Archives of Cardiovascular Disease (2012) 105, 218—225

Available online at

www.sciencedirect.com

REVIEW

Diabetic cardiomyopathy: Myth or reality?

Cardiomyopathie diabétique : mythe ou réalité?

Laura Ernande a,∗,b, Geneviève Derumeaux a,b

a
Services des explorations fonctionnelles cardiovasculaires, hôpital Louis-Pradel,
59, boulevard Pinel, 69500 Bron, France
b
Unité Inserm 1060, laboratoire CarMeN, université de Lyon, 8, avenue Rockefeller, 69373
Lyon cedex 8, France

Received 20 September 2011; received in revised form 9 November 2011; accepted 14 November
2011
Available online 9 March 2012

KEYWORDS Summary Diabetes mellitus has reached an epidemic level worldwide. Cardiovascular
Diabetic diseases are the primary cause of death in diabetic patients, not only because of coronary
cardiomyopathy; artery disease and associated hypertension but also because of a direct adverse effect of dia-
Diabetic heart betes on the heart, independent of other potential aetiological factors. However, the existence
disease; of this ‘diabetic cardiomyopathy’ remains controversial. We aimed to review current evidence
Noninvasive cardiac for the existence of diabetic cardiomyopathy, focusing particularly on the clinical setting.
imaging © 2012 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé Le diabète a atteint un niveau épidémique sur le plan mondial. Les pathologies car-
Cardiomyopathie diovasculaires représentent la première cause de décès chez les patients atteints de diabète
diabétique ; non seulement du fait des cardiopathies ischémiques et de l’hypertension artérielle associées
Imagerie cardiaque au diabète mais également du fait d’un effet délétère du diabète lui-même sur le plan car-
diaque indépendamment de tout autre facteur étiologique potentiel. Cependant, l’existence de
cette « cardiomyopathie diabétique » reste controversée. Le but de cette revue de la littérature
est de discuter des preuves de l’existence d’une cardiomyopathie diabétique en s’intéressant
principalement au champ clinique.
© 2012 Elsevier Masson SAS. Tous droits réservés.

Abbreviations: BMI, body mass index; CI, confidence interval; CITP, carboxy-terminal telopeptide of collagen type I;
DCM, diabetic cardiomyopathy; LV, left ventricular; MMP, matrix metalloproteinase; PICP, carboxy-terminal propeptide of procollagen
type I; STI, speckle tracking imaging; TDI, tissue Doppler imaging; TIMP, tissue inhibitors of matrix metalloproteinase.
∗ Corresponding author. Fax: +33 4 27 86 92 22.

E-mail address: laura.ernande@gmail.com (L. Ernande).

1875-2136/$ — see front matter © 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.acvd.2011.11.007
Diabetic cardiomyopathy: Myth or reality? 219

Background
A tsunami of obesity has been recently described, with
1.46 billion overweight adults (BMI ≥ 25 kg/m2 ) in 2008,
including 500 million who were obese (BMI ≥ 30 kg/m2 ) [1].
Consequently, diabetes mellitus has reached an epidemic
level worldwide, with a prevalence of 4% in 1995 and an
anticipated prevalence of 5.4% in 2025, corresponding to
300 million adults with diabetes worldwide [2]. Cardiovas-
cular diseases represent the primary cause of death in this
population because of coronary artery disease [3] or asso-
ciated hypertension but also because of a direct adverse
effect of diabetes mellitus on the heart, called DCM. Dia-
betes mellitus is a complex metabolic disorder that includes
insulin resistance (in type 2), often associated with hyper-
tension and obesity [4]. All those conditions are associated
with a high risk of coronary artery disease but may also
exert a direct negative effect on the myocardium. Among
them, the specific negative effect of diabetes mellitus on
the heart, leading to DCM, has been extensively investigated
in the last three decades. Controversies exist regarding the
existence of a specific DCM, as this concept has mainly
emerged from experimental models [5]. In this review, we
aimed to discuss the current evidence for the existence of
DCM, focusing particularly on the clinical setting.

Figure 1. Physiopathology of diabetic cardiomyopathy (DCM). LV:

Definition of diabetic cardiomyopathy
(DCM)
DCM was first described 40 years ago, based on post-mortem
observations in four diabetic patients with heart failure but
no coronary artery disease or other aetiological conditions
explaining heart failure [6]. The authors observed LV hyper-
trophy associated with myocardial fibrosis in those patients
and introduced for the first time the concept of DCM [6].
Five years later, Regan et al. [7] confirmed those results and
described cases of heart failure in familial diabetes without
coronary artery disease, hypertension or obesity. A higher
myocardial collagen and lipid content was also reported in
those cases compared with control subjects [7].
Since those initial studies, DCM has been defined as the
existence of LV dysfunction in diabetic patients without
coronary artery disease, hypertension or other potential
aetiological condition.
Experimental evidence
Numerous experimental studies, mainly based on rodent
models, have demonstrated a direct negative effect of dia-
betes mellitus on the myocardium [8,9]. Pathophysiological
mechanisms include metabolic alterations with impaired
calcium homeostasis, alteration of substrate utilization
(increase in lipid use and decrease in glucose oxidation),
lipotoxicity, glucotoxicity with intervention of advanced gly-
cation end products, mitochondrial dysfunction, increase in
oxidative stress, renin-angiotensin-aldosterone system acti-
vation and cardiac dysautonomia. All these mechanisms lead
to an increase in myocardial cellular death (necrosis and
apoptosis) and to myocardial fibrosis, with the consequent
left ventricular.
development of myocardial dysfunction and overt heart
failure (Fig. 1) [8,9].
Epidemiological evidence
In the clinical setting, the most convincing evidence for the
existence of DCM comes from large epidemiological studies.
Two years after the study of Rubler et al. [6], the Framing-
ham Heart Study investigators demonstrated that diabetes
mellitus was an independent risk factor for heart failure
[10]. Risk of heart failure was 2.4-fold and 5-fold higher in
diabetic men and women, respectively, than in non-diabetic
subjects. The increased incidence of heart failure in diabetic
patients persisted even after adjustment for age, hyper-
tension, obesity, coronary artery disease or dyslipidaemia
[10].
Diabetes mellitus as an independent risk factor for heart
failure has been confirmed in numerous epidemiological
studies [11—17]. In a prospective study including 2700
elderly subjects (mean age 81 ± 9 years), the incidence
of heart failure during a 43-month follow-up was 1.3-fold
higher in diabetes mellitus than in euglycaemic subjects
after adjustment for age, hypertension, coronary artery
disease and sex [11]. The Cardiovascular Health Study,
including 5888 subjects aged more than 65 years with a mean
delay of 5.5 years follow-up, reported an incidence rate for
heart failure of 19.3/1000 person-years, with a substantially
higher incidence (approximately 2-fold) associated with dia-
betes mellitus [15]. In a large case-control study, Bertoni
et al. [12] tested the hypothesis that diabetes mellitus was
independently associated with idiopathic cardiomyopathy.
After adjusting for age, sex, race and hypertension, diabetes
220
mellitus was significantly associated with idiopathic car-
diomyopathy (relative odds 1.58, 95% CI 1.55—1.62). Those
results were confirmed in a second case-control study [13].
In the French EPICAL Study, prevalence of diabetes mellitus
among patients with non-ischaemic advanced heart failure
was 19.7% [17]. In the Reykjavik Study, Thrainsdottir et al.
[16] explored the associations between heart failure and
abnormal glucose regulation (impaired glucose tolerance or
impaired fasting glucose) or type 2 diabetes mellitus in a
population-based cohort of 19,381 participants. The odds
ratio was 2.8 (95% CI 2.2—3.6) for the association between
type 2 diabetes mellitus and heart failure and 1.7 (95%
CI 1.4—2.1) for the association between abnormal glucose
regulation and heart failure.
Finally, the Strong Heart Study recently confirmed dia-
betes mellitus as an independent risk factor of heart
failure [14]. In a population-based cohort of 1204 sub-
jects, the authors showed a 1.5-fold higher risk of heart
failure in patients with diabetes mellitus after adjust-
ment for multiple cofactors (age, sex, obesity, central fat
distribution, antihypertensive medications, atrial fibrilla-
tion, urinary albumin/creatinine ratio, plasma cholesterol,
Hb1Ac, smoking habit, alcohol use, educational level and
physical activity). Interestingly, for the first time, intercur-
rent myocardial infarction was censored in this analysis [14].
Noninvasive evidence for adverse effects
of diabetes mellitus on the heart (left
ventricular structure, remodelling and
function)
Noninvasive evidence for structural
myocardial abnormalities associated with
diabetes
Myocardial fibrosis
Myocardial fibrosis, as initially described by Rubler et al.
[6] and confirmed in both histological studies in humans
[7,18,19] and experimental studies [20], is a major conse-
quence of the adverse effects of diabetes mellitus on the
heart [8]. Backscatter is an ultrasound tissue characteri-
zation technique based on the measurement of myocardial
tissue echoreflectivity, which is related to myocardial colla-
gen content [21]. Di Bello et al. [22] showed an increase
in myocardial echodensity as assessed by the integrated
backscatter index in 26 insulin-dependent diabetic nor-
motensive patients compared with 17 age- and sex-matched
control subjects. Fang et al. [23] confirmed these results
using calibrated integrated backscatter in a larger study.
Biomarkers of collagen synthesis (PICP; PINP, amino-
terminal propeptide of procollagen type I; PIIICP, carboxy-
terminal propeptide of procollagen type III; PIIINP, amino-
terminal propeptide of procollagen type III) or collagen
degradation (CITP) have been showed to be of clinical
interest in detecting myocardial fibrosis [24]. In addition,
markers of extracellular matrix turnover (such as MMP)
and their inhibitors (TIMP, tissue inhibitors of MMP) might
also be useful [24]. However, few studies have used these
biomarkers in diabetic patients. An increase in CITP was
L. Ernande, G. Derumeaux
recently described in type 2 diabetic patients compared
with control subjects and was correlated with diastolic func-
tion (mitral A duration minus pulmonary vein atrial reversal
velocity duration) [25]. MMP-7 has also been shown to be
associated with diastolic dysfunction with microvascular
complications (nephropathy) [26]. Patients with diastolic
dysfunction demonstrated an increase in MMP-9 and a
decrease in TIMP-1/MMP-9 [26]. Finally, in a small group
of diabetic patients, correlation was found between PICP
and LV systolic variables (fractional shortening and midwall
fractional shortening) [27].
Myocardial steatosis
An increase in myocardial lipid content (myocardial steato-
sis) has been demonstrated in diabetic patients using
1H-magnetic resonance spectroscopy. McGavock et al. [28]
showed an increase in myocardial triglyceride content in glu-
cose intolerant patients and in patients with type 2 diabetes
mellitus compared with controls. Myocardial triglyceride
content was associated with diastolic function variables (E/A
ratio and E wave deceleration time) [29]. In a group of 42
men with type 2 diabetes mellitus, patients with a high
myocardial triglyceride content (superior to the median of
the population) presented a decrease in systolic strain and
strain rate whereas LV ejection fraction was similar in the
two groups [30].
These structural abnormalities are associated
with morphological and functional
abnormalities
Concentric remodelling and left ventricular
hypertrophy
Concentric remodelling is defined as an increase in relative
wall thickness ([2 × posterior wall thickness]/end-diastolic
diameter) with normal LV mass index values, whereas LV
hypertrophy is defined as abnormal LV mass index values
[31]. Concentric remodelling and LV hypertrophy, known
to be of adverse prognostic value [32], are the most fre-
quently described morphological abnormalities associated
with diabetes mellitus [33—37]. In the Framingham Heart
Study, Galderisi et al. [35] showed an increase in LV mass and
wall thickness independently associated with diabetes mel-
litus, but in multivariable analysis, statistical significance
was reached only in women. In the Cardiovascular Health
Study, an increase in LV mass was independently associ-
ated with diabetes mellitus even after adjustment for body
weight, blood pressure, heart rate and prevalent coronary
or cerebrovascular disease [36]. However, in contrast to pre-
vious findings, this association was significant in both men
and women [36]. The Strong Heart Study confirmed these
results in a large cohort of American Indians (1810 par-
ticipants with diabetes mellitus and 944 glucose-tolerant
subjects) [33]. In this population, increases in wall thick-
ness and LV mass were associated with a slight decrease in
LV fractional shortening and midwall fractional shortening in
diabetic patients compared with glucose-tolerant subjects
[33]. All these studies described concentric remodelling and
LV hypertrophy associated with diabetes mellitus, indepen-
dent of other confounding factors such as age, obesity (BMI)
and hypertension. However, more recently, the NOMAS Study
Diabetic cardiomyopathy: Myth or reality?
described diabetes mellitus as an independent determinant
of LV mass but in addition to central obesity as assessed by
waist circumference [34].
Impact of diabetes on left ventricular remodelling
The impact of diabetes mellitus on LV remodelling over the
course of a lifetime has been demonstrated more recently.
Indeed, the Framingham Heart Study investigators showed,
in a first report, an increase in LV mass during a 16-year
follow-up [38]. Diabetic subjects (without heart failure
or previous myocardial infarction) experienced a steeper
increase in LV mass with advancing age than non-diabetic
subjects [38]. In a second report, Cheng et al. [39] demon-
strated an increase in wall thickness with advancing age
associated with a decrease in LV diameter and a concomi-
tant increase in fractional shortening. This study pointed
out the influence of diabetes mellitus, in addition to sex
and hypertension, on LV remodelling over life. Indeed, dia-
betes mellitus was associated with a greater increase in wall
thickness coupled with a smaller decrease in LV diameter
[39].
Finally, Markus et al. [40] also reported the influence
of diabetes mellitus on LV remodelling. During a 10-year
follow-up in a population-based cohort of 1005 subjects,
the authors observed a greater increase in LV mass in
patients with prevalent diabetes mellitus associated with
an increase in LV end-diastolic diameter, whereas this last
variable remained stable over time in euglycaemic subjects
[40]; this was associated with a decrease in LV ejection frac-
tion in prevalent diabetic subjects whereas an increase was
observed in euglycaemic subjects [40].
Functional abnormalities
Longitudinal systolic impairment
Myocardial strain imaging, such as TDI and STI, is use-
ful for detecting ischaemia [41]. These techniques also
facilitate demonstration of subclinical impairment of sys-
tolic function in asymptomatic diabetic patients without
overt heart disease and a normal standard echocar-
diography compared with controls [23,42—50]. Whereas
conventional methods such as LV ejection fraction and
fractional shortening were insensitive in terms of detect-
ing early preclinical abnormalities, longitudinal dysfunction
was demonstrated in many studies using both TDI
[23,42,44,45,48—50] and STI [43,46,47]. For some authors,
longitudinal strain decrease was correlated with dia-
betes imbalance (glycated haemoglobin) or microvascular
complications (microalbuminuria) [50]. However, longitu-
dinal alteration is independently associated with diabetes
mellitus, regardless of LV hypertrophy [23] or other conven-
tional risk factors [43].
Radial systolic impairment
Radial systolic function has been investigated less fre-
quently in this population. Indeed, only a few studies
have assessed radial function, with conflicting results
[43,44,46,47,50]. The initial studies suggested that radial
function was increased [44,50] or preserved [47] to com-
pensate for longitudinal function alteration. However, most
of these studies were based on TDI and its derived velo-
city and strain rate measurements that depend on Doppler
angle [44,50]. The TDI measurements are limited to the
221
segments in which motion and deformation are aligned
with the ultrasound beam and hence do not provide an
optimal evaluation of radial function. STI is an angle-
independent method and allows a more robust and extensive
evaluation of radial function (Fig. 2) [51]. Among reports
based on STI, the study by Ng et al. [47] described pre-
served radial function compared with euglycemic subjects
(radial strain 40.6 ± 11.1 vs. 42.7 ± 12.1%, respectively; P
not significant). However, this study was based on a highly
selected population that included uncomplicated patients
and only men with a short duration of diabetes mellitus
(4 years) and a strictly controlled haemoglobinA1c concen-
tration (6.4 ± 0.7%). Conversely, our group demonstrated in
a population of 114 diabetic subjects, a decrease in both
radial strain (50 ± 16 vs. 56 ± 12%; P = 0.003) and longitudi-
nal strain (—19 ± 3 vs.—22 ± 2%; P < 0.001) compared with
88 age-matched controls without cardiovascular risk factors
[43]. In multivariable analysis, diabetes mellitus was inde-
pendently associated with longitudinal strain (in addition to
sex) and radial strain. These findings remained stable in a
subgroup analysis of 42 strictly age-, sex- and BMI-paired
patients and controls [43].
Contractile reserve
Whether diabetes mellitus is also responsible for a decrease
in contractile reserve in asymptomatic patients without
overt heart disease is a controversial issue [50,52—54].
Galderisi et al. [53] demonstrated an impaired inotropic
response to dobutamine in 24 diabetic patients com-
pared with 16 controls. With dobutamine, myocardial strain
assessed by TDI increased by 36.4 ± 15.9% in diabetic
patients vs. 57.1 ± 22.1% in controls (P = 0.0001). Ha et al.
[54] showed impairment of longitudinal function reserve (as
assessed by mitral annular systolic velocity) during exercise.
However, Fang et al. [52] reported a normal response to
dobutamine stress, suggesting that ischaemia due to small
vessel disease might not be important in early diabetic heart
muscle disease.
Diastolic dysfunction
Diastolic dysfunction has been extensively studied in
diabetic patients without overt heart disease [55—63].
Prevalence of diastolic dysfunction is high in diabetic
patients, ranging from 21% to 75% [55—63]. However, hetero-
geneity of populations enrolled and methodological issues
regarding the assessment of diastolic function account for
the highly variable prevalence reported in these studies
[55—63]. Indeed, most of the reports were based on one
single abnormal variable using mitral inflow pattern [63],
its variation with the Valsalva manoeuvre [62] or combined
indices derived from mitral inflow pattern and pulmonary
venous flow [60]. More recently, some authors analysed
TDI diastolic velocities and derived indices [55—58] but
only two studies were based on a more complex diagnos-
tic algorithm and a comprehensive evaluation of diastolic
function [59,61]. However, in the study of Poulsen et al.
[61], including a population of patients with type 2 dia-
betes mellitus, 9% presented a LV ejection fraction less
or equal than 50% and 30% of patients presented perfu-
sion abnormalities assessed by scintigraphy. Kiencke et al.
[59] included 100 patients with type 2 diabetes mellitus
and explored diastolic function using a comprehensive algo-
rithm close to the current recommendations; they found a
222 L. Ernande, G. Derumeaux

Figure 2. Example of myocardial strain assessment by speckle tracking imaging (STI): radial strain (upper panel); longitudinal strain (lower
panel).

prevalence of diastolic dysfunction of 48%. Recently, in a
study strictly based on the current European Association
of Echocardiography/American Society of Echocardiogra-
phy recommendations, our group reported a prevalence of
diastolic dysfunction of 47% (33% grade I and 14% grade
II).
Diastolic dysfunction has been traditionally considered
as the first marker of DCM [56,58,60]. However, whether
diastolic dysfunction reported in diabetic patients is an
independent adverse effect of diabetes mellitus has been
poorly investigated. Indeed, the association between poten-
tial confounding factors (such as hypertension, obesity, age
Diabetic cardiomyopathy: Myth or reality?
and sex) and diastolic function was not taken into account
in many studies. We recently demonstrated that in con-
trast to systolic impairment in diabetic patients, diastolic
variables are mainly associated with other factors (inclu-
ding age, rate pressure product, history of hypertension and
BMI) and that some of the most frequently used diastolic
variables (E/A ratio, é velocity) are not independently asso-
ciated with diabetes mellitus [64]. In addition, standard LV
systolic variables are mostly insensitive to detecting systolic
impairment. When using myocardial systolic strain, we found
that 28% of patients presented longitudinal dysfunction with
normal diastolic function [64].
Nevertheless, diastolic variables are related to prognosis
in diabetic patients without patent heart disease [57—59]. In
a first retrospective study, including 486 diabetic patients,
From et al. [57] demonstrated that the E/é ratio was asso-
ciated with an increase in global mortality after adjustment
for age, sex, coronary artery disease, hypertension, LV ejec-
tion fraction, left atrial volume and delay between diabetes
diagnosis and echocardiography. In a second retrospective
study, including 1760 diabetic patients, the same authors
demonstrated that an E/é ratio more than 15 was associ-
ated with a cumulative probability of development of heart
failure at 5 years of 36.9% compared with 16.8% for patients
with an E/é ratio less or equal than 15 (P = 0.001) and, with a
higher global mortality (30.8% vs. 12.1% at 5 years; P < 0.001)
[58]. Kiencke et al. [59] confirmed that patients with dia-
stolic dysfunction had a lower overall event-free survival
rate than patients without diastolic dysfunction (54 vs. 87%;
P = 0.001).
Microvascular alteration
Alteration of microvessels associated with endothelial dys-
function has been described in both experimental models of
diabetes [65] and humans [66]. Those abnormalities result
in a decrease in myocardial blood flow reserve that has been
described using myocardial contrast echocardiography (with
dipyridamole and exercise) [67], technetium 99 m sestamibi
scintigraphy (with dipyridamole) [68] or positron emission
tomography (with dipyridamole or cold pressor test) [69,70].
However, the association between perfusion reserve alte-
ration and myocardial dysfunction remains unclear. Indeed,
Moir et al. [67] found no association between systolic strain
alteration and perfusion.
Therapeutic perspectives
At the stage of heart failure, treatment of DCM is currently
based on common heart failure guidelines [71]. However,
the main challenge in this pathology is to develop pre-
ventive therapeutic options in order to avoid or delay the
progression of early myocardial dysfunction associated with
diabetes mellitus to overt heart failure. Indeed, modern
imaging techniques allow the detection of adverse effects of
diabetes mellitus on the myocardium at a very early precli-
nical stage but the prognostic value of those alterations
needs to be defined in order to develop a preventive strat-
egy for patients at high risk. To date, because of the
paucity of the data, no preventive therapy is recommended
at the preclinical stage of DCM. Based on pathophysio-
logical mechanisms, renin-angiotensin-aldosterone system
223
antagonists [72,73] or antioxidative therapy [74—76] might
be of interest.
Conclusions
In summary, there is much evidence in favour of the exist-
ence of DCM:
• post-mortem and histological studies introduced the
concept of DCM;
• epidemiological studies demonstrated that diabetes is an
independent risk factor for heart failure;
• experimental studies explored the pathophysiology and
demonstrated an adverse effect of diabetes on the heart
in animal models;
• alteration of myocardial content (myocardial fibrosis and
steatosis) was demonstrated with noninvasive techniques;
• and finally, noninvasive imaging (especially echocardiog-
raphy) demonstrated a preclinical form of diabetic heart
disease with subtle alterations in LV morphology, remo-
delling and systolic and diastolic function.
However, whether the preclinical form of DCM is of prog-
nostic significance and leads to overt heart failure with
increased mortality remains to be investigated. In addition,
prevention therapies that could avoid the evolution to overt
heart failure need to be defined.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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