Since the seminal studies by Morris et al.1 and Paffenbarger et al.,2 physical activity (PA) has been consistently reported as a protective factor for cardiovascular disease (CVD) and all-cause mortality.3–8 Moreover, PA has been associated with a lower risk of fatal and nonfatal CVD.3,9 It has been estimated that physical inactivity causes 6% of the burden of coronary heart disease, 7% of the burden of diabetes, and 9% of the burden of premature mortality.10 Therefore, the World Health Organization recommends that adults achieve at least 150minutes of moderate-intensity aerobic PA or 75minutes of vigorous-intensity aerobic PA throughout the week, or an equivalent combination of moderate- and vigorous-intensity PA, which approximately corresponds to 600 MET-min/wk or 85 MET-min/d.11 Unfortunately, these recommended levels are not achieved by 24.5% (11.6%-46.5%) of adults in Europe12 and 35% of adults in Spain.13

In the study of the relationship between PA and health, several domains (occupation, household, active commuting, and leisure) and dimensions (type, frequency, duration, and intensity) have been defined.14 The frequency, duration, and intensity of PA practice within each domain are used to estimate the amount of PA. Leisure-time PA (LTPA) is the domain showing the strongest beneficial effects on health.15 Moreover, the intensity and amount of PA could be relevant to defining its health effects. A recent meta-analysis suggested that the relationship between LTPA and mortality is linear,6 but others have reported that the effect of LTPA on mortality or other outcomes follows a nonlinear J-shaped inverse relationship.3,7–9 The pattern of the dose-response relationship and the role of PA intensity are relevant aspects to consider, especially to define adequate recommendations for the general population.

Three prospective cohort studies have analyzed the relationship between LTPA and cardiovascular or mortality outcomes in Spain16–19 but the dose-response relationship, taking into consideration the intensity of PA, has been specifically analyzed only in the PREDIMED cohort, which includes older adults with high vascular risk.19 The aim of this study was to determine the linear and nonlinear dose-response association of LTPA, considering PA intensity, with CVD and all-cause mortality risk in a population-based cohort.

Among 11 158 participants who agreed to participate, 72 were excluded due to duplication of data among the 3 cohorts and 210 due to values of T-LTPA=0. The final study population totalled 10 876 participants. Baseline characteristics of the participants stratified by quartiles of T-LTPA are presented in table 1. The participants with higher amounts of T-LTPA were older, with a higher proportion of men, former smokers, and treatment for diabetes and hypercholesterolemia, compared with those with lower T-LTPA levels. The most common types of PA practiced in our population were: walking (light-intensity LTPA), brisk walking (moderate-intensity LTPA), gardening (moderate-intensity LTPA), walking trails (vigorous-intensity LTPA), climbing stairs (vigorous-intensity LTPA), and sports activities (vigorous-intensity LTPA).

Physical activity and all-cause mortality

After a median of 7.24 [interquartile range 5.89-9.37] years of follow-up, 863 deaths were reported. The generalized additive model showed a significant nonlinear association between T-LTPA and all-cause mortality (figure 1). In the bootstrapping analysis, the best cutpoint to define a change in the linear dose-response association was around 350 to 400 MET-min/d, and we selected the latter as the best cutpoint. Below this threshold and adjusted by confounders, increasing levels of T-LTPA from 0 to 400 MET-min/d had a protective effect on all-cause mortality, with a HR of 0.89 for any increase of 100 MET-min/d and 95% confidence interval (95%CI) of 0.83 to 0.96 (table 2). Higher amounts of T-LTPA (> 400 MET-min/d) did not provide additional benefit (figure 1).

Figure 1.

Predicted relative risk (with 95% confidence limits) of all-cause mortality (A), cardiovascular mortality (B), and total cardiovascular events (C) related to increasing levels of total leisure-time physical activity (MET-min/d). The graph was produced using a generalized additive model with spline smoothing functions and 4 degrees of freedom. MET, metabolic equivalent.

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Table 2.

Hazard ratio (95% confidence interval) of the association between LTPA practice from 0 to 400 MET-min/d and all-cause mortality, CVD mortality, and cardiovascular disease morbidity or mortality. The effect size of the association is expressed for each increase of 100 MET-min/d in LTPA

	Total LTPA	Moderate-to-vigorous LTPA	Light LTPA
Model 1
All-cause mortality*	0.89 (0.83-0.96)	0.84 (0.77-0.91)	1.02 (0.94-1.10)
CVD mortality	0.75 (0.63-0.89)	0.76 (0.63-0.93)	0.85 (0.70-1.03)
CVD mortality + nonfatal CVD event	0.87 (0.77-0.98)	0.89 (0.79-1.01)	0.93 (0.83-1.05)
Model 2
All-cause mortality*	0.90 (0.82-0.98)	0.87 (0.80-0.95)	1.00 (0.92-1.09)
CVD mortality	0.78 (0.64-0.94)	0.80 (0.65-0.99)	0.84 (0.68-1.04)
CVD mortality + nonfatal CVD event	0.91 (0.80-1.03)	0.95 (0.83-1.08)	0.94 (0.83-1.08)

CVD, cardiovascular disease; LTPA, leisure-time physical activity; MET, metabolic equivalent.

Model 1: Adjusted for age, sex and survey

Model 2: Adjusted for age, sex, survey, smoking, high-density cholesterol cholesterol, low-density cholesterol, cholesterol treatment, systolic blood pressure, antihypertensive treatment, glucose, diabetes treatment, body mass index and family history of CVD.

*

In the case of all-cause mortality models 1 and 2 were also adjusted for personal history of CVD.

When our analysis incorporated PA intensity, moderate and vigorous-intensity LTPA showed a protective association with mortality (table 2). Below the 400 MET-min/d threshold, each 100 MET-min/d increase in moderate and vigorous-intensity LTPA was associated with a 16% decrease in all-cause mortality risk (HR, 0.84; 95%CI, 0.77-0.91). The fully-adjusted model showed similar results.

We observed no significant interaction between LTPA and age or sex on mortality.

In this study, we observed a nonlinear relationship between LTPA and cardiovascular events and mortality risk. An inverse linear association was observed between LTPA and these 2 clinical outcomes up to a threshold of 400 MET-min/d, with no further benefit above this amount. Moreover, only moderate and vigorous intensity, but not light-intensity, LTPA was associated with a beneficial effect.

These results concur with current guidelines for adults that recommend at least 150minutes of moderate-intensity or 75minutes of vigorous-intensity aerobic PA throughout the week, or an equivalent combination of the 2 intensities.11 This amount of PA represents an approximate energy expenditure of 600 MET-min/wk or 85 MET-min/d. Guidelines also state that additional health benefits can be obtained if this practice is increased to 300min/wk of moderate-intensity or 150min/wk of vigorous-intensity PA.

The relationship of PA to CVD, events, and mortality has been widely studied in the past. However, the dose-response pattern of this association remains controversial. Cheng et al.6 recently published a systematic review and meta-analysis suggesting that this relationship is linear, yet this affirmation relies on results showing moderate to high heterogeneity between studies. However, other pooled- and meta-analyses have reported a nonlinear association. Arem et al.8 performed a pooled analysis of 6 cohorts including more than 650 000 individuals and reported that meeting the PA recommendations is associated with a significant longevity benefit. They reported an upper threshold for mortality benefit at 3 to 5 times the current PA recommendations, which would be roughly equivalent to 250 to 400 MET-min/d. In a meta-analysis of 33 studies (9 allowing quantitative estimates of PA), Sattelmair et al.9 concluded that individuals engaging in PA equivalent to the recommendations had a 14% lower risk of coronary heart disease, while those engaging in 2 times the recommendations had a 20% lower risk, with modest decreases in risk at higher levels of PA practice. A recent meta-analyses including studies with objective measurement of PA also reports a nonlinear dose-response relationship between PA and all-cause mortality with a maximum benefit around 15 to 20min/d of MVPA.3 When considering the 3 Spanish cohorts in the EPIC-Spain study, Huerta et al.16 included over 38 000 individuals with more than 13 years of follow-up. They found no association between recreational PA and cardiovascular or overall mortality, although a significant inverse association was observed in women when recreational and household activities were considered. In the SUN cohort, Alvarez-Alvarez et al.17 included more than 1000 university alumni with a median follow-up of 10 years. They reported a lower CVD risk among those with LTPA> 750 MET-min/wk (∼100 MET-min/d) and those with a LTPA> 1500 MET-min/wk (HR, 0.77 and 0.75, respectively), although these associations were not statistically significant, probably due to the low number of events.17 The PREDIMED cohort included 7356 older adults with high vascular risk and more than 6 years of follow-up. The authors reported that higher LTPA levels, regardless of intensity (total, light, and moderate-to-vigorous) were associated with lower all-cause mortality, and that this association was nonlinear with a maximum effect around 300 MET-min/d.19

In our study, we observed a nonlinear association with a maximum benefit at around 350 to 400 MET-min/d, with no additional benefit above this point. The inconsistencies between studies in terms of the linear vs nonlinear pattern of the association, and of the different upper threshold definitions, could be explained by several reasons: differences in the length of follow-up (the longer the follow-up the greater the benefit), mean age of participants (greater benefits in younger participants), and mainly the accuracy of the method used to assess PA. The nonlinear association is consistent with the results reported by Elelund et al.,3 Arem et al.,8 and Sattelmair et al.9 We obtained a threshold similar to that reported by Arem et al.8 but higher than that of Sattelmair et al.9 (approximately 200 MET-min/d); however, their analysis only considered coronary heart disease. Moreover, most of these studies used questionnaires to measure PA, and differences in the instruments used could introduce significant heterogeneity between their results.14 Ekelund et al.3 showed that when using objective methods to assess PA the effect size of the association between PA and mortality are about twice as large compared with those reported in studies using self-reported PA.

Regarding PA intensity, our results provide evidence that longevity and cardiovascular benefits are related to moderate- and vigorous-intensity LTPA. This is concordant with current guidelines11 and previous studies.7,8,28 Some studies report that light-intensity PA might also be beneficial.3,4,19,29,30 Saint-Maurice et al.30 suggested that, despite an association between light-intensity PA and reduced mortality, an approximately equal volume of moderate-to-vigorous PA had greater benefits. On the other hand, most of these studies were performed in older individuals. In our previous study in a Spanish population, we reported that light-intensity PA was associated with lower risk of myocardial infarction in persons aged 65 to 74 years but not in the younger population.31 However, we did not observe this association in the present analysis, likely because the outcomes of interest were different. A meta-analysis published in 2019 concludes that, although light-intensity PA could play an important role in improving adult cardiometabolic health and reducing mortality risk, definitive conclusions cannot yet be established.3

This study lends support to the public health relevance of PA contributing to the prevention of CVD and all-cause mortality, even in a European country with a low incidence of diseases of the circulatory system. Furthermore, our results support a nonlinear relationship between moderate-vigorous PA and CVD and all-cause mortality: a large part of the benefits of PA can be obtained with low-moderate levels of practice, with a maximum benefit around 3 to 5 times the current recommendations. This is an important message to encourage the general population to engage in PA practice, supporting the “some is better than none, more is slightly better” approach.

This project was funded by the Carlos III Health Institute–European Regional Development Fund (FIS PI12/00232; FIS PI15/00051, CIBERCV, CIBERESP), and the Government of Catalonia through the Agency for Management of University and Research Grants (PERIS SLT002/16/00088, 2017SGR222). A. Fernández-Sanlés was funded by the Spanish Ministry of Economy and Competitiveness (BES-2014–069718).

No conflict of interest to declare.