Understanding Exercise Intolerance And Low Fitness Levels

By Hugo Francisco de SouzaReviewed by Benedette Cuffari, M.Sc.

What Is Exercise Tolerance?
Physiological Basis Of Exercise Tolerance
Causes Of Reduced Exercise Tolerance
Exercise Testing and Clinical Assessment 
Improving Exercise Tolerance
Clinical Significance
References
Further Reading

Exercise tolerance captures how efficiently the body delivers and utilizes oxygen during physical activity, making it a powerful indicator of functional capacity, disease burden, and response to rehabilitation. Its decline reflects complex, multisystem impairments, while improvements signal meaningful gains in physiological resilience and long-term health.

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Exercise tolerance, which is the ability to sustain physical activity, is influenced by cardiovascular, pulmonary, and metabolic function. It is increasingly recognized as an integrative measure of whole-body physiological function, reflecting the coordinated performance of cardiac output, pulmonary gas exchange, and skeletal muscle metabolism. Reduced exercise tolerance can indicate underlying disease, emphasizing the importance of accurate assessment and a clear understanding of the various physiological factors that determine functional capacity.¹

What Is Exercise Tolerance?

Exercise tolerance is defined as an individual’s physiological ability to perform physical activity, irrespective of its perceived or measured intensity. Conversely, impaired exercise tolerance is characterized by the onset of significant breathlessness or fatigue. Some studies have found that this condition is strongly associated with poor quality of life (QoL) outcomes and increased mortality risk.¹

Exercise tolerance can be monitored using objective metrics such as peak oxygen consumption (VO_2Peak), which is the highest rate of oxygen uptake attained during exercise. VO_2Peak is widely considered the gold standard for cardiorespiratory fitness and, as a result, is clinically used as an integrative marker of ventilatory efficiency and circulatory reserve. Importantly, incremental increases in VO_2Peak are associated with significant reductions in all-cause mortality and adverse cardiovascular outcomes in heart failure populations.²

Reduced exercise tolerance is directly related to an increased risk of all-cause mortality, cardiovascular mortality, and hospitalization across diverse patient populations. Consequently, exercise tolerance is increasingly used as a prognostic indicator in patients, with public health guidelines emphasizing that functional capacity assessment is essential for determining eligibility for advanced treatments and risk stratification.⁴

Physiological Basis Of Exercise Tolerance

Exercise tolerance is determined by the continuous delivery of oxygen to the mitochondria and its subsequent utilization for adenosine triphosphate (ATP) production. The efficiency of this process depends on the cardiovascular system's ability to increase cardiac output through altering stroke volume and heart rate. In addition to central hemodynamics, peripheral factors such as skeletal muscle perfusion, mitochondrial density, and oxidative enzyme activity play a critical role in determining exercise capacity. Both the extraction capacity, which reflects the peripheral oxygen exchange by working muscles, and the efficiency of the pulmonary system for gas exchange similarly predict exercise tolerance.¹

Physiological limitation patterns are primarily identified by analyzing the patient’s ventilatory efficiency (VE/VCO₂) slope and anaerobic threshold. Among healthy individuals, the ventilatory threshold, which reflects the point at which minute ventilation increases disproportionately to VO₂, typically occurs between 45 % and 65 % of VO_2peak. Elevated VE/VCO₂ slope values are indicative of ventilatory inefficiency and are strongly associated with worse prognosis in heart failure populations.^1,2

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Causes Of Reduced Exercise Tolerance

Among patients with heart failure, reduced tolerance is due to impaired cardiac reserve, as the heart cannot increase its output to meet the metabolic demands of the activity. This leads to chronotropic incompetence, in which an individual’s heart rate fails to increase sufficiently due to a blunted response to adrenaline.¹

In patients diagnosed with heart failure with preserved ejection fraction (HFpEF), diastolic dysfunction and high filling pressures contribute to pulmonary congestion, further exacerbating shortness of breath. Exercise intolerance in heart failure is multifactorial and also involves abnormalities in pulmonary function, vascular regulation, and skeletal muscle metabolism.¹

Moreover, pulmonary disorders like chronic obstructive pulmonary disease (COPD) are often implicated in ventilation-perfusion (V/Q) mismatch and dynamic hyperinflation that traps air in the lungs. Herein, exercise-induced hyperinflation flattens the diaphragm and increases the metabolic exertion of breathing.⁵

In metabolic conditions such as type 2 diabetes (T2DM), reduced activity of rate-limiting enzymes like citrate synthase and cyclooxygenase II (COX-II) contributes to metabolic inflexibility and impaired mitochondrial oxidative capacity. Exercise training has been shown to significantly improve mitochondrial oxidative capacity and antioxidant defenses in patients with T2DM. Post-viral conditions like long-coronavirus disease (COVID) are similarly characterized by a significant reduction in patients’ functional capacity, with rehabilitation interventions demonstrating meaningful short-term improvements in exercise capacity (e.g., increases in 6MWT distance exceeding 100 meters).^6,7

Exercise Testing and Clinical Assessment 

Cardiopulmonary exercise testing (CPET) is considered the gold standard for clinically establishing exercise tolerance limits in both patients and athletes. CPET provides an integrated assessment of cardiovascular, pulmonary, and metabolic responses to exercise through breath-by-breath analysis. CEPT comprises a holistic evaluation of cardiopulmonary health by analyzing gas exchange data breath-by-breath, focusing on VO_2max, the ventilatory threshold, and respiratory exchange ratio (RER).¹

In clinical populations where a traditional VO₂ plateau is rarely observed due to suboptimal cardiovascular fitness, a verification phase is used to confirm that a true maximal effort was achieved. Evidence indicates that verification phase protocols produce comparable VO₂ values to CPET, supporting their validity in confirming maximal oxygen uptake in clinical populations.⁸

When maximal effort measurements are not required, CPET is often substituted with the six-minute walk test (6MWT), which quantifies the distance that an individual can walk at a comfortable pace in six minutes. A 6MWT distance of less than 300 meters, which is often observed in HF patients, has been validated as an independent predictor of increased mortality and correlates with advanced symptom stages.^1,7

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Improving Exercise Tolerance

Historically, high-intensity interval training (HIIT) is considered superior to moderate continuous training (MCT) for achieving optimal exercise tolerance gains. Nevertheless, comparisons between these modalities have not identified a significant difference in functional outcomes for HFpEF patients, suggesting that HIIT and MCT are effectively interchangeable.⁹

In the context of coronary artery disease, HIIT has shown superior gains in VO_2peak compared to MCT. Peripheral adaptations are primarily responsible for these improvements, as endurance training stimulates mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and increasing mitochondrial fusion markers.^6,9

In clinical populations with severe respiratory limitations, specialized modalities like eccentric aerobic exercise (ECC) are employed. ECC, which involves muscle lengthening modalities such as walking down a hill, effectively improves metabolic strength and ventilatory outcomes. By imposing four to five times less strain on the heart and lungs than concentric exercises, ECC significantly mitigates breathlessness and reduces heart rate by an average of approximately 14 beats per minute.⁵

Clinical Significance

In a systematic review of 20.9 million observations, individuals with high cardiorespiratory fitness were 53 % less likely of all-cause mortality as compared to those with low fitness. These benefits are dose-dependent, with every 1-MET increase in fitness reducing the risk of death and heart failure by 11-17 % and 18 %, respectively.³

Modern medicine posits reduced exercise tolerance as one of the strongest independent predictors of adverse clinical outcomes, including premature mortality. Accordingly, improving exercise capacity is a central therapeutic target across cardiovascular, pulmonary, and metabolic diseases. Importantly, improvements in exercise tolerance are directly associated with reduced healthcare utilization and improved systemic health trajectories.³

References

1. Del Buono, M. G., Arena, R., Borlaug, B. A., et al. (2019). Exercise Intolerance in Patients With Heart Failure. Journal of the American College of Cardiology 73(17); 2209-2225. DOI: 10.1016/j.jacc.2019.01.072. https://www.jacc.org/doi/10.1016/j.jacc.2019.01.072
2. Prokopidis, K., Irlik, K., Piasnik, J., et al. (2025). Prognostic Impact of Peak Oxygen Consumption in Heart Failure: A Systematic Review and Meta-Analysis. ESC Heart Failure 12(5); 3624-3642. DOI: 10.1002/ehf2.15391. https://academic.oup.com/eschf/article/12/5/3624/8488241
3. Lang, J. J., Prince, S. A., Merucci, K., et al. (2024). Cardiorespiratory fitness is a strong and consistent predictor of morbidity and mortality among adults: an overview of meta-analyses representing over 20.9 million observations from 199 unique cohort studies. British Journal of Sports Medicine 58(10); 556-566. DOI: 10.1136/bjsports-2023-107849. https://bjsm.bmj.com/content/58/10/556
4. Heidenreich, P. A., Bozkurt, B., Aguilar, D., et al. (2022). 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145(18). DOI: 10.1161/cir.0000000000001063. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063
5. Magunagoikoetxea-Comins, G., Jiménez- García, M., Pérez-Ferreiro, M., & Fernandez-Pardo, T. (2025). Effects on Exercise Tolerance and Functional Outcomes of Eccentric versus Concentric Aerobic Exercise in People with COPD: A Systematic Review and Meta-Analysis. International Journal of Chronic Obstructive Pulmonary Disease 20; 4061-4078. DOI: 10.2147/copd.s558167. https://www.dovepress.com/effects-on-exercise-tolerance-and-functional-outcomes-of-eccentric-ver-peer-reviewed-fulltext-article-COPD
6. Zhu, W., Zhou, Z., Sun, J., & Si, J. (2025). Effects of exercise training on skeletal muscle mitochondrial outcomes in type 2 diabetes: a systematic review and meta-analysis. Frontiers in Physiology 16. DOI: 10.3389/fphys.2025.1671926. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2025.1671926/full
7. Chakraverty, S., et al. (2026). Rehabilitation in Long COVID: A Systematic Review and Meta-Analysis. ERJ Open Research, 00133–02026. DOI – 10.1183/23120541.00133-2026. https://publications.ersnet.org/content/erjor/early/2026/02/26/2312054100133-2026
8. Costa, V. A. B., Midgley, A. W., Baumgart, J. K., et al. (2024). Confirming the attainment of maximal oxygen uptake within special and clinical groups: A systematic review and meta-analysis of cardiopulmonary exercise test and verification phase protocols. PLOS ONE 19(3); e0299563. DOI: 10.1371/journal.pone.0299563. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299563
9. Li, H., Liu, Y., Liu, Y., et al. (2025). Impact of exercise training on exercise tolerance, cardiac function and quality of life in individuals with heart failure and preserved ejection fraction: a systematic review and meta-analysis. BMC Cardiovascular Disorders 25(1). DOI: 10.1186/s12872-025-04649-0. https://link.springer.com/article/10.1186/s12872-025-04649-0
10. Carlier, M., & Delevoye-Turrell, Y. (2017). Tolerance to exercise intensity modulates pleasure when exercising in music: The upsides of acoustic energy for High Tolerant individuals. PLOS ONE 12(3); e0170383. DOI: 10.1371/journal.pone.0170383. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170383

Further Reading

• All Exercise Content
• How Tabata Training Improves VO2 Max and Cardio Fitness
• Exerkines Explained: The Exercise Molecules That Prevent Chronic Disease
• How to Safely Return to Exercise After Prolonged Physical Inactivity
• Where Did 10,000 Steps a Day Come From?

Last Updated: May 4, 2026