Contemporary Reviews in Cardiovascular Medicine

Exercise Dose in Clinical Practice

Meagan M. Wasfy, MD; Aaron L. Baggish, MD

Abstract—There is wide variability in the physical activity patterns of the patients in contemporary clinical cardiovascular
practice. This review is designed to address the impact of exercise dose on key cardiovascular risk factors and on
mortality. We begin by examining the body of literature that supports a dose-response relationship between exercise and
cardiovascular disease risk factors, including plasma lipids, hypertension, diabetes mellitus, and obesity. We next explore
the relationship between exercise dose and mortality by reviewing the relevant epidemiological literature underlying
current physical activity guideline recommendations. We then expand this discussion to critically examine recent data
pertaining to the impact of exercise dose at the lowest and highest ends of the spectrum. Finally, we provide a framework
for how the key concepts of exercise dose can be integrated into clinical practice. (Circulation. 2016;133:2297-2313.
DOI: 10.1161/CIRCULATIONAHA.116.018093.)
Key Words: exercise ◼ hypertension ◼ lipids ◼ mortality

L ivelihood of the human species has depended on routine

physical activity (PA) for thousands of our years. Until
recent times, the successful procurement of basic life-sus-
taining commodities such as food and water required us to
move on a regular basis. We therefore evolved the capacity
to walk and to run, oftentimes over long distances, and our
survival depended on our ability to do so. In parallel with the
development of adaptations that facilitated PA were those that
promoted fuel storage and conservation of energy. The bal-
ance between acquired traits that enabled PA and those that
supported nutrient storage and encouraged rest and recovery
has, until recently, served our species well.
Once a necessary part of life, routine PA is no longer a
requirement in contemporary developed society. Technology
obviating the need to walk, including cars, escalators, eleva-
tors, and moving walkways, are a ubiquitous part of daily life.
In addition, numerous societal influences, both at home and
in the workplace, promote sedentary living at the expense of
physically active work and play. This transition represents a
paradigm shift for the human species with potentially grave
consequences, including the epidemic of obesity and the
burden of chronic diseases attributable to physical inactiv-
ity. However, for reasons including the pursuits of health,
fitness, and recreation, a substantial number of people vol-
untarily choose to engage in some form of PA, ranging from
low-intensity walking to extreme endurance sports. Thus, the
PA “dose” to which our species is exposed has never been so
variable and so complex.
Heterogeneity in PA habits is relevant to clinical cardio-
vascular practice on a patient-by-patient basis. Routine PA is
an effective way to increase longevity and to reduce the risk
of cardiovascular disease (CVD). It is now standard of care to
counsel sedentary or inadequately active patients to increase
PA for both the primary and secondary prevention of CVD.
In addition, recent data suggesting that high levels of PA
may lead to significant cardiovascular consequences have led
highly active patients and their clinicians to question the risk/
benefit ratio of high exercise dose exposure. This review was
designed to address the concept of exercise dose in contempo-
rary cardiovascular practice with an emphasis on the relation-
ship between PA and key response outcomes. We begin with
an overview of fundamental exercise dose principles, high-
light data describing the relationship between PA and specific
clinically relevant outcomes, address recent data examining
the impact of exercise at both ends of the dose spectrum, and
conclude with a brief discussion of integrating the exercise
dose concept into clinical practice. This review focuses on the
effects of exercise on cardiovascular risk factor modification
and overall mortality because the impact of exercise on CVD
prevalence, CVD mortality, and secondary prevention, includ-
ing the role of formal cardiac rehabilitation, has recently been
discussed elsewhere.1,2
Exercise Dose: Historical Considerations
Although the concept that PA habits affect health and longev-
ity dates back to the writings of ancient scholars, including
Hippocrates and Galen,3 most of what is now known about
this topic stems from recent decades. In 1953, Professor J.N.
Morris and colleagues4,5 from the United Kingdom published
tandem landmark studies examining the interactions between
occupational PA and incident coronary heart disease and lon-
gevity. In this observational work, London streetcar conduc-
tors, who spent their working time walking up and down aisles
and double-decker staircases, had approximately half the rate
of coronary heart disease of substantially more sedentary
streetcar drivers. Morris and colleagues6,7 observed similar

From Cardiovascular Performance Program, Massachusetts General Hospital, Boston.

Correspondence to Aaron L. Baggish, MD, Cardiovascular Performance Program, Massachusetts General Hospital, Yawkey Ste 5B, 55 Fruit St, Boston,
MA 02114. E-mail abaggish@partners.org
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.116.018093

2297 College London (ucl) / England on June 6, 2016

Downloaded from http://circ.ahajournals.org/ at University
2298 Circulation June 7, 2016
results among alternative vocations, including postal workers
and civil servants.
As occupational activity declined as a proportion of an
individual’s total PA, researchers shifted their focus away
from examining this domain, instead focusing on quantifying
PA exposure during to leisure-time activity or across the entire
day.8 With this new focus, large, prospective, cohort studies,
including the Harvard Alumni Health Study and the Women’s
Health Initiative, have subsequently further clarified the rela-
tionship between exercise dose and both cardiovascular health
and longevity.9–11 These epidemiological studies relied on a
common observational approach in which exercise exposure,
conventionally obtained with standardized self-reported sur-
vey tools, were quantified in large numbers of people who were
followed up with respect to clinical outcomes over extended
time periods. These cohorts, when stratified as a function of
habitual PA practices, thus provide valuable information about
the relationship between exercise dose and clinical outcomes.
In aggregate, epidemiology literature has evaluated the asso-
ciations between PA and key health outcomes among large
numbers of participants across heterogeneous populations and
thus serves as the invaluable foundation for current public
health guidelines.
However, it must be acknowledged that data derived from
epidemiological investigation have several key limitations.
First, they may be subject to unmeasured bias and confound-
ing that preclude definitive determination of causality. For
example, subsequent investigations by Heady et al12 found
that streetcar drivers had, on average, greater waist circumfer-
ence as derived from uniform measurements than conductors.
Although subsequent analyses adjusted for this identified con-
founder and still found important differences in coronary heart
disease,13 other differences between the 2 occupations likely
remained unidentified. Second, epidemiological studies typi-
cally rely on the use of self-reported PA habits, which may be
inaccurate despite the use of the most rigorous survey tools.
Finally, epidemiological data sets typically contain very small
numbers of people who routinely participate in the highest lev-
els of exercise and thus are almost universally underpowered
to examine the upper end of the exercise dose-response curve.
The randomized, controlled trial (RCT) design, the gold-
standard approach to clinical hypothesis testing, has the
potential to overcome many of the limitations of observational
work. The RCT approach, as discussed in subsequent sec-
tions, has been successfully applied to examine the biological
impact of PA. RCTs are, however, among the most resource-
intense, logistically complex study designs. Therefore, all
exercise RCTs to date have used the rapidly responsive sur-
rogate markers of disease risk or burden (ie, plasma lipids,
physical fitness, myocardial structure) rather than hard clini-
cal end points. Exercise RCTs have therefore greatly enhanced
our understanding of exercise physiology, perhaps delineating
mechanisms that underlie the outcome trends reported in com-
paratively larger observational work, but they provide little
information about the impact of exercise on definitive health
outcomes such as mortality. The design and implementation
of exercise RCTs powered to examine hard clinical outcomes,
although a logistic and resource-intense challenge, represents
an important future goal for the broad scientific community.
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Exercise Dose: Common Definitions
PA is defined as any bodily movement resulting from the con-
traction of skeletal muscle that increases energy expenditure
above the basal level.14 Exercise, as a subcategory of PA, is
defined as any planned and structured action with the objec-
tive of improving or maintaining physical fitness or health. All
exercise involves some combination of isometric (static) and
isotonic (dynamic) stress, which serves as the basis for the
physiological classification of competitive sports. In clinical
practice, exercise is most commonly divided into the broad
subgroups of aerobic/endurance (ie, running, walking) and
resistance (ie, weight lifting) activity, although many sport
and exercise modalities integrate both physiological disci-
plines. Although data describing the cardiovascular impact
of resistance exercise are mounting, this review focuses
exclusively on aerobic/endurance exercise, given the rela-
tively well-developed concept of exercise dose response for
this modality. Within the broad category of aerobic/endur-
ance exercise, common modalities include walking/running,
cycling, rowing, and swimming. Although methods of mea-
suring exercise exposure vary across these different forms of
exercise, universal concepts for the quantification of exercise
dose are described below.
Quantification of exercise exposure is typically accom-
plished with the concept of exercise dose. At the most basic
conceptual level, exercise dose is determined by 3 discrete
variables, duration, frequency, and intensity, and in aggre-
gate, exercise dose can be described as the product of these
3 parameters. Duration reflects the amount of time accrued in
a single exercise session and, for aerobic/endurance exercise,
is most often characterized as minutes or hours. Frequency
captures the number of exercise sessions over more extended
periods (ie, days, weeks, or months). In sum, these 2 param-
eters reflect the total amount of time spent in exercise over a
given period.
Exercise intensity, a relatively more complex concept, is
typically quantified in absolute terms as the metabolic cost of
an exercise session or in relative terms as the performance of a
given activity as a function of some percentage of measurable
maximal capacity (Table 1). For aerobic/endurance exercise,
absolute exercise intensity is commonly measured in kilo-
calories burned per unit of time or in metabolic equivalents
(METs; Table 1). Using standardized estimates of METs or
kcal expenditure, these metrics of absolute intensity are useful
for the estimation of exercise dose in community-based pop-
ulations and thus are commonly used in large observational
studies of exercise dose. A limitation of absolute intensity
metrics is their innate inability to account for the large vari-
ability in fitness that exists across individuals. For example,
intensity exercise of 5 METs may simultaneously represent
a peak exercise effort for a patient with advanced CVD and a
relatively easy effort for a competitive athlete.
In contrast, indexes of relative exercise intensity account
for differences in individual fitness levels by defining inten-
sity as a percentage of some peak or maximal physiological
parameters (ie, heart rate and oxygen consumption; Table 1).
In the example provided above, exercise performed . at a relative
intensity of 75% peak oxygen consumption (VO2) may trans-
late into a treadmill walk at 3 mph for a patient with advanced
 Wasfy and Baggish Exercise Dose in Clinical Practice 2299

Table 1. Quantification of Exercise Intensity and Dose

Intensity Unit and Definition Intensity Range Pros (+)/Cons (−) Weekly Exercise Dose
Absolute intensity: energy required to perform activity
Kilocalories/time: Not defined (+) Relatable to energy intake Kilocalories/week
1 L O2 consumption=5 kcal (−) Varies based on body mass
(−) Impractical to measure directly
(−) Not individualized based on fitness
MET: Sedentary: 1–1.5 METs (+) Intensity of the activity may be expressed MET-hours/week
1 MET=3.5 mL O2 Low: 1.6–2.9 METs simply as multiple of resting energy
MET-minutes/week
consumption/kg·min = quiet sitting expenditure
Moderate: 3.0–5.9 METs
(−) MET estimations for a given activity vary on
High: >6.0 METs
the basis of body composition, sex, and age
(−) Not individualized on the basis of fitness
Relative intensity: percentage of maximal exercise capacity
.
Percent of VO2 Very light: <25% (+) Determined relative to individual’s fitness Minutes/week of given
Light: 25%–44% (−) Requires prior exercise testing intensity
Moderate: 45%–59% (−) Impractical to measure during routine exercise
Hard: 60%–84%
Very hard: 85%–99%
Maximal: 100%
Percent of maximal heart rate Very light: <30% (+) Accounts for individual’s fitness Minutes/week of given
Light: 30%–49% (+) Easy to monitor during routine exercise with intensity
Moderate: 50%–69% heart rate monitor
Hard: 70%–89% (+) Good correlation with energy expenditure
during moderate- to high-intensity steady-
Very hard: 90%–99%
state exercise
Maximal: 100%
(−) Requires prior exercise testing
(−) In absence of an exercise test, estimation of
maximal heart rate may be inaccurate for a
given individual
Rate of perceived exertion Borg Scale: (+) Accounts for individual’s fitness Minutes/week of given
Very light: <10 (+) Easy to assess during exercise intensity
Light: 10–11 (−) Large interindividual variation even at similar
Moderate: 12–13 fitness levels
Hard: 14–16
Very hard: 17–19
Maximal: 20
MET indicates metabolic equivalents.

CVD and a treadmill run at 8 mph for a competitive athlete.
The use of relative exercise intensity is commonplace in clini-
cal practice for the generation of exercise prescription and in
high-quality observational and interventional exercise stud-
ies. Relative exercise intensity metrics may be preferable to
absolute intensity metrics when they can be applied with rigor.
However, it must be emphasized that effective application of
a relative intensity metric requires accurate determination of a
peak value for the metric of choice, which typically involves
some form of laboratory- or field-based exercise assessment.
This is typically a resource-intensive process that may not be
feasible for large population-based studies. Although the use
of equations or predictive algorithms for metrics such as peak
heart rate have been developed, the application of these tools
is often associated with considerable inaccuracy.
Both metrics of intensity can be used effectively to mea-
sure cumulative exercise dose by multiplying by exercise
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
duration and frequency. When exercise is measured in terms
of absolute intensity, this translates to total dose expressed as
kilocalories per week, MET-hours per week, or MET-minutes
per week (Table 1). These values are commonly used in epi-
demiological studies of exercise dose because they can be
extrapolated from self-reported activity patterns, but they
have proved difficult to apply in clinical practice during the
assessment of exercise habits and the prescription of exer-
cise interventions. Conversely, when exercise is measured
in terms of relative intensity, total dose is instead expressed
as time per week spent in light/moderate/vigorous exercise.
These terms may be more patient-friendly but, as noted above,
require some knowledge of an individual patient’s physiol-
ogy and exercise capacity. Both approaches have intrinsic
strengths and limitations and consequently may be more or
less appropriate in specific clinical and research settings. As
detailed below, both the total exercise dose and the relative
2300 Circulation June 7, 2016
contribution of its 3 cardinal components may affect the rela-
tionship between exercise exposure and a given clinical or
physiological outcome.
Exercise Dose and Clinical Outcomes
Numerous observational studies and several well-designed
exercise intervention studies have examined the impact of
exercise dose on cardiometabolic risk factors, physical fitness,
and mortality. Careful examination of the existing data sug-
gests that the optimal dose of aerobic exercise, more specifi-
cally the exercise dose required to produce the most benefit,
varies considerably across key outcomes of clinical relevance.
In clinical practice, this means that the prescription of an exer-
cise dose may best be accomplished by identifying a specific
therapeutic target for each individual patient.15–28
Plasma Lipids
The impact of aerobic exercise training on serum lipoproteins
has been studied extensively. Representative exercise inter-
vention studies that have specifically examined the aspects
of exercise dose are summarized in Table 2. The response of
high-density lipoprotein (HDL) to exercise training appears
to be modest but favorable. A 2007 meta-analysis of 25 exer-
cise intervention RCTs reported a mean net increase in HDL
of ≈2.5 mg/dL.29 In this study, the estimated minimal weekly
exercise energy expenditure and duration required for this
HDL response were 900 kcal and 120 minutes, respectively,
which approximates the minimum exercise dose recom-
mended by current PA guidelines of at least 150 minutes of
moderate-intensity exercise or 75 minutes of vigorous-inten-
sity exercise weekly.14,30 A 2007 meta-analysis demonstrated
that HDL augmentation was not significantly affected by
exercise interventions using training sessions of <30 minutes,
was more robust among subjects with higher initial total cho-
lesterol and lower body mass index, and was not associated
with exercise frequency or intensity.29 This meta-analysis con-
tained relatively few studies examining exercise interventions
exceeding the 2000-kcal/wk range and thus does not provide
sufficient data to clarify the HDL–exercise dose relationship
above this level of energy expenditure. A prior observational
study examining changes in lipids over a 20-day road race
suggested that exercise at this high dose may translate into
a greater HDL rise than reported with more moderate levels
of exercise.31 The concept that an exercise dose that is well in
excess of PA recommendations may incrementally improve
lipids above more modest exercise exposure is supported by
observational data characterizing lipid profiles among endur-
ance athletes.32–34
The impact of aerobic exercise training on serum low-den-
sity lipoprotein (LDL) is not consistent across available stud-
ies. Two large meta-analytic studies found that HDL but not
LDL was significantly improved by exercise training when
confounding variables (diet, body weight, etc) were consid-
ered.35,36 Conversely, a series of meta-analyses by Kelley et
al37–40 found that routine exercise produced a clinically favor-
able but small reduction in LDL of 4 to 6 mg/dL among various
adult populations. Similarly, recreational middle-aged male
runners participating in an 18-week jogging program in prepa-
ration for a marathon road race experienced a 5% reduction in
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
total LDL.41 An important, well-designed, randomized, con-
trolled study (Studies of Targeted Risk Reduction Intervention
Through Defined Exercise [STRRIDE]) examined the impact
of several doses of moderate- and high-intensity aerobic exer-
cise (walking and jogging, respectively; Table 2). Despite neg-
ligible changes in total LDL, study participants demonstrated
significant reductions in both the size and number of athero-
genic LDL subfractions that were greater in those jogging ≈17
miles/wk than in those walking or jogging ≈11 miles/wk, sug-
gestive of a significant dose response.15,42
The response of triglycerides to exercise training inter-
ventions has been similarly inconsistent and highly variable.
A meta-analysis examining aerobic exercise training in an
unselected adult population demonstrated decreases in triglyc-
erides of 5 to 38 mg/dL or 4% to 37%,35 although other stud-
ies have shown smaller reductions in triglycerides.37–40 The
greater heterogeneity in the response of triglycerides com-
pared with HDL may be partially explained by the fact that
triglyceride levels are affected acutely by the last exercise ses-
sion to a greater degree than HDL.43 Results from STRRIDE
suggested a significant dose response for triglycerides, with
higher total amounts of exercise (≈17 miles of jogging ver-
sus ≈11 miles of walking or jogging) resulting in greater tri-
glyceride reduction. Interestingly, STRRIDE also suggested
that moderate-intensity compared with high-intensity exer-
cise, even when total exercise dose (ie, energy expenditure)
is kept consistent, may result in a greater initial decrement
in triglycerides and a more sustained reduction after training
cessation.15,42 However, the notion that exercise intensity is a
key determinant of triglyceride response has not been a con-
sistent finding. The majority of studies have shown that when
a reduction in triglycerides is observed, overall exercise dose
is the most important determinant.35
In summary, routine exercise has clearly been demon-
strated to have a beneficial impact on serum lipids. The effect
of exercise appears strongest and most consistent for HDL,
whereas the impact of exercise appears both less consistent
and smaller in magnitude for LDL, subfractionated lipopro-
teins, and triglycerides. Although the magnitude of the impact
of routine exercise on lipids at the individual patient level is
small, lowering of total cholesterol by as little as 10% through
either dietary or pharmacological intervention has been shown
to result in a 27% reduction in incident CVD.44 Although no
such analysis exists for the specific impact of exercise on lip-
ids, these data suggest that the small changes in serum lip-
ids with exercise may have the potential to reduce the risk of
CVD and CVD-related mortality significantly when translated
across broader populations. Both cross-sectional data and
exercise intervention studies appear to conclude that the mini-
mum exercise dose required to produce favorable changes
in serum lipids approximates that recommended by current
PA guidelines and that incremental benefit may be achieved
with exercise doses that exceed these levels. At the present
time, there does not appears to be an upper level of exercise
dose above which deleterious effects on serum lipids occur;
available epidemiological data support a continuous incre-
mental beneficial impact on HDL through doses of exercise
far in excess of current PA guidelines. However, the relation-
ships between high-dose exercise, lipids, and complementary

Table 2. Selected Intervention Studies Examining the Impact of Exercise Dose on Plasma Lipids, BP, Metabolic Health, and Body Mass
Study Population
Lipids
Kraus et al15 Overweight dyslipidemics,
(STRRIDE) n=86, 58% male, age=52±8 y
Duncan et al16 Premenopausal healthy, n=59,
all women, age=20–40 y
Woolf-May et al17 Healthy, n=56, 33% male,
age=40–66 y
BP
Braith et al18 Healthy, n=44, age=60–70 y
Molmen-Hansen et al19 Hypertensive, n=88, 56%
male, age=52±8 y
Marceau et al20 Hypertensive, n=9, 90% male,
age=35-55 y
Hagberg et al21 Hypertensive, n=30,
age=64±3 y
Insulin and glucose metabolism
DiPietro et al22 Healthy women, n=25,
age=73±10 y
Coker et al23 Overweight, n=18,
age=74±10 y
Tjonna et al24 Metabolic syndrome, n=28,
46% male, age=52±4 y
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Wasfy and Baggish Exercise Dose in Clinical Practice 2301
Exposure
Exercise Levels Time Key Findings
1. “High amount, high intensity”: 8 mo TG ↓, HDL ↑, and LDL
.
jogging (65%–80% VO2max), ≈17 miles/week subfractions improved more in
high amount than low amount
2. “Low amount, high intensity”: jogging, ≈11
groups
miles/wk
No ∆ in total LDL
3. “Low amount, moderate intensity”:
. No impact of exercise intensity
Walking (40%–55% VO2max), ≈11 miles/wk
1. “Aerobic” walking: 6–7 METs, ≈ 11 miles/ 24 wk HDL ↑ 4%–6%
wk No ∆ in TG, LDL
2. Brisk walking: 5 METs, ≈11 miles/wk No impact of walking pace
3. “Strolling”: 3–4 METs, ≈11 miles/wk
.
Brisk walking (70%–75% VO2max), 170 min/ 8 wk LDL ↓ 6%–8% only with longer
wk divided into: walking sessions (≥ 10 min)
1. 20–40 min/session
2. 10–15 min/session
3. 5–10 min/session
1. Moderate-intensity walking: 70% HR 6 mo SBP ↓ 8–9 mm Hg and DBP
reserve, 135 min/wk ↓−8 mm Hg in both groups.
2. High-intensity walking: 80%–85% HR No impact of walking intensity
reserve, 115 min/wk*
.
1. HIIT: 85%–90% VO2max 12 wk HIIT: greater ↓ SBP (12 vs 5
2. Moderate-intensity continuous walking: mm Hg) and ↓ DBP (8 vs 4
.
60% VO2max* mm Hg) than walking
.
1. Low-intensity cycling: 50% VO2max, 180 10 wk each SBP and DBP ↓ 5 mm Hg in
min/wk (crossover both groups
.
2. Moderate-intensity cycling: 70% VO2max, design) Low intensity: ↓ daytime BP
180 min/wk Moderate intensity: ↓ nighttime
BP
.
1. Low-intensity walking: 50% VO2max, ≈150 9 mo Low-intensity group: greater ↓
min/wk SBP than moderate-intensity
2. Moderate-intensity jogging/cycling: 70%– group (20 vs 8 mm Hg)
.
85% VO2max, ≈ 150 min/wk DBP ↓ 11-12 mm Hg in both
groups
Confounding: moderate-
intensity group greater
antihypertensive use (50%
vs 9%)
1. High-intensity group: greater ↑
. Moderate-intensity activities: 65% 9 mo
VO2max, 260 min/wk glucose uptake (21% vs 16%)
.
2. High-intensity activities: 80% VO2max, than moderate-intensity group
220 min/wk*
.
1. Moderate-intensity activities: 50% VO2max, 12 wk High-intensity group: greater ↑
≈1000 kcal/wk insulin sensitivity (20% vs 0%)
.
2. High-intensity activities: 75% VO2max, than moderate-intensity group
≈1000 kcal/wk*
1. HIIT: 90% maximum HR, 120 min/wk 16 wk HIIT: greater ↑ insulin sensitivity
2. Moderate-intensity continuous walking/ (+15% vs −14%) and lower
jogging: 70% maximum HR, 140 min/wk* prevalence of MS (46% vs 37%)
than moderate-intensity group
Both groups with similar reduction
body mass (−3% to 4%).
(Continued )
2302 Circulation June 7, 2016

Table 2. Continued
Exposure
Study Population Exercise Levels Time Key Findings
Johnson et al25 (STRRIDE) Overweight dyslipidemics, 40% 1. “High amount, high intensity”: jogging 8 mo Moderate intensity: greater ↓
.
metabolic syndrome, n=171, (65%–80% VO2max), ≈17 miles/wk in MS than high intensity at
53% male, age=53±7 y 2. “Low amount, high intensity”: jogging,≈11 same “low” exercise amount,
miles/wk but highest overall dose (high
amount/high intensity group)
3. “Low amount, moderate intensity”: walking
. had greatest ↓ in MS
(40%–55% VO2max), ≈11 miles/wk
Body mass
Irwin et al26 Overweight, postmenopausal Moderate-intensity activities: 60%–75% 12 mo Body mass ↓ 1.4%, similar
women, n=168, age=50–75 y maximum HR, variable time: across groups
1. >195 min/wk Most active group greater ↓
2. 135–195 min/wk body fat (4.2% vs 06%) than
3. <135 min/wk least active group

Slentz et al27 Overweight, dyslipidemics, 1. “High amount,

. high intensity”: jogging 8 mo High amount group greater
(STRRIDE) n=175, 52% male, (65%–80% VO2max), ≈17 miles/wk ↓ weight (−3% vs −1%) and
age=53±7 y 2. “Low amount, high intensity”: jogging,≈11 body fat (−7% vs 0%) than low
miles/wk amount groups
3. “Low amount, moderate intensity”: walking No impact of exercise intensity
.
(40%–55% VO2max), ≈11 miles/wk)
McTiernan et al28 Sedentary, healthy, n=202, Moderate- to high-intensity activities: 60% 12 mo Body mass ↓ 1.4%
50% male, age=40–75 y to 85% max HR, ≈360 min/wk, variable Higher amount activity: greater ↓
compliance. in body mass and fat.
In all selected studies, there was not a sizable reduction in body mass with exercise training unless otherwise noted. BP indicates blood pressure; DBP, diastolic
blood pressure; HDL, high-density lipoprotein; HIIT, high-intensity interval training; HR, heart rate; LDL, low-density lipoprotein; MS, metabolic syndrome; SBP,
.
systolic blood pressure; STRRIDE, Studies of Targeted Risk Reduction Intervention Through Defined Exercise; TG, triglycerides; and VO2max, maximal oxygen
consumption.

indexes of CVD risk (eg, inflammatory biomarkers) have not
yet been examined in controlled, longitudinal studies.
Blood Pressure
The relationship between exercise training and blood pressure
(BP) has been the topic of extensive study. In large, observational
studies, greater amounts of leisure-time PA have been associ-
ated with a reduction in incident hypertension,45–48 although this
relationship has been less consistent among women and blacks.
Controlled exercise intervention studies and meta-analyses that
have examined the BP response to exercise training suggest a
modest but clinically significant effect. Specifically, exercise
training appears to translate into a 3– to 5–mm Hg reduction in
systolic BP (∆2%–4%) and 2– to 4–mm Hg reduction in dia-
stolic BP (∆2%–3%).49–53 BP reduction attributable to exercise
is generally greater among hypertensive individuals (reductions
of 6–8 mm Hg in systolic BP and 5–6 mm Hg in diastolic BP)
and slightly less in normotensive individuals (reductions of
2–3 mm Hg in SBP and 1–2 mm Hg in DBP).49,50,54
There does not appear to be a clear minimal exercise dose
threshold for BP lowering or any clear independent effect of
the key components of exercise dose: exercise frequency, bout
duration, or intensity. One small, controlled study in hyper-
tensive older men suggested that lower-intensity exercise
was associated with a greater. reduction in SBP than higher-
intensity exercise (<70% V O2max, ∆20 mm Hg versus >70%
.
Vo2max, ∆ 8 mm Hg; Table 2).21 The finding that low-intensity
exercise was superior to high-intensity exercise for lowering
BP supported prior animal model data.55,56 It is noteworthy that
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
although this concept has persisted in the literature for years,
neither subsequent controlled exercise intervention stud-
ies that have directly compared different exercise intensities
(Table 2) nor any meta-analytic studies have replicated these
results in humans. On the contrary, several studies comparing
high-intensity interval-based training with moderate continu-
ous-intensity exercise have found that high-intensity training
is at best superior or at least equivalent to similar amounts of
moderate-intensity continuous training for BP lowering.19,20,24
In summary, the impact of exercise on BP has been clearly
demonstrated in studies that have used exercise doses in the
range of current PA recommendations.14,30 However, a clear
dose response has not been demonstrated, and there is neither
definitive evidence to support a minimum exercise threshold
for BP lowering nor any data to support an upper limit of exer-
cise dose beyond which the BP reduction is diminished.
Insulin and Glucose Metabolism
Exercise increases insulin sensitivity and non–insulin-medi-
ated skeletal muscle glucose metabolism, and epidemiologi-
cal data suggest that exercise training improves metabolic
heath.57,58 Several large RCTs have examined the impact of
exercise on the prevention or treatment of metabolic syn-
drome (MS) and diabetes mellitus (DM). However, most have
included exercise as part of a more comprehensive “lifestyle
intervention” that typically includes dietary changes and
weight loss, thereby making it difficult to examine the inde-
pendent effects of exercise. Two such large studies, the Finnish
Diabetes Prevention Study59 and the US Diabetes Prevention
 Wasfy and Baggish
Study,60 prescribed exercise doses of 240 and 150 min/wk of
moderate-intensity exercise, respectively. Post hoc analyses of
both studies indicated that weight loss rather than exercise was
the most important determinant of incident DM risk reduction.
In the US Diabetes Prevention study, exercise was not signifi-
cantly associated with reduced risk of DM when adjusted for
weight change.61 However, participants in the Finnish study,
who increased their exercise exposure the most, even after
adjustment for weight loss and dietary changes, appeared to
reduce the risk of DM significantly more than those whose
exercise habits did not change.62
It appears that increasing exercise doses lead to incremen-
tal improvements in markers of metabolic health. In a post
hoc analysis of the STRRIDE study, the prevalence of MS
declined from 41% to 27% among those who completed an
exercise intervention but remained unchanged in the control
group (Table 2). Furthermore, the “high-amount, high-inten-
sity” group, whose overall gross exercise energy expenditure
was highest, had the greater improvement in MS character-
istics compared with the lower-dose exercise groups.25 In
similar fashion, a recent study of healthy subjects found that
the dose of prescribed exercise was directly associated with
improvements in insulin sensitivity in a graded fashion with-
out evidence for a minimum required threshold or maximal
effect.63
Although it appears clear that there is a dose response for
exercise and insulin and glucose metabolism, there are con-
flicting data on the optimal exercise intensity for improving
metabolic health.25 In the STRRIDE study, moderate-intensity
exercise (ie, walking) improved MS to a greater degree than
high-intensity exercise (ie, jogging) of a similar total dose (≈11
miles/wk, ≈1,100 kcal/wk). As discussed above, the potential
superiority of moderate-intensity exercise for attenuating inci-
dent MS was similarly shown for serum triglycerides. This
raises the possibility that moderate-intensity exercise uniquely
affects the metabolic pathways that link insulin resistance,
impaired postprandial lipolysis, and triglyceride excursion.64
In contrast, other studies in both healthy subjects and those
with MS have found that high-intensity exercise, including
steady-state and interval-based training, is superior to mod-
erate-intensity exercise of equivalent energy expenditure in
improving insulin sensitivity.22–24 In sum, the above studies
confirm a beneficial association between exercise and meta-
bolic health but provide no clear conclusions about which
exercise intensity optimizes this relationship.
In summary, comprehensive lifestyle interventions,
including exercise, diet, and associated weight loss, have
clearly been shown to be beneficial in preventing MS and
DM. The exercise programs that have been specifically
studied in large trials are similar to that in the current PA
guidelines, although the bulk of available data suggest that
a higher dose of exercise results in greater improvements in
insulin sensitivity.
Body Mass
Weight loss is among the most popular reasons that exercise
is prescribed because it is indisputable that changes in body
mass are driven by changes in net energy balance. To what
degree a given exercise intervention will favorably affects
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Exercise Dose in Clinical Practice 2303
energy balance depends on concomitant changes in caloric
intake. Numerous organizations have published guidelines
that address the role of exercise for the prevention and treat-
ment of obesity.65–67 Using cross-sectional data describing the
PA levels associated with a normal body mass index, these
organizations recommend an exercise dose that is approxi-
mately double that of the current PA guidelines for weight loss
or the prevention of weight regain.
Data from several recent RCTs estimate that a weekly
exercise dose ranging from 13 to 26 MET-hours weekly is
required for minimal weight loss (1%–3%) or weight stabil-
ity.26–28,68 There appears to be a direct dose-response relation-
ship between exercise and body mass. The STRRIDE study
found that although those who exercised at a “high” amount
(jogging ≈17 miles/wk) experienced small but significant
reductions in weight (−3%) and body fat (−7%), those par-
ticipating in “low” amounts of exercise (walking or jogging
≈11 miles/wk) had stable weight and visceral adiposity.27 Two
other RCTs, both that prescribed a single exercise dose to all
subjects and then analyzed results on the basis of tertiles of
PA as determined by variable compliance, found that higher
exercise dose was associated with greater weight and body fat
loss.26,28 It is noteworthy that these studies did not concomi-
tantly use specific diet interventions and that the authors of
one of these studies calculated that subjects should have lost
almost 8 kg instead of the observed 1 to 2 kg on the basis of
the energy expenditure of the exercise program..28 To achieve
substantial weight loss (>5% decrease in body mass), 2
approaches have been proposed: a concomitant dietary inter-
vention (either maintenance of pre-exercise intake or reduc-
tion in intake)69,70 or exercise of a sufficient dose to expend a
high amount of calories, at least 26 MET-h/wk (eg, walking at
3 mph for 60 minutes daily or jogging at 6 mph for 20 minutes
daily).71,72
In summary, the minimum exercise dose required to
maintain optimal weight or to stimulate weight loss appears
to be substantially higher than the minimum dose required
to favorably affect other CVD risk factors (lipids, BP, insu-
lin sensitivity). There is a clear dose response with exer-
cise and weight loss. Available data suggest that a dose
of at least approximately double that of the current PA
guidelines is necessary to reliably establish and maintain a
healthy weight and that more activity is required to achieve
more substantial weight loss. In clinical practice, we rou-
tinely emphasize the importance of coupling exercise with
deliberate control of caloric intake for patients who seek to
reduce body mass.
Physical Fitness
Numerous observational studies suggest that there are inverse
relationships between cardiorespiratory fitness and both all-
cause and CVD-attributable mortality.73–75 For example, the
adjusted hazard ratio for death declined by 12% for every
1-MET increase in peak exercise capacity among older male
veterans followed up over 20 years.75 Fitness can be improved
by increasing exercise dose through the augmentation of any
the principal dose components (frequency, intensity, or dura-
tion)76,77 among people of all ages and both sexes.78,79 For
example, the STRRIDE study demonstrated that an exercise
2304 Circulation June 7, 2016
program consisting of variable exercise intensity at fixed
total exercise dose (ie, jogging versus walking ≈11
. miles/wk)
resulted in equivalent improvements in peak VO2, whereas a
program with variable dose but fixed intensity (ie, walking ≈17
.
versus ≈11 miles/wk) led to greater improvement in peak VO2
in the group who walked more.77 Physical fitness is determined
by numerous factors other than exercise dose, including age,
sex, body mass, and genetics.80 The individual response to
exercise training therefore varies widely, as evidenced by the
observation that 8 months of standardized exercise exposure
.
(jogging 17 miles/wk) led to changes in peak VO2 that ranged
from −5% to +70%.77 In addition, the relationship between
objectively measured fitness and exercise dose is further com-
plicated by exercise modality, particularly among the very fit
who may train primarily with a form of exercise (Nordic ski-
ing, swimming, etc) that may not easily be reproduced during
laboratory-based testing.
Finally, it noteworthy that physical fitness appears to be
far more responsive to exercise training than any of the more
traditional cardiovascular risk factors discussed above. This
observation may in part reconcile the finding that routine PA
attenuates the risk of CVD and mortality more than can be
explained by its impact on risk factor modulation. Specifically,
an analysis of data from the Women’s Health Study suggested
that exercise-mediated modification of traditional risk factors
explains only 59% of the inverse association between PA and
cardiovascular events.81 This finding suggests that we have
much to learn about the protective effects of exercise and
that a sizable portion of the overall beneficial effect of exer-
cise appears to be delivered through mechanisms that remain
elusive.82 Therefore, understanding the relationship between
traditional risk factors and exercise dose is not adequate to
describe the dose-response curve for exercise and mortality.
It is clear that there is a dose-response relationship between
exercise and fitness, although to what degree exercise dose
prescriptions should target objective physical fitness goals
remains unknown.
Mortality
To date, no RCTs have been designed to examine the impact
of PA on mortality. However, a compelling indirect relation-
ship between routine PA habits and mortality has been clearly
demonstrated. For example, the Harvard Alumni Health Study,
which began in 1962 with the enrollment of ≈17 000 healthy
male alumni and prospectively followed up this cohort for >30
years, demonstrated a direct and graded relationship between
exercise dose (from 500 to >3500 kcal/ wk) and mortality.
Importantly, the most marked reduction in risk was associated
with moving from the <500- to the 500- to 999-kcal/wk PA
category. Numerous other high-quality observational studies
have similarly shown that increasing routine PA is associated
with reductions in CVD risk and mortality in a dose-response
fashion.11,81,83–89
Exercise Versus Total PA: 30
Minutes Versus 10 000 Steps
Exercise, an important subset of PA, is relatively easy to
quantify and thus has historically been the primary focus in
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
studies examining PA. There is now growing interest in defin-
ing the relationship between total daily PA, including but not
limited to dedicated exercise dose, and key health outcomes.
The concept that “nonexercise” PA (nonmotorized commut-
ing, occupational activity, etc) beneficially affects health has
been demonstrated by several recent studies that show strong
associations between time spent sitting and mortality90 and
routine standing breaks interspersed within typically seated
routine activities of daily living.91 In addition, mortality risk
among individuals who routinely meet or exceed current PA
guidelines through structured exercise may be significantly
moderated by PA habits during the nonexercise portions of
the day.92,93
Advances in our understanding of total PA exposure have
been facilitated by technology. Commercially available fit-
ness monitors designed to estimate daily energy expenditure
or to measure daily step counts have become widely avail-
able. Although most of these devices accurately measure step
counts during exercise that involves walking or running, they
may be less accurate for step accrual during nonexercise PA
and may significantly underestimate and overestimate daily
energy expenditure without predictable variation patterns.94
In addition, step counts provide no information about the
intensity during which steps are accumulated and thus are not
useful for accurately determine daily energy expenditure or
exercise dose as defined in research settings. In clinical prac-
tice, a common recommendation is to aim for 10 000 steps per
day. This recommendation originates from a Japanese pedom-
eter developed in the 1960s that was named and marketed as
the “10 000 steps meter,” not from any rigorous science link-
ing this step count with clinical outcomes. Although there is
now emerging literature supporting a link between daily PA
in this approximate range and beneficial health outcomes,95
more work is required to define the optimal daily step count
and other similar metrics of nonexercise PA. In the interim, we
support the use of fitness monitors in clinical practice because
patients often find that they provide motivation that translates
into substantive increases in overall PA dose.96
Current Exercise Recommendations:
The Data Behind the Dose
As evidence supporting the link between exercise and favor-
able health outcomes continued to mount, 3 independently
generated PA guidelines were published in the 1990s to 2000s.
Writing groups representing the American College of Sports
Medicine and the Centers for Disease Control, the National
Institutes of Health, and the US Department of Health and
Human Services (HHS) each concluded that routine moder-
ate-intensity exercise was an effective means to reduce the
overall risk of chronic disease. The consistent recommenda-
tion across these initial guidelines was that all people should
engage in at least 30 minutes of moderate-intensity exercise on
most, preferably all, days of the week.97–99 This approximate
recommended dose remains the cornerstone of public health
PA guidelines. The most recent guidelines by the HHS in 2008
and the World Health Organization in 2010 suggest a total of
at least 150 minutes of weekly moderate-intensity activity
(3–6 METs) or ≈450 to 900 MET-min/wk.14,100 More recent
 Wasfy and Baggish
guidelines by the American Heart Association and American
College of Cardiology recommended a similar total amount
of exercise, although divided into sessions of longer duration
(40 versus 30 minutes) and performed less frequently (3–4
rather than 5 sessions per week), on the basis of their review
of the literature specific to reduction in BP and improvement
in lipids.30 Walking at 3 mph (3.3 METs) for 150 minutes
achieves the minimum target of ≈500 MET-minutes that all
of these guidelines have in common. However, for those who
choose higher-intensity activity (>6 METs), the HHS guide-
lines endorse a shorter total duration of exercise. For example,
jogging at 6 mph (10 METs) for a weekly total of 75 minutes
amounts to 750 MET-minutes, thus meeting the dose target.
It is noteworthy that the HHS guidelines recognize an exer-
cise dose of 450 to 900 MET-min/wk as the minimum neces-
sary to promote health and acknowledge the potential role of
higher total doses and intensities of exercise for individuals
with specific goals, including fitness optimization or weight
management.
A strong literature base supports the 2008 HHS recom-
mendation for an exercise dose of 450 to 900 MET-min/
wk. Authors of these guidelines reviewed a total of 73 stud-
ies published from 1995 to 2007, of which the majority were
prospective, observational studies.14 This aggregate cohort
included >1 million subjects with substantial age, ethnicity,
and sex heterogeneity and captured ≈140 000 deaths over a
median follow-up of ≈12 years. The overall relative risk of
death after adjustment for measured confounders was 0.69 (ie,
31% risk reduction for death) when the most active subjects
were compared with the least active subjects. Findings were
similar for men and women, and risk reduction (0.56) was
even greater in individuals >65 years old.101–109
The specific dose recommendation of 150 minutes
of moderate-intensity weekly exercise was based on the
observation that 2 to 2.5 hours of moderate-intensity PA
appeared to be the minimum amount required reduce the
all-cause mortality rate. However, careful inspection of the
exercise dose–mortality relationship does not demonstrate a
meaningful inflection point at this specific dose of exercise
(Figure 1). On the basis of data from 11 large, epidemio-
logical studies that each contained at least 5 levels of exer-
cise dose and in which exercise dose could be converted to a
common metric of hours per week of moderate to vigorous
exercise, the exercise dose-response mortality curve appears
curvilinear, with the largest risk reduction occurring at the
lowest end of the exercise dose spectrum. Compared with an
essentially sedentary lifestyle (<0.5 h/wk of moderate to vig-
orous exercise), 1.5 hours of moderate- to vigorous-intensity
exercise is associated with a 20% risk reduction in mortal-
ity. To attain an additional 20% risk reduction (for a total
of 40% risk reduction in mortality), an additional 5.5 hours
of moderate to vigorous exercise was required for a total of
7 h/wk. At the range of exercise examined (up to 7 h/wk
of moderate to vigorous exercise), mortality risk continued
to decrease as dose increased. Although increasing exercise
doses were associated with diminishing returns, there was
no exercise dose at which more did not yield progressive
benefit. It is important to note that the methods used to pro-
duce these estimates preclude any statistical evaluation of
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Exercise Dose in Clinical Practice 2305
the shape of the curve. Therefore, these data do not permit
a determination of the minimum dose required for benefit
or the maximum dose at which point the added benefit of
exercise may end. Since the publication of the 2008 HHS
guidelines, several important, large, epidemiological studies
have further addressed both ends of the exercise spectrum, as
discussed below (Table 3).110–112
Low-Dose Exercise: “Some
Is Better Than None”
Current PA recommendations were designed to optimize
health outcomes, not to determine minimum exercise doses
that afford tangible benefit. It is becoming increasingly recog-
nized that relatively small doses of routine exercise have the
potential to confer significant health benefit. In the Nurse’s
Health Study, a study of middle-aged and older women, a
significant reduction in all-cause mortality was found with as
little as 1 to 1.9 hours of weekly moderate to vigorous exer-
cise (adjusted relative risk [RR], 0.82; 95% confidence inter-
val [CI], 0.76–0.89), and further increases in exercise dose of
up to ≥7 h/wk were associated with only minimal (and sta-
tistically insignificant) additional risk reduction.106 A study of
elderly men similarly found that as little as 1 hour of walk-
ing or cycling per week was associated with reduced all-cause
mortality risk (adjusted relative risk, 0.69; 95% CI, 0.58–
0.88), whereas another investigation of elderly people found
that even being an “occasional” exerciser (<1 time per week)
conferred a mortality risk reduction of 28%.104 The risk of
CVD (coronary disease and stroke) has recently been shown
to be similarly reduced by low-dose exercise in older adults,
with those walking as little as 6 to 12 blocks per week having
significantly reduced risk of incident CVD (hazard ratio, 0.7;
95% CI, 0.58–0.83).113
Several recent large, prospective, cohort studies in adult
populations with broader age ranges have found benefit from
small doses of exercise. In a large cohort (661 137 participants
pooled from 6 individual studies) with 116 686 deaths over a
median follow-up of 14.2 years, small amounts of exercise
(0.1–7.5 MET-h/wk) conferred a 20% relative mortality risk
reduction (hazard ratio, 0.80; 95% CI, 0.78–0.82) compared
with a sedentary lifestyle.112 This study also found that rela-
tive death risk continued declining by an additional 9% with
exercise levels approximating current guidelines (7.5–15
MET-hours) and an additional 9% with doses of exercise
that exceed guideline recommendations by 3 to 5 times (39%
risk reduction, 22.5–45 MET-hours). In a separate study of
Taiwanese adults, a cohort suggested by the authors as having
lower baseline PA than Western adults, subguideline exercise
doses (4.5 MET-hours or 90 minutes of moderate activity per
week) were associated with a significant reduction in all-cause
mortality risk of 14% (relative risk, 0.86; 95% CI, 0.81–0.91)
and improvement in life expectancy by 3 years.110 In sum-
mary, exercise doses well below those proposed by current
guidelines appear to have a significant impact on health and
longevity. In clinical practice, this translates into the impor-
tant concept that it is the least active individuals who stand to
benefit the most from even the smallest increments in exercise
and PA.
2306 Circulation June 7, 2016
High-Dose Exercise: “More May Not Be
Better but Is Not Necessarily Bad”
A growing segment of the global population chooses to
participate in high levels of strenuous exercise for myriad
reasons, including athletic performance, socialization, and
weight management. Epidemiological data examining prior
elite athletes, a group that by definition engages in exception-
ally high exercise doses with respect to frequency, duration,
and intensity during their first few decades of life, consis-
tently document desirable late-life outcomes. Specifically,
previously elite athletes appear to use comparatively less
hospital resources114; require fewer asthma, cardiovascular,
and anti-inflammatory medications115; and live longer than
nonathletic counterparts.116–118 Despite these compelling prior
studies, there has been recent concern that high levels of
strenuous exercise may do more harm than good. It has been
suggested that the upper end of the exercise dose–response
curve for mortality may be reverse J or even U shaped with
the highest exercise doses reducing or completely eliminat-
ing the tangible health benefits afforded by lower doses. The
contemporary basis for this largely theoretical concern stems
from several lines of evidence, including recently published
epidemiological, exercise physiology/cardiac biomarker, and
cardiac structure/function data, as recently summarized and
debated.119,120
Assessment of mortality risk for the upper end of exer-
cise dose is hindered by the fact that most population-based
cohort studies have relatively few individuals who exercise at
doses that substantially exceed PA recommendations. In the
Copenhagen City Heart Study, an observational study that
demonstrated favorable longevity among light- and moderate-
dose joggers, individuals who were “strenuous” regular jog-
gers had a higher hazard ratio for death (hazard ratio, 1.97,
0.48–8.14) than the reference group of sedentary control
subjects. This observation raised concerns about a possible
U-shaped association between mortality and jogging dose.121
However, as reflected by the wide and overlapping CIs, this
conclusion is not supported by statistical significance owing
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Figure 1. Exercise dose and mortality. In a
broad-based literature review, the 2008 US
Department of Health and Human Services
(HHS) physical activity guidelines identified
12 epidemiological studies examining the
exercise dose response and mortality that
included at least 5 exercise levels.9,10,87,101–109
The relative risk (RR) of mortality across
exercise levels in each study is plotted. Of
these studies, 11 used an exercise dose unit
that was convertible to hours of moderate
to vigorous exercise. The median exercise
amount (h/wk) at each exercise level is shown
in the chart. The median RR of mortality at
each exercise level in these 11 studies (large
black circles) demonstrates a curvilinear
shape of the dose-response curve. Adapted
from Physical Activity Guidelines Advisory
Committee Report, 2008.14
to low representation of strenuous joggers in the study group
(4%) and a correspondingly small number of deaths (n=2)
during the follow-up period.
Two recent studies have attempted to more accurately
define the risk of mortality at the upper end of exercise dose.
The Aerobics Center Longitudinal Study evaluated all-cause
and CVD mortality in >13 000 runners over a mean follow-
up of 15 years.111 Using quintiles of weekly running dose and
thereby analyzing groups with equal participant numbers, the
investigators found that the jogging dose and mortality curve
was J shaped, not U shaped. This finding reinforces the notion
that light to moderate doses of exercise have a substantial
positive impact on health but that continued dose escalation
appears neither incrementally better nor worse. Similarly,
Arem et al112 recently pooled 6 separate studies with exer-
cise dose data from the National Cancer Institute Cohort
Consortium to amass a cohort of >600 000 participants. The
most active group (n=4077) reported exercise levels that were
≈10 times the levels recommended by HHS guidelines (ie,
75 MET-h/wk of activity, >176 min/wk of running) and were
found to have lower rates of mortality than sedentary people
and mortality rates statistically similar to those who were
exposed to more moderate exercise doses. Careful inspection
of the group at the highest exercise dose in this study reveals
a slight trend toward increasing mortality and a widening of
the CI around this point estimate. Although this may again
reflect a relatively smaller sample size compared the group at
the next lowest exercise dose (40–75 MET-h/wk of activity,
n=18 831), it is possible if not probable that there is a hetero-
geneous response to such high levels of exercise. In summary,
the majority of currently available data suggest that high-dose
exercise is associated with lower risks of CVD and mortality
than a sedentary lifestyle. Whether some portion of the pro-
tective benefits of exercise is lost at the highest ends of the
dose spectrum remains uncertain. If benefit attenuation at high
exercise doses does indeed occur, there is an emerging list of
potential mechanistic mediators that have arisen from recent
observational work.
 Wasfy and Baggish Exercise Dose in Clinical Practice 2307

Table 3. Selected Large Contemporary Epidemiological Studies of Exercise Dose and All-Cause Mortality
Mortality at Lowest
(Nonsedentary) Exercise Exercise Dose With Mortality at Highest
Study Population Dose Lowest Mortality Exercise Dose Key Points
Wen et al 110
Taiwanese adults, HR=0.86 HR=0.65 HR=0.65 (95% CI, Very low-level PA (ie, 90 min/wk
n=416 175 (95% CI, 0.81-0.91)* (95% CI, 0.65–0.77)* 0.65–0.77)* at moderate intensity) significantly
Follow-up: 8 y Dose: 3.75–7.49 Dose: Dose: ≥25.5 MET-h/wk ↓ mortality
MET-h/wk ≥25.5 MET-h/wk No upper limit of mortality benefit
Dose-response trend: curvilinear
Lee et al111 Adults, n=55 137 (24% HR=0.70 HR=0.67 HR=0.77 (95% CI, All doses of running similarly
runners) (95% CI, 0.58–0.85)* (95% CI, 0.55–0.82)* 0.63–0.92)* reduced mortality vs nonrunners
Follow-up: 15 y Dose: Dose: Dose: >176 min/wk No additional benefit but also
<51 min/wk running 81-119 min/wk running running no statistically significant harm
apparent beyond 120 min/wk
Dose-response trend: J-shaped
curve
Arem et al112 Adults, n=661 137 HR=0.80 HR=0.61 HR=0.69 (95% CI, Low-level PA (less than current
Follow-up: 14 y (95% CI, 0.78–0.82)* (95% CI, 0.58-0.64)* 0.59–0.78)* recommendations) significantly ↓
Dose: Dose: Dose:≥75 MET-h/wk mortality
0.1–7.5 MET-h/wk 40-75 MET-h/wk Mortality risk reduction plateaued
at ≈3–10 times the recommended
PA levels and ↑ nonsignificantly at
higher levels
Dose-response trend: J-shaped
curve
CI indicates confidence interval; HR, hazard ratio; MET-h, metabolic equivalents·hours of exercise; and PA, physical activity.
*Significantly lower than baseline risk of mortality in sedentary individuals.

It has been suggested that high-dose exercise may cause
or accelerate coronary atherosclerosis on the basis of 1 study
that demonstrated higher coronary artery calcium scores in
older marathon runners than among sedentary control subjects
matched for Framingham Risk Score.122 It is notable that more
than half of the marathon runners in this study were former
smokers and thus had a plausible explanation for the pres-
ence of coronary atherosclerosis independently of marathon
training. In our opinion, it is unlikely that high-dose vigor-
ous exercise initiated the process of coronary atherosclerosis
but very possible that it potentiated the atherosclerotic process
by inducing repetitive hemodynamic arterial shear stress or
a chronic proinflammatory state. To what degree high-dose
exercise modulates the underlying biology of atherosclerosis
remains a complex and poorly understood topic.
There have now been numerous observational reports
of cardiac troponin elevation after long-duration endurance
races.123 These observations have led to the hypothesis that
such sporting events, particularly when engaged in repeti-
tively over many years, may precipitate permanent myocardial
damage in the form of fibrosis.124,125 However, studies pairing
cardiac imaging with necrosis marker assessment have not
consistently shown an association between troponin elevation
and acute or chronic myocardial dysfunction,126–129 and care-
fully controlled laboratory-based exercise testing has dem-
onstrated that acute exercise-induced troponin elevation is a
nearly ubiquitous phenomenon among healthy subjects.130,131
Benign and perhaps adaptive explanations for exercise-
induced troponin elevation and alternative pathogenic mech-
anisms for ventricular fibrosis among athletes have been
proposed.132 It is most likely that high-dose exercise injures
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
the heart muscle infrequently and only among athletes with an
additional susceptibility factor such as subclinical myocardi-
tis, surreptitious performance-enhancing drug use, or occult
genetic susceptibility.
Although it remains unclear whether vigorous, long-
term endurance exercise may accelerate atherosclerosis or
cause adverse cardiac remodeling in some people, it is well-
established that acute bouts of physical exercise transiently
increase the risk of sudden death.133,134 The risk of sudden
death during exercise appears to be highest among people har-
boring underlying genetic or acquired CVD,135–137 and prelim-
inary observational data suggest that vigorous exercise may
accelerate the phenotypic expression of arrhythmogenic right
ventricular cardiomyopathy.138,139 These findings emphasize
the potential importance of conservative exercise dose recom-
mendations among patients with established CVD in second-
ary prevention clinical settings. As recently reviewed, cardiac
rehabilitation programs provide a useful resource for starting
and tailoring an exercise program in patients with established
CVD.2 However, the risk of an acute cardiac event during
exercise appears coupled with an overall reduction in rates of
sudden death among those who engage in the highest levels
of PA and exercise. This apparent exercise paradox must be
considered when counseling avid exercisers about the inherent
risks and benefits of high-dose exercise.
Clinical Implications: Exercise
Dose in the Clinical Practice
Careful consideration of data defining the relationships
between exercise dose and clinical outcomes is required for
meaningful application of exercise dose counseling in clinical
2308 Circulation June 7, 2016
cardiovascular practice. In our clinical cardiology practice, we
encounter the entire spectrum of PA, from completely seden-
tary patients to highly active elite athletes who seek care in
our sports cardiology program. We assess PA habits and exer-
cise dose exposure with each patient on a routine basis. As
previously suggested,140 we endorse the use of a PA vital sign
that captures each element of exercise dose, including inten-
sity, duration, and frequency. These data can be accurately
ascertained, rapidly quantified, and recorded in the medical
record. We recommend using data reflected in the PA vital
sign to classify patients into 1 of 3 PA categories: routinely
fails to meet PA recommendations, routinely meets PA recom-
mendations, and routinely exceeds PA recommendations. An
algorithm for downstream management considerations based
on this simple classification scheme is shown in Figure 2.
Evaluating PA in this manner during every clinical visit may
be difficult because of competing priorities. Thus, we advo-
cate addressing PA at least annually and more often in those
who continually fail to meet PA recommendations.
Patients who routinely fail to meet PA recommendations
represent the clinician’s greatest opportunity for clinical out-
come–directed exercise dose counseling. This discussion is
often best initiated by addressing the numerous risks associ-
ated with physical inactivity. On a patient-by-patient basis, it
is crucial to address both perceived and objective barriers to
performing adequate doses of PA. Perceived barriers to increas-
ing PA, including time constraints, lack of motivation, and fear
Figure 2. Integration of exercise dose in clinical practice. Algorithmic approach to the assessment and management of patients in clinical
practice based on habitual physical activity (PA) and exercise dose exposure. PAR indicates physical activity recommendation.
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
of injury or adverse outcomes, are common but amenable to
revision through discussion. Objective barriers, including
orthopedic limitations and physiological limitations imposed
by medications or comorbid disease, are similarly common and
represent areas for directed interventions in the form of refer-
ral to clinicians with musculoskeletal expertise and tailored
pharmacotherapy with an emphasis on maximizing exercise
capacity. Following these steps, it becomes possible to devise a
PA/exercise dose recommendation that is geared to eventually
meeting current PA recommendations. As discussed above, the
use of wearable fitness trackers has become increasingly com-
mon. These devices provide data defining PA habits of accept-
able accuracy for some types of activity,141 although it remains
to be seen whether they can effect long-term change in exercise
habits. In our experience, the use of wearable devices coupled
with the provision of quantitative exercise prescriptions is often
helpful to motivate patients to meet their individualized PA
goals. This process often requires multiple clinic visits and may
best be accomplished by a team approach that includes physi-
cians and advanced care providers, including nurses, physi-
cian assistants, and exercise physiologists.
Patients who routinely meet PA recommendations deserve
positive reinforcement. The process of reinforcement almost
uniformly contributes to positive patient-provider interac-
tions and ultimately may facilitate long-term PA recommen-
dation compliance. We encourage routine discussions about
key ingredients for success and subsequent documentation
 Wasfy and Baggish
of these findings. In our experience, a priori knowledge of
patient PA patterns is of tremendous value in subsequent clinic
interactions when PA/exercise habits may have regressed to
suboptimal levels.
Patients who routinely exceed PA recommendations are
increasingly common both in general cardiovascular practice
and in specialized sports cardiology programs. These patients
often present with distinct psychosocial profiles, medical
concerns, and atypical disease presentation. Despite the fact
that routine exposure to high exercise doses confers relative
protection from CVD, it must be emphasized that no level of
exercise confers immunity. It is essential to avoid the tendency
to minimize the importance of subjective complaints, particu-
larly those of exertional symptoms and relative reductions in
exercise, among patients who are capable of high levels of
exercise. In this patient population, atypical symptoms and
small but significant decrements in exercise capacity are often
indicators of evolving CVDs.
With patients who chose to exceed PA recommenda-
tions, we routinely discuss the concept of diminishing returns
with respect to health outcomes. Practically, exercising at the
extreme high end of the exercise dose spectrum is not required
for health optimization. We routinely approach patients who
choose to exercise at high doses with an open discussion about
both theoretical and data-driven risks and benefits. In essence,
this conversation is about potential tradeoffs, including bal-
ancing negative attributes such as increased risk of atrial fibril-
lation with positive attributes such as traditional risk factor
management and in some cases overall quality of life. In our
experience, patients who chose to exercise at high doses do
not uniformly adapt other healthy lifestyle choices. Therefore,
we encourage active screening for unhealthy dietary intake,
excessive alcohol consumption, and unchecked exposure
to psychological stress, as we would in any other patient
population.
Conclusions
Decades of scientific inquiry have led to the indisputable
fact that routine exercise or high levels of PA confer posi-
tive cardiovascular health benefits. Exercise and PA, much
like medications used in clinical practice, are best measured
and prescribed by consideration of dose, which is a func-
tion of 3 principal attributes: intensity, duration, and fre-
quency. PA guidelines are based on a solid epidemiological
foundation, and numerous RCTs have begun to delineate the
mechanisms by which exercise leads to health and longev-
ity. In clinical cardiovascular practice, exercise dose and
PA habits can and should be addressed with each patient
with an ultimate goal of individualized counseling and exer-
cise prescription. Although progress has been made, there
is much to be learned. Refinements in our understanding
of how exercise dose across the spectrum affects cardiovas-
cular health are needed. Future gains will best be accom-
plished by the use of complementary strategies that include
prioritized scientific funding, widespread application of
technology designed to measure exercise dose both in clini-
cal trials and in real-world living, and focused translational
work geared toward delineating cellular and biochemical
responses to exercise.
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Exercise Dose in Clinical Practice 2309
Sources of Funding
Dr Wasfy is supported by research grant funding from the American
College of Cardiology (American College of Cardiology/Merck
Fellowship). Dr Baggish is supported by research grants from the
National Institutes of Health (RO1 DA029141, RO1 HL117037, RO1
HL125869)
Disclosures
None.
References
1. Shiroma EJ, Lee IM. Physical activity and cardiovascular health:
lessons learned from epidemiological studies across age, gender,
and race/ethnicity. Circulation. 2010;122:743–752. doi: 10.1161/
CIRCULATIONAHA.109.914721.
2. Eijsvogels TM, Molossi S, Lee DC, Emery MS, Thompson PD. Exercise
at the extremes: the amount of exercise to reduce cardiovascular events. J
Am Coll Cardiol. 2016;67:316–329. doi: 10.1016/j.jacc.2015.11.034.
3. Berryman J. The tradition of the “six things non-natural”: exercise and
medicine from Hippocrates through ante-bellum America. In: Holloszy
JO, ed. Exercise and Sports Sciences Reviews. Baltimore, MD: Williams
& Wilkins; 1989:515-559.
4. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary heart-
disease and physical activity of work. Lancet. 1953;265:1053–1057; contd.
5. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary heart-
disease and physical activity of work. Lancet. 1953;265:1111–1120;
concl.
6. Morris JN, Kagan A, Pattison DC, Gardner MJ. Incidence and pre-
diction of ischaemic heart-disease in London busmen. Lancet.
1966;2:553–559.
7. Morris JN, Chave SP, Adam C, Sirey C, Epstein L, Sheehan DJ. Vigorous
exercise in leisure-time and the incidence of coronary heart-disease.
Lancet. 1973;1:333–339.
8. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activ-
ity and the incidence of coronary heart disease. Annu Rev Public Health.
1987;8:253–287. doi: 10.1146/annurev.pu.08.050187.001345.
9. Lee IM, Hsieh CC, Paffenbarger RS Jr. Exercise intensity and longevity in
men. The Harvard Alumni Health Study. JAMA. 1995;273:1179–1184.
10. Lee IM, Paffenbarger RS Jr. Associations of light, moderate, and vigor-
ous intensity physical activity with longevity: the Harvard Alumni Health
Study. Am J Epidemiol. 2000;151:293–299.
11. Manson JE, Hu FB, Rich-Edwards JW, Colditz GA, Stampfer MJ,
Willett WC, Speizer FE, Hennekens CH. A prospective study of walk-
ing as compared with vigorous exercise in the prevention of coronary
heart disease in women. N Engl J Med. 1999;341:650–658. doi: 10.1056/
NEJM199908263410904.
12. Heady JA, Morris JN, Raffle PA. Physique of London busmen; epidemiol-
ogy of uniforms. Lancet. 1956;271:569–570.
13. Heady JA, Morris JN, Kagan A, Raffle PA. Coronary heart disease in
London busmen: a progress report with particular reference to physique.
Br J Prev Soc Med. 1961;15:143–153.
14. Physical Activity Guidelines Advisory Committee. Physical Activity
Guidelines Advisory Committee Report, 2008. Washington, DC: US
Department of Health and Human Services; 2008
15. Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB,
McCartney JS, Bales CW, Henes S, Samsa GP, Otvos JD, Kulkarni
KR, Slentz CA. Effects of the amount and intensity of exercise on
plasma lipoproteins. N Engl J Med. 2002;347:1483–1492. doi: 10.1056/
NEJMoa020194.
16. Duncan JJ, Gordon NF, Scott CB. Women walking for health and fitness:
how much is enough? JAMA. 1991;266:3295–3299.
17. Woolf-May K, Kearney EM, Owen A, Jones DW, Davison RC, Bird SR.
The efficacy of accumulated short bouts versus single daily bouts of brisk
walking in improving aerobic fitness and blood lipid profiles. Health Educ
Res. 1999;14:803–815.
18. Braith RW, Pollock ML, Lowenthal DT, Graves JE, Limacher MC.
Moderate- and high-intensity exercise lowers blood pressure in normoten-
sive subjects 60 to 79 years of age. Am J Cardiol. 1994;73:1124–1128.
19. Molmen-Hansen HE, Stolen T, Tjonna AE, Aamot IL, Ekeberg IS, Tyldum
GA, Wisloff U, Ingul CB, Stoylen A. Aerobic interval training reduces
blood pressure and improves myocardial function in hypertensive patients.
Eur J Prev Cardiol. 2012;19:151–160. doi: 10.1177/1741826711400512.
2310 Circulation June 7, 2016
20. Marceau M, Kouamé N, Lacourcière Y, Cléroux J. Effects of different
training intensities on 24-hour blood pressure in hypertensive subjects.
Circulation. 1993;88:2803–2811.
21. Hagberg JM, Montain SJ, Martin WH 3rd, Ehsani AA. Effect of exercise
training in 60- to 69-year-old persons with essential hypertension. Am J
Cardiol. 1989;64:348–353.
22. DiPietro L, Dziura J, Yeckel CW, Neufer PD. Exercise and improved
insulin sensitivity in older women: evidence of the enduring benefits of
higher intensity training. J Appl Physiol (1985). 2006;100:142–149. doi:
10.1152/japplphysiol.00474.2005.
23. Coker RH, Hays NP, Williams RH, Brown AD, Freeling SA, Kortebein
PM, Sullivan DH, Starling RD, Evans WJ. Exercise-induced changes in
insulin action and glycogen metabolism in elderly adults. Med Sci Sports
Exerc. 2006;38:433–438. doi: 10.1249/01.mss.0000191417.48710.11.
24. Tjønna AE, Lee SJ, Rognmo Ø, Stølen TO, Bye A, Haram PM, Loennechen
JP, Al-Share QY, Skogvoll E, Slørdahl SA, Kemi OJ, Najjar SM, Wisløff
U. Aerobic interval training versus continuous moderate exercise as
a treatment for the metabolic syndrome: a pilot study. Circulation.
2008;118:346–354. doi: 10.1161/CIRCULATIONAHA.108.772822.
25. Johnson JL, Slentz CA, Houmard JA, Samsa GP, Duscha BD, Aiken
LB, McCartney JS, Tanner CJ, Kraus WE. Exercise training amount
and intensity effects on metabolic syndrome (from Studies of a Targeted
Risk Reduction Intervention through Defined Exercise). Am J Cardiol.
2007;100:1759–1766. doi: 10.1016/j.amjcard.2007.07.027.
26. Irwin ML, Yasui Y, Ulrich CM, Bowen D, Rudolph RE, Schwartz RS,
Yukawa M, Aiello E, Potter JD, McTiernan A. Effect of exercise on total
and intra-abdominal body fat in postmenopausal women: a randomized
controlled trial. JAMA. 2003;289:323–330.
27. Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, Tanner
CJ, Duscha BD, Kraus WE. Inactivity, exercise, and visceral fat:
STRRIDE: a randomized, controlled study of exercise intensity and
amount. J Appl Physiol (1985). 2005;99:1613–1618. doi: 10.1152/
japplphysiol.00124.2005.
28. McTiernan A, Sorensen B, Irwin ML, Morgan A, Yasui Y, Rudolph RE,
Surawicz C, Lampe JW, Lampe PD, Ayub K, Potter JD. Exercise effect
on weight and body fat in men and women. Obesity (Silver Spring).
2007;15:1496–1512. doi: 10.1038/oby.2007.178.
29. Kodama S, Tanaka S, Saito K, Shu M, Sone Y, Onitake F, Suzuki E,
Shimano H, Yamamoto S, Kondo K, Ohashi Y, Yamada N, Sone H. Effect
of aerobic exercise training on serum levels of high-density lipoprotein
cholesterol: a meta-analysis. Arch Intern Med. 2007;167:999–1008. doi:
10.1001/archinte.167.10.999.
30. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard
VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM,
Smith SC Jr, Svetkey LP, Wadden TA, Yanovski SZ, Kendall KA, Morgan
LC, Trisolini MG, Velasco G, Wnek J, Anderson JL, Halperin JL, Albert NM,
Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ,
Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF;
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to
reduce cardiovascular risk: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation.
2014;129(suppl 2):S76–S99. doi: 10.1161/01.cir.0000437740.48606.d1.
31. Dressendorfer RH, Wade CE, Hornick C, Timmis GC. High-density lipo-
protein-cholesterol in marathon runners during a 20-day road race. JAMA.
1982;247:1715–1717.
32. Williams PT. High-density lipoprotein cholesterol and other risk factors for
coronary heart disease in female runners. N Engl J Med. 1996;334:1298–
1303. doi: 10.1056/NEJM199605163342004.
33. Williams PT. Relationship of distance run per week to coronary heart
disease risk factors in 8283 male runners: the National Runners’ Health
Study. Arch Intern Med. 1997;157:191–198.
34. Drygas W, Jegler A, Kunski H. Study on threshold dose of physical activ-
ity in coronary heart disease prevention, part I: relationship between lei-
sure time physical activity and coronary risk factors. Int J Sports Med.
1988;9:275–278. doi: 10.1055/s-2007-1025021.
35. Durstine JL, Grandjean PW, Davis PG, Ferguson MA, Alderson NL,
DuBose KD. Blood lipid and lipoprotein adaptations to exercise: a quanti-
tative analysis. Sports Med. 2001;31:1033–1062.
36. Leon AS, Sanchez OA. Response of blood lipids to exercise train-
ing alone or combined with dietary intervention. Med Sci Sports Exerc.
2001;33(suppl):S502–S515.
37. Kelley GA, Kelley KS, Tran ZV. Walking, lipids, and lipoproteins: a meta-
analysis of randomized controlled trials. Prev Med. 2004;38:651–661. doi:
10.1016/j.ypmed.2003.12.012.
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
38. Kelley GA, Kelley KS, Tran ZV. Aerobic exercise and lipids and
lipoproteins in women: a meta-analysis of randomized controlled tri-
als. J Womens Health (Larchmt). 2004;13:1148–1164. doi: 10.1089/
jwh.2004.13.1148.
39. Kelley GA, Kelley KS, Tran ZV. Exercise, lipids, and lipoproteins in older
adults: a meta-analysis. Prev Cardiol. 2005;8:206–214.
40. Kelley GA, Kelley KS. Effects of aerobic exercise on lipids and lipo-
proteins in adults with type 2 diabetes: a meta-analysis of randomized-
controlled trials. Public Health. 2007;121:643–655. doi: 10.1016/j.
puhe.2007.02.014.
41. Zilinski JL, Contursi ME, Isaacs SK, Deluca JR, Lewis GD, Weiner RB,
Hutter AM Jr, d’Hemecourt PA, Troyanos C, Dyer KS, Baggish AL.
Myocardial adaptations to recreational marathon training among middle-
aged men. Circ Cardiovasc Imaging. 2015;8:e002487. doi: 10.1161/
CIRCIMAGING.114.002487.
42. Slentz CA, Houmard JA, Johnson JL, Bateman LA, Tanner CJ, McCartney
JS, Duscha BD, Kraus WE. Inactivity, exercise training and detraining,
and plasma lipoproteins: STRRIDE: a randomized, controlled study of
exercise intensity and amount. J Appl Physiol (1985). 2007;103:432–442.
doi: 10.1152/japplphysiol.01314.2006.
43. Holloszy JO, Skinner JS, Toro G, Cureton TK. Effects of a six month pro-
gram of endurance exercise on the serum lipids of middle-aged man. Am J
Cardiol. 1964;14:753–760
44. Law MR, Wald NJ, Thompson SG. By how much and how quickly does
reduction in serum cholesterol concentration lower risk of ischaemic heart
disease? BMJ. 1994;308:367–372.
45. Pereira MA, Folsom AR, McGovern PG, Carpenter M, Arnett DK, Liao
D, Szklo M, Hutchinson RG. Physical activity and incident hypertension
in black and white adults: the Atherosclerosis Risk in Communities Study.
Prev Med. 1999;28:304–312.
46. Parker ED, Schmitz KH, Jacobs DR, Dengel DR, Schreiner PJ. Physical
activity in young adults and incident hypertension over 15 years of follow-
up: the CARDIA study. Am J Public Health. 2007;97:703–709
47. Paffenbarger RS Jr, Jung DL, Leung RW, Hyde RT. Physical activity and
hypertension: an epidemiological view. Ann Med. 1991;23:319–327.
48. Paffenbarger RS Jr, Lee IM. Intensity of physical activity related to inci-
dence of hypertension and all-cause mortality: an epidemiological view.
Blood Press Monit. 1997;2:115–123.
49. Fagard RH. Exercise characteristics and the blood pressure
response to dynamic physical training. Med Sci Sports Exerc.
2001;33(suppl):S484–S492.
50. Cornelissen VA, Fagard RH. Effects of endurance training on blood
pressure, blood pressure-regulating mechanisms, and cardiovascu-
lar risk factors. Hypertension. 2005;46:667–675. doi: 10.1161/01.
HYP.0000184225.05629.51.
51. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pres-
sure: a meta-analysis of randomized, controlled trials. Ann Intern Med.
2002;136:493–503.
52. Halbert JA, Silagy CA, Finucane P, Withers RT, Hamdorf PA, Andrews
GR. The effectiveness of exercise training in lowering blood pressure: a
meta-analysis of randomised controlled trials of 4 weeks or longer. J Hum
Hypertens. 1997;11:641–649.
53. Kelley G, Tran ZV. Aerobic exercise and normotensive adults: a meta-
analysis. Med Sci Sports Exerc. 1995;27:1371–1377.
54. Kelley GA, Kelley KA, Tran ZV. Aerobic exercise and resting blood
pressure: a meta-analytic review of randomized, controlled trials. Prev
Cardiol. 2001;4:73–80.
55. Tipton CM, Matthes RD, Marcus KD, Rowlett KA, Leininger JR.
Influences of exercise intensity, age, and medication on resting systolic
blood pressure of SHR populations. J Appl Physiol Respir Environ Exerc
Physiol. 1983;55:1305–1310.
56. Tipton CM, Sebastian LA, Overton JM, Woodman CR, Williams SB.
Chronic exercise and its hemodynamic influences on resting blood pres-
sure of hypertensive rats. J Appl Physiol (1985). 1991;71:2206–2210.
57. Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitiv-
ity. Annu Rev Med. 1998;49:235–261. doi: 10.1146/annurev.med.49.1.235.
58. Henriksen EJ. Invited review: effects of acute exercise and exercise train-
ing on insulin resistance. J Appl Physiol (1985). 2002;93:788–796. doi:
10.1152/japplphysiol.01219.2001.
59. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-
Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas
M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group.
Prevention of type 2 diabetes mellitus by changes in lifestyle among sub-
jects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–
1350. doi: 10.1056/NEJM200105033441801.
 Wasfy and Baggish
60. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM,
Walker EA, Nathan DM; Diabetes Prevention Program Research Group.
Reduction in the incidence of type 2 diabetes with lifestyle interven-
tion or metformin. N Engl J Med. 2002;346:393–403. doi: 10.1056/
NEJMoa012512.
61. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty
L, Hoskin M, Kriska AM, Mayer-Davis EJ, Pi-Sunyer X, Regensteiner J,
Venditti B, Wylie-Rosett J. Effect of weight loss with lifestyle interven-
tion on risk of diabetes. Diabetes Care. 2006;29:2102–2107. doi: 10.2337/
dc06-0560.
62. Laaksonen DE, Lindström J, Lakka TA, Eriksson JG, Niskanen L,
Wikström K, Aunola S, Keinänen-Kiukaanniemi S, Laakso M, Valle TT,
Ilanne-Parikka P, Louheranta A, Hämäläinen H, Rastas M, Salminen
V, Cepaitis Z, Hakumäki M, Kaikkonen H, Härkönen P, Sundvall J,
Tuomilehto J, Uusitupa M; Finnish Diabetes Prevention Study. Physical
activity in the prevention of type 2 diabetes: the Finnish Diabetes
Prevention Study. Diabetes. 2005;54:158–165.
63. Dubé JJ, Allison KF, Rousson V, Goodpaster BH, Amati F. Exercise dose
and insulin sensitivity: relevance for diabetes prevention. Med Sci Sports
Exerc. 2012;44:793–799. doi: 10.1249/MSS.0b013e31823f679f.
64. Kraus WE, Slentz CA. Exercise training, lipid regulation, and insu-
lin action: a tangled web of cause and effect. Obesity (Silver Spring).
2009;17(suppl 3):S21–S26. doi: 10.1038/oby.2009.384.
65. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate,
Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington,
DC: National Academy Press; 2002.
66. World Health Organization Consultation on Obesity. Obesity: Preventing
and Managing the Global Epidemic: Report of a WHO Consultation
on Obesity. Geneva, Switzerland: World Health Organization, Division
of Noncommunicable Disease, Programme of Nutrition Family and
Reproductive Health; 1998.
67. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato
KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen
BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe
BM, Yanovski SZ, Jordan HS, Kendall KA, Lux LJ, Mentor-Marcel R,
Morgan LC, Trisolini MG, Wnek J, Anderson JL, Halperin JL, Albert NM,
Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ,
Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli
GF; American College of Cardiology/American Heart Association Task
Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS
guideline for the management of overweight and obesity in adults: a
report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines and The Obesity Society. Circulation.
2014;129(suppl 2):S102–S138. doi: 10.1161/01.cir.0000437739.71477.ee.
68. Donnelly JE, Hill JO, Jacobsen DJ, Potteiger J, Sullivan DK, Johnson SL,
Heelan K, Hise M, Fennessey PV, Sonko B, Sharp T, Jakicic JM, Blair
SN, Tran ZV, Mayo M, Gibson C, Washburn RA. Effects of a 16-month
randomized controlled exercise trial on body weight and composition in
young, overweight men and women: the Midwest Exercise Trial. Arch
Intern Med. 2003;163:1343–1350. doi: 10.1001/archinte.163.11.1343.
69. Wing RR. Physical activity in the treatment of the adulthood overweight
and obesity: current evidence and research issues. Med Sci Sports Exerc.
1999;31(suppl):S547–S552.
70. Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I.
Reduction in obesity and related comorbid conditions after diet-induced
weight loss or exercise-induced weight loss in men: a randomized, con-
trolled trial. Ann Intern Med. 2000;133:92–103.
71. Ades PA, Savage PD, Toth MJ, Harvey-Berino J, Schneider DJ, Bunn JY,
Audelin MC, Ludlow M. High-calorie-expenditure exercise: a new approach
to cardiac rehabilitation for overweight coronary patients. Circulation.
2009;119:2671–2678. doi: 10.1161/CIRCULATIONAHA.108.834184.
72. Saris WH, Blair SN, van Baak MA, Eaton SB, Davies PS, Di Pietro
L, Fogelholm M, Rissanen A, Schoeller D, Swinburn B, Tremblay A,
Westerterp KR, Wyatt H. How much physical activity is enough to prevent
unhealthy weight gain? Outcome of the IASO 1st Stock Conference and
Consensus Statement. Obes Rev. 2003;4:101–114
73. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, Clark DG, Cooper KH,
Gibbons LW. Physical fitness and all-cause mortality: a prospective study
of healthy men and women. JAMA. 1989;262:2395–2401.
74. Blair SN, Kampert JB, Kohl HW 3rd, Barlow CE, Macera CA,
Paffenbarger RS Jr, Gibbons LW. Influences of cardiorespiratory fitness
and other precursors on cardiovascular disease and all-cause mortality in
men and women. JAMA. 1996;276:205–210.
75. Kokkinos P, Myers J, Faselis C, Panagiotakos DB, Doumas M, Pittaras
A, Manolis A, Kokkinos JP, Karasik P, Greenberg M, Papademetriou
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
Exercise Dose in Clinical Practice 2311
V, Fletcher R. Exercise capacity and mortality in older men: a 20-year
follow-up study. Circulation. 2010;122:790–797. doi: 10.1161/
CIRCULATIONAHA.110.938852.
76. Wenger HA, Bell GJ. The interactions of intensity, frequency and dura-
tion of exercise training in altering cardiorespiratory fitness. Sports Med.
1986;3:346–356.
77. Duscha BD, Slentz CA, Johnson JL, Houmard JA, Bensimhon DR, Knetzger
KJ, Kraus WE. Effects of exercise training amount and intensity on peak
oxygen consumption in middle-age men and women at risk for cardiovascu-
lar disease. Chest. 2005;128:2788–2793. doi: 10.1378/chest.128.4.2788.
78. Spina RJ. Cardiovascular adaptations to endurance exercise training in
older men and women. Exerc Sport Sci Rev. 1999;27:317–332.
79. Seals DR, Hagberg JM, Hurley BF, Ehsani AA, Holloszy JO. Endurance
training in older men and women, I: cardiovascular responses to exercise.
J Appl Physiol Respir Environ Exerc Physiol. 1984;57:1024–1029.
80. Bouchard C, Rankinen T. Individual differences in response to regular
physical activity. Med Sci Sports Exerc. 2001;33(suppl):S446–S451.
81. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced
risk of cardiovascular events: potential mediating mechanisms. Circulation.
2007;116:2110–2118. doi: 10.1161/CIRCULATIONAHA.107.729939.
82. Baggish AL. Mechanisms underlying the cardiac benefits of exercise:
still running in the dark. Trends Cardiovasc Med. 2015;25:537–539. doi:
10.1016/j.tcm.2015.01.006.
83. Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA.
Physical activity and mortality in postmenopausal women. JAMA.
1997;277:1287–1292.
84. Bijnen FC, Caspersen CJ, Feskens EJ, Saris WH, Mosterd WL, Kromhout D.
Physical activity and 10-year mortality from cardiovascular diseases and all
causes: the Zutphen Elderly Study. Arch Intern Med. 1998;158:1499–1505.
85. Hakim AA, Petrovitch H, Burchfiel CM, Ross GW, Rodriguez BL, White
LR, Yano K, Curb JD, Abbott RD. Effects of walking on mortality among
nonsmoking retired men. N Engl J Med. 1998;338:94–99. doi: 10.1056/
NEJM199801083380204.
86. Andersen LB, Schnohr P, Schroll M, Hein HO. All-cause mortality associ-
ated with physical activity during leisure time, work, sports, and cycling
to work. Arch Intern Med. 2000;160:1621–1628.
87. Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in
relation to cardiovascular disease and total mortality among men with
type 2 diabetes. Circulation. 2003;107:2435–2439. doi: 10.1161/01.
CIR.0000066906.11109.1F.
88. Hu G, Eriksson J, Barengo NC, Lakka TA, Valle TT, Nissinen A, Jousilahti
P, Tuomilehto J. Occupational, commuting, and leisure-time physical
activity in relation to total and cardiovascular mortality among Finnish
subjects with type 2 diabetes. Circulation. 2004;110:666–673. doi:
10.1161/01.CIR.0000138102.23783.94.
89. Manini TM, Everhart JE, Patel KV, Schoeller DA, Colbert LH, Visser M,
Tylavsky F, Bauer DC, Goodpaster BH, Harris TB. Daily activity energy
expenditure and mortality among older adults. JAMA. 2006;296:171–179.
doi: 10.1001/jama.296.2.171.
90. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time
and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med.
2012;172:494–500. doi: 10.1001/archinternmed.2011.2174.
91. Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter
DA. Sedentary time and its association with risk for disease incidence,
mortality, and hospitalization in adults: a systematic review and meta-
analysis. Ann Intern Med. 2015;162:123–132. doi: 10.7326/M14-1651.
92. Matthews CE, George SM, Moore SC, Bowles HR, Blair A, Park Y,
Troiano RP, Hollenbeck A, Schatzkin A. Amount of time spent in seden-
tary behaviors and cause-specific mortality in US adults. Am J Clin Nutr.
2012;95:437–445. doi: 10.3945/ajcn.111.019620.
93. Patel AV, Bernstein L, Deka A, Feigelson HS, Campbell PT, Gapstur SM,
Colditz GA, Thun MJ. Leisure time spent sitting in relation to total mortal-
ity in a prospective cohort of US adults. Am J Epidemiol. 2010;172:419–
429. doi: 10.1093/aje/kwq155.
94. Nelson MB, Kaminsky LA, Dickin DC, Montoye AH. Validity of con-
sumer-based physical activity monitors for specific activity types [pub-
lished online ahead of print March 25, 2016]. Med Sci Sports Exerc. doi:
10.1249/MSS.0000000000000933. http://journals.lww.com/acsm-msse/
pages/articleviewer.aspx?year=9000&issue=00000&article=97563&type
=abstract. Accessed April 1, 2016.
95. Pillay JD, van der Ploeg HP, Kolbe-Alexander TL, Proper KI, van Stralen M,
Tomaz SA, van Mechelen W, Lambert EV. The association between daily
steps and health, and the mediating role of body composition: a pedome-
ter-based, cross-sectional study in an employed South African population.
BMC Public Health. 2015;15:174. doi: 10.1186/s12889-015-1381-6.
2312 Circulation June 7, 2016
96. Bravata DM, Smith-Spangler C, Sundaram V, Gienger AL, Lin N, Lewis
R, Stave CD, Olkin I, Sirard JR. Using pedometers to increase physical
activity and improve health: a systematic review. JAMA. 2007;298:2296–
2304. doi: 10.1001/jama.298.19.2296.
97. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C,
Buchner D, Ettinger W, Heath GW, King AC. Physical activity and
public health: a recommendation from the Centers for Disease Control
and Prevention and the American College of Sports Medicine. JAMA.
1995;273:402–407.
98. Physical activity and cardiovascular health: NIH Consensus
Development Panel on Physical Activity and Cardiovascular Health.
JAMA. 1996;276:241–246
99. U.S. Department of Health and Human Services. Physical Activity and
Health: A Report of the Surgeon General. Atlanta, GA: U.S. Department
of Health and Human Services, Centers for Disease Control and
Prevention, National Center for Chronic Disease Prevention and Health
Promotion, 1996.
100. World Health Organization. Global Recommendations on Physical
Activity for Health. Geneva, Switzerland: World Health Organization,
2010.
101. Fried LP, Kronmal RA, Newman AB, Bild DE, Mittelmark MB, Polak
JF, Robbins JA, Gardin JM. Risk factors for 5-year mortality in older
adults: the Cardiovascular Health Study. JAMA. 1998;279:585–592.
102. Kujala UM, Kaprio J, Sarna S, Koskenvuo M. Relationship of leisure-
time physical activity and mortality: the Finnish twin cohort. JAMA.
1998;279:440–444.
103. Wannamethee SG, Shaper AG, Walker M. Changes in physical activity,
mortality, and incidence of coronary heart disease in older men. Lancet.
1998;351:1603–1608. doi: 10.1016/S0140-6736(97)12355-8.
104. Rockhill B, Willett WC, Manson JE, Leitzmann MF, Stampfer MJ,
Hunter DJ, Colditz GA. Physical activity and mortality: a prospective
study among women. Am J Public Health. 2001;91:578–583.
105. Sundquist K, Qvist J, Sundquist J, Johansson SE. Frequent and occasional
physical activity in the elderly: a 12-year follow-up study of mortality.
Am J Prev Med. 2004;27:22–27. doi: 10.1016/j.amepre.2004.03.011.
106. Trolle-Lagerros Y, Mucci LA, Kumle M, Braaten T, Weiderpass E,
Hsieh CC, Sandin S, Lagiou P, Trichopoulos D, Lund E, Adami HO.
Physical activity as a determinant of mortality in women. Epidemiology.
2005;16:780–785.
107. Carlsson S, Andersson T, Wolk A, Ahlbom A. Low physical activ-
ity and mortality in women: baseline lifestyle and health as alterna-
tive explanations. Scand J Public Health. 2006;34:480–487. doi:
10.1080/14034940600551293.
108. Janssen I, Jolliffe CJ. Influence of physical activity on mortality in elderly
with coronary artery disease. Med Sci Sports Exerc. 2006;38:418–417.
doi: 10.1249/01.mss.0000191185.58467.be.
109. Lan TY, Chang HY, Tai TY. Relationship between components of lei-
sure physical activity and mortality in Taiwanese older adults. Prev Med.
2006;43:36–41. doi: 10.1016/j.ypmed.2006.03.016.
110. Wen CP, Wai JP, Tsai MK, Yang YC, Cheng TY, Lee MC, Chan HT, Tsao
CK, Tsai SP, Wu X. Minimum amount of physical activity for reduced
mortality and extended life expectancy: a prospective cohort study.
Lancet. 2011;378:1244–1253. doi: 10.1016/S0140-6736(11)60749-6.
111. Lee DC, Pate RR, Lavie CJ, Sui X, Church TS, Blair SN. Leisure-time
running reduces all-cause and cardiovascular mortality risk. J Am Coll
Cardiol. 2014;64:472–481. doi: 10.1016/j.jacc.2014.04.058.
112. Arem H, Moore SC, Patel A, Hartge P, Berrington de Gonzalez A,
Visvanathan K, Campbell PT, Freedman M, Weiderpass E, Adami
HO, Linet MS, Lee IM, Matthews CE. Leisure time physical activ-
ity and mortality: a detailed pooled analysis of the dose-response
relationship. JAMA Intern Med. 2015;175:959–967. doi: 10.1001/
jamainternmed.2015.0533.
113. Soares-Miranda L, Siscovick DS, Psaty BM, Longstreth WT Jr,
Mozaffarian D. Physical activity and risk of coronary heart disease and
stroke in older adults: the Cardiovascular Health Study. Circulation.
2016;133:147–155. doi: 10.1161/CIRCULATIONAHA.115.018323.
114. Kujala UM, Sarna S, Kaprio J, Koskenvuo M. Hospital care in later life
among former world-class Finnish athletes. JAMA. 1996;276:216–220.
115. Kujala UM, Sarna S, Kaprio J. Use of medications and dietary supple-
ments in later years among male former top-level athletes. Arch Intern
Med. 2003;163:1064–1068. doi: 10.1001/archinte.163.9.1064.
116. Marijon E, Tafflet M, Antero-Jacquemin J, El Helou N, Berthelot G,
Celermajer DS, Bougouin W, Combes N, Hermine O, Empana JP, Rey
G, Toussaint JF, Jouven X. Mortality of French participants in the Tour
Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
de France (1947-2012). Eur Heart J. 2013;34:3145–3150. doi: 10.1093/
eurheartj/eht347.
117. Farahmand BY, Ahlbom A, Ekblom O, Ekblom B, Hållmarker U, Aronson
D, Brobert GP. Mortality amongst participants in Vasaloppet: a classical
long-distance ski race in Sweden. J Intern Med. 2003;253:276–283.
118. Garatachea N, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C,
Pareja-Galeano H, Emanuele E, Lucia A. Elite athletes live longer than
the general population: a meta-analysis. Mayo Clin Proc. 2014;89:1195–
1200. doi: 10.1016/j.mayocp.2014.06.004.
119. Levine BD. Can intensive exercise harm the heart? The ben-
efits of competitive endurance training for cardiovascular struc-
ture and function. Circulation. 2014;130:987–991. doi: 10.1161/
CIRCULATIONAHA.114.008142.
120. La Gerche A, Heidbuchel H. Can intensive exercise harm the heart? You
can get too much of a good thing. Circulation. 2014;130:992–1002. doi:
10.1161/CIRCULATIONAHA.114.008141.
121. Schnohr P, O’Keefe JH, Marott JL, Lange P, Jensen GB. Dose of jogging
and long-term mortality: the Copenhagen City Heart Study. J Am Coll
Cardiol. 2015;65:411–419. doi: 10.1016/j.jacc.2014.11.023.
122. Möhlenkamp S, Lehmann N, Breuckmann F, Bröcker-Preuss M,
Nassenstein K, Halle M, Budde T, Mann K, Barkhausen J, Heusch G,
Jöckel KH, Erbel R; Marathon Study Investigators; Heinz Nixdorf Recall
Study Investigators. Running: the risk of coronary events: prevalence and
prognostic relevance of coronary atherosclerosis in marathon runners.
Eur Heart J. 2008;29:1903–1910. doi: 10.1093/eurheartj/ehn163.
123. Shave R, Baggish A, George K, Wood M, Scharhag J, Whyte G, Gaze D,
Thompson PD. Exercise-induced cardiac troponin elevation: evidence,
mechanisms, and implications. J Am Coll Cardiol. 2010;56:169–176.
doi: 10.1016/j.jacc.2010.03.037.
124. Wilson M, O’Hanlon R, Prasad S, Deighan A, Macmillan P, Oxborough
D, Godfrey R, Smith G, Maceira A, Sharma S, George K, Whyte G.
Diverse patterns of myocardial fibrosis in lifelong, veteran endurance
athletes. J Appl Physiol (1985). 2011;110:1622–1626. doi: 10.1152/
japplphysiol.01280.2010.
125. La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, Bogaert J,
Macisaac AI, Heidbüchel H, Prior DL. Exercise-induced right ventricu-
lar dysfunction and structural remodelling in endurance athletes. Eur
Heart J. 2012;33:998–1006. doi: 10.1093/eurheartj/ehr397.
126. Neilan TG, Januzzi JL, Lee-Lewandrowski E, Ton-Nu TT, Yoerger
DM, Jassal DS, Lewandrowski KB, Siegel AJ, Marshall JE, Douglas
PS, Lawlor D, Picard MH, Wood MJ. Myocardial injury and ventricu-
lar dysfunction related to training levels among nonelite participants in
the Boston marathon. Circulation. 2006;114:2325–2333. doi: 10.1161/
CIRCULATIONAHA.106.647461.
127. George K, Shave R, Oxborough D, Cable T, Dawson E, Artis N, Gaze
D, Hew-Butler T, Sharwood K, Noakes T. Left ventricular wall segment
motion after ultra-endurance exercise in humans assessed by myocardial
speckle tracking. Eur J Echocardiogr. 2009;10:238–243. doi: 10.1093/
ejechocard/jen207.
128. Mousavi N, Czarnecki A, Kumar K, Fallah-Rad N, Lytwyn M, Han SY,
Francis A, Walker JR, Kirkpatrick ID, Neilan TG, Sharma S, Jassal DS.
Relation of biomarkers and cardiac magnetic resonance imaging after
marathon running. Am J Cardiol. 2009;103:1467–1472. doi: 10.1016/j.
amjcard.2009.01.294.
129. Trivax JE, Franklin BA, Goldstein JA, Chinnaiyan KM, Gallagher MJ,
deJong AT, Colar JM, Haines DE, McCullough PA. Acute cardiac effects
of marathon running. J Appl Physiol (1985). 2010;108:1148–1153. doi:
10.1152/japplphysiol.01151.2009.
130. Fu F, Nie J, Tong TK. Serum cardiac troponin T in adolescent runners:
effects of exercise intensity and duration. Int J Sports Med. 2009;30:168–
172. doi: 10.1055/s-0028-1104586.
131. Middleton N, George K, Whyte G, Gaze D, Collinson P, Shave R. Cardiac
troponin T release is stimulated by endurance exercise in healthy humans.
J Am Coll Cardiol. 2008;52:1813–1814. doi: 10.1016/j.jacc.2008.03.069.
132. Schnell F, Claessen G, La Gerche A, Bogaert J, Lentz PA, Claus P, Mabo
P, Carré F, Heidbuchel H. Subepicardial delayed gadolinium enhance-
ment in asymptomatic athletes: let sleeping dogs lie? Br J Sports Med.
2016;50:111–117. doi: 10.1136/bjsports-2014-094546.
133. Thompson PD, Funk EJ, Carleton RA, Sturner WQ. Incidence of
death during jogging in Rhode Island from 1975 through 1980. JAMA.
1982;247:2535–2538.
134. Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary
cardiac arrest during vigorous exercise. N Engl J Med. 1984;311:874–
877. doi: 10.1056/NEJM198410043111402.
 Wasfy and Baggish Exercise Dose in Clinical Practice 2313

135. Kim JH, Malhotra R, Chiampas G, d’Hemecourt P, Troyanos C, Cianca
J, Smith RN, Wang TJ, Roberts WO, Thompson PD, Baggish AL; Race
Associated Cardiac Arrest Event Registry (RACER) Study Group.
Cardiac arrest during long-distance running races. N Engl J Med.
2012;366:130–140. doi: 10.1056/NEJMoa1106468.
136. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ,
Muller JE. Triggering of acute myocardial infarction by heavy physical
exertion: protection against triggering by regular exertion: Determinants
of Myocardial Infarction Onset Study Investigators. N Engl J Med.
1993;329:1677–1683. doi: 10.1056/NEJM199312023292301.
137. Albert CM, Mittleman MA, Chae CU, Lee IM, Hennekens CH,
Manson JE. Triggering of sudden death from cardiac causes by vig-
orous exertion. N Engl J Med. 2000;343:1355–1361. doi: 10.1056/
NEJM200011093431902.
138. James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H,
Tedford RJ, Judge DP, Calkins H. Exercise increases age-related pene-
trance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/
cardiomyopathy-associated desmosomal mutation carriers. J Am Coll
Cardiol. 2013;62:1290–1297. doi: 10.1016/j.jacc.2013.06.033.
139. Ruwald AC, Marcus F, Estes NA 3rd, Link M, McNitt S, Polonsky B,
Calkins H, Towbin JA, Moss AJ, Zareba W. Association of competi-
tive and recreational sport participation with cardiac events in patients
with arrhythmogenic right ventricular cardiomyopathy: results from
the North American Multidisciplinary Study of Arrhythmogenic Right
Ventricular Cardiomyopathy. Eur Heart J. 2015;36:1735–1743. doi:
10.1093/eurheartj/ehv110.
140. Coleman KJ, Ngor E, Reynolds K, Quinn VP, Koebnick C, Young DR,
Sternfeld B, Sallis RE. Initial validation of an exercise “vital sign” in
electronic medical records. Med Sci Sports Exerc. 2012;44:2071–2076.
doi: 10.1249/MSS.0b013e3182630ec1.
141. Rosenberger ME, Buman MP, Haskell WL, McConnell MV, Carstensen
LL. Twenty-four hours of sleep, sedentary behavior, and physical activ-
ity with nine wearable devices. Med Sci Sports Exerc. 2016;48:457–465.
doi: 10.1249/MSS.0000000000000778.

Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016
 Exercise Dose in Clinical Practice
Meagan M. Wasfy and Aaron L. Baggish

Circulation. 2016;133:2297-2313
doi: 10.1161/CIRCULATIONAHA.116.018093
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/133/23/2297

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at:

http://circ.ahajournals.org//subscriptions/

Downloaded from http://circ.ahajournals.org/ at University College London (ucl) / England on June 6, 2016