Second in a series on diabetes and the heart: diabetic cardiomyopathy - mechanisms and mode of diagnosis

KEYWORDS

Diabetic cardiomyopathy

Oxidative stress

Left and right ventricle

Abbreviations

AGEs - Advanced glycation end products

CAD - Coronary artery disease

CT - Computed tomography

DAG - Diacylglycerol

DCM - Diabetic cardiomyopathy

DM - Diabetes mellitus

HFPEF - Heart failure with preserved ventricular function

HFREF - Heart failure with reduced ventricular function

MRI - Magnetic resonance imaging

PET - Positron emission tomography

PKC - Phosphokinase cyclase

RAAS - Renin-angiotensin-aldosterone system

ROS - Reactive oxygen species

SPECT - Stress single-photon emission computed tomography

STE - Speckle tracking echocardiography

TDI - Tissue Doppler imaging

TTE - Transthoracic echocardiography

Introduction

Although it is perceived to be a complicated terminology, the concept of diabetic cardiomyopathy (DCM) was introduced long ago and has subsequently been widely reported and used by epidemiologists and clinicians across the globe. Diabetic cardiomyopathy refers to diabetes-associated structural and functional myocardial dysfunction not related to other confounding traditional factors such as coronary artery disease (CAD), hypertension, congenital heart diseases or valvular heart diseases [1-3]. Several postulated pathological mechanisms have been described and implicated in the pathogenesis of DCM in diabetic patients. The mechanistic changes in ventricular myocardial structure, calcium signaling mechanistic pathways and metabolism are some early defects reported in animal models; which may precede clinical manifestations of cardiac dysfunction in humans with DCM. Although transthoracic echocardiography (TTE) is regarded as a gold standard non-invasive imaging modality to evaluate ventricular myocardial dysfunction in the current era, DCM presents with subtle functional changes early in the course of the disease’s process which may be difficult to detect with conventional TTE; however, these early changes can be detected if specifically looked for. To date, the concept of “diabetic cardiomyopathy” remains controversial. As a result, no specific treatment strategies have been established to treat or prevent myocardial dysfunction in diabetes mellitus (DM). We opted to review the literature on ventricular myocardial dysfunction in DM. In particular, we shall review the basic pathogenic mechanisms and diagnosis of “diabetic cardiomyopathy”.

Pathological mechanism of diabetic cardiomyopathy

Diabetic cardiomyopathy has been previously differentiated into two phenotypes, namely restrictive or heart failure with preserved left ventricular ejection fraction (HFPEF) and dilated or heart failure with impaired or reduced left ventricular ejection fraction (HFREF). The phenotype-specific pathophysiological mechanisms for the DCM phenotypes proposed for left ventricular (LV) remodeling and dysfunction consist of coronary microvascular endothelial dysfunction and cardiomyocyte cell death for HFPEF and HFREF, respectively. Similarly, the preference of endothelial or cardiomyocyte cell compartments in DM patients could explain the development of DCM into two subtypes, restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus-induced metabolic derangements such as hyperglycemia, lipotoxicity, and hyperinsulinemia favor development of DCM with the restrictive/HFPEF type, which is more prevalent in obesity. In contrast, autoimmunity predisposes to the dilated/HFREF phenotype, which manifests itself more in type 1 DM. Finally, coronary microvascular rarefaction and advanced glycation end products (AGEs) deposition are relevant pathognomic abnormalities in both phenotypes.

Changes in molecular and cellular processes in diabetic cardiomyopathy

The molecular and cellular pathological mechanistic processes for DCM are summarized and presented in Figure 1.

Hyperglycemia

Hyperglycemia is the major pathogenic mechanism of DCM in patients with the diagnosis of DM. The formation of high levels of AGEs from the non-enzymatic glycation and oxidation of proteins and lipids are implicated as the instigating pathogens of high glucose-induced cellular injury in diabetes (Figure 1) [1]. To support this, autopsy reports have demonstrated high levels of AGEs in the myocardium and cardiac tissues of patients with DM [1].

Figure 1. Pathways leading to the development of diabetic cardiomyopathy. ACC: acetyl coenzyme A carboxylase; ACoA: acetyl coenzyme A; AGEs: advanced glycation end products; CE: cardiac efficiency; FA: fatty acids; FFA: free fatty acids; GLUTs: glucose transporters; MCD: malonyl coenzyme A; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; PKC: protein kinase C; PPARα: peroxisome proliferator-activated receptor alpha; TG: triglycerides [2, 5]

Cell survival and signaling pathways

Diabetes is associated with impairment in myocardial performance as a result of abnormalities in contractile and regulatory protein expression, and in cardiomyocyte calcium sensitivity. The cell survival and signaling pathways are presented in Figure 1.

Protein kinase cyclase activation

Hyperglycemia exerts its deleterious myocardial and cardiovascular effects through protein kinase C/diacylglycerol (PKC/DAG) signaling pathway, leading to cardiac fibrosis through activation of the connective tissue growth factor [1]. The activation of PKC/DAG pathways induces multiple changes in DCM which include reduction in tissue blood flow, enhanced extracellular matrix deposition, capillary basement membrane thickening and increased vascular permeability with alterations in neovascularization [1,4]. Left ventricular hypertrophy, myocardial and cardiovascular fibrosis and impaired LV function are some of the common cardiovascular manifestations of DCM. However, these changes were commonly reported in animal models, in the LV myocardium of study subjects with overexpression of PKC. In addition to the deleterious effects of PKC, adenosine monophosphate-activated protein kinase has also been reported in DM patients with cardiac dysfunction and decreased cardiac autophagy [1].

Lipotoxicity

Diabetic cardiomyopathy is characterized by significant deposition of lipofuscin demonstrated in transmural LV biopsies obtained from diabetic patients [5]. In addition, significantly increased myocardial triglyceride (TG) and cholesterol content have also been reported in the myocardial samples of DM patients [5], independent of circulating levels of TG in DM, and also in obesity, insulin resistance and impaired glucose tolerance. The increase in cardiac TG accumulation is often associated with diastolic but not systolic dysfunction. Type 2 DM which is most often associated with obesity leads to myocardial lipotoxicity that may in turn lead to cell death and subsequently cardiac dysfunction, particularly diastolic dysfunction [5]. An increase in myocardial fatty acid uptake and oxidation has also been reported in both human and animal subjects with diabetes [5]. The changes in the composition of endoplasmic reticulum (ER) membrane phospholipids have also been reported in lipotoxicity, which precipitate ER swelling and ER stress long-chain fatty acids, all interfere with the dynamics of plasma and mitochondrial membranes by altering phospholipid composition [5]. The saturated long-chain fatty acid, palmitate, is another substance which induces apoptosis in cardiomyocytes by diminishing the mitochondrial anionic phospholipid, cardiolipin. The isolated increase in myocardial lipid uptake is sufficient to precipitate cardiomyopathy in individuals with no documentation of DM or in those with biochemical evidence of hyperglycemia.

Oxidative stress

Oxidative stress plays a critical role in the pathogenesis of DCM, as increased oxidative stress is associated with lipid overload. Moreover, oxidative stress is increased in the cardiovascular system and hearts of patients with diabetes. Lipids, particularly free fatty acids, are important in generating reactive oxygen species (ROS), which are deleterious in DM patients (Figure 1) [1, 2, 5, 6]. In addition, diabetic hearts are characterized by increased cardiac lipid accumulation and mitochondrial free fatty acid oxidation, which play an important role in the mechanism of DCM [5]. This specifies the importance of cardiovascular and myocardial insulin resistance which may predispose cardiac mitochondria to ROS overproduction via mechanisms that remain to be elucidated. The augmented pathological mechanisms of ROS in myocardial injury are related to the interaction of ROS with other potential synergistic molecules including nitric oxide (NO). The end products of NO including nitrotyrosine species are increased in diabetic myocardial biopsies. In addition, increased ROS contribute to the switch in cardiac myosin heavy chain which could be detrimental in patients with long-standing DM [5].

Myocardial or interstitial fibrosis

Myocardial fibrosis has been previously described as one of the major pathological consequences of long-standing DM in diabetic hearts, which has been confirmed histologically in both experimental animals and humans models [7, 14].

Interstitial and perivascular fibrosis are pathological hallmarks of DCM [4, 5, 7, 14]. In addition, studies have reported collagen deposition around intramural vessels and also between the myofibers in diabetic heart, which signifies the importance of endomyocardial biopsy to exclude DCM in diabetic patients [5]. Diastolic dysfunction in diabetes has been correlated with pro-collagen type I carboxy-terminal peptide. This plays a crucial role in the pathological mechanism of myocardial fibrosis in diabetic patients with documented LV myocardial dysfunction [4, 5]. Extracellular fibrosis and collagen deposition which resembles LV myocardium of a human with type 2 diabetes, with an increase in transforming growth factor (TGFβ1) receptor II density in the myocardium has been reported in animal studies [5]. TGFβ is one of several cytokines in gene expression enhanced by diabetes [5].

Apoptosis

Apoptosis is an important component of various normal or pathological processes such as normal cell turnover, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Apoptosis is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. These mechanisms are highly complex and sophisticated, and involve an energy-dependent cascade of molecular events. 

Myocyte cell death correlates with fibroblast replacement which could lead to interstitial fibrosis, the pathway which is primarily mediated by TGFß [1, 6]. Even though a few potential mechanisms have been postulated regarding the development of DCM, myocardial cell death is considered primarily the result of the induction of cardiac oxidative stress. Studies analyzing samples obtained from atrial appendage of DM patients at the time of coronary angiography or full right heart catheterization revealed high levels of apoptotic and necrotic chemicals [5].

Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. Clinical and experimental evidence suggests that angiotensin II (Ang II), a component of RAAS, has detrimental effects on cardiac and vascular structures associated with other cardiovascular conditions such as systemic hypertension, coronary heart disease, myocarditis, and congestive heart failure, in addition to the effects on volume and electrolyte homeostasis. Although RAAS is an endocrine system, the cardiac and cardiovascular system, and several other important tissues possess some components of this system.

The RAAS is a well-recognized and extensively reported system with detrimental effects in patients with congestive heart failure. The role of RAAS activation in the development of DCM is a well-recognized postulate; however, more work still needs to be done to understand its pathological mechanism on both molecular and cellular levels in human subjects [2]. Although Ang II receptor density and mRNA expression have been reported in heart failure patients, these are also elevated in diabetic hearts [2]. Moreover, activation of the RAAS in diabetes has been reported as well as demonstrated to be associated with increased oxidative stress, cardiomyocyte and endothelial cell apoptosis and necrosis in diabetes [2, 4]. The activation of RAAS in diabetic hearts contributes to increased interstitial fibrosis, which is an important pathological entity leading to DCM and heart failure [2, 5].

Mitochondrial dysfunction

The mitochondrion is the site of respiration, generating chemical energy in the form of ATP by fuels with the assistance of molecular oxygen. Mitochondrion has its own circular DNA and reproduces independently of the original cell. It is able to produce energy and metabolites which are required by the host cell. Many of the critical metabolic steps of cellular respiration are catalyzed by enzymes that are able to diffuse through the mitochondrial matrix.

Studies have evaluated the morphological and functional capacities of mitochondria in DM and have shown changes in mitochondrial morphology, remodeling of the mitochondrial proteome and decreased respiratory capacity in DM [2, 5]. In addition, a significant increase in the number of mitochondria with pleomorphism from myocardial biopsies, reduced mitochondrial oxygen consumption and increased hydrogen peroxide emission in DM during mitochondrial functional assessment have also been reported [2, 5]. Apart from these biochemical changes, mitochondrial uncoupling has also been reported as an additional defect contributing to mitochondrial dysfunction and also to an increase in oxygen consumption with no compensatory increase in ATP production, resulting in further cardiac dysfunction in diabetic hearts [2, 5]. Mitochondrial ROS or lipid peroxides also play an important pathological role in activating uncoupling mechanisms of mitochondrial proteins in myocardial mitochondria [5].

Changes in biventricular cardiac function in diabetic cardiomyopathy

Impaired contractile reserve

Diabetes mellitus may induce cardiac contractile dysfunction, which is ascribed to multiple metabolic derangements, subsequently evolving into DCM (Figure 1, Figure 2). In addition, it is well established that DM is preceded by a variable period of abnormal glucose metabolism, which is associated with progressive insulin resistance and β-cell dysfunction (Figure 1). Moreover, extensive epidemiological evidence suggests that the metabolic disorder in diabetes precedes cardiac decomposition, leading eventually to cardiac dysfunction and overt heart failure.

Important mechanisms leading to reduced contractile reserves with subsequent diastolic and systolic dysfunction in DM include accumulation of AGEs, adipokines, impaired myocardial insulin signaling pathways, abnormal calcium homeostasis and lipotoxicity (Figure 1, Figure 2). Impaired cardiac performance after exercise has been implicated as a potential tool to detect early contractile dysfunction in patients with long-standing DM. Impaired exercise-induced augmentation reflects the impairment of myocardial sympathetic innervations.

Figure 2. The proposed cellular and molecular mechanisms ascribed to diabetic cardiac contractility dysfunction. AGEs: advanced glycation end products; ATP: adenosine triphosphate

Left ventricular diastolic dysfunction

Diabetes mellitus can cause detrimental changes within the cardiac structure and function, which may develop without evidence of atherosclerotic disease [8]. The LV diastolic dysfunction occurs as an earliest preclinical manifestation in DCM, before systolic dysfunction, which may evolve to symptomatic heart failure [8]. Doppler echocardiography imaging has emerged as an important non-invasive measure, which could easily reveal diastolic and systolic abnormalities [8, 9]. With the currently evolving advances in echocardiography, the accuracy in diagnosing LV diastolic dysfunction has improved significantly.

DCM is characterized by a disproportionate increase in LV mass and myocardial fibrosis as early myocardial complications of DM, manifested echocardiographically by diastolic dysfunction preceding abnormalities in systolic function [1, 4]. The diastolic dysfunction in DCM is characterized by increased ventricular wall stiffness and longer diastolic relaxation time, commonly at an early stage of the disease course. Tissue Doppler imaging (TDI) is more sensitive to detect LV dysfunction than conventional TTE [7, 9] and enables measurement of myocardial tissue velocities in the longitudinal direction, and peak early diastolic myocardial velocity which reflects global LV diastolic function [7].

Left ventricular systolic dysfunction

Although the pathogenesis of DCM is believed to be multifactorial, its exact causes remain to be determined, as numerous mechanisms such as hyperglycemia and hyperinsulinemia have been reported to play a pivotal role in its etiology (Figure 1, Figure 2) [6]. The other important postulates include abnormal changes in free fatty acid metabolism, increased oxidative stress, increased apoptosis, activation of the RAAS, autonomic neuropathy and, rarely, derangements in copper metabolism (Figure 1).

There has been discrepancy regarding detection of LV systolic dysfunction using LV fractional shortening (LVFS), attributable to load dependence and the relative insensitivity of LVFS in detecting subtle features of LV systolic dysfunction [4]. Currently, the more sensitive echocardiographic indices used to evaluate LV systolic function include TDI and speckle tracking echocardiographic strain rate imaging which consistently detect subclinical LV systolic dysfunction in DM [4, 7]. The subtle features of LV systolic dysfunction have previously been reported in DM with no evidence of concomitant CAD, primary LV myocardial dysfunction, congenital heart diseases or valvular heart disease, using tissue Doppler strain analysis, speckle tracking strain rate and measurements of peak systolic velocity [6]. The load-dependent and independent indices of LV systolic dysfunction using magnetic resonance imaging (MRI) or even invasive catheterization should be implemented in diabetic patients; however, these approaches have not been introduced routinely in current clinical practice.

Right ventricular dysfunction

The right ventricle (RV) has an important contribution to the overall cardiac function; however, data regarding RV function in DM are still rather incomplete. Diabetes mellitus, particularly type 2 DM, affects RV diastolic function in the presence of normal RV systolic function. Myocardial dysfunction in DM is not confined to the LV, but also involves the RV. The impairment of RV function encompasses both systolic and diastolic abnormalities as well [10]. Tissue Doppler imaging is a useful tool to detect early abnormalities of RV diastolic and systolic dysfunction in patients with DM [10-12]. The alterations in myocardial function may be attributed to ventricular interdependence as well as to the uniform effect of diabetes on the cardiac function [10]. Impairment in RV myocardial function is evident mainly by the application of TDI-derived indices, which tend to correlate significantly with the severity and complications of DM. Type 2 DM has been reported to influence the RV function in the absence of CAD, diastolic dysfunction, and pulmonary hypertension [12].

Although studies have reported the effect of diabetes on the functionality and geometry of the LV, data are still limited to show that diabetes is equally detrimental for the RV [7, 11]. Previous reports demonstrated ventricular-ventricular interaction in other pathological conditions. As a result, one should assume that in DCM patients RV will be influenced both by the LV, via a biventricular interaction mechanism, and by DM [7]. In animal models, studies have demonstrated that RV changes caused by diabetes are similar to those seen in the LV; however, the changes in geometry and remodeling are not similar [7]. In addition, the LV changes reported are characterized by myocyte hypertrophy without dilation, while the opposite is true with the RV.

Diagnostic approach

Diagnosis of DCM requires impairment of the glucose metabolism and a thorough approach to exclude other causes of ventricular dysfunction such as coronary, valvular, hypertensive, or congenital heart disease and infections such as viral myocarditis or toxins-induced, familial or infiltrative cardiomyopathies [7]. Although the chief cause of DCM is diabetes, the following risk factors which might exacerbate DCM need special attention: obesity, chronic high blood glucose, high blood pressure, dyslipidemia, smoking and alcohol consumption.

A relevant diagnostic approach should be employed to diagnose DCM, which should include a thorough history and a proper physical examination: relevant investigative approach including urine analysis to test for the presence of proteinuria, stress test, chest X-ray, electrocardiography and echocardiography (Table 1). Invasive measures should also be considered in some situations including myocardial biopsy, cardiac catheterization to evaluate cardiac chamber blood flow, pressures and coronary blood flow.

Table 1. Diagnostic approaches employed in the diagnosis of DCM.

Echocardiography

Although 2D-TTE is cheap and easily accessible, it is hampered by the inability to detect the subtle features of myocardial dysfunction in DM. Newer technologies, such as TDI, look promising as they apply a high-velocity low-amplitude filter to the myocardium, enabling an assessment of myocardial tissue velocities with relative ease [13]. The advantage of TDI over standard Doppler echocardiographic indices is that the results are independent of changes in ventricular pre-load. However, TDI is unable to differentiate between active contraction and passive movement of a myocardial segment.

Speckle tracking echocardiography (STE)

Strain and strain rate echocardiography is a unique technique for assessing myocardial systolic and diastolic function. STE has improved the quantitative assessment of regional or segmental wall motion and also the accuracy and reproducibility of test readings. STE is a new advanced imaging tool which is highly sensitive and reproducible to evaluate subtle features of ventricular myocardial dysfunction. Changes in ventricular systolic strain and strain rate have the potential ability to discriminate between different myocardial viability states. Measurement of the diastolic rate of deformation can differentiate physiological from pathological hypertrophy and restrictive from constrictive cardiomyopathy.

Contrast echocardiography

Contrast echocardiography is useful in current clinical practice as proper delineation of the endocardial border observed after contrast administration increases the clarity of the images and improves the results provided by the algorithms orientated to the assessment of ventricular motion. Moreover, direct assessment of myocardial blood flow and flow reserve is possible with contrast echocardiography, as microbubble contrast agents remain entirely within the intravascular space [13]. In any myocardial segment, contrast echocardiography denotes the status of microvascular perfusion within that region, which is important in patients with long-standing diabetes. Contrast LV opacification allows more accurate measurements of LV size and mass, and myocardial contrast echocardiography could provide an alternative non-invasive imaging method to evaluate the coronary anatomy to exclude CAD.

Three-dimensional echocardiography

Real-time three-dimensional echocardiography is used in conjunction with strain rates for further evaluation of regional LV systolic and diastolic function. A similar approach could be used to evaluate LV and RV function in patients with long-standing DM or DCM.

Computed tomography scan

Similarly, coronary artery calcification (CAC) can increase significantly in asymptomatic patients with long-standing type 2 DM compared with non-diabetic subjects [14-19]. The CAC score, derived originally from electron-beam computed tomography (CT) and more recently from multislice CT, correlates strongly with the presence and severity of histological and angiographic evidence of coronary atherosclerosis and conventional coronary heart disease risk factors, in particular C-reactive protein, reflecting stable and unstable plaques [15-17].

Magnetic resonance imaging

Cardiac MRI has recently emerged as a useful imaging tool for structural and functional myocardium disorders. It is also an important non-invasive modality to detect diastolic dysfunction and myocardial steatosis in DM and other pathological myocardial disease [14, 20, 21, 22]. Gadolinium-enhanced cardiac MRI has been useful in predicting major adverse cardiac events in diabetic patients with no prior history of ischemic heart disease. Although MRI is an emerging imaging and diagnostic technique that can both perform myocardial perfusion imaging (MPI) and assess myocardial flow reserve, it is also useful to assess diastolic function accurately without the limitations encountered with the application of echocardiographic indices for the assessment of diastolic function [14, 23]. Although coronary vessel lumenography is not routinely assessed in MPI, functional MRI has been applied both in the research field and, to a lesser extent, in the clinical arena [13].

Stress single-photon emission computed tomography

Stress single-photon emission computed tomography (SPECT) is a validated imaging tool providing information on the physiological significance of flow-limitation and sarcolemmal membrane integrity. It is also a cost-effective risk assessment tool for major adverse cardiac events in the general and diabetic populations. Moreover, LV function analysis by SPECT enhances its prognostic and diagnostic ability, particularly in the prediction of cardiac death. Reliable automatic algorithms of SPECT provide semiquantitative assessment of myocardial perfusion, LVEF, LV volumes, regional myocardial wall motion and thickening and diastology.

A simultaneous assessment of myocardial perfusion and LV function is important for the diagnosis of cardiomyopathy, particularly dilated cardiomyopathy, and could also be useful in DCM. SPECT can accurately assess both myocardial perfusion and ventricular function in diabetic patients, providing important information for their management. It also has high sensitivity in differentiating ischemic from non-ischemic cardiomyopathy [14]. Nevertheless, factors other than coronary narrowing could play a role in the pathogenesis of myocardial dysfunction in diabetic patients, including endothelial dysfunction, interstitial edema and fibrosis, coronary collateral circulation, impaired modulation of vascular growth and remodeling. As a result, SPECT could be helpful in these situations.

Positron emission tomography

Among the available imaging modalities, only positron emission tomography (PET) allows quantitative assessment of myocardial blood flow using radiotracer kinetics. However, the combined images by MRI and PET provide a high spatial resolution detection of myocardial metabolic abnormalities and currently represent the most valuable imaging analysis for diagnosis and prognosis in DM [13]. This recent sophisticated imaging modality is also indicated particularly in the case of diabetic patients with or at risk of CAD, since CT is currently considered very reliable in evaluating coronary artery calcium plaque burden and, with the aid of contrast agents, it provides an accurate evaluator of the coronary arterial system [13].

Conclusion

There is a large body of evidence to support a finding that DM is associated with detrimental myocardial and cardiovascular dysfunction, with subsequent development of DCM, which is a common pathological condition previously reported in multiple studies. Extensive reports have indicated that diabetic patients are prone to important perturbations at cellular and molecular levels, leading to structural and functional abnormalities in the myocardium and vasculature. Moreover, advanced imaging modalities in early detection of DCM in patients with long-standing DM must be facilitated in current daily clinical practice. This is an important area that needs further improvement. New insights into mechanisms related to DCM might lead to advanced novel treatment strategies in patients with DM.