# Exercise as it relates to Disease/Effects of exercise on pulmonary arterial hypertension

This is a critique of "Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi + 12 trial". A study completed by González-Saiz, L., Fiuza-Luces, C., Sanchis-Gomar, F., Santos-Lozano, A., Quezada-Loaiza, C. A., Flox-Camacho, A., Munguía-Izquierdo, D., Ara, I., Santalla, A., Morán, M., Sanz-Ayan, P., Escribano-Subías, P., and Lucia, A., published in the International Journal of Cardiology in 2017.

## What is the background to this research?

This study explored whether, over the course of eight weeks, patients diagnosed with pulmonary arterial hypertension (PAH), or inoperable chronic thromboembolic pulmonary hypertension (CTEPH), could improve muscle power, physical activity and other variables through resistance, inspiratory and aerobic training.
PAH is a progressive, fatal condition acquired genetically, or secondary to conditions such as HIV, connective tissue disorders, or CTEPH. It causes symptoms such as being short of breath, dizziness, and muscle weakness, ultimately leading to right ventricular (RV) failure. PAH significantly restricts exercise capability due to the aforementioned symptoms, and from limited blood oxygen availability due to progressive RV remodelling.
CTEPH occurs with chronic pulmonary artery obstruction, displaying similar symptoms and effects on exercise capability to PAH, however, can be cured surgically.
PAH treatment aims to improve life quality through medication or surgery. This has helped increase survival rates; however, PAH still has a one-year survival rate of 85% and seven-year survival of 49%, with certain types still untreatable. New therapies are required to find a cure for this severely life-limiting disease.
This study sought to close research gaps by using the combination of exercise aforementioned, the use of heavier weight training, and use of a shorter time period.

## Where is the research from?

The study was completed in Madrid, Spain, at the Hospital 12 de Octubre, where six of the authors conduct research through the hospital's i+12 Research Institute, which was established in 2009.
At least 10 of the 13 authors completed prior research in PAH, CTEPH or other cardiac conditions, including two medical doctors practicing within the hospital's Pulmonary Hypertension Unit. The authors have nearly all completed prior research exploring the effects of various types of physical activity and exercise on PAH, CTEPH and other cardiac conditions.
Inclusion criteria included:
* Aged 18-65
* Living in Madrid
* Outpatient at Hospital 12 de Octubre
* New York Heart Association (NYHA) class I - III
* Currently stable, no altered treatments for six months prior
* No other exercise limiting conditions
No conflicts of interest were stated, however, POWERbreathe supplied devices for inspiratory training. POWERbreathe sells inspiratory training devices to medical professionals and the public, making claims their product can lower blood pressure and is beneficial to athletes. It could be argued that this company has a vested interest in supporting inspiratory training research, as this may increase their sales. Funding was provided by Real Madrid Graduate School-Universidad Europea which, as an exclusively sports focused graduate university, may be more likely to provide funding for exercise based research.

## What kind of research was this?

This study was a randomised controlled trial (RCT), where only researchers determining eligibility and results were blinded to the groups.
The placebo group continued to receive their normal course of treatment.
Other studies show similar evidence in regards to the outcomes of exercise in PAH patients among comparable results such as peak oxygen uptake, Six-Minute Walk Distance (6MWD) and aerobic threshold.

## What did the research involve?

Over an eight-week period a total of 40 participants participated.
20 participants completed:
* aerobic exercise five times per week
* resistance exercise three times per week
* inspiratory muscle training twice daily, six times per week.
All sessions were completed at the hospital under supervision with one trainer to one participant, apart from the second daily session of inspiratory training which was completed at home.
The remaining 20 participants completed their normal treatment.
When designed well, RCT's are the gold standard when investigating new treatment methods. The researchers also made data corrections to reduce possibility of statistical type I error.
However, limitations include:
* Training load – Participants completed 20 sessions per week for eight weeks, near entirely supervised. Therefore, results could not be generalised to populations unsupervised or at lower workloads.
* Selection criteria – Participants were excluded if living outside of Madrid, or if not a current hospital patient. Results cannot be generalised to patients outside of these areas.
* Group allocation – Control group displayed several baseline measures higher than the intervention group. The researchers do not state how groups were randomised, if this was done poorly, results may be due to factors other than those manipulated.
* Small sample size – Larger sample sizes may yield different results.
* Stage of disease – Exercise and control groups contained 80% and 90% participants in class I - II, respectively. Results cannot be generalised to more severe patients.
* CTEPH participants – With only two, this could not provide meaningful results for this population.
* Study design – RCT's are highly controlled, and not always accurate in the real world.

## What were the basic results?

Findings included:
* Muscle power and strength – Exercise group increased, control relatively stable
* VO$_{2peak}$ – Exercise group increased, slight decrease in control
* Safety – No significant health or safety events during exercise
* Moderate-vigorous physical activity minutes per day – Both groups decreased
* Minutes inactive per day – Exercise group increased, control decreased
The researchers reinforced improved muscle strength, power, VO$_{2peak}$ , and safety. They acknowledged limitations, including that some physicality tests (such as 6MWD) may have been too simple to elicit results from healthier participants, and that they did not investigate haemodynamics.
They failed to discuss the decreased amount and intensity of daily physical activity that occurred.

## What conclusions can we take from this research?

The combination of exercise appeared to significantly increase VO$_{2peak}$ and muscle strength, particularly lower body, and demonstrated safety of exercise in PAH and inoperable CTEPH patients. Importantly, most participants were in earlier stages of disease, with less affected baseline VO$_{2peak}$ and exercise ability. Points to consider if implementing this advice in real world settings, includes the detrimental effect to inactivity and intensity of physical activity, which warrants further exploration, no significant change in several physical activity variables, and the level of supervision, participant workload and time required.
Numerous other studies, both prior to and after the study, also resoundingly support various combinations of resistance, aerobic and inspiratory training as beneficial and safe for PAH patients. Moderate intensity exercise appears to have gained most support, however, there is still no consensus on ideal type, duration, intensity, and amount of supervision to provide best patient outcomes. There also seems to be some questions as to exactly how exercise benefits PAH patients, which requires further research.

## Practical advice

Exercise appears a beneficial and safe addition to existing treatment in PAH patients, as supported by this study and others. Heavier resistance exercise may be beneficial in re-building muscle strength in higher functioning sufferers, however no exercise guidelines currently exist for this population.
With these considerations, completing any exercise will provide more benefits than no exercise, along with improving quality of life.
The patient should consult with their medical team before commencing a new exercise program, and all exercise programming and supervision should be completed by an appropriately qualified exercise professional.

## Further information/resources

* PAH and Exercise
* Lifestyle Changes For Heart Failure
* More PAH information and support - America and Australia

## References

* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 González-Saiz, L., Fiuza-Luces, C., Sanchis-Gomar, F., Santos-Lozano, A., Quezada-Loaiza, C. A., Flox-Camacho, A., Munguía-Izquierdo, D., Ara, I., Santalla, A., Morán, M., Sanz-Ayan, P., Escribano-Subías, P., & Lucia, A. (2017). Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi+12 trial. International Journal of Cardiology, 231, 277-283. https://doi.org/10.1016/j.ijcard.2016.12.026
* 1 2 3 Genetic & Rare Disease Information Centre. (n.d.). Pulmonary arterial hypertension. Retrieved 03/09/2021 from https://rarediseases.info.nih.gov/diseases/7501/pulmonary-arterial-hypertension
* 1 2 3 4 5 6 Zolty, R. (2020, 2020/10/01/). Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacology & Therapeutics, 214, 107576. https://doi.org/https://doi.org/10.1016/j.pharmthera.2020.107576
* ↑ Beshay, S., Sahay, S., & Humbert, M. (2020, 2020/09/01/). Evaluation and management of pulmonary arterial hypertension. Respiratory Medicine, 171, 106099. https://doi.org/https://doi.org/10.1016/j.rmed.2020.106099
* ↑ Voelkel, N. F., Quaife, R. A., Leinwand, L. A., Barst, R. J., McGoon, M. D., Meldrum, D. R., Dupuis, J., Long, C. S., Rubin, L. J., Smart, F. W., Suzuki, Y. J., Gladwin, M., Denholm, E. M., & Gail, D. B. (2006). Right Ventricular Function and Failure. Circulation, 114(17), 1883-1891. https://doi.org/10.1161/circulationaha.106.632208
* ↑ Genetic & Rare Diseases Information Centre. (n.d.). Chronic thromboembolic pulmonary hypertension. https://rarediseases.info.nih.gov/diseases/13124/chronic-thromboembolic-pulmonary-hypertension
* ↑ Prisco, S. Z., Thenappan, T., & Prins, K. W. (2020, 2020/12/01/). Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. JACC: Basic to Translational Science, 5(12), 1244-1260. https://doi.org/https://doi.org/10.1016/j.jacbts.2020.07.011
* ↑ Hospital 12 de Octubre Research Institute - Quality and Strategic Planning Unit. (2015). Institute Overview. Retrieved 03/09/2021 from https://imas12.es/wp-content/uploads/2018/DocCorpo/i+12%20overview%20ENG.pdf
* 1 2 3 POWERbreathe. (n.d.). POWERbreathe. Retrieved 04/09/2021 from https://www.powerbreathe.com/
* ↑ Linking Education. (n.d.). Real Madrid Graduate School Universidad Europea - TRAIN YOUR DREAMS. Retrieved 04/09/2021 from https://linkingeducation.com/our-partners/real-madrid-graduate-school/
* ↑ Real Madrid. (n.d.). Real Madrid Graduate School-Universidad Europea. Retrieved 04/09/2021 from https://www.realmadrid.com/en/about-real-madrid/club/ue-real-madrid
* 1 2 3 4 Albanaqi, A. L., Rahimi, G. R. M., & Smart, N. A. (2021). Exercise Training for Pulmonary Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Biological Research For Nursing, 23(3), 442-454. https://doi.org/10.1177/1099800420982376
* 1 2 Fox, B. D., Kassirer, M., Weiss, I., Raviv, Y., Peled, N., Shitrit, D., & Kramer, M. R. (2011, 2011/03/01/). Ambulatory Rehabilitation Improves Exercise Capacity in Patients With Pulmonary Hypertension. Journal of Cardiac Failure, 17(3), 196-200. https://doi.org/https://doi.org/10.1016/j.cardfail.2010.10.004
* 1 2 Mereles, D., Ehlken, N., Kreuscher, S., Ghofrani, S., Hoeper, M. M., Halank, M., Meyer, F. J., Karger, G., Buss, J., Juenger, J., Holzapfel, N., Opitz, C., Winkler, J. R., Herth, F. F. J., Wilkens, H., Katus, H. A., Olschewski, H., & GrüNig, E. (2006). Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients With Severe Chronic Pulmonary Hypertension. Circulation, 114(14), 1482-1489. https://doi.org/10.1161/circulationaha.106.618397
* 1 2 3 Kabisch, M., Ruckes, C., Seibert-Grafe, M., & Blettner, M. (2011). Randomized Controlled Trials. Deutsches Aerzteblatt Online. https://doi.org/10.3238/arztebl.2011.0663
* 1 2 3 4 5 6 Arena, R., Lavie, C. J., Borghi-Silva, A., Daugherty, J., Bond, S., Phillips, S. A., & Guazzi, M. (2016, 2016/07/01/). Exercise Training in Group 2 Pulmonary Hypertension: Which Intensity and What Modality. Progress in Cardiovascular Diseases, 59(1), 87-94. https://doi.org/https://doi.org/10.1016/j.pcad.2015.11.005
* ↑ Arena, R. (2011, 2011/05/01/). Exercise Testing and Training in Chronic Lung Disease and Pulmonary Arterial Hypertension. Progress in Cardiovascular Diseases, 53(6), 454-463. https://doi.org/https://doi.org/10.1016/j.pcad.2011.02.003
* 1 2 3 4 Yılmaz, B. C., Güçlü, M. B., Keleş, M. N., Taçoy, G. A., & Çengel, A. (2020, 2020/09/01/). Effects of upper extremity aerobic exercise training on oxygen consumption, exercise capacity, dyspnea and quality of life in patients with pulmonary arterial hypertension. Heart & Lung, 49(5), 564-571. https://doi.org/https://doi.org/10.1016/j.hrtlng.2020.04.006
* ↑ Mereles, D., Ehlken, N., Kreuscher, S., Ghofrani, S., Hoeper, M. M., Halank, M., Meyer, F. J., Karger, G., Buss, J., Juenger, J., Holzapfel, N., Opitz, C., Winkler, J. R., Herth, F. F. J., Wilkens, H., Katus, H. A., Olschewski, H., & GrüNig, E. (2006). Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients With Severe Chronic Pulmonary Hypertension. Circulation, 114(14), 1482-1489. https://doi.org/10.1161/circulationaha.106.618397
* 1 2 3 4 Tran, D., Munoz, P., Lau, E. M. T., Alison, J. A., Brown, M., Zheng, Y., Corkery, P., Wong, K., Lindstrom, S., Celermajer, D. S., Davis, G. M., & Cordina, R. (2021, 2021/03/01/). Inspiratory Muscle Training Improves Inspiratory Muscle Strength and Functional Exercise Capacity in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Randomised Controlled Study. Heart, Lung and Circulation, 30(3), 388-395. https://doi.org/https://doi.org/10.1016/j.hlc.2020.06.006
* 1 2 3 Madonna, R., De Caterina, R., & Geng, Y.-J. (2016, 2016/12/01/). Aerobic exercise-related attenuation of arterial pulmonary hypertension: A right arrow targets the disease? Vascular Pharmacology, 87, 6-9. https://doi.org/https://doi.org/10.1016/j.vph.2016.10.002
* ↑ American Lung Association. (2020). How Pulmonary Arterial Hypertension Is Treated. Retrieved 07/09/2021 from https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/treating-and-managing