C ARDIORESPIRATORY FITNESS AS A MARKER OF RISK AND DISEASE

Over the last three decades, a wide variety of studies examining the associations between CRF and various health outcomes has been published. In 2009, Kodama et al. summarized the predictive value of CRF on CVD events and all-cause mortality showing, respectively, 15%

and 13% lower risk per one MET higher CRF.¹⁰⁷ Inverse associations have also been shown between CRF and incidence of sub-types of CVD such as CHD, stroke, and heart failure, and other outcomes such as cancer, dementia, and disability.^17,108,109 A few studies have also found associations between changes in CRF and all-cause mortality.^110–114 However, the available evidence has dominantly been based on indirect measures of CRF, as opposed to directly measured VO2peak by ventilatory gas analysis. In fact, at the start of planning this thesis, only a few cohorts had examined associations between VO2peak and future events of CVD and/or mortality in healthy populations, showing inverse associations. One of the cohorts, based on the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), consists of a large sample of 2,682 men who performed direct assessment of VO2peak by cycle ergometry between 1984 and 1989.¹¹⁵ Several interesting studies have emerged from various sub-populations of this cohort on the association between VO2peak and CVD and mortality end-points,109,111,115–117 but the

limited age-span of 42 to 60 years in addition to including only men limits generalizability.

Furthermore, VO2peak was assessed by cycle-ergometry, which known to yield lower values,¹¹⁸ and the cohort is based in an area known for its very high CVD risk.¹¹⁵ Contemporary care may also have changed since the cohort was assembled in the late 1980s. The second cohort, based on The Baltimore Longitudinal Study of Aging (BLSA), measured VO2peak directly during maximal treadmill exercise in 689 participants who were consequently assessed for future events of CHD.¹¹⁹ Although they had a larger age-span then the KIHD cohort (mean 51.6, standard deviation (SD) 16.8) the cohort consisted only of men, and the number of events over a mean 13.4 years of follow-up was only 63. Lastly, a third cohort of 506 male veterans referred for exercise testing reported mortality outcomes based on a dichotomized measure of VO2peak

(over/under 16 mL/kg/min).¹²⁰ In a 2017 review of new evidence on the association between CRF and all-cause and disease-specific mortality since the 2009 meta-analysis by Kodama et al., Harber et al. indeed pointed out the under-representation of women, that many studies were performed on clinical populations referred for exercise testing, and that studies using direct measurement of VO2peak by CPET was lacking.¹⁰⁸

1.5.1. Cardiorespiratory fitness and cardiovascular risk factors

The relationship between cardiovascular risk factors and measures of CRF has been recognized for decades.¹²¹ Furthermore, animal studies performing selective rat breeding by CRF status have suggested that CRF and cardiovascular risk factors share common genetic and molecular pathways,¹²² and genetic studies indicate that genes associated with low CRF are inversely associated with cardiovascular risk factor levels.¹²³ Cross-sectional epidemiological studies have shown how CRF is inversely associated with traditional cardiovascular risk such as systolic and diastolic blood pressure (BP), unfavorable cholesterol levels, triglycerides, resting heart rate, and measures of obesity and glycemic control, both when assessed individually^76,124 and clustered as e.g. the metabolic syndrome or other measures of risk factor clustering.^76,124–

132 Data from the Aerobics Center Longitudinal Study (ACLS) cohort have further shown CRF-dependent trajectories of lipids and lipoproteins¹²⁸ and BP¹³³ across the life-span. Associations between change in CRF and future incidence of unfavorable risk factor states such as hypertension, dyslipidemia, and metabolic syndrome, have been found in several studies,^134–136 including studies using directly measured VO2peak.^137,138 There is also evidence from short-term RCTs showing how high-intensity exercise, producing higher VO2peak increments compared to moderate intensity training,¹³⁹ may yield more beneficial changes in cardiovascular risk factors

long-term randomized exercise trials are challenging, thus long-term effects of changes in exercise habits and CRF are preferably investigated by observational designs. Noteworthily, few thoroughly conducted studies have examined concurrent changes in CRF and changes in various cardiovascular risk factor levels. As summarized in Table 1, only one study used directly measured VO2peak as the measure of CRF, and most studies have a limited age-span and predominantly consist of men.

Table 1. Studies assessing concurrent change in CRF and cardiovascular risk factors.

Population Design Findings

In multiple regression models increase in treadmill time was associated with rise in HDL (high-density lipoprotein), and decrease in total to HDL-cholesterol

ratio and serum uric acid.

Decrease in VO2peak was associated with change in a clustered continuous cardiometabolic risk score and

Those increasing their CRF had a significantly lower constructed continuous metabolic syndrome sum of z-scores compared to those decreasing their CRF in age-and-sex adjusted and multi-adjusted analyses. For the individual components the analyses did not show significant findings besides waist circumference and age, sex baseline and change in percent body fat showed that change in CRF was inversely associated

with change in systolic and diastolic BP, waist circumference, triglycerides, HDL and total cholesterol, but not with change in fasting glucose.

Rhéaume et al. 2011.¹⁴⁶

Change in CRF associated with change in HDL and a metabolic syndrome score after adjustment for visceral

adiposity, age, sex and baseline level of risk factors.

Associations were not significant for BP, insulin resistance, triglycerides, or inflammatory markers.

Changes in CRF was classified into improvement, unchanged, and deteriorated. The increase in BP in the group improving CRF was significantly lower than the other two groups after adjusting for initial BP, CRF, life-style variables and family history of hypertension.

Sternfeld et al. 1999.¹⁴⁸

Modest correlations (Pearson) between change in CRF and change in total cholesterol, HDL, low-density lipoprotein, and triglycerides. In analyses adjusted for

weight partial correlation coefficients only showed significant correlations to HDL.