G Model JSAMS-1059; No. of Pages 6
ARTICLE IN PRESS Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Science and Medicine in Sport journal homepage: www.elsevier.com/locate/jsams
Original research
Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease Erin J. Howden a,∗ , Kassia Weston a , Rodel Leano b , James E. Sharman d , Thomas H. Marwick d , Nicole M. Isbel b,c , Jeff S. Coombes a a
School of Human Movement Studies, The University of Queensland, Australia School of Medicine, The University of Queensland, Australia c Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia d Menzies Research Institute, University of Tasmania, Hobart, Australia b
a r t i c l e
i n f o
Article history: Received 25 March 2014 Received in revised form 4 June 2014 Accepted 10 July 2014 Available online xxx Keywords: Exercise physiology Echocardiography Arterial stiffness Cardiac function Functional capacity Physical activity
a b s t r a c t Objectives: Reduced functional capacity is associated with poor prognosis. In patients with chronic kidney disease the factors that contribute to low cardiorespiratory fitness are unclear. The objective of this study was to evaluate the cardiorespiratory and cardiovascular response to exercise in chronic kidney disease patients, and secondly investigate the relationships between cardiorespiratory fitness and cardiovascular burden. Design: Cross-sectional analysis. Methods: Baseline demographic, anthropometric and biochemical data were examined in 136 patients with moderate chronic kidney disease (age 59.7 ± 9.6 yrs, eGFR 40 ± 9 ml/min/1.73 m2 , 55% male, 39% with a history of cardiovascular disease, 38% diabetic and 17% current smokers). Cardiorespiratory fitness was measured as peak VO2 , left ventricular morphology and function using echocardiography, central arterial stiffness by aortic pulse wave velocity and left ventricular afterload using augmentation index. Physical activity levels were assessed using the Active Australia questionnaire. Results: Peak VO2 (22.9 ± 6.5 ml/kg/min) and peak heart rate (148 ± 22 bpm) were 17% and 12% lower than the age-predicted values, respectively. The low fit group were significantly older, and were more likely to have type II diabetes, cardiovascular disease, a higher BMI and be less active than the high fit group (P < 0.05). The independent predictors of peak VO2 were age, type II diabetes, hemoglobin level, physical activity, aortic pulse wave velocity, augmentation index, and global longitudinal strain. Conclusion: In patients with chronic kidney disease, the peak VO2 and heart rate response is markedly impaired. Reduced cardiorespiratory fitness is independently associated with increased aortic stiffness, increased left ventricle afterload, poor left ventricle function and higher burden of cardiovascular risk. © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
Chronic kidney disease (CKD) is associated with a significant reduction in exercise capacity and a marked increase in the risk of atherosclerosis and cardiovascular disease (CVD),1 which is not fully explained by a high number of traditional risk factors. Like the general population, low cardiorespiratory fitness2 (CRF) and physical activity3 are associated with increased risk of morbidity and mortality in CKD. It has been irrefutably demonstrated over the past 50 years that higher levels of physical activity and CRF lowers the risk of CVD in the general population.4–6 Whether higher
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (E.J. Howden).
levels of fitness and physical activity contribute beneficially to lower cardiovascular risk in patients with CKD is unknown. CKD patients have an increased burden of CVD, which includes ischemic heart disease, systolic and diastolic dysfunction and increased arterial stiffness.1,7 Moreover, a large proportion of patients are obese and inactive,8 which perpetuates deconditioning, muscle wasting and chronic low-grade inflammation,9 and may lower fitness. Surprisingly, the relationship between CRF and possible contributory factors has not been previously evaluated in this population. Due to the integrative nature and coordinated response of multiple systems, CRF is an excellent indicator of overall cardiovascular health. Therefore the aim of this study was to evaluate the cardiorespiratory and cardiovascular response to exercise in CKD patients, and secondly investigate the relationship between CRF and cardiovascular burden. We hypothesized that individuals
http://dx.doi.org/10.1016/j.jsams.2014.07.005 1440-2440/© 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Howden EJ, et al. Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.005
G Model JSAMS-1059; No. of Pages 6
ARTICLE IN PRESS E.J. Howden et al. / Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
2
with CKD and higher CRF would demonstrate enhanced cardiovascular function as assessed by left ventricular (LV) and vascular function, and better traditional cardiovascular risk factor profiles than individuals with lower fitness.
1. Methods This study was a cross-sectional analysis of patients with stage 3 and 4 CKD enrolled in an interventional randomized controlled trial of cardiovascular risk modification. Details of the interventional study have been published.10 Briefly, patients were eligible for inclusion if they were aged 18–75 yrs, had moderate CKD (eGFR 25–60 ml/min/1.73 m2 ) and one or more uncontrolled cardiovascular risk factors. Exclusion criteria for the study were: Intervention for or symptomatic coronary artery disease (within 3 months), current heart failure (NYHA class III and IV) or significant valvular heart disease, pregnant or planning to become pregnant, life expectancy or anticipated time to dialysis or transplant 24 hrs), peak HR was below the age-predicted HR value for all groups (P < 0.001). In total 50% (n = 64) of patients failed to achieve 80% of their age predicted heart rate maximum, suggesting chronotropic incompetence. The majority of patients with chronotropic incompetence also fell in the lowest fitness tertile (22%, n = 28), while 21% (n = 21) were in the middle tertile and 12% (n = 15) were in the highest tertile. Systolic BP increased significantly with maximal exercise (137 ± 22 to 179 ± 23 mmHg, P < 0.001), while diastolic BP did not change (82 ± 13 to 83 ± 12 mmHg). There was an inverse correlation between VO2 and HR peak, and age (Supplemental material, Figs. I and II). The low fitness group performed poorly in the functional assessments – 6MWT, and the muscular strength and power tests (Table 2). There was a significantly higher rate of inducible ischemia on exercise stress echo in the low fit group (16%) compared to the high (2%). Systolic function (ejection fraction, s , global longitudinal strain) was well preserved (Table 2). Likewise, traditional measures of diastolic filling were not different, but E/e was significantly higher in the low fitness group. Vascular stiffness (aPWV and AIx75) was also higher in the low fit group when compared to the high fitness group (Table 2). The significant univariate correlates of VO2 peak are presented in the supplemental material (Table I, Figs. III and IV). To determine the differential effects of clinical, vascular and cardiac covariates of VO2 peak, we constructed three multivariate backward regression models (Table 3). Model 1 which, included age, diabetes status, history of CVD, hemoglobin and physical activity levels explained 32% of the variability in VO2 peak (Table 3). Model 2 included the variables from Model 1 and AIx75 and aPWV, which improved the model fit (Model 2: R2 = 0.39, n = 100, P < 0.001). The final model included the addition of cardiac variables (subclinical ischemia, E/e and GLS), which further improved the model fit (Model 3: R2 = 0.41, n = 100, P < 0.001). The incremental value of the vascular and cardiac variables over the clinical variables in predicting VO2 peak was compared. Using the enter method a multivariate model of significant clinical variables (Model 1) plus the addition of variables from Model 2, significantly improved the predictive power of the model by 6.6% (adjusted R2 = 0.40, P = 0.008 for change). The power of the model was improved further by addition of
3
the cardiac variable by 5.9% (adjusted R2 = 0.46, P = 0.026 for change). 3. Discussion In this study, we examined the cardiorespiratory and cardiovascular response to peak exercise in CKD patients, and sought to evaluate the relationship between CRF and indicators of cardiovascular health. The main findings of this current study can be summarized as: (1) peak VO2 and HR were markedly reduced compared to age-predicted values in the majority of patients; (2) higher CRF was associated with lower aortic stiffness, AIx and better LV function; (3) the variance in CRF can be largely explained by cardiovascular risk factors (e.g. increasing age, type II diabetes and physical activity). Although we are unable to infer cause and effect, these findings suggest that CKD patients who maintain CRF also benefit from lower cardiovascular burden. Perhaps one of the most striking findings from this current study was the high rate of physical inactivity. Only 30 percent of participants met current physical activity recommendations.19 The number of CKD patients in Australia who meet the recommendations of the physical activity guidelines have dramatically decreased from 50 percent in 2009.23 The decline in physical activity levels is concerning, as it has occurred during a period where the Australian Government has increased public health campaigns to raise awareness of the benefits of being physically active. Given the association between higher levels of physical activity and improved survival in CKD patients,3 interventional studies are urgently required to determine the optimal way to increase physical activity levels and improve fitness in CKD patients, and ultimately determine if these interventions improve survival. Indeed, a 1 MET increase in fitness improves survival by 12 percent,12 while exercise tolerance of >10 METs in individuals with significant burden of subclinical atherosclerosis greatly improved cardiovascular prognosis.24 Interventions that incorporate a multidisciplinary approach will likely be the most effective in increasing physical activity levels due to the high cardiovascular burden and limited level of exercise counseling provided by nephrologists.25 In addition to low levels of physical activity, we found that peak CRF was also markedly impaired. In a small study of 32 patients with CKD (eGFR 29.9 ± 17.0), VO2 peak was found to be reduced compared to age-predicted norms.26 We extend these findings by showing that: (a) peak HR is also significantly reduced below agepredicted values, and (b) like the general population increasing age is associated with a decline in fitness albeit at a faster rate in patients with CKD. The reduction in VO2 peak may partially be explained by the blunted HR response to exercise and thus reduced central component to oxygen delivery. The HR response to dynamic exercise is complex, however a blunted HR response may reflect autonomic disturbances, and is associated with increased mortality and coronary heart disease incidence.27 Maximal HR clearly declines with age,13 however the rate of decline in patients with CKD is greater with the majority of our patients failing to achieve their age-predicted maximum response. Prior studies in ESKD have demonstrated that maximal HR is significantly reduced compared to healthy controls, but is increased following kidney transplantation28 suggesting impaired kidney function influences the central response to exercise. No prior studies have evaluated the relationship between fitness, LV function and arterial stiffness in CKD patients. In this study, patients with lower fitness had significantly higher central arterial stiffness and AIx when compared to the high fit group. Increased arterial stiffness is independent predictors of cardiovascular and all-cause mortality in kidney disease.29 The combination of poor CRF, low physical activity levels and increased arterial
Please cite this article in press as: Howden EJ, et al. Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.005
G Model
ARTICLE IN PRESS
JSAMS-1059; No. of Pages 6
E.J. Howden et al. / Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
4
Table 1 Characteristics of patients grouped by cardiorespiratory fitness tertiles. All (n = 136)
Low fitness (n = 44)
Moderate fitness (n = 46)
High fitness (n = 46)
P ANOVA
Demographics Age (yr) Male sex (%) BMI (kg/m2 ) History CVD, n (%) Diabetes type II, n (%) Current smoker, n (%) Physically active, n (%) Positive ESE, n (%)
60 ± 10 75 (55) 33 ± 7 53 (39) 52 (38) 23 (17) 41 (30) 13 (10)
62 ± 8a 21 (48) 36 ± 6ac 23 (52)a 26 (59)a 8 (18) 9 (20)a 7 (16)a
62 ± 8b 25 (54) 32 ± 7 17 (37) 19 (41)b 7 (15) 10 (22)b 5 (12)
55 ± 11 29 (63) 31 ± 7 13 (28) 7 (15) 8 (17) 22 (48) 1 (2)
0.001 0.96 0.002 0.005
ARTICLE IN PRESS Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Science and Medicine in Sport journal homepage: www.elsevier.com/locate/jsams
Original research
Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease Erin J. Howden a,∗ , Kassia Weston a , Rodel Leano b , James E. Sharman d , Thomas H. Marwick d , Nicole M. Isbel b,c , Jeff S. Coombes a a
School of Human Movement Studies, The University of Queensland, Australia School of Medicine, The University of Queensland, Australia c Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia d Menzies Research Institute, University of Tasmania, Hobart, Australia b
a r t i c l e
i n f o
Article history: Received 25 March 2014 Received in revised form 4 June 2014 Accepted 10 July 2014 Available online xxx Keywords: Exercise physiology Echocardiography Arterial stiffness Cardiac function Functional capacity Physical activity
a b s t r a c t Objectives: Reduced functional capacity is associated with poor prognosis. In patients with chronic kidney disease the factors that contribute to low cardiorespiratory fitness are unclear. The objective of this study was to evaluate the cardiorespiratory and cardiovascular response to exercise in chronic kidney disease patients, and secondly investigate the relationships between cardiorespiratory fitness and cardiovascular burden. Design: Cross-sectional analysis. Methods: Baseline demographic, anthropometric and biochemical data were examined in 136 patients with moderate chronic kidney disease (age 59.7 ± 9.6 yrs, eGFR 40 ± 9 ml/min/1.73 m2 , 55% male, 39% with a history of cardiovascular disease, 38% diabetic and 17% current smokers). Cardiorespiratory fitness was measured as peak VO2 , left ventricular morphology and function using echocardiography, central arterial stiffness by aortic pulse wave velocity and left ventricular afterload using augmentation index. Physical activity levels were assessed using the Active Australia questionnaire. Results: Peak VO2 (22.9 ± 6.5 ml/kg/min) and peak heart rate (148 ± 22 bpm) were 17% and 12% lower than the age-predicted values, respectively. The low fit group were significantly older, and were more likely to have type II diabetes, cardiovascular disease, a higher BMI and be less active than the high fit group (P < 0.05). The independent predictors of peak VO2 were age, type II diabetes, hemoglobin level, physical activity, aortic pulse wave velocity, augmentation index, and global longitudinal strain. Conclusion: In patients with chronic kidney disease, the peak VO2 and heart rate response is markedly impaired. Reduced cardiorespiratory fitness is independently associated with increased aortic stiffness, increased left ventricle afterload, poor left ventricle function and higher burden of cardiovascular risk. © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
Chronic kidney disease (CKD) is associated with a significant reduction in exercise capacity and a marked increase in the risk of atherosclerosis and cardiovascular disease (CVD),1 which is not fully explained by a high number of traditional risk factors. Like the general population, low cardiorespiratory fitness2 (CRF) and physical activity3 are associated with increased risk of morbidity and mortality in CKD. It has been irrefutably demonstrated over the past 50 years that higher levels of physical activity and CRF lowers the risk of CVD in the general population.4–6 Whether higher
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (E.J. Howden).
levels of fitness and physical activity contribute beneficially to lower cardiovascular risk in patients with CKD is unknown. CKD patients have an increased burden of CVD, which includes ischemic heart disease, systolic and diastolic dysfunction and increased arterial stiffness.1,7 Moreover, a large proportion of patients are obese and inactive,8 which perpetuates deconditioning, muscle wasting and chronic low-grade inflammation,9 and may lower fitness. Surprisingly, the relationship between CRF and possible contributory factors has not been previously evaluated in this population. Due to the integrative nature and coordinated response of multiple systems, CRF is an excellent indicator of overall cardiovascular health. Therefore the aim of this study was to evaluate the cardiorespiratory and cardiovascular response to exercise in CKD patients, and secondly investigate the relationship between CRF and cardiovascular burden. We hypothesized that individuals
http://dx.doi.org/10.1016/j.jsams.2014.07.005 1440-2440/© 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Howden EJ, et al. Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.005
G Model JSAMS-1059; No. of Pages 6
ARTICLE IN PRESS E.J. Howden et al. / Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
2
with CKD and higher CRF would demonstrate enhanced cardiovascular function as assessed by left ventricular (LV) and vascular function, and better traditional cardiovascular risk factor profiles than individuals with lower fitness.
1. Methods This study was a cross-sectional analysis of patients with stage 3 and 4 CKD enrolled in an interventional randomized controlled trial of cardiovascular risk modification. Details of the interventional study have been published.10 Briefly, patients were eligible for inclusion if they were aged 18–75 yrs, had moderate CKD (eGFR 25–60 ml/min/1.73 m2 ) and one or more uncontrolled cardiovascular risk factors. Exclusion criteria for the study were: Intervention for or symptomatic coronary artery disease (within 3 months), current heart failure (NYHA class III and IV) or significant valvular heart disease, pregnant or planning to become pregnant, life expectancy or anticipated time to dialysis or transplant 24 hrs), peak HR was below the age-predicted HR value for all groups (P < 0.001). In total 50% (n = 64) of patients failed to achieve 80% of their age predicted heart rate maximum, suggesting chronotropic incompetence. The majority of patients with chronotropic incompetence also fell in the lowest fitness tertile (22%, n = 28), while 21% (n = 21) were in the middle tertile and 12% (n = 15) were in the highest tertile. Systolic BP increased significantly with maximal exercise (137 ± 22 to 179 ± 23 mmHg, P < 0.001), while diastolic BP did not change (82 ± 13 to 83 ± 12 mmHg). There was an inverse correlation between VO2 and HR peak, and age (Supplemental material, Figs. I and II). The low fitness group performed poorly in the functional assessments – 6MWT, and the muscular strength and power tests (Table 2). There was a significantly higher rate of inducible ischemia on exercise stress echo in the low fit group (16%) compared to the high (2%). Systolic function (ejection fraction, s , global longitudinal strain) was well preserved (Table 2). Likewise, traditional measures of diastolic filling were not different, but E/e was significantly higher in the low fitness group. Vascular stiffness (aPWV and AIx75) was also higher in the low fit group when compared to the high fitness group (Table 2). The significant univariate correlates of VO2 peak are presented in the supplemental material (Table I, Figs. III and IV). To determine the differential effects of clinical, vascular and cardiac covariates of VO2 peak, we constructed three multivariate backward regression models (Table 3). Model 1 which, included age, diabetes status, history of CVD, hemoglobin and physical activity levels explained 32% of the variability in VO2 peak (Table 3). Model 2 included the variables from Model 1 and AIx75 and aPWV, which improved the model fit (Model 2: R2 = 0.39, n = 100, P < 0.001). The final model included the addition of cardiac variables (subclinical ischemia, E/e and GLS), which further improved the model fit (Model 3: R2 = 0.41, n = 100, P < 0.001). The incremental value of the vascular and cardiac variables over the clinical variables in predicting VO2 peak was compared. Using the enter method a multivariate model of significant clinical variables (Model 1) plus the addition of variables from Model 2, significantly improved the predictive power of the model by 6.6% (adjusted R2 = 0.40, P = 0.008 for change). The power of the model was improved further by addition of
3
the cardiac variable by 5.9% (adjusted R2 = 0.46, P = 0.026 for change). 3. Discussion In this study, we examined the cardiorespiratory and cardiovascular response to peak exercise in CKD patients, and sought to evaluate the relationship between CRF and indicators of cardiovascular health. The main findings of this current study can be summarized as: (1) peak VO2 and HR were markedly reduced compared to age-predicted values in the majority of patients; (2) higher CRF was associated with lower aortic stiffness, AIx and better LV function; (3) the variance in CRF can be largely explained by cardiovascular risk factors (e.g. increasing age, type II diabetes and physical activity). Although we are unable to infer cause and effect, these findings suggest that CKD patients who maintain CRF also benefit from lower cardiovascular burden. Perhaps one of the most striking findings from this current study was the high rate of physical inactivity. Only 30 percent of participants met current physical activity recommendations.19 The number of CKD patients in Australia who meet the recommendations of the physical activity guidelines have dramatically decreased from 50 percent in 2009.23 The decline in physical activity levels is concerning, as it has occurred during a period where the Australian Government has increased public health campaigns to raise awareness of the benefits of being physically active. Given the association between higher levels of physical activity and improved survival in CKD patients,3 interventional studies are urgently required to determine the optimal way to increase physical activity levels and improve fitness in CKD patients, and ultimately determine if these interventions improve survival. Indeed, a 1 MET increase in fitness improves survival by 12 percent,12 while exercise tolerance of >10 METs in individuals with significant burden of subclinical atherosclerosis greatly improved cardiovascular prognosis.24 Interventions that incorporate a multidisciplinary approach will likely be the most effective in increasing physical activity levels due to the high cardiovascular burden and limited level of exercise counseling provided by nephrologists.25 In addition to low levels of physical activity, we found that peak CRF was also markedly impaired. In a small study of 32 patients with CKD (eGFR 29.9 ± 17.0), VO2 peak was found to be reduced compared to age-predicted norms.26 We extend these findings by showing that: (a) peak HR is also significantly reduced below agepredicted values, and (b) like the general population increasing age is associated with a decline in fitness albeit at a faster rate in patients with CKD. The reduction in VO2 peak may partially be explained by the blunted HR response to exercise and thus reduced central component to oxygen delivery. The HR response to dynamic exercise is complex, however a blunted HR response may reflect autonomic disturbances, and is associated with increased mortality and coronary heart disease incidence.27 Maximal HR clearly declines with age,13 however the rate of decline in patients with CKD is greater with the majority of our patients failing to achieve their age-predicted maximum response. Prior studies in ESKD have demonstrated that maximal HR is significantly reduced compared to healthy controls, but is increased following kidney transplantation28 suggesting impaired kidney function influences the central response to exercise. No prior studies have evaluated the relationship between fitness, LV function and arterial stiffness in CKD patients. In this study, patients with lower fitness had significantly higher central arterial stiffness and AIx when compared to the high fit group. Increased arterial stiffness is independent predictors of cardiovascular and all-cause mortality in kidney disease.29 The combination of poor CRF, low physical activity levels and increased arterial
Please cite this article in press as: Howden EJ, et al. Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.005
G Model
ARTICLE IN PRESS
JSAMS-1059; No. of Pages 6
E.J. Howden et al. / Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
4
Table 1 Characteristics of patients grouped by cardiorespiratory fitness tertiles. All (n = 136)
Low fitness (n = 44)
Moderate fitness (n = 46)
High fitness (n = 46)
P ANOVA
Demographics Age (yr) Male sex (%) BMI (kg/m2 ) History CVD, n (%) Diabetes type II, n (%) Current smoker, n (%) Physically active, n (%) Positive ESE, n (%)
60 ± 10 75 (55) 33 ± 7 53 (39) 52 (38) 23 (17) 41 (30) 13 (10)
62 ± 8a 21 (48) 36 ± 6ac 23 (52)a 26 (59)a 8 (18) 9 (20)a 7 (16)a
62 ± 8b 25 (54) 32 ± 7 17 (37) 19 (41)b 7 (15) 10 (22)b 5 (12)
55 ± 11 29 (63) 31 ± 7 13 (28) 7 (15) 8 (17) 22 (48) 1 (2)
0.001 0.96 0.002 0.005
