World Journal of Cardiovascular Diseases, 2013, 3, 26-32 WJCD http://dx.doi.org/10.4236/wjcd.2013.35A005 Published Online August 2013 (http://www.scirp.org/journal/wjcd/) Diabetic cardiomyopathy—What do we know about it? Muhammad Asrar ul Haq1,2, Vivek Mutha 1,2, Nima Rudd1,2, Chiew Wong1,2 1Department of Medicine, University of Melbourne, Melbourne, Australia 2Department of Cardiology, The Northern Hospital, Melbourne, Australia Email: muhammad.asrar@unimelb.edu.au Received 9 May 2013; revised 12 June 2013; accepted 29 June 2013 Copyright © 2013 Muhammad Asrar ul Haq et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Diabetic cardiomyopathy is defined as the presence of myocardial dysfunction in patients with diabetes in the absence of coronary artery disease, hypertension, or other known cardiac disease. Diabetes has been shown to affect the heart through various cellular me- chanisms leading to enhanced myocardial fibrosis, left ventricular hypertrophy, systolic and diastolic dys- function. With increasing incidence of type II dia- betes mellitus, it has continuously rising health and fi- nancial implications in both developed and develop- ing countries. Hyperglycaemia seems to be the main deriving force, and careful glycaemic control as well as early administration of neurohormonal antagonists currently remains the mainstay of therapy. Many ne- wer treatment targets are currently being explored. Here we present a brief review of its pathophysiology, association with heart failure symptoms, and mana- gement strategies. Keywords: Cardiomyopathy; Diabetes; Heart Failure 1. INTRODUCTION Diabetic cardiomyopathy is defined as the presence of myocardial dysfunction in patients with diabetes in the absence of coronary artery disease and hypertension, or other known cardiac disease [1]. Diabetes has been shown to affect the heart through various cellular mechanisms leading to enhanced myocardial fibrosis, left ventricular hypertrophy (LVH), systolic and diastolic dysfunction [1]. With increasing incidence of type II diabetes mellitus, it has continuously rising health and financial implica- tions in both developed and developing countries. Hyper- glycaemia seems to be the main deriving force [2], and careful glycaemic control as well as early administration of neurohormonal antagonists currently remains the main- stay of therapy. The risk for heart failure (HF) in diabetics independent of other confounding factors is increased upto 2.4:1 in males and 5:1 in females [3-8]. Elevated glycated hae- moglobin (HbA1c) is itself associated with an 8% in- crease in HF incidence [9]. More specifically, up to 75% of asymptomatic normotensive diabetic patients with nor- mal ejection fraction (LVEF) will have diastolic abnor- malities [10]. 2. PATHOPHYSIOLOGY Angiographic and autopsy studies have confirmed higher prevalence of cardiomyopathy in diabetics when com- pared to non-diabetic patients, as well as more extensive disease patterns and more severe proximal and distal CAD [11-18]. With similar infarct sizes, diabetic patients have a far greater risk of developing HF post-myocardial infarction (MI) since the compensatory mechanisms to maintain cardiac output in surviving myocardium, eg hy- perkinesis to compensate for non viable myocardium, are not as active due to various intra- and extra-myocardial factors and reduced coronary blood flow [19-23]. There is also enhanced thickening of capillary basement mem- brane, myocellular atrophy and hypertrophy with myo- cardial and interstitial fibrosis, which further reduce my- ocardial function [24-26]. 2.1. Hyperglycaemia Hyperglycaemia is the main trigger factor. One of the principle abnormali ties is impaired coron ary vasodilation capacity seconday to increased production of AGEs (ad- vanced glycation end-products). Increased generation of mitochondrial free radicals (Reactive oxygen species; ROS) is another mechanism, which affects the contractil- ity [27,28]. Severity of diastolic dysfunction correlates positively with HbA1c lev els [9] which may b e related to the activity of increased ROS causing increased collagen deposition in the myocardium leadin g to fibrosis [29,30]. 2.2. Fatty Acids In healthy individuals the energy required for cardiac OPEN ACCESS
M. Asrar ul Haq et al. / World Journal of Cardiovascular Diseases 3 (2013) 26-32 27 function comes from glucose metabolism and free fatty acids (FFAs). Cardiac ischaemia or increased intra-ven- tricular pressure changes cardiac ATP production to a predominant glucose oxidation [31]. This phenomenon does not occur in diabetic patients and only 10% of the myocardial energy comes from glucose. This is mainly due to depleted glucose transporter proteins (glucose tran- sporter-1 and -4). This results in a more pronounced be- ta-oxidation of FFAs [32]. Elevated FFAs are associa- ted with insulin resistance and calcium transporter pro- tein dysfunction, both leading to impaired cardiac func- tion. Increased fatty acids are also associated with the activation of proliferation activated receptor-α (PPARα), suspected to promote mitoch ondr ial un coup lin g of ox ida- tive phosphorylation [33 ], a mechanism that reduces my- ocardial high-energy reserves and contractile dysfunction [34]. Increased intracellular FFAs may directly lead to apoptosis. 2.3. Protein Kinase C Protein kinase C, an intracellular signalling molecule, is activated in diabetes and can lead to endothelial dysfun c- tion by reducing the concentration of nitric oxide and increasing free radical production. Protein kinase C can also enhance leukocyte adhesion, increase albumin per- meability, and impair fibrinolysis [35,36]. 2.4. Renin Angiotensin Aldosterone System (RAAS) In a non-diabetic patient RAAS is activated by myocar- dial stretch owing to the stretch receptors. In diabetic subjects, however, an upregulation of RAAS occurs de- spite minimal changes in myocardial loading [37]. It has been suggested that aldosterone and glucose can cause cardiac fibrosis through stimulation of myofibroblast growth in patients with a dysregulated RAAS especially with concomitant hyperglycaemia [38]. 2.5. Hypoxia-Inducible Factor-1 Normally, chronic cardiac ischaemia promotes angioge- nesis and collateral vessel fo rmation, mainly through h y- poxia-inducible factor-1 (HIF-1), a transcriptional regu- lator complex present in many gene promoters, including vascular endothelial growth factor (VEGF). In diabetic patients, this angiogenic response to myocardial ischae- mia is blunted [39] mainly secondary to markedly re- duced (40% - 70%) VEGF and its receptors VEGF-R1 and VEGF-R2 as suggested by animal studies. 2.6. Endothelial Dysfunction Hyperglycaemia results in impairment of endothelial cell nitrous oxide (NO) production, increased production of vasoconstrictor prostaglandins, glycated proteins, endo- thelium adhesion molecules and vascular growth factors, which cumulatively enhance vasomotor tone and vascu- lar permeability, growth and remodelling [35]. Hyper- glycaemia also enhances endothelial cell matrix produc- tion, which may contribute to basement membrane thick- ening [40]. All these changes will cause increased athero- sclerosis and reduced collateral circulation formation in diabetic patients, which may explain the increased infarct extension and congestive HF after MI in these patients. 2.7. Arterial Stiffness It is well established that hypertension and diabetes lead to increased arterial stiffness [29,41] mainly because of endothelial dysfunction. Reduced compliance of the large arteries in turn affect central systolic pressure and LV afterload, resulting in decreased central diastolic and co- ronary perfusion pressures [42]. These changes will ulti- mately result in chronic myocardial ischaemia leading to interstitial fibrosis and HF [43 ]. 2.8. Autonomic Neuropathy Cardiac autonomic neuropathy is associated with diasto- lic dysfunction in diabetic patients. It starts with an in- crease in resting heart rate and a loss of heart rate vari- ability. This can influence the chronotropic and ino tropic response of the myocardium. Ventricular filling abnor- malities are also prevalent in diabetic patients with auto- nomic neuropathy independent of duration of diabetes, presence of retinopathy, HbA1, or blood glucose levels [44]. A significant correlation has been described be- tween the E/A ratio and autonomic neuropathy [45]. 2.9. Disordered Copper Metabolism Alterations in copper metabolism have also been propo- sed as an important contributor to the development and progression of diabetic cardiomyopathy. Elevated serum copper levels are found in patients with diabetes, and the highest levels are found in those with microvascular com- plications and hypertension [46]. Hyperglycaemia can damage the copper binding properties of ceruloplasmin and albumin (the main copper binding proteins in plas- ma), resulting in increased copper levels in the extracel- lular matrix [47,48]. Increased copper in the extracellular matrix is thought to activate the ox idation-reduction sys- tem, leading to an enhanced production of free radicals resulting in increased oxidative stress and fibrosis [49]. 2.10. Stem Cell Involvement A recent study has proposed that diabetic cardiomyopa- thy may be a stem cell disease. Increased oxidative stress in diabetes can alter cardiac progenitor cell (CPC) func- Copyright © 2013 SciRes. OPEN ACCESS
M. Asrar ul Haq et al. / World Journal of Cardiovascular Diseases 3 (2013) 26-32 28 tion, leading to defective cardiac progenitor cell growth and myocyte formation, causing premature myocardial aging, apoptosis and heart failure. It was also noted that cardiac progenitor cell apoptosis and heart failure were ameliorated by ablation of the p66shc gene in an animal model [50]. 3. CLINICAL PRESENTATION Diabetic cardiomyopathy presents with LVH and/or sys- tolic & diastolic dysfunction which can be categorised into 4 stages depending on the symptoms. 3.1. Diastolic Dysfunction in Diabetes LV Diastolic dysfunction is much more common than initially reported in subjects with well-controlled type 2 diabetes who are asymptomatic for myocardial disease. In a study of well-controlled type II diabetic patients without any evidence of diabetic complications, hyper- tension, coronary artery disease, congestive heart failure, thyroid or overt renal disease, LV diastolic dysfunction was present in 60% of subjects, of whom 28% had a pse- udonormal pattern of ventricular filling (indicating raised filling pressure), and 32% had impaired relaxation [51]. A similar study of you ng type I diabetic patients without known cardiac disease demonstrated reduced early and increased late peak mitral velocity, as well as prolonged deceleration time and isovolumic relaxation time com- pared with controls, despite normal LV dimensions and systolic function [52]. Some studies comparing type I and type II diabetes have reported that preclinical myo- cardial disease is more prevalent in type II diabetes [53, 54]. 3.2. Systolic Dysfunction in Diabetes In the context of diabetic cardiomyopathy, systolic dy- sfunction occurs late, often when patients have already developed significant diastolic dysfunction. Studies have reported that many of those who have normal LV systolic function at rest may show abnormalities during exercise or dobutamine stress [55,56], indicating that LV systolic reserve is reduced in these patients. Diabetic patients have been shown to have a lower cardiac output during supine exercise than controls, with no difference at rest mainly due to a lower stroke volume [57]. It has been suggested that an abnormal EF response during exercise may be due to alterations in ventricular loading conditions and/or cardiac autonomic innervation rather than to abnormalities of con tractility itself. Despite subgroups show ing an abnormal EF r esponse to ex ercise, all patients with diabetes had a normal response to after- load manipulation, normal baseline ventricular contracti- lity as assessed by load- and heart rate-independent end- systolic indexes and normal contractile reserve, as asse- ssed with dobutamine challenge [58]. 4. STAGES OF DIABETIC CARDIOMYOPATHY Clinical symptoms of heart failure such as class 1 dysp- noea, according to the New York Heart Association (NYHA), can be absent at an early stage or may be very mild. Maisch et al. [59] have recently proposed the fol- lowing classification of diabetic cardiomyopathy based on the clinical phenotypes: 4.1. Stage 1 Diabetic Cardiomyopathy Heart failure with preserved EF (HFPEF) in diabetic pa- tients often associated with hypertrophy without relevant hypertension. Relevant CAD, valvular disease and un- controlled hypertension are not present. It is the earliest form of diabetic cardiomyopathy and can be detected in 75% of asymptomatic diabetic patients [10]. 4.2. Stage 2 Diabetic Cardiomyopathy Systolic and diastolic heart failure with dilatation and re- duced ejection (HFREF) in diabetic patients excluding relevant CAD, valvular disease and uncontrolled hyper- tension, although CAD and hypertension could play a minor role. Myocardial infarction or uncontrolled hyper- tension should not be p resent . 4.3. Stage 3 Diabetic Cardiomyopathy Systolic and/or diastolic heart failure in diabetic patients with small vessel disease (microvascular disease) and/or microbial infection and/or inflammation and/or hyper- tension but without CAD. Hypertension, microangiopa- thy and viral heart disease with or without myocarditis can be the contributing factors. 4.4. Stage 4 Diabetic Cardiomyopathy If heart failure may also be attributed to infarction or ischemia and remodelling in addition to stage 3, the term should be heart failure in diab etes or stage 4 diabetic car- diomyopathy. 5. MANAGEMENT OF DIABETIC CARDIOMYOPATHY 5.1. Glycaemic Control Prompt and appropriate treatment of diabetes is clinically relevant because of its role in the pathogenesis of heart failure. Although there is some data sug gesting that poor glycaemic control contributes to myocardial dysfunction, evidence that improvements in glycaemic control are the- rapeutic are limited. The UKPDS (UK Prospective Dia- Copyright © 2013 SciRes. OPEN ACCESS
M. Asrar ul Haq et al. / World Journal of Cardiovascular Diseases 3 (2013) 26-32 29 betes Study) failed to show a significant benefit of inten- sive blood glucose control using either sulphonylureas or insulin on the risk of developing macrovascular disease in patients with Type II diabetes [60]. This study how- ever had significant methodological limitations which merit consideration when interpreting the results [61]. These include that the study was unblinded and continu- ed when no difference was observed at the initial agreed time point for analysis, patients in the diet-only group actually received drug treatment if the fasting plasma glucose was > 15 mmol/l, and at 9 years only 25% of pa- tients were on monotherapy. Hansen et al. [62] more recently showed that both myocardial function and myocardial blood volume were reduced in patients with insulin dependent diabetes, and after administration of C peptide a 12% improvement of function was seen in association with improvements of myocardial blood volume and flow. Similarly in another study, von Bibra et al. [63] reported improvements of myocardial function and perfusion with insulin. They also noted that the degree of both mechanical change and perfusion was related to the degree of change of fasting insulin with treatment. There is some data suggesting that diabetic cardio- myopathy does not develop in patients with tightly con- trolled type 1 diabetes, supporting an important role for hyperglycaemia in the pathogenesis of diabetic cardio- myopathy [64]. There is not much da ta currently on the choice of glu- cose lowering agents in diabetic cardiomyopathy. Glu- cagon-like peptide-1 analogues have been associated with improvement in hemodynamic variables in diabetic patients without overt heart failure [65]. Improved car- diac parameters were also noted with this agent class post-infarction and in advanced heart failure. Use of thi- azolidinediones in the management of patients with dia- betic cardiomyopathy is difficult due to complications with fluid overload. As a consequence of unforeseen in- crease in cardiovascular mortality with thiazolidinedo- ines therapy, US FDA now mandates that all new hypo- glycaemic agents should be trialled for diabetic popula- tion. In general, the choice of glucose lowering approach should be directed towards clinical characteristics, such as the presence or absence renal dysfunction, risk of hy- poglycaemia, age, volume status, and concomitant drug therapy. 5.2. Blood Pressure Control No specific data related to changes of myocardial func- tion in diabetes with improved blood pressure control are available. However improvement in mortality was ob- served with tight blood pressure control in the UKPDS trial [66], with a 15% reduction of mortality for every 10 mm Hg reduction of systolic blood pressure. 5.3. Treatment of Fibrosis The important role of the RAAS in the pathogenesis of complications in diabetic patients has been discussed above. There is evidence suggesting that angiotensin con- verting enzyme inhibitors (ACE inhibitors) can prevent myocardial fibrosis, cardiac hypertrophy, and myocardial mechanical dysfunction associated with diabetic cardio- myopathy [67-69]. ACE inhibitors and angiotensin-1 receptor blocking agents have also been shown to pre- vent coronary perivascular fibrosis and collagen deposi- tion [70,71]. Evidence also suggests a beneficial effect of aldosterone antagonism in diastolic heart failure by its effects on cardiac hypertrophy and fibrosis [72,73]. 5.4. Cross Link Breakers Fibrillar proteins, such as collagens type I and III, and elastin form an intricate widespread network in the ex- tracellular matrix and provide a basis for maintaining the physical structure of the heart and vessels as well as car- diovascular function. Collagen and elastin fibres are en- zymatically cross-linked to form matrix. In addition to these enzymatically formed cross-links, collagen fibres may be linked non-enzymatically, most notably by formation of advanced glycation end-products (AGEs). In addition to diabetes as mentioned earlier, AGEs are also formed increasingly in hypertension and they accumulate with aging. Various effects of AGEs on cardiovascular structure and function have been describ- ed above, forming the basis of breaking AGEs (e.g. ala- nine aminotransferase 711) as a potential tool in the the- rapy of cardiovascular injury related to diabetes, hyper- tension and aging. Limited animal and human data indicate benefit with cross-link breakers. In studies of aging non-diabetic dogs, cross-link breakers caused a significant reduction (appro- ximately 40%) in left ventricular stiffness, which was ac- companied by imp rovement in ca rd i a c f unction [ 7 4]. Another study in diabetic dogs, cross-link breaker s re- stored LV ejection fraction, reduced aortic stiffness and LV mass with no reduction in blood glucose level, and reversed the up regulation of collagen type I and type III [75]. 5.5. Other Novel Therapies Targeting Diabetic Cardiomyopathy In addition to the above mentioned cross-link breakers, other therapies directed toward prevention and progress- sion of diabetic cardiomyopathy targeting either enhan- ced fibrosis/collagen deposition or alterations in cardio- myocyte metabolism which are still in experimental sta- ges include AGEs inhibitors (e.g. aminoguanidine, alani- Copyright © 2013 SciRes. OPEN ACCESS
M. Asrar ul Haq et al. / World Journal of Cardiovascular Diseases 3 (2013) 26-32 30 ne aminotransferase 946, and pyridoxamine), copper che- lation therapy (e.g. trientin e), and modulators of free fat- ty acid metabolism (e.g. trimetazidine). Modulators of free fatty acid metabolism have proven useful in the management of angina, but their efficacy on diabetic cardiomyopathy is unknown. Newer agents like Exenatide (recombinant glucagon-like peptide-1,) or Si- tagliptin (DPP4 inhibitor) are yet to be studied specifi- cally in patients with diabetic cardiomyopathy despite promising cardiac effects with glucagon-like peptide-1 infusion in mechanistic studies. 6. CONCLUSION Diabetic cardiomyopathy is common and can present with symptomatic or asymptomatic myocardial dysfunc- tion. With the rising prevalence of diabetes, it has major financial and health implication on the healthcare sys- tems. 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