Physical Activity and Cardiorespiratory Fitness as Major Markers of Cardio-

vascular Risk: Their Independent and Interwoven Importance to Health Status

Jonathan Myers, Paul McAuley, Carl Lavie, Jean-Pierre Despres, Ross

Arena, Peter Kokkinos

PII: S0033-0620(14)00143-1
DOI: doi: 10.1016/j.pcad.2014.09.011
Reference: YPCAD 623

To appear in: Progress in Cardiovascular Diseases

Please cite this article as: Myers Jonathan, McAuley Paul, Lavie Carl, Despres
Jean-Pierre, Arena Ross, Kokkinos Peter, Physical Activity and Cardiorespiratory
Fitness as Major Markers of Cardiovascular Risk: Their Independent and Interwo-
ven Importance to Health Status, Progress in Cardiovascular Diseases (2014), doi:
10.1016/j.pcad.2014.09.011

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Physical Activity and Cardiorespiratory Fitness as Major

Markers of Cardiovascular Risk: Their Independent and

T
Interwoven Importance to Health Status

P
RI
1,2
Jonathan Myers, PhD, 3Paul McAuley, PhD, 4Carl Lavie, MD,
5
Jean-Pierre Despres, PhD, 6Ross Arena, PhD, 7Peter Kokkinos, PhD,

SC
1
Division of Cardiology, Veterans Affairs Palo Alto Health Care System, 2Stanford

NU
University School of Medicine, 3Winston-Salem State University, 5Quebec Heart and
Lung Institute, 6Department of Physical Therapy and Integrative Physiology Laboratory,
MA
College of Applied Health Sciences, University of Illinois Chicago,
7
Veterans Affairs Medical Center, Washington DC
ED
PT
CE

Short Title: Physical Activity, Cardiorespiratory Fitness and CVD Risk

AC

Address for Correspondence:

Jonathan Myers, PhD

VA Palo Alto Health Care System
Cardiology 111C
3801 Miranda Ave
Palo Alto, CA 94304
(650) 493-5000 x64661
drj993@aol.com

1
 ACCEPTED MANUSCRIPT

Abstract

The evolution from hunting and gathering to agriculture, followed by

industrialization, has had a profound effect on human physical activity (PA) patterns.

T
Current PA patterns are undoubtedly the lowest they have been in human history, with

P
RI
particularly marked declines in recent generations, and future projections indicate

further declines around the globe. Non-communicable health problems that afflict

SC
current societies are fundamentally attributable to the fact that PA patterns are markedly

NU
different than those for which humans were genetically adapted. The advent of modern

statistics and epidemiological methods has made it possible to quantify the independent
MA
effects of cardiorespiratory fitness (CRF) and PA on health outcomes. Based on more

than five decades of epidemiological studies, it is now widely accepted that higher PA
ED

patterns and levels of CRF are associated with better health outcomes. This review will
PT

discuss the evidence supporting the premise that PA and CRF are independent risk

factors for cardiovascular disease (CVD) as well as the interplay between both PA and
CE

CRF and other CVD risk factors. A particular focus will be given to the interplay
AC

between CRF, metabolic risk and obesity.

2
 ACCEPTED MANUSCRIPT

Abbreviations

ACSM – American College of Sports Medicine

AHA – American Heart Association

T
BMI – Body mass index

P
CDC – Centers for Disease Control

RI
CHD – Coronary heart disease

SC
CT – Computed tomography

CRF – Cardiorespiratory fitness

NU
CVD – Cardiovascular disease MA
EPIC - European Prospective Investigation into Cancer and Nutrition

HF – Heart failure
ED

HTN-Hypertension

MET – Metabolic equivalent

PT

MESA - Multi-ethnic Study of Atherosclerosis

MI- Myocardial Infarction

CE

NHS – Nurse’s Health Study

AC

PA – Physical Activity

PF-Physical Fitness

US – United States

VO2 – Oxygen consumption

WHR – Waist-to-hip circumference ratio

WISE - Women’s Ischemic Syndrome Evaluation

3
 ACCEPTED MANUSCRIPT

Introduction

Evolution of Physical Inactivity and Low Cardiorespiratory Fitness (CRF) as

Cardiovascular Disease (CVD) Risk Factors

T
The evolution from hunting and gathering to agriculture, followed by

P
RI
industrialization, has had a profound effect on human physical activity (PA) patterns.

Beginning with primitive civilizations, in which large amounts of energy expenditure

SC
were required to survive in the natural environment, human energy expenditure has

NU
progressively declined. Current PA patterns are undoubtedly the lowest they have been

in human history, with particularly marked declines in recent generations and future
MA
projections indicate further declines around the globe (1-4). This is attributable to trends

in automation and transportation, other social and environmental changes, and

ED

increased screen time (computers, television, etc). Non-communicable health problems

PT

that afflict current societies are undoubtedly attributable to the fact that PA patterns are

markedly different than those for which humans were genetically adapted (1-4).
CE

Recognition of the association between PA, health, and longevity is probably as

AC

old as there are historical records. The writings of the classic Greek physicians

Herodicus, Hippocrates, and Galen are replete with references to fitness; each believed

that a healthy body was a prerequisite for mental well-being (5). They recommended

moderate PA to promote health, but also advised that excessive exertion may have

detrimental effects on health. In the early 18th century the Italian physician Bernardino

Ramazzini, considered the father of occupational medicine (6), compared diseases that

afflicted various occupations. He noted that professional messengers, most of whom

were exceptional runners, avoided the health hazards common to more sedentary

4
 ACCEPTED MANUSCRIPT

occupations such as tailors and cobblers (7). He stated, “Let tailors be advised to take

physical exercise at any rate on holidays. Let them make the best use they can of some

one day, and so to counteract the harm done by many days of sedentary life”. The

T
United States (US) founding fathers were also conscious of the importance of physical

P
RI
fitness (PF). Benjamin Franklin advocated 15 minutes of brisk stair climbing at intervals

throughout the day, along with swimming and the use of dumbbells for health purposes

SC
(8). Thomas Jefferson recognized the need for activity when he wrote, “Not less than 2

NU
hours a day should be devoted to exercise and the weather shall be little regarded. If

the body is feeble, the mind will not be strong.” (9). The perspectives from these
MA
historical figures, stressing the importance of what we now refer to as PA and CRF,

have all proven to be true.

ED

The advent of modern statistics and epidemiological methods has made it

PT

possible to quantify the independent effects of CRF and PA on health outcomes. Based

on more than five decades of epidemiological studies, it is now widely accepted that
CE

higher PA patterns and levels of CRF are associated with better health outcomes. The
AC

genesis of modern epidemiology in the context of PA is commonly attributed to

Professor Jeremy Morris and his colleagues in the mid-20th century (10). In a series of

studies, they used modern quantitative analyses, including consideration of biases due

to selection and other potential confounding variables, to demonstrate that regular PA

offers protection against the development of CVD. Their early work included the

observation that drivers of double-decker buses in London experienced roughly twice

the CVD mortality than the comparatively more physically active bus conductors (11).

Further studies among British civil servants demonstrated that physically active postal

5
 ACCEPTED MANUSCRIPT

service workers appeared to be protected against CVD when compared to less active

clerks, telephone operators and other government workers. These studies further

suggested that when CVD did develop among those in more active occupations, it

T
developed at later ages and was less severe. These findings were confirmed and

P
RI
extended by others, most notably Paffenbarger and colleagues, initially among San

Francisco longshoremen and later among Harvard Alumni (12-14). Dr. Paffenbarger’s

SC
work more precisely identified the amounts and types of PA that were associated with

NU
longevity, along with the risks associated with being chronically inactive.

In 1956, President Eisenhower established the President's Council on Youth

MA
Fitness, a result of the growing concern for the lack of PF among American youth. The

Council on Youth Fitness was specifically a response to the perception that many young
ED

men were unfit for military duty, and that poor PF was attributable to dramatic changes
PT

mechanization and thus the nature of work and recreation. A month after his

inauguration in 1961, John F. Kennedy convened a national conference on PF. With the
CE

cooperation of 19 US educational and medical organizations, the president’s council

AC

initiated a school curriculum with the goal of improving PF, including a minimum amount

of time devoted to vigorous PA daily. For much of the mid–twentieth century, the focus

of these efforts was on youth PF, but an appreciation for the health consequences of

physical inactivity in adults was evolving through epidemiologic studies. In 1961, Hans

Kraus and Wilhelm Raab published the text Hypokinetic Disease, which many consider

to be a landmark publication linking many chronic conditions to physical inactivity (15).

Health problems associated with sedentary lifestyles became a focus of study by

numerous medical and research communities. In the 1970s, the American College of

6
 ACCEPTED MANUSCRIPT

Sports Medicine (ACSM) Guidelines for Exercise Testing and Prescription were first

published, and the 8 subsequent editions of this text have provided evidence-based and

widely-applied recommendations on the volume, duration, and intensity of exercise to

T
promote health (16).

P
RI
During the last two decades, a wealth of epidemiologic studies has documented

the health benefits of regular PA. It is now widely appreciated that higher CRF and PA

SC
patterns are not only beneficial for the prevention of CVD, but also site-specific cancers,

NU
type 2 diabetes mellitus (T2DM), improved bone health, reduced disability, and

increased longevity;PA patterns provide information on risk that is independent from

MA
traditional CVD risk factors (17,18). Expert panels convened by organizations such as

the Centers for Disease Control and Prevention (CDC), the ACSM, the European
ED

Working Group on Cardiac Rehabilitation and Exercise Physiology, and the American
PT

Heart Association (AHA) (16,19-22), along with the US Surgeon General’s Report on

Physical Activity and Health (23) have synthesized and reinforced the volume of
CE

scientific evidence linking regular PA to various measures of health. Given the well-
AC

documented association between physical inactivity and adverse health outcomes

worldwide, the current prevalence of physical inactivity, and the growth in the

prevalence of obesity in the US and Europe in recent decades (24-27), the health care

provider’s role is more critical than ever in terms of encouraging both patients and the

public to increase PA, and to develop strategies that promote the adoption of physically

active lifestyles.

Although a great deal has been learned from these epidemiologic studies on the

association between PA, CRF, and health, PA remains underused as an intervention to

7
 ACCEPTED MANUSCRIPT

reduce risk for CVD, all-cause mortality, and other outcomes (28,29). Most health care

providers do not appreciate the independent role of PA in prevention, nor do they

recognize the fact that higher PA patterns and CRF have an important moderating

T
influence on the traditional CVD risk factors. In the following, low levels of CRF and PA

P
RI
as independent risk factors for CVD are outlined, and the interplay between PA and

other CVD risk factors is discussed with particular focus on metabolic risk and obesity.

SC
Physical Inactivity and Low CRF: The Overlooked Risk Factors

NU
Since the above-mentioned landmark work of Morris and coworkers published

more than 60 years ago (11), evidence has accumulated from occupational, leisure time
MA
and PF assessment studies that supports a strong, inverse, graded and independent

association between PA, health and both CVD and overall mortality in apparently
ED

healthy individuals, regardless of race or gender as well as those with documented

PT

CVD. This association is independent from traditional CVD risk factors and as robust as

that of the traditional CVD risk factors (17,18). In fact, many scientists and clinicians in
CE

the field now recognize physical inactivity and low CRF as traditional risk factors
AC

themselves, which is highly justified based on the longstanding body of evidence

supporting this supposition.

A number of noteworthy studies assessing CRF by standardized exercise tests

have quantified risk of mortality based on peak metabolic equivalent (MET) levels

achieved. These studies have permitted quantification of the dose (amount of exercise

or degree of CRF) and response (mortality risk-reduction) relationship by expressing

exercise capacity in the context of survival benefit per MET. The reduction in mortality

risk per 1-MET increase in exercise capacity ranges between 10% and 25% in both

8
 ACCEPTED MANUSCRIPT

men and women (17,18,28). Recent evidence suggests the mortality risk reduction may

be higher than this in low fit individuals (peak MET level <5) with CVD who participate in

cardiac rehabilitation and improve their peak MET level (≈30% reduction per MET

T
improvement) (30). In addition, studies have established that the risk reduction is

P
RI
graded and that it falls precipitously beyond an age-dependent peak exercise capacity

threshold of approximately 5-6 METs. A recent study more specifically defined age-

SC
specific fitness thresholds to identify mortality risk (31). For each age category, the risk

NU
was progressively higher for those with a peak MET level below the age-specific

threshold and progressively lower for those with a peak MET level above it. The five and
MA
10-year mortality risk estimates followed similar patterns. Importantly, these studies

suggest that only modest amounts of exercise are necessary to achieve significant
ED

health benefits. In this regard, a recent study found markedly lower mortality risk in
PT

those who jog slowly as little as 5-10 minutes per day (32).

Other studies have reported inverse relationships between CRF and mortality
CE

risk in the context of dyslipidemia, obesity, T2DM and hypertension (HTN) with and
AC

without additional risk factors. In HTN and T2DM, the increased risk associated with a

low CRF (≤5 METs) and additional CVD risk factors was virtually eliminated by relatively

small increases in exercise capacity (i.e., a 1 quartile increase from ≤5 to 5-7 METs).

Together, these studies suggest that increased CRF strongly attenuates the risk of

mortality imposed by a CVD risk factor or a cluster of risk factors (17).

Two recent and notable studies assessed the independent and synergistic

effects of CRF status and stain therapy on mortality risk in dyslipidemic (33) and

hypertensive (34) individuals. In both studies, the risk reduction associated with a

9
 ACCEPTED MANUSCRIPT

moderately higher CRF level alone was similar to that achieved by statin therapy. This

was despite a less favorable lipid profile in those not treated with statins, suggesting

CRF was protective via different mechanism(s). The combination of increased CRF and

T
statin treatment was more effective in lowering risk than either condition alone. The

P
RI
exercise capacity necessary to achieve similar or an even greater reduction in risk than

that achieved by statin therapy alone was just over 5 METs. It is also noteworthy that

SC
the mortality risk in moderate and high-fit hypertensive individuals (>6.5 METs) not

NU
treated with statins was 24% and 52% lower, respectively, than that among individuals

in the lowest CRF category treated with statins. These findings support the concept that
MA
higher CRF is at least as effective as statin therapy in lowering mortality risk. Among

individuals with Stage 2 HTN, moderate intensity aerobic exercise lowered blood
ED

pressure significantly after 16 and 32 weeks even with a 33% lower use of
PT

antihypertensive medication (35). The efficacy of exercise as therapy was strongly

supported by a recent meta-analysis involving more than 339,000 individuals (36), in

CE

which it was reported that exercise interventions were as effective as drug therapy for
AC

secondary prevention of coronary heart disease (CHD), treatment of heart failure (HF)

and prevention of T2DM.

The overwhelming evidence supporting a strong link between PA and health and

the deleterious effects of inactivity led to the classification of physical inactivity as the

fourth primary risk factor for CAD by the AHA more than 20 years ago (37). The

importance of increased PA for all ages was also stated by the US Surgeon General’s

Report on PA and Health (23) with the compelling message that adding moderate

amounts of daily PA can substantially improve health and quality of life. Efforts to

10
 ACCEPTED MANUSCRIPT

emphasize the concept that physical inactivity is a major, otherwise defined as

traditional, risk factor and the importance of increased PA for all ages has been

underscored by expert panels organized by the CDC, ACSM, the European Working

T
Group on Cardiac Rehabilitation and Exercise Physiology, and AHA (19-22, 37).

P
RI
Moreover, numerous studies have reported fewer health problems and lower health

care costs among more physically active individuals. Population-based or worksite

SC
wellness programs have consistently reported that individuals who are comparatively

NU
sedentary have higher overall health care costs, which has been attributed to factors

including greater illness and hospitalization, disability, and lower productivity (28,38).
MA
The Overlooked Risk Factors. Despite the plethora of evidence worldwide related

to the independent and powerful influence of PA and CRF on human health, and
ED

despite the efforts of many health organizations to increase awareness of this evidence,
PT

physical inactivity and low CRF remain overlooked and underutilized risk factors. The

pressing question is “Why is this so?” Many approaches have been attempted with
CE

various levels of success, and barriers have been identified. In general, efforts to
AC

increase PA, which would presumably increase CRF, have been fragmented. For a

paradigm shift, it is essential that a unified plan be developed and implemented. Such a

plan must involve healthcare providers, industry, health insurance companies, the

government and the public. Healthcare providers have the greatest potential to promote

PA in their patients (28). However, unwarranted fears of an acute CVD event as a result

of exercise recommended by a health care provider, lack of reimbursement for patient

consultation, time constraints, lack of resources for both health care providers and the

public and the perceived ineffectiveness of counseling are barriers to greater

11
 ACCEPTED MANUSCRIPT

investments in PA by healthcare providers. Education regarding the safety of exercise

among health care providers and the public is critical. For example, although there is a

small increase in the risk of a CVD event with strenuous exercise, numerous studies

T
have shown that individuals at the highest risk for an exercise-related event are those

P
RI
who are habitually inactive (39). Thus, the public health message must include efforts to

allay unwarranted fears related to risks associated with PA.

SC
It is also time to seriously consider reimbursement for patient consultation and

NU
incentives implemented by the health insurance industry and employers for the public to

initiate and maintain an active lifestyle. The public must also take an active role. Our
MA
health should not only be the responsibility of the physician and the drug companies,

but our own. Time constrains as a reason not to exercise are largely invalidated by
ED

evidence supporting marked reductions in mortality risk by ≈3-10 minute sessions of

PT

moderate PA per day, and the recent evidence showing that even slow running just 5-

10 minutes per day reduces risk (32). In addition, businesses should provide facilities
CE

and allocate time for employees to exercise in the workplace. Finally, the federal
AC

government must take the lead and set the example by fostering PA in government

facilities.

A Focus on the Interplay between PA, CRF and Body Habitus

Recent evidence from cardiac magnetic resonance imaging studies indicates that

higher levels of PA are associated with more favorable cardiac structure and function

(40). Higher levels of PA also attenuate the CVD mortality risk associated with obesity

(41-47). Conversely, the CVD risk associated with obesity is compounded by physical

inactivity. Since a sedentary lifestyle is more common among obese than normal-

12
 ACCEPTED MANUSCRIPT

weight individuals (42), the association of obesity with increased CVD risk may be

mediated in part by habitual physical inactivity.

To assess the full impact of physical inactivity as a CVD risk factor, it is

T
necessary to examine interactions among PA and other lifestyle indicators. In this

P
RI
regard, several recent large scale studies with >10 years of follow-up have attempted to

specifically quantify the combined effects of physical inactivity and obesity on CVD risk.

SC
For example, in an investigation of over 116,000 women from the Nurse’s Health Study

NU
(NHS) with 24 years of follow-up, CVD mortality was 62% higher for women who were

obese and inactive compared to obese women who were active (43). Similar results
MA
were reported in a subsequent study of 24,684 women and 22,528 men from Finland

aged 25 to 64 years during a mean follow up of 18 years (44). Obese men and women
ED

who were inactive were 45% and 90% more likely, respectively, to die of CVD than their
PT

active counterparts. In another follow-up investigation from the (NHS), inactive versus

active obese women had a 39% higher risk for CHD events (including nonfatal
CE

myocardial infarction/MI and fatal CHD) during 20 years of follow-up (45). Data from the
AC

Women’s Ischemic Syndrome Evaluation (WISE) study on 38,987 women during a

mean follow up of 11 years revealed that obese women who were inactive had a 35%

higher risk for developing CHD (defined as a CVD event including nonfatal MI, coronary

artery bypass graft, percutaneous transluminal coronary angioplasty, or CHD death)

compared to their active counterparts (46). Taken together, these studies provide

compelling evidence that CVD risk is substantially higher (from ~35% to ~90%) for

obese individuals who were physically inactive compared with their obese counterparts

who were active.

13
 ACCEPTED MANUSCRIPT

Nevertheless, the interplay between physical inactivity and other lifestyle factors

including obesity, as well as obesity-related metabolic disorders, are complex and not

well understood. A few recent studies have attempted to unravel these intricacies by

T
examining simultaneous measures of PA, obesity, and other risk factors. For example,

P
RI
the association between insulin resistance and obesity is greatly altered by PA level. In

a recent study from the Multi-ethnic Study of Atherosclerosis (MESA) study, among

SC
obese men and women, those who were physically inactive had an 88% higher odds for

NU
insulin resistance compared to those who were physically active (47). In a previous

MESA report, Allison et al. (48) found that physical inactivity was associated with a less
MA
favorable profile of adiposity-associated markers that were independent of other

relevant factors. Arsenault et al. (49) quantified the combined impact of physical
ED

inactivity and abdominal obesity in 21,729 men and women from the European
PT

Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study during 11

years of follow-up. The influence of physical inactivity on abdominal obesity was

CE

heterogeneous with respect to sex. Abdominally obese men who were inactive were
AC

27% more likely to develop CHD than their active counterparts. Far less of a difference

was observed in abdominally obese women, among whom those who were inactive had

a 10% higher CHD risk compared to their active counterparts. Overall, the

compounding influence of physical inactivity on abdominal obesity appears to be far

less than that observed for general obesity, indicating perhaps more co-linearity

between inactivity and abdominal obesity. However, to ascertain cause and effect

relationships, randomized clinical trials with PA as a long-term (i.e., >10 years)

intervention will be required.

14
 ACCEPTED MANUSCRIPT

Obesity, Obesity Paradox, and CRF

Substantial evidence during the last two decades indicates that CRF markedly

alters the relationship between adiposity and subsequent major health outcomes (50).

T
Although clearly excess body weight and low CRF are associated with worse CVD risk

P
RI
factors and increased prevalence of CVD, the relative and combined importance of both

remains somewhat controversial (50). Recently, Barry and colleagues (51) performed a

SC
meta-analysis of ten studies and quantified the joint association of CRF and weight on

NU
mortality and demonstrated that compared to normal weight-fit individuals, unfit

individuals had a two-fold higher risk of mortality regardless of body mass index (BMI).
MA
Overweight-fit and obese-fit individuals had a similar mortality risk as normal weight

individuals.
ED

Additionally, in a study of 3,148 healthy adults, changes over time in both

PT

adiposity and CRF predicted development of HTN, metabolic syndrome, and

hypercholesterolemia, but the impact of CRF seems somewhat better than adiposity for
CE

future risk of these disorders (52). In another study, a 1-MET increase in CRF on two
AC

maximal exercise tests separated by an average of 6.3 years was associated with

reductions in all-cause and CVD mortality of 15 and 19%, respectively, among 14,345

men (53). In this large cohort, BMI changes were not associated with CVD or all-cause

mortality after adjusting for changes in CRF and other confounders. Therefore, the

constellation of these data suggests that CRF may be more important than adiposity

regarding long-term health outcomes.

During the past decade, substantial evidence has supported an obesity paradox

among many cohorts with known CVD (50, 54). Despite the adverse effects that

15
 ACCEPTED MANUSCRIPT

overweight and obesity have on multiple CVD risk factors and the fact that overweight

and obesity increase the prevalence of most CVDs, including HTN, CHD, and HF,

among others, overweight and obese patients with these established CVDs seem to

T
have a better prognosis than do their leaner or normal BMI counterparts with the same

P
RI
CVDs, which has been termed the "obesity paradox".

The contribution of CRF to the obesity paradox has recently been reviewed in

SC
detail elsewhere (50,54). Considerable evidence in both CHD and HF suggest that

NU
CRF markedly impacts the relationship of adiposity with subsequent prognosis

(50,54,55,56). In a recent study of 9,563 patients with known or suspected CHD, only
MA
those in the bottom tertile of gender- and age- related CRF demonstrated a strong

obesity paradox, with the leaner patients (by BMI, % body fat, as well as central
ED

obesity/waist circumference) having higher CVD and all-cause mortality than do heavier
PT

patients who are also un-fit (55). Fitter CVD patients had a favorable prognosis

regardless of fatness. In a large group of 2,066 patients with HF, CRF was assessed by
CE

peak oxygen consumption (VO2); divided into un-fit with peak VO2 < 14 mlkg-1min-1
AC

and fit as ≥ 14 mlkg-1min-1) (56). Patients with low CRF had a poor prognosis,

particularly the normal BMI patients, whereas the best prognosis was observed in those

with BMI ≥ 30 kg/m2. On the other hand, the relatively fit patients had a good overall

survival and no obesity paradox was noted (56). Therefore, CRF markedly impacts the

obesity paradox (50,55,56). Although CRF can be impacted by genetic factors, the

strongest reversible component of CRF comes from PA. Therefore, PA, which leads to

higher CRF, also markedly alters the relationship between adiposity and prognosis in

the general population as well as those with CVD, such as CHD and HF.

16
 ACCEPTED MANUSCRIPT

Body fat distribution, metabolic risk and PA

As discussed in other sections of this paper, although it is well recognized that

obesity and lack of PA are both associated with increased morbidity and mortality from

T
CVD, both risk factors are associated with each other, and this interaction is complex.

P
RI
Obesity is generally defined by an excess of body fat causing prejudice to health and is

most commonly evaluated in clinical practice by BMI expressed as the ratio of weight in

SC
kg over height in meters squared. However, although the links between obesity and

NU
alterations in some CVD risk factors such as blood pressure, lipids, insulin resistance

and T2DM have been long recognized, not every obese patient is characterized by
MA
these risk factors (57).

Body Fat Distribution: The Pioneers In the late 1940s, a French physician, Jean
ED

Vague, was the first to propose the notion that the health complications of obesity were
PT

more closely related to body shape, namely to an altered body fat distribution, rather

than to excess body weight/fat (58). As Vague did not have sophisticated imaging tools
CE

to validate his hypothesis, it took more than 35 years before these early clinical
AC

observations were confirmed by a series of metabolic and prospective population-based

studies. In those studies, investigators used a very simple anthropometric index, the

waist-to-hip circumference ratio (WHR), to crudely assess the proportion of abdominal

fat, the rationale being that a preferential accumulation of abdominal fat produces a

selective increase in waist circumference compared to hip girth. With the help of the

WHR, a stream of reports have suggested that Vague’s hypothesis was worthwhile to

explore further as this index was found to be a powerful correlate of an altered

cardiometabolic profile and an independent predictor of CVD outcomes and T2DM.

17
 ACCEPTED MANUSCRIPT

Body Fat Distribution: The “Modern” Imaging Studies The introduction of imaging

techniques such as computed tomography (CT) and magnetic resonance has been a

revolution in the study of the link between excess fatness, body fat distribution and

T
various health outcomes. With the availability of these noninvasive methods, it became

P
RI
possible to measure with great accuracy not only the amount of total body fat but to also

precisely assess the accumulation of fat at any site of the body. For instance, with the

SC
use of CT, two research groups (59,60) almost simultaneously proposed that the

NU
amount of adipose tissue found in the abdominal cavity, the so-called visceral or intra-

abdominal adipose tissue, was a critical correlate of the metabolic complications which
MA
had been in the past related to excess fatness per se. Indeed, these studies suggested

that in the absence of excess visceral adiposity, excess body fatness alone was not
ED

associated with glucose intolerance or pro-atherogenic dyslipidemic profile (i.e., high

PT

triglycerides, apolipoprotein B, and small low-density lipoprotein-cholesterol as well as

low high-density lipoprotein-cholesterol). However, for any given BMI or level of total
CE

body fat, an excess of visceral adipose tissue has been clearly associated with more
AC

severe insulin resistance leading to glucose intolerance and T2DM as well as with the

pro-atherogenic dyslipidemic profile (57,59,61). Several recent imaging studies

conducted on large populations have now confirmed the notion that excess visceral

adiposity is a good imaging marker of T2DM and CVD risk in overweight and obese

individuals (62,63).

Why Does Excess Visceral Adiposity Cause Prejudice to

Cardiometabolic/Vascular Health? The combination of the above imaging techniques

with metabolic profiling studies has allowed us to better understand why excess visceral

18
 ACCEPTED MANUSCRIPT

adiposity is such a good predictor of health outcomes in overweight obese individuals.

Firstly, biochemical and metabolic analyses conducted on visceral adipose tissue

studied in vitro have shown that this fat has a peculiar metabolic profile with a very lively

T
lipolysis that is resistant to the antilipolytic action of insulin (64). As a result, active

P
RI
tissue is drained by the portal vein; the typically insulin resistant, hyperinsulinemic,

viscerally obese male patient exposes his liver to high concentrations of free fatty acids,

SC
which contributes to impaired liver metabolism with an increased secretion of

NU
triglyceride-rich lipoproteins packed with apolipoprotein B as well as with an increased

hepatic glucose output, contributing to the hyperglycemic state often found in viscerally
MA
obese patients (57). Secondly, the expanded visceral adipose tissue has been shown to

be loaded with macrophages which contribute to the pro-inflammatory profile of visceral

ED

obesity (65). Finally, a third explanation is that excess visceral adiposity is a marker of
PT

the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink

when a physically inactive individual is exposed to a surplus of calories (66). Under

CE

such a state of chronic positive energy balance, subcutaneous fat expansion through
AC

hyperplasia (more fat cells) creates an expanded metabolic reservoir protecting lean

tissues against accumulation of harmful undesired lipids. However, if a given individual

is unable, for whatever reason, to produce new subcutaneous fat cells, the energy then

accumulates in normally lean tissue such as the liver, the heart, the kidney and the

skeletal muscle, a phenomenon described as “ectopic fat deposition” (61).

Visceral Obesity and Health: Ectopic Fat, The #1 Suspect or a Key Partner in

Crime? It would be beyond the scope of this article to review the recent literature on the

topic of ectopic fat deposition and health. However, a few points must be highlighted.

19
 ACCEPTED MANUSCRIPT

Firstly, all ectopic fat depots assessed in large imaging studies have been shown to be

related to an altered cardiometabolic risk profile (66,67). There is, therefore, a debate as

to which of these ectopic fat depots is (are) the key actor(s). Although it is

T
acknowledged that probably none of them are innocent bystanders, it is likely that the

P
RI
increased liver fat accumulation associated with visceral obesity is key cause of the

hyperglycemic, hypertriglyceridemic/apolipoprotein B and hyperinsulinemic state found

SC
in visceral obesity (61). However, the specific contribution of the ectopic fat

NU
accumulation in skeletal muscle has been suggested as an important cause of systemic

insulin resistance (68). In addition, studies have suggested that the amount of fat
MA
located in the renal sinus, a tiny ectopic fat depot, could nevertheless be associated

with hypertension independently from excess visceral fat (66). Accordingly, although
ED

excess epi/pericardial fat has been associated with all features of an altered
PT

cardiometabolic risk profile, it is possible that some key local aspects such as regulation

of coronary blood flow and atherosclerosis or myocardial metabolism and function, to

CE

only name a couple of heart-related functions, may be related to the quantity and the
AC

quality of this local fat (66,67). Epicardial fat has even been shown to contain brown and

even beige adipocytes, which functions remain to be established (69).

Thus, as the size of all the above ectopic fat depots has been related to the

amount of visceral adipose tissue, a key remaining question will be to quantify the

specific contribution of all these depots to the various clinical outcomes that have been

related to visceral obesity (66,67). For example, one could envision that some

combinations of ectopic fat depots may be more related to specific outcomes , such as

HF, whereas others could be more related to CHD or to T2DM. This question will be a

20
 ACCEPTED MANUSCRIPT

very fertile area of investigation with potentially important clinical consequences. For the

time being, studies suggest that excess visceral adiposity is an excellent marker of

ectopic fat deposition, its specific role among the ectopic fat depots having to be defined

T
by future and extensive cardiometabolic/imaging studies (61,67).

P
RI
Excess Visceral/Ectopic Fat: Is PA/Exercise the Magic Bullet? Population studies

have documented the relationship between the level of overall PA participation to total

SC
adiposity. Although there is clearly a selection bias, the most spectacular example of

NU
this relationship is the body composition of highly trained endurance athletes which

have a very high energy expenditure and a low body fat content despite a fairly high
MA
energy intake. However, studies conducted among initially sedentary and

overweight/obese individuals have generally shown more modest weight losses with PA
ED

(70). In fact, greater weight loss has been generally obtained over the short term by
PT

caloric restriction compared to exercise training. The explanation for this phenomenon is

relatively simple given that a net daily energy deficit of 500 kcal per day requires almost
CE

one hour of moderate intensity exercise. Thus, one needs to exercise a lot to lose
AC

weight without caloric restriction (71).

However, when we debate the respective roles of PA vs. diet in the management

of overweight/obese individuals, three aspects should be addressed. First, regular

exercise substantially reduces mortality/morbidity risk, even in the absence of weight

loss (67). For instance, it has been shown that even in the presence of CVD risk factors

such as T2DM or abdominal obesity/metabolic syndrome, individuals afflicted by these

conditions but who report being very active are characterized by a about a 50%

reduction in their risk of CVD compared to inactive individuals (72). This finding

21
 ACCEPTED MANUSCRIPT

supports the view that getting patients out of their sedentary behaviours should be a top

priority in clinical practice, even before aiming at weight loss. Secondly, long-term

caloric restriction, although showing efficacy over the short term, does not seem to work

T
over years (71). Studies generally indicate that regular PA favors the maintenance of a

P
RI
reduced body weight and that it is the combined use of moderate caloric restriction and

PA/exercise that confers the best long term prognosis. Finally and more importantly,

SC
imaging studies have shown that regular PA induces a selective mobilization of visceral

NU
adipose tissue and of other ectopic fat depots (67,70). Furthermore, such ectopic fat

mobilization could even be observed in the absence of weight loss if the patient’s
MA
muscle mass is increased by the exercise program. The latter finding has led us (67)

and others (70) to suggest that a reduction in waist circumference may represent a
ED

better outcome than weight loss when patients are removed from their sedentary
PT

behaviours and start being physically active at work and during their leisure time.

Finally, as discussed in other sections of this article, regular exercise has the potential
CE

to improve CRF which is one of the key predictors of health outcomes irrespective of the
AC

patient’s health status (17,18,22,28,36-39). Because of the importance of CRF and of

abdominal obesity (associated with excess visceral/ectopic fat), it has been proposed

that reducing a patient’s waistline and improving his/her CRF through regular exercise

may represent more clinically relevant therapeutic targets than weight loss alone (69).

Conclusion

The evidence supporting the value of physical inactivity and low CRF is beyond

dispute. Given the evidence supporting their value, the current healthcare model should

quickly move toward integrating PA or CRF assessments into clinical practice. Given

22
 ACCEPTED MANUSCRIPT

the evidence, the paradigm illustrated in Figure 1 depicts the way PA and CRF might

be viewed in CVD risk assessment. No matter what an individual’s health status (i.e.,

the traditional CVD risk factors to the left of Figure 1), higher levels of PA and CRF

T
improve the overall CVD risk profile. Given this evidence-based statement, why

P
RI
shouldn’t PA or CRF assessment be the final gatekeeper in determining CVD risk?

Given the poor outcomes associated with physical inactivity and low CRF, it would

SC
make sense that they become primary intervention targets. Clearly, Exercise is

NU
Medicine ,and it is time that this premise is universally accepted.
MA
ED
PT
CE
AC

23
 ACCEPTED MANUSCRIPT

References

1) Eaton SB, Eaton SB. An evolutionary perspective on human physical activity:

Implications for health. Comparative Biochemistry and Physiology Part A

T
2003;136:153-159.

P
2) Archer E, Blair S. Physical activity and the prevention of cardiovascular disease:

RI
From evolution to epidemiology. Progress in Cardiovascular Diseases
2011;53:387-396.

SC
3) O’Keefe JH, Vogel R, Lavie CJ, Cordain L. Exercise like a hunter-gatherer: A
prescription for organic physical fitness. Progress in Cardiovascular Diseases
2011;53:471-479.

NU
4) Ng SW 1, Popkin BM. Time use and physical activity: a shift away from movement
MA
across the globe. Obes Rev. 2012 Aug;13(8):659-80. doi: 10.1111/j.1467-
789X.2011.00982.x. Epub 2012 Jun 14.
5) Berryman JW. The tradition of “the six things non-natural”: Exercise and
ED

medicine from Hippocrates through ante-bellum America. Exerc Sport Sci Rev.
1989;17:515–559.
PT

6) Franco G. Bernardino Ramazzini: The father of occupational medicine. American

Journal of Public Health 2001;91(9):1382.
CE

7) Ramanazzi B. De Morbis Artificum Diatriba (translated from the Latin text of

1713, revised, with translation and notes by Wilmer Cave Wright). Chicago: The
University of Chicago Press, 1940.
AC

8) Franklin B. The Papers of Benjamin Franklin. Available at:

http://www.franklinpapers.org. Accessed April 25, 2009.

9) Karolides NJ, Karlides M. Focus on Fitness: A Reference Handbook. Santa

Barbara. Calif: ABC-CLIO Publishers; 1993.

10) Berridge V. Celebration Jerry Morris. International Journal of Epidemiology

2001;30:1141-1145.

11) Morris JN, Heady JA, Raffle PAB, Roberts CG, Parks JW. Coronary heart-
disease and physical activity of work. The Lancet 1953;262:1111-1120.

12) Paffenbarger RS, Laughlin ME, Gima AS, et al. Work activity of longshoremen
as related to death from coronary heart disease and stroke. N Engl J Med 1970;
282:1109-1114.

24
 ACCEPTED MANUSCRIPT

13) Paffenbarger RS, Hale WE. Work activity and coronary heart mortality. N Engl J
Med 1975;292:545-550.Paffenbarger RS, Wing AL, Hyde RT. Physical activity as
an index of heart attack risk in college alumni. Am J Epidemiol 1978;108:161-
175.
14) Paffenbarger RS,Hyde RT,Wing AL, et al. Physical activity, all-cause mortality,

T
and longevity of college alumni. N Engl JMed 1986;314:605-613.

P
15) Kraus H, Raab W. Hyokinetic Disease: Diseases Produced by Lack of Exercise.

RI
Springfield, Ill; Thomas, 1961.

SC
16) American College of Sports Medicine. Guidelines for Exercise Testing and
Prescription, 9th edition. Baltimore: Lippincott Williams & Wilkins, 2013.

NU
17) Kokkinos P, Myers J. Exercise and physical activity: Clinical outcomes and
applications. Circulation 2010;122:1637-1648.
MA
18) 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.
ED

19). American College of Sports Medicine Position Stand: The recommended

quantity and quality of exercise for developing and maintaining cardiorespiratory and
muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc 1998;30:975-
PT

991.

20). Fletcher GF, Balady G, Amsterdam EA, et al: Exercise standards for testing and
CE

training: A statement for healthcare professionals from the American Heart

Association. Circulation 2001;104:1694-1740.
AC

21) Pate RR, Pratt MP, Blair SN, et al: 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.

22) Giannuzzi P, Mezzani A, Saner H. et al: Physical activity for primary and
secondary prevention. Position paper of the working group on cardiac rehabilitation
and exercise physiology of the European society of cardiology. Eur J Cardiovasc
Prevention Rehab 2003;10:319-327.

23) U.S. Public Health Service, Office of the Surgeon General: Physical Activity and
Health: A Report of the Surgeon General. Atlanta, U.S. Department of Health and
Human Services, Centers for Disease Control and Prevention, National Center for
Chronic Disease Prevention and Health Promotion, 1996.

24) Centers for Disease Control and Prevention. Facts about physical activity.
http://www.cdc.gov /physical activity/data/facts.html. Accessed 7/1/2014.

25
 ACCEPTED MANUSCRIPT

25) World Health Organization. Physical Activity and Health in Europe: Evidence for
Action. 2006: http://www.euro.who.int/__data/assets/pdf_file/0011/87545/E89490.pdf.
Accessed 7/1/2014.

26) American Heart Association. Statistical Fact Sheet 2013 Update. Overweight and

T
Obesityhttp://www.heart.org/idc/groups/heart-
public/@wcm/@sop/@smd/documents/downloadable/ucm_319588.pdf

P
RI
27) Church TS, Thomas DM, Tudor-Locke C, Katzmarzyk PT, Earnest CP, Rodarte
RQ, Martin CK, Blair SN, Bouchard C. Trends over 5 decades in U.S. occupation-
related physical activity and their associations with obesity. Plos one

SC
2011;6(5):e19657.

28) Myers J. On the health benefits and economics of physical activity. Current

NU
Sports Medicine Reports 7:314-316, 2008.

29) Martin BJ1, Arena R, Haykowsky M, Hauer T, Austford LD, Knudtson

MA
M, Aggarwal S, Stone JA; APPROACH Investigators. Cardiovascular fitness and
mortality after contemporary cardiac rehabilitation. Mayo Clin Proc. 2013
May;88(5):455-63. doi: 10.1016/j.mayocp.2013.02.013.
ED

30) Sallis RE. Exercise is medicine and physicians need to prescribe it! Br J Sports
Med 2009;43: 3-4.
PT

31) Kokkinos P, Faselis C. Myers J, Sui X, Zhang J, Blair SN. Age-Specific Exercise
Capacity Threshold for Mortality Risk Assessment in Male Veterans. Circulation
CE

2014.

32) Lee D, Pate RR, Lavie CJ, Sui X, Church TS, Blair SN. Leisure-Time Running
AC

Reduces All-Cause and Cardiovascular Mortality Risk. JACC 2014; 64:472-481.

33) Kokkinos P, Faselis C, Myers J, Panagiotakos D, Doumas M. Interactive effects

of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a
cohort study. Lancet 2012; 381(9864):394-399.

34) Kokkinos PF, Faselis C, Myers J, et al. Statin Therapy, Fitness and Mortality
Risk in Middle-Aged Hypertensive Male Veterans. American Journal of Hypertension
2014; 27:422-430.

35) Kokkinos PF, Narayan P, Colleran J, Pittaras A, Notargiacomo A, Reda D,

Papademetriou V Effects of regular exercise on blood pressure and left ventricular
hypertrophy in African-American men with severe hypertension. N Engl J Med 1995;
333:1462-1467.

26
 ACCEPTED MANUSCRIPT

36) Naci H, Ioannidis HPA. Comparative effectiveness of exercise and drug

interventions on mortality outcomes: metaepidemiological study: BMJ 2013;
347:f5577.

37) Fletcher GF, Balady G, Blair SN, Blumenthal J, et al. Statement on exercise:

T
Benefits and Recommendations for Physical Activity Programs for all Americans. A
statement for Health Professionals by the Committee on Exercise and Cardiac

P
Rehabilitation of the Council on Clinical Cardiology, American Heart Association.

RI
1996; 94:857-862.

38) Franklin BA. Physical activity to combat chronic diseases and health care costs:

SC
The unfilled prescription. Current Sports Medicine Reports 2008; 7:121-125.

39) Thompson PD, Buchner D, Piña IL, et al. Exercise and Physical Activity in the

NU
Prevention and Treatment of Atherosclerotic Cardiovascular Disease. A Statement
From the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation,
and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism
MA
(Subcommittee on Physical Activity). Circulation 2003;107: 3109-3116.

40) Turkbey EB, Jorgensen NW, Johnson WC, et al. Physical activity and
physiological cardiac remodeling in a community setting: the Multi-Ethnic Study of
ED

Atherosclerosis (MESA). Heart 2010;96:42-48.

41) Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of
PT

obesity? Br J Sports Med 2009;43(1):49-51.

42) Dwyer T, Hosmer D, Hosmer T, et al. The inverse relationship between number
CE

of steps per day and obesity in a population-based sample: the AusDiab study. Int J
Obes 2007;31:797-804.
AC

43) Hu FB, Willett WC, Li T, et al. Adiposity as compared with physical activity in
predicting mortality among women. N Engl J Med 2004;351:2694-703.

44) Hu G, Tuomilehto J, Silventoinen K, et al. The effects of physical activity and

body mass index on cardiovascular, cancer and all-cause mortality among 47 212
middle-aged Finnish men and women. Int J Obes (Lond) 2005;29:894-902.

45) Li TY, Rana JS, Manson JE, et al. Obesity as compared with physical activity in
predicting risk of coronary heart disease in women. Circulation 2006;113:499-506.

46) Weinstein AR, Sesso HD, Lee IM, et al. The joint effects of physical activity and
body mass index on coronary heart disease risk in women. Arch Intern Med
2008;168:884-90.

27
 ACCEPTED MANUSCRIPT

47) McAuley PA, Chen H, Lee DC, Artero EG, Bluemke DA, Burke GL. Physical
Activity, Measures of Obesity, and Cardiometabolic Risk: The Multi-Ethnic Study of
Atherosclerosis (MESA). J Phys Act Health 2014;11(4):831-837.

48) Allison MA, Jensky NE, Marshall SJ, Bertoni AG, Cushman M. Sedentary

T
behavior and adiposity-associated inflammation: the Multi-Ethnic Study of
Atherosclerosis. Am J Prev Med. 2012;42:8-13.

P
RI
49) Arsenault BJ, Rana JS, Lemieux I, et al. Physical inactivity, abdominal obesity
and risk of coronary heart disease in apparently healthy men and women. Int J Obes
(Lond) 2010;34:340-7.

SC
50) Lavie CJ, McAuley PA, Church TS, Milani RV, Blair SN. Obesity and
cardiovascular diseases: implications regarding fitness, fatness and severity in the

NU
obesity paradox. J Am Coll Cardiol 2014;63:1345-1354.

51) Barry VW, Baruth M, Beets MW, et al. Fitness vs fatness on all-cause mortality:
MA
a meta-analysis. Prog Cardiovasc Dis 2014;56:382-390.

52) Lee DC, Sui X, Church TS, et al. Changes in fitness and fatness on the
development of cardiovascular disease risk factors: hypertension, metabolic
ED

syndrome, and hypercholesterolemia. J Am Coll Cardiol 2012;59:665-672.

53) Lee DC, Sui X, Artero EG, et al. Long-term effects of changes in
PT

cardiorespiratory fitness and body mass index on all-cause and cardiovascular

disease mortality in men: the Aerobics Center Longitudinal Study. Circulation
2011;124:2483-2490.
CE

54) De Schutter A, Lavie CJ, Milani RV. The impact of obesity on risk factors and
prevalence of coronary heart disease: the obesity paradox. Prog Cardiovasc Dis
AC

2014;56:401-408.

55) McAuley PA, Artero EG, Sui X, et al. The obesity paradox, cardiorespiratory
fitness, and coronary heart disease. Mayo Clin Proc 2012;87:443-451.

56) Lavie CJ, Cahalin LP, Chase P, et al. Impact of cardiorespiratory fitness on the
obesity paradox in patients with heart failure. Mayo Clin Proc 2013;88:251-258.

57) Després JP, Moorjani S, Lupien PJ, et al: Regional distribution of body fat,
plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 10:497-511, 1990.

58) Vague J: Sexual differentiation, a factor affecting the forms of obesity. Presse
Méd 30:339-340, 1947.

28
 ACCEPTED MANUSCRIPT

59) Després JP, Moorjani S, Ferland M, et al: Adipose tissue distribution and plasma
lipoprotein levels in obese women. Importance of intra-abdominal fat. Arteriosclerosis
9:203-210, 1989.

60) Fujioka S, Matsuzawa Y, Tokunaga K, et al: Contribution of intra-abdominal fat

T
accumulation to the impairment of glucose and lipid metabolism in human obesity.
Metabolism 36:54-59, 1987.

P
RI
61) Després JP, Lemieux I, Bergeron J, et al: Abdominal obesity and the metabolic
syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol
28:1039-1049, 2008.

SC
62) Preis SR, Massaro JM, Robins SJ, et al: Abdominal subcutaneous and visceral
adipose tissue and insulin resistance in the Framingham Heart Study. Obesity (Silver

NU
Spring) 18:2191-2198, 2010.

63) Neeland IJ, Ayers CR, Rohatgi AK, et al: Associations of visceral and abdominal
MA
subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese
adults. Obesity (Silver Spring) 21:E439-447, 2013.

64) Smith JD, Borel AL, Nazare JA, et al: Visceral adipose tissue indicates the
ED

severity of cardiometabolic risk in patients with and without type 2 diabetes: results
from the INSPIRE ME IAA study. J Clin Endocrinol Metab 97:1517-1525, 2012.
PT

65) Weisberg SP, McCann D, Desai M, et al: Obesity is associated with macrophage
accumulation in adipose tissue. J Clin Invest 112:1796-1808, 2003.
CE

66) Britton KA, Fox CS: Ectopic fat depots and cardiovascular disease. Circulation
124:e837-841, 2011.
AC

67) Després JP: Body fat distribution and risk of cardiovascular disease: an update.
Circulation 126:1301-1313, 2012.

68) Samuel VT, Petersen KF, Shulman GI: Lipid-induced insulin resistance:
unravelling the mechanism. Lancet 375:2267-2277, 2010.

69) Fitzgibbons TP, Czech MP: Epicardial and perivascular adipose tissues and their
influence on cardiovascular disease: basic mechanisms and clinical associations.
Journal of the American Heart Association 3:e000582, 2014.

70) Ross R, Bradshaw AJ: The future of obesity reduction: beyond weight loss. Nat
Rev Endocrinol 5:319-325, 2009.

71) Hill JO: Understanding and addressing the epidemic of obesity: an energy
balance perspective. Endocr Rev 27:750-761, 2006.

29
 ACCEPTED MANUSCRIPT

72) Broekhuizen LN, Boekholdt SM, Arsenault BJ, et al: Physical activity, metabolic
syndrome, and coronary risk: the EPIC-Norfolk prospective population study. Eur J
Cardiovasc Prev Rehabil 18:209-217, 2011.

P T
RI
SC
NU
MA
ED
PT
CE
AC

30
 ACCEPTED MANUSCRIPT

Figure 1: All roads go through physical activity and cardiorespiratory fitness

status in determining cardiovascular disease risk.

T
Lipids

P
RI
Blood
Pressure

SC
Blood
Glucose

NU
PA/CRF CVD Risk
Smoking MA
Diet
ED

Body
habitus
PT

Legend: PA, Physical Activity; CRF, Cardiorespiratory fitness

CE
AC

31