Exercise Testing and Coronary Disease: Pushing Fitness to Higher Peaks

Sanjay Sharma; Aneil Malhotra


Eur Heart J. 2019;40(20):1640-1642. 

Participation in regular physical activity is associated with a lower incidence of cardiovascular (CV) deaths compared with the sedentary population. Such benefits also apply to individuals with established risk factors for atherosclerotic CV disease,[1] including those with markedly increased coronary artery calcium scores.[2] Although cardiorespiratory fitness (CRF) has a genetic component, it is a surrogate marker of habitual physical activity. Improving CRF through increased physical activity accrued from general day to day activities, or from a concerted effort to exercise regularly, attenuates acquired risk factors for atherosclerosis such as obesity, metabolic syndrome, hypertension, and hyperlipidaemia. Additionally, regular exercise produces several beneficial effects on autonomic profile, systemic vasculature, skeletal muscle, inflammatory markers, and hormonal profile, to mention a few; therefore, it is not a surprising independent predictor of CV mortality, all-cause mortality, and, possibly, longevity of life.[3]

Traditional measures of CRF have relied on estimation of metabolic equivalents (METS) from subjective reports of physical activity or from conventional treadmill or bicycle tests.[1,4] Few studies have used simultaneous cardiopulmonary gas exchange measurements to determine peak oxygen consumption (pVO2), which is considered the 'gold standard' for assessing CRF. Existing studies utilizing pVO2 were conducted in relatively small cohorts, or estimated pVO2 from anthropometric data.[3]

In this issue of the European Heart Journal, Letnes and colleagues[5] report the association between pVO2 and fatal and non-fatal coronary heart disease (CHD) in a subset population of 4527 healthy Norwegian adults who were enrolled in the larger Nord-Trondelag Health Study (HUNT3).[6] Participants were aged 48.2 ± 13.5 years, and 51% were female. All participants were reportedly free from CV or respiratory disease, cancer, and hypertension. The vast majority (83.5%) had a low 10-year risk of CV disease at baseline. The mean VO2 peak values were 44.4 and 36.0 mL/kg/min (12.7 and 10.3 METS, respectively) for men and women, respectively (Figure 1), and 80% achieved the maximal predicted oxygen consumption for age and size, indicating that this was a considerably fitter cohort compared with a previous study[1] that investigated the relationship between CRF and CHD. Over a follow-up period of 8.8 years, 147 (3.2%) subjects reached the primary endpoint of a diagnosis of CHD, coronary revascularization, or death from CHD. There was an overall 15% lower risk of meeting the primary endpoint per one MET higher pVO2 after adjusting for sex, and a 16% lower risk per one MET when additionally adjusted for established risk factors. This figure is very similar to other studies investigating older individuals with a higher burden of CV risk factors and lower CRF.[1] In this study, women showed a slightly attenuated effect, presumably because they were similar in age yet develop clinical CHD ~10 years later than men. Furthermore, a larger proportion of women had a low 10-year risk profile (94.3% vs. 72.3%) and fewer achieved primary endpoints (105 vs. 42) compared with men. Between the highest and lowest quartile of pVO2, there was a 48% lower risk of a fatal or non-fatal CHD event. Other cardiopulmonary gas exchange parameters such as oxygen pulse and ventilatory equivalents of oxygen and carbon dioxide also demonstrated significance in predicting the primary endpoint. The authors conclude that even among a healthy, low-risk population, pVO2 was inversely associated with CHD.

Figure 1.

The impact of cardiorespiratory fitness in healthy middle-aged men and women. CHD, coronary heart disease; MET, metabolic equivalent.

The investigators studied a relatively large subset of fit healthy individuals, and CRF was determined with pVO2 which is recognized as the most accurate objective marker of fitness. During a follow-up of 40 000 person-years, data pertaining to primary endpoints were obtained from mandatory national registries, which strengthens the validity of the results. Furthermore, 51% of the cohort were women, in whom there is a paucity of population-based data. Whereas previous studies have focused on individuals achieving ≤12 METS, we estimated (from the authors' Supplementary table S2) that ~60% of men and 50% of women in this study achieved >12 METS and >10 METS, respectively. Indeed, within the highest quartile, men achieved 17–21.5 METS and women achieved 13.8–19 METS.

Previous studies in participants with recognized atherosclerotic risk factors have revealed a 12–20% reduction in CV events per one MET achieved, with an ongoing inverse relationship up to 12 METS. This study adds to the current literature by demonstrating a similar benefit in an ostensibly healthy population with an incremental benefit that continues beyond 12 METS and suggests that there is no obvious upper threshold for the cardioprotective effects of exercise.[7]

Although the number of subjects is laudable, there are several points to note. Only a third of eligible low-risk participants volunteered for and completed the cardiopulmonary exercise stress test; hence, there is an unavoidable but inherent selection bias towards those who were motivated to attend for functional cardiac assessment and who were arguably more aware of lifestyle measures to mitigate CV disease.

The cohort consisted of a relatively young healthy population with a low 10-year CV event risk; therefore, a follow-up period of 8.8 years is modest. These factors may partly explain the low incidence of the primary endpoint. Despite the authors postulating that their findings support several biological mechanisms through which CRF affects multiple organ systems, this study did not demonstrate any difference between pVO2 and all-cause mortality. Apart from the young age of the population, we believe that a highly selected low-risk population without overt features of cardiac and respiratory disease is the most likely explanation for this lack of association. Based on the pVO2 values provided (Supplementary table S2), a considerable proportion of participants in their seventh and eight decades would have achieved much higher than predicted values for age, demonstrating an overall healthy cohort with a lower than expected all-cause mortality during the follow-up period.

A very recent study enrolled >5000 Danish males of a similar age to this cohort and followed them up for 46 years.[3] During this period, 4700 (92%) men died (42% from CV disease). Men with high-normal or above normal estimated pVO2 values lived 2.9 years and 4.9 years longer, respectively, compared with men with below normal pVO2 values, and this effect was consistent for CV deaths and all-cause mortality. These results suggest that early benefits of CRF noted by Letnes and colleagues are likely to persist into the sixth, seventh, eighth, and ninth decades if CRF is maintained.

Letnes and colleagues largely reinforce what is known already. Cardiorespiratory fitness is inversely related to CHD, even among a healthy population. This holds true whether physical activity is determined through systematic health questionnaires, conventional exercise tests, or using pVO2, and is applicable to both sexes and individuals with established risk factors and subclinical CV disease. The additional benefit of adding peak VO2 to standard risk stratification scores in this population was slight, but we suspect that a larger study with longer follow-up would have provided a stronger predictive value. Nevertheless, in an era where primary prevention is playing an increasingly significant role in society, this study helps highlight that improving CRF is a pivotal factor in reducing CV risk and mortality. Regular physical activity and measures of CRF should be incorporated into clinical practice and CV risk models. All individuals should be encouraged to exercise to the minimal level recommended by the European guidelines for disease prevention,[8] although the observations of Letnes and colleagues and several others suggest that substantially higher physical activity levels and CRF provide additional prognostic benefit.[9] For those who are compromised due to co-morbidities or functional status, there is overwhelming evidence that some physical activity is better than none.