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Diabetic Cardiomyopathy – A Non coronary
complication of Diabetes Mellitus
Abstract
Diabetes mellitus is growing at an epidemic proportion across the
globe and increasing burden of cardiovascular disease.There is an
increasing recognition that diabetes patients suffer from diabetic
cardiomyopathy – a non coronary complication of diabetes.
Diabetes cardiomyopathy has a long latent phase which is
asymptomatic followed by overt signs of congestive heart failure.
The diagnosis of diabetic cardiomyopathy depends on exclusion
of coronary artery disease and presence of LV dysfunction on
commonly performed investigation like 2D Echocardiography.
Treatment of overt congestive heart failure is more or less similar
to treatment of congestive heart failure due to any other cause.
Novel therapy for treatment of diabetic cardiomyopathy is need
of the hour.
Introduction
The epidemic of diabetes mellitus is of growing concern. Global
studies have projected that the number of adults affected with
diabetes will increase from 135 million in 1995 to 300 million
by 2025.1 80% of deaths among diabetic patients is due to
cardiovascular disease and much of which has been attributed to
Coronary Artery Disease (CAD). However, there is an increasing
recognition that diabetic patients suffer from an additional cardiac
insult termed ‘diabetic cardiomyopathy’.This entity was originally
described by Rubler et al in 1972 on the basis of observations
in four diabetic patients who presented with heart failure
(HF) without evidence of hypertension (HT),CAD, valvular or
congenital heart disease.2 Since then, diabetic cardiomyopathy
has been defined as ventricular dysfunction (systolic and diastolic)
that occurs independently of CAD and HT. The increasing
detection of this added cardiac insult is supported by data from
epidemiological, molecular as well as diagnostic studies.
Epidemiology
The prevalence of a diabetic cardiomyopathy in humans is suggested
by many epidemiological and clinical studies over the last three
decades. 3,4 The Framingham study was the first epidemiologic
study to document the increased incidence of congestive HF
in diabetes males (2.4: 1) and females (5:1) independent of
H M Mardikar, Parag Admane,
Manjusha Mardikar, N V Deshpande,
Jhumki Mardikar, Nagpur
age,HT,obesity, CAD and hyperlipidaemia.5
Similar results had been obtained from studies using independent
population databases which showed increased HF rates in subjects
with diabetes mellitus in cross-sectional analyses and increased
risk for developing heart failure in prospective analyses, even after
correction for confounding variables.6 Many studies of diabetic
populations have shown echocardiographic changes consistent
with systolic dysfunction and left ventricular (LV) hypertrophy and
may suggest an increased risk for the subsequent development of
heart failure, particularly in the presence of coexisting HT.7 It is
now believed that diastolic dysfunction precedes the development
of systolic dysfunction.8 The evidence of this is documented in
Type-I and Type II DM Patients. Echocardiography performed
in 87 patients with Type I diabetes mellitus without known
coronary artery disease exposed diastolic dysfunction with a
reduction in early diastolic filling, an increase in atrial filling, an
extension of isovolumetric relaxation, and increased numbers of
supraventricular premature beats.9 Carugo et al studied similar
subjects with uncomplicated type 1 diabetes without clinically
apparent macrovascular or microvascular complications and
concluded early structural and functional cardiac alterations such
as increased LV wall thickness and LV mass index, an age-related
decline in ejection fraction, and an age-related increase in diastolic
diameter.10 Similar approaches in well-controlled subjects with
type 2 diabetes have shown a prevalence of diastolic dysfunction
of up to 30% . 11 The use of flow and tissue Doppler Techniques
suggests much higher prevalence of diastolic dysfunction (as high
as 40% to 60%) in community surveys and in smaller studies of
individuals with type 1 and type 2 diabetes without overt coronary
artery disease. 12
Pathogenesis
The pathogenesis of diabetic cardiomyopathy is complex.
Autonomic dysfunction, metabolic derangements, abnormalities
in ion homeostasis, alteration in structural proteins, and interstitial
Diabetic Cardiomyopathy – A Non Coronary Complication of Diabetes Mellitus
Doppler criteria may be sufficient, 26 and the tissue Doppler
imaging of mitral annular motion may be particularly helpful to
make the diagnosis.27
fibrosis.13 are some of the proposed hypothesis. Sustained
hyperglycemia may also increase glycation of interstitial proteins
such as collagen, which results in myocardial stiffness and impaired
contractility.14 .Several mechanisms 15 which are involved in
decreasing myocardial contractility in diabetes mellitus are (1)
impaired calcium homeostasis,16 -17 (2) upregulation of the reninangiotensin system,18-19 (3) increased oxidative stress,20-21 (4) altered
substrate metabolism,22-23 and (5) mitochondrial dysfunction.24A
detailed discussion about the mechanisms is beyond the scope
of this article.
Clinical Presentations
One unique feature of diabetic cardiomyopathy is the long
progression phase which is completely asymptomatic. It is
frequently detected with concomitant HT or CAD in most cases.
One of the initial sign is mild left ventricular diastolic dysfunction
with little effect on ventricular filling.Also, the diabetic patient may
show subtle signs of diabetic cardiomyopathy related to decreased
left ventricular compliance or left ventricular hypertrophy or a
combination of both. In the jugular venous pulse, a prominent “a”
wave can also be noted, and the cardiac apical impulse may be
overactive or sustained throughout systole.After the development
of systolic dysfunction, left ventricular dilation and symptomatic
HF, the jugular venous pressure may become elevated; the apical
impulse would be displaced downward and to the left. It is not
unusual to find systolic mitral murmur in these cases. These
changes are accompanied by a variety of electrocardiographic
changes that may be associated with diabetic cardiomyopathy in
60% of patients without structural heart disease, although usually
not in the early asymptomatic phase. Later in the progression,
a prolonged QT interval may be indicative of fibrosis. Given
that diabetic cardiomyopathy’s definition excludes concomitant
atherosclerosis or HT, there are no changes in perfusion or in
atrial natriuretic peptide levels up until the very late stages of
the disease25, when the hypertrophy and fibrosis become very
pronounced.
Diagnostic Methods
The clinical diagnosis of diabetic cardiomyopathy has two
important components: the detection of myocardial abnormalities
and the exclusion of other contributory causes of cardiomyopathy.
A challenge in the clinical diagnosis of diabetic cardiomyopathy has
been the lack of any pathognomonic histologic changes or imaging
characteristics associated with the diagnosis. The diagnosis of
diabetic cardiomyopathy currently rests on noninvasive imaging
techniques.
The earliest sign of diastolic dysfunction is impaired ventricular
relaxation and is characterized by decreases in the peak early
filling velocity of mitral inflow (E).The rate of decrease of velocity
following the E velocity (deceleration time) is also prolonged. As
diastolic dysfunction progresses and left atrial pressures increase,
the pressure gradient between the left atrium and ventricle rises
and the E velocity returns toward normal, producing a pseudonormal mitral filling pattern. During later stages of the disease,
as symptoms of HF appear, left ventricular chamber compliance
decreases further and causes a restrictive filling pattern to emerge.
This pattern is manifested by a high E velocity and lower velocity
during atrial (A) contraction.A limitation in interpreting transmitral
flow patterns is that alterations in flow velocities are dependent on
the loading conditions of the heart. Among other criteria, tissue
Doppler imaging of mitral annular motion to determine the ratio
of mitral annulus velocity during early diastole (e′) to the velocity
of mitral annulus motion during atrial systole (a′) can provide a
relatively preload-independent assessment of diastolic function.
The ratio of E/e′ has been proposed as a sensitive index of left
ventricular filling pressures. E/e′ greater than 10 in spontaneously
ventilated and greater than 7.5 in mechanically ventilated patients
is both sensitive and specific for the presence of increased filling
pressures, and changes in left ventricular filling pressures after
volume expansion are accurately assessed by repeated E/e′
determinations.28 Acute changes in loading conditions may have
a profound effect on overall ventricular performance in patients
with diabetic cardiomyopathy. Even relatively small increases in
afterload may provoke increases in left ventricular filling pressures
and lead to congestive HF despite preservation of systolic function.
Precipitation of myocardial ischemia during the perioperative
period may also exacerbate diastolic dysfunction.29
Newer noninvasive tools are being used to assess the presence
of LVH and systolic/ diastolic dysfunction which help to provide
prognostic information in diabetic patients suspected of having
cardiomyopathy.
MRI
MRI is an emerging diagnostic technique that can both perform MPI
(myocardial perfusion imaging) and assess MFR (myocardial flow
reserve ).30Furthermore MRI is also a very useful tool to assess
diastolic function accurately without the drawbacks observed
with echocardiographic assessment of diastolic function.31
Treatment and Therapy
Echocardiography
Echocardiography is the accepted standard for the assessment of
alterations in systolic and diastolic function that occur in diabetes.
Nevertheless, there is no consensus on the specific criteria to
be used to confirm the diagnosis of diabetic cardiomyopathy.
However, it is suggested that the combination of two or more
359
Glycemic Control
Poor glycemic control increases the risk of developing heart
failure in diabetes. Evidence suggests that good glycemic control
is beneficial in the early stages of myocardial dysfunction.32, 33
Evidence also suggests that diabetic cardiomyopathy doesnot
Medicine Update 2010  Vol. 20
develop in patients with strict control type 1 diabetes, supporting
an important role for hyperglycemia in the pathogenesis of
diabetic cardiomyopathy. Microvascular complications in diabetes
is caused by hyperglycemia , and because microvascular alterations
are thought to contribute significantly to the pathogenesis of
diabetic cardiomyopathy,good glycemic control is perhaps the
most important component in the overall management of diabetic
cardiomyopathy.
Strong recommendations regarding the choice of current glucose
–lowering therapies in patients with diabetic cardiomyopathy
cannot be made because of lack of evidence. In general, the
choice of antidiabetic therapy in diabetic cardiomyopathy should
be dictated by clinical characteristics, such as the presence or
absence renal dysfunction, risk of hypoglycemia, age, volume status,
and concomitant drug therapy.
Neurohormonal Antagonism
and mortality which needs intervention at multiple levels for
prevention. It is believed that cardiovascular mortality is solely
due to atherosclerosis and its complications. Now there are
compelling data available from epidemiological and clinical studies
suggesting increased risk of cardiac heart failure irrespective
of other risk factors. Needless to say coexisting morbidities
enhance the likelihood of developing heart failure in diabetes.As
mechanisms of cardiomyopathy get unraveled there is a growing
possibility of developing novel therapies to treat this not so
uncommon noncoronary complications of diabetes – diabetic
cardiomyopathy
References
1.
King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–
2025: prevalence, numerical estimates, and projections. Diabetes Care.
1998; 21: 1414–1431.
2.Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A.
New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972; 30: 595–602.
The important role of the renin-angiotensin-aldosterone system
in the pathogenesis of complications in diabetic patients is well
described. Evidence supports the use of angiotensin-converting
enzyme inhibitors in preventing myocardial fibrosis, cardiac
hypertrophy, and myocardial mechanical dysfunction associated
with diabetic cardiomyopathy.34 Evidence suggests a beneficial
effect of aldosterone antagonism in diastolic heart failure by virtue
of their beneficial effects on cardiac hypertrophy and fibrosis.35
3.
Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up
study. Diabetes. 1974; 23: 105–111.
4.
Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive
heart failure: the Framingham study. Am J Cardiol. 1974; 34: 29–34.
5.
Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA. 1979; 241: 2035–2038.
6.Bertoni AG,Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care. 2003; 26:
2791–2795.
Metabolic Modulation
Recently the aberrant metabolism in HF is well defined by
M.Faadiel Essop et al. 36 The therapies that may help in restoring
metabolic normalcy are ACE and inhibitors,ARBs & Beta blockers
.The metabolic modulators such as Trimetazidine and Perhexilene
increase the free fatty acid utilization as substrate. The study
of trimetazidine in non ischemic cardiomyopathy has shown
improvement in LVEF from 30.9% to 34.8% and reduced acid
oxidation.
7.Bella JN, Devereux RB, Roman MJ, Palmieri V, Liu JE, Paranicas M, Welty
TK, Lee ET, Fabsitz RR, Howard BV. Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure
and function in American Indians (the Strong Heart Study). Am J Cardiol.
2001; 87: 1260–1265.
Novel Therapies
Therapies directed toward the prevention and progression
of diabetic cardiomyopathy is in the early stages of clinical
development and has targeted enhanced fibrosis /collagen
deposition or alterations in cardiomyocyte metabolism.
Prominent among these novel agents are advanced glycation end
product inhibitors (aminoguanidine,alanine aminotransferase 946
,and pyridoxamine);advanced glycation end product cross-link
breakers (eg,alanine aminotransferase 711);and copper chelation
therapy (eg,trientine).32Modulators of free fatty acid metabolism
,such as trimetazidine,have proven useful in the management of
angina but their efficacy on diabetic cardiomyopathy is unknown.
Most of the above agents are in experimental stages and have not
been approved for use in diabetic cardiomyopathy.
Conclusion
8.
Liu JE, Palmieri V, Roman MJ, Bella JN, Fabsitz R, Howard BV, Welty TK,
Lee ET, Devereux RB. The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart
Study. J Am Coll Cardiol. 2001; 37: 1943–1949.
9.
Schannwell CM, Schneppenheim M, Perings S, Plehn G, Strauer BE. Left
ventricular diastolic dysfunction as an early manifestation of diabetic
cardiomyopathy. Cardiology. 2002; 98: 33–39.
10. Carugo S, Giannattasio C, Calchera I, Paleari F, Gorgoglione MG, Grappiolo A, Gamba P, Rovaris G, Failla M, Mancia G. Progression of functional and structural cardiac alterations in young normotensive uncomplicated patients with type 1 diabetes mellitus. J Hypertens. 2001; 19:
1675–1680.
11. Di Bonito P, Cuomo S, Moio N, Sibilio G, Sabatini D, Quattrin S, Capaldo
B. Diastolic dysfunction in patients with non-insulin-dependent diabetes mellitus of short duration. Diabet Med. 1996; 13: 321–324.
12. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the
community: appreciating the scope of the heart failure epidemic. JAMA.
2003; 289: 194–202.
13. Spector KS. Diabetic cardiomyopathy. Clin Cardiol. 1998; 21: 885–887.
14. Avendano GF, Agarwal RK, Bashey RI, Lyons MM, Soni BJ, Jyothirmayi
GN, Regan TJ. Effects of glucose intolerance on myocardial function and
collagen-linked glycation. Diabetes. 1999; 48: 1443–1447.
15. Sihem Boudina, PhD; E. Dale Abel, MBBS, DPhil. Diabetic Cardiomyopathy Revisited. (Circulation. 2007; 115:3213-3223.)
Diabetes mellitus is a major public health problem and
cardiovascular disease remains the leading cause of morbidity
16. Zhao XY, Hu SJ, Li J, Mou Y, Chen BP, Xia Q. Decreased cardiac sarco-
360
Diabetic Cardiomyopathy – A Non Coronary Complication of Diabetes Mellitus
plasmic reticulum Ca2+ -ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats. J Physiol Biochem. 2006; 62:
1–8.
17. Lopaschuk GD, Tahiliani AG, Vadlamudi RV, Katz S, McNeill JH. Cardiac
sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic
rats. Am J Physiol Heart Circ Physiol. 1983; 245: H969–H976.
18. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence,
mechanisms, and therapeutic implications. Endocr Rev19. Frustaci A,
Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B,
Anversa P. Myocardial cell death in human diabetes. Circ Res. 2000; 87:
1123–1132.
20. Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ. Attenuation by
metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol. 2006; 48: 1688–1697.
2003; 289:194-202
27.Boyer JK,Thanigaraj S, Schechtman KB, Perez JE: Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with
diabetes mellitus. Am J Cardiol 2004; 93:870-5
28. Combes A, Arnoult F, Trouillet JL: Tissue Doppler imaging estimation of
pulmonary artery occlusion pressure in ICU patients. Intensive Care
Med 2004; 30:75-81
29. Nishimura R, Tajik AJ: Evaluation of diastolic filling of left ventricle in
health and disease: Doppler echocardiography is the clinician’s Rosetta
stone. J Am Coll Cardiol 1997; 30:8-18
30. Dolye,M.,Fuisez,A.,Kortright,E.etal.(2003)The impact of myocardial
flow reserve on the detection of coronary artery disease by perfusion imaging methods:an NHLBI WISE study.J.Cardiovasc.Magn.Reson.5,475-485
31. Ficaro,E.P.and Corbett,J.R.(2004) Advances in quantitative perfusion
SPECT imaging .J.Nucl.Cardiol.11,62-70
21. Cai L. Suppression of nitrative damage by metallothionein in diabetic
heart contributes to the prevention of cardiomyopathy. Free Radic Biol
Med. 2006; 41: 851–861.
22. Lopaschuk GD. Metabolic abnormalities in the diabetic heart. Heart Fail
Rev. 2002; 7: 149–159.
23. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of
the heart in diabetes, part I: general concepts. Circulation. 2002; 105:
1727–1733.
24.Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to
reduced cardiac efficiency in diabetes. Physiology (Bethesda). 2006; 21:
250–258.
25 Ferri C, Piccoli A, Laurenti O, et al. (March 1994). “Atrial natriuretic
factor in hypertensive and normotensive diabetic patients”. Diabetes
Care 17 (3): 195–200. doi:10.2337/diacare.17.3.195. PMID 8174447
32. Ashish Aneja, MD W.H.Wilson Tang, MD sameer Bansilal, MD, Mario
J.Garcia,MD.Diabetic Cardiomyopathy:Insights into Pathogenesis,
Diagnostic Challenges, and Therapeutic Options.The American Journal of
Medicine (2008)121,748-757.
33. Von Bibra H, Hansen A, Dounis V,et al. Augmented metabolic control
improves myocardial diastolic function and perfusion in patients with
non –insulin dependent diabetes. Heart .2004;90:1483-1484
34.Rosen R,Rump AF,Rosen P.The ACE-inhibitor captopril improves
myocardial perfusion in spontaneously diabetic (BB) rats.Diabetologia
1995;38:509-517
35.Orea-Tejeda A,Colin –Ramirez E,Castillo –Martinez L,et al.Aldosterone
receptor antagonists induce favorable cardiac remodeling in diastolic
heart failure patients. Rev Invest Clin .2007; 59:103-107.
26. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ: Burden of systolic and diastolic ventricular dysfunction in the
community: Appreciating the scope of the heart failure epidemic. JAMA
36. M.Faadiel Essop, Lionel H.Opie .Metabolic therapy for Heart failure.
European Heart Journal (2004) 25, 1765-1768.
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