Diabetic Cardiomyopathy: Cause or Consequence of Diabetes Mellitus?
María Luz Gunturiz A1*, Pablo Chaparro2
1Public Health Research Division, National Institute of Health. Bogotá, D.C, Colombia
2National Health Observatory Division, National Institute of Health. Bogotá, D.C, Colombia
*Corresponding Author: María Luz Gunturiz A, Public Health Research Division, National Institute of Health. Bogotá, D.C, Colombia
Received: 27 June 2017; Accepted: 04 July 2017; Published: 07 July 2017View / Download Pdf Share at Facebook
The pathogenesis of diabetic cardiomyopathy (DC) is not understood completely. DC is an important complication of longstanding diabetes that is associated with high mortality and morbidity rates, being its progression controlled by multiple factors. Within the mechanisms that have been proposed for DC are included metabolic and microvascular disorders, insulin resistance, myocardial fibrosis and cardiac autonomic dysfunction, among others.
Its suggested that the Chronic hyperglycemia play an important role in the development of DC although multiple complex mechanisms and interplay of many molecular and metabolic events within the myocardium they could be involved with the pathogenesis. Some of the metabolic disorders associated with diabetes are hyperlipidemia, hyperglycemia and inflammation, which promote the formation of reactive species of oxygen and nitrogen, or other free radicals that induce the increase of diabetic nephropathy and cardiomyopathy.
Several adaptive responses caused by the metabolic alterations mentioned, trigger cardiovascular disorders including heart failure. In this article, we review some of the animal models and molecular mechanisms potentially implicated in the progression of DC. In this article, we review some of the animal models and molecular mechanisms potentially implicated in the progression of DC.
Diabetic Cardiomyopathy; Diabetes Mellitus; Heart Disease; Ischemic Heart Disease
CAD - Coronary artery disease
DC - Diabetic cardiomyopathy
HTA - Arterial hypertension
DM - Diabetes mellitus
IC - Heart failure incidence
CD - Cardiovascular disease
HF - Heart failure
LV - Left ventricle
EF - Ejection fraction
NIDC - Non-ischemic diabetic cardiomyopathy
AGEs - Advanced glycation end products
ECM - Extracellular matrix
STZ - Streptozotocin
Diabetic cardiomyopathy (DC) is a pathological condition that increases morbidity and mortality rates associated with diabetes. In the underlying mechanisms of DC that lead to myocardial injury and cardiomyopathy, the hyperglycemia, hyperinsulinemia and oxidative stress play a relevant role in inducing, for example, the increase of advanced glycation end products (AGEs), inflammation, fibrosis, hypertrophy and apoptosis.
The Diabetes mellitus (DM) is considered a public health problem. The multiple complications associated with DM, increase the incidence, morbidity and mortality in diabetic patients, where heart disease is the leading cause of death.
It has been reported that one of the major causes of heart failure and death in diabetic patients (HF) is coronary artery disease (CAD). The risk of HF continues to increase despite adjustment for CAD and hypertension . Rubler et al., Described DC as "a cardiac entity, defined as ventricular dysfunction in the absence of CAD and hypertension" . At the clinical level, DC has been characterized by cardiac hypertrophy and diastolic dysfunction, which generally results in HC with preserved ejection fraction (HFpEF).
In some articles it is argued that DC can lead to systolic heart failure (HFrEF), although more evidence is needed to support this finding . By 2015 it is estimated that the diabetic population will be almost 300 million, due to an increase in obesity and physical inactivity.
50% of the deaths occurring in the diabetic population are due to cardiovascular disease (CD), causing an annual mortality twice that observed in non-diabetic population and a reduction in the life expectancy of 5-10 years. The cardiovascular damage caused by diabetes occurs at different levels, in epicardial arteries, autonomic malfunction, DC and microvascular coronary disease, being common the coexistence of multiple affections [4, 5].
In the diabetic patients one exists developing predominance, so much of HF as of malfunction ventricular (systolic, diastolic or mixed) asymptomatic not related with cardiovascular disease, hypertension, alcoholism, illness valve or congenital, so called entity “diabetic cardiomyopathy”, which it determines a prognosis typically of major adversity . DM is a predictive indicator of cardiovascular mortality considering only ischemic patients.
Both the study SOLVD and the BEST not they demonstrated major mortality risk in diabetics with cardiomyopathy of origin not ischemic [7, 8]. Several epidemiological studies from the 1970s to 1979 support the high incidence of HF in DM, with a 2-fold risk in men and 5-fold in women, compared to the non-diabetic population matched by age and sex [4, 5].
2. Clinical Diabetic Cardiomyopathy
Although many studies on DC have been published and there is more clinical evidence, the debate on the existence of this pathology remains controversial, because DC does not have classic features of cardiomyopathy, such as ventricular dilatation and significant systolic dysfunction.
DC includes a connection of molecular myocardial abnormalities predisposing to myocardial dysfunction, particularly in the presence of additional stressors such as hypertension and CAD. . The definition of diabetic cardiomyopathy (DC) is still discussed, since the CI in diabetic patients frequently collaborates with hypertension and CE, being difficult to unleash the myocardial damage caused by these two pathologies.
There are studies in which it is questioned that the DM by one is sufficient to explain the cardiomyopathy and only the myocardial one accepts the structural damage because of the diabetes associated with the AHT, which would take the ventricular malfunction as the first statement and in last Instance the IC . Bell  states that if diabetes is not complicated by neuropathy, nephropathy, retinopathy, ETS or EC does not cause ventricular malfunction.
Nevertheless, when one associates not treated HTA and/or to ischemic myocardial the proper light subclinical cardiomyopathy of the diabetes can advance quickly to a diastolic malfunction clinically clearly and, more lately, to a malfunction systolic . Pathologic changes in the myocardial interstitium, including AGE formation, impaired compliance and ischemia from the disease in the vasa vasorum, occur during the progression of DC.
These alterations lead to a deregulation of cardiac contractility, although the myocardial cells and coronary vessels maintain their morphological characteristics integrally . When DC begins, LV hypertrophy occurs due to an enlargement of the cardiac cells, in addition to interstitial and perivascular fibrosis, thickening of the basement membrane of the capillaries and formation of microaneurysms in small capillary vessels .
The systemic proinflammatory state, with vascular inflammation and endothelial dysfunction, observed in diabetic patients also leads to the undesirable effects of LV hypertrophy and diastolic stiffening seen in DC. The endothelial dysfunction involving the coronary vasculature and central cardiac endothelium limits nitric oxide (NO) bioavailability to adjacent cardiomyocytes, decreasing cyclic guanosine monophosphate (cGMP) production and protein kinase G (PKG) activity in cardiomyocytes, culminating with the histological and functional alterations of DC .
Other pathogenic mechanisms are produced to impair cardiac function and promote cardiomyocyte injury in diabetes: impairment of calcium homeostasis, altered signal transduction (insulin signaling and renin-angiotensin system up regulation), altered cell homeostatic processes such as apoptosis and autophagy, changes in gene regulation (activation of transcription factors, microRNAs and epigenetic mechanisms), post-translational modifications of structural and signaling proteins, increased oxidative stress, cardiac autonomic neuropathy (CAN) and mitochondrial dysfunction [15-18].
When diabetic patients develop ventricular dysfunction in the absence of atherosclerosis and hypertension, the diagnosis may be focused towards a DC [18-22]. Despite this, DC can go unnoticed for a long time, before the appearance of clinical signs or symptoms . In asymptomatic diabetic patients, cardiac abnormalities most frequently observed include diastolic cardiac dysfunction and left ventricular hypertrophy (LVH) [18, 24-26].
The progression of cardiomyopathy involves the onset of time-dependent heart muscle disease, which includes a subclinical period in which the symptoms and frequent signs of the disease are absent. Therefore, the most significant evidence to diagnose DC is the verification of ventricular malfunction in asymptomatic young diabetic patients, with no other concomitant pathologies capable of affecting the cardiac muscle, and in which myocardial anomalies are due exclusively to adequate diabetes.
Marcinkiewicz et al.  defined DC as the long-lasting process, which affects the myocardium, which is established, at a very early stage of metabolic changes (such as insulin resistance or overexpression of resistin), Even before diabetes is diagnosed. Its onset is accelerated by progressive myocardial ischemia .
In addition to cardiac malfunction related to ischemia, there are studies that show association between heart failure and diabetes in both type 1 and type 2 diabetes mellitus. The molecular and physiological mechanisms of non-ischemic diabetic cardiomyopathy (NIDC) are still unclear and the Studies on the mechanics of the myocardium in the early stages of the disease are rare.
However, several studies in both humans and animal models have described the occurrence of early myocardial hyperdynamics during the course of the disease. The theory that emerges is that NIDC may be nonlinear and initially present an asymptomatic subclinical phase of myocardial hypercontractility that precedes the long-term development of cardiac dysfunction associated with diabetes and, ultimately, the HF .
Metabolic alterations induced by diabetes can lead to a contradictory inotropic increase and a mechanical deregulation of the myocardium that eventually result in a gradual deterioration of myocardial performance. Accordingly, diabetic patients should undergo periodic examinations during the course of the disease using, among others, ultra-sensitive images of myocardial deformation in order to identify patients at risk for heart failure associated with diabetes.
In addition, hyperdynamic myocardial deformation may improve the diagnosis of non-ischemic cardiomyopathy of ischemic diabetic cardiomyopathy. Further studies are needed to elucidate the underlying pathophysiological mechanisms as well as the spatiotemporal evolution of DC and its long-term relationship with clinical outcome parameters .
3. Pathogenesis of Diabetic Cardiomyopathy
The pathogenesis of DC is complex and has not been well understood until recently. Several mechanisms have been proposed, each of which acting lonely or in combination with the others, it can give place to the DC. The main ones are the following ones: metabolic illness, interstitial fibrosis, myocellular hypertrophy, microvascular illness and autonomic malfunction. Impaired calcium handling, altered metabolism, increased oxidative stress, remodeling of extracellular matrix (ECM), endothelial and mitochondrial dysfunction are some of the alterations involved in DC [29-32].
DM is pathology involved in HF, despite the absence of alterations in coronary artery disease, hypertension, left ventricle (LV) and ejection fraction (EF). This condition is known as diabetic cardiomyopathy [33-35]. Although the diagnosis of CD is believed to be multifactorial, the exact cause remains unknown. Several mechanisms, including hyperglycemia and hyperinsulinemia, play a relevant role in its etiology.
These alterations are observed as changes in free acid metabolism, increased apoptosis, activation of the renin-angiotensin system, abnormalities in copper metabolism, autonomic neuropathy, stem cell defect, and increased oxidative stress among others. The underlying pathological conditions may change cardiac structure and lead to cardiac fibrosis .
DC is a left ventricular diastolic dysfunction, identified in patients with DM as the earliest functional alteration in the progression of diabetic cardiomyopathy [33-35], constituting an important prognostic parameter. In addition, LV longitudinal myocardial systolic dysfunction has been identified in patients with DM with preserved FEVES without evident coronary disease or HF .
Other investigators have found that LV myocardial systolic dysfunction, rather than LV diastolic dysfunction, could be considered as the first sign of a preclinical form of a preclinical form of DC in patients with DM with FEVES preserved without open IC [33-37]. In spite of this, the characteristics of the patients with DM that are associated with alteration of the longitudinal systolic myocardial function of the LV are still unclear.
4. Metabolic Illness
At cellular level, the DC associates with anomalies of the metabolism of the greasy acids and of the homeostasis of the calcium, what can produce major rigidity of left ventricular wall and deterioration of the contractility the cardiac cell .
Studies in animals have shown that diabetes induced experimentally produces defects in cellular calcium transport, defects in contractile proteins and increased production of collagen that causes small anatomical and physiological changes in the myocardium of monkeys [38-40]. In other studies it has been suggested that using more fatty acids associated with decreased glucose consumption leads to an accumulation of toxic intermediate fatty acids which subsequently inhibit this consumption of glucose into the myocardium.
This can derive a depletion of ATP, prevention in the production of lactate and increase in the oxygen consumption myocardial, quite which leads to a deterioration of the yield myocardial [41, 42].
5. Model Animals And Molecular Targets
In spite of the studies, the initial response of myocardial tissue to a short period of hyperglycemia in terms of proliferative properties of myocytes and alterations in the storage of cardiac stem cells is still to be investigated before the cardiomyopathic phenotype is evident.
A detailed knowledge of the changes that occur at the beginning of diabetes, when cardiac electromechanical performance remains normal, could serve to generate effective therapeutic strategies aimed at the prevention of mechanical dysfunction and arrhythmogenesis, which characterize the more advanced stages of DC. For the development of one animal model in rats for diabetes, intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) is used in a single dose.
In this model, rats show hyperglycemia and hyperlipidemia together with hyperinsulinemia . Ventricular dysfunction and marked structural damage occur over 12 weeks posttreatment with STZ. The first detrimental effect of metabolic changes is a marked loss of ventricular mass, with no signs of cardiomyocyte hypertrophy or accumulation of extracellular matrix . However, in STZ-injected rats, it is not possible to state that the symptoms presented in these animals are related, with a permanent toxic action of STZ [45, 46].
As has been reported, wild rodents are resistant to the development of CAD unless mutations are introduced that induce the development of atherosclerosis, making these animals a good model for the study of DC. [47-49]. In various rodent models for type 2 diabetes including db / db, ob / ob and Zucker diabetic obese rats, cardiac hypertrophy has been observed with increased LV wall mass and thickness, and diastolic dysfunction measured by echocardiography or RM [47, 49-52].
In these models systolic dysfunction is observed dependent on the degree of hyperglycemia and diabetes, confounded by echocardiography or ex vivo techniques such as heart perfusion of Langendorff or in the isolated heart model [51,53,54]. Several mechanisms have been described to demonstrate the development of diabetic cardiomyopathy, with other manifestations associated with heart failure, including, among others, oxidative stress, mitochondrial dysfunction, increased fibrosis, deterioration in calcium management, increased inflammation, increased Cell death and increased activation of the renin-angiotensin system .
The pathological alterations observed in cardiomyocytes are generally produced by systemic metabolic alterations such as hyperglycemia, hyper and dyslipidemia, hyperinsulinemia and insulin resistance. Increased myocardial fatty acid uptake and the generation of toxic lipid intermediates induce increased apoptosis, oxidative stress, and LV dysfunction. It is noteworthy that insulin resistance may contribute to mitochondrial dysfunction and decoupling, oxidative stress, cardiovascular inefficiency, and myocardial energy depletion [49,55-57].
Thus, in the rodent models for type 2 diabetes as in humans it has been possible to observe the occurrence of the DC, as well as associated diastolic dysfunction.
In STZ and Akita diabetic mice, diastolic dysfunction is characterized by increased LV diastolic pressure with cardiac catheterization and abnormal patterns of mitral and venous pulmonary flow [49, 58-60]. On the other hand, in systolic function, there is damage of the ejection fraction and cardiac dysfunction [57, 61].
In a reported study, the authors evaluated by magnetic resonance the early characteristics of DC, in STZ mice, one week after their inoculation observing early reduction of LV volumes which may be explained by hypovolemia due to hyperglycemic osmotic diuresis, inferring a hemodynamic mechanism contributing to cardiac dysfunction in this model of DC [49, 62].
In cardiomyocytes isolated from OVE26 mice, disruption of contractility has been observed, but not in heart perfusion [63, 64]. In Akita diabetic mice, both young and adult, systolic function is conserved both in vivo and ex vivo [65, 66]. In these mice, cardiac hypertrophy is not observed, but isolated hearts are smaller than in non-diabetic controls [66, 67].
This observation may be related to the lack of insulin`s effect on cellular growth and protein synthesis, as also underlined by decreased cardiac size in mice lacking insulin receptors specifically in cardiomyocytes . In the description of the underlying mechanisms of DC, but not in all the models studied nor for all the associated alterations, many observations seem to overlap with the alterations found in the hearts of type 2 diabetes.
Akita diabetic mice apparently do not develop fibrosis, no myocardial inflammation, oxidative stress or decreased cardiac efficiency are observed, although some typical features of DC, such as disruption in calcium management, mitochondrial dysfunction or increased use of Fatty acids [60, 64, 65]. Likewise, mice with STZ-induced type 1 diabetes do not exhibit decreased cardiac efficiency unless they develop insulin resistance, as observed in type 2 diabetic hearts, induced by insulin receptor deletion.
For STZ mice, it can not be ruled out that this drug may induce extrapancreatic toxic effects that may alter the cardiac phenotype [49, 66, 67]. Similarly in humans, in type 1 diabetic animals, insulin therapy can reverse phenotypes and abnormalities such as diastolic dysfunction, decreased expression of the sarcoendoplasmic reticulum Ca2 + -ATPase 2a (SERCA2a), mitochondrial dysfunction or oxidative stress [49, 60, 68].
According to the above, both the phenotype and the molecular mechanisms seem to be different, for the type 1 and 2 diabetes models studied. At the molecular level, several proteins and signaling pathways have been implicated in the development of DC, including protein kinase C, nuclear factor kB, peroxisome proliferator-activated receptor, phosphatidylinositol 3 kinase (PI3K) And the MAPK pathway [32, 69, 70].
In this context, microRNAs (miRs or miRNAs) may be involved in the pathogenesis of DC, as these molecules have been associated with several biological processes, including cell proliferation, apoptosis, necrosis, migration and differentiation. Deregulation of these small RNAs may influence the progression and severity of diabetes and cardiovascular diseases [71-74].
For example, miR-126, miR-17, miR-92a, miR-145, miR-155, miR-133 and miR-208a were identified to be associated with coronary artery disease; miR-1, miR-21, miR-208, miR-133a/b, miR-499 were identified as important in the diagnosis of acute cardiac infarction. Furthermore, miR-24, miR-125b, miR-195, miR-199a and mir-214 were associated with heart failure [32, 74-76].
Huo et al. , produced a model of DC rats in which the expression of the long non-coding RNA H19 is decreased. Other authors studied the role of H19 in DC and showed that overexpression of H19 in diabetic rats decreases autophagy of cardiomyocytes and improves LV function. In addition, they reported that high glucose levels reduced H19 expression and increased autophagy in neonatal cardiomyocyte cell cultures.
Immunoprecipitation of RNA-binding and chromatin (ChIP) binding proteins showed that H19 can bind directly to EZH2 in cardiomyocytes and that the decrease in H19 expression may inhibit the binding of EZH2 and the formation of complexes of H3K27me3 in the promoter Of DIRAS3. On the other hand, it was demonstrated that H19 overexpression decreases the expression of DIRAS3, promotes mTOR phosphorylation and inhibits the activation of autophagy in cardiomyocytes exposed to high glucose levels, which in turn induces increased expression of DIRAS3 as well As of autophagy by inhibiting mTOR signaling in cardiomyocytes. These studies show that H19 inhibit autophagy by epigenetic silencing de DIRAs 3 in cardiomyocytes, which might provide novel insights into understanding the molecular mechanisms of DC .
On the other hand, SIRT1 is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from proteins which can be implicated in DCP.
SIRT1 regulates the expression of several proteins related to hyperglycemia and inhibits the expression of transcriptional factors, such as p300, NF-? B, P38MAPK, Histone 3, MMP-9, FOXO3a and p53. Additionally, SRT1 induces the increase in the expression of, SERCA2a, ERK1 /2/Homer1, eNOS, PGC-1 and AMPK, therefore, this gene, decreases cardiac dysfunction and improve DC .
The DC is a pathological condition that increases morbidity and mortality rates associated with structural, functional and metabolic changes. As the mechanisms involved in the pathogenesis of DC continue to be elucidated, it is necessary the study the risk factors in patients with DC as well as the animal models and target molecules that can generate knowledge to create more specific and effective therapies for the patients with this pathology. From this perspective, is diabetic cardiomyopathy a cause or consequence of diabetes mellitus?
The authors wish to acknowledge the support provided by the National Institute of Health of Colombia.
All authors contributed to the writing of this review.
Conflicts of Interest
The authors declare no conflict of interest.
- Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 241 (1979): 2035?2038.
- Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30 (1972): 595?602.
- Seferovi? PM, Paulus WJ. Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes. Eur Heart J 36 (2015):1718-1727.
- Andersson B, Waagstein F. Spectrum and outcome of congestive heart failure in a hospitalised population. Am Heart J 126 (1993): 632-640.
- Cosme García JL, Urrutia A, González B, Herreros J, Altimir S, et al. Significado pronóstico de la diabetes mellitus en una población con insuficiencia cardiaca: mortalidad e ingreso por insuficiencia cardiaca a 1 año. Med Clin (Barc) 25 (2005): 182-3.
- Domanski M, Krause-Steinrauf H, Deedwania P, Follman D, Ghali JK, et al. The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol 42 (2003): 914-922.
- De Groote P, Lamblin N, Mouquet F, Plichon D, McFadden E, et al. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 25 (2004): 656-662.
- Dries DL, Sweitzer NK, Drazner MH, Gersch BJ. Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of left ventricular systolic dysfunction. J Am Coll Cardiol 38 (2001): 421-428.
- Hölscher ME, Bode C, Bugger H. Diabetic Cardiomyopathy: Does the Type of Diabetes Matter?. Int J Mol Sci 17 (2016): 2136.
- Factor SM, Borczuk A, Charron MJ, Fein FS, van Hoeven KH, et al. Myocardial alterations in diabetes and hypertension. Diabetes Res Clin Pract 31 (1996): S133-S142.
- Bell DSH. Diabetic cardiomiopathy: A unique entity or a complication of coronary artery disease?. Diabetes Care 18 (1995): 708-714.
- Factor SM, Minase T, Sonnenblick EH. Clinical and morphological features of human hypertensive-diabetic cardiomyopathy. Am. Heart J 99 (1980): 446-458.
- Factor SM, Bhan R, Minase T, Wolinsky H, Sonnenblick EH. Hypertensive diabetic cardiomyopathy in the rat: an experimental model of human disease. Am. J. Pathol 102 (1981): 219-228.
- Lam CS. Diabetic cardiomyopathy: An expression of stage B heart failure with preserved ejection fraction. Diab Vasc Dis Res 12 (2015): 1-5.
- Tarquini R, Lazzeri C, Pala L., Rotella CM, Gensini GF. The diabetic cardiomyopathy. Acta Diabetol 48 (2011): 173-181.
- Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57 (2014): 660-671.
- An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291 (2006): H1489-H1506.
- Soares Felício J, Cavalcante Koury C, Tavares Carvalho C, Abrahão Neto JF. Present Insights on Cardiomyopathy in Diabetic Patients. Curr Diabetes Rev 12 (2016): 384-395.
- Francis G.S. Diabetic cardiomyopathy: fact or fiction? Heart 85 (2001): 247-248.
- Picano E. Diabetic cardiomyopathy. The importance of being earliest. J Am Coll Cardiol 42 (2003): 454-457.
- Avogaro A, Kreutzenberg SV, Negut C, Tiengo A, Scognamiglio R. Diabetic cardiomyopathy: a metabolic perspective. Am J Cardiol 93 (2004): 13A-16A.
- Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem 261 (2004): 187-191.
- Hayat SA, Patel B, Khattar RS, Malik RA. Diabetic cardiomyopathy: mechanisms, diagnosis, and treatment. Clin Sci 107 (2004): 539-557.
- Rutter MK, Parise H, Benjamin EJ, et al. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation 107 (2003): 448-454.
- Tenenbaum A, Fisman EZ, Schwammenthal E, et al. Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus. Cardiovasc Diabetol 2 (2003): 14.
- Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care 26 (2003): 2791-2795.
- Marcinkiewicz A, Ostrowski S,Drzewoski J. Can the onset of heart failure be delayed by treating diabetic cardiomyopathy? Diabetol Metab Syndr 9 (2017): 21
- Hensel KO. Non-ischemic diabetic cardiomyopathy may initially exhibit a transient subclinical phase of hyperdynamic myocardial performance. Med Hypotheses 94 (2016): 7-10.
- Wegner M, Neddermann D, Piorunska-Stolzmann M, Jagodzinski PP. Role of epigenetic mechanism in the development of chronic complications of diabetes. Diabetes Res Clin Pract 105 (2014): 164-175.
- Trachanas K, Sideris S, Aggeli C, Poulidakis E, Gatzoulis K, et al. Diabetic cardiomyopathy: from pathophysiology to treatment. Hellenic j Cardiol 55 (2014): 411-421.
- Asrih M, Steffens S. Emerging role of epigenetics and miRNA in diabetic cardiomyopathy. Cardiovasc Pathol 22 (2013): 117-125.
- Liu, X, Liu S. Role of microRNAs in the pathogenesis of diabetic cardiomyopathy. Biomed Rep 6 (2017): 140-145.
- Mochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, et al. Clinical features of subclinical left ventricular systolic dysfunction in patients with diabetes mellitus. Cardiovasc Diabetol 14 (2015): 37.
- Bando YK, Murohara T. Diabetes-related heart failure. Circ J 78 (2014): 576-583.
- Sacre JW, Franjic B, Jellis CL, Jenkins C, Coombes JS, et al. Association of cardiac autonomic neuropathy with subclinical myocardial dysfunction in type 2 diabetes. JACC Cardiovasc Imaging 3 (2010): 1207-1215.
- From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 55 (2010): 300-305.
- Tadic M, Ilic S, Cuspidi C, Stojcevski B, Ivanovic B, Bukarica L, et al. Left ventricular mechanics in untreated normotensive patients with type 2 diabetes mellitus: A Two- and Three-dimensional speckle tracking study. Echocardiography (Mount Kisco, NY). 2014.
- Feener EP, King GL. Vascular dysfunction in diabetes mellitus. Lancet 350 (1997): 9-13.
- Giacomelli F, Weiner J. Primary myocardial disease in the diabetic mouse: an ultrastructural study. Lab Invest 40 (1979): 460-473.
- Regan TJ, Wu CF, Oldewurtel HA, Haider B. Myocardial composition and function in diabetes: the effects of chronic insulin use. Circ Res 49 (1981): 1268-1277.
- Rodrigues B, McNeill JH. The diabetic heart: metabolic causes for the development of a cardiomyopathy. Cardiovasc Res 26 (1992): 913-922.
- Codinach Huix P, Freixa Pamiasan R. Miocardiopatía diabética: concepto, función cardiaca y patogenia. Med Interna (Madrid) 19 (2002): 313-320.
- Stilli D, Lagrasta C, Berni R, Bocchi L, Savi M, et al. Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling. Basic Res Cardiol 102 (2007): 488-499.
- Okamoto T, Kanemoto N, Ohbuchi Y, Okano M, Fukui H, et al. Characterization of STZ-Induced Type 2 Diabetes in Zucker Fatty Rats. Exp Anim 57 (2008): 335-345.
- El-Omar MM, Yang ZK, Phillips AO, Shah AM. Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus. Basic Res Cardiol 99 (2004): 133-141.
- Camacho P, Fan H, Liu Z, He JQ. Small mammalian animal models of heart disease. Am J Cardiovasc Dis 6 (2016): 70-80.
- Bugger H, Abel ED. Rodent models of diabetic cardiomyopathy. Dis Model Mech 2 (2009): 454-466.
- Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Investig 93 (1994):1885-1893.
- Westermeier F, Riquelme JA, Pavez M, Garrido V, Díaz A, et al. New Molecular Insights of Insulin in Diabetic Cardiomyopathy. Front Physiol 7 (2016): 125.
- Cheng Y, Ji R, Yue J, Yang J, Liu X, et al. MicroRNAs are aberrantly expressed in hypertrophic heart: Do they play a role in cardiac hypertrophy? Am J Pathol 170 (2007): 1831-1840.
- Semeniuk LM, Kryski AJ, Severson DL. Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am J Physiol Heart Circ Physiol 283 (2002): H976-H982.
- Stuckey DJ, Carr CA, Tyler DJ, Aasum E, Clarke K. Novel MRI method to detect altered left ventricular ejection and filling patterns in rodent models of disease. Magn Reson Med 60 (2008): 582-587.
- Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 53 (2004): 2366-2374.
- Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146 (2005): 5341-5349.
- Zlobine I, Gopal K, Ussher JR. Lipotoxicity in obesity and diabetes-related cardiac dysfunction. Biochim. Biophys Acta 1861 (2016): 1555-1568.
- Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Investig 109 (2002): 629-639.
- Abel ED, O’Shea KM, Ramasamy R. Insulin resistance: Metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol 32 (2012): 2068-2076.
- Kajstura J, Fiordaliso F, Andreoli AM, Li B, Chimenti S, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50 (2001): 1414-1424.
- Lacombe VA, Viatchenko-Karpinski S, Terentyev D, Sridhar A, Emani S, et al. Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol 293 (2007): R1787-R1797.
- Basu R, Thimmaiah TG, Chawla JM, Schlicht P, Fagiolini A, et al. Changes in metabolic syndrome parameters in patients with schizoaffective disorder who participated in a randomized, placebo-controlled trial of topiramate. Asian J Psychiatry 2 (2009): 106-111.
- Nielsen LB, Bartels ED, Bollano E. Overexpression of apolipoprotein B in the heart impedes cardiac triglyceride accumulation and development of cardiac dysfunction in diabetic mice. J Biol Chem 277 (2002): 27014-2720.
- Joubert M, Bellevre D, Legallois D, Elie N, Coulbault L, et al. Hyperglycemia-induced hypovolemia is involved in early cardiac magnetic resonance alterations in streptozotocin-induced diabetic mice: A comparison with furosemide-induced hypovolemia. PLoS ONE 11 (2016): e0149808
- Liang Q, Carlson EC, Donthi RV, Kralik PM, Shen X, et al. Overexpression of metallothionein reduces diabetic cardiomyopathy. Diabetes 51 (2002): 174-181.
- Ye G, Metreveli NS, Ren J, Epstein PN. Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52 (2003): 777-783.
- LaRocca TJ, Fabris F, Chen J, Benhayon D, Zhang S, et al. Na+/Ca2+ exchanger-1 protects against systolic failure in the Akitains2 model of diabetic cardiomyopathy via a CXCR4/NF-?B pathway. Am J Physiol Heart Circ Physiol 303 (2012): H353-H367.
- Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, et al. Type 1 diabetic Akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 57 (2008): 2924-2932.
- Bolzán AD, Bianchi MS. Genotoxicity of streptozotocin. Mutat Res 512 (2002): 121-134.
- Lashin OM, Szweda PA, Szweda LI, Romani AMP. Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. Free Radic Biol Med 40 (2006): 886-896.
- Liu JW, Liu D, Cui KZ, Xu Y, Li YB, et al. Recent advances in understanding the biochemical and molecular mechanism of diabetic cardiomyopathy. Biochem Biophys Res Commun 427 (2012): 441-443.
- Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 142 (2014): 375-415.
- Zhou Q, Lv D, Chen P, Xu T, Fu S, Li J, Bei Y. MicroRNAs in diabetic cardiomyopathy and clinical perspectives. Front Genet 5 (2014): 185.
- Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116 (2004): 281-297.
- Bauersachs J, Thum T. Biogenesis and regulation of cardiovascular microRNAs. Circ Res 109 (2011): 334-347.
- Udali S, Guarini P, Moruzzi S, Choi SW, Friso S. Cardiovascular epigenetics: From DNA methylation to microRNAs. Mol Aspects Med 34 (2013): 883-901.
- Fichtlscherer S, Zeiher AM, Dimmeler S, Sessa WC. Circulating microRNAs: Biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol 31 (2011): 2383-2390.
- Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res 107 (2010): 677-684.
- Zhuo C, Jiang R, Lin X, Shao M. LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy. Oncotarget 8 (2017): 1429-1437.
- Karbasforooshan H, Karimi G. The role of SIRT1 in diabetic cardiomyopathy. Biomed Pharmacother 90 (2017): 386-392.