Is it Possible to Recover Cardiac Functions After Total Knee Arthroplasty?

Abstract

Background:

Patients suffering from knee osteoarthritis lead a less active life than their healthy peers. It is well known that insufficient physical activity is the most common cause of chronic diseases. However, there is not enough research to enlighten the effect of increased functional capacity on cardiac functions after Total Knee Arthroplasty (TKA). This study aimed to investigate whether the orthopedic surgeons can predict that the patients will be healthier after TKA in terms of cardiac functions or not?

Methods:

109 patients who underwent TKA were prospectively followed for one year. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and short form 36 (SF-36) surveys, BMI measures, average step count per day, the six-minute walking test (6MWT), the Five-Times-Sit-to-Stand Test (FTSST) and Doppler echocardiography were performed both in the preoperative and postoperative period.

Results:

After TKA, there was a substantial improvement in terms of WOMAC and SF36 survey scores. The average step count increased from 2199.6±690.8 steps/day to 4124.3±1638.8 steps/day. 6MWT and FTSST improved significantly as well. The average brisk walking time was 174.23±95.11 minutes/week. The means of early and late mitral inflow velocity ratios (E/A and Em/Am ratios) increased from 0.71±0.12 to 0.77±0.13 and from 0.66±0.13 to 0.76± 0.15 at the first year follow-up visit, respectively (p<0.001).

Conclusion:

In the first year, objective physical capacity measures increased together with the expected improvements in disease-specific and generic measures. After TKA, left ventricular diastolic functions may be considered to have recovered in the light of the healing signs via echocardiography.

1. INTRODUCTION

Knee osteoarthritis is the most common type of osteoarthritis characterized by pain and decreased health-related quality of life values [1, 2]. Consequently, patients suffering from knee arthritis lead a less active life than their healthy peers. It is also a well-known fact that people at a relatively older age are under higher risk of morbidity and mortality [2, 3]. Different aspects of physical functioning are monitored using the following procedures: Self-report questionnaires associated with Health-Related Quality Of Life (HRQOL) such as disease-specific and generic measures, functional capacity measurements such as 6MWT and FTSST, step count by pedometer and actual physical activity measurements using activity monitor [4, 5]. Although the patient’s perception of physical function is improved after TKA, the findings of an increase in actual physical activity and decrease in sedentary behavior have been debated [6, 7]. Whether actual physical activity level increases after TKA or not is an important issue. However, there is an increase in functional capacity measured by objective testing procedures as well [5, 7]. Irrespective of the arguments about actual physical activity status after TKA, the effects of the objectively measured increase of functional capacity and physical activity to general health should be considered as another important point. With aging and inactivity, as a consequence of structural and functional changes, left ventricular diastolic dysfunction occurs [8]. There are some evidence demonstrating left ventricular diastolic functional changes associated with aging decrease with physical activity [9-11]. But there is not enough study about the consequence of left ventricular diastolic dysfunction after TKA. The present study aimed to investigate whether the orthopedic surgeons can predict that the patients will be healthier after TKA in terms of cardiac functions or not?

2. MATERIALS AND METHODS

This study was approved by Malatya Ethical Committee (Institutional Review Board of Turgut Ozal Medical Center, Inonu University, Malayta/Turkey, Protocol Number: 2014/178). Patients who underwent TKA were followed prospectively for at least one year after the operation. On the 45th day of follow-up, patients were advised to walk at a brisk rate for 30 minutes every day in fifteen-minute sessions in the morning and the afternoon. The targeted walking time was 150 minutes per week. Patients with the following conditions were excluded from the study as these conditions prevent them from brisk walking: neurological diseases, lumber disc herniation, advanced osteoarthritis or disorders of hip, contralateral knee and ankle joints, systolic heart failure, coronary arterial diseases, advanced heart valve disease, congenital heart disease, hypertrophic cardiomyopathy, atrial fibrillation, pulmonary hypertension, chronic obstructive pulmonary disease. Patients with postoperative complications, such as pulmonary thromboembolism were also excluded as they caused immobility and prevented patients from taking part in the walking program. Patients who cannot use the pedometer properly, and those who have undergone any major surgical procedures that may prevent mobility after TKA were also excluded from the study. 205 patients were hospitalized for TKA. 36 patients with bilaterally advanced knee osteoarthritis were excluded since they could not adapt to the brisk walking program due to excessive pain on the other knee. 2 patients did not want to participate in the study. 13 patients had no ability to perform the walking program due to other disorders. Thus, preoperative evaluations were carried out on 154 patients. 6 operations were cancelled. Then, a brisk walking program was planned for 148 patients. 1 patient was hospitalized in an intensive care unit on the second postoperative day due to pulmonary thromboembolism. This patient was excluded due to a special rehabilitation program requirement. Deep vein thrombosis was diagnosed in 1 patient on the third postoperative day. This patient was treated successfully and included in the study. 148 patients were given a brisk walking program. 1 patient underwent drainage and debridement in the third month due to persistent pain and high levels of erythrocyte sedimentation rate and C-reactive protein. Patients who could not properly use a pedometer and record times and those who did not come to follow-ups regularly and could not complete the brisk walking program were excluded. The patient inclusion flow diagram is presented in Fig. (1). Finally, 109 patients were followed at least one year and completed the brisk walking program and all evaluations.

Infection prophylaxis was performed using 1gr cefazolin one hour before the operation. Ice therapy and the ankle pump exercise were started immediately after the operation. Isotonic and isometric knee exercises were started on the first postoperative day. Then patients were encouraged to sit in bed and bedside and mobilized with walker immediately. Patients were discharged after the forth postoperative day. Low molecular weight heparin was used for thromboembolism prophylaxis. 40 mg/0.4 ml enoxaparin sodium (Clexane®4000 anti-Xa/ 0.4ml pre-filled syringes, Sanofi Aventis) was given subcutaneously 12 hours after the operation and continued once a day for 3 weeks. Morbid obese patients were given 60 mg/0.6 ml enoxaparin sodium (Clexane® 6000 anti-Xa/ 0.6 ml pre-filled syringes, Sanofi Aventis). WOMAC [12] as a disease-specific and SF-36 survey [13] as a generic HRQOL, BMI, the average step count per day, the six-minute walk test (6MWT), the Five-Times-Sit-To-Stand Test (FTSST) and Doppler echocardiography were performed both in the preoperative and postoperative period. Pedometer (SW-200 Yamax Digiwalker) was used to count the steps. For staged operations, preoperative evaluations were performed before second TKA operation. WOMAC and SF36 evaluations, BMI measure, 6MWT and FTSST were performed one week before the operation, and repeated in a follow-up session one year after the operation. Average step count per day was measured during last week preoperatively and the average of one week before 6th, 9th, 12th months follow-ups postoperatively. The patients were asked to record both the number of daily steps and brisk walking time one week before the follow-up visits. Brisk walking time was estimated by taking into account the averages recorded one week before the 6th, 9th, 12th-month follow-ups postoperatively. Preoperative and postoperative echocardiographs were performed by the same two cardiologists.

Fig. (1). Patient inclusion flow diagram.

Preoperative WOMAC score, SF36 survey, BMI, average step counts per day and echocardiography parameters were compared with postoperative values. 6MWT is a valid testing procedure, evaluating the exercise capacity of the elderly, rather than their daily activities. Patients were asked to walk on a 30-meter track with their pace. They were allowed to rest when they felt tired [14]. At FTSST, patient sits with arms folded across chest and with their back against a 16 inches standard height chair. Then, patient is asked loudly to stand up and sit again five times as quickly as possible. The duration till 5th standing position is recorded. The five-times-sit-to-stand test is reported as a valid test in terms of dynamic balance and functional mobility in older adults [15]. All echocardiographic examinations were performed with the 4-mhz transducer of Vivid 7 pro (Vivid 7 pro, GE Vingmed, Milwauikee, Wisconsin, USA). Interpretation of echocardiographic examinations was performed by two cardiologists blinded to ECG measurements of the study population. Two-dimensional and pulsed Doppler measurements were performed according to the criteria of the American society of echocardiography. The following two-dimensional parameters were measured: Left Ventricular End-Diastolic Diameter (LVEDD, mm) Left Ventricular End Systolic Diameter (LVESD, mm), Left Ventricular Ejection Fraction (LVEF, %), diameters of Left Atrium (LA). The LVEF was estimated using Simpson’s rule. Statistical analyses were performed using SPSS Statistics for Windows, version 21.0 (IBM Corp., Armonk, NY). Kolmogorov Smirnov test was used to check whether the data were normally distributed or not. If the data was normally distributed, paired samples t-test was used. Two related sample t-tests were used in the case of non-normally distributed data. It was supposed that α equaled 0.05 and 1-β (power) equaled 0.80 for the power analyses. A p-value <0.05 was considered statistically significant.

The mean age was 66.75±6.25 (54-85) years (Table 1 for patients’ characteristics). The BMI decreased from 31.65±3.95 (23.1-41.5) kg/m2 to 30.97±3.9 (21.23-40.6) kg/m2 (p <0.001). There was a statistically significant increase in terms of WOMAC scores and SF36 survey scores with the exception of a subscale which is role limitation due to emotional problems (Tables 2 and 3). Average step count per day increased from 2199.6±690.8 (453-3800) steps/day to 4124.3±1638.8 (1700-12096) steps/day (p <0.001). 6MWT and FTSST scores significantly improved (p <0.001) (Table 4).

Table 1.
Patients’ characteristics.
Patients’ characteristics
Number 109
Age 66.75±6.25 (54-85) years-old
Sex 96 female. 13 male
BMI 31.65±3.95(23.1-41.5) kg/m2
Comorbidities 55 hypertension
26 diabetes mellitus
9 respiratory (asthma with mild symptoms)
42 other (headache, peptic, treated cancer, bowel diseases, renal diseases relatively mild skeletal disorders)
Postoperative rehabilitation No inpatient
Family practitioner, or by oneself
Living status 3 patients home alone
106 patients live with family
Adverse conditions 2 Haematoma (treated by surgical decompression)
5 wound closure defect (small necrosis in suture line treated via dressing)
1 joint infection (treated via drainage and debridement, insert exchanging and antibiotics)
2 superficial infection (treated via antibiotics)
1 deep vein thrombosis (treated successfully and included in the study)
1 pulmonary thromboembolism (hospitalized in extensive care unit)
Hospitalization time 5.44 (4-15) days
Table 2.
WOMAC scores.
*WOMAC Subscales Preoperative Postoperative First Year P-value
Pain 17.78±1.66 (14-20) 4.78±2.80 (0-18) <0.001
Stiffness 4.31±1.6 (1-8) 2.84±0.88 (1-5) <0.001
Physical function 58.54±3.26(49-66) 21.82±7.82 (6-52) <0.001
*The WOMAC index [12] is a disease specific measure and includes 24 questions. The questions are grouped into three subscales as pain (20 points), stiffness (8 points), and physical function (68 points). Higher scores demonstrate poor results.
Table 3.
SF36 survey outcomes.
SF36 subscales Preoperative Postoperative First Year P value
PF 27.19±8.89 (10-55) 65.87±9.37 (35-85) <0.001
BP 8.14±10.33 (0-35) 71.00±16.27 (10-100) <0.001
RP 2.75±7.86 (0-25) 66.28±22.66 (0-100) <0.001
RE 77.96±23.06 (0-100) 80.72±21.21 (0-100) 0.11
VT 41.37±13.34 (10-70) 56.10±13.35 (10-85) <0.001
MH 63.89±17.67 (16-96) 69.74±14.00 (32-96) <0.001
SF 36.78±15.66 (0-75) 79.59±16.37 (37.50-100) <0.001
GH 53.89±13.77 (10-85) 59.03±11.04 (15-85) <0.001
PF: physical functioning, BP: bodily pain, RP: role limitation due to physical problems, RE: role limitation due to emotional problems, VT: energy and vitality, SF: social functioning, GH: general heath perception, MH: mental health, Maximum score of each subscale was 100 points [13].
Table 4.
Objective physical capacity measures.
Measures Preoperative Postoperative First Year P-value
Average step count per day 2199.6±690.8 (453-3800) 4124.3±1638.8 (1700-12096) <0.001
6MWT (meter) 261.08±65.88 (46-385) 311.92±63.29 (105-422) <0.001
6MWT (step) 422.65±107.38 (70-615) 502.36±103.16 (180-689) <0.001
FTSST (sec) 26.73±7.23 (16-56) 22.79±7.59 (13-60) <0.001
6MWT: six-minute walk test (6MWT): FTSST: the five-times-sit-to-stand test.

Average brisk walking time was 24.88±13.58 (10-63) minutes/day and 174.23± 95.11 (70-441) minutes/week. The means of E/A and Em/Am values increased from 0.71±0.12 (0.40-0.97) to 0.77±0.13 (0.48-1.26) and from 0.66±0.13 (0.33-1.22) to 0.76±0.15 (0.41-1.42), respectively, at first-year follow-up visit (p<0.001). There were no significant differences in diameters of LV dimensions (LVEDD, LVESD, IVSd), diameters of LA and LVEF between the preoperative and postoperative first-year follow-up visit (Table 5).

Table 5.
Doppler echocardiographic parameters.
Parameters Preoperative Postoperative First Year P-value
LA (mm) 3.62 ±0.29 (3.00-4.50) 3.62±0.32 (2.90-4.40) 0.54
LVEDD (mm) 4.74±0.31(4.00-5.70) 4.72±0.34 (4.00-5.60) 0.36
LVESD (mm) 2.65±0.26 (2.5-2.85) 2.61±0.31(2.40-2.94) 0.42
IVSd (mm) 1.08±0.12 (0.90-1.40 1.09±0.10 (0.90-1.40) 0.17
LVEF (%) 60.23±2.75 (50-65) 60.50±1.92 (55-65) 0.22
E/A 0.71±0.12 (0.40-0.97) 0.77±0.13 (0.48-1.26) <0.001
Em/Am 0.66±0.13 (0.33-1.22) 0.76± 0.15 (0.41-1.42) <0.001
LA: left atrium; LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end systolic diameter; IVSd: Interventricular septum diameter; LVEF: left ventricular ejection fraction; E/A and Em/Am: early and late mitral inflow velocity ratios.

4. DISCUSSION

Aging is a major risk factor that increases the incidence of osteoarthritis [16]. It is obvious that left ventricular diastolic functional changes take place with aging as well [8, 17]. The present study was designed since there is not enough research to enlighten the effect of increased functional capacity on cardiac functions after TKA. Contrary to the traditional view that associates the surgical success with the implant survival, 20% of the patients who have undergone the TKA complain functional inabilities and/or residual pain [2]. In this context, the evaluation of HRQOL derived from patients becomes more important [1, 2]. In the present study, HRQOL evaluation was performed via WOMAC as a disease-specific measure and SF36 survey as a generic measure. The objective functional capacity evaluation was performed via average step count per day, 6MWT and FTSST. Left ventricular diastolic functions were evaluated by Doppler echocardiography. There was a statistically significant increase both in HRQOL and objective functional capacity measures. There was a statistically significant increase in early and E/A and Em/Am ratios.

It has been reported in a number of previous studies that although there was an increase in HRQOL values, there was no measurable increase in actual physical activity levels [6, 7, 18]. Harding et al. [6] reported that the patients gave positive feedback indicating a serious reduction of pain and subjective functional healing after hip or knee arthroplasties; however, they could not find an increase in actual physical activity levels. The current study, however, focuses on whether objective functional capacity increase has any effect on cardiac functions or not instead of the level of actual physical activity. With the exception of SF36 subscale which is the role limitation due to emotional problems, increased HRQOL values were confirmed by the increase in objective capacity measures in the present study. Insufficient physical activity is the most common cause of chronic diseases [7, 19, 20]. It is known that physical activity decreases morbidity and mortality [21-23]. There is no consensus about the amount and intensity of physical activity to help maintain health enhancement; however, it is suggested in different references that 30-minute moderate exercises five days a week, 20-minute vigorous exercise three days a week, or 10000 steps/days can be enough [7, 19, 20, 24]. It has been reported that especially, older adults above 65 years of age cannot reach these activity levels [17]. In the last decades, the increase in older age population has brought out sedentary behavior due to mobilization problems such as osteoarthritis, but in order to maintain health enhancement, it is necessary to provide minimum physical activity levels [20].

However, there is still an ongoing debate concerning the right type, frequency and intensity of physical activity to be used after TKA with no detrimental effect to the implant survival [3, 7, 25, 26]. Cycling, aqua fit, swimming and power walking are favored aerobic activities [25]. It has been also reported that after TKA, patients could not reach aforementioned physical activity levels [6, 7, 18]. Walk was determined to be the optimum type of physical activity in the present study due to the socio-economic facts. A number of previous studies have reported some findings of inverse linear dose-response relationship between physical activity volume and mortality rate [19, 20]. Besides, it has been reported that walking pace is more important in reducing the risk of cardiovascular disease and all-cause mortality risk than walking volume [29]. In order to provide health enhancement, only vigorous activities were recommended by some authors. In contrast, others suggested that moderate activities, such as 10-minute moderate intensity walk are enough [7, 20, 28-30]. Tudor-Locke et al. recommended 10-minute moderate intensity walk as a pace of 100 steps/min and completed to 150 minutes per week [30]. These authors proposed 7100 steps/day for physical activity for older adults, indicating physical activity levels of the older adults who have a disability or chronic disease may be less than this [30]. In the present study in order to achieve 150-minute walk per week, the patients were advised to walk in two15-minute sessions of brisk walking, totally 30 min per day. At the end of the first year, brisk walking time was 24.88±13.58 (10-63) minutes/day and 174.23±95.11 (70-441) minutes/week.

With aging, prolongation of early and late mitral inflow velocities (decreasing E/A and Em/Am ratios) and isovolumetric relaxation time take place [11]. It has been suggested that endurance training can prevent deceleration of diastolic filling and myocardial relaxation [8, 11]. Guirado GN et al. reported that after 6-months of exercise program, there was no change in left ventricular diastolic functions in older adults [8]. However, it has been reported that with regular and intense physical activity in relatively healthy older adults, left ventricular diastolic functions can be preserved without being affected by aging [9, 11]. In the present, there was a statistically significant increase in E/A and Em/Am ratios in the first year compared to the preoperative echocardiography results, which can be considered as the signs of healing in left ventricular diastolic functions. Left ventricular diastolic functions were evaluated via two-dimensional pulsed Doppler echocardiography in the current study. However, in the following studies, more comprehensive examinations, such as three-dimensional echocardiography and left atrium volume measure can be performed to evaluate left ventricular diastolic functions.

This study had some limitations. The accelerometer is reported to be the most accurate objective instrument to measure physical activity [6, 7]. However, we used the pedometer in our study to measure physical activity as it is less costly and easier to use compared to the accelerometer. Besides, the patients with serious mobility problems were excluded due to the nature of this study. Therefore, it might be difficult to compare the current study with others in terms of the findings derived from the patients and objective measures.

CONCLUSION

After TKA, there was a significant increase in disease-specific, generic evaluations and objective physical capacity measures in the first year and left ventricular diastolic functions may be considered to have recovered in the light of the healing signs via echocardiography.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This study was approved by Malatya Ethical Committee (Institutional Review Board of Turgut Ozal Medical Center, Inonu University, Malayta/Turkey, Protocol Number: 2014/178).

HUMAN AND ANIMAL RIGHTS

All procedures were performed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and later versions.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

1
Bourne RB. Measuring tools for functional outcomes in total knee arthroplasty. Clin Orthop Relat Res 2008; 466(11): 2634-8.
2
Shan L, Shan B, Suzuki A, Nouh F, Saxena A. Intermediate and long-term quality of life after total knee replacement: A systematic review and meta-analysis. J Bone Joint Surg Am 2015; 97(2): 156-68.
3
Healy WL, Sharma S, Schwartz B, Iorio R. Athletic activity after total joint arthroplasty. J Bone Joint Surg Am 2008; 90(10): 2245-52.
4
de Groot IB, Bussmann JB, Stam HJ, Verhaar JA. Actual everyday physical activity in patients with end-stage hip or knee osteoarthritis compared with healthy controls. Osteoarthritis Cartilage 2008; 16(4): 436-42.
5
de Groot IB, Bussmann HJ, Stam HJ, Verhaar JA. Small increase of actual physical activity 6 months after total hip or knee arthroplasty. Clin Orthop Relat Res 2008; 466(9): 2201-8.
6
Harding P, Holland AE, Delany C, Hinman RS. Do activity levels increase after total hip and knee arthroplasty? Clin Orthop Relat Res 2014; 472(5): 1502-11.
7
Naal FD, Impellizzeri FM. How active are patients undergoing total joint arthroplasty?: A systematic review. Clin Orthop Relat Res 2010; 468(7): 1891-904.
8
Guirado GN, Damatto RL, Matsubara BB, et al. Combined exercise training in asymptomatic elderly with controlled hypertension: Effects on functional capacity and cardiac diastolic function. Med Sci Monit 2012; 18(7): CR461-5.
9
Arbab-Zadeh A, Dijk E, Prasad A, et al. Effect of aging and physical activity on left ventricular compliance. Circulation 2004; 110(13): 1799-805.
10
Galetta F, Franzoni F, Femia FR, Bartolomucci F, Carpi A, Santoro G. Left ventricular diastolic function and carotid artery wall in elderly athletes and sedentary controls. Biomed Pharmacother 2004; 58(8): 437-42.
11
Prasad A, Popovic ZB, Arbab-Zadeh A, et al. The effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol 2007; 99(12): 1629-36.
12
Tüzün EH, Eker L, Aytar A, Daşkapan A, Bayramoğlu M. Acceptability, reliability, validity and responsiveness of the Turkish version of WOMAC osteoarthritis index. Osteoarthritis Cartilage 2005; 13(1): 28-33.
13
Demiral Y, Ergor G, Unal B, et al. Normative data and discriminative properties of short form 36 (SF-36) in Turkish urban population. BMC Public Health 2006; 6: 247.
14
Bautmans I, Lambert M, Mets T. The six-minute walk test in community dwelling elderly: Influence of health status. BMC Geriatr 2004; 4: 6.
15
Goldberg A, Chavis M, Watkins J, Wilson T. The five-times-sit-to-stand test: Validity, reliability and detectable change in older females. Aging Clin Exp Res 2012; 24(4): 339-44.
16
Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin North Am 2013; 39(1): 1-19.
17
Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB. Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation 1994; 89(4): 1648-55.
18
Vissers MM, Bussmann JB, de Groot IB, Verhaar JA, Reijman M. Physical functioning four years after total hip and knee arthroplasty. Gait Posture 2013; 38(2): 310-5.
19
Blair SN, LaMonte MJ, Nichaman MZ. The evolution of physical activity recommendations: How much is enough? Am J Clin Nutr 2004; 79(5): 913S-20S.
20
Lee IM, Skerrett PJ. Physical activity and all-cause mortality: What is the dose-response relation? 2001.
21
Barry HC, Eathorne SW. Exercise and aging. Issues for the practitioner. Med Clin North Am 1994; 78(2): 357-76.
22
Blair SN, Kohl HW III, Barlow CE, Paffenbarger RS Jr, Gibbons LW, Macera CA. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA 1995; 273(14): 1093-8.
23
Paffenbarger RS Jr, Hyde RT, Wing AL, Hsieh CC. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med 1986; 314(10): 605-13.
24
Bohannon RW. Number of pedometer-assessed steps taken per day by adults: A descriptive meta-analysis. Phys Ther 2007; 87(12): 1642-50.
25
Kuster MS. Exercise recommendations after total joint replacement: A review of the current literature and proposal of scientifically based guidelines. Sports Med 2002; 32(7): 433-45.
26
Naal FD, Impellizzeri FM, Leunig M. Which is the best activity rating scale for patients undergoing total joint arthroplasty? Clin Orthop Relat Res 2009; 467(4): 958-65.
27
Murphy MH, Nevill AM, Murtagh EM, Holder RL. The effect of walking on fitness, fatness and resting blood pressure: A meta-analysis of randomised, controlled trials. Prev Med 2007; 44(5): 377-85.
28
Lee IM, Sesso HD, Oguma Y, Paffenbarger RS Jr. Relative intensity of physical activity and risk of coronary heart disease. Circulation 2003; 107(8): 1110-6.
29
Morris JN, Everitt MG, Pollard R, Chave SP, Semmence AM. Vigorous exercise in leisure-time: protection against coronary heart disease. Lancet 1980; 2(8206): 1207-10.
30
Tudor-Locke C, Craig CL, Aoyagi Y, et al. How many steps/day are enough? For older adults and special populations. Int J Behav Nutr Phys Act 2011; 8: 80.