Cardiorespiratory fitness,a promising modality for treatment and risk prediction

Cardiorespiratory fitness (CRF) is considered an integrated measure of function in multiple systems, including pulmonary ventilation/diffusion, ventricular–arterial coupling, the ability of the vasculature efficiently to transport blood from the heart to the peripheral tissue precisely matching its requirements for oxygen/nutrients with the supply by blood flow, as well as to communicate these metabolic demands to the cardiovascular control centre. ¹ In exercise physiology, CRF is considered one of the best indicators of the athlete’s cardiopulmonary function and aerobic endurance.

CRF can be measured directly as maximal oxygen consumption (VO₂ max, the maximum amount of oxygen that an individual can utilise during intense exercise) or estimated from a symptom-limited exercise test or from non-exercise equations. Although measured VO₂ is more precise, many studies have shown that both measured and estimated CRF strongly predict health outcomes. ¹ Higher CRF and exercise is associated with a favourable risk factor profile, including low blood pressure, less inflammation ² and a desirable lipid profile.^3,4

Given these favourable changes in cardiovascular risk factors associated with CRF and its nature reflecting ‘total body health’, studies have shown that CRF is a strong independent predictor of cardiovascular and all-cause mortality.^5–9 Both genetic and non-genetic factors are thought to determine one’s CRF by about 50% for each. ¹⁰ Thus, one can improve their CRF by training and modifying physical activity. In fact, more than half the reduction in all-cause and cardiovascular disease mortality can occur when moving from the least fit group to the next least fit group. ¹

In this issue of the journal, Ekblom-Bak and colleagues conducted a community-based cross-sectional study on a sample of 678 men and women in Sweden to explore an association between CRF and subclinical coronary atherosclerosis assessed with coronary artery calcium (CAC) scoring by the method of Agatston. ¹¹ CAC is a known robust predictor for coronary disease, other atherosclerotic cardiovascular diseases and death,^12,13 and a CAC score of 100 or greater is a commonly used cut off.^12,14 The authors examined whether the association is statistically independent of sedentary time, moderate to vigorous physical activity (MVPA) and conventional risk factors. They also explored potential effect modification by CRF on the association between the metabolic syndrome (MetS) and CAC.

The main finding of the study was that individuals with higher levels of CRF had lower odds of a CAC score of 100 or greater, and the observed positive association was marginally independent of sedentary time, but further adjustment for MVPA and components of MetS resulted in attenuation to non-significance (seen in Table 2). For secondary objectives (presented in their joint analysis), the significantly elevated odds of a CAC score of 100 or greater was only observed in a low CRF group with MetS (odds ratio (OR) 2.49, 95% confidence interval (CI) 1.23–5.05), but not in a moderate/high CRF group with MetS (OR 1.22, 95% CI 0.53–2.82). As the authors noted in their Discussion section, this observed effect modification by CRF seems to be mediated in part by conventional risk factors because further adjustment for components of MetS and for low-density lipoprotein cholesterol resulted in attenuation in the association (ORs were 2.21 and 1.17 for low CRF with MetS and high/moderate CRF with MetS, respectively). Being consistent with this finding, a larger cross-sectional study in women (n = 5341) reported a similar but more complete attenuation in the association of CRF and CAC after adjustment for conventional risk factors. ¹⁵

However, the possibility remains that CRF carries a true protective effect on atherosclerosis beyond conventional risk factors. For example, some longitudinal studies have shown an independent relationship of CRF at baseline with subsequent subclinical atherosclerosis in coronary ¹⁶ and carotid ¹⁷ arteries. Regardless of the mechanism by which CRF is associated with better health outcomes, mounting evidence has convincingly shown that adding CRF to a traditional risk prediction score, such as the Framingham risk equation, improves its prediction. ¹ To my knowledge, despite being such a powerful predictor, CRF has not been incorporated into cardiovascular risk prediction in any recent guidelines.

In this context, the study by Ekblom-Bak et al., in combination with the current literature, underscores the importance of CRF for primary prevention. The study has confirmed an inverse association of CRF with advanced coronary atherosclerosis defined as a CAC score of 100 or greater. It also suggests a beneficial effect of CRF in preventing cardiovascular diseases even in the presence of MetS. This provides much needed encouragement for the patient with MetS as it gives them the opportunity to intervene in their own prognosis, adding an important piece of evidence to the existing literature. ¹⁸

However, it is worth discussing limitations of the study. First, it did not report on sex-specific results, although the authors reported no evidence of interaction between men-only versus sex-combined results. Given the very low percentage of women in the study with CAC scores of 100 or greater relative to men (2–7% in women vs. 11–29% in men, as seen in Table 1), their results were likely to have been influenced by the men. Second, because of its cross-sectional design, causal inference for the effect of CRF on CAC is difficult to address as discussed by the authors. Third, the predetermined exclusion of obese individuals limits the generalisability of the results. Finally, the authors’ statement that MVPA and CRF ‘should be evaluated and considered separately in future analyses’ is not well supported by the presented data, requiring future investigation. The strengths of the study include the use of highly valid methods in estimating VO₂ max, the use of objectively measured MVPA and sedentary time, and a broad age range of men and women recruited from a community.

In summary, the paper by Ekblom-Bak and colleagues helps us to pay more attention to CRF as a treatment modality for primary prevention of cardiovascular diseases. Much more work is needed better to utilise CRF as a promising preventive treatment as well as a powerful prognostic marker in risk prediction for broad health outcomes including coronary heart disease. The finding that being fit can have health benefits in subjects with the MetS is important. The likelihood that this could include other health conditions is a real possibility that warrants consideration.