Higher cardiorespiratory fitness may mitigate increased heart failure risk in men with elevated systolic blood pressure: a prospective cohort study

Heart failure (HF), a clinical syndrome which was designated as a new epidemic in 1997, is associated with substantial morbidity and mortality and has a considerable impact on health economies.1 With HF being the end-stage manifestation of most forms of cardiovascular disease (CVD), established cardiovascular risk factors such as hypertension, diabetes, smoking, hyperlipidaemia, and physical inactivity play a major role in its aetiogenesis.1 Recent experimental evidence has shown that the coexistence of three common comorbidities (diabetes, hypercholesterolemia, and hypertension) triggers a cascade of events including systemic inflammation, oxidative stress, and myocardial stiffening, resulting in left ventricular diastolic dysfunction and ultimately HF.2 Population-based data on the joint contributions of modifiable risk factors to HF risk are limited. Elevated high blood pressure (BP) or hypertension (defined as systolic and/or diastolic hypertension) has the strongest evidence of a causal relevance to CVD among major cardiovascular risk factors.3 Systolic BP (SBP) is more commonly considered in the determination of cardiovascular risk, as elevated SBP has been documented to have a greater impact on adverse cardiovascular outcomes than elevated diastolic BP.4 Genetically predicted elevated SBP has been shown to be associated with increased HF risk.5 Regular physical activity (PA) or exercise training is documented to reduce the risk of vascular diseases including HF.6 Cardiorespiratory fitness (CRF), a physiological measure of whole-body physical function largely and influenced by PA behaviours, is a robust predictor of adverse vascular outcomes including HF.7,8 Cardiorespiratory fitness has been proposed as a vital sign due to its stronger association with adverse vascular outcomes compared with traditional risk factors such as Type 2 diabetes (T2D) and smoking;7 accumulating evidence shows the potential of higher CRF levels to substantially attenuate or offset the adverse effects of other risk factors.9–11 Taking the overall evidence together, we hypothesized that higher CRF levels would favourably impact (attenuate or mitigate) on the relationship between elevated SBP and increased HF risk. In this context, we aimed to evaluate the interplay between SBP, CRF, and HF risk. This analysis employed the ongoing Kuopio Ischemic Heart Disease (KIHD) risk factor study, a prospective cohort study comprising a general population sample of men aged 42–61 years recruited from Eastern Finland.9 Screening and baseline assessments were performed from March 1984 to December 1989. The research protocol was approved by the Research Ethics Committee of the University of Eastern Finland; all participants provided written informed consent. Resting BP 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; the mean of all available measurements was estimated. Cardiorespiratory fitness was assessed using peak oxygen uptake, which was directly assessed using gas exchange analyses (Medical Graphics, USA) during a maximal symptom-limited exercise-tolerance test on an electrically braked cycle ergometer.12 The diagnostic classification of HF cases was based on ICD-10 codes.12 We excluded men with a prevalent history of HF, and all incident HF events that occurred from study entry through to 2018 were included. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) with 95% CIs for HF. Systolic BP was categorized as normal and high (<140 and ≥140 mmHg, respectively) and CRF into lower and higher levels, to maintain consistency with BP guidelines and previous reports.9–11 Evaluation of the joint contribution of SBP and CRF to HF risk was based on the following four exposure groups: normal SBP–higher CRF (reference comparison), normal SBP–lower CRF, high SBP–higher CRF, and high SBP–lower CRF. All statistical analysis employed Stata version MP 16 (Stata Corp, College Station). The analysis was based on 1831 men with no prevalent history of HF, who had complete information on SBP, CRF, HF outcomes and relevant confounders (see Supplementary material online, Material S1). Their mean ± standard deviation (SD) age, SBP, and CRF at baseline were 52 ± 5 years, 134 ± 16 mmHg, and 30.8 ± 7.9 mL/kg/min, respectively. After a median (interquartile range) follow-up duration of 27.3 (18.6, 31.2) years, 364 HF events were recorded. High vs. normal SBP was associated with an increased risk of HF in age-adjusted analysis (HR 1.76: 95% CI, 1.43–2.17) (Figure 1, Model 1), which was attenuated to (HR 1.43: 95% CI, 1.14–1.81) following further adjustment for total cholesterol, high-density lipoprotein cholesterol, body mass index, heart rate, smoking status, prevalent hypertension, T2D and coronary heart disease, socioeconomic status, and PA (Figure 1, Model 2). The association remained when SBP was modelled as per 10 mmHg increase. Following adjustment for the covariates in Models 1 and 2, respectively, lower vs. higher CRF was associated with an increased risk of HF: (HR 2.03: 95% CI, 1.63–2.52) and (HR 1.38: 95% CI, 1.09–1.75) (Figure 1, Models 1 and 2). The association remained when CRF was modelled as per 1 SD decrease. The HRs remained similar when SBP was further adjusted for CRF and CRF further adjusted for SBP (Figure 1, Model 3). Separate and combined associations of systolic blood pressure and cardiorespiratory fitness with HF. CI, confidence interval; CRF, cardiorespiratory fitness; HF, heart failure; HR, hazard ratio; ref, reference; SBP, systolic blood pressure. Model 1: adjusted for age; Model 2: Model 1 plus total cholesterol, high-density lipoprotein cholesterol, body mass index, heart rate, smoking status, prevalent hypertension, Type 2 diabetes and coronary heart disease, socioeconomic status, and physical activity; Model 3: Model 2 plus mutual adjustment for each exposure. Men with high SBP-lower CRF compared with normal SBP-higher CRF had an increased risk of HF (HR 2.00: 95% CI, 1.43–2.79), with no evidence of an association between men with high SBP-higher CRF and HF risk (HR 1.34: 95% CI, 0.93–1.94) (Figure 1, Model 2). The per cent attenuation in the HR from 2.00 to 1.34 was 66%. There was weak evidence of additive and multiplicative interactions as suggested by the following estimates: relative excess risk due to interaction = 0.33 (95% CI: −0.29, 0.95; P = 0.30), attributable proportion = 0.16 (95% CI: −0.13, 0.46; P = 0.28), synergy index = 1.49 (95% CI: 0.62, 3.59; P = 0.38), and the ratio of HRs = 1.12 (95% CI: 0.62, 1.62; P = 0.25). Using a SBP cut-off of ≥130 mmHg, high vs. normal SBP was not significantly associated with HF risk in multivariable analysis 1.10 (95% CI, 0.87–1.38). We have confirmed the independent associations of elevated SBP (using the cut-off of 140 mmHg) and lower CRF levels with an increased HF risk. New findings based on the joint contribution of SBP and CRF showed the risk of HF was two-fold higher in men who had high SBP and lower CRF levels compared with men with normal SBP and higher CRF; however, this risk was offset in men with high SBP and higher CRF levels. On the assumption that the increased risk of HF persisted in men with high SBP and higher CRF levels (given a HR of 1.34), the per cent attenuation in risk is still substantially high at 66%. Interaction analysis showed some evidence that the association between the combined exposures (i.e. high SBP and lower CRF) and HF risk exceeded the sum as well as the product of their individual associations. Given that CRF is mainly influenced through regular PA and/or exercise training apart from genetic factors,7 the potential preventive roles of higher CRF on HF risk are likely via the effects of PA and exercise training. These include (i) beneficial modulation of cardiovascular risk factors such as hypertension, obesity, and coronary artery disease; (ii) improving cardiac, pulmonary, renal, and vascular performance; (iii) and preventing adverse changes in cardiac structure and function.13 Long-standing elevated BP causes structural and functional changes in the heart, subsequently leading to HF. These new findings emphasize the strong protective effects of higher fitness levels and its ability to attenuate or eliminate the adverse effects of other risk factors. There is a continual need to achieve or maintain higher levels of CRF during adulthood to prevent or delay the progression of HF and other adverse outcomes. The most established way of doing this is via regular PA and/or exercise training. Though the intensity, frequency, and/or duration of PA needed to achieve certain levels of CRF are not clear, evidence suggests that middle-aged individuals who meet guideline recommendations for moderate intensity PA are more likely to achieve at least moderate levels of CRF;14 guideline recommendations for moderate intensity PA is currently 150–300 min per week.15 For populations that are unable to meet recommended PA levels because of their busy lifestyles, a weekend warrior PA pattern (guideline recommended PA patterns concentrated in one or two sessions per week) may be a potential option.16 For individuals or population groups with exercise limitations, it has been suggested that nutrition and medical therapies may play a potential role in increasing levels of CRF.17 The strengths of this evaluation include the use of a prospective cohort design based on a relatively large general population-based sample with long follow-up, comprehensive analysis including exploration for interactive effects and the use of an objective gold-standard measure of CRF. The limitations were inherent to the study design, which included the (i) inability to generalize the findings beyond middle-aged and older Finnish men, (ii) inability to assess the differential impact of the exposures on the risk of HF with preserved vs. reduced ejection fractions because these data were not available, and (iii) known biases of observational studies such as reverse causation, residual confounding, and regression dilution. There is an interplay between SBP, CRF, and risk of HF. The risk of HF is two-fold higher in men who have high SBP and lower CRF levels compared with men with normal SBP and higher CRF; however, this risk is offset in men with high SBP and higher CRF levels. 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. S.K.K. and J.A.L. contributed to the conception and design of the work. S.K.K. and J.A.L. contributed to the acquisition, analysis, or interpretation of data for the work. S.K.K. drafted the manuscript. S.K.K. and J.A.L. critically revised the manuscript. S.K.K. and J.A.L. gave final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy. S.K.K. is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and Leicester NIHR Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR, or the Department of Health and Social Care. J.A.L. is 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.