We next computed HRs and 95% CIs as measures of the strength of association for CRF and LDL with adjusted CHD mortality (Table 3). HRs of mortality across categories of CRF were 1.0 (referent), 1.18 (0.94–1.47), and 2.10 (1.65–2.67) for high, moderate, and low fit men, P for trend <0.0001. Further adjustment for LDL had little effect on the strength or pattern of the association (data not shown). Adjusted HRs of CHD mortality across incremental categories of LDL were 1.0 (referent), 1.30 (0.87–1.95), 1.54 (1.04–2.28), 2.16 (1.45–3.21), and 2.02 (1.31–3.13), P for trend <0.0001. Further adjustment for CRF had little effect on the strength or pattern of the association (data not shown).
We further regressed CHD mortality rates on CRF and LDL exposures (Fig. 1). As shown, adjusted HRs for mortality were higher across decreasing CRF categories within each LDL category. The lowest risk of mortality was observed in men with moderate and high CRF with LDL values <100 mg·dL−1 (referent), whereas the highest risk was present in men with low CRF and LDL 160–189 mg·dL−1, (HR = 4.74, 2.34–9.61). Although the number of deaths in the lowest LDL category (<100 mg·dL−1) was low (n = 29), the HR for the low CRF category was 2.92-fold higher than for the moderate and high CRF categories. This pattern was similar in the three LDL categories within the range of <100 to 159 mg·dL−1. However, at higher LDL levels, although HRs in the low CRF category remained the highest, HRs in the moderate CRF category were higher than that in the high CRF category. In other words, in the high CRF categories, increasing LDL levels had relatively little effect on HRs for CHD mortality. In the moderate CRF categories, increasing LDL had progressively greater effect on mortality at LDL levels of ≥160 mg·dL−1.
To our knowledge, this is the first article that has examined the joint associations between measures of CRF and LDL with subsequent CHD mortality in men. There was a strong positive trend in adjusted CHD mortality across decreasing CRF categories. Within each LDL category, men with low CRF had higher mortality than men with moderate to high CRF. Importantly, 60.3% of CHD deaths occurred in men with LDL levels below 160 mg·dL−1, and 27.3% of deaths occurred in those with LDL levels below 130 mg·dL−1. Within these LDL categories, a disproportionate number of deaths occurred in men with low CRF. Thus, even with moderate, low, or very low LDL levels, low CRF still carries a relatively high risk for CHD mortality.
An important point to consider when interpreting the joint associations of CRF and LDL with mortality is the method in which CRF was grouped for this analysis. Currently, there is not a widely accepted method of defining CRF levels for use in clinical or public health research. Our group has standardized the definition of low fit (unfit) to the bottom 20% of the age-standardized distribution of maximal exercise duration within the overall cohort; individuals in the remaining 80% of the distribution are considered to be fit (8). These definitions are in accord with the observation in the Cooper Center Longitudinal Study that individuals in the lower 20% of the CRF distribution have disproportionately high all-cause mortality.
Clinical trials with LDL-lowering drugs have shown that even when low LDL levels are present, the likelihood of CHD events depends on the severity of concomitant risk factors, for example, hypertension (4), HDL (5), diabetes (31), and metabolic syndrome (13). The current findings are in accord with this observation; the CRF categories modify risk for each LDL level. However, the HR patterns within each LDL category were not the same. Within each of the three lowest LDL categories, moderate and high CRF provided very similar protection from CHD mortality. However, within the two highest LDL categories, there was a greater attenuation of risk in the high CRF compared with the moderate CRF categories. CRF appears to be an unusually powerful mortality risk predictor. Although the reasons for this risk potency are not fully understood, previous studies in this cohort have shown that individuals in the lowest CRF category carry the highest burden of standard coronary risk factors. In addition, CRF is influenced by habitual physical activity. Multiple studies have shown that CRF can be improved by exercise training (26,27,33), and other reports show that exercise training associates with a lower risk for CHD (12,33).
To qualify for the moderate CRF category, a 50- to 59-yr-old man would need to achieve a maximal MET level of 8.9 or higher. This is equivalent to covering approximately 1.2 miles in the Cooper 12-min run–walk test (11) or achieving a treadmill time of approximately 8.5 min on a standard Bruce treadmill exercise test. This level of CRF can be achieved by many, perhaps even most, apparently healthy men through moderate amounts and intensities of regular physical activity such as brisk walking. The powerful relationship between CRF and CHD mortality observed in this study is unlikely to be explained entirely by differences in habitual physical activity among the groups. Individuals with high CRF likely do exercise regularly, which could contribute to their lower CHD risk. However, differences in mortality between groups at low and moderate CRF levels almost certainly cannot be explained entirely by differences in exercise habits. Several factors other than lack of exercise training have been reported to predispose to a low CRF level. These include total body obesity, upper body obesity, insulin resistance of muscle, cigarette smoking, asthma, and unrecognized CHD (20). Furthermore, Bouchard et al. (9) estimated that genetic factors contribute upward of 50% to the variability in CRF. All these factors could contribute in one way or another to increased CHD mortality in individuals with low CRF.
Among the strengths of the current study are a large and well-characterized cohort of men, an extensive follow-up with a relatively large number of CHD deaths for analysis, and the use of objective measures for CRF, BMI, and blood lipid exposures. We adjusted mortality rates for several confounders including age, examination year, smoking, family history of cardiovascular disease, and BMI. To decrease the likelihood that preexisting subclinical disease was present at baseline, we excluded men with a BMI <18.5 kg·m−2 as well as those with <2 yr of follow-up.
This study also has limitations. The cohort is primarily white and from middle to upper socioeconomic strata; therefore, our findings must be cautiously interpreted when generalized to other populations. However, the homogeneity of sociodemographic factors in our population sample strengthens the internal validity of our findings by reducing potential confounding by these issues. We also point out that the median-estimated V˙O2max for Cooper Center Longitudinal Study men is actually very similar to the values obtained during NHANES, which uses a stratified random sample of the US population. For example, the median-estimated V˙O2max for Cooper Center Longitudinal Study versus NHANES men in the 40- to 49-yr age group is 40.1 and 40.9 mL·kg−1·min−1, respectively, (32). Although we excluded men with <2 yr of follow-up, we cannot completely rule out the possibility that the higher CHD mortality in the lowest CRF category was due in part to subclinical CHD at baseline. We did not have sufficient data for medication use to include in this analysis, which is a potential confounder. A lowering of LDL levels due to drugs could contribute to the lower CHD risk in the lower LDL categories, but LDL-lowering drugs should not have affected the relative risk in each of the three CRF levels in each LDL range. We also did not have more extensive information on smoking habits, such as the number of pack-years. We note that the HR (2.02) for men with LDL ≥190 mg·dL−1 is somewhat lower than expected as compared with the HR (2.16) for men with LDL 160–189 mg·dL−1. We speculate that this may be due to the relatively small sample size in the former group (n = 2574). As the number of men with LDL ≥190 mg·dL−1 increases in our cohort over time, we would obtain a higher level of statistical power.
This study raises the question of whether measurement of CRF should be used in routine cardiovascular risk assessment and risk management. There is a well-accepted principle that for management of risk factors, such as elevated LDL, the intensity of therapy should be adjusted to absolute, not relative, risk (15). Persons with established CHD are known to be at high absolute risk for future coronary events and thus are deserving of intensive LDL-lowering therapy; further risk assessment adds little to form treatment strategies. In individuals without atherosclerotic cardiovascular disease risk, absolute risk is best estimated by multiple risk factor algorithms, such as those of the Framingham Heart Study. However, Gupta et al. (16) recently reported that measuring CRF improved prediction of cardiovascular disease mortality beyond traditional risk factors. Thus, identifying persons with low CRF should allow physicians to raise the absolute risk estimate beyond that predicted by standard risk factor algorithms. Patients who are at low risk by standard risk factors may be good candidates for an LDL-lowering drug if they have both low CRF and LDL cholesterol above 100 mg·dL−1. The JUPITER trial showed the benefit of LDL-lowering therapy in middle-age persons with low LDL levels when their risk was raised by elevation of an inflammatory marker (28). Measurement of CRF may be an additional tool for identifying persons at increased risk.
Available evidence indicates that lifestyle factors such as physical inactivity, obesity, and cigarette smoking contribute to low CRF. This evidence justifies intensive lifestyle intervention, and persons found to have a low level of CRF should achieve further risk reduction beyond LDL lowering.
The authors thank Kenneth H Cooper, MD, MPH, for establishing the Cooper Center Longitudinal Study; William L. Haskell, PhD, for helpful comments and suggestions; and Melba Morrow for editorial assistance.
There is no conflict of interest to declare by any of the authors.
There are no funding sources to declare.
The results of the present study do not constitute endorsement by American College of Sports Medicine.
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Keywords:©2012The American College of Sports Medicine
FITNESS; LDL CHOLESTEROL; CARDIOVASCULAR DISEASE; CHD; JOINT ASSOCIATION