Recent Advances in Preventive Cardiology and
Lifestyle Medicine
Recent Advances in Preventive Cardiology and
Lifestyle Medicine
A Themed Series
Barry A. Franklin, PhD; Mary Cushman, MD, MSc
M ultifactorial risk factor modification and control, espe-
cially interventions designed to reduce total cholester-
ol, systolic blood pressure, smoking prevalence, overweight/
obesity, diabetes mellitus, and physical inactivity, can have a
profound and favorable impact on decreasing the incidence of
initial and recurrent cardiovascular events. Between 1980 and
2000, mortality rates from coronary heart disease (CHD) fell
by ⬎40%. Using a previously validated statistical model
(IMPACT), researchers attempted to determine how much of
this decrease could be explained by the use of medical and
surgical treatments as opposed to changes in risk factors
among US adults aged 25 to 84 years. Approximately half of
the decline in cardiovascular deaths was attributed to reduc-
tions in major risk factors (obesity and diabetes mellitus were
notable exceptions), and approximately half was attributed to
evidence-based medical therapies (eg, secondary prevention
medications, rehabilitation, and initial treatments for acute
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myocardial infarction [AMI]).1 In contrast, emergent and
elective revascularization accounted for only 7% of the
overall decline in deaths from CHD. Recently, similar results
were reported in a Canadian study that evaluated the decrease
in CHD mortality between 1994 and 2005.2
Over the past decade, mortality rates from CHD and stroke
in the United States decreased by ⬎25% (Figure 1).3 Al-
though there were also impressive reductions in the preva-
lence of uncontrolled high blood pressure, elevated blood
cholesterol, and, to a lesser extent, cigarette smoking, there
was only limited impact on other risk factors, including
increases in the prevalence of obesity and diabetes mellitus,
and a small reduction in those not engaged in moderate or
vigorous physical activity.3 These indicators represent major
challenges to achieving future goals for cardiovascular health
promotion and disease reduction.
In 2009, a task force representing numerous professional
organizations/associations developed a Competence and
Training Statement on the Prevention of Cardiovascular
Disease.4 More recently, the American Heart Association
From the Departments of Medicine and Cardiology, Cardiac Rehabilitation and Exercise Laboratories, William Beaumont Hospital, Royal Oak,
MI (B.A.F.); and Departments of Medicine and Pathology, University of Vermont College of Medicine, Burlington (M.C.). Dr Franklin is
Immediate Past Chair, American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Dr Cushman is Immediate Past Chair,
American Heart Association Council on Epidemiology and Prevention.
Correspondence to Barry A. Franklin, PhD, Cardiac Rehabilitation and Exercise Laboratories, William Beaumont Hospital, Beaumont Health Center,
4949 Coolidge Hwy, Royal Oak, MI 48073. E-mail bfranklin@beaumont.edu
(Circulation. 2011;123:2274-2283.)
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
2274
(AHA) released its bold new impact goal for the next 10
years, the 2020 Impact Goal: “to improve the cardiovascular
health of all Americans by 20% while reducing deaths from
cardiovascular diseases and stroke by 20%.”3 This 2020 goal
has an innovative new element to improve clinically relevant
health and behavioral factors. Cardiovascular health is de-
fined in 3 categories of ideal, intermediate, and poor on the
basis of 7 simple health factors and modifiable behaviors,
as detailed in the My Life Check assessment tool at
http://www.mylifecheck.heart.org.
This review provides a compendium of important ad-
vances in preventive and lifestyle medicine during the past
decade, including discussion of some emerging but un-
proven interventions (ie, the polypill) as well as the value
of conducting large-scale randomized clinical trials rather
than relying on biological hypotheses and observational
data (ie, the homocysteine story). We also provide a call to
action to support the AHA’s 2020 goals, summarize the
impact of preventive interventions as a first-line strategy to
combat stable cardiovascular disease (CVD), and discuss
the potential impact of behavioral and complementary
interventions in reducing the burden of CVD. Finally, we
detail the goals of a new Circulation series of publications
on Preventive Cardiology and Lifestyle Medicine.
A Decade of Discovery: Implications for
Primordial, Primary, and Secondary Prevention
Prevention can be divided into 3 types: primordial (preven-
tion of risk factors); primary (treatment of risk factors); and
secondary (prevention of recurrent cardiovascular events)
(Figure 2). Much of the success in reducing CVD in recent
years has been through the latter 2 methods; however,
additional emphasis on primordial prevention is needed to
meet the AHA 2020 Impact Goal of improving cardiovascu-
lar health and achieving an additional 20% reduction in death
from CVD and stroke.
DOI: 10.1161/CIRCULATIONAHA.110.981613
 Franklin and Cushman
Figure 1. Mortality rates from coronary heart disease and
stroke, rate of uncontrolled blood pressure, and prevalence of
high cholesterol from 2004 to 2008. Reproduced from Lloyd-
Jones et al.3
The importance of risk factors in the development of CVD
has received increased attention over the past decade. In
addition, along with cardioprotective medications, the roles
of lifestyle interventions, psychosocial factors, air pollution,
dietary patterns, physical inactivity, low cardiorespiratory
fitness, obesity, cardiac rehabilitation, and inflammation have
been better elucidated as modulators of CVD and as targets
for education, behavioral interventions, and policy ap-
proaches to improving health. Newer statin drugs, in partic-
ular, which markedly decrease and increase low-density
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lipoprotein and high-density lipoprotein cholesterol, respec-
tively, have been heralded as a potential breakthrough to
prevent initial and recurrent atherosclerotic events.5 Consider
the following key reports of the 2000s.
Risk Factors as Antecedents of Cardiovascular
Disease: Debunking the Only 50% Myth
The INTERHEART study examined the risk factors associ-
ated with first AMI in 52 countries, including 15 152 cases
and 14 820 controls.6 Collectively, 9 risk factors (abnormal
lipids, smoking, hypertension, diabetes mellitus, abdominal
obesity, psychosocial variables, consumption of fruits and
Preventive Cardiology and Lifestyle Medicine 2275
vegetables, regular alcohol consumption, regular physical
activity) accounted for 90% of the population attributable risk
in men and 94% in women. Similarly, Khot et al7 and
Greenland et al8 examined data from 14 randomized clinical
trials (n⫽122 458) and 3 prospective cohort studies
(n⫽386 915), reporting that ⬎80% of patients who devel-
oped CHD and ⱖ87% of patients who experienced a fatal
coronary event had antecedent exposure to ⱖ1 of the 4
conventional cardiovascular risk factors (cigarette smoking,
dyslipidemia, hypertension, diabetes mellitus). People with
optimal levels of cardiovascular risk factors and lifestyle
behaviors at 50 years of age demonstrate a marked survival
advantage and only a 5% and 8% lifetime risk of developing
CVD for men and women, respectively.9 Collectively, these
data and other recent reports discount the longstanding claim
that only 50% of CHD is attributable to conventional risk
factors, and suggest that a more rigorous focus on these and
the lifestyle behaviors that promote them has great potential
to reduce the burden of atherosclerotic heart disease.10,11
Lifestyle and Mortality in Coronary Patients
One review of prospective cohort studies and randomized,
controlled trials among patients with established CHD sought
to provide evidence for a prognostic benefit of lifestyle and
dietary recommendations.12 Effect estimates for smoking
cessation, higher levels of physical activity, and moderate
alcohol consumption varied from a 20% to 35% lower risk of
all-cause mortality. For individual dietary goals, data were
too limited to provide reliable effect size estimates. If these
estimates reflect the true value, they compare favorably with
mortality reductions reported for low-dose aspirin, statins,
␤-blockers, and angiotensin-converting enzyme inhibitors
after AMI.12 On the other hand, there are no randomized trials
showing that alcohol consumption improves health, and the
overall harms are well known: addiction, social dysfunction,
and motor vehicle accidents.13 One large-scale study showed
that low to moderate alcohol consumption may be associated
with an increased risk of cancer in women.14
Cigarette Smoking, Mortality, and Effects of
Secondhand Smoke
A landmark study of 50 years of observation of 34 439 male
British physicians found that, on average, cigarette smokers die
Figure 2. Risk factor framework and the progres-
sion of cardiovascular disease, with types of pre-
vention interventions. Illustrated are primordial,
primary, and secondary prevention, which have
environmental modulators, including healthcare
access; the built environment; public policy initia-
tives; and locations where interventions can be
made (eg, personal, family, school, workplace).
Cardiovascular health markers/interventions
include the American Heart Association’s Life’s
Simple 7 (smoking status, body mass index, physi-
cal activity, healthy diet score, total cholesterol,
blood pressure, fasting plasma glucose), pharma-
cotherapies (eg, aspirin, ␤-blockers, statins, angio-
tensin-converting enzyme inhibitors) when indi-
cated, and coronary revascularization, when
appropriate. MI indicates myocardial infarction;
CHF, congestive heart failure; and PAD, peripheral
arterial disease.
 2276 Circulation May 24, 2011
⬇10 years younger than nonsmokers.15 For someone who has
smoked since adulthood, cessation at age 50 years halved the
hazard, and cessation at age 30 years avoided almost all of it.
Quitting smoking at age 60 or 40 years increased life expectancy
by ⬇3 and 9 years, respectively. More recently, using data from
the Survival and Ventricular Enlargement trial, investigators
reported that in selected patients with left ventricular dysfunction
after AMI, smoking cessation is associated with a 40% lower
hazard of all-cause mortality compared with persistent smokers
over an average follow-up of 42 months.16
A moderate-sized randomized clinical trial, involving a 10-
week smoking cessation program that included strong physician
counseling and 12 group sessions using behavior modification
and nicotine gum, plus either ipratropium or a placebo inhaler,
found that over a 14.5-year follow-up, the intervention reduced
the risk of death by 18% compared with a usual-care control
group.17 It should be noted, however, that these findings applied
to a special group of heavy smokers who had preexisting airway
obstruction. Because the relative risk for lung cancer is so high
among smokers, the need for randomized trials is less compel-
ling. On the other hand, nearly all risk factors associated with
CHD have effect sizes that are much smaller, making them
seriously vulnerable to confounding variables and selection
biases when evaluated in observational studies.
Although it is tempting to believe that the tobacco war has
been won because of the important strides that have been
made in tobacco control, in terms of both interventions and
outcomes, the prevalence of smoking in the United States
hovers at 20%, ⬎8 million people are sick or disabled as a
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result of tobacco use, and smoking kills an estimated 450 000
Americans annually.18 Even a very short period of passive
smoke exposure has persistent vascular consequences, such as
the mobilization of dysfunctional endothelial progenitor cells
with blocked nitric oxide production.19 Secondhand smoke is
responsible for an estimated 603 000 deaths worldwide each
year, and more than half of the deaths (379 000) are due to
CVD.20 Accordingly, despite the current emphasis on healthcare
reform, escalating medical costs, and childhood obesity, ciga-
rette smoking remains by far the most common cause of
preventable death and disability in the United States.18 Unless
legal challenges delay or defeat government plans, in 2012 each
cigarette pack sold in the United States will carry powerful
graphic label warnings of the dangers of smoking, which may
serve to reduce smoking rates among younger people.
Prevention of Type 2 Diabetes Mellitus With
Lifestyle Intervention
Considerable data now strongly support the role of lifestyle
intervention to improve glucose and insulin homeostasis. The
Finnish Diabetes Prevention Study reported that a lifestyle
intervention (reducing body weight by ⱖ5%; decreasing fat
and saturated fat intake to ⬍30% and ⬍10% of energy intake,
respectively; increasing fiber intake to ⱖ15 g/1000 kcal; and
an increase in exercise to ⱖ30 min/d) resulted in a 58%
reduction in the development of diabetes mellitus in high-risk
overweight subjects with impaired glucose tolerance compared
with a usual-care control group over 3.2 years.21 Similarly, the
Diabetes Prevention Program Research Group demonstrated that
a lifestyle modification program with goals of ⱖ7% weight loss
Table. Physiological Responses to Psychosocial Risk Factors
That May Be Associated With the Development and Clinical
Manifestations of Cardiovascular Disease26,27
● Activation of systemic inflammatory cytokines
● Enhanced platelet activation/reactivity
● Increased ambulatory heart rate and blood pressure
● Increased sympathetic nervous system activity
● Endothelial injury and dysfunction
● Vasoconstriction
● Increased proarrhythmogenic potential3arrhythmias
● Hemostatic changes and hemoconcentration
● Polymorphism of the serotonin transporter gene promoter
● Hypercortisolemia
● Decreased heart rate variability
● Impaired vagal control
● Reduced baroreflex cardiac modulation
● Increased circulating catecholamines
● Altered plasma viscosity and/or fibrinolytic activity
and ⱖ150 minutes of physical activity per week in overweight
patients with impaired fasting glucose resulted in a 58% reduc-
tion in the incidence of diabetes mellitus, whereas there was a
31% reduction with metformin (850 mg twice daily) compared
with placebo.22 The Diabetes Prevention Program (http://www.
ClinicalTrials.gov; NCT00004992) and its long-term outcome
study (NCT00038727) will determine whether the lifestyle-
induced reduction in diabetes mellitus translates into a reduction
in major coronary events.23,24
Impact of Psychosocial Risk Factors on
Cardiovascular Disease
An escalating body of research provides compelling evidence
for an association of psychosocial factors with risk of CVD
and prognosis of patients with CHD.25 Psychological risk
factors such as depressive symptoms, anxiety, and vital
exhaustion may worsen or exacerbate the development of
CVD through associated unhealthy behaviors and physiological
responses (Table) that may lead to clinical consequences, includ-
ing myocardial ischemia, threatening ventricular arrhythmias,
vulnerable plaque, and increased thrombosis potential and in-
flammation.26 –29 Recognizing this relationship offers an impor-
tant potential target for cardiovascular risk reduction that re-
quires testing in appropriately designed trials.30 This may
maximize the potential for cardiovascular risk reduction by
addressing at least a portion of the 10% to 25% incidence of
CHD that is unexplained by traditional risk factors.11,31
Patients with clinical depression are at least 3 times more
likely to die during the first year after AMI than are patients
without depression.32 Although the reasons for this are
unclear, it appears that patients with depression after AMI are
less likely to take prescribed medications and adhere to
recommended behavior and lifestyle changes intended to
reduce the risk of recurrent cardiovascular events.33 More-
over, investigators recently reported that depression is asso-
ciated with a decrement in composite health score that is
significantly greater than that associated with other chronic
 Franklin and Cushman
diseases, including angina, arthritis, asthma, and diabetes
mellitus.34 When depression occurred in conjunction with
other chronic diseases, it was associated with significantly
greater decrements in overall health than the medical condi-
tion alone, particularly in persons with diabetes mellitus.
Although a recent AHA Science Advisory recommended
screening for depression in patients with CVD,30 there have
been no large-scale randomized trials showing that screening
prevents major cardiovascular events.
Ineffectiveness of Homocysteine Lowering on the
Incidence of Cardiovascular Events
Although homocysteine levels have been directly associated
with cardiovascular risk in many observational studies,35
several randomized, double-blind, placebo-controlled clinical
trials have discounted the hypothesis that supplementation
with folic acid and other B vitamins that lower homocysteine
would prevent acute cardiovascular events. After 7.3 years of
treatment and follow-up, Albert and associates36 found that a
combination pill of folic acid, vitamin B6, and vitamin B12 did
not reduce the incidence of cardiovascular events among
5442 women with prior CVD or ⱖ3 coronary risk factors,
despite significant homocysteine lowering. In the Heart
Outcomes Prevention Evaluation Trial (HOPE 2),37 the same
homocysteine-lowering treatment did not reduce the risk of
major cardiovascular events among 5522 patients aged ⱖ55
years with vascular disease or diabetes mellitus over an
average of 5 years. These results are consistent with a prior
meta-analysis of randomized, controlled trials performed
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primarily among men with known vascular disease38 and do
not support the use of B vitamins as preventive interventions
for CVD in at-risk populations. The homocysteine story is an
excellent example of why prevention enthusiasts must insist
on large-scale randomized trials and not rely on biological
hypotheses and observational data.
A Cardioprotective Polypill: Need for a Fully
Powered Trial?
Wald and Law39 proposed a theoretical cardioprotective
polypill, on the basis of a review of the scientific literature
(including ⬎750 trials with ⬇400 000 participants), as a
population strategy to combat CVD. The daily formulation
would include a statin, 3 blood pressure–lowering drugs, folic
acid, and aspirin, and could theoretically reduce coronary
events by 88% and stroke by 80%. Others have reported that
a similar polypill (Polycap formulation) effectively reduced
multiple risk factors and estimated cardiovascular risk in
middle-aged individuals; however, the combined projected
risk reductions for coronary events and stroke were lower
than the aforementioned estimates, at 62% and 48%, respec-
tively.40 The investigators emphasized that the effects of the
polypill cannot be assumed to equal the combined effects of
its individual components. On the basis of the homocysteine
report, the expected benefit of including folic acid could also
be questioned. More recently, a small, double-blind, random-
ized, placebo-controlled trial of a polypill reported more
modest reductions in lipid levels and blood pressure than
anticipated.41 Because of the independent and additive bene-
fits of lifestyle modification on cardioprotective pharmaco-
Preventive Cardiology and Lifestyle Medicine 2277
therapies,42– 44 it has been suggested that treatment with the
polypill, or treatment with its components, be accompanied
by the following user directions: “Take medication each day
in the prescribed dosage, followed or preceded by ⱖ30
minutes of moderate to vigorous physical activity, in combi-
nation with a low-fat, low-cholesterol diet, weight manage-
ment, and the avoidance or cessation of cigarette smoking.”45
Lifestyle Factors Associated With Lower
Cardiovascular Risk
According to 2 recent studies, favorable lifestyle factors are
associated with dramatically reduced risks of hypertension
and heart failure.46,47 In the first study, an analysis of data
from the longitudinal Nurses’ Health Study II, adherence to 6
lifestyle factors—normal body mass index (⬍25 kg/m2); a
low-sodium diet high in fruits, vegetables, and low-fat dairy
products; a daily average of 30 minutes of vigorous exercise;
modest alcohol intake (up to 10 g/d); infrequent use of
nonnarcotic analgesics (less than once per week); and folic
acid supplementation (ⱖ400 ␮g/d)—was associated with a
significantly lower incidence of self-reported hypertension.46
The authors acknowledged that if these associations were causal
and independent, then lifestyle modification could have the
potential to prevent a large proportion of new-onset hypertension
occurring in young women. Similarly, the PREMIER random-
ized clinical trial reported that individuals with above optimal
blood pressure, including stage 1 hypertension (120 to
159 mm Hg systolic and 80 to 95 mm Hg diastolic), who were
not taking antihypertensive medications, can make multiple
lifestyle changes that lower blood pressure and reduce cardio-
vascular risk.48 In another report, data were analyzed from
20 900 apparently healthy men (mean age at baseline, 53.6
years) in the Physicians’ Health Study who were followed for
22.4 years, during which time 1200 developed heart failure.47
Men who adhered to ⱖ4 of 6 healthy lifestyle habits (normal
body weight, not smoking, regular exercise, moderate alcohol
intake, consumption of breakfast cereals, and a diet high in fruits
and vegetables) had a 10% risk of developing heart failure. Men
who did not adhere to any of these factors had a 21% risk of
developing heart failure.
Because the healthy adherer effect is well known, these
reports from observational studies should be interpreted with
caution. The Coronary Drug Project showed that individuals
who adhere to placebo therapy generally have better health
outcomes.49 Accordingly, people who adhere to healthy
lifestyle practices often do better, but it remains unclear
whether it is due to the intervention per se.
Air Pollution and Cardiovascular Risk
Numerous epidemiological studies have demonstrated con-
sistent associations between short-term elevations in particu-
late matter (air pollution) and increases in nonfatal and fatal
cardiovascular events, including myocardial ischemia and
infarction, ventricular arrhythmia, heart failure exacerbation,
and stroke.50,51 The pathways linking air pollution exposure
to the onset of acute cardiovascular events may be explained
by the direct effects from agents that cross the pulmonary
epithelium into the circulation, including gases and the
soluble constituents of particles (eg, transition metals). Al-
 2278 Circulation May 24, 2011
though the increase in relative risk for CVD due to air
pollution for an individual may be small compared with the
impact of conventional risk factors, this omnipresent expo-
sure likely translates into a substantial increase in total
mortality within the population.52 The potential to substan-
tially decrease cardiovascular morbidity and mortality by
lowering particulate matter levels to current Environmental
Protection Agency standards is apparent.50
Dietary Pattern and Risk of
Cardiovascular Disease
A substantial and expanding body of evidence has now
associated a healthy dietary pattern with lower rates of major
coronary events and diabetes mellitus.53–56 One systematic
review found strong evidence of a causal relationship for
cardioprotective dietary practices, including vegetables, nuts,
and Mediterranean eating patterns, as well as associations for
harmful factors, including intake of trans fatty acids and
foods with a high glycemic index or load, and CHD.56 Modest
reductions in dietary salt may also substantially reduce
cardiovascular events and associated medical costs.57 Epide-
miological and controlled interventional studies have consis-
tently demonstrated the beneficial effects of omega-3 fatty
acid consumption, especially the longer-chain fatty acids
(ⱖ20 carbons) from marine sources, on cardiovascular end
points.58 Moreover, a 2-year study of weight loss diets, using
either low-fat, Mediterranean, or low-carbohydrate strategies,
reported a significant regression of carotid atherosclerosis,
irrespective of the dietary intervention.59 On the other hand,
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the Women’s Health Initiative Dietary Modification Trial, the
largest long-term randomized, controlled trial of a dietary
intervention conducted to date, including 48 835 postmeno-
pausal women aged 50 to 79 years who were followed over a
mean of 8.1 years, showed that a dietary intervention that
reduced total fat intake and increased intakes of vegetables,
fruits, and grains did not significantly reduce the risk of CHD,
stroke, or CVD, and achieved only modest effects on CVD
risk factors.60 Nevertheless, subgroup analyses showed posi-
tive trends toward greater reductions in low-density lipopro-
tein cholesterol levels and rates of CHD in women with the
lowest intakes of saturated fat or trans fat or highest intakes
of vegetables/fruits. Because the trial was designed to test the
hypothesis that a dietary intervention could lower rates of
breast and colorectal cancer rather than CVD, the investiga-
tors suggested that more focused diet and lifestyle interven-
tions may be needed to reduce CVD risk.
Mortality Benefits of Cardiac Rehabilitation in
Modern Cardiology
Among older patients with documented CHD who undergo
cardiac rehabilitation, mortality rates are generally 21% to
34% lower than among nonusers,61 and a significant dose-
response relationship exists between the number of cardiac
rehabilitation sessions attended and cardiovascular outcomes
at 4 years.62 It has been suggested that contemporary
thrombolytic and emergent revascularization procedures,
which markedly diminish early postinfarction mortality, and
newer cardioprotective drug therapies may serve to attenuate
the impact of adjunctive exercise-based cardiac rehabilitation.
Although a recent review of 48 randomized trials concluded
that the mortality benefits of cardiac rehabilitation persist in
modern cardiology,63 meta-analyses like these are suggestive
but cannot be considered definitive.64,65 Despite the potential
survival advantage and related beneficial outcomes, cardiac
rehabilitation services remain vastly underutilized among
Medicare beneficiaries.66
Pharmacotherapies and Lifestyle Modification in
Patients With Acute Coronary Syndrome
Although individual drug therapies, such as antiplatelet med-
ications, ␤-blockers, angiotensin-converting enzyme inhibi-
tors, and lipid-lowering agents, are effective in reducing
mortality in patients with acute coronary syndrome, it appears
that the combination of these agents may have incremental
and even synergistic benefits. Researchers created a compos-
ite appropriateness score for 6-month mortality based on the
number of drugs used divided by the number of drugs
potentially indicated for each patient, as follows: 0, none of
the indicated medications used; I, 1 medication used if 3 or 4
medications indicated; II, 2 medications used if 3 or 4
medications indicated or 1 medication used if 2 medications
indicted; III, 3 medications used if 4 medications indicated;
and IV, all indicated medications used. The odds ratio for
death for appropriate levels IV, III, II, and I were 0.10, 0.17,
0.18, and 0.36, respectively.67 A more recent study reported
that adherence to behavioral advice (modify diet, exercise,
and quit smoking) after acute coronary syndrome was asso-
ciated with a substantially lower risk of recurrent cardiovas-
cular events.68 Collectively, these data suggest that a combi-
nation of evidence-based medical therapies and behavioral
recommendations in the immediate postevent care of patients
with acute coronary syndrome should be given a high priority
by physicians and adjunctive healthcare providers.
Physical Activity, Cardiorespiratory Fitness,
and Mortality
A recent systematic review and meta-analysis of 33 physical
activity studies (n⫽883 372 participants) reported risk reduc-
tions of 30% to 50% for cardiovascular mortality and of 20%
to 50% for all-cause mortality, with pooled risk reductions of
35% and 33%, respectively.69 There are multiple mechanisms
by which moderate to vigorous physical activity may de-
crease mortality rates associated with CVD (Figure 3),
including antiatherosclerotic, antithrombotic, anti-ischemic,
antiarrhythmic, and psychological effects. Numerous studies
also suggest that cardiorespiratory fitness, expressed as met-
abolic equivalents (1 metabolic equivalent⫽3.5 mL O2 per
kilogram per minute) is 1 of the strongest prognostic markers
in persons with and without CHD.70 In healthy men and
women, each 1-metabolic equivalent increase in exercise
capacity confers a 13% and 15% reduction in all-cause
mortality and cardiovascular events, respectively. Partici-
pants with an aerobic capacity ⱖ7.9 metabolic equivalents
had the most favorable health outcomes.71 Dutcher et al72
reported that cardiorespiratory fitness more accurately pre-
dicts 5-year mortality than left ventricular ejection fraction in
patients with ST-segment elevation MI treated with percuta-
neous coronary intervention (PCI). On the other hand, a
 Franklin and Cushman
Figure 3. Mechanisms by which moderate to vigorous exercise
training may reduce the risk of nonfatal and fatal cardiovascular
events. The cardioprotective vascular conditioning effect may
include enhanced nitric oxide vasodilator function, improved
vascular reactivity, altered vascular structure, or combinations
thereof. BP indicates blood pressure; EPCs, endothelial progeni-
tor cells; CACs, cultured/circulating angiogenic cells; and HR,
heart rate. Adapted from Franklin BA, McCullough PA.74
disproportionate number of acute cardiovascular events occur
in habitually sedentary individuals with known or occult
CHD performing unaccustomed vigorous physical activity.73
Collectively, these data suggest that the least active, least fit,
“high-risk” patient cohort (bottom 20%) may especially
benefit from structured exercise, increased lifestyle activity,
or both to improve survival.74 Future large-scale event-driven
trials of moderate to vigorous physical activity, in varied
populations, would be helpful in further clarifying the car-
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dioprotective benefits and risks of this widely recommended
intervention.
Obesity Is Strongly Associated With Acute
Coronary Events Occurring Prematurely
In 1998, in response to an emerging body of scientific
evidence, the AHA reclassified obesity as a major modifiable
risk factor for CHD.75 Subsequently, numerous studies have
substantiated that obesity confers an independent and additive
risk of all-cause and cardiovascular mortality, even in the
absence of metabolic syndrome.76,77 Other reports suggest
that excess adiposity is strongly associated with the prema-
ture occurrence of AMI.78,79 Although some obese patients
with CVD have lower adverse events and mortality than their
metabolically leaner counterparts (ie, the “obesity para-
dox”),80 numerous studies now support purposeful weight
reduction in this escalating patient subset.81
With the use of serial data and appropriate follow-up from
the National Health and Nutrition Examination Surveys (I, II,
III), the Centers for Disease Control and Prevention found
that underweight and obesity, particularly high levels of
obesity, were associated with increased mortality relative to
the normal weight category.82 On the other hand, overweight
(body mass index 25 to ⬍30 kg/m2) was not associated with
increased mortality, a finding recently echoed in patients with
CHD.83 A normal or desirable body mass index is classified
between 19.0 and 24.9 kg/m2; however, this is primarily
because body mass indexes ⱖ25 kg/m2 are associated with
increased morbidity.3 Other recent studies emphasize the
Preventive Cardiology and Lifestyle Medicine 2279
importance of waist circumference as a risk factor for
mortality in older adults, regardless of body mass index.84
Inflammation, Low-Density Lipoprotein
Cholesterol, and Statin Therapy: Implications for
Primary Prevention?
Although numerous studies have highlighted the potential
role of inflammation in the genesis of CVD and atherothrom-
bosis85 and there is mounting evidence supported by guide-
lines of the clinical utility of inflammation assessment with
biomarkers such as C-reactive protein,86 some investigators
remain unconvinced that measurement of inflammation
markers in practice is useful in risk prediction.87 The Justifi-
cation for the Use of Statins in Primary Prevention: An
Intervention Trial Evaluating Rosuvastatin) (JUPITER) trial
enrolled 17 802 men and women without documented CVD
or diabetes mellitus with low-density lipoprotein cholesterol
levels ⱕ130 mg/dL and C-reactive protein levels ⱖ2 mg/L
and randomly assigned them to rosuvastatin 20 mg daily or
placebo.88 The investigation was designed to test the hypoth-
esis that statin therapy, in people with levels of low-density
lipoprotein cholesterol below currently recommended thresh-
olds for treatment, would decrease the rate of first major
cardiovascular events by virtue of the inflammation- and
lipid-lowering potential of this treatment. The trial was
stopped prematurely after a median follow-up of 1.9 years,
demonstrating a 44% reduction in incident cardiovascular
events and a 20% reduction in all-cause mortality. These data
have potential implications for primary prevention by provid-
ing treatment to a large segment of the population that would
not normally be prescribed a statin.89 Others contend that a
significant proportion of the JUPITER subjects were not
healthy, and warranted aggressive management, regardless of
the concentration of C-reactive protein.90 Their analyses
suggested that failure to adhere to currently accepted guide-
lines for care probably resulted in a spuriously high event rate
that was conducive to the demonstration of benefit from statin
therapy. Optimally designed trials to test the hypothesis of
risk reduction with inflammation lowering would require a
trial of a specific inflammation-lowering agent or a trial
randomizing participants to usual care or to C-reactive
protein testing as a guide to treatment.
Value of Percutaneous Coronary Intervention
in Stable Coronary Heart Disease? Prevention
as a First-Line Strategy to Combat
Cardiovascular Disease
Primary PCI, with mechanical revascularization, reduces
mortality in patients presenting with AMI.91 However, in
patients with symptomatic or asymptomatic myocardial is-
chemia, the benefits of elective PCI are not as robust. In 2003,
investigators evaluated the 7-year outcome of angioplasty
versus medical therapy as the initial treatment strategy for
chronic angina.92 Although symptoms were improved and use
of antianginal medications decreased, the incidence of death
or MI was slightly higher in the angioplasty cohort than in the
medically treated patients, at 7.3% versus 4.1%, respectively.
The Atorvastatin Versus Revascularization Treatment
(AVERT) study rekindled the debate concerning the pre-
 2280 Circulation May 24, 2011
ferred therapeutic strategy in patients with stable single- or
double-vessel coronary artery disease.93 After 18 months’
follow-up, 22 of the 164 patients (13%) receiving atorvastatin
had an ischemic event compared with 37 of 177 (21%)
assigned to angioplasty and usual care, signifying a 36%
reduction (P⬍0.05) in the group that received aggressive
lipid-lowering therapy. In another clinical trial, men with
single-vessel coronary disease were randomized to PCI ver-
sus a 12-month exercise program.94 Significantly higher
event-free survival occurred with exercise training (88%
versus 70%). Increased exercise capacity, reduced need for
hospitalization, and decreased numbers of repeat revascular-
izations were also noted in patients randomized to the
exercise intervention. Accordingly, Green et al95 suggested
the following: “Coronary interventions treat a very short
segment of the diseased coronary tree, whereas exercise
exerts beneficial effects on endothelial function and disease
progression in the entire arterial bed.”
In 2005, Katritsis and Ioannidis96 performed a meta-anal-
ysis of 11 randomized trials, including a total of 2950
patients, comparing PCI with conservative medical manage-
ment in patients with stable coronary artery disease. In the
absence of a recent MI, there was no significant difference
between the 2 treatment strategies in terms of death, MI, or
the need for subsequent revascularization. The COURAGE
trial randomized 2287 patients with objective evidence of
myocardial ischemia and stable coronary disease to PCI with
optimal medical therapy versus optimal medical therapy
alone. Again, lack of mortality benefit from PCI was ob-
Downloaded from http://ahajournals.org by on April 20, 2022
served.97 Similarly, the Bypass Angioplasty Revasculariza-
tion Investigation 2 Diabetes (BARI 2D) Study Group re-
ported no significant difference in the rates of death and
major cardiovascular events among patients with type 2
diabetes mellitus and stable ischemic heart disease undergo-
ing prompt revascularization versus medical therapy alone.98
Despite these sobering reports, in 2006, 1.3 million coro-
nary angioplasty procedures were performed at a cost approx-
imating $60 billion, and 448 000 coronary bypass operations
were performed the same year throughout the United States,
at an estimated cost of ⬎$44 billion.99 Total healthcare
spending in 2006 exceeded $2 trillion or $6700 per person,
representing 16% of the gross domestic product. This trend is
expected to increase at similar levels over the next few years,
reaching $4 trillion in 2015 or 20% of the gross domestic
product.100 Thus, in the near future, according to current
projections, healthcare will account for $1 of every $5 spent
in the United States. Currently, costs associated with chronic
diseases (eg, obesity, diabetes mellitus, hypertension, coro-
nary artery disease) account for ⬇75% of the nation’s annual
healthcare costs. Accordingly, we must find ways to imple-
ment effective preventive interventions (eg, medications,
weight reduction, healthier eating practices, regular physical
activity) as a first-line strategy to combat CVD.100
Behavioral Interventions and Complementary
Preventive Strategies
Behavioral patterns represent the No. 1 factor contributing to
premature death, exceeding genetic predisposition, social
circumstances, environmental exposure, and access to health-
care.101 Given the estimated number of preventable deaths
associated with the health factors comprising the AHA’s
Life’s Simple 7, which are cigarette smoking (465 000 per
year), hypertension (395 000), obesity (216 000), physical
inactivity (191 000), elevated blood glucose levels (190 000),
high levels of low-density lipoprotein cholesterol (113 000),
and other dietary risk factors,102 the AHA 2020 Strategic Plan
offers an enormous opportunity to improve health system
performance and public health. Nevertheless, disparities in
health are large in the United States and globally, and
strategies to increase national health rankings must focus on
the poor and less fortunate.101
Unfortunately, the prevalence of optimal levels of risk
factors and health behaviors is very low in the US population.
The Behavioral Risk Factor Surveillance System reported in
2000 that only 3% of 153 805 adults had 4 of 4 healthy
lifestyle characteristics of current nonsmoking, body mass
index 18.5 to 24.9 kg/m2, consumption of 5 fruits and
vegetables per day, and regular physical activity.103 The rate
was lower in blacks than in whites, at 1.4% and 3.3%,
respectively. These percentages were even lower in prelimi-
nary findings from the Reasons for Geographic and Racial
Differences in Stroke (REGARDS) cohort, a national cohort
of blacks and whites recruited in 2003–2007. Among 17 326
participants, only 0.5% of blacks and 2.1% of whites met all
4 lifestyle characteristics.104
Despite these sobering statistics, behavioral interventions
must be complemented by other strategies to further reduce
the burden of CVD. Clearly, we have prevented many
cardiovascular events by widely prescribing antihypertensive
drugs, aspirin, and statins. Intriguing data exist that bariatric
surgery may favorably modify risk factors, induce remission
of diabetes mellitus, and reduce death rates.105–107 In other
cases, public laws or policies may lead to better outcomes;
examples include taxes on sugary beverages, bans on trans
fats, smoking bans, and regulated decrements in salt content
of processed foods. The impact of these interventions can be
examined by quasi-experimental methods.108,109
Goals of the Prevention Series
The science volunteers of the AHA have become energized
early toward the achievement of the AHA 2020 Impact Goal
and the role that prevention will have in improving cardio-
vascular health. Accordingly, this special Prevention series
will review new insights in preventive cardiology, lifestyle
interventions, and cardiac rehabilitation, with a focus on
emerging clinical and psychosocial risk factors, cardioprotec-
tive drug and dietary recommendations, smoking cessation,
cardiorespiratory fitness/physical activity, and counseling of
patients regarding cardioprotective lifestyle changes. The
series will explore the independent and additive benefits that
may result when aggressive lifestyle modification is super-
imposed on optimal medical therapy (eg, cardioprotective
medications). Interest in this area spans multiple dimensions
involving traditional prevention strategies, improving com-
pliance, lifestyle medicine, methods of education of health-
care providers, the built environment (where people live),
strategies for health promotion in underserved ethnic groups,
including the economically disadvantaged, childhood inter-
 Franklin and Cushman
ventions, complementary and alternative therapies, and pub-
lic policy interventions. Figure 2 illustrates a general frame-
work for integration of these activities.
In summary, we hope that the new Circulation series will
serve as a stimulus for leaders in preventive cardiology and
lifestyle medicine to reflect on current knowledge and pro-
pose concepts for well-designed, large-scale randomized
clinical trials and quasi-experimental studies that are needed
to prove or disprove the many hypotheses listed herein.
Equally, we hope that the reader will be stimulated to pursue
changing paradigms and perceptions of these important top-
ics. New studies should serve to complement the armamen-
tarium of clinical, public health, and advocacy initiatives that
will be needed to achieve further reductions in death from
CVD and stroke. The challenge is yours!
Disclosures
None.
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KEY WORDS: lifestyle medicine 䡲 preventive cardiology