Effects of exercise on lipoproteins and hemostatic factors

INTRODUCTION — Regular physical activity is important for the primary and secondary prevention of coronary heart disease (CHD). Although the mechanisms by which physical activity protects against CHD are not fully understood, the benefits may be mediated, in part, by the favorable influence of aerobic exercise on plasma lipoproteins and hemostatic factors. This topic will review the influence of exercise on lipoproteins and hemostatic risk factors. Other effects of exercise on cardiovascular disease prevention are discussed elsewhere. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

INFLUENCE OF EXERCISE ON LIPIDS AND LIPOPROTEINS — Early cross-sectional studies comparing middle-aged male runners with sedentary men suggested a beneficial effect of exercise on lipoproteins [1,2]. The runners had significantly lower serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides, as well as a higher concentration of high-density lipoprotein (HDL) cholesterol. Subsequent studies have confirmed the benefits of exercise on lipids and lipoproteins, including among older adults [3-8]. However, it remains uncertain as to whether an increase in HDL cholesterol level and/or functional HDL measures due to exercise or other interventions necessarily results in a decrease in cardiovascular disease risk. This is discussed in detail elsewhere. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'Effect of increasing HDL cholesterol on clinical outcome'.)

Baseline lipid levels — Exercise may be particularly helpful in persons with low HDL cholesterol and elevated triglycerides [9,10]. For example, in the Health, Risk Factors, Exercise Training, and Genetics (Heritage) Family Study, which characterized 200 men on the basis of baseline triglyceride and HDL cholesterol concentrations and enrolled them in a 20-week endurance exercise program [9], men with high triglyceride/low HDL cholesterol profiles had the greatest HDL cholesterol raising effect from exercise (4.9 percent) compared with men with normal levels and men with isolated low HDL cholesterol.

Intensity of exercise — Exercise intensity has an effect on expected changes to lipoproteins.

STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) was a trial that investigated the effects of exercise amount and intensity on serum lipoproteins in overweight and obese adults with mild to moderate dyslipidemia. Study participants were randomized to a control group or one of three exercise groups that included high-amount, high-intensity exercise, defined as the equivalent of jogging 20 miles per week at 65 to 80 percent of peak oxygen consumption; low-amount, high-intensity exercise, which was the equivalent of jogging 12 miles at 65 to 80 percent of peak oxygen consumption; and low-amount, moderate exercise, which was the equivalent of walking 12 miles per week at 40 to 55 percent of peak oxygen consumption. After eight months, the high amount of high-intensity exercise group had higher levels of HDL cholesterol and large HDL particle concentration than the control group or other exercise regimens. These data support that recommendations designed to increase HDL require high amounts of high-intensity exercise performed over many months [11]. The STRRIDE-PD trial (in individuals with prediabetes) investigated the effects of exercise on HDL cholesterol efflux in 106 volunteers with prediabetes [12]. High amounts of high-intensity exercise increased global radiolabeled efflux capacity by 6.2 percent when compared with the other STRRIDE-PD groups. However, exercise had no effect on BODIPY-labeled cholesterol efflux.

In a small randomized study of the effects of eight weeks of moderate-intensity exercise in patients with known CHD, the exercise group had a significant reduction in triglyceride level and an increase in HDL cholesterol compared with the sedentary control group. The change in triglyceride was associated with an increase in apoC3, a key triglyceride modulating factor. No change in LDL cholesterol was observed with exercise [13]. Similar results were observed in a community-based exercise intervention program in 131 obese adults with metabolic syndrome. After six months of aerobic exercise, the intervention group had a significant increase in HDL cholesterol, as well as lower waist circumference and blood pressure [14].

Amount of exercise — Some studies show the magnitude of the beneficial effect of exercise on lipoproteins is related to the amount and frequency of exercise rather than the intensity of exercise or level of fitness achieved [6,15-20]. This concept is supported in a study that randomly assigned 149 men and 120 postmenopausal women to one of three exercise programs for two years [6]:

●High-intensity (73 to 85 percent peak heart rate), group-based; there were three 40-minute sessions per week

●High-intensity, home-based

●Low-intensity (60 to 73 percent peak heart rate), home-based; there were five 30-minute sessions per week

Serum HDL cholesterol did not change at one year but showed a small but significant increase above baseline at two years in subjects in the two home-based programs. Over half (51.7 percent) of participants in the low-intensity, home-based group had an increase in HDL cholesterol of greater than 5 mg/dL compared with a third or less in the high-intensity home-based and group-based groups (35.2 and 32.0 percent, respectively). The elevation in HDL cholesterol was more pronounced in the low-intensity program, suggesting that increased frequency of exercise may be important and that maximum increase in fitness (as seen with high-intensity exercise) is not required.

Results from one of the best-performed prospective studies in which 111 sedentary, overweight adults with mild to moderate dyslipidemia were randomly assigned to one of four groups are described below [11]:

●High-amount, high-intensity exercise for eight months, the caloric equivalent of jogging 20 miles (32 km) per week at 65 to 80 percent of peak oxygen consumption

●Low-amount, high-intensity exercise for eight months, the caloric equivalent of jogging 12 miles (19.2 km) per week at 65 to 80 percent of peak oxygen consumption

●Low-amount, moderate-intensity exercise for eight months, the equivalent of walking 12 miles (19.2 km) per week at 40 to 55 percent of peak oxygen consumption

●Control group

Compared with controls, all exercising groups had potentially beneficial changes in plasma lipoproteins, including a decrease in VLDL, triglycerides, and an increase in the size of LDL particles. An increase in HDL cholesterol and HDL particle size, and the largest effects on LDL, were seen only with high-amount, high-intensity exercise.

Similarly, exercise intensity had a greater effect on lipids in a study in obese adolescent females. Twelve weeks of high-intensity interval training was superior to continuous moderate-intensity exercise for improving lipid levels, specifically triglycerides and total cholesterol, as well as waist circumference [21].

Non-weightbearing exercise — Some patients may not be able to participate in weightbearing exercise due to obesity or orthopedic problems. Some studies have evaluated the effect of aquatic exercise or cycling on lipids.

In a meta-analysis of 10 trials, participants randomized to regular aquatic endurance exercise showed improvement in lipid and lipoprotein levels compared with those not exercising [22].

In a study of 116 sedentary older women, those randomized to swimming had reduced total and LDL cholesterol at 12 months compared with those randomized to walking [23].

An observational study of 9768 participants investigated the association between various forms of leisure-time physical activity and cardiometabolic outcomes in the Singapore Multi-Ethnic Cohort [24]. Running and strength exercises were associated with lower triglycerides, whereas cycling, dancing, running, strength and fitness were associated with higher HDL cholesterol.

Independence from weight loss — The beneficial effect of exercise on lipoproteins is not related to weight loss [11,15]. A meta-analysis of 19 randomized trials among 984 participants found that aerobic exercise resulted in an 11 percent increase in HDL2 cholesterol, independent of weight loss [25].

Interplay of diet and physical activity — Some studies [26,27] have found that exercise training produces different results on the lipoprotein profiles in males and females. As an example, one study randomly assigned 132 men and 132 women to diet only (step 1 American Heart Association diet), diet plus exercise, and a control condition [26]. Exercise consisted of brisk walking and jogging three days per week for 25 to 45 minutes at 60 to 80 percent of maximum heart rate. After one year, the following findings were observed:

●Males and females in both intervention groups lost weight (primarily fat). However, weight loss by diet alone did not change serum HDL cholesterol compared with controls.

●In men, serum HDL cholesterol, HDL2 cholesterol, and apolipoprotein (apo) A-1 concentrations increased significantly more with diet plus exercise group than in the other two groups (+13 versus +2 and -4 percent with diet alone or control).

●In women, a Step 1 National Cholesterol Education Program (NCEP) diet (low cholesterol, low saturated fat) alone was associated with reductions in serum HDL cholesterol (-10 percent), HDL2 cholesterol, and apo A-1. When exercise was added, the decrease in HDL cholesterol was no longer evident and was not statistically different from controls.

●Serum triglyceride concentrations decreased in the combined intervention groups, whereas the LDL/HDL cholesterol ratio, total cholesterol, LDL cholesterol, and apo B levels were reduced in both intervention groups.

Another study of 180 postmenopausal women and 197 men who were randomized to exercise (brisk walking for one hour three days per week), a step 2 diet, diet plus exercise, or control found that after one year, there was no change in HDL cholesterol in either sex in any study group [27]. There was no change in total or LDL cholesterol in the diet only group; however, compared with controls, there was a significant reduction in total and LDL cholesterol levels in the diet plus exercise group. These data underscore the importance of diet and physical activity in the treatment of elevated LDL cholesterol.

High-density lipoprotein function — HDL function has emerged as an important consideration in evaluating the effects of interventions on HDL [28]. The major functional atheroprotective properties include participation in macrophage cholesterol efflux and reverse cholesterol transport, protection against oxidative modification of LDL and inflammatory responses in the arterial wall, mitigation of apoptosis, and protection against infections [28,29].

HDL particles remove excess cholesterol from peripheral sites and return it to the liver for further processing. Although observational studies have repeatedly shown an inverse relationship between HDL cholesterol and coronary heart disease (CHD) events, genetic studies have failed to demonstrate a link between elevated HDL cholesterol and lower risk of cardiovascular disease, and clinical trials of drug therapies that raise HDL cholesterol failed to show a clinical benefit. Therefore, researchers have turned their attention to the complexity of HDL particles, specifically their quality as opposed to quantity, and HDL’s ability to serve as a shuttle for removing excess cholesterol from lipid-laden macrophages within peripheral tissues. However, the anti-atherogenic functionality of HDL is altered by inflammation and other markers of cardiovascular disease risk.

In a study of 22 obese men with the metabolic syndrome, pre- and posttreatment effects of diet and exercise were evaluated at three weeks. Following exercise, the intervention reduced lipid peroxides and improved the antioxidant effect of HDL as measured by platelet-activating factor acetyl hydrolyase activity [30].

A 2011 study evaluated the early effects of exercise training on HDL cholesterol levels and HDL functional characteristics in a small group of sedentary patients with metabolic syndrome (MS) versus those without MS [31]. Following three months of moderate-intensity bicycle exercise, the MS group had lower triglycerides but no change in LDL or HDL cholesterol levels. However, an increase in the HDL’s subfraction oxidative capacity and paraoxonase 1 activity increased following exercise training. Further, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL. The study demonstrates a dissociation between the level of HDL cholesterol and qualitative changes after short-term exercise training in MS patients, thus highlighting the need to explore the functionality of HDL in addition to the level of HDL.

Genetic variability — Exercise training produces characteristic changes in lipids in most, but not all, people, which may be partially due to genetic factors. As an example, apo E variants may modify the response to exercise based on genotype. Apo E facilitates triglyceride clearance by mediating the binding of VLDL and intermediate-density lipoproteins to hepatic receptors. A study of response to exercise training in 120 individuals selected to equally represent the three most common apo E variants (E2/3, E3/3, and E3/4) found trends toward different lipoprotein responses to exercise among the various subgroups [32]. A subsequent study examined the effects of apo E genotype on the response of lipoprotein subclass concentrations to six months of exercise. Results showed that apo E variants influenced the LDL subpopulation response to exercise, and subjects homozygous for apo E3 experienced the most beneficial lipoprotein effects from exercise training [33]. Exercise also produced different HDL subfraction patterns based on genetic variation at the apo A-1 gene promoter [34]. Apo A-1 is the major apolipoprotein associated with HDL cholesterol.

The variable effect of exercise on HDL cholesterol is partly impacted by certain HDL-regulating polymorphisms. In a prospective cohort study of 22,939 healthy United States women of European ancestry, a genome-wide association examined the effect modification of physical activity with HDL cholesterol levels [35]. Per-minor-allele increases in HDL cholesterol among active versus inactive women were observed in carriers of rs1800588 in LIPC, rs1532624 in CETP, and rs10096633 at LPL. Further, a reduced risk of myocardial infarction was associated with minor-allele carrier status at the LPL single nucleotide polymorphism (SNP; hazard ratio [HR] 0.51; 95% CI 0.30-0.86) but not among inactive women (HR 1.13; 95% CI 0.79-1.61; p-interaction = 0.007). No associations between carrier status in LIPC and CETP SNPs and myocardial infarction risk was noted. Protection from myocardial infarction associated with higher plasma levels of HDL cholesterol may depend both on variation in the genetic determinants of those levels and healthy behaviors.

Exercise for secondary prevention — Exercise training programs produce favorable changes in the lipoprotein profile in patients who already have CHD. A meta-analysis of 10 randomized trials (n = 1260) found that aerobic exercise in patients with cardiovascular disease increased HDL cholesterol by 9 percent and decreased triglycerides by 11 percent [36]. No significant changes occurred in total cholesterol or LDL cholesterol, and no relationship was observed between changes in lipoproteins and body weight.

One study evaluated the long-term benefits of exercise rehabilitation on lipoproteins in 553 males and 166 females with CHD [37]. After one year, all participants had a significant increase in serum HDL cholesterol; however, serum HDL cholesterol continued to increase over five years only in females. Serum total cholesterol and LDL cholesterol decreased significantly more in females, while no sex difference was observed for serum triglycerides. Other studies have also suggested that females have a greater increase in HDL cholesterol in response to exercise than males [38]. Females often begin cardiac rehabilitation programs at lower estimated metabolic equivalents (METS) and a higher percent body fat compared with males. Therefore, they may have potential for greater benefit from exercise. The usual cardiac rehabilitation exercise intervention is three days per week, 30 to 45 minutes in duration, at 70 to 80 percent maximum heart rate or Vo₂max, for 12 to 29 weeks. (See "Cardiac rehabilitation programs".)

Potential mechanisms of benefit — The mechanisms by which aerobic exercise has a favorable impact on the lipoprotein profile are not fully understood; however, some information has come from the measurement of enzymes involved in lipoprotein metabolic pathways. Exercise increases lipoprotein lipase activity and reduces hepatic lipase activity [2,39-41]. The elevation in lipoprotein lipase activity suggests that enhanced lipolysis of triglyceride-rich lipoproteins may be an initial step in higher serum levels of HDL cholesterol (see "HDL cholesterol: Clinical aspects of abnormal values", section on 'Inherited causes'). Furthermore, hepatic lipase catalyzes the conversion of the larger HDL2 particles to the smaller HDL3 particles; reduced hepatic lipase with exercise may lead to slower catabolism of HDL2, which may be more cardioprotective.

Exercise is also associated with a reduction in the serum cholesteryl ester transfer protein (CETP) concentration [42] and an elevation in the serum lecithin cholesterol acyltransferase (LCAT) concentration [43].

●CETP catalyzes the net flux of cholesterol from HDL cholesterol to VLDL cholesterol and LDL cholesterol. Basal CETP concentrations have been shown to correlate negatively with HDL cholesterol after exercise training [42].

●LCAT catalyzes the esterification of cholesterol located on the particle surface; cholesterol is subsequently displaced to the core, which is the initial event in the conversion of HDL3 to the cholesterol-rich HDL2 particles.

Exercise training also may have a modest effect on serum LDL cholesterol. Studies have evaluated the influence of exercise on the chemical composition of LDL. Smaller and more dense LDL particles tend to be more atherogenic than the larger, more buoyant LDL subfraction [44] (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia"). Although calculated serum LDL cholesterol levels are usually unchanged after exercise, LDL peak particle diameter increases [45], consistent with improved insulin sensitivity, and changes in the chemical composition of LDL (increased LDL free cholesterol, cholesterol ester, and phospholipid content) are associated with decreased adiposity, abdominal girth, and plasma insulin and glucose concentrations [44].

INFLUENCE OF EXERCISE ON HEMOSTATIC FACTORS — Hemostatic factors play important roles in the pathogenesis and progression of cardiovascular disease. Endogenous fibrinolytic status is considered a biomarker for future cardiovascular risk [46]. Tests of endogenous fibrinolysis include plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA), thrombin activatable fibrinolysis inhibitor (TAFI), complement C3, D-dimer, and lipoprotein (a). Other hemostatic biomarkers include platelets, high levels of plasma fibrinogen, and increased blood viscosity. Impaired endogenous fibrinolysis has been shown to identify individuals at increased cardiovascular risk in case-control studies; however, these studies have been criticized by selection bias, reverse causality, and presumptions about the level of the hemostatic factor prior to the cardiovascular event [46]. The effects of exercise on these and other hemostatic risk factors have been evaluated in several studies. However, although exercise is associated with improvements in several hemostatic factors, it has not been definitively established that improvements in these parameters are the mechanism by which exercise confers a lowered risk of cardiovascular disease.

The following effects have been noted:

●Moderate-intensity exercise for eight weeks in men reduced resting and postexercise platelet adhesion and aggregation compared with controls; return to pretraining values occurred after 12 weeks of deconditioning [47].

●In a cross-sectional study of physically active and sedentary postmenopausal women, Vo₂max was 83 percent higher, and PAI-1 activity and t-PA antigen were significantly lower in the physically active women; plasma fibrinogen levels were the same in both groups [48].

●In a study of the effect of walking exercise on platelet function in sedentary older adults, monocyte platelet aggregates (MPAs) increased in the no-exercise group, while there was a minimal decrease in the walking group. However, the change in MPAs was significant between groups [49].

●A large-scale observational study of 3522 subjects found an inverse association between self-reported leisure-time physical activity and plasma viscosity [50]. However, in another report, a 10-week program of moderate-intensity aerobic exercise did not alter whole blood viscosity in patients with coronary heart disease (CHD) [51].

●A small study found that men with intermittent claudication who underwent a six-month exercise program experienced significant improvements in fibrinolytic activity, while no change was seen in matched controls [52]. However, ankle-brachial indices did not improve with exercise, although walking ability did improve.

●In 15 male cyclists, short-duration, high-intensity exercise increased tissue factor, tissue factor pathway inhibitor, thrombin-antithrombin complexes, and D-dimer. Further, a time-of-day effect was observed for preexercise tissue factor, peaking at 08:30 AM [53]. Markers of coagulation and fibrinolysis have been observed to possess circadian variation peaking in the morning. Although aerobic exercise improves hemostatic factors associated with thrombosis in several studies, high-intensity exercise may result in a transient shift toward a hypercoagulable state, presumably from acute dehydration. Therefore, clinicians should be cautious in recommending high-intensity, short-duration exercise during the morning hours in populations predisposed to hypercoagulability.

SUMMARY

●Exercise training programs produce favorable changes in the lipoprotein profile, including in patients who already have coronary heart disease (CHD). Most studies have shown a significant increase in serum high-density lipoprotein (HDL) cholesterol and a decrease in serum triglycerides. Exercise training also may have a modest lowering effect on serum low-density lipoprotein (LDL) cholesterol. (See 'Influence of exercise on lipids and lipoproteins' above and 'Exercise for secondary prevention' above.)

●Exercise has variable effects based on the amount and intensity, and there is some genetic variability in response to exercise. (See 'Intensity of exercise' above and 'Amount of exercise' above and 'Genetic variability' above.)

●The beneficial effect of exercise on lipoproteins appears to be unrelated to weight loss. (See 'Independence from weight loss' above.)

●Non-weightbearing exercise is also beneficial. (See 'Non-weightbearing exercise' above.)

●There are many potential mechanisms of benefit; however, these are not well understood. Exercise training may influence the functionality of lipoproteins as well as the levels of lipoproteins. (See 'Potential mechanisms of benefit' above.)

●Exercise may alter hemostatic risk factors by reducing the risk of acute thrombus formation, improving blood viscosity, and positively influencing rate of progression of atherosclerotic lesions. (See 'Influence of exercise on hemostatic factors' above.)