Low plasma levels of high-density lipoprotein (HDL) cholesterol strongly correlate with increased risk for atherosclerotic cardiovascular diseases. A number of interventions have been shown to increase plasma levels of HDL cholesterol, including exercise, moderate alcohol consumption, and drugs that decrease plasma triglyceride and cholesterol levels. The ability to increase plasma HDL cholesterol levels and to improve its cardioprotective effect is particularly important in patients at high risk and in subjects with active atherosclerotic cardiovascular diseases.

High-density lipoprotein cholesterol is a complex particle composed of a hydrophobic core, which in normolipidemic states is occupied mostly with esterified cholesterol.1 The surface of the HDL particle is populated by multiple proteins that play a critical role in determining the overall cardioprotective effects of the lipoprotein. One such protein is paraoxonase 1 (PON1), an enzyme capable of protecting the HDL particle from oxidative modification, thereby preserving its cardioprotective effects. Both genetic and biochemical studies in animal models and in humans suggest that increased serum PON activity is atheroprotective, decreasing the risk for major adverse cardiovascular events.2,3 Furthermore, in humans, there is a large individual-to-individual variability in serum PON activity that is apparently controlled by genetic as well as environmental factors.4 Therefore, the identification and understanding of mechanisms that modulate the activity of serum PON is of direct relevance to reduction in the risk of atherosclerotic cardiovascular disease, particularly in patients with active coronary heart disease.

In this issue, Goldhammer et al5 reported on the effect of aerobic exercise on serum PON activity in 37 patients, 23 men and 14 women, with coronary artery disease. Patients included in this study suffered a myocardial infarction, subjected to percutaneous coronary intervention or coronary artery bypass surgery 21 to 45 days prior to enrollment. All patients received aspirin, 95% were under statin treatment, 43% received hypoglycemic drugs, and none was treated with fibrates, fish oil, or vitamin supplements. Patients were admitted into a routine cardiac rehabilitation program consisting of 36 sessions of 45 minutes of aerobic exercise over the course of 12 weeks. The main end point was levels of serum PON activity that was determined before and upon completion of the 12-week exercise program. The most important observation in this study was that 12 weeks of aerobic exercise significantly increased serum PON activity by 16.7%, despite no significant changes in plasma HDL cholesterol or triglyceride levels. These findings are highly promising, and suggest that in patients with active coronary heart disease, moderate physical activity in conjunction with other cardioprotective therapies can improve the quality of the HDL particle independent of its cholesterol content. The present findings thus suggest a new potential mechanism through which cardiac rehabilitation and improved cardiovascular fitness decreases the risk for coronary artery disease events through modulation of HDL particle PON activity.

Albeit promising, the interpretation of Goldhammer's findings deserves some caution. It should be noted that the literature on exercise and PON activity in patients with coronary artery disease has not been settled yet. Another study in a cohort of subjects with increased risk for cardiovascular diseases and clinically active coronary artery disease examined the effect of aerobic exercise on serum activity of enzymes involved in oxidative stress.6 This study found no significant effect for exercise on serum PON1 activity and stresses the need for additional studies that will clarify the exercise effect on serum PON activity.

Of particular interest is the dissociation of exercise effect on PON activity and HDL cholesterol level. These findings support the notion that interventions that favorably modify HDL metabolism may do so not only through effects on quantitative measures, such as plasma HDL cholesterol levels, but also through modification of qualitative properties of the HDL particle. The importance of qualitative HDL properties is further supported by experimental and genetic observations. Studies that examined the properties of HDL in patients with coronary artery disease and controls concluded that proinflammatory properties of these particles, such as capacity to attract monocytes, fare better than HDL cholesterol levels in discriminating subjects in the 2 groups.7 Moreover, a role for qualitative HDL properties may gain further support from rare inborn errors in HDL metabolism such as Apo A-I Milano and others mutations in the Apo A-I gene, where decreased plasma HDL cholesterol levels are not associated with increased risk of coronary heart disease.1

As pointed out, the regulation of PON activity is multifactorial and depends on genetic and environmental determinants. Animal studies have shown that PON is linked to antioxidant actions, a mechanism through which its antiatherosclerotic activity is thought to be mediated.8 Conversely, PON1 is also easily inhibited by oxidative processes, perhaps contributing to the large interindividual variability observed in PON levels. Furthermore, polymorphism at the PON1 locus has been shown to associate with serum PON activity, and recent studies emphasized the role of anxiety as a modifier of this activity.3,4 Indeed, and as expected, Goldhammer et al found considerable individual-to-individual differences in PON activity. However, the authors did not provide information on individual variation in activity in response to exercise or the relationship of responsiveness to polymorphism at the PON1 locus. Furthermore, recent studies suggest that PON activity is affected by anxiety, with anxiety state inversely correlated with PON activity.9 These studies may suggest a role for the autonomic nerve system in controlling plasma antioxidative activity.

In summary, the findings in the Goldhammer et al study are encouraging and provide further support to cardiac rehabilitation programs that prescribe aerobic exercise for patients that suffered a recent coronary event and suggest that, among other benefits, exercise may improve qualitative HDL properties such as PON activity. Such findings thus suggest that the functional properties of the HDL particle in high-risk subjects who complete a cardiac rehabilitation program improve. These findings call for larger prospective studies that examine the relationship of successful cardiac rehabilitation and longer-term aerobic exercise programs on both PON activity and cardiovascular outcomes.

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