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise.Clin Sci Lond. 1989; 76: 277-282PubMed Google Scholar, 11Muza S.R. Silverman M.T. Gilmore G.C. Hellerstein H.K. Kelsen S.G. Comparison of scales used to quantitate the sense of effort to breathe in patients with chronic obstructive pulmonary disease.Am Rev Respir Dis. 1990; 141: 909-913Crossref PubMed Google Scholar, 12Wilson R.C. Jones P.W. Long-term reproducibility of Borg scale estimates of breathlessness during exercise.Clin Sci Lond. 1991; 80: 309-312PubMed Google Scholar The NYHA class of all patients was assessed by 1 of the cardiologists of the TAVI team, who was unaware of the 6MWT results, at baseline and at 6 months of follow-up. Continuous variables are expressed as the mean ± SD or the median (25th to 75th interquartile range), depending on the variable distribution. The univariate normality assumptions were verified with the Shapiro-Wilk tests. A comparison of the numerical variables was performed using the Student t test (unpaired and paired) or the Wilcoxon rank test. The relations between the clinical characteristics and the delta (Δ) distance walked are expressed with point biserial or Pearson's correlations coefficients. Parameters with p <0.05 were candidates for a stepwise linear regression analysis to find the predictors of exercise capacity improvement at the follow-up visit. Statistical interactions between the Δ-distance walked and Δ-NYHA class were assessed using a multivariate regression model, including a multiplicative interaction term. The results were considered significant at p <0.05. All analyses were conducted using SAS, version 9.1.3 (SAS Institute, Cary, North Carolina). The clinical, echocardiographic, and procedural characteristics of the study population are listed in Table 1. All patients performed the 6MWT with no complications. The results of the 6MWT are summarized in Table 2. The mean distance walked improved from 165.3 ± 79.7 m at baseline to 231.7 ± 88.9 m at 6 months after TAVI, for a mean increase of 66.4 ± 81.7 m (Δ83%, 95% confidence interval 39 to 127) versus baseline (p <0.0001). However, this mean distance walked remained much shorter than the expected distance in a healthy population of the same age, gender, weight, and height (363.7 ± 49.8 m, p <0.0001). Of the 64 patients, 48 (75%) showed some degree of improvement in the distance walked compared to baseline, and 16 patients (25%) had no increase or even a decrease in the distance walked compared to baseline (Figure 1). Among those 28 patients unable to perform the 6MWT at 6 months of follow-up, the distance walked at the baseline 6MWT was 137.1 ± 77.4 m (p = 0.12 compared to the study population). The relation between the baseline clinical, echocardiographic, and procedural characteristic of the patients according to the changes (Δ) in the distance walked before and 6 months after TAVI are listed in Table 3. After adjustment for the distance walked at baseline, the variables independently associated with a lower improvement in exercise capacity at 6 months of follow-up were a greater degree of renal dysfunction as evaluated by the creatinine values (estimated −18.5 ± 9.8, r2Tolep K. Kelsen S.G. Effect of aging on respiratory skeletal muscles.Clin Chest Med. 1993; 14: 363-378PubMed Google Scholar = 0.05, p = 0.03), lower postprocedural hemoglobin values (estimated −18.6 ± 6.6, r2Tolep K. Kelsen S.G. Effect of aging on respiratory skeletal muscles.Clin Chest Med. 1993; 14: 363-378PubMed Google Scholar = 0.13, p = 0.001), and longer hospitalization (estimated −3.1 ± 1.1, r2Tolep K. Kelsen S.G. Effect of aging on respiratory skeletal muscles.Clin Chest Med. 1993; 14: 363-378PubMed Google Scholar = 0.08, p = 0.007). At 6 months of follow-up, the mean aortic gradient, aortic valve area, and left ventricular ejection fraction, were 10.5 ± 4.9 mm Hg, 1.53 ± 0.3 cm2, and 57 ± 13%, respectively. The changes in the left ventricular ejection fraction, pulmonary pressure, mean gradient, and aortic valve area did not correlate with the changes in the distance walked between the baseline and follow-up 6MWT.Table 1Baseline and periprocedural characteristics of study population (n = 64)CharacteristicValueClinical Age (years)80 ± 8 Men21 (33%) Weight (kg)66.9 ± 14.3 Body mass index (kg/m2)26.2 ± 3.9 Diabetes mellitus17 (27%) Dyslipidemia⁎Dyslipidemia defined as low-density cholesterol levels >3.50 mmol/L or treatment with lipid-lowering medication.54 (84%) Hypertension†Hypertension defined as blood pressure ≥140/90 mm Hg or treatment with antihypertensive medication.59 (92%) Current smokers4 (6%) History of congestive heart failure38 (59%) New York Heart Association class III64 (100%) Coronary artery disease‡Coronary artery disease defined as presence of untreated coronary stenosis ≥50% or previous coronary revascularization (percutaneous coronary intervention, coronary artery bypass grafting).40 (63%) Cerebrovascular disease14 (22%) Peripheral vascular disease23 (36%) Chronic obstructive pulmonary disease14 (22%) Porcelain aorta18 (28%) Frailty10 (16%) Serum creatinine (mg/dl)1.34 ± 0.84 Estimated glomerular filtration rate (ml/min/1.73 m2)53 ± 21 Hemoglobin (g/dl)11.9 ± 1.5 Logistic European System for Cardiac Operative Risk Evaluation (%)21 ± 15 Society of Thoracic Surgeons score (%)7.5 ± 3.9Echocardiographic Left ventricular ejection fraction (%)56 ± 13 Left ventricular ejection fraction <55%16 (25%) Peak systolic transvalvular gradient (mm Hg)71 ± 4 Mean transvalvular gradient (mm Hg)43 ± 17 Aortic valve area (cm2)0.60 ± 0.15 Pulmonary artery systolic pressure (mm Hg)43 ± 14 Moderate/severe mitral regurgitation18 (28%)Periprocedural Approach Transapical50 (78%) Transfemoral14 (22%) Successful procedure64 (100%) Major vascular complications3 (5%) Minor vascular complications6 (9%) Life-threatening or disabling bleeding§According to Valve Academic Research Consortium definitions.309 (14%) Major bleeding§According to Valve Academic Research Consortium definitions.3030 (47%) Minor bleeding§According to Valve Academic Research Consortium definitions.3010 (16%) Decrease in hemoglobin level (g/dl)3.2 ± 1.5 Lowest postprocedural hemoglobin (g/dl)8.7 ± 1.3 Need for transfusions34 (53%) Median number of units1 (0–1) Myocardial infarction1 (2%) Stroke2 (3%) Sepsis3 (5%) Need for hemodialysis0 Median hospitalization days7 (6–11)Data are presented as n (%), mean ± SD, or median (interquartile range). Dyslipidemia defined as low-density cholesterol levels >3.50 mmol/L or treatment with lipid-lowering medication.† Hypertension defined as blood pressure ≥140/90 mm Hg or treatment with antihypertensive medication.‡ Coronary artery disease defined as presence of untreated coronary stenosis ≥50% or previous coronary revascularization (percutaneous coronary intervention, coronary artery bypass grafting).§ According to Valve Academic Research Consortium definitions.30Leon M.B. Piazza N. Nikolsky E. Blackstone E.H. Cutlip D.E. Kappetein A.P. Krucoff M.W. Mack M. Mehran R. Miller C. Morel M.A. Petersen J. Popma J.J. Takkenberg J.J. Vahanian A. van Es G.A. Vranckx P. Webb J.G. Windecker S. Serruys P.W. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium.J Am Coll Cardiol. 2011; 57: 253-269Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Open table in a new tab Table 2Exercise capacity assessment at baseline and 6 months after transcatheter aortic valve implantation (TAVI)VariableBefore TAVIAfter TAVIΔp ValueDistance walked (m)165.3 ± 79.7231.7 ± 88.966.4 ± 81.7<0.0001Oxygen saturation at rest (%)96 (95–97)96 (95–98)0 (−1–1)0.25Oxygen saturation after exercise (%)95 (94–97)95 (94–97)0 (−1–1)0.88Pre-test Borg scale0 (0–3)0 (0–0)0 (−3–0)0.06Post-test Borg Scale, median (min-max)4 (0–9)3 (0–7)−1 (−8–5)0.003Visual Analogue Scale7 (4–8)4 (2–5)−2 (−4–1)<0.0001Data are expressed as mean SD or median (interquartile range). Open table in a new tab Table 3Correlations between baseline characteristics and changes in distance walked (Δ meters) between baseline and 6 months of follow-upCharacteristicDistance Walked (Δ Meters) r, p ValueClinical Age−0.23, 0.07 Men0.10, 0.45 Height−0.04, 0.74 Weight−0.14, 0.28 Body mass index−0.13, 0.32 Diabetes mellitus0.20, 0.12 Dyslipidemia0.14, 0.28 Hypertension−0.07, 0.56 Current smokers−0.02, 0.87 Coronary artery disease0.17, 0.18 Peripheral vascular disease0.14, 0.31 Chronic obstructive pulmonary disease−0.11, 0.41 Porcelain aorta0.17, 0.19 Frailty0.17, 0.18 Serum creatinine−0.29, 0.02 Estimated glomerular filtration rate0.27, 0.03 Hemoglobin0.10, 0.43 Logistic European System for Cardiac Operative Risk Evaluation score−0.04, 0.78 Society of Thoracic Surgeons score−0.23, 0.07Echocardiographic data Left ventricular ejection fraction0.13, 0.33 Left ventricular ejection fraction <55%−0.12, 0.34 Peak systolic transvalvular gradient (mm Hg)0.13, 0.28 Mean transvalvular gradient (mm Hg)0.16, 0.21 Aortic valve area−0.11, 0.38 Pulmonary artery systolic pressure−0.02, 0.91 Moderate/severe mitral regurgitation0.14, 0.28Periprocedural variables Approach (transfemoral/transapical)−0.21, 0.09 Any vascular complications0.0, 1.0 Life-threatening or disabling bleeding−0.07, 0.57 Major bleeding−0.35, 0.005 Minor bleeding0.07, 0.57 Decrease in hemoglobin level−0.30, 0.01 Lowest postprocedural hemoglobin0.40, 0.001 Need for transfusions−0.32, 0.01 Number of red blood cell units−0.24, 0.06 Myocardial infarction−0.11, 0.38 Stroke−0.01, 0.93 Sepsis−0.13, 0.30 Hospitalization days−0.40, 0.0013 Open table in a new tab Data are presented as n (%), mean ± SD, or median (interquartile range). Data are expressed as mean SD or median (interquartile range). All patients were in NYHA functional class III at baseline, and all but 1 had improved their functional class at follow-up (p <0.0001). Significant improvements were also observed in the Borg scale and VAS between baseline and follow-up (p = 0.02 and p <0.0001, respectively; Figure 1). At 6 months of follow-up, 30 patients (47%) were in NYHA class I and 33 (52%) in class II. Those patients in NYHA class I walked a longer distance in the 6MWT (265.8 ± 76.2 m vs 205.9 ± 85.1 m, p = 0.005) and experienced better improvement in the Borg scale and VAS (p <0.0001 and p = 0.0002, respectively) compared to those in NYHA class II at 6 months of follow-up (Figure 2). Furthermore, greater improvement in the NYHA class between baseline and follow-up (class III to II vs III to I) correlated with the Δ-distance walked (43.9 ± 67.9 m vs 94.4 ± 87.7 m, p = 0.01) and the Δ-Borg scale and Δ-VAS (p = 0.01, p = 0.02, respectively), between baseline and follow-up (Figure 3). A good correlation was observed between the Δ-distance walked and the Δ-VAS (r = −0.36, p = 0.0033); however, no correlation was found between the Δ-distance walked and Δ-Borg scale at 6 months after TAVI (Figure 4). Multivariate regression analyses including interaction terms showed that the improvement in the distance walked and NYHA class between baseline and follow-up had multiplicative effects on the improvement in functional tests such as the VAS (p = 0.0001) and Borg scale (p = 0.03).Figure 3Individual changes (Δ) in distance walked (A), Borg scale (B), and VAS (C) 6 months after TAVI, grouped according to Δ-NYHA functional class. *Between Δ-NYHA class I and II.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Correlation between changes (Δ) in VAS (A), and Borg scale (B), with the Δ-distance walked in the 6MWT 6 months after TAVI.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The present study showed the usefulness of the 6MWT in a high-risk population of octogenarian patients with severe symptomatic AS. The exercise capacity of these patients was very poor (mean distance walked <200 m), and TAVI was associated with a significant increase in the mean distance walked at 6 months after TAVI. However, up to 25% of the patients did not improve or even decreased their exercise capacity at 6 months after TAVI. A greater degree of renal dysfunction, lower postprocedural hemoglobin values, and longer hospitalization were the predictive factors of the lack of improvement in exercise capacity. Also, despite the increase in the mean distance walked at 6 months after TAVI, the exercise capacity of these patients remained lower than that expected for healthy patients of the same age, gender, height, and weight. Finally, all patients but 1 had improved their functional status at 6 months of follow-up as evaluated by the NYHA functional class. Also, the degree of NYHA class improvement correlated with the changes in the distance walked and the VAS at 6 months after TAVI. These findings further support the use of a more objective and reliable method such as the 6MWT to assess patients' functional exercise capacity before and after TAVI procedures. Clavel et al4Clavel M.A. Fuchs C. Burwash I.G. Mundigler G. Dumesnil J.G. Baumgartner H. Bergler-Klein J. Beanlands R.S. Mathieu P. Magne J. Pibarot P. Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study.Circulation. 2008; 118: S234-S242Crossref PubMed Scopus (190) Google Scholar evaluated 101 patients with severe AS and a low left ventricular ejection fraction with no adverse events associated with the test, and de Arenaza et al5de Arenaza D.P. Pepper J. Lees B. Rubinstein F. Nugara F. Roughton M. Jasinski M. Bazzino O. Flather M. Preoperative 6-minute walk test adds prognostic information to Euroscore in patients undergoing aortic valve replacement.Heart. 2010; 96: 113-117Crossref PubMed Scopus (75) Google Scholar performed the 6MWT in 200 patients scheduled for conventional aortic valve replacement, also with no complications. Moreover, a reduced 6MWT distance was found to be a strong independent predictor of adverse events. The mean distance walked in these 2 studies was >300 m, much greater than the <200 m observed in our study population. The uniqueness of our study is that we evaluated an extremely high-risk population that consisted of very old patients with a high prevalence of cardiac and noncardiac co-morbidities, such as frailty. The vast majority of the patients included were considered nonoperable and would have been excluded from previous studies. Both the gradual reduction of skeletal muscle mass and strength and the increasing prevalence of debilitating conditions often associated with the aging process would result in a shorter distance walked by elderly patients.1American Thoracic SocietyATS Statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med. 2002; 166: 111-117Crossref PubMed Scopus (8582) Google Scholar, 2Tolep K. Kelsen S.G. Effect of aging on respiratory skeletal muscles.Clin Chest Med. 1993; 14: 363-378PubMed Google Scholar, 3Bootsma-van der Wiel A. Gussekloo J. De Craen A.J. Van Exel E. Bloem B.R. Westendorp R.G. Common chronic diseases and general impairments as determinants of walking disability in the oldest-old population.J Am Geriatr Soc. 2002; 50: 1405-1410Crossref PubMed Scopus (95) Google Scholar, 13Fleg J.L. Lakatta E.G. Role of muscle loss in the age-associated reduction in VO2 max.J Appl Physiol. 1988; 65: 1147-1151PubMed Google Scholar Although a significant increase in exercise capacity was observed after TAVI, the mean distance walked at 6 months of follow-up remained much lower than the previously reported distance walked by healthy elderly subjects.7Enright P.L. McBurnie M.A. Bittner V. Tracy R.P. McNamara R. Arnold A. Newman A.B. The 6-min walk test: a quick measure of functional status in elderly adults.Chest. 2003; 123: 387-398Crossref PubMed Scopus (601) Google Scholar, 14Lord S.R. Menz H.B. Physiologic, psychological, and health predictors of 6-minute walk performance in older people.Arch Phys Med Rehabil. 2002; 83: 907-911Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 15Simar D. Dauvilliers Y. Préfaut C. Varray A. Caillaud C. Caillaud C. Aerobic and functional capacities in a selected active population of European octogenarians.Int J Sports Med. 2005; 26: 128-133Crossref PubMed Scopus (10) Google Scholar, 16Gremeaux V. Iskandar M. Kervio G. Deley G. Perennou D. Casillas J.M. Comparative analysis of oxygen uptake in elderly subjects performing two walk tests: the six-minute walk test and the 200-m fast walk test.Clin Rehabil. 2008; 22: 162-168Crossref PubMed Scopus (30) Google Scholar The mean expected distance walked by our study population, determined by applying the Enright's formula,7Enright P.L. McBurnie M.A. Bittner V. Tracy R.P. McNamara R. Arnold A. Newman A.B. The 6-min walk test: a quick measure of functional status in elderly adults.Chest. 2003; 123: 387-398Crossref PubMed Scopus (601) Google Scholar was 363.7 ± 49.8 m. Previous studies regarding the exercise performance of octogenarians have systematically shown a mean distance walked of >300 m in the 6MWT.7Enright P.L. McBurnie M.A. Bittner V. Tracy R.P. McNamara R. Arnold A. Newman A.B. The 6-min walk test: a quick measure of functional status in elderly adults.Chest. 2003; 123: 387-398Crossref PubMed Scopus (601) Google Scholar, 14Lord S.R. Menz H.B. Physiologic, psychological, and health predictors of 6-minute walk performance in older people.Arch Phys Med Rehabil. 2002; 83: 907-911Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 15Simar D. Dauvilliers Y. Préfaut C. Varray A. Caillaud C. Caillaud C. Aerobic and functional capacities in a selected active population of European octogenarians.Int J Sports Med. 2005; 26: 128-133Crossref PubMed Scopus (10) Google Scholar, 16Gremeaux V. Iskandar M. Kervio G. Deley G. Perennou D. Casillas J.M. Comparative analysis of oxygen uptake in elderly subjects performing two walk tests: the six-minute walk test and the 200-m fast walk test.Clin Rehabil. 2008; 22: 162-168Crossref PubMed Scopus (30) Google Scholar Moreover, the exercise capacity remained similar to, or lower than, the preprocedural levels in ¼ of the patients, reflecting the high variability of the functional response to TAVI in this particular subset of patients (Figure 1). Gotzmann et al17Gotzmann M. Hehen T. Germing A. Lindstaedt M. Yazar A. Laczkovics A. Mumme A. Mugge A. Bojara W. Short-term effects of transcatheter aortic valve implantation on neurohormonal activation, quality of life and 6-minute walk test in severe and symptomatic aortic stenosis.Heart. 2010; 96: 1102-1106Crossref PubMed Scopus (94) Google Scholar showed an improvement in exercise capacity at 1 month of follow-up in 44 patients who underwent TAVI. However, no details were provided regarding the frequency or factors associated with the lack of improvement in exercise capacity after the procedure. Although patients systematically improved their functional status as evaluated by the NYHA functional class after TAVI, ¼ of them were unable to improve their exercise capacity as determined by the 6MWT in our study. A greater degree of renal dysfunction, lower postprocedural hemoglobin values, and longer hospitalization stays determined the lower improvement in exercise capacity after TAVI. The relation between renal dysfunction and poorer functional capacity is probably multifactorial, including factors such as malnutrition, physical inactivity, anemia, hyperparathyroidism, skeletal muscle atrophy, and co-morbidities such as cardiovascular disease.18Padilla J. Krasnoff J. Da Silva M. Hsu C.Y. Frassetto L. Johansen K.L. Painter P. Physical functioning in patients with chronic kidney disease.J Nephrol. 2008; 21: 550-559PubMed Google Scholar, 19Clyne N. Jogestrand T. Lins L.E. Pehrsson S.K. Ekelund L.G. Factors limiting physical working capacity in predialytic uraemic patients.Acta Med Scand. 1987; 222: 183-190Crossref PubMed Scopus (38) Google Scholar It is well known that the presence of anemia negatively affects walking performance,20Chaves P.H. Ashar B. Guralnik J.M. Fried L.P. Looking at the relationship between hemoglobin concentration and prevalent mobility difficulty in older women: should the criteria currently used to define anemia in older people be reevaluated?.J Am Geriatr Soc. 2002; 50: 1257-1264Crossref PubMed Scopus (221) Google Scholar, 21Penninx B.W. Guralnik J.M. Onder G. Ferrucci L. Wallace R.B. Pahor M. Anemia and decline in physical performance among older persons.Am J Med. 2003; 115: 104-110Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 22Penninx B.W. Pahor M. Cesari M. Corsi A.M. Woodman R.C. Bandinelli S. Guralnik J.M. Ferrucci L. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly.J Am Geriatr Soc. 2004; 52: 719-724Crossref PubMed Scopus (431) Google Scholar and, as it has been shown in our study, this complication is very frequent during TAVI procedures, with a mean lowest hemoglobin value after TAVI of <9 g/dl. The fact that most patients underwent TAVI using a transapical approach, which requires a minithoracotomy and is probably associated with greater blood loss than the transfemoral approach, might have influenced the low postprocedural hemoglobin values observed in the present study. The hospitalization length is usually associated with prolonged inactivity, immobility, and bed rest, which can result in a significant reduction of functional capacity in multiple organ systems, known as "deconditioning."23Topinkova E. Aging, disability and frailty.Ann Nutr Metab. 2008; 52: 6-11Crossref PubMed Scopus (342) Google Scholar, 24Okawa Y. Nakamura S. Kudo M. Ueda S. An evidence-based construction of the models of decline of functioning Part 1: two major models of decline of functioning.Int J Rehabil Res. 2009; 32: 189-192Crossref PubMed Scopus (17) Google Scholar Some studies have shown that this process is even more important in elderly patients.25Lazarus B.A. Murphy J.B. Coletta E.M. McQuade W.H. Culpepper L. The provision of physical activity to hospitalized elderly patients.Arch Intern Med. 1991; 151: 2452-2456Crossref PubMed Scopus (46) Google Scholar Also, patients undergoing TAVI currently are usually very old, and many of them are considered frail. Frailty has been associated with a greater risk of postoperative complications and reduced acute and midterm survival after surgical interventions.26Lee D.H. Buth K.J. Martin B.J. Yip A.M. Hirsch G.M. Frail patients are at increased risk for mortality and prolonged institutional care after cardiac surgery.Circulation. 2010; 121: 973-978Crossref PubMed Scopus (526) Google Scholar, 27Makary M.A. Segev D.L. Pronovost P.J. Syin D. Bandeen-Roche K. Patel P. Takenaga R. Devgan L. Holzmueller C.G. Tian J. Fried L.P. Frailty as a predictor of surgical outcomes in older patients.J Am Coll Surg. 2010; 210: 901-908Abstract Full Text Full Text PDF PubMed Scopus (1553) Google Scholar A slowed walking speed, as evaluated by the 15-ft walking test, is 1 important factor included in a validated scoring system to define frailty,28Fried L.P. Tangen C.M. Walston J. Newman A.B. Hirsch C. Gottdiener J. Seeman T. Tracy R. Kop W.J. Burke G. McBurnie M.A. Frailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156Crossref PubMed Google Scholar and the 6MWT might also be of interest in the evaluation of this group of patients. Therefore, despite a significant improvement in patients' hemodynamics after TAVI, their exercise capacity might remain poor because of these noncardiac conditions. These preliminary results support the use of the 6MWT to objectively evaluate the results of TAVI in this high-risk group of patients. Also, for the first time, we provide data on the occurrence and predictive factors of "survival with no functional improvement" in these patients. In addition, the results of our study highlight the importance of establishing cardiac rehabilitation programs29Opasich C. De Feo S. Pinna G.D. Furgi G. Pedretti R. Scrutinio D. Tramarin R. Distance walked in the 6-minute test soon after cardiac surgery: toward an efficient use in the individual patient.Chest. 2004; 126: 1796-1801Crossref PubMed Scopus (54) Google Scholar for such patients; implementing exercise intervention programs would be even more important if we want to see the hemodynamic benefits of TAVI translated into functional improvement. The present study had several limitations. A significant number of potential candidates for TAVI were unable to perform the 6MWT either at baseline or follow-up, mostly because of logistical reasons. Our tertiary university center covers a very large territory in the eastern part of the province of Quebec. Thus, very frequently, the patients live in places located very far from our center and many were unable or refused to come for the 6MWT, especially the test performed at 6 months of follow-up. Also, TAVI is currently being applied to very old and extremely high-risk patients with multiple co-morbidities, and this might limit the systematic use of the 6MWT in the objective evaluation of TAVI results in a large cohort of patients. Thus, studies of a larger number of patients are needed to confirm these results and further establish the factors determining the absence of functional improvement after TAVI in this challenging subset of patients. Also, the potential prognostic value of the 6MWT in the setting of TAVI needs to be explored further. We thank Jacinthe Aubé, RN, for her outstanding work on the 6MWTs and patient follow-up and Ms. Nathalie Boudreault for patient follow-up. Rodrigo Bagur, MD, received a 1-year scholarship from the "Centre de Recherche de l'Institute Universitaire de Cardiologie et Pneumologie de Québec."