Subclinical Myocardial Impairment in Metabolic Diseases

JACC: CARDIOVASCULAR IMAGING

VOL. 10, NO. 6, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jcmg.2017.04.001

STATE-OF-THE-ART PAPER

Subclinical Myocardial Impairment in Metabolic Diseases Wojciech Kosmala, MD, PHD,a Prash Sanders, MBBS, PHD,b Thomas H. Marwick, MD, PHDc

JACC: CARDIOVASCULAR IMAGING CME/MOC CME/MOC Editor: Ragavendra R. Baliga, MD

the development of disturbances of cardiac rhythm, function, and structure; 2) understand the relationship between metabolic de-

This article has been selected as this issue’s CME/MOC activity, available online at http://www.acc.org/jacc-journals-cme by selecting the CME/MOC tab on the top navigation bar.

rangements, associated measures of cardiac function and morphology, and the future occurrence of heart failure and cardiovascular events; and 3) emphasize the significance of nonconventional echocardiographic methods, especially LV longitudinal deformation assessment, in identi-

Accreditation and Designation Statement

fying those individuals that may be at risk of the progression of pre-

The American College of Cardiology Foundation (ACCF) is accredited by

clinical impairment to symptomatic disease, as well as more likely to

the Accreditation Council for Continuing Medical Education (ACCME) to

benefit from behavioral and pharmacological interventions.

provide continuing medical education for physicians. CME/MOC Editor Disclosure: JACC: Cardiovascular Imaging CME/MOC The ACCF designates this Journal-based CME/MOC activity for a maximum

Editor Ragavendra R. Baliga, MD, has reported that he has no relation-

of 1 AMA PRA Category 1 Credit(s) TM. Physicians should only claim credit

ships to disclose.

commensurate with the extent of their participation in the activity. Author Disclosures: Dr. Sanders was supported by a Practitioner Method of Participation and Receipt of CME/MOC Certificate To obtain credit for this CME/MOC activity, you must: 1. Be an ACC member or JACC: Cardiovascular Imaging subscriber. 2. Carefully read the CME/MOC-designated article available online and in this issue of the journal.

Fellowship from the National Health and Medical Research Council of Australia; has served on the advisory board for Biosense Webster, Medtronic, St. Jude Medical, Boston Scientific, and CathRx; has received lecture and/or consulting fees from Biosense Webster, Medtronic, St. Jude Medical, and Boston Scientific; and has received research funding from Medtronic, St. Jude Medical, Boston

3. Answer the post-test questions. At least 2 out of the 3 questions

Scientific, Biotronik, and Sorin. All other authors have reported that

provided must be answered correctly to obtain CME/MOC credit.

they have no relationships relevant to the contents of this paper to

4. Complete a brief evaluation. 5. Claim your CME/MOC credit and receive your certificate electronically by following the instructions given at the conclusion of the activity. CME/MOC Objective for This Article: After reading this article, the reader

disclose. Medium of Participation: Print (article only); online (article and quiz). CME/MOC Term of Approval

should be able to: 1) review the potential impact of metabolic abnor-

Issue Date: June 2017

malities associated with diabetes, obesity, and metabolic syndrome on

Expiration Date: May 31, 2018

From the aCardiology Department, Wroclaw Medical University, Wroclaw, Poland; bCentre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; and the cBaker Heart and Diabetes Institute, Melbourne, Australia. Dr. Sanders was supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia; has served on the advisory board for Biosense Webster, Medtronic, St. Jude Medical, Boston Scientific, and CathRx; has received lecture and/or consulting fees from Biosense Webster, Medtronic, St. Jude Medical, and Boston Scientific; and has received research funding from Medtronic, St. Jude Medical, Boston Scientific, Biotronik, and Sorin. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received March 2, 2017; revised manuscript received April 11, 2017, accepted April 12, 2017.

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

Subclinical Myocardial Impairment in Metabolic Diseases Wojciech Kosmala, MD, PHD,a Prash Sanders, MBBS, PHD,b Thomas H. Marwick, MD, PHDc

ABSTRACT Type 2 diabetes mellitus (T2DM) and obesity are important contributors to nonischemic heart failure (HF) and atrial fibrillation. There is a 2- to 5-fold increase in HF associated with T2DM, and there is a 5% in HF risk in men and 7% increment in women for every unit increment in body mass index, after adjustment for traditional cardiovascular risk factors. Likewise, the risk of atrial fibrillation increases by about 6% per unit increase in body mass index. Metabolic cardiomyopathy leads to a number of changes in cardiac structure and function that can be recognized by imaging in the asymptomatic phase, and these parameters can be used for monitoring the progression of disease or the response to therapy. The purpose of this review is to familiarize clinicians with the potential benefits of early detection of preclinical myocardial abnormalities, as well as the mechanisms that might inform interventions to prevent disease progression in patients with T2DM and obesity. (J Am Coll Cardiol Img 2017;10:692–703) © 2017 by the American College of Cardiology Foundation.

T causes

ype 2 diabetes mellitus (T2DM) and obesity

interventions that might be undertaken to prevent

(and

and

disease progression in patients with subclinical

obstructive sleep apnea) are the principal

disease due to T2DM and obesity (Central Illustration).

of

their

sequelae,

functional

and

hypertension

structural

myocardial

disease that are independent of coronary, congenital,

MECHANISMS

or valvular heart disease (1,2). T2DM has been reported by the Framingham Heart Study to be

CELLULAR

responsible for a 2- to 5-fold increase in heart failure

background of myocardial impairment in metabolic

(HF) risk, with an even higher frequency in the

diseases is multifactorial. Metabolic derangements

elderly (3). Analogous obesity data obtained from

play a central role among a broad spectrum of putative

the same cohort indicate an increase in HF risk of

mechanisms responsible for cardiac structural and

5% in men and 7% in women for every unit increase

functional alterations. Predominant changes in car-

in body mass index (BMI), after adjustment for tradi-

diomyocyte energetics, with a significant reduction in

tional cardiovascular risk factors, and a 9% to 14%

glucose supply and utilization, are associated with the

increment of risk associated purely with weight

depletion of the sarcolemmal glucose transporter type

excess (4). The presence of subclinical disease confers

4 and with inhibition of pyruvate dehydrogenase by

an increased cardiovascular risk, with the risk of total

increased beta-oxidation of free fatty acids (FFA), as

mortality increased 2.9-fold for men and 1.7-fold

well as with tumor necrosis factor alpha–mediated

for women (5). Several population studies have also

dysfunction of insulin receptors (7). Direct or indirect

provided evidence of a strong and dose-dependent

effects of hyperglycemia, excess FFA, and triglyceride

association of obesity and risk of atrial fibrillation

uptake and accumulation in cardiomyocytes, oxida-

(AF) with a 29% increase in AF risk per 5-unit increase

tive stress, and insulin resistance (IR) have been

in BMI (6). Imaging techniques, especially echocardi-

widely recognized to contribute to myocardial alter-

ography and cardiac magnetic resonance (CMR), are

ations in metabolic diseases (7–11) (Table 1).

the mainstay of the recognition of asymptomatic metabolic

cardiomyopathy,

as

well

as

further

METABOLISM. The

pathophysiologic

The progression of myocardial fibrosis—one of the key mechanisms underlying cardiac dysfunction is

monitoring of pathological alterations and potential

intensified

responses to therapy. Accordingly, in the context of

neurohormonal factors favoring collagen formation,

by

metabolic,

proinflammatory

and

the increasing prevalence of metabolic disorders,

with special contribution from increased local angio-

the purpose of this review is to familiarize clinicians

tensin II, aldosterone, transforming growth factor

with the pathophysiologic processes that underlie

(TGF)- b1, and protein kinase C activity. At the same

preclinical myocardial abnormalities, the mecha-

time, collagen degradation is reduced by increased

nisms whereby they develop, and the potential

glycosylation of the lysine residues (7).

693

694

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

ABBREVIATIONS

Small vessel disease is incriminated in

AND ACRONYMS

the development of myocardial derange-

AF = atrial fibrillation BMI = body mass index cIB = calibrated integrated backscatter

CMR = cardiac magnetic resonance

CFR = coronary flow reserve 0

E/e ratio = peak early diastolic mitral flow velocity/peak early

may be modified by changes in conduit artery stiffness and increased blood pressure (11).

ments in metabolic disorders. This process

Previous controversies regarding an independent

may be structural or functional, including

link between T2DM and increased LV mass have

association with a number of pathologies,

been clarified by some studies demonstrating an

particularly capillary rarefaction, basement

association between T2DM and LV hypertrophy in

membrane thickening with reduced perme-

the absence of hypertension and coronary artery

ability, increased oxygen diffusion distance to

disease (12). The echocardiographic recognition of

cardiomyocyte mitochondria, and endothelial

LV hypertrophy in metabolic diseases strictly de-

dysfunction with a reduced availability and

pends on the LV mass indexation method (i.e., either

half-life of nitric oxide (7,8).

to body surface area, height 1.7, or height2.7, with

Finally, myocardial systolic and diastolic

indexing for height being a more suitable option for

FFA = free fatty acids

function can be affected in patients with DM

overweight and obese subjects). CMR allows for a

HbA1c = glycosylated

by reduced sympathetic innervation and

better definition of cardiac volumes and mass, and

hemoglobin

disturbed beta-adrenergic signaling (7,8).

may provide a valuable diagnostic alternative espe-

diastolic mitral annular velocity

HF = heart failure

cially in obese patients with a suboptimal acoustic

IR = insulin resistance

PARACRINE

LV = left ventricular

impact of obesity on cardiovascular system is

Abnormalities of right heart hemodynamics, espe-

RV = right ventricular

closely linked with the endocrine milieu

cially the elevation of pulmonary artery and right

provided by adipose tissue. The increase in

atrial pressures, can be seen in severely obese sub-

body fat content, especially in its visceral

jects. However, these findings are less common in the

TGF = transforming growth factor

INFLUENCES. The

negative

compartment, is associated with augmented release

window (13).

asymptomatic stage (11).

of cardioinhibitory cytokines and fibrosis mediators,

DIASTOLIC DYSFUNCTION. Abnormalities of LV dia-

and promotion of IR, even in subjects with normal

stolic performance in preclinical metabolic disease

BMI. There is a specific population of people having

are usually characterized by delayed relaxation, with

so-called

at

increased LV filling pressure being less common.

an increased cardiovascular risk. Despite being

However, the use of conventional Doppler for LV

asymptomatic, these individuals have disturbances

filling assessment as well as left atrial enlargement

of left ventricular (LV) systolic and diastolic function

may be somewhat problematic in overweight pa-

that are independently associated with the extent of

tients, in whom the effects of increased loading can

abdominal fat deposits and the magnitude of the

be an impediment to adequate interpretation of

profibrotic state, reduced insulin sensitivity, and

findings. Tissue Doppler imaging is of value in iden-

proinflammatory activation (9). The paracrine mech-

tification of diastolic dysfunction in these individuals

anisms are also a component of the adverse effects of

(14–18) (Figure 1). The frequency of LV diastolic

epicardial fat. The secretome from epicardial adipose

dysfunction ranges from 23% to 75% in metabolic

normal-weight

obesity

that

are

tissue can induce myocardial fibrosis and may explain

diseases depending on the diagnostic criteria (18–20).

the association between epicardial fat and atrial SYSTOLIC DYSFUNCTION. LV ejection fraction and

fibrosis, mediated by Activin A (10).

fractional shortening have been reported to be

PATHOPHYSIOLOGY

normal (or even supranormal in obesity) in the asymptomatic stage of metabolic cardiomyopathy (21).

Table 2 summarizes the potential impact of obesity

Ejection fraction seems to be insufficiently sensitive

and metabolic disturbances on myocardial structure

to detect minor systolic abnormalities, which usually

and function. In short, all cardiac chambers and all

appear concomitantly with or even precede diastolic

phases of cardiac function are influenced.

impairment (18). A number of studies have demon-

CARDIAC

REMODELING

AND

HEMODYNAMIC

strated that the identification of early systolic

ALTERATIONS. Over time, the previous substructural

derangements can be achieved with the use of

changes evolve into specific morphological pheno-

myocardial deformation (Figure 2), assessed either by

types, including LV concentric hypertrophy, as well as

speckle tracking (which is preferred, as it is most

eccentric hypertrophy, especially in severe obesity (8).

robust) or tissue Doppler imaging, or systolic myocar-

Excess weight is associated with an increase in blood

dial velocities (14,18).

volume and cardiac output, the latter attributable to

Longitudinal, circumferential, and radial functions

increased lean body mass. Systemic vascular resis-

may not change simultaneously, with the earliest

tance is reduced in pure obesity; however, LV afterload

onset of contractile abnormalities in the longitudinal

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

C ENTR AL I LL U STRA T I O N Pathophysiological Mechanisms, Cardiac Abnormalities, and Therapeutic Interventions in Metabolic Heart Disease

Kosmala, W. et al. J Am Coll Cardiol Img. 2017;10(6):692–703.

Association of biochemical mechanisms (cardiomyocyte fat metabolism, oxidative stress, hyperglycemia, insulin resistance) with pathophysiologic processes (myocardial fibrosis, cardiac morphology, left ventricular [LV] and right ventricular [RV] function, LV stress response, left atrial [LA] function, coronary microcirculation). A variety of interventions (weight reduction, behavioral and therapeutic) have been undertaken to prevent disease progression in patients with subclinical disease due to type 2 diabetes mellitus and obesity. An enhanced version of the Central Illustration is available at: http://jaccimage.acc.org/video/2017/17-0304% 20CI%20Marwick_comp_v1.gif. FFA ¼ free fatty acids; TG ¼ triglyceride.

direction, reflecting involvement of subendocardial

disturbances, adequacy of glycemic control, levels of

fibers in the pathological process (22). Circumferential

FFA and triglycerides, BMI (and other measures of

and radial strains have been found to be preserved

excessive fat deposition such as waist-to-hip ratio,

(23), decreased (18), or increased (radial) presumably

waist circumference, and estimated fat mass), IR,

to compensate for reduced longitudinal contraction

presence of complications such as nephropathy and

(22). The prevalence of reduced global longitudinal

autonomic neuropathy, tumor necrosis factor alpha,

deformation in asymptomatic metabolic disease has

and TGF- b1. The effects of T2DM and obesity on LV

been reported to range from 37% to 54% (23).

performance, although enhanced by coexisting LV

Another abnormality of LV mechanics found in T2DM and obesity with speckle tracking echocardiog-

hypertrophy, are independent of increased LV mass (15).

raphy or CMR is increased LV torsion or untwisting rate

LV deformation, systolic and diastolic tissue ve-

(24). The significance of this finding is not clearly

locities all decrease gradually from overweight

defined, with putative explanations linking the altered

through class I and II to class III obese subjects (11).

rotational function to a compensatory mechanism

However, in the absence of comorbidities or compli-

contributing

LV

cations, the progression of myocardial dysfunction in

contractility or to a distinct pathology associated with

patients with overweight may be very slow, spanning

cardiac autonomic or microvascular dysfunction (24).

a period of even 20 years. Incremental effects of

The extent of LV diastolic and systolic dysfunction

metabolic disturbances on cardiac performance are

is

to

determined

the

by

maintenance

the

duration

of

of

global

metabolic

clearly seen in the metabolic syndrome, where

695

696

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

DYSFUNCTIONAL LV STRESS RESPONSE. Additional

T A B L E 1 Cardiodepressant Effects of Metabolic Aberrations

Aberration

stratification of the risk of myocardial dysfunction in subclinical metabolic heart disease can be accom-

Effect

Hyperglycemia

Mitochondrial superoxide production, nitric oxide and cGMP; protein kinase G activity; hypophosphorylation of titin; myocardial deposition of advanced glycation products due to nicotinamide adenine dinucleotide phosphate oxidase and inflammatory activation

plished with stress testing. Patients with metabolic disorders may demonstrate reduced myocardial systolic and diastolic reserve, as evidenced by blunted response during exercise or dobutamine stress echo-

FFA uptake into cardiomyocytes

Mitochondrial dysfunction with uncoupling of oxidative phosphorylation; cardiomyocyte lipoapoptosis

cardiography. This has been shown for numerous

Myocardial triglyceride accumulation

Cardiomyocyte lipoapoptosis

stolic tissue velocities, longitudinal strain and strain

Oxidative stress

Nuclear factor kappa B; cardioinhibitory and profibrotic cytokines; dysregulation of intracellular Caþ2 turnover (effect on Caþ2-sensitive contractile proteins, Naþ/Caþ2 exchanger and sarcoplasmic or endoplasmic reticulum Caþ2–ATPase pump)

Insulin resistance and hyperinsulinemia

Cardiomyocyte hypertrophy and intrinsic stiffness by the activation of phosphoinositide 3-kinase/protein kinase B cascade; activation of insulin-like growth factor 1 response to angiotensin II; sodium retention receptors, with intravascular volume expansion

ATPase ¼ adenosine triphosphatase; cGMP ¼ cyclic guanosine monophosphate; FFA ¼ free fatty acids.

aspects of LV function, including systolic and diarate, and peak early diastolic mitral flow velocity/ peak early diastolic mitral annular velocity ratio (E/e0 ) (27), as well as for parameters that usually show normal values at rest (ejection fraction, fractional shortening, stroke volume, and ventricular-arterial coupling). It should be noted, however, that the reduction in stress-induced increase in LV contractility has not been uniformly observed. This might suggest an association with differences in the progression of pathophysiological abnormalities among the studied populations (28). The inconsistency of

myocardial dysfunction increases with the number of

data on the contribution of poor glycemic control to

components (25). LV functional abnormalities detec-

reduced functional reserve in subclinical metabolic

ted by echocardiography have been shown to corre-

cardiomyopathy may suggest a role for the non-

late with the reduced exercise capacity of patients

metabolic factors such as myocardial fibrosis and

with metabolic heart disease—even in the preclinical

cardiac autonomic neuropathy (27). Some data indi-

stage

cate that a deficient functional response to stress in

(16).

LV

dysfunction

(global

longitudinal

strain <18%) in asymptomatic patients with DM has been associated with the progression of adverse LV remodeling over 3 years of observation (26).

patients with T2DM has prognostic significance (29). RIGHT VENTRICULAR DYSFUNCTION. Patients with

T2DM or obesity demonstrate abnormalities of right ventricular (RV) systolic (Figure 3) and diastolic

T A B L E 2 Imaging Characteristics of Metabolic Heart Disease

Domain

Findings

Cardiac morphology

LV concentric or eccentric hypertrophy

Myocardial tissue characterization

Higher cIB and shorter post-contrast CMR-derived T1 time, both indicative of enhanced myocardial fibrosis

LV diastolic function

Usually delayed relaxation, evidence of LV filling pressure elevation less common in preclinical phase

LV systolic function

EF and FS usually normal or even supranormal in obesity Decrease in longitudinal function (strain or myocardial systolic velocities) Circumferential and radial deformations unchanged, decreased, or increased (radial)

LV rotational function

Increased LV torsion and untwisting rate

RV function

Systolic and diastolic abnormalities evidenced by longitudinal strain and myocardial velocities

LA function

Impaired LA deformation (reduced function)

LV response to stress

Usually reduced systolic and diastolic reserve, as evidenced by tissue velocities, longitudinal strain and strain rate, E/e0 ratio, EF, FS, stroke volume, and ventriculoarterial coupling

Coronary microvascular function

Reduced coronary flow reserve and diminished endotheliumdependent and independent vasodilation, as demonstrated by myocardial contrast echocardiography, distal coronary Doppler flow, and PET, usually with a vasodilating stressor agent (dipyridamole, adenosine, regadenoson) or with dobutamine

cIB ¼ calibrated integrated backscatter; CMR ¼ cardiac magnetic resonance; E/e0 ratio ¼ peak early diastolic mitral flow velocity/peak early diastolic mitral annular velocity; EF ¼ ejection fraction; FS ¼ fractional shortening; LA ¼ left atrial; LV ¼ left ventricular; PET ¼ positron emission tomography; RV ¼ right ventricular.

function, which have been evidenced by tissue Doppler and strain imaging (30,31). These changes are independent of comorbidities (e.g., sleep apnea), although sleep-disordered breathing may potentiate RV dysfunction in obesity through the increase in pulmonary artery pressure in response to hypoxiainduced vasoconstriction of small pulmonary arteries (31). As demonstrated, disturbances of RV performance may correlate with exercise capacity; however, their prevalence has not been established and their clinical significance remains uncertain. LEFT ATRIAL DYSFUNCTION. Detrimental effects of

metabolic disturbances have also been identified in the atrial myocardium. Abnormal left atrial strain has been shown in patients with T2DM, irrespective of the extent of atrial structural involvement (32), including also subjects with a normal left atrial size and LV filling pressure, which may suggest that the underlying cause is not of hemodynamic origin (32). This observation supports the notion of left atrial deformation abnormalities in DM precede atrial volumetric changes.

A functional atriopathy in

obesity is

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

associated with left atrial dilatation resulting from chronic volume overload.

F I G U R E 1 Negative Impact of Insulin Resistance on Early Diastolic Septal Velocity

CORONARY MICROVASCULAR IMPAIRMENT. Coro-

nary microangiopathy, even in the absence of epicardial coronary atherosclerosis, is thought to be an important part of the pathophysiological framework in metabolic heart disease. The clinical manifestations of this pathology include reduced coronary flow reserve (CFR) and diminished endotheliumdependent and independent vasodilation. Impaired CFR is a strong predictor of cardiovascular mortality in DM, and subjects without epicardial coronary artery disease and with preserved CFR have low event rates, irrespective of whether they have T2DM (33). The imaging techniques used for assessment of coronary

microvascular

status

are

myocardial

contrast echocardiography, distal coronary Doppler flow (usually in the left anterior descending artery), and positron emission tomography, usually with a coronary vasodilator (dipyridamole, adenosine, or regadenoson)

or

sometimes

with

dobutamine.

Reduced CFR in metabolic diseases has been reported in numerous studies (34). The coexistence of T2DM, obesity, and lipid disturbances is associated with a cumulative

adverse

effect

on

microvascular

dysfunction (35). Conflicting data exist regarding the pre-diabetic

state,

with

CFR

being

normal

or

abnormal; however, these discrepancies may depend on the presence of other clinical determinants (36,37). The direct contribution of microvascular disease to

resting

subclinical

LV

dysfunction

remains

controversial (34). However, repeated episodes of the mismatch between oxygen demand and supply due to

microvascular

impairment

might

promote

morphological changes such as interstitial fibrosis, being responsible for LV functional abnormalities. Coronary microvascular dysfunction can be at least partially reversed by treatment. Intensified glycemic control with insulin improved both myocardial perfusion and LV diastolic function (38). A salutary effect on CFR has been shown with metformin (39), thiazolidinediones (40), aldosterone antagonists (41), and C peptide (42).

Decreased early diastolic septal velocity of the mitral annulus in an obese patient with insulin resistance (bottom) in comparison with an obese patient without insulin resistance (top): 4 cm/s versus 7 cm/s.

MYOCARDIAL TISSUE CHARACTERIZATION BY IMAGING TECHNIQUES. Structural

myocardial

Increased cIB is not highly specific for myocardial

tissue in metabolic disease have been assessed by

alterations

of

fibrotic changes and may also reflect cardiac steatosis

CMR-derived T1 mapping and ultrasound calibrated

and lipoapoptosis (44). As cyclic variation of inte-

integrated backscatter (cIB). Shorter post-contrast

grated backscatter is a marker of regional LV perfor-

T1 time is associated with a larger amount of diffuse

mance, LV functional derangements may contribute

myocardial

fibrosis.

T1

mapping

abnormalities

to abnormal cIB. Higher levels of myocardial tissue

demonstrated in T2DM are associated with LV systolic

reflectivity by cIB in T2DM, obesity, and the meta-

and diastolic dysfunction and impaired exercise ca-

bolic syndrome (Figure 4) are associated with LV

pacity, and correlate with IR and central adiposity (43).

systolic and diastolic disturbances, reduced exercise

697

698

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

F I G U R E 2 Decreased Left Ventricular Longitudinal Deformation in an Asymptomatic Patient With Obesity and Type 2 Diabetes Mellitus

Global longitudinal strain 13.8%.

capacity, IR, and increased body weight and abdom-

and function improvements than have changes in

inal fat deposition (45). The associations of both T1

other measures of obesity, such as BMI or waist

time and cIB are consistent with the mechanisms of

circumference (47,48).

promotion of myocardial collagen deposition and the biological effects of cardiac fibrosis.

Epicardial fat has been found to be associated with AF risk independent of other obesity measures (49).

EPICARDIAL FAT. In addition to contributing to the

Recent data suggest that epicardial adipose tissue

car-

may promote atrial fibrosis in obesity. The contiguity

diodepressant compounds, epicardial fat deposits

of epicardial fat and atrial tissue may lead to fat

may detrimentally affect the myocardium by local

infiltration of the adjacent myocardium (50). This

effects. These include natural compression and local

results not only in mechanical alteration of function

delivery of FFA and cardioactive hormones, adipo-

but acts as a conduction barrier to further promote

systemic

source

of

proinflammatory

and

kines, and mediators, linked with LV hypertrophy

arrhythmias.

and dysfunction. Epicardial fat can be quantified

IMAGING BIOMARKERS VERSUS BLOOD BIOMARKERS.

by echocardiography, computed tomography, and

Imaging biomarkers obtained from echocardiogra-

CMR, and its amount closely correlates with visceral

phy and, to a lesser extent, CMR are the mainstay

adiposity. Previous studies demonstrated a role of

for identification of subclinical metabolic heart dis-

epicardial fat in the prediction of increased car-

ease. The limited usefulness of B-type natriuretic

diometabolic risk and its potential utility as a marker

peptide measurement for this purpose can be linked

of therapeutic effect (46). Increased epicardial fat

with the absence of increased wall stress—the main

thickness or volume has been linked with higher LV

trigger for the release of this peptide—in the

mass as well as LV and RV systolic and diastolic

asymptomatic phase of myocardial impairment (8).

function derangements (47), and these associations

Obesity has been found to be associated with low

have been observed over a wide range of obesity.

B-type natriuretic peptide (51). Other blood bio-

Measurements of epicardial fat have been used for

markers, especially those reflecting inflammatory

monitoring in some surgical and behavioral programs

activation and fibrosis, might be taken into consid-

aimed at treating obesity. A decrease in epicardial fat

eration, however their clinical utility is still poorly

with intervention has correlated better with LV mass

validated.

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

F I G U R E 3 Progressive Decrement in RV Longitudinal Deformation With Increase in Body Weight

Top left panel shows right ventricular (RV) strain of 32.8% in a patient with body mass index (BMI) of 23.5 kg/m2, top right panel shows strain of 27.0% in a patient with BMI 29.7 kg/m2, and bottom panel shows RV strain of 21.7% in a patient with BMI 37.3 kg/m2.

GUIDING MANAGEMENT

SURGICAL

AND

BEHAVIORAL

INTERVENTIONS

WITH WEIGHT LOSS. Weight reduction attained by

Table 3 summarizes the mechanisms and effects of

bariatric surgery or lifestyle modification with caloric

generic and specific interventions in metabolic heart

restriction and increased physical activity can reverse

disease.

cardiac structural and functional abnormalities caused

IMPACT OF SUBCLINICAL LV DYSFUNCTION ON

by obesity alone or with coexisting T2DM. Despite

PROGNOSIS. Current guidelines on cardiovascular

its efficacy, the surgical approach is reserved for

screening in T2DM do not consider the routine use

morbidly obese patients (54). Even modest weight

of imaging techniques to identify early myocardial

reduction (5% to 10%), which is achievable with

abnormalities (52). The presence of subclinical LV

behavioral changes, may be beneficial in improving

dysfunction detected by echocardiography is of

cardiometabolic risk (55). Significant weight loss is

prognostic significance in this condition. A number of

associated with a decrease in blood volume, stroke

studies

functional

volume and cardiac output, with a variable effect on

impairment in both diastole (E/e 0 ) and systole (global

systemic vascular resistance and, most commonly,

longitudinal strain) are independently associated

with an improvement in pulmonary hemodynamics.

with adverse outcomes in asymptomatic patients

A reduction in LV mass, diastolic size, and wall thick-

with DM but without cardiovascular complications

ness demonstrated in the majority of studies is attrib-

and comorbidities (19,53). This information is inde-

utable to favorable alterations in cardiac loading

pendent of and incremental to demographic and

conditions, as well as the neurohormonal and metabolic

clinical factors. However, to change the guidelines,

milieu (11).

have

demonstrated

that

LV

there is a need to accumulate evidence to show that

The salutary effect of weight loss on both diastolic

therapeutic responses to these findings alter the

and systolic function (as assessed by transmitral and

onset or progression of HF.

pulmonary vein Doppler indices, mitral annular

699

700

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

F I G U R E 4 Calibrated IB in Normoglycemic and Type 2 DM Subjects

Normoglycemic subjects are shown in the left panel and type 2 diabetes mellitus (DM) subjects are shown in the right panel. Calibrated integrated backscatter (IB) measured as a difference in signal intensity between the myocardium (yellow, interventricular septum; green, left ventricular posterior wall) and pericardium (red) at end-diastole. Higher (¼ less negative) values of calibrated IB in type 2 DM, both within the interventricular septum and posterior wall (15.2 dB vs. 22.4 dB and 19.2 dB vs. 25.4 dB, respectively).

velocities, and LV longitudinal deformation parame-

intracellular

ters), achieved either by surgical or lifestyle modifi-

improvement in IR by exercise-induced increase in

cation approaches, has been reported in all classes of

skeletal muscle glucose uptake and metabolism.

obesity. This corresponds with improvements in body

These exercise-based interventions exert a positive

weight, glycosylated hemoglobin (HbA 1c), myocardial

effect on the development and progression of only LV

triglyceride content, and IR, all of which contribute to

diastolic dysfunction (61), or both LV systolic and

the observed cardiac benefit (54–56). The favorable

diastolic performance, and LV torsion in T2DM (62),

associations of cardiac morphological and functional

as well as improved both LV longitudinal deformation

characteristics with a decline in body weight are

and diastolic function indices, and cardiac synchrony

paralleled by an increment in cardiorespiratory

in moderately obese subjects (63). The concomitant

fitness (57).

improvement in aerobic fitness was, however, less

calcium-handling

abnormalities

and

Our preliminary data show that reductions in left

obvious, with differences in program regimens and

atrial volumes, myocardial mass, and pericardial fat

durations, and patient adherence being likely to

content resulting from weight loss have been associ-

affect the clinical efficacy of this kind of treatment. A

ated with decrease in AF symptom burden (58),

recently published report on a 6-month intervention

maintenance of sinus rhythm, and improved ablation

in the metabolic syndrome based on dietary man-

outcomes (59).

agement and increased physical activity showed sig-

BEHAVIORAL INTERVENTIONS WITHOUT WEIGHT

nificant improvements in LV systolic and diastolic

LOSS. According to the current guidelines, at least

longitudinal deformation and diastolic tissue veloc-

150 min/week of moderate-intensity exertion is

ities, and the strongest predictor of these favorable

advisable for patients with T2DM (60). The impact of

changes was a reduction of epicardial fat (47).

exercise training without purposeful weight reduc-

Improved cardiorespiratory fitness has been asso-

tion on LV performance and functional capacity has

ciated with an additive impact to weight loss on

been assessed both in T2DM and obesity. Putative

arrhythmia free survival in patients with AF (64).

mechanisms behind the beneficial influence of exer-

PHARMACOLOGICAL INTERVENTIONS FOR GLYCEMIC

tion on the myocardium may involve attenuation of

CONTROL. Despite the apparent deleterious impact of

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

increased glucose concentration on myocardial characteristics, there is little supportive evidence that tightened glycemic control is capable of improving cardiac performance. A recent paper revealed that the intensification of hypoglycemic treatment for 12

T A B L E 3 Therapeutic Interventions in Metabolic Heart Disease

Mechanisms

Effects

Surgical or behavioral with weight loss

Intervention

Decrease in blood volume, stroke volume, and cardiac output Increase in systemic vascular resistance in normotensive subjects, but no change or decrease in hypertensive subjects. Decrease in pulmonary artery, RV, and right atrial pressures Decrease in cardiac preload Improvement in metabolic control (decrease in HbA1c, insulin resistance, and triglyceridemia) Decrease in neurohormonal activation Reduced pericardial fat

Decrease in LV mass and wall thicknesses Improvement in LV diastolic and systolic performance Improvement in cardiorespiratory fitness Decrease in LA size Reduced AF burden

Behavioral without intentional weight loss

Improvement in intracellular Improvement in only diastolic calcium handling and insulin function or both diastolic and resistance due to increase in systolic function, LV torsion skeletal muscle glucose uptake in T2DM, and cardiac and metabolism synchrony in obesity Less apparent improvement in aerobic fitness

Pharmacological for glycemic control

Improvement in only diastolic Better metabolic control with function, both systolic and decrease in HbA1c and glycemia diastolic function, or no improvements demonstrated

Antifibrotic with spironolactone

Inhibition of aldosterone effects, Improvement in LV systolic and especially promotion of fibrosis diastolic function, reduction in LV mass, and amelioration of cIB and serological fibrosis markers in metabolic syndrome and obesity Improvements in LV filling and cIB and no changes in serological fibrosis markers and T1 mapping in T2DM

months led to improvements in LV longitudinal strain and tissue e 0 velocity, with the decrease in HbA 1c being associated with the amelioration of both systolic and diastolic dysfunction (65). Myocardial benefits were seen even with slight decrements in HbA 1c, and worsening of glycemic status found in some participants was accompanied by further deterioration of the initial LV function abnormalities. In another study, intensified insulin therapy improved LV diastolic but not LV systolic myocardial velocities (38), whereas other studies failed to show favorable alterations in cardiac function despite the better metabolic control (66). The important issue determining the effects of improved glycemia on the heart muscle seems to be a sufficiently long duration of intervention, allowing for the positive changes in LV function. ANTIFIBROTIC TREATMENTS. The recognized role

of renin-angiotensin-aldosterone system activation and subsequent promotion of myocardial fibrosis in metabolic heart disease provided the rationale for the use of aldosterone antagonists to attenuate LV abnormalities in this disorder. The beneficial impact of this therapeutic approach on LV functional and structural remodeling observed in stage C (symp-

AF ¼ atrial fibrillation; HbA1c ¼ glycosylated hemoglobin; T2DM ¼ type 2 diabetes mellitus; other abbreviations as in Table 2.

tomatic) HF, as well as in hypertensive heart disease suggested that similar changes might be expected in asymptomatic stage B of metabolic etiology. The institution of 25 mg of spironolactone to therapy for 6 months in subjects with obesity and metabolic syndrome resulted in improvements in LV function (increase in global longitudinal strain and tissue e 0 velocity, and decrease in E/e 0 ) and morphology (reduction of LV mass), as well as in amelioration of fibrosis markers: myocardial reflectivity (cIB) and blood analytes (procollagen peptides and TGF-b 1) (67,68).

These

701

Cardiac Dysfunction With Metabolic Disease

changes

were

independent

of

concomitant blood pressure reduction associated with spironolactone. The results of analogous investigations restricted to T2DM population showed

a lower severity of disease might be the reason of scarcely evident response to spironolactone in the T2DM study. In addition, the inconsistency of results may imply that the contribution of fibrosis to early stages of subclinical diabetic cardiomyopathy may be less important than previously believed. Moreover, it should be noted that the link between larger effect of aldosterone antagonism and more intense fibrosis demonstrated in a preclinical stage may not apply to more advanced symptomatic disease, likely to have a lower potential for reversibility.

CONCLUSIONS

only a limited benefit received from spironolactone, with improvements of LV filling and myocardial tis-

Alterations in cardiac structure and function that may

sue characterization, and no changes demonstrated

predispose to HF and atrial fibrillation are among a

for the serological markers and CMR-derived T1

multitude of effects of both T2DM and obesity on the

mapping reflecting fibrosis intensity (69). The bene-

circulation (including on vascular function and heart

ficial effects of spironolactone in studies with obesity

valves). Multiple metabolic, inflammatory, neuro-

and the metabolic syndrome were not seen in pa-

hormonal, and hemodynamic abnormalities underlie

tients with less fibrosis or preserved LV function, and

myocardial impairment in these disease conditions.

702

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

Given its widespread accessibility and relatively low

further studies are needed to formulate specific

cost, echocardiography represents a feasible diag-

therapies that could be more effective in preventing

nostic approach to identify subclinical cardiac dis-

and reversing metabolic heart disease.

turbances as well as track the progression of disease in-

ADDRESS FOR CORRESPONDENCE: Dr. Thomas H.

terventions aimed at improving cardiac abnormalities

Marwick, Baker Heart and Diabetes Institute, 75

through the improvement of pathophysiological

Commercial

milieu provide variable results. In view of this,

Australia. E-mail: [email protected].

and

responses

to

treatment.

Therapeutic

Road,

Melbourne,

Victoria

3004,

REFERENCES 1. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–6. 2. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007; 49:565–71. 3. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34:29–34. 4. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002; 347:305–13. 5. Kuller LH, Shemanski L, Psaty BM, et al. Subclinical disease as an independent risk factor for cardiovascular disease. Circulation 1995;92:720–6. 6. Wong CX ST, Sun MT, et al. Obesity and the risk of incident, post-operative, and post-ablation atrial fibrillation: a meta-analysis of 626,603 individuals in 51 studies. J Am Coll Cardiol EP 2015;1: 139–52. 7. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543–67. 8. Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 2015;36: 1718–27, 1727a–1727c. 9. Kosmala W, Jedrzejuk D, Derzhko R, PrzewlockaKosmala M, Mysiak A, Bednarek-Tupikowska G. Left ventricular function impairment in patients with normal-weight obesity: contribution of abdominal fat deposition, profibrotic state, reduced insulin sensitivity, and proinflammatory activation. Circ Cardiovasc Imaging 2012;5:349–56. 10. Venteclef N, Guglielmi V, Balse E, et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipofibrokines. Eur Heart J 2015;36:795–805a.

left ventricular function in obesity. Obesity (Silver Spring) 2013;21:881–92. 14. Fang ZY, Schull-Meade R, Downey M, Prins J, Marwick TH. Determinants of subclinical diabetic heart disease. Diabetologia 2005;48: 394–402. 15. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol 2003;41:611–7. 16. Wong CY, O’Moore-Sullivan T, Leano R, Byrne N, Beller E, Marwick TH. Alterations of left ventricular myocardial characteristics associated with obesity. Circulation 2004;110:3081–7. 17. Kosmala W, Kucharski W, PrzewlockaKosmala M, Mazurek W. Comparison of left ventricular function by tissue Doppler imaging in patients with diabetes mellitus without systemic hypertension versus diabetes mellitus with systemic hypertension. Am J Cardiol 2004;94:395–9. 18. Ernande L, Bergerot C, Rietzschel ER, et al. Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 2011;24:1268–75.e1. 19. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes

metabolic syndrome: impact of cumulative metabolic burden. Obesity (Silver Spring) 2013;21: E679–86. 26. Ernande L, Bergerot C, Girerd N, et al. Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus. J Am Soc Echocardiogr 2014;27:479–88. 27. Jellis CL, Stanton T, Leano R, Martin J, Marwick TH. Usefulness of at rest and exercise hemodynamics to detect subclinical myocardial disease in type 2 diabetes mellitus. Am J Cardiol 2011;107:615–21. 28. Fang

ZY,

Najos-Valencia

O,

Leano

R,

Marwick TH. Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 2003; 42:446–53. 29. Kim SA, Shim CY, Kim JM, et al. Impact of left ventricular longitudinal diastolic functional reserve on clinical outcome in patients with type 2 diabetes mellitus. Heart 2011;97:1233–8. 30. Kosmala W, Przewlocka-Kosmala M, Mazurek W. Subclinical right ventricular dysfunction in diabetes mellitus–an ultrasonic strain/strain rate study. Diabet Med 2007;24:656–63.

mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 2010; 55:300–5.

31. Wong CY, O’Moore-Sullivan T, Leano R, Hukins C, Jenkins C, Marwick TH. Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 2006;47:611–6.

20. Boyer JK, Thanigaraj S, Schechtman KB, Pérez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 2004; 93:870–5.

32. Muranaka A, Yuda S, Tsuchihashi K, et al. Quantitative assessment of left ventricular and left atrial functions by strain rate imaging in diabetic patients with and without hypertension. Echocardiography 2009;26:262–71.

21. Turkbey EB, McClelland RL, Kronmal RA, et al.

33. Murthy VL, Naya M, Foster CR, et al. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation 2012;126: 1858–68.

The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol Img 2010;3:266–74. 22. Fang ZY, Leano R, Marwick TH. Relationship between longitudinal and radial contractility in subclinical diabetic heart disease. Clin Sci (Lond) 2004;106:53–60.

34. Moir S, Hanekom L, Fang ZY, et al. Relationship between myocardial perfusion and dysfunction in diabetic cardiomyopathy: a study of quantitative contrast echocardiography and strain rate imaging. Heart 2006;92:1414–9.

11. Alpert MA, Agrawal H, Aggarwal K, Kumar SA, Kumar A. Heart failure and obesity in adults: pathophysiology, clinical manifestations and management. Curr Heart Fail Rep 2014;11: 156–65.

23. Wang Y, Marwick TH. Update on echocardiographic assessment in diabetes mellitus. Curr Cardiol Rep 2016;18:85.

12. Eguchi K, Boden-Albala B, Jin Z, et al. Association between diabetes mellitus and left ventric-

24. Piya MK, Shivu GN, Tahrani A, et al. Abnormal left ventricular torsion and cardiac autonomic

ular hypertrophy in a multiethnic population. Am J Cardiol 2008;101:1787–91.

dysfunction in subjects with type 1 diabetes mellitus. Metabolism 2011;60:1115–21.

35. Ahmari SA, Bunch TJ, Modesto K, et al. Impact of individual and cumulative coronary risk factors on coronary flow reserve assessed by dobutamine stress echocardiography. Am J Cardiol 2008;101: 1694–9.

13. Di Bello V, Fabiani I, Conte L, et al. New echocardiographic techniques in the evaluation of

25. Crendal E, Walther G, Vinet A, et al. Myocardial deformation and twist mechanics in adults with

36. Atar AI, Altuner TK, Bozbas H, Korkmaz ME. Coronary flow reserve in patients with diabetes

Kosmala et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 6, 2017 JUNE 2017:692–703

Cardiac Dysfunction With Metabolic Disease

mellitus and prediabetes. Echocardiography 2012; 29:634–40.

review and meta-analysis. Obes Rev 2015;16: 406–15.

the American Heart Association. Circulation 2009; 119:3244–62.

37. Erdogan D, Yucel H, Uysal BA, et al. Effects of

49. Wong CX, Abed HS, Molaee P, et al. Pericardial

prediabetes and diabetes on left ventricular and coronary microvascular functions. Metabolism 2013;62:1123–30.

fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011;57: 1745–51.

38. von Bibra H, Hansen A, Dounis V, Bystedt T,

50. Mahajan R, Lau DH, Brooks AG, et al. Elec-

61. Hare JL, Hordern MD, Leano R, Stanton T, Prins JB, Marwick TH. Application of an exercise intervention on the evolution of diastolic dysfunction in patients with diabetes mellitus: efficacy and effectiveness. Circ Heart Fail 2011;4:441–9.

Malmberg K, Rydén L. Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart 2004;90:1483–4.

trophysiological, electroanatomical, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol 2015;66: 1–11.

62. Cassidy S, Thoma C, Houghton D, Trenell MI. High-intensity interval training: a review of its impact on glucose control and cardiometabolic

39. Topcu S, Tok D, Caliskan M, et al. Metformin

51. Mehra MR, Uber PA, Park MH, et al. Obesity

63. Schuster I, Vinet A, Karpoff L, et al. Diastolic

therapy improves coronary microvascular function in patients with polycystic ovary syndrome and insulin resistance. Clin Endocrinol (Oxf) 2006;65: 75–80.

and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol 2004;43: 1590–5.

dysfunction and intraventricular dyssynchrony are restored by low intensity exercise training in obese men. Obesity (Silver Spring) 2012;20: 134–40.

40. Quiñones

MJ,

Hernandez-Pampaloni

M,

Schelbert H, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med 2004;140:700–8. 41. Garg R, Rao AD, Baimas-George M, et al. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes 2015;64:236–42. 42. Hansen A, Johansson BL, Wahren J, von Bibra H. C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 2002;51: 3077–82. 43. Jellis C, Wright J, Kennedy D, et al. Association of imaging markers of myocardial fibrosis with metabolic and functional disturbances in early diabetic cardiomyopathy. Circ Cardiovasc Imaging 2011;4:693–702. 44. Di Bello V, Santini F, Di Cori A, et al. Obesity cardiomyopathy: is it a reality? An ultrasonic tissue characterization study. J Am Soc Echocardiogr 2006;19:1063–71. 45. Kosmala W, Przewlocka-Kosmala M, Wojnalowicz A, Mysiak A, Marwick TH. Integrated backscatter as a fibrosis marker in the metabolic syndrome: association with biochemical evidence of fibrosis and left ventricular dysfunction. Eur Heart J Cardiovasc Imaging 2012;13:459–67.

52. American Diabetes Association. (8) Cardiovascular disease and risk management. Diabetes Care 2015;38 Suppl:S49–57. 53. Holland DJ, Marwick TH, Haluska BA, et al. Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus. Heart 2015;101: 1061–6. 54. Ikonomidis I, Mazarakis A, Papadopoulos C, et al. Weight loss after bariatric surgery improves aortic elastic properties and left ventricular function in individuals with morbid obesity: a 3-year follow-up study. J Hypertens 2007;25:439–47. 55. Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–83. 56. Leung M, Xie M, Durmush E, Leung DY, Wong VW. Weight loss with sleeve gastrectomy in obese type 2 diabetes mellitus: impact on cardiac function. Obes Surg 2016;26:321–6. 57. Kosmala W, O’Moore-Sullivan T, Plaksej R, Przewlocka-Kosmala M, Marwick TH. Improvement of left ventricular function by lifestyle intervention in obesity: contributions of weight loss and reduced insulin resistance. Diabetologia 2009;52:2306–16.

46. Iacobellis G, Willens HJ. Echocardiographic

58. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and

epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr 2009;22: 1311–9, quiz 1417–8.

severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013;310: 2050–60.

47. Serrano-Ferrer J, Crendal E, Walther G, et al. Effects of lifestyle intervention on left ventricular

59. Pathak RK, Middeldorp ME, Meredith M, et al. Long-Term Effect of Goal-Directed Weight Man-

regional myocardial function in metabolic syndrome patients from the RESOLVE randomized trial. Metabolism 2016;65:1350–60.

agement in an Atrial Fibrillation Cohort: A LongTerm Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65:2159–69.

48. Rabkin SW, Campbell H. Comparison of reducing epicardial fat by exercise, diet or bar-

60. Marwick TH, Hordern MD, Miller T, et al. Exercise training for type 2 diabetes mellitus: impact

iatric surgery weight loss strategies: a systematic

on cardiovascular risk: a scientific statement from

health. Diabetologia 2017;60:7–23.

64. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation: The CARDIO-FIT Study. J Am Coll Cardiol 2015;66:985–96. 65. Leung M, Wong VW, Hudson M, Leung DY. Impact of improved glycemic control on cardiac function in type 2 diabetes mellitus. Circ Cardiovasc Imaging 2016;9:e003643. 66. Jarnert C, Landstedt-Hallin L, Malmberg K, et al. A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study. Eur J Heart Fail 2009;11:39–47. 67. Kosmala W, Przewlocka-Kosmala M, Szczepanik-Osadnik H, Mysiak A, O’MooreSullivan T, Marwick TH. A randomized study of the beneficial effects of aldosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome. J Am Coll Cardiol Img 2011;4:1239–49. 68. Kosmala W, Przewlocka-Kosmala M, Szczepanik-Osadnik H, Mysiak A, Marwick TH. Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade. Heart 2013;99:320–6. 69. Jellis CL, Sacre JW, Wright J, et al. Biomarker and imaging responses to spironolactone in subclinical diabetic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2014;15:776–86.

KEY WORDS insulin resistance, LV function, obesity, stage B heart failure, type 2 diabetes

Go to http://www.acc. org/jacc-journals-cme to take the CME/MOC quiz for this article.

703