In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

We use cookies to optimise the design of this website and make continuous improvement. By continuing your visit, you consent to the use of cookies. Learn more

First in a series on diabetes and the heart: The impact of diabetes on the heart, a broad perspective

In addition to their established risk for coronary heart disease (CHD) and hypertension, diabetic subjects may also develop direct myocardial involvement that contributes to their cardiac burden. Alterations in myocardial metabolism contribute to mitochondrial damage and contractile dysfunction resulting in diabetic cardiomyopathy (DMCMO). Hyperglycemia and insulin resistance promote excessive production and release of reactive oxygen species, which induce oxidative stress, leading to abnormal gene expression and cardiomyocyte apoptosis. Myocyte hypertrophy and the deposition of AGEs result in increased myocardial stiffness and diastolic dysfunction. Cardiomyocyte death and neurohormonal activation trigger eccentric remodelling, leading to ventricular dilatation and systolic dysfunction. Early changes in ventricular dysfunction have been detected by tissue Doppler echocardiography and magnetic resonance imaging.

Diabetes and the Heart

The risk of heart failure in diabetes

The association of diabetes with hypertension, obesity and coronary heart disease, is well established and predisposes diabetic subjects to heart failure (HF) [1]. This has been linked to duration of diabetes and the extent of glycemic control [2]. Cardiovascular morbidity and mortality in diabetes are strikingly high with a reduction in life expectancy. A recent Cambridge study has shown that individuals in their sixties who have a combination of diabetes and heart disease have an average reduction in life expectancy of about 15 years [3]. Four decades ago the Framingham study firmly established the epidemiologic link between diabetes and HF [4], showing that diabetes predicted heart failure independent of hypertension, age, obesity, dyslipidemia and coronary disease. When CHD and valve disease were excluded, the relative risk of HF remained elevated at 3.8 fold in diabetic men and 5.5 fold in diabetic women. It is now recognized that in addition to accelerating and worsening the consequences of coronary artery disease and hypertension, diabetes also has a direct effect on the myocardium, placing the diabetic subject at an increased risk of developing heart failure.

Diabetes increases the odds of a non-ischemic dilated cardiomyopathy (odds ratio: 1.75; 95% CI: 1.71-1.79), which has been associated with increased myocardial stiffness [5]. This entity of a unique diabetic cardiomyopathy (DMCMO) was originally proposed by Lundbeek [6], and subsequently confirmed at autopsy by Rubler et al in 1972 [7] in four diabetic patients who presented with heart failure (HF) and showed no evidence of hypertension (HT), CAD, or valvular disease. Rubler found evidence of myocardial hypertrophy, fibrosis, and microvascular changes in keeping with dilated cardiomyopathy. The development of myocardial dysfunction in diabetes has been attributed to the effects of lipotoxicity, microvascular AGEs deposition, microvascular rarefaction, and autoimmunity, all of which contribute to produce myocardial fibrosis and/or myocardial hypertrophy, the hallmarks of DMCMO [8] that are described below (Table 1).

Table 1. Contribution of pathophysiological mechanisms to the phenotypes of diabetic cardiomyopathy

Metabolic overload effects



Insulin resistance/hyperinsulinemia






Lipotoxicity & oxidative stress



AGEs deposition



Microvascular rarefaction 






Structural changes

Functional effects

Stimulus to ventricular remodeling

Endothelial dysfunction

Autoimmune cell death

Effects of microvascular dysfunction

Low NO availability

Hypoxic damage

Cardiomyocyte changes

Hypertrophy & stiffening

Stiffening & apoptosis

Myocardial matrix changes

AGEs +reactive fibrosis

AGEs + replacement fibrosis


Diastolic dysfunction

Systolic dysfunction


AGEs: advanced glycation end-products; HFPEF: heart failure with preserved ejection fraction; HFREF: heart failure with reduced ejection fraction; NO: nitric oxide

Adapted from Seferovic and Paulus [11].

Pathogenetic mechanisms of myocardial dysfunction in diabetes

Role of hyperglycemia

Hyperglycemia (Figure 1) increases the level of free fatty acids and growth factors in the myocardium, and causes abnormalities in substrate supply and utilization. Furthermore, it is toxic to the endothelial cell, causes mitochondrial damage [9] and induces oxidative stress and the release of superoxides, leading to abnormal gene expression, impaired production of nitric oxide (NO) and reduced distensibility of cardiomyocytes.

Hyperglycemia activates the renin-angiotensin system in myocardial cells (Figure 1) leading to cell growth and cardiac hypertrophy and these damaging effects can be further aggravated by oxidative stress. In addition, it stimulates collagen production and crosslinking as well as the production and deposition of non-enzymatic formation of advanced glycation end-products (AGEs) in the coronary microvasculature and the myocardial interstitium. AGEs trigger vascular inflammation, lower myocardial NO bioavailability and contribute to concentric LV remodeling. AGEs-induced crosslinking in collagen and elastin and result in increased myocardial stiffness and impaired cardiac relaxation in the diabetic heart that has been correlated with tissue Doppler indices of diastolic dysfunction [10].  

Figure 1. Cardiometabolic mechanisms in myocyte injury.

Insulin resistance/hyperinsulinemia

Insulin resistance (IR) affects a number of signaling pathways, causing cardiomyocyte hypertrophy, reactive interstitial fibrosis and expression of myocardial titin, all of which contribute to the reduction in cardiomyocyte distensibility. Central obesity (associated with IR) and microvascular rarefaction cause the release of proinflammatory cytokines and the generation of reactive oxygen species (ROS), leading to an inflammatory state in the coronary microvasculature with a reduction in nitric oxide (NO) bioavailability, increased vessel permeability and programmed cell death (apoptosis). This coronary microvascular endothelial dysfunction is thought to drive the development of myocyte hypertrophy with concentric remodeling and myocardial stiffening resulting in LV diastolic dysfunction (Figure 2) [11].

Figure 2. Transmitral and tissue Doppler in a normal subject and in a subject with diabetic cardiomyopathy.

Transmitral (upper panels) and tissue Doppler (lower panels) in a normal subject (A) and a subject with diabetic cardiomyopathy (B). Notice the reduced E’ compared to the A’ (tissue velocities) in (B). The calculated E/E’ratio was 8 in the normal and 15 in the diabetic subject.


Lipotoxicity and mitochondrial dysfunction

Insulin resistance results in a reduction of myocardial energy supply due to changes in substrate utilization from glucose to free fatty acids. It impairs myocardial glucose utilization and leads to excess fatty acid uptake into cardiomyocytes and eventually induces mitochondrial dysfunction, reduction in ATP availability and eventual cell death (lipotoxicity) [10]. The defect in myocardial energy production impairs myocyte contractile function, manifesting initially as diastolic function. Excess myocardial triglyceride content (myocardial steatosis) is demonstrable on proton-MR spectroscopy and has been correlated with echocardiographic left ventricular diastolic dysfunction as well as with longitudinal strain measurements [12].

Impaired coronary flow reserve in diabetes

Several factors: reduced NO production, AGEs- mediated stiffening of coronary media, and perivascular fibrosis, contribute to a reduction in coronary flow reserve. In addition, cardiomyocyte hypertrophy is associated with a reduction in capillary density (microvascular rarefaction) that leads to impaired myocardial perfusion, lowers NO bioavailability and contributes to myocardial stiffness that is typical of diastolic dysfunction. Tissue hypoxia results in the further release of ROS leading to myocyte cell death (apoptosis) and a decline in systolic function accompanied by remodeling with ventricular dilatation [11].

Microvascular disease and ischemia

Microangiopathy, characterized by thickening of the capillary basement membrane and the media of the arteriole, and associated with perivascular fibrosis, has been observed in autopsy samples of diabetic patients. Microaneurysms and spiral deformation of microvessels in the myocardium of type 2 DM, similar to retinal vascular changes of diabetes, have also been described. It has been shown that expression of vascular endothelial cell growth factor (VEGF) in the heart is downregulated in diabetes and that this downregulation is closely associated with the reduction in capillary density, apoptosis of endothelial cells and interstitial fibrosis [13].

The microangiopathy in diabetes explains why microalbuminuria/proteinuria is not only associated with nephropathy, but with widespread microvascular disease, including the heart. In the heart, diabetic autonomic neuropathy contributes to impaired autoregulation and lack of flow reserve, a factor that may account for increased rates of sudden cardiac death as well as a higher overall cardiovascular mortality rate in diabetic patients.


In type 1 DM subjects, cardiac myosin autoantibody and troponin T release are thought to trigger an immune response leading to myocyte cell death and replacement fibrosis. It has been proposed that this immune response, combined with the effects of worsening tissue hypoxia described above, probably provide the stimulus to the development of eccentric ventricular remodeling, resulting in ventricular dilatation and systolic dysfunction leading to the picture of dilated cardiomyopathy that has been described in type 1DM [11] (see below).

Development of myocardial dysfunction

As explained above, excess chronic oxidative stress produced by the release of ROS from the mitochondria and from proinflammatory cytokines and leucocytes, cause direct damage to plasma membrane cell organelles leading to myocardial damage. This may account for the increased oxidative injury resulting in the excessive morbidity and mortality after myocardial infarction in patients with diabetes when compared to patients without diabetes. Oxidative stress is the unifying factor in the development of diabetes-related cardiac complications, including atherosclerosis (Figure 1).

Myocardial damage in the absence of epicardial coronary disease (macrovascular) is most likely related to microvascular dysfunction, leading to diabetic cardiomyopathy (DMCMO).

Recent evidence has shown that insulin resistance-induced arterial stiffness in normotensive subjects contributes to diastolic dysfunction independent of age, blood pressure and body mass index. Together with activation of the sympathetic nervous system, the increase in afterload and impaired ventricular-vascular coupling as a result of arterial stiffness increase likelihood of heart failure development in these subjects [14].

Based on the fact that subjects with diastolic dysfunction have more LV hypertrophy and stiffness (attributed to AGEs deposition and stiff cardiomyocytes), while subjects with systolic dysfunction have a dilated left ventricle (following cardiomyocyte cell death and replacement fibrosis) [15], a new model of diabetic cardiomyopathy has been proposed. In a recent review Seferovic and Paulus [11] proposed that the deposition of AGEs in the myocardium and coronary microvascular rarefaction contribute to both diastolic and systolic dysfunction. Hyperglycemia, lipotoxicity, and hyperinsulinemia lead to myocyte hypertrophy, increased diastolic stiffness and the development of the restrictive/HFPEF phenotype, typical in obese type 2 DM patients (Figure 1). Autoimmunity with myocyte cell death leads to the dilated/HFREF phenotype that is more prevalent in type 1 DM patients. In this model, more selective involvement of endothelial cells in the coronary microvasculature drives the progression to diastolic dysfunction, while cardiomyocyte damage and ensuing myocyte loss trigger eccentric remodeling and decline in systolic function. (Table 1). 


Because of the structural and functional changes that occur in DMCMO, subjects develop functional changes early in the course of their disease. Diastolic dysfunction is the most frequent echocardiographic finding in both type 1 DM and type 2 DM patients and precedes the development of symptoms. The prevalence of asymptomatic diastolic abnormalities detected on TDI in a population-based study is high (23%) with over a third developing heart failure at 5 years [16]. In the early stages of type 1 DM, subclinical myocardial dysfunction is frequent, but clinical signs of heart failure are infrequent and developed in 3.7% of subjects over a 12-year follow-up period in one study [17]. Subjects who developed heart failure were older and had a longer duration of diabetes (35±9 years); they had higher blood pressure and a higher prevalence of albuminuria and retinopathy than those without heart failure. Diabetic patients with microvascular complications showed the strongest association with cardiomyopathy and this relationship paralleled the duration and severity of hyperglycemia [16]. These findings have been confirmed in a recent large case-controlled study from the Swedish national registry that showed a fourfold increase in the risk of heart failure in type 1 DM, especially in subjects with poor glycemic control and impaired renal function [18].

Clinical markers and implications for treatment

Asymptomatic diastolic dysfunction offers an opportunity for the primary prevention of heart failure in at-risk diabetic subjects if changes can be detected early and appropriate therapy instituted. Since there is little evidence to support the use of biomarkers in detecting the early stages of DMCMO, a strategy of screening asymptomatic diabetic subjects for impaired LV function with natriuretic peptides is not recommended. It is suggested that diabetic subjects at risk of developing DMCMO (such as those with atrial fibrillation, microalbuminuria/proteinuria, autonomic neuropathy, retinopathy, metabolic syndrome) should undergo non-invasive imaging [13] using tissue Doppler imaging and strain rate imaging as well as magnetic resonance spectroscopy, to enable early detection of DMCMO.

Subclinical changes of diastolic dysfunction has been demonstrated across the spectrum of IR and may present before the onset of diabetes, presenting an even larger disease burden for primary prevention of heart failure in diabetes [14,19]. There is evidence that glycemic control and lifestyle measures started earlier in the course of the IR spectrum (early diabetes, prediabetes and metabolic syndrome) could address the metabolic milieu before they have become established and may be beneficial. In this respect the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has shown that intensive treatment of hyperglycemia, targeting glycated hemoglobin levels below 7%, when initiated early in patients with short duration of diabetes and low cardiovascular risk, results in a significant 42% reduction of cardiovascular events in the long term [20].


The diagnosis of diabetic cardiomyopathy may be inferred when myocardial disease in patients with diabetes cannot be attributed to any other known cardiovascular disease. Metabolic and microvascular mechanisms contribute to the pathogenesis. At a subcellular level in the mitochondrion, oxidative stress, coupled with loss of normal microvessels and remodeling of the extracellular matrix, lead to an inflammatory state with decline in cardiomyocyte contractile function. The disease course consists of a hidden subclinical period, during which endothelial dysfunction drives the cellular and matrix changes that result in diastolic stiffness, while autoimmune responses result in myocyte loss and decline in systolic function.

Subjects at risk of DMCMO are those with a long duration of poorly controlled diabetes, evidence of microvascular disease elsewhere, atrial fibrillation and those with markers of insulin resistance such as central obesity and metabolic syndrome.


  1. Bell David SH. Heart Failure: A Serious and Common Comorbidity of Diabetes. Clinical Diabetes. 2004 April;22(2):61-65.
  2.  Parry HM, Deshmukh H, Levin D, Van Zuydam N, Elder DH, Morris AD, Struthers AD, Palmer CN, Doney AS, Lang CC. Both high and low HbA1c predict incident heart failure in type 2 diabetes mellitus. Circ Heart Fail. 2015 Mar;8(2):236-42.
  3.  The Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, O'Keeffe LM, Gao P, Wood AM, Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Håheim LL, Gillum RF, Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, Selmer R, Crespo CJ, Rodriguez B, Verschuren WM, Salomaa V, Svärdsudd K, van der Harst P, Björkelund C, Wilhelmsen L, Wallace RB, Brenner H, Amouyel P, Barr EL, Iso H, Onat A, Trevisan M, D'Agostino RB Sr, Cooper C, Kavousi M, Welin L, Roussel R, Hu FB, Sato S, Davidson KW, Howard BV, Leening MJ, Rosengren A, Dörr M, Deeg DJ, Kiechl S, Stehouwer CD, Nissinen A, Giampaoli S, Donfrancesco C, Kromhout D, Price JF, Peters A, Meade TW, Casiglia E, Lawlor DA, Gallacher J, Nagel D, Franco OH, Assmann G, Dagenais GR, Jukema JW, Sundström J, Woodward M, Brunner EJ, Khaw KT, Wareham NJ, Whitsel EA, Njølstad I, Hedblad B, Wassertheil-Smoller S, Engström G, Rosamond WD, Selvin E, Sattar N, Thompson SG, Danesh J. Association of Cardiometabolic Multimorbidity with Mortality. JAMA. 2015 Jul 7;314(1):52-60.
  4. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974 Jul;34:29-34. 
  5. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care. 2003 Oct;26:2791-5.
  6. Lundbaek K. Is there a diabetic cardiopathy? in: Schettler G. (ed.). Pathogenetische faktoren des myokardinfarkts”. Schattauer, Stuttgart, 1969, p.63-71.
  7. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972 Nov 8;30:595–602. 
  8. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006 Mar 17;98:596-605.
  9. Shenouda SM, Widlansky, ME Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA, Duess MA, Levit A, Kim B, Hartman ML, Joseph L, Shirihai OS, Vita JA. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011 Jul 26;124:444-53.
  10. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kühl U, Schultheiss HP, Tschöpe C. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and crosslinking in heart failure and normal ejection fraction. J Am Coll Cardiol. 2011 Feb 22;57:977-85.
  11. Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015 Jul 14;36(27):1718-27, 1727a-1727c.
  12. Rijzewijk L J, van der Meer RW, Smit, JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008 Nov 25;52:1793-9.
  13. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. 2013 Mar;18(2):149-66.
  14. Fontes-Carvalho R, Ladeiras-Lopes R, Bettencourt P, Leite-Moreira A, Azevedo, A. Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes. Cardiovasc Diabetol. 2015 Jan 13;14:4.
  15. van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006 Apr 25;113(16):1966-73.
  16. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes and pre-clinical diastolic dysfunction: a population-based study. J Am Coll Cardiol. 2010 Jan 26;55(4):300-5.
  17. Torffvit O, Lövestam-Adrian M, Agardh E, Agardh CD. Nephropathy, but not retinopathy, is associated with the development of heart disease in type 1 diabetes: a 12-year observation study of 462 patients. Diabet Med. 2005 Jun;22(6):723-9.
  18. Rosengren A, Vestberg D, Svensson AM, Kosiborod M, Clements M, Rawshani A, Pivodic A, Gudbjörnsdottir S, Lind M. Long-term excess risk of heart failure in people with type 1 diabetes: a prospective case-control study. Lancet Diabetes Endocrinol. 2015 Nov;3(11):876-85.
  19. Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, Kramer F, Krahn T, Klein RM, Barroso MC, Füth R. Insulin resistance and glycemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabetol. 2010 Oct 15;9:63.
  20. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30-Year Follow-up. Diabetes Care. 2016 Feb 9. pii: dc151990. [Epub ahead of print].

Notes to editor


Professor Datshana P. Naidoo, MD, FRCP

University of KwaZulu Natal,

Inkosi Albert Luthuli Central Hospital,

800 Bellair Rd,

Cato Manor 4091,


South Africa

Tel: +27 31 240 2207



Address for correspondence:

Professor Datshana P. Naidoo

Nelson R Mandela School of Medicine

University of KwazuluNatal

King George V Ave,



South Africa



Author disclosures: The author has no conflicts of interest to declare.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.