Editorial

Circulation Research Compendium on Obesity, Diabetes, and Cardiovascular Diseases

Obesity, Diabetes, and Cardiovascular Diseases: A Compendium
Epigenetic Changes in Diabetes and Cardiovascular Risk
Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications
Lipid Use and Misuse by the Heart
Obesity and Cardiovascular Disease
Vascular Complications of Diabetes
Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease
Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes
Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes
Treatment of Obesity: Weight Loss and Bariatric Surgery
Cardiac Dysfunction and Vulnerability in Obesity and Diabetes
Philipp E. Scherer and Joseph A. Hill, Editors

Obesity, Diabetes, and Cardiovascular Diseases

A Compendium
Philipp E. Scherer, Joseph A. Hill

E xcess body weight, a burgeoning problem worldwide, is

a major risk factor for cardiovascular disease. Diabetes
affects >180 million people around the world, and the number
of patients is anticipated to increase to 300 million by 2025.1
Recent data indicate that diabetes prevalence in adults has in-
creased since 1980 virtually in every country of the world;
the end-result is a near quadrupling of the number of adults
worldwide with diabetes.2
Within this escalating healthcare problem of monumen-
tal proportions, obesity-associated type 2 diabetes accounts
for 90% to 95% of all diagnosed diabetes cases in adults.1 In
fact, diabetes and insulin resistance are powerful predictors
of cardiovascular morbidity and mortality, and each is an in-
dependent risk factor for death in patients with heart failure.
Yet, the complex mechanisms underlying the deleterious im-
pact of diabetes on the heart and the vasculature are poorly
characterized.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Touchstone Diabetes Center (P.E.S.), Departments of Internal
Medicine (P.E.S., J.A.H.), Cell Biology (P.E.S.), and Cardiology and
Molecular Biology (J.A.H.), University of Texas Southwestern Medical
Center, Dallas.
Correspondence to Philipp E. Scherer, PhD, Touchstone Diabetes
Center, University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd, Dallas, TX 75390. E-mail philipp.scherer@utsouthwestern.
edu or Joseph A. Hill, MD, PhD, Division of Cardiology, University of
Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX
75390. E-mail Joseph.Hill@UTSouthwestern.edu
(Circ Res. 2016;118:1703-1705.
DOI: 10.1161/CIRCRESAHA.116.308999.)
2016 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.116.308999
1703
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Diabetes-associated cardiovascular diseases arise by a va-
riety of mechanisms. Atherosclerotic disease often emerges in
multiple vascular beds. Also, patients with diabetes are often
hypertensive. Obesity is associated with a proinflammatory
state marked by chronic elevations of systemic adrenergic
activity, dyslipidemia, and hyperglycemia. Circulating levels
of a variety of bioactive molecules are perturbed. Clearly, the
underlying pathophysiology is complex.
Constant and unremitting metabolic stress on the heart
leads over time to progressive deterioration of myocardial
structure and function, and heart failure is a typical end-result.
Sadly, current therapies are insufficient to arrest the progres-
sion of heart failure, and developing new therapies will require
greater understanding of molecular mechanisms underlying
pathological cardiac remodeling. This suggests that therapeu-
tic interventions early in the disease, targeting specific meta-
bolic and structural derangements, may be required. This is
especially relevant as rigid control of hyperglycemia, however
central to treatment, has not fulfilled hopes of meaningful
morbidity and mortality benefit.3 Recent and ongoing research
into mechanisms of metabolic control, insulin resistance, and
diabetes-associated derangements portend novel therapies de-
signed to benefit the rapidly expanding cohort of patients with
diabetes, a benefit with tremendous societal impact.
In light of these realities, we have assembled thought lead-
ers from around the world to review recent developments in
the complex biology of obesity-associated diabetes and car-
diovascular disease. In so doing, we present a compendium of
10 articles that touch on all critical aspects of this complex and
fascinating biology.
In an article entitled Epigenetic Changes in Diabetes
and Cardiovascular Risk, Keating et al4 provide an overview
1704Circulation ResearchMay 27, 2016
of epigenetic mechanisms contributing to macrovascular dis-
ease in diabetes. The authors highlight the recent identifi-
cation of chromatinized changes associated with perturbed
gene expression relevant to atherosclerosis in endothelial
cells, smooth muscle, and circulating immune cells. Their
review also discusses challenges associated with pharmaco-
logical targeting of epigenetic networks to restore dysregu-
lated gene expression.
Bhupathiraju et al,5 in an article entitled Epidemiology
of Obesity and Diabetes and Their Cardiovascular
Complications, discuss the diabesity epidemic. They point
to sex-related differences, as well as racial and ethnic dispari-
ties, in the prevalence and trends of obesity and diabetes. The
authors discuss a wide range of contributing factors, includ-
ing the obesogenic diet, marked by increased portion sizes of
calorie-laden foods. They also highlight the contributions of
limited access to healthy food choices, agricultural policies,
physical activity, and sleep patterns.
Cardiac myocytes rely heavily on fatty acid oxidation as a
predominant source of fuel; in the context of insulin resistance,
where glucose utilization is suppressed, fatty acid catabolism
is enhanced. Schulze et al,6 in an article entitled Lipid Use
and Misuse by the Heart, discuss diabetes-associated altera-
tions in fatty acid oxidation within cardiac myocytes. The au-
thors also review evidence for intracellular accumulation of
lipids, including some species of lipid that may contribute to
cardiac dysfunction. The authors go on to discuss preclinical
and clinical data suggesting that efforts to deplete toxic lipids
may have therapeutic relevance.
Ortega et al,7 in an article entitled Obesity and
Cardiovascular Disease, discuss the complex relationship be-
tween obesity and cardiovascular disease. They discuss how
the extent, distribution, and duration of obesity affect car-
diovascular events. The authors go on to discuss the fat but
fit paradigm, the notion of an obese and yet metabolically
healthy phenotype. Finally, they review and discuss the obe-
sity paradox in cardiovascular disease.
Beckman et al,8 in their contribution entitled Vascular
Complications of Diabetes, highlight the fact that diabetes
promotes disease in nearly all blood vessel types and sizes.
They discuss the fact that patients with diabetes are at substan-
tially increased risk for both microvascular and cardiovascular
adverse events. Indeed, the authors remind us that vascular
complications are responsible for most of the morbidity, hos-
pitalizations, and mortality in patients with diabetes. Indeed,
once cardiovascular disease develops, diabetes exacerbates
disease progression and worsens outcomes.
Fuster et al,9 in their section entitled Obesity-Induced
Changes in Adipose Tissue Microenvironment and Their
Impact on Cardiovascular Disease, discuss the role of adi-
pose tissue in obesity-associated diabetes and cardiovascular
disease. The authors highlight the concept of obesity-driven
adipose tissue dysfunction and the associated inflammatory
state. Adipose tissues secrete many biologically active mole-
cules termed adipokines, and several of these are capable of
promoting the proinflammatory state of diabetes. The authors
provide a thorough overview of this biology.
Shah et al,10 in their article entitled Molecular and Cellular
Mechanisms of Cardiovascular Disorders in Diabetes, point
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to the importance of the toxic accumulation of reactive oxy-
gen species in accelerated atherosclerosis. Whereas reactive
oxygen species signaling is fundamental to many normal cel-
lular events, excessive reactive oxygen species synthesis or
diminished reactive oxygen species removal, can be toxic. The
authors organize their discussion by categorizing these events
as either hyperglycemia-induced mechanisms or insulin resis-
tancerelated mechanisms.
Standl et al,11 in a section entitled Heart Failure
Consideration of Antihyperglycemic Medications for Type
2 Diabetes, point to the remarkable growth of new antihy-
perglycemic medications that has occurred in recent years.
The authors discuss these agents, noting that some seem to
be particularly beneficial with respect to heart failurerelated
effects; others pose no significant harm. Finally, the authors
discuss the agents where the cardiovascular effects, good or
bad, are less apparent.
In many instances, obesity is the proximal trigger that
culminates ultimately in diabetes and cardiovascular dis-
ease. Eckel et al,12 in a piece entitled Treatment of Obesity:
Weight Loss and Bariatric Surgery discuss the roles of life-
style changes, pharmacotherapy, and surgical approaches in
the treatment of obesity. In each case, the authors review the
relative efficacies and roles of the intervention.
As in all living cells, intermediary metabolism provides
energy substrates essential to fuel cardiac myocytes and their
contractile function. Taegtmeyer and Abel (in press)13 discuss
mechanisms by which a shifted metabolic milieu or intrinsic
changes can impair the performance of the heart in obesity
and diabetes. The dysregulated metabolic state touches the
heart at multiple levels. Their review focuses on consequences
of altered insulin signaling, altered mitochondrial metabo-
lism, altered redox state, and additional mechanisms that cor-
rupt cardiac function, with the ultimate goal of optimizing the
treatment of diabetic patients with heart failure.
We have been fortunate to work with a panel of thought
leaders to assemble a compendium of review articles that
spans molecular mechanisms, cell biology, clinical medicine,
and epidemiologyand across multiple cell types and tissues.
The world faces an epidemic of diabetes-driven cardiovascu-
lar disease, and elucidation of underlying pathophysiological
mechanisms is urgently required. Looking to the future, it has
been suggested that the thrombocardiologist of the 20th cen-
tury is being replaced by the diabetocardiologist of the 21st
century (Eugene Braunwald, personal communication). It is
our fervent hope that these authoritative review articles will
help to stem the tide.
Disclosures
None.
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Key Words: Editorials body weight heart failure obesity type 2
diabetes
 Obesity, Diabetes, and Cardiovascular Diseases: A Compendium
Philipp E. Scherer and Joseph A. Hill

Circ Res. 2016;118:1703-1705

doi: 10.1161/CIRCRESAHA.116.308999
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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