High fitness levels attenuate the increased risk of cardiovascular deaths in individuals with high systolic blood pressure

Established risk factors such as high blood pressure, type 2 diabetes (T2D), dyslipidaemia, and smoking explain a large proportion of the risk of cardiovascular disease (CVD), the leading cause of global mortality. Though there is a myriad of data on the relationships between these individual risk factors and cardiovascular outcomes, single risk factor modulation is less effective in preventing the risk of CVD. Effective ways of preventing CVD include simultaneous modulation of these risk factors such as engaging in regular physical activity, consumption of a healthy diet, achieving healthy weights, and avoiding smoking.1 Data on the joint contributions of these risk factors to CVD risk are sparse. Among major modifiable risk factors for CVD, high blood pressure has the strongest evidence of a causal relevance to CVD.2 Though elevated systolic and diastolic pressure each independently predict adverse cardiovascular outcomes, systolic blood pressure (SBP) elevation is known to have a greater effect on major CVD outcomes.3 Cardiorespiratory fitness (CRF), a measure of aerobic exercise capacity, is one of the strongest predictors of all-cause and CVD mortality.4–6 Cardiorespiratory fitness modifies the associations between adverse levels of risk factors and adverse outcomes, and higher levels of CRF have been shown to reduce or even eliminate the risks of these adverse outcomes.7,8 Given the strongly documented relationship between high SBP and increased CVD risk, it would be useful to know if a higher level of CRF could modify or even eliminate this risk. To assess this hypothesis, we evaluated the interplay between SBP, CRF, and CVD mortality risk in a prospective cohort of 2280 middle-aged and older men. We used the Kuopio Ischemic Heart Disease (KIHD) study, an ongoing population-based prospective cohort study that was designed to investigate risk factors for atherosclerotic CVD. The study recruited a general population sample of 2682 men aged 42–61 years who were residents in eastern Finland (see Supplementary material online, S1). The screening and baseline assessments were carried out between March 1984 and December 1989. The protocol (reference #:143/97) was approved by the Research Ethics Committee of the University of Eastern Finland and all study participants provided written informed consent. Resting blood pressure was measured on three occasions between 8:00 and 10:00 a.m. following a supine rest of 5 min using a random-zero sphygmomanometer and the mean of all available measurements was calculated. Cardiorespiratory fitness measured by peak oxygen uptake (VO2peak) was used as a measure of CRF and was directly assessed using gas analysis (Medical Graphics, USA) during a maximal symptom-limited exercise-tolerance test on an electrically braked cycle ergometer.9 We included all CVD mortality cases that occurred from baseline to 2018. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for CVD mortality. In line with guidelines10 and previous reports,5 SBP was categorized as normal and high (<140 and ≥140 mmHg, respectively) and CRF as tertiles. To evaluate the joint associations of SBP and CRF with CVD mortality risk, study participants were grouped into the following: normal SBP–high CRF (reference comparison); normal SBP–low CRF; high SBP–high CRF; and high SBP–low CRF. Additive and multiplicative interactions between SBP and CRF in relation to CVD mortality risk were evaluated. Stata version MP 16 (Stata Corp., College Station) was employed for all analyses. The mean (standard deviation) age, SBP, and CRF for study participants at baseline was 53 (5) years, 134 (17) mmHg, and 30.3 mL/kg/min, respectively (see Supplementary material online, S2). Of the 2280 men who were followed up for a median (IQR) duration of 28.5 (19.1–31.3) years, there were 644 deaths related to CVD. High vs. normal SBP was associated with an increased risk of CVD mortality in analysis adjusted for several established risk factors 1.39 (95% CI: 1.17–1.63) (Figure 1—Model 2). Systolic blood pressure modelled as per 10 mmHg increase was associated with increased CVD mortality risk. Following additional adjustment for Model 2 covariates, the bottom vs. top CRF tertile was associated with an increased risk of CVD mortality 1.74 (95% CI: 1.35–2.23) (Figure 1—Model 2). The HRs were similar after mutual adjustment for each exposure (Figure 1—Model 3). Separate and combined associations of systolic blood pressure and cardiorespiratory fitness with cardiovascular disease mortality. CI, confidence interval; CRF, cardiorespiratory fitness; CVD, cardiovascular disease; HR, hazard ratio; ref, reference; SBP, systolic blood pressure. Model 1: adjusted for age. Model 2: Model 1 plus body mass index, total cholesterol, high-density lipoprotein cholesterol, smoking status, history of Type 2 diabetes, history of coronary heart disease, use of antihypertensive medication, alcohol consumption, physical activity, socioeconomic status, and high sensitivity C-reactive protein. Model 3: Model 2 plus mutual adjustment for each exposure. Men with high SBP–low CRF compared with normal SBP–high CRF had a substantially increased risk of CVD mortality 2.35 (95% CI: 1.81–3.04), with attenuated but persisting evidence of an association between men with high SBP–high CRF and CVD mortality risk 1.55 (95% CI: 1.16–2.07) (Figure 1—Model 2). There was weak evidence of additive and multiplicate interactions as suggested by the following measures and their estimates: relative excess risk due to interaction = 0.04 (95% CI: −0.52, 0.60; P = 0.89), attributable proportion = 0.02 (95% CI: −0.22, 0.25; P = 0.89), synergy index = 1.03 (95% CI: 0.67, 1.58; P = 0.89), and the ratio of HRs = 0.86 (95% CI: 0.56, 1.16). Using the systolic hypertension cut-off of ≥130 mmHg,11 we conducted a subsidiary analysis in which SBP was categorized as low and high (<130 and ≥130 mmHg, respectively). The results were consistent with the main findings (see Supplementary material online, S3). Evaluation of the joint contributions of SBP and CRF to CVD mortality showed a substantially increased risk in men with high SBP and low CRF levels, which was substantially attenuated in men with high SBP and high CRF levels. There was weak evidence suggesting the association between the combination of high SBP and low CRF, and CVD mortality risk exceeded the sum or product of their associations considered separately. High levels of CRF are achieved mainly through increased physical activity and exercise training. The protective effect of high CRF levels on vascular risk is mediated through the effects of increased physical activity. The risk of CVD mortality in men with high SBP was attenuated in the presence of high CRF levels, which is likely due to the strong protective effects of high fitness levels for serious CVD events. Being the first study to evaluate the joint effects of fitness and blood pressure on cardiovascular mortality risk, the findings cannot be directly compared. However, previous studies on the joint effects of CRF and other risk factors, such as socioeconomic status and inflammation, have shown that high levels of fitness eliminate the adverse risk due to these risk factors.7,8 The inability of CRF to completely eliminate the risk of CVD mortality in those with high SBP could partly be due to the strong, independent, and causal relationship between SBP and CVD. Nevertheless, the results suggest that having high fitness levels may reduce the risk of death due to CVD in individuals with high blood pressure. It is well known that regular physical activity and exercise training, the most established ways of increasing levels of CRF, play a major role in the management of high blood pressure;11 regular aerobic exercise has been shown to produce mean reductions in blood pressure of 5–7 mmHg in individuals with hypertension, which translate to a 20–30% reduction in the risk of CVD.12 These findings add to the emerging evidence that achieving and maintaining the highest level of CRF during adulthood is important for lowering the risk of chronic disease outcomes as well as death and the most effective way of doing this is through regular and increased physical activity or exercise training. In addition to the novelty and formal assessment of interactions, other strengths include the relatively large study sample, prospective cohort design, and assessment of CRF using the gold standard of cardiopulmonary exercise testing. Some of the study limitations are the inability to generalize the findings to women and other populations, biases such as residual confounding, reverse causation, and regression dilution bias, and inability to establish cause and effect. In conclusion, high SBP and low CRF levels are each associated with an increased risk of CVD mortality independently of established and emerging risk factors. High CRF levels may attenuate but do not eliminate the increased risk of CVD mortality in individuals with elevated SBP. Large-scale prospective studies are needed to replicate these findings and definitive trials required to provide the highest level of evidence. J.A.L., S.Y.J., S.K., and S.K.K. contributed to the conception and design of the work. All authors contributed to the acquisition, analysis, or interpretation of data for the work. J.A.L. and S.K.K. drafted the manuscript. All authors critically revised the manuscript. All authors have given final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy. Supplementary material is available at European Journal of Preventive Cardiology online. We thank the staff of the Kuopio Research Institute of Exercise Medicine and the Research Institute of Public Health and University of Eastern Finland, Kuopio, Finland, for the data collection in the study. This research was supported by the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. The data underlying this article will be shared on reasonable request to the corresponding author.