Dose–response association between moderate to vigorous physical activity and incident morbidity and mortality for individuals with a different cardiovascular health status: A cohort study among 142,493 adults from the Netherlands

Moderate to vigorous physical activity (MVPA) is strongly associated with risk reductions of noncommunicable diseases and mortality. Cardiovascular health status may influence the benefits of MVPA. We compare the association between MVPA and incident major adverse cardiovascular events (MACE) and mortality between healthy individuals, individuals with elevated levels of cardiovascular risk factors (CVRF), and cardiovascular disease (CVD).

Methods and findings
A cohort study was performed in the 3 northern provinces of the Netherlands, in which data were collected between 2006 and 2018, with a median follow-up of 6.8 years (Q25 5.7; Q75 7.9). A total of 142,493 participants of the Lifelines Cohort Study were stratified at baseline as (1) healthy; (2) CVRF; or (3) CVD. Individuals were categorized into “inactive” and 4 quartiles of least (Q1) to most (Q4) active based on self-reported MVPA volumes. Primary outcome was a composite of incident MACE and all-cause mortality during follow-up. Cox regression was used to estimate hazard ratios (HRs), 95% confidence intervals (CIs) and P values.

The main analyses were stratified on baseline health status and adjusted for age, sex, income, education, alcohol consumption, smoking, protein, fat and carbohydrate intake, kidney function, arrhythmias, hypothyroid, lung disease, osteoarthritis, and rheumatoid arthritis. The event rates were 2.2% in healthy individuals (n = 2,485 of n = 112,018), 7.9% in those with CVRF (n = 2,214 of n = 27,982) and 40.9% in those with CVD (n = 1,019 of n = 2,493). No linear association between MVPA and all-cause mortality or MACE was found for healthy individuals (P = 0.36) and individuals with CVRF (P = 0.86), but a linear association was demonstrated for individuals with CVD (P = 0.04). Adjusted HRs in healthy individuals were 0.81 (95% CI 0.64 to 1.02, P = 0.07), 0.71 (95% CI 0.56 to 0.89, P = 0.004), 0.72 (95% CI 0.57 to 0.91, P = 0.006), and 0.76 (95% CI 0.60 to 0.96, P = 0.02) for MVPA Q1 to Q4, respectively, compared to inactive individuals. In individuals with CVRF, HRs were 0.69 (95% CI 0.57 to 0.82, P < 0.001), 0.66 (95% CI 0.55 to 0.80, P < 0.001), 0.64 (95% CI 0.53 to 0.77, P < 0.001), and 0.69 (95% CI 0.57 to 0.84, P < 0.001) for MVPA Q1 to Q4, respectively, compared to inactive individuals.

Finally, HRs for MVPA Q1 to Q4 compared to inactive individuals were 0.80 (95% CI 0.62 to 1.03, P = 0.09), 0.82 (95% CI 0.63 to 1.06, P = 0.13), 0.74 (95% CI 0.57 to 0.95, P = 0.02), and 0.70 (95% CI 0.53 to 0.93, P = 0.01) in CVD patients. Leisure MVPA was associated with the most health benefits, nonleisure MVPA with little health benefits, and occupational MVPA with no health benefits. Study limitations include its observational nature, self-report data about MVPA, and potentially residual confounding despite extensive adjustment for lifestyle risk factors and health-related factors.

Conclusions
MVPA is beneficial for reducing adverse outcomes, but the shape of the association depends on cardiovascular health status. A curvilinear association was found in healthy and CVRF individuals with a steep risk reduction at low to moderate MVPA volumes and benefits plateauing at high(er) MVPA volumes. CVD patients demonstrated a linear association, suggesting a constant reduction of risk with higher volumes of MVPA. Therefore, individuals with CVDs should be encouraged that “more is better” regarding MVPA. These findings may help to optimize exercise prescription to gain maximal benefits of a physically active lifestyle.

Author summary
Why was this study done?
There is debate to whether cardiovascular health status affects the dose–response association between physical activity (PA) and health outcomes.
Studies among cardiovascular diseases (CVDs) patients found different associations between PA and mortality reductions, which were described as linear, J shaped, or U shaped.
Recent studies suggested that the cardiovascular health benefits or risk of death of PA may be domain specific as different outcomes were reported for leisure versus occupational PA.
What did the researchers do and find?
A cohort study (median follow-up 6.8 years) was performed comparing the association between moderate to vigorous physical activity (MVPA) and incident major adverse cardiovascular events (MACE) and all-cause mortality between healthy individuals (n = 112,018), individuals with cardiovascular risk factors (CVRF) (n = 27,982), and CVD (n = 2,493).
The shape of dose–response association between MVPA and cardiovascular events and death is curvilinear for healthy individuals and those with CVRF, whereas a linear relationship was found in individuals with CVDs.
The association between MVPA and the risk of CVD or mortality is domain specific as leisure activities were associated with the most benefits, nonleisure activities with little benefits, and occupational activities with no benefits.


What do these findings mean?
MVPA is associated with risk reductions in all groups, but, especially, CVD patients should be encouraged that “more is better” regarding PA.
PA recommendations could be optimized by taking cardiovascular health status and the domain of MVPA into account.

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