PHYSICAL ACTIVITY AND NONTRADITIONAL CHD RISK FACTORS:

New Pathways for Primordial Prevention of Coronary Heart Disease

Abstract

Coronary heart disease (CHD) has gained recognition as being preventable through primary or secondary interventions.

Scientific advancements over the years have led to a better understanding of the pathogenesis and clinical

manifestations of this disease process, and as a result, have led to the identification of a host of traditional and

nontraditional factors for use in CHD risk assessment. In addition to traditional and nontraditional factors associated

with increased risk, the cardiovascular benefits of physical activity (PA) have been well established and extend well

beyond relationships with these conventional CHD risk factors. In recent years, substantial data from observational

cohort and exercise training studies, as well as from randomized controlled trials, support that the existence of

cardioprotective effects of PA or planned exercise may be mediated by several nontraditional CHD risk predictors.

These include markers of inflammation and thrombosis, autonomic nervous system (ANS) regulation, and endothelial

function. The purpose of this review is to discuss the epidemiological and experimental evidence for the role that PA

has in modifying these new, up-and-coming clinical determinants of CHD risk. The frequency, duration, and intensity

of exercise used in these studies generally are consistent with the consensus recommendations for cardiovascular

benefits in apparently healthy and clinical populations. Available data are not

clear as to whether PA-related improvements in these emerging risk predictors

represent a different pathway for prevention of clinical CHD events. Future

research studies should examine whether different PA-related pathways for

cardiovascular health exist and define the impact that PA and planned exercise

has on these pathways.

Introduction

Coronary heart disease (CHD) has a lengthy incubation period during which

biological risk factors interact with genetic and environmental influences to

initiate and promote atherosclerotic plaque development, endothelial cell

dysfunction, and arterial stenosis. Eventually these events precipitate clinical

manifestations of angina, myocardial infarction, and sudden death.1,2 Current

CHD prevention is based on a “high-risk” framework wherein risk factor

thresholds guide the initiation and intensity of clinical interventions.3

Advancements in the clinical management of biological risk factors have

afforded considerable progress in the prevention of initial (primary

prevention) and recurrent (secondary prevention) clinical CHD events.4

Primordial prevention is a less often used term and refers to modifying the

primal or earliest contributors of disease occurrence (Figure 1).4,5 Only a

small proportion of individuals will express clinical CHD because of genetic

predisposition.6 For most individuals the principal determinant is their

lifestyle.7,8 Thus, primordial prevention of CHD requires elimination of the

environmental and lifestyle origins of atherosclerotic risk factors rather than

simply treating risk factors that have exceeded a clinical threshold.5 In this

regard, physical activity (PA) has been recognized as a central element in

primordial CHD prevention.4

Series 6, No. 4 Dec. 2005

Published quarterly by the

President’s Council on

Physical Fitness and Sports

Washington, D.C.

★

Guest Authors:

Radim Jurca, Ph.D.,

Michael J. LaMonte, Ph.D.

Division of Epidemiology

The Cooper Institute

J. Larry Durstine, Ph.D.

Department of Exercise Science

Arnold School of Public Health

University of South Carolina

★

Co-edited by:

Dr. Deborah Young, University of

Maryland, Dr. Robert P. Pangrazi,

Arizona State University, and

Dr. Barbara Ainsworth,

San Diego State University

President’s Council on Physical Fitness and Sports

ResearchDi est
Higher levels of PA are associated with favorable CHD

risk factor profiles.9 Observational studies support an

inverse dose-response association between PA and

CHD events that is independent of traditional CHD risk

factors (e.g., smoking, hypertension, dyslipidemia, etc).10

Recent advancements in understanding the pathogenesis

of CHD have identified a host of new potential CHD

risk predictors.2,11 Whether these nontraditional risk

markers are intermediate in the causal pathway

between PA and CHD is not well understood, but there

may be additional pathways through which PA exerts

primordial CHD prevention. 

Two previous papers in the Research Digest focused on

the cardioprotective aspects of PA. Haskell broadly

reviewed the quality and strength of existing evidence

supporting physical activity for primary and secondary

CHD prevention,12 and more recently, Bassuk and

Manson provided a review on physical activity and

cardiovascular disease prevention in women.13 Here,

we will expand on these previous works by discussing

epidemiological and experimental evidence of the role

that physical activity has in modifying new and

emerging clinical determinants of CHD risk. In order to

achieve this objective our focus is specifically on three

aspects of atherogenesis for which the influence of PA

has recently been evaluated: (1) inflammation and

thrombosis, (2) autonomic nervous system dysfunction,

and (3) endothelial dysfunction and vascular

conductivity. 

Inflammation and Thrombosis

Inflammation plays a key role in the initiation,

progression and thrombotic manifestations of CHD.2,14

Observational studies on apparently healthy cohorts of

women and men show that several inflammatory

markers, including C-reactive protein (CRP),

fibrinogen, white-blood cell count (WBC), and

numerous cytokines (e.g., IL-1, IL-6, TNF-alpha), are

associated with increased risk of CHD events, and are

independent of most CHD risk factors.15

The relationship of inflammatory markers with selfreported PA levels or measures of cardiorespiratory

2

Primordial Prevention

Primary Prevention

Secondary Prevention

Physical Inactivity, Poor Diet, Smoking, Alcohol Intake, Social Stress, etc.

Traditional Nontraditional

2nd event

1st event

•Sudden cardiac death

•Heart attack

•Stroke

•Angina

•Coronary Artery Calcium

•Left ventricular hypertrophy

•Systolic/diastic dysfunction

•Carotid intima media thickness

•Hypertension

•Diabetes

•Dyslipidemia

•Obesity

•C-reactive protein

•Fibrinogen

•White blood cells

•Cytokines

•Endothelial dysfunction

•Autonomic dysfunction

Environment

GeneticsOrigins

Risk Factors

Subclinical Disease

Clinical Events

Figure 1
independent of biological factors and three selected

CRP genotypes.27 A study of 199 Japanese women

(mean age 52±10 years; 54% postmenopausal) who

completed 8 weeks of moderate intensity aerobic

exercise training for 110-140 minutes per week had

reductions of 35% and 8% in mean CRP and WBC,

respectively (P<0.001 each). These changes were

independent of changes in insulin sensitivity and

weight loss.28 Exercise training also has been related to

reductions in inflammatory markers in patients with

clinically manifest CHD. Milani et al.29 reported a 41%

reduction in the median CRP concentration (P<0.01) in

235 patients (mean age 67±11 years; 29% women)

following 3 months of Phase II rehabilitation that

included 3 days per week of aerobic exercise at 70-85%

peak heart rate. Reductions in plasma CRP remained

significant even when patients were grouped on lipidlowering drug use and weight loss characteristics. 

Reductions in CRP following exercise training provide

compelling evidence of an anti-inflammatory effect

from regular moderate intensity PA. However, the

above-reported studies were not randomized controlled

trials, thus caution is required when interpreting and

generalizing the reported findings. The US Diabetes

Prevention Program recently reported 1-year changes in

CRP and fibrinogen in 3,234 adults with impaired

glucose tolerance following randomization to a lifestyle

intervention (physical activity, diet modification, weight

loss), metformin (an insulin-sensitizing drug), or a

control group.30 A 2% reduction in mean fibrinogen

concentrations was seen in the lifestyle group (P<0.01

with placebo and metformin groups). CRP was reduced

by 30% in the lifestyle group (P<0.001 with placebo

and metformin groups), though partial correlations

suggested that weight loss was more influential in

lowering CRP than was increased physical activity. 

Autonomic nervous system dysfunction

Through its parasympathetic and sympathetic divisions,

the autonomic nervous system (ANS) supplies both

afferent and efferent nerves to the heart and circulatory

system. Thus, the ANS is a major component in

cardiovascular regulation. Defects in many reflex

control mechanisms are often associated with manifest

signs of CHD such as increased peripheral vascular

resistance, reduced cardiac parasympathetic control,

altered baroreceptor function, and reduced sympathetic

activity in response to variety of stimuli.31-34 Clinical

assessment of ANS function is difficult, and as a result,

ANS parameters have not been routinely used in

individual CHD risk assessment. 

fitness (CRF) has recently been examined in large

observational cohorts. Significant inverse associations

with PA and CRF are reported for CRP, fibrinogen and

WBC in middle-aged16-19 and older20,21 individuals.

These associations generally have a dose-response

gradient and are independent of age, sex, race,

medication usage, and CHD risk factors including

smoking and body mass index (BMI). Hormone

replacement therapy also is associated with higher

levels of CRP in women.22 However, available data

suggest that the inverse relationship between CRP and

PA or CRF is independent of hormone replacement

therapy.23-25 Most studies adequately address issues

pertaining to acute illness, smoking, and exercise at the

time of the baseline blood collection, use appropriate

statistical methods for the typically skewed distribution

of CRP, and exclude excessively high CRP

concentrations (e.g., >10 mg/L) from the analysis.

Although cross-sectional data suggest an antiinflammatory effect of regular PA, such analyses are

not sufficient for establishing causal relationships.

Observational data on changes in PA and related

changes in inflammatory markers provide more

convincing evidence of cause and effect. A recent 20-year

follow-up study of 3,810 British men 40-59 years old

indicated that changes in reported leisure-time PA were

associated with changes in CRP, fibrinogen, and WBC.21

Most importantly, men who reported increased activity

had significantly lower levels of each inflammatory

marker than men who reported sustained physical

inactivity or whose PA decreased during follow-up. 

Experimental evidence is required to definitively

determine whether increased levels of PA result in

lower markers of subclinical inflammation. Several

recent studies addressed this issue. Lakka et al.26

reported changes in CRP concentrations in 652 initially

sedentary women and men (mean age 35.6±13.7 years;

33% African American) following 20 weeks of aerobic

exercise training at 55-75% of VoO2max for 90-150

minutes per week. A 24% reduction in CRP

concentration (P<0.001) was seen in participants with

initial CRP levels >3.0 mg/L, independent of sex, race,

and changes in most traditional CHD risk factors

including plasma insulin and body weight. There were

no exercise-related changes in CRP in participants with

baseline CRP<3.0 mg/L. In another study of 63 women

and men 50-75 years of age, 24 weeks of aerobic

exercise training at 50-70% of VoO2max for 60-120

minutes per week resulted in a 15% reduction in mean

CRP concentrations. These reductions were

3
4

Analysis of heart rate variability (HRV) is

accomplished by using the electrocardiogram (ECG).

Because the ECG reflects both sympathetic and

parasympathetic function, it is the most common

measure of cardiovascular autonomic function. Other

noninvasive methods of assessing ANS function

include determination of baroreflex sensitivity and

heart rate recovery after termination of exercise. 

Lower HRV is associated with an increased risk of

cardiac events and mortality in apparently healthy

individuals and in CHD patients.35-41 In the

Atherosclerosis Risk in Communities Study (ARIC), 2-

minute beat-to-beat HRV assessed with a resting ECG

was inversely associated with the risk of developing

CHD.37 Individuals in the lowest category of HRV had

a 72% (P<0.05) higher risk of incident CHD compared

with the upper 75th percentile of the HRV distribution

independent of age, sex, race, education, medication

use and CHD risk factors. However, the relatively short

period of HRV data collection used in ARIC36,37 and

other studies,40 provides only a limited assessment of

sympathetic activity. In the Framingham Heart Study,

HRV was assessed from 2-hour ambulatory ECG

recordings in 1,101 men and 1,400 women who were

free of CHD at baseline.35 During a mean follow-up

period of 3.5 years, a 1 standard deviation decrement in

HRV was associated with a 47% (P<0.05) increased

risk of new cardiac events.35 Depressed parasympathetic

activity was positively associated with the development

of arrhythmia and cardiac events in CHD patients42,43

and apparently healthy individuals.35,38,40

Few cross-sectional studies have examined the

association between PA and the autonomic nervous

system. In general, available data indicate that

physically active individuals have significantly higher

HRV than their sedentary peers.44,45 In a large

observational study of British Civil Servants,45 total

leisure-time PA and both moderate- and vigorousintensity activity were associated with higher HRV in

men. The association occurred in a dose-response

gradient independent of age, and was observed across

strata of BMI. Consistent with other findings,46,47 HRV

was not associated with PA in women in this study. 

Other investigators evaluated the association between

HRV and CRF by using objective measures such as

recent PA habits and cardiac functional reserve.48-50 De

Meersman48 observed higher CRF and HRV in 72 male

runners (aged 15 to 83 years) compared to 72 age- and

weight-matched sedentary control subjects.

Furthermore, Davy et al.50 showed that age contributes

to a decline in HRV in women independent of CRF

levels. However, women with higher CRF had higher

HRV at any age compared with their sedentary peers.

Carnethon et al.51 evaluated the relationship between

habitual physical activity levels and heart rate change

during recovery from a maximal exercise tolerance test.

Post-exercise recovery heart rate was used as a measure

of cardiac vagal reactivation, and thus, a surrogate of

ANS function (e.g., faster recovery heart rate reflects

better vagal reactivation and better ANS function)

among 3,446 women and men from the Coronary

Artery Risk Development in Young Adults (CARDIA)

study.51 In women and men, higher levels of selfreported PA was associated with faster post-exercise

heart rate decline, independent of age, sex, race, BMI,

and other CHD risk factors. Furthermore, maximal

exercise testing repeated at 7 years post-baseline

showed that participants who reported decreased PA

during the 7-year follow-up had significantly slower

heart rate recovery than did participants who reported

maintaining or increasing their PA.

Although cross-sectional reports suggest that regular

PA is associated with better autonomic function, data

from exercise training studies demonstrate conflicting

results. A meta-analysis by Sandercock et al.52

examined whether aerobic exercise interventions in

healthy subjects is associated with increases in HRV.

The overall finding was a small but significant

correlation between HRV and aerobic exercise training,

which supports the current theory that aerobic exercise

training favorably alters the cardiac neuroregulatory

control in healthy women and men. Investigations

included in this meta-analysis had small sample sizes

and lacked control groups, but still found trends

towards enhanced HRV that were not statistically

significant. 

Studies in apparently healthy adults provide support for

substantial benefits in parasympathetic autonomic

control that occurs within the first 2-4 months of

moderate intensity aerobic exercise training.53-55

Recently, 88 sedentary overweight postmenopausal

women with elevated blood pressure were randomly

assigned to a control group or 2 months of moderate

intensity (50% VoO2max) aerobic exercise training for an

average of 141 minutes per week.53 Women in the

exercise group experienced a 25% increase in HRV

(P<0.01) that was independent of reductions in resting

heart rate, whereas women in the control group had a

5% decrease in HRV. More prolonged and intense
exercise training does not appear to systematically

enhance these adaptations.54,56 The largest randomized

controlled trial to examine the effect of aerobic exercise

on HRV was conducted in 140 Finnish men (age 57±3

years) who exercised 5 times per week at 40-60% at

VoO2max for 45-60 minutes per session over a 5-year

intervention period.57 Despite a mean increase of 11%

in submaximal CRF at 12 months among men in the

intervention group, exercise training had no effect on

HRV or at a subsequent 5-year evaluation. However,

exercise compliance was low (~39%).

Regular physical activity as a part of a comprehensive

rehabilitation program has also been shown to produce

beneficial effects on autonomic function in CHD

patients.58-60 Iellamo et al.60 showed that short-term

intense exercise training after myocardial

revascularization significantly increased CRF,

baroreflex sensitivity and HRV. Blumenthal et al.61

randomized CHD patients into a 16-week aerobic

exercise training intervention and observed a significant

improvement in baroreflex sensitivity compared with

usual care controls. This finding is important because

abnormal baroreflex sensitivity is associated with

poorer prognosis in patients who recently had a

myocardial infarction.43 Thus, exercise training might

be an effective nonpharmacological tool to enhance

autonomic cardiac control in CHD patients.

The biological mechanisms through which exercise

enhances autonomic cardiovascular control are poorly

understood. Important functional cardiac adaptations to

prolonged endurance exercise training include improved

diastolic function and increased stroke volume. These

changes, together with small decreases in afterload

resulting from peripheral adaptations to endurance

exercise, enhance the volume work and lower the

pressure work completed by the heart. This change in

the type of cardiac work completed in turn lowers

myocardial metabolic demand and results in a lower

heart rate and enhanced HRV at a given external work

rate. Endurance exercise training also contributes to

lower circulating catecholamine levels, which may

improve autonomic regulation by enhancing

parasympathetic cardiovascular control. Future

consideration should be given to whether ANS

parasympathetic function may also be enhanced by the

effect that regular PA has on conventional CHD risk

factors such as glucose and insulin levels, lipid profiles,

and arterial blood pressure. Studies are needed to more

fully elucidate the specific mechanisms that underlie the

associations between PA, ANS function and CHD risk.

Endothelial dysfunction and vascular

conductivity

One of the earliest manifestations of atherogenesis is

endothelial dysfunction, preceding angiographic or

ultrasonic evidence of atherosclerotic plaque.62 Many

investigators have shown that coronary endothelial

dysfunction is associated with increased CHD risk.63-65

Because the healthy endothelium serves as a 

“gatekeeper” regulating substances moving in and out

of the arterial wall, the preservation of endothelial

function is a major goal in the prevention and

management of CHD.

Direct assessment of endothelial function can enhance

the identification of asymptomatic individuals who are

at high risk for CHD events. However, the invasive

nature of these techniques limit their routine use in

clinical practice.11 The most common indirect 

method of assessing endothelial dysfunction uses 

high-resolution ultrasound to measure brachial artery

diameter in response to reactive hyperemia, a transient

increase in local blood flow following a brief arterial

occlusion.66 The increased blood flow and resulting

shear stress on the arterial wall stimulates the 

release of nitric oxide, a potent vasodilator and

important chemical messenger for normal 

endothelial regulatory functions. Referred to as 

flow-mediated vasodilation (FMD), this phenomenon

is a marker of endothelial-dependent vascular

reactivity and is inversely associated with adverse

CHD risk factor profiles.67

Physically active individuals tend to demonstrate

better endothelial function compared with their

sedentary peers. Rinder et al.68 reported greater FMD

in older male athletes (mean age = 68±2 years) whose

VoO2max was 42 ml/kg/min as compared with agematched sedentary men whose VoO2max was 27

ml/kg/min. These findings suggest that prolonged

participation in physical activities and preservation of

CRF may attenuate age-related declines in endothelial

function. Exercise training in asymptomatic

individuals with normal endothelial function produces

relatively little or no added benefit on endothelial

function. The majority of studies undertaken in

subjects with impaired endothelial function, however,

have shown improvements in the endothelial function

of conductance vessels. Hambrecht et al.69 reported

that 4 weeks of supervised cycle ergometry exercise at

80% of peak heart rate in CHD patients (mean age

60±2 years) was associated with a significant

5
Summary

Primary and secondary CHD prevention is currently

employed in a high-risk setting where risk factor

thresholds guide the initiation and intensity of

intervention. Because the burden of CHD is large,

advancements in our understanding of the pathogenesis

and clinical expression of CHD have led to the

identification of a host of traditional and nontraditional

factors for use in CHD risk assessment. The

cardiovascular benefits of physical activity are well

established and extend beyond relationships with

conventional CHD risk factors. Considerable data from

observational cohort and exercise training studies as

well as a limited amount of data from randomized

controlled trials suggest that the cardioprotective

effects of PA or planned exercise may be mediated by

several nontraditional CHD risk predictors such as

markers of inflammation and thrombosis, ANS

regulation, and endothelial function. The frequency,

duration, and intensity of exercise used in these studies

generally was consistent with the consensus

recommendation for cardiovascular benefits in

apparently healthy and clinical populations.73 However,

few studies have quantified the physical activity data as

caloric expenditure. The lack of complete exercise

caloric quantification information makes comparisons

and contrasts for reported findings in the literature

difficult. Considerably more research is needed using

diverse samples of women and men to determine the

dose-response characteristics between PA and each of

the risk factors discussed in this review. Whether 

PA-related improvements in these risk predictors

represent another pathway for primordial prevention 

of clinical CHD events remains to be seen, and 

should be considered in future research on PA and

cardiovascular health.

6

improvement in coronary artery endothelial

responsiveness to acetylcholine administration

measured invasively by Doppler. Hambrecht et al.70

also recently reported on 101 men with stable CHD

who were randomized to 1 year of aerobic exercise

training at 70% peak heart rate or to percutaneous

revascularization. Significantly higher 1 year event-free

survival was seen in the men who exercised compared

with those who underwent revascularization (88%

versus 70%, P=0.02). Both groups experienced

significantly improved myocardial perfusion, however,

cardiovascular functional capacity (e.g., VoO2max)

increased only in the exercise group.70 These studies

underscore the importance of exercise training for

improving coronary flow reserve and myocardial

perfusion in CHD patients. 

Exercise training also improves endothelial function in

the peripheral arterial system. Hambrecht et al.71 found

that 6 months of moderate intensity (70% VoO2max)

aerobic exercise training for 20 minutes per day was

associated with a 20% reduction in total peripheral

resistance versus 6% increase in the control group. The

exercise training improvement in peripheral resistance

was also accompanied by improved skeletal endothelial

function.

The consistency of the published data indicates that

exercise training improves endothelial function in

individuals with existing vascular disease, independent

of conventional CHD risk factors. Impaired FMD

secondary to depressed bioactivity of nitric oxide may

respond to exercise training in as little as 4 weeks,

however, sustained physical inactivity rapidly reverse

this process.72
7

Please Post

President’s Council on Physical Fitness & Sports

200 Independence Avenue, S.W., Washington, DC 20201

(202) 690-9000 • FAX (202) 690-5211

The consistency of the 

published data indicates that

exercise training improves

endothelial function in 

individuals with existing 

vascular disease, independent of

conventional CHD risk factors.

Radim Jurca, Ph.D.,

Michael J. LaMonte, Ph.D.

Division of Epidemiology

The Cooper Institute

J. Larry Durstine, Ph.D.

Department of Exercise Science

Arnold School of Public Health

University of South Carolina
8

40. Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short

electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men.

The Zutphen Study. Am J Epidemiol. 1997;145:899-908.

41. van Ravenswaaij-Arts C, Kollee L, Hopman J, Stoelinga G, Geijn H. Heart rate variability. Ann Intern

Med. 1993;118:436-447.

42. Bigger JTJ, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain

measures of heart period variability and mortality after myocardial infarction. Circulation.

1992;85:164-171.

43. La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate

variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone

and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351:478-484.

44. Melanson EL. Resting heart rate variability in men varying in habitual physical activity. Med Sci Sports

Exerc. 2000;32:1894-901.

45. Rennie KL, Hemingway H, Kumari M, Brunner E, Malik M, Marmot M. Effects of moderate and vigorous

physical activity on heart rate variability in a British study of civil servants. Am J Epidemiol.

2003;158:135-143.

46. Rossy LA, Thayer JF. Fitness and gender-related differences in heart period variability. Psychosom

Med. 1998;60:773-781.

47. Huikuri HV, Pikkujamsa SM, Airaksinen KE, Ikaheimo MJ, Rantala AO, Kauma H, Lilja M, Kesaniemi YA.

Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation.

1996;94:122-125.

48. De Meersman RE. Heart rate variability and aerobic fitness. Am Heart J. 1993;125:726-731.

49. Yataco AR, Fleisher LA, Katzel LI. Heart rate variability and cardiovascular fitness in senior athletes. Am

J Cardiol. 1997;80:1389-1391.

50. Davy KP, DeSouza CA, Jones PP, Seals DR. Elevated heart rate variability in physically active young and

older adult women. Clin Sci (Colch). 1998;94:579-84.

51. Carnethon MR, Jacobs DR, Jr., Sidney S, Sternfeld B, Gidding SS, Shoushtari C, Liu K. A longitudinal

study of physical activity and heart rate recovery: CARDIA, 1987-1993. Med Sci Sports Exerc.

2005;37:606-612.

52. Sandercock GR, Bromley PD, Brodie DA. Effects of exercise on heart rate variability: inferences from

meta-analysis. Med Sci Sports Exerc. 2005;37:433-439.

53. Jurca R, Church TS, Morss GM, Jordan AN, Earnest CP. Eight weeks of moderate-intensity exercise

training increases heart rate variability in sedentary postmenopausal women. Am Heart J.

2004;147:e21.

54. Iwasaki K, Zhang R, Zuckerman JH, Levine BD. Dose-response relationship of the cardiovascular

adaptation to endurance training in healthy adults: how much training for what benefit? J Appl Physiol.

2003;95:1575-1583.

55. Tulppo MP, Hautala AJ, Makikallio TH, Laukkanen RT, Nissila S, Hughson RL, Huikuri HV. Effects of

aerobic training on heart rate dynamics in sedentary subjects. J Appl Physiol. 2003;95:364-372.

56. Loimaala A, Huikuri H, Oja P, Pasanen M, Vuori I. Controlled 5-mo aerobic training improves heart rate

but not heart rate variability or baroreflex sensitivity. J Appl Physiol. 2000;89:1825-9.

57. Uusitalo AL, Laitinen T, Vaisanen SB, Lansimies E, Rauramaa R. Physical training and heart rate and

blood pressure variability: a 5-yr randomized trial. Am J Physiol Heart Circ Physiol. 2004;286:H1821-

H1826.

58. Fletcher GF, Balady G, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein S, Sivarajan Froelicher

ES, Froelicher VF, Pina IL, Pollock ML. Statement on exercise: benefits and recommendations for

physical activity programs for all Americans. A statement for health professionals by the Committee on

Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association.

Circulation. 1996;94:857-862.

59. O’Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM, Paffenbarger RS, Jr., Hennekens CH. An

overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation.

1989;80:234-244.

60. Iellamo F, Legramante JM, Massaro M, Raimondi G, Galante A. Effects of a residential exercise training

on baroreflex sensitivity and heart rate variability in patients with coronary artery disease: A

randomized, controlled study. Circulation. 2000;102:2588-92.

61. Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Waugh R, Georgiades A, Bacon SL, Hayano J,

Coleman RE, Hinderliter A. Effects of exercise and stress management training on markers of

cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA.

2005;293:1626-1634.

62. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657-671.

63. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on

adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899-1906.

64. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Jr., Lerman A. Long-term follow-up of

patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101:948-

954.

65. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA.

Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653-658.

66. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J,

Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound

assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the

International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257-265.

67. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF, Jr., Lehman BT, Fan S,

Osypiuk E, Vita JA. Clinical correlates and heritability of flow-mediated dilation in the community: the

Framingham Heart Study. Circulation. 2004;109:613-619.

68. Rinder MR, Spina RJ, Ehsani AA. Enhanced endothelium-dependent vasodilation in older endurancetrained men. J Appl Physiol. 2000;88:761-766.

69. Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of exercise on

coronary endothelial function in patients with coronary artery disease. N Engl J Med. 2000;342:454-

460.

70. Hambrecht R, Walther C, Mobius-Winkler S, Gielen S, Linke A, Conradi K, Erbs S, Kluge R, Kendziorra K,

Sabri O, Sick P, Schuler G. Percutaneous coronary angioplasty compared with exercise training in

patients with stable coronary artery disease: a randomized trial. Circulation. 2004;109:1371-1378.

71. Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, Schoene N, Schuler G. Effects of exercise

training on left ventricular function and peripheral resistance in patients with chronic heart failure:

A randomized trial. JAMA. 2000;283:3095-3101.

72. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic

heart failure. Circulation. 1996;93:210-214.

73. Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F,

Franklin B, Fletcher GF, Gordon NF, Pate RR, Rodriguez BL, Yancey AK, Wenger NK. Exercise and

physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement

from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and

the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity).

Circulation. 2003;107:3109-3116.

Reference List

11. Hopkins PN, Williams RR. Identification and relative weight of cardiovascular risk factors. Cardiology

Clinics. 1986;4:3-31.

12. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111:3481-3488.

13. Pearson TA, McBride PE, Miller NH, Smith SC. 27th Bethesda Conference: matching the intensity of risk

factor management with the hazard for coronary disease events. Task Force 8. Organization of

preventive cardiology service. J Am Coll Cardiol. 1996;27:1039-1047.

14. Benjamin EJ, Smith SC, Jr., Cooper RS, Hill MN, Luepker RV. Task force #1—magnitude of the

prevention problem: opportunities and challenges. 33rd Bethesda Conference. J Am Coll Cardiol.

2002;40:588-603.

15. Yanowitz FG. Atherosclerosis: process versus origins. In: Yanowitz FG, editor. Coronary Heart Disease

Prevention. New York: Marcel Dekker Inc, 1992: 17-31.

16. Hopkins PN, Williams RR. Human genetics and coronary heart disease: a public health perspective.

Annu Rev Nutr. 1989;9:303-345.

17. Hu FB, Stampfer MJ, Manson JE, Grodstein F, Colditz GA, Speizer FE, Willett WC. Trends in the

incidence of coronary heart disease and changes in diet and lifestyle in women. N Engl J Med.

2000;343:530-537.

18. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in

women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

19. Physical activity and cardiovascular health: A national consensus. Champaign,IL: Human Kinetics, 1997.

10. Kohl HW, III. Physical activity and cardiovascular disease: evidence for a dose response. Med Sci

Sports Exerc. 2001;33:S472-S483.

11. Smith SC, Jr., Greenland P, Grundy SM. AHA Conference Proceedings. Prevention conference V: Beyond

secondary prevention: Identifying the high-risk patient for primary prevention: executive summary.

American Heart Association. Circulation. 2000;101:111-116.

12. Haskell WL. Physical activity in the prevention and management of coronary heart disease. President's

Council on Physical Fitness and Sports Research Digest. 1995;2:1-12.

13. Bassuk S, Manson J. Preventing cardiovascular disease in women: How much physical activity is

enough? President's Council on Physical Fitness and Sports Research Digest. 2004;5:1-9.

14. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143.

15. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, III, Criqui M, Fadl YY, Fortmann SP,

Hong Y, Myers GL, Rifai N, Smith SC, Jr., Taubert K, Tracy RP, Vinicor F. Markers of inflammation and

cardiovascular disease: application to clinical and public health practice: a statement for healthcare

professionals from the Centers for Disease Control and Prevention and the American Heart Association.

Circulation. 2003;107:499-511.

16. Ford ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S.

adults. Epidemiology. 2002;13:561-568.

17. Church TS, Finley CE, Earnest CP, Kampert JB, Gibbons LW, Blair SN. Relative associations of fitness

and fatness to fibrinogen, white blood cell count, uric acid and metabolic syndrome. Int J Obes.

2002;26:805-813.

18. Church TS, Barlow CE, Earnest CP, Kampert JB, Priest EL, Blair SN. Associations between

cardiorespiratory fitness and C-reactive protein in men. Arteriosclerosis Thrombosis Vascular Biology.

2002;22:1869-1876.

19. Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Rimm EB. Leisure-time physical activity and reduced

plasma levels of obesity-related inflammatory markers. Obes Res. 2003;11:1055-1064.

20. Geffken DF, Cushman M, Burke GL, Polak JF, Sakkinen PA, Tracy RP. Association between physical activity

and markers of inflammation in a healthy elderly population. Am J Epidemiol. 2001;153:242-250.

21. Wannamethee SG, Lowe GD, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and

hemostatic and inflammatory variables in elderly men. Circulation. 2002;105:1785-1790.

22. Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD,

Pettinger MB, Ridker PM. Inflammatory biomarkers, hormone replacement therapy, and incident

coronary heart disease: prospective analysis from the Women's Health Initiative observational study.

JAMA. 2002;288:980-987.

23. LaMonte MJ, Durstine JL, Yanowitz FG, Lim T, DuBose KD, Davis P, Ainsworth BE. Cardiorespiratory

fitness and C-reactive protein among a tri-ethnic sample of women. Circulation. 2002;106:403-406.

24. Manns PJ, Williams DP, Snow CM, Wander RC. Physical activity, body fat, and serum C-reactive protein

in postmenopausal women with and without hormone replacement. Am J Hum Biol. 2003;15:91-100.

25. Stauffer BL, Hoetzer GL, Smith DT, DeSouza CA. Plasma C-reactive protein is not elevated in physically

active postmenopausal women taking hormone replacement therapy. J Appl Physiol. 2004;96:143-148.

26. Lakka TA, Lakka HM, Rankinen T, Leon AS, Rao DC, Skinner JS, Wilmore JH, Bouchard C. Effect of

exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study.

Eur Heart J. 2005.

27. Obisesan TO, Leeuwenburgh C, Phillips T, Ferrell RE, Phares DA, Prior SJ, Hagberg JM. C-reactive

protein genotypes affect baseline, but not exercise training-induced changes, in C-reactive protein

levels. Arterioscler Thromb Vasc Biol. 2004;24:1874-1879.

28. Okita K, Nishijima H, Murakami T, Nagai T, Morita N, Yonezawa K, Iizuka K, Kawaguchi H, Kitabatake A.

Can exercise training with weight loss lower serum C-reactive protein levels? Arterioscler Thromb Vasc

Biol. 2004;24:1868-1873.

29. Milani RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein through cardiac rehabilitation and

exercise training. J Am Coll Cardiol. 2004;43:1056-1061.

30. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, Marcovina S, Mather K, Orchard T,

Ratner R, Barrett-Connor E. Intensive lifestyle intervention or metformin on inflammation and

coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566-1572.

31. Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med. 1976;294:1165-1170.

32. Barron HV, Lesh MD. Autonomic nervous system and sudden cardiac death. J Am Coll Cardiol.

1996;27:1053-1060.

33. Malliani A, Schwartz PJ, Zanchetti A. Neural mechanisms in life-threatening arrhythmias. Am Heart J.

1980;100:705-715.

34. Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart.

Circulation. 1990;82:1095-1105.

35. Tsuji H, Larson MG, Venditti FJJ, Manders ES, Evans JC, Feldman CL, Levy D. Impact of reduced heart

rate variability on risk for cardiac events. The Framingham Heart Study. Circulation. 1996;94:2850-2855.

36. Dekker JM, Crow RS, Folsom AR, Hannan PJ, Liao D, Swenne CA, Schouten EG. Low heart rate

variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several

causes: the ARIC Study. Atherosclerosis Risk In Communities. Circulation. 2000;102:1239-1244.

37. Liao D, Cai J, Rosamond WD, Barnes RW, Hutchinson RG, Whitsel EA, Rautaharju P, Heiss G. Cardiac

autonomic function and incident coronary heart disease: a population-based case-cohort study. The

ARIC Study. Atherosclerosis Risk in Communities Study. Am J Epidemiol. 1997;145:696-706.

38. Tsuji H, Venditti FJ, Jr., Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate

variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation.

1994;90:878-83.

39. de Bruyne MC, Kors JA, Hoes AW, Klootwijk P, Dekker JM, Hofman A, van Bemmel JH, Grobbee DE.

Both decreased and increased heart rate variability on the standard 10-second electrocardiogram

predict cardiac mortality in the elderly: the Rotterdam Study. Am J Epidemiol. 1999;150:1282-1288.