Exercise training in heart failure with preserved and reduced ejection fraction: A systematic review and meta-analysis

Journal article

Edwards, J. and O'Driscoll, J. 2022. Exercise training in heart failure with preserved and reduced ejection fraction: A systematic review and meta-analysis. Sports Medicine - Open. 8 (1), p. 76. https://doi.org/10.1186/s40798-022-00464-5
AuthorsEdwards, J. and O'Driscoll, J.
Abstract

Background
While exercise training (ET) is an established tool in heart failure (HF), no research to date has analysed the efficacy of ET in both preserved (HFpEF) and reduced (HFrEF) ejection fraction phenotypes across the same clinically important parameters.

Methods
A comprehensive systematic search was performed to identify trials published between 1990 and May 2021. Controlled trials of adults reporting pre- and post-ET peak VO2, 6-min walk distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Kansas City Cardiomyopathy Questionnaire (KCCQ) and left ventricular ejection fraction (LVEF) were considered. Parameters of cardiac diastolic function, brain natriuretic peptides (BNP)/N-terminal prohormone of BNP (NTproBNP) and follow-up hospitalisation and mortality data were also analysed.

Results
Ninety-three studies (11 HFpEF and 82 HFrEF) were included in the final analysis, with a pooled sample size of 11,081 participants. HFpEF analysis demonstrated significant improvements in peak VO2 (weighted mean difference: 2.333 ml·min-1·kg-1, Pfixed < 0.001), 6MWD (WMD: 35.396 m, Pfixed < 0.001), MLHFQ (WMD: − 10.932, Prandom < 0.001), KCCQ (WMD: 3.709, Pfixed = 0.037) and E/e′ (WMD: − 1.709, [95% CI] = − 2.91–0.51, Prandom = 0.005). HFrEF analysis demonstrated significant improvements in peak VO2 (WMD: 3.050 ml·min-1·kg-1, Prandom < 0.001), 6MWD (WMD: 37.299 m, Prandom < 0.001), MLHFQ (WMD: − 10.932, Prandom < 0.001), LVEF (WMD: 2.677%, Prandom = 0.002) and BNP/NTproBNP (SMD: − 1.349, Prandom < 0.001). Outcome analysis was only performed in HFrEF, which found no significant changes in hospitalisation, all-cause mortality or composite end-points.

Conclusion
ET significantly improves exercise capacity and quality of life in both HFpEF and HFrEF patients. In HFpEF patients, ET significantly improved an important index of diastolic function, with significant improvements in LVEF and NTproBNP/BNP seen in HFrEF patients only. Such benefits did not translate into significantly reduced hospitalisation or mortality after short-term follow-up.

KeywordsHeart Failure; Exercise Training; Hfpef; Hfref
Year2022
JournalSports Medicine - Open
Journal citation8 (1), p. 76
PublisherSpringer
ISSN2198-9761
2199-1170
Digital Object Identifier (DOI)https://doi.org/10.1186/s40798-022-00464-5
Official URLhttps://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-022-00464-5
Publication dates
Online08 Jun 2022
Print01 Jun 2022
Publication process dates
Accepted13 May 2022
Deposited16 Jun 2022
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Open
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Wiles, J., Rees-Roberts, Melanie, O'Driscoll, J., Doulton, Timothy, MacInnes, D., Short, Vanessa, Pellatt-Higgins, Tracy, Saxby, Katie, Gousia, K., West, Alan, Smith, Maggie, Santer, E., Darby, John and Farmer, Chris K 2021. Feasibility study to assess the delivery of a novel isometric exercise intervention for people with stage 1 hypertension in the NHS: protocol for the IsoFIT-BP study including amendments to mitigate the risk of COVID-19. Pilot and Feasibility Studies. 7 (1), p. 192. https://doi.org/10.1186/s40814-021-00925-w
Planned delivery to improve postpartum cardiac function in women with preterm pre-eclampsia: the PHOEBE mechanisms of action study within the PHOENIX RCT
McCarthy, F., O'Driscoll, J., Seed, P., Brockbank, A., Cox, A., Gill, C., Green, M., Marber, M., Poston, L., Placzek, A., Shennan, A., Sparkes, J., Leeson, P., Thilaganathan, B. and Chappell, L. 2021. Planned delivery to improve postpartum cardiac function in women with preterm pre-eclampsia: the PHOEBE mechanisms of action study within the PHOENIX RCT. Efficacy and Mechanism Evaluation. 8 (12), pp. 1-28. https://doi.org/10.3310/eme08120
Multicenter cohort study, with a nested randomized comparison, to examine the cardiovascular impact of preterm preeclampsia
McCarthy, F.P., O'Driscoll, J., Seed, P.T., Placzek, A., Gill, C., Sparkes, J., Poston, L., Marber, M., Shennan, A.H., Thilaganathan, B., Leeson, P. and Chappell, L.C. 2021. Multicenter cohort study, with a nested randomized comparison, to examine the cardiovascular impact of preterm preeclampsia. Hypertension. https://doi.org/10.1161/HYPERTENSIONAHA.121.17171
Risk of atrial fibrillation in athletes: a systematic review and meta-analysis.
Newman, William, Parry-Williams, Gemma, Wiles, Jonathan, Edwards, Jamie, Hulbert, Sabina, Kipourou, Konstantina, Papadakis, Michael, Sharma, Rajan and O'Driscoll, Jamie 2021. Risk of atrial fibrillation in athletes: a systematic review and meta-analysis. British Journal of Sports Medicine. https://doi.org/bjsports-2021-103994
Validity and reliability of RPE as a measure of intensity during isometric wall squat exercise
Lea, J., O'Driscoll, J., Coleman, D. and Wiles, J. 2021. Validity and reliability of RPE as a measure of intensity during isometric wall squat exercise. Journal of Clinical and Translational Research. 7 (2), pp. 248-256. https://doi.org//10.18053/jctres.07.202102.007
Validity and reliability of the ‘Isometric Exercise Scale’ (IES) for measuring ratings of perceived exertion during continuous isometric exercise
Lea, J., O'Driscoll, J., Coleman, D. and Wiles, J. 2021. Validity and reliability of the ‘Isometric Exercise Scale’ (IES) for measuring ratings of perceived exertion during continuous isometric exercise. Scientific Reports. 11 (5334). https://doi.org/10.1038/s41598-021-84803-8
Real-world performance and accuracy of stress echocardiography: the EVAREST observational multi-centre study
Woodward, W., Dockerill, Cameron, McCourt, Annabelle, Upton, Ross, O'Driscoll, Jamie, Balkhausen, Katrin, Chandrasekaran, Badrinathan, Firoozan, Soroosh, Kardos, Attila, Wong, Kenneth, Woodward, Gary, Sarwar, Rizwan, Sabharwal, N., Benedetto, Elena, Spagou, Nancy, Sharma, Rajan, Augustine, Daniel, Tsiachristas, Apostolos, Senior, R., Leeson, P., Boardman, Henry, d’Arcy, Joanna, Abraheem, Abraheem, Banypersad, Sanjay, Boos, Christopher, Bulugahapitiya, Sudantha, Butts, Jeremy, Coles, Duncan, Easaw, Jacob, Hamdan, Haytham, Jamil-Copley, Shahnaz, Kanaganayagam, Gajen, Mwambingu, Tom, Pantazis, Antonis, Papachristidis, Alexandros, Rajani, Ronak, Rasheed, Muhammad Amer, Razvi, Naveed A, Rekhraj, Sushma, Ripley, David P, Rose, Kathleen, Scheuermann-Freestone, Michaela, Schofield, Rebecca and Sultan, Ayyaz 2021. Real-world performance and accuracy of stress echocardiography: the EVAREST observational multi-centre study. European Heart Journal - Cardiovascular Imaging. 23 (5), pp. 689-698. https://doi.org/10.1093/ehjci/jeab092
Continuous cardiac autonomic and haemodynamic responses to isometric exercise in females
O'Driscoll, J., Boucher, C., Vilda, M., Taylor, K. and Wiles, J. 2020. Continuous cardiac autonomic and haemodynamic responses to isometric exercise in females. European Journal of Applied Physiology and Occupational Physiology. https://doi.org/10.1007/s00421-020-04525-z
Ambulatory blood pressure adaptations to high-intensity interval training: a randomized controlled study
Edwards, J., Taylor, K.A., Cottam, C., Jalaludeen, N., Coleman, D.A., Wiles, J.D., Sharma, R. and O'Driscoll, J.M. 2020. Ambulatory blood pressure adaptations to high-intensity interval training: a randomized controlled study. Journal of Hypertension. https://doi.org/10.1097/HJH.0000000000002630
Centre of pressure, vertical ground reaction forces and neuromuscular responses of special-forces soldiers to 43km load carriage in the field
Scales, J., O'Driscoll, J., Coleman, D., Giannoglou, D, Gkougkoulis, I, Ntontis, I, Zisopoulou, C and Brown, M. 2020. Centre of pressure, vertical ground reaction forces and neuromuscular responses of special-forces soldiers to 43km load carriage in the field. Journal of Applied Biomechanics. 36 (5), pp. 307-312. https://doi.org/10.1123/jab.2019-0283
Left atrial mechanics and aortic stiffness following high intensity interval training: a randomised controlled study
Jalaludeen, N., Bull, S., Taylor, K. A., Wiles, J., Coleman, D., Mukhtar, O., Cheriyan, J., Wilkinson, I.B., Sharma, R. and O'Driscoll, J. 2020. Left atrial mechanics and aortic stiffness following high intensity interval training: a randomised controlled study. European Journal of Applied Physiology. https://doi.org/10.1007/s00421-020-04416-3
Differentiation between athlete’s heart and dilated cardiomyopathy in athletic individuals
Millar, L. M., Fanton, Z., Finnochiaro, G., Sanchez-Fernandez, G., Dhutia, H., Malhotra, A., Merghani, A., Papadakis, M., Behr, E. R., Bunce, N., Oxborough, D., Reed, M., O'Driscoll, J., Tome Esteban, M. T., D'Silva, A., Carr-White, G., Sharma, R. and Sharma, S. 2020. Differentiation between athlete’s heart and dilated cardiomyopathy in athletic individuals. Heart. https://doi.org/10.1136/heartjnl-2019-316147
The impact of demographic, anthropometric and athletic characteristics on left atrial size in athletes.
O'Driscoll, J. and Christou, G. 2020. The impact of demographic, anthropometric and athletic characteristics on left atrial size in athletes. Clinical Cardiology. 43 (8), pp. 834-842. https://doi.org/10.1002/clc.23368
Speckle tracking echocardiography: new ways of translational approaches in preeclampsia to detect cardiovascular dysfunction
Kraker, K., Schutte, T., O'Driscoll, J., Birukov, A., Patey, O., Herse, F., Muller, D.N., Thilaganathan, B., Haase, N. and Dechend, R. 2020. Speckle tracking echocardiography: new ways of translational approaches in preeclampsia to detect cardiovascular dysfunction. International Journal of Molecular Sciences. 21 (3). https://doi.org/10.3390/ijms21031162
Challenge and threat: a critical review of the literature and an alternative conceptualization
Uphill, M., Rossato, C., Swain, J. and O'Driscoll, J. 2019. Challenge and threat: a critical review of the literature and an alternative conceptualization. Frontiers in Psychology. https://doi.org/10.3389/fpsyg.2019.01255
Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study
Green, D., Vassallo, D., Handley, K., Ives, N., Wheatley, K., Chrysochou, C., Hegarty, J., Wright, J., Moss, J., Patel, R., Deighan, C., Webster, J., Rowe, P., Carr, S., Cross, J., O'Driscoll, J., Sharma, R., Mark, P. and Kalra, P. 2019. Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study. BMC Nephrology. https://doi.org/10.1186/s12882-019-1406-y
Characteristics of torque production of the lower limb are significantly altered after 2 hours of treadmill load carriage
Scales, J., Coleman, D., O'Driscoll, J. and Brown, M. 2018. Characteristics of torque production of the lower limb are significantly altered after 2 hours of treadmill load carriage. Translational Sports Medicine. 2 (1). https://doi.org/10.1002/tsm2.54
The impact of gestational diabetes on maternal cardiac adaptation to pregnancy.
Buddeberg, B.S., Sharma, R., O'Driscoll, J., Kaelin, A., Khalil, A. and Thilaganathan, B. 2019. The impact of gestational diabetes on maternal cardiac adaptation to pregnancy. Ultrasound in Obstetrics and Gynecology. https://doi.org/10.1002/uog.21941
Statins Reverse Postpartum Cardiovascular Dysfunction in a Rat Model of Preeclampsia
Kräker, Kristin, O’Driscoll, Jamie M., Schütte, Till, Herse, Florian, Patey, Olga, Golic, Michaela, Geisberger, Sabrina, Verlohren, Stefan, Birukov, Anna, Heuser, Arnd, Müller, Dominik N., Thilaganathan, Basky, Dechend, Ralf and Haase, Nadine 2019. Statins Reverse Postpartum Cardiovascular Dysfunction in a Rat Model of Preeclampsia. Hypertension. 75 (1), pp. 202-210. https://doi.org/10.1161/hypertensionaha.119.13219
Left ventricular function and cardiac biomarker release – the influence of exercise intensity, duration and mode: a systematic review and meta-analysis
Donaldson, J., Wiles, J., Coleman, D., Papadakis, M., Sharma, R. and O'Driscoll, J. 2019. Left ventricular function and cardiac biomarker release – the influence of exercise intensity, duration and mode: a systematic review and meta-analysis. Sports Medicine. https://doi.org/10.1007/s40279-019-01142-5
Cardiac maladaptation in obese pregnancy at term
Buddeberg, B., Sharma, R., O'Driscoll, J., Kaelin Agten, A., Khalil, A. and Thilaganathan, B. 2018. Cardiac maladaptation in obese pregnancy at term. Ultrasound in Obstetrics and Gynecology. https://doi.org/10.1002/uog.20170
A 4-week resistance training intervention improves stability, strength and neuromuscular activity in the lower limb: a case study of a cerebral palsy adult
McManus, A., Bembridge, M., Scales, J., Wiles, J., Coleman, D. and O'Driscoll, J. 2018. A 4-week resistance training intervention improves stability, strength and neuromuscular activity in the lower limb: a case study of a cerebral palsy adult. International Journal of Sports Science & Medicine. 2 (2), pp. 050-055.
Neurohumoral and ambulatory haemodynamic adaptations following isometric exercise training in unmedicated hypertensive patients
Taylor, K., Wiles, J., Coleman, D., Leeson, P., Sharma, R. and O'Driscoll, J. 2018. Neurohumoral and ambulatory haemodynamic adaptations following isometric exercise training in unmedicated hypertensive patients. Journal of Hypertension. https://doi.org/10.1097/HJH.0000000000001922
Cardiac autonomic and left ventricular mechanics following high intensity interval training: a randomised cross-over controlled study.
O'Driscoll, J., Wrigth, S., Taylor, K., Coleman, D., Sharma, R. and Wiles, J. 2018. Cardiac autonomic and left ventricular mechanics following high intensity interval training: a randomised cross-over controlled study. Journal of Applied Physiology. https://doi.org/10.1152/japplphysiol.00056.2018
Cardiac maladaptation in term pregnancies with preeclampsia
Buddeberg, B., Sharma, R., O'Driscoll, J., Kaelin Agten, A., Khalil, A. and Thilaganathan, B. 2018. Cardiac maladaptation in term pregnancies with preeclampsia. Pregnancy Hypertension. 13, pp. 198-203. https://doi.org/10.1016/j.preghy.2018.06.015
The safety of isometric exercise: rethinking the exercise prescription paradigm for those with stage 1 hypertension.
Wiles, J., Taylor, K., Coleman, D., Sharma, R. and O'Driscoll, J. 2018. The safety of isometric exercise: rethinking the exercise prescription paradigm for those with stage 1 hypertension. Medicine. 97 (10). https://doi.org/10.1097/MD.0000000000010105
An alternative approach to isometric exercise training prescription for cardiovascular health
Wiles, J., Goldring, N., O'Driscoll, J., Taylor, K. and Coleman, D. 2018. An alternative approach to isometric exercise training prescription for cardiovascular health. Translational Journal of the American College of Sports Medicine. 3 (2), pp. 10-18. https://doi.org/10.1249/TJX.0000000000000052
Baseline mitral regurgitation predicts outcome in patients referred for dobutamine stress echocardiography
O'Driscoll, J., Gargallo-Fernandez, P., Araco, M., Perez-Lopez, M. and Sharma, R. 2017. Baseline mitral regurgitation predicts outcome in patients referred for dobutamine stress echocardiography. International Journal of Cardiovascular Imaging. https://doi.org/10.1007/s10554-017-1163-6
Blood pressure responses to isometric exercise: safety considerations for exercise prescription
Wiles, J., Taylor, K., Coleman, D., Sharma, R. and O'Driscoll, J. 2017. Blood pressure responses to isometric exercise: safety considerations for exercise prescription.
Ambulatory blood pressure responses to home-based isometric exercise training in pre-hypertensive males
Taylor, K., Wiles, J., Coleman, D., Sharma, R. and O'Driscoll, J. 2017. Ambulatory blood pressure responses to home-based isometric exercise training in pre-hypertensive males.
Cardiac autonomic modulation and high intensity interval training in physically inactive men
O'Driscoll, J., Wright, S., Taylor, K., Coleman, D. and Wiles, J. 2017. Cardiac autonomic modulation and high intensity interval training in physically inactive men.
A higher effort-based paradigm in physical activity and exercise for public health: making the case for a greater emphasis on resistance training
Steele, J., Fisher, J., Skivington, M., Dunn, C., Arnold, J., Tew, G., Batterham, A., Nunan, D., O'Driscoll, J., Mann, S., Beedie, C., Jobson, S., Smith, D., Vigotsky, A., Phillips, S., Estabrooks, P. and Winett, R. 2017. A higher effort-based paradigm in physical activity and exercise for public health: making the case for a greater emphasis on resistance training. BMC Public Health. https://doi.org/10.1186/s12889-017-4209-8
Continuous cardiac autonomic and haemodynamic responses to isometric exercise in pre-hypertensive males
Taylor, K., Wiles, J., Coleman, D., Sharma, R. and O'Driscoll, J. 2017. Continuous cardiac autonomic and haemodynamic responses to isometric exercise in pre-hypertensive males. Medicine & Science in Sports & Exercise (MSSE). https://doi.org/10.1249/MSS.0000000000001271
Acute cardiac functional and mechanical responses to isometric exercise in pre-hypertensive males
O'Driscoll, J., Taylor, K., Wiles, J., Coleman, D. and Sharma, R. 2017. Acute cardiac functional and mechanical responses to isometric exercise in pre-hypertensive males. Physiological Reports. https://doi.org/10.14814/phy2.13236
Body mass index mortality paradox in chronic kidney disease patients with suspected cardiac chest pain
O'Driscoll, J., Slee, A. and Sharma, R. 2017. Body mass index mortality paradox in chronic kidney disease patients with suspected cardiac chest pain. Journal of Cachexia, Sarcopenia and Muscle Clinical Reports. 2 (1).
Strongman training – Needs analysis and integration into strength and conditioning programming: part 2.
McManus, A., O'Driscoll, J., Coleman, D. and Wiles, J. 2016. Strongman training – Needs analysis and integration into strength and conditioning programming: part 2. Professional Strength & Conditioning. 44, pp. 7-15.
Strongman training – a rationale for its inclusion in strength & conditioning: part 1
McManus, A., Wiles, J., Coleman, D. and O'Driscoll, J. 2016. Strongman training – a rationale for its inclusion in strength & conditioning: part 1. Professional Strength & Conditioning. 43, pp. 7-18.
Acute cardiac autonomic responses to an incremental isometric exercise test in pre-hypertensive males
Taylor, K., Wiles, J., Coleman, D., Sharma, R. and O'Driscoll, J. 2016. Acute cardiac autonomic responses to an incremental isometric exercise test in pre-hypertensive males.
Transthoracic echocardiography provides important long-term prognostic information in selected patients undergoing endovascular abdominal aortic repair
O'Driscoll, J., Bahia, S., Gravina, A., Di Fino, S., Thompson, M., Karthikesalingam, A., Holt, P. and Sharma, R. 2016. Transthoracic echocardiography provides important long-term prognostic information in selected patients undergoing endovascular abdominal aortic repair. Circulation Cardiovascular Imaging. https://doi.org/10.1161/CIRCIMAGING.115.003557
Reverse left ventricular remodelling - effect of cardiac rehabilitation exercise training in myocardial infarction patients with preserved ejection fraction
McGregor, G., Gaze, D., Oxborough, D., O'Driscoll, J. and Shave, R. 2015. Reverse left ventricular remodelling - effect of cardiac rehabilitation exercise training in myocardial infarction patients with preserved ejection fraction. European Journal of Physcial and Rehabilitation Medicine. 52 (3), pp. 370-378.
The prognostic value of dobutamine stress echocardiography amongst British Indian Asian and Afro-Caribbean patients: a comparison with European white patients
O'Driscoll, J., Rossato, C., Gargallo-Fernandez, P., Araco, M., Giannoglou, D., Sharma, S. and Sharma, R. 2015. The prognostic value of dobutamine stress echocardiography amongst British Indian Asian and Afro-Caribbean patients: a comparison with European white patients. Cardiovascular Ultrasound. 13 (36). https://doi.org/10.1186/s12947-015-0028-1
Non-invasive assessment of the autonomic nervous system
O'Driscoll, J. and Sharma, R. 2015. Non-invasive assessment of the autonomic nervous system. International Journal of Clinical Therapeutics and Diagnosis. 3 (3), pp. 85-91.
Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia
Sharma, R., O'Driscoll, J., Saha, A., Sritharan, M., Sutton, R. and Rosen, S. 2015. Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia. The Journal of Physiology. 593 (9), pp. 2171-2184. https://doi.org/10.1113/JP270063
The safety and clinical usefulness of dobutamine stress echocardiography among octogenarians
O'Driscoll, J., Marciniak, A., Ray, K., Schmid, K., Smith, R. and Sharma, R. 2014. The safety and clinical usefulness of dobutamine stress echocardiography among octogenarians. Heart. 2014 (100), pp. 1001-1007. https://doi.org/10.1136/heartjnl-2013-305229
The implementation of problem based learning styles to teach the Coach-Athlete relationship to undergraduate Sport and Exercise Science students
Rossato, C. and O'Driscoll, J. 2013. The implementation of problem based learning styles to teach the Coach-Athlete relationship to undergraduate Sport and Exercise Science students. International Journal of Sport Studies. 3, pp. 859-864.
Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia
Sharma, R., O'Driscoll, J., Bromley, P., Sritharan, M. and Rosen, S. 2008. Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia.
Dobutamine stress echocardiography accurately detects significant coronary artery disease in Indian Asians living in the United Kingdom
Itam, S., O'Driscoll, J., Milad, E. and Sharma, R. 2008. Dobutamine stress echocardiography accurately detects significant coronary artery disease in Indian Asians living in the United Kingdom.
The effects of a high-protein, paleolithic-type diet on body composition and exercise performance in amateur mixed martial artists
Slee, A., O'Driscoll, J., Burnet, S., Hughes, G. and Chen, M. 2009. The effects of a high-protein, paleolithic-type diet on body composition and exercise performance in amateur mixed martial artists.
Subjective global assessment is an independent predictor of cardiac ischaemia in patients with mild chronic kidney disease
Aldous, G., Sharma, R., O'Driscoll, J., Ashby, D., Tarn, F. and Choi, P. 2010. Subjective global assessment is an independent predictor of cardiac ischaemia in patients with mild chronic kidney disease.
A National Health Service hospital's cardiac rehabilitation programme: a qualitative analysis of provision
O'Driscoll, J., Shave, R. and Cushion, C. 2007. A National Health Service hospital's cardiac rehabilitation programme: a qualitative analysis of provision. Journal of Clinical Nursing. 16 (10), pp. 1908-1918. https://doi.org/10.1111/j.1365-2702.2007.01815.x
Inequalities in the training and implementation of cardiac rehabilitation in the United Kingdom
O'Driscoll, J. and Sharma, R. 2009. Inequalities in the training and implementation of cardiac rehabilitation in the United Kingdom. in: Bennington, E. (ed.) Horizons in World Cardiovascular Research Hauppauge, New York Nova Science Publishers.