The prevalence of ARs for select risk factors varied from 8.3% for the exercise training-induced changes in FI to 13.3% for the changes in HDL-C, with about 7% of participants experiencing adverse changes in two or more risk factors. This subgroup should receive urgent attention. The prevalence of ARs appears to be similar at low and high doses of exercise. However, we do not know whether some adverse responders would revert to a more positive response pattern if exposed to different exercise doses or exercise modalities.
It is important to differentiate between ARs for risk factors for common chronic diseases, as referred to in the present study, from other more acute ARs such as cardiac events related to exertion during an exercise bout 
, sudden cardiac death during or immediately after exercise typically associated with a cardiomyopathy or a congenital abnormality 
, or even exercise intolerance due to abnormal skeletal muscle energy metabolism 
. These events are fortunately rare among physically active people. In contrast, ARs as defined herein for common cardiometabolic and diabetes risk factors are much more prevalent and become evident with exposure to regular exercise. It is not known whether such ARs can be detected after a single or a few bouts of exercise.
Even though the presence of ARs was first detected among completers in Blacks and Whites of the HERITAGE Family Study, in which subjects were confirmed to be sedentary at baseline, with a rather healthy profile, the phenomenon was confirmed in five other exercise intervention studies. The consistency in the prevalence of ARs across heterogeneous studies in terms of health status of subjects at baseline and of exercise training regimen is notable.
One question that may arise is whether ARs are the result of unwarranted exercise-drug interaction effects. The question cannot be answered with direct experimental data at the moment, but based on our analysis of the results of the six studies, it is highly unlikely that it is the case. For instance, HERITAGE and JYVASKYLA subjects were healthy adults taking no medication for high blood pressure, hypercholesterolemia, or hyperglycemia. However, many subjects in DREW, INFLAME, MARYLAND, and STRRIDE were taking medications for high blood pressure, hyperglycemia, or dyslipoproteinemia. Yet substantial numbers of subjects with or without medication in these cohorts experienced one or more ARs.
The challenge is now to investigate whether baseline predictors of ARs can be identified to screen individuals at risk so that they can be offered alternative approaches to modifying cardiometabolic risk factors. Research based on HERITAGE has amply demonstrated that the response pattern to exercise training aggregates in families 
. In fact, the heritability of the changes induced by the exercise program reached about 30% for plasma HDL-C and TG 
and about 20% to 25% for indicators of insulin metabolism and resting SBP 
. There are strong indications from a baseline skeletal muscle gene expression profile and from a genome-wide association study performed on the Whites of HERITAGE that the genetic component of a response trait can be defined in terms of RNA abundance observed in the sedentary state or by specific genomic variants 
. This suggests that it may be possible with further research to identify molecular predictors of the inability to benefit from regular exercise and of adverse changes in specific cardiometabolic and diabetes risk factors.
In summary, we did not find any evidence for differences in the prevalence of ARs between Blacks and Whites or between men and women. Moreover, the AR traits are not explained by prior health status of subjects, age, amount of exercise imposed by the program, or lack of improvement in cardiorespiratory fitness. No evidence could be found for the hypothesis that ARs were the result of drug-exercise interactions. Thus, some individuals experience ARs when exposed to regular exercise, but the causes of the phenomenon are unknown at this time. The observations reported herein need to be extended to other cardiometabolic and diabetes risk factors such as LDL-cholesterol, small, dense LDL particles, markers of low-grade inflammation, adiposity traits, and ectopic fat depots. We conclude that it is critical to search for potential physiological and molecular predictors so that individuals at risk for adverse response patterns can be identified and offered proper guidance in an exercise medicine preventive or therapeutic context.