Imaging Targets in Diabetic Cardiomyopathy: Current Status and Perspective

CANADIAN JOURNAL OF DIABETES. 2011;35(4):353-362.

ImagIng In DIabetIc carDIomyopathy | 353

ABSTRACTDiabetes is an independent predictor of cardiovascular disease and heart failure. Despite improvements in cardio-vascular health in recent years, the prevalence of type 2 diabetes continues to increase. Diabetic cardiomyopathy describes the changes in cardiac structure and function secondary to diabetes, independent of hypertension or coronary artery disease. Although several studies have referenced diabetic cardiomyopathy and the importance of screening patients with diabetes at increased risk of heart disease, the diagnostic and prognostic criteria remain poorly defined. Imaging modalities such as echocardiography, car-diovascular magnetic resonance and nuclear imaging may also provide means of distinguishing the markers and pro-gression of disease. Metabolic imaging may provide insight into pathogenesis and define imaging markers associated with these biochemical alterations. Here, we review the imaging approaches that may be used for researching the pathophysiologic markers of diabetic cardiomyopathy, with a focus on cardiovascular magnetic resonance imaging.

KEYWORDS: cardiovascular disease, cardiovascular magnetic resonance, diabetes, diabetic cardiomyopathy, imaging

RÉSUMÉLe diabète est un prédicteur indépendant de la maladie cardiovasculaire et de l’insuffisance cardiaque. Malgré les progrès réalisés ces dernières années au chapitre de la santé cardiovasculaire, la prévalence du diabète de type 2 continue d’augmenter. La cardiomyopathie diabétique désigne les changements de la structure et de la fonc-tion du cœur attribuables au diabète et indépendants de l’hypertension ou de la coronaropathie. Bien que plusieurs études aient fait mention de la cardiomyopathie diabétique et de l’importance du dépistage chez les patients atteints de diabète exposés à la cardiopathie, les critères du diagnos-tic et du pronostic demeurent mal définis. Les techniques d’imagerie comme l’échocardiographie, la résonance ma-

gnétique cardiovasculaire et l’imagerie nucléaire pourraient permettre de distinguer les marqueurs de la maladie et d’en déterminer la progression. L’imagerie métabolique pourrait permettre de mieux comprendre la pathogenèse et de définir les marqueurs d’imagerie associés à ces altéra-tions biochimiques. L’article passe en revue les techniques d’imagerie pouvant être utilisées pour la recherche des marqueurs physiopathologiques de la cardiomyopathie diabétique et met l’accent sur l’imagerie par résonance ma-gnétique cardiovasculaire.

MOTS CLÉS : maladie cardiovasculaire, résonance magné-tique cardiovasculaire, diabète, cardiomyopathie diabé-tique, imagerie

INTRODUCTION Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among people with type 2 diabetes (1). Diabetes is an independent predictor of CVD, and is known to portend an unfavourable prognosis, including accelerated development of atherosclerosis (2), autonomic dysfunction (3), increased tendency for thrombotic events and plaque rupture (4), and increased risk of mortality following myocardial infarction (5). Moreover, the major-ity of heart failure and CVD population studies have a conspicuously high representation of patients with type 2 diabetes (1,6). The increasing prevalence of type 2 diabe-tes—estimated to reach 300 million people worldwide by 2025—underscores the importance of primary and second-ary prevention approaches for associated CVD (7).

Diabetic cardiomyopathy (CMP) describes the observed changes in cardiac structure and function induced by the metabolic alterations associated with diabetes mellitus, without relevant ischemic heart disease (8). More spe-cifically, diabetic CMP is identified by impaired myocardial relaxation dynamics or diastolic dysfunction (9), left ven-tricular hypertrophy (LVH) (10), interstitial fibrosis (11) and microvascular dysfunction (12) in the absence of significant

anna r. Schmidt1,2 ba, matthias g. Friedrich1,2,3 mD FeSc Facc

1Stephenson cardiovascular mr centre at the Libin cardiovascular Institute of alberta, calgary, alberta, canada 2Departments of cardiac Sciences and radiology, University of calgary, calgary, alberta, canada.3montreal heart Institute, Department of cardiology, Université de montréal, montréal, Québec, canada

address for correspondence: Matthias Friedrich, Stephenson Cardiovascular Magnetic Resonance Centre,

1403 29th Street NW, Suite 0700 SSB, Calgary, Alberta, Canada T2N 2T9. E-mail: [email protected]

REvIEW

Imaging Targets in Diabetic Cardiomyopathy: Current Status and Perspective

354 | CANADIAN JOURNAL OF DIABETES

hypertension, coronary artery disease (CAD) and valvular disease (8,13). Accompanied by comorbidities such as obe-sity, these complications often precede the development of systolic dysfunction, hypertension, CAD and heart failure (1,8). The formal definition of diabetic CMP as a distinct clinical entity remains vague due to the lack of an accepted set of diagnostic criteria and information on subclinical CVD in the early stages of diabetes. Consequently, the inci-dence of diabetic CMP, although considered frequent, has not been established.

Of note, diabetic CMP appears to have an extensive preclinical course (Figure 1). Chronic, uncontrolled hyper-glycemia has been indicated as an important contributor to the multifactorial pathogenesis of diabetic CMP (13). Additionally, alterations in myocardial substrate metabo-lism precede lipotoxicity and increased oxidative stress–contributing pathological factors in diabetic CMP (14). Despite considerable research into the pathophysiology of diabetic CMP, cardiovascular complications are generally only detected once overt clinical disease has developed.

The American Diabetes Association recommends screen-ing patients with type 2 diabetes and 2 or more cardiac risk factors for CVD (15). In contrast, the results of the recently published Detection of Ischemia in Asymptomatic Diabetics (DIAD) trial indicated that screening of asymp-tomatic patients with nuclear imaging did not improve cardiac event rates (16). Nevertheless, the independent contribution of diabetes as a risk factor for CVD and the subsequent need for the early detection of subclinical CVD remain undisputed (17). Although cardiovascular mortal-ity has decreased in the general population, it has risen by 23% among women with diabetes over the past 3 decades (18), and autopsy studies have found that 75% of patients with diabetes had high-grade atherosclerosis, despite being asymptomatic before death (19). Accurate risk stratifica-tion in this population will allow primary care providers to pursue aggressive and targeted risk factor management to improve patient outcomes.

Despite the known and recognized contributions of dia-betes as a risk equivalent of CAD, there is no established

Figure 1. Metabolic changes in diabetes mellitus and their relationship to pathogenic factors of heart failure

Type 2 diabetes

Heart failure

Oxidative damage/apoptosis Steatosis Mitochondrial uncoupling

Systolicdysfunction

Diastolicdysfunction

Glucotoxicity

ROS ROS Impaired Ca++ handlingPKC AGEs LipotoxicityRAAS activation

Increased FA oxidationChronic hyperglycemia

Reduced GLUT expression Reduced glycolysis

Reduced glucose oxidation

Fatty acyl CoA TG accumulation

AGEs = advanced glycation end-productsCoA = coenzyme AFA = fatty acidGLUT = glucose transporterLVH = left ventricular hypertrophy

PKC = protein kinase CRAAS = renin-angiotensin-aldosterone systemROS = reactive oxygen speciesTG = triglyceride

Overview of the metabolic changes and pathophysiology underlying the clinical and subclinical manifestations of diabetic cardiomyopathy

Endothelial and microvascular dysfunction

Interstitial fibrosis, LVH

Impaired relaxation



standard diagnostic approach for diabetic CMP. Current assessment is often nonspecific, based on imaging findings of left ventricular (LV) dysfunction in the absence of other cardiomyopathies or hypertension to determine a probable diagnosis of diabetic CMP (20). In part, this may be due to incomplete knowledge about the complex pathophysiologyand progression of diabetic CMP. Additionally, current diagnostic techniques do not provide accurate prognos-tic information, and their impact on patient outcomes is unclear. Basic research, including metabolic imaging, may provide information on the contribution of metabolic alterations, while in vivo tissue characterization may help determine structural alterations and assess cardiac function and morphology.

Imaging is likely to play a dominant role because of its noninvasive nature and ability to investigate regional abnor-malities. Besides echocardiography, cardiovascular magnetic resonance (CMR) has a uniquely strong potential as a ver-satile, comprehensive, accurate and reproducible modality (20,21). This paper will review current knowledge relating to the cardiovascular manifestations attributed to diabetic CMP and imaging approaches to identify and study these findings, with a focus on CMR imaging.

PATHOPHYSIOLOGY OF DIABETIC CMP As mentioned above, diabetic CMP appears to have an exten-sive preclinical course, inducing significant changes in myo-cardial tissue characterization even before the onset of relevant symptoms. Alterations in myocardial substrate metabolism have been the subject of considerable research (14,22). In diabetes, the absolute or relative lack of insulin and subse-quent reduction in available intracellular glucose predicts a shift in substrate metabolism to favour fatty acid oxidation, further inhibiting glucose uptake and oxidation (22,23). This process has been associated with alterations in LV structure and function through the accumulation of triglycerides and mitochondrial reactive oxygen species (ROS) production, yielding lipotoxicity, increased oxidative stress and apoptosis (14,23). Fatty acid metabolism is also less oxygen-efficient, leading to decreased cardiac efficiency (24).

Chronic hyperglycemia is considered to be an important contributor to the multifactorial pathogenesis of diabetic CMP (25,26). Optimizing glycemic control is therefore a primary therapeutic target for reducing CVD risk in patients with diabetes (25,27). Hyperglycemia contributes to myo-cardial collagen deposition and interstitial fibrosis through increased levels of advanced glycation end-products (AGEs) (14,26). AGEs can form irreversible cross-links with struc-tural proteins such as collagen, augmenting LV stiffness and cardiac dysfunction (28,29). Impaired calcium handling and cellular efflux may further contribute to impaired relaxation, or diastolic dysfunction (30).

The pro-atherogenic biochemical milieu associated with type 2 diabetes also contributes to microvascular dysfunction through increased protein kinase C activation, mitochondrial ROS production, oxidative stress, reduced nitric oxide pro-duction and, therefore, impaired vasodilatation (12,16,31). ROS may further react with nitric oxide to decrease bioavail-ability and impair vasodilation (32). Microvascular function is widely accepted as an early marker for atherosclerosis and associated diseases, and is therefore considered an important subclinical alteration in diabetes (31,32).

IMAGING TARGETS IN DIABETIC CMPWhile the pathophysiology of diabetic CMP has yet to be fully elucidated, a number of cardiovascular imaging targets have already been identified. Current imaging approaches are able to assess some of these myocardial changes as diag-nostic markers (see Table 1).

LVhAs early as 1974, the Framingham Heart Study found increased LV mass by echocardiography in women with type 2 diabetes independent of age, cholesterol or hyperten-sion (33). Increased LV mass is considered to be an early manifestation of clinically significant LVH, and LVH is an important indicator of CVD prognosis (34). The causes and mechanisms of LVH are poorly understood, and the predic-tive value of LVH for complications related to diabetic CMP is not known.

Echocardiography is an inexpensive, readily available and safe imaging method; it is however, operator-dependent and has inadequate acoustic access, which may be particularly limited in obese patients (35). Although standard echocar-diography methods are routinely used for LVH assessment, the accuracy and reproducibility of quantitative echocar-diography data are limited compared to CMR (36). Greater inter-observer variability also makes echocardiography less

Table 1. Diagnostic imaging targets in diabetic CMP

Left ventricular hypertrophy

• Increasedcardiacmass

Diastolic dysfunction

• Impairedrelaxation• Reducedcompliance

Interstitial fibrosis

• Regionalfibrosis• Diffusefibrosis

Microvascular disease

• Endothelialdysfunction• Reducedvasodilatorycapacity• Reducedcapillarydensity• Autonomicneuropathy• Increasedvascularpermeability• Basalmembranethickening

Metabolic alterations

• Triglycerideaccumulation• Reducedglucoseuptake

CMP = cardiomyopathy


relaxation and compliance (20,43) and have been used to detect early manifestations of diabetic CMP in 47% to 75% of otherwise asymptomatic patients with diabetes (9,44). Most studies in diabetes use transmitral Doppler imaging of transmitral flow velocities; the ratio of early (E) to late (A) maximal velocity—or E/A—serves as a marker of LV relax-ation (9,41). However, transmitral Doppler is dependent on pre-load conditions and is therefore less reproducible (41,43). Tissue Doppler imaging (TDI) echocardiography may also be used to assess diastolic function by measur-ing tissue rather than flow velocities, and it is believed to be more pre-load independent than transmitral Doppler echocardiography (9,43). TDI echocardiography is there-fore able to detect abnormal diastolic function even in the presence of normal E/A ratio with transmitral Doppler measurements (pseudonormalization) (41). The use of echocardiography to visualize left atrium size as an indicator of diastolic dysfunction has also been suggested, although studies in patients with diabetes are lacking (13,45).

LV function patterns can also be assessed by 2D speckle tracking echocardiography (STE). Tracking the movement of myocardial tissue, STE is used to determine longitudinal, radial and circumferential contraction and relaxation pat-terns (46). Using 2D STE to evaluate strain and strain rate (SR), Nakai and colleagues observed diastolic dysfunction and subclinical LV longitudinal dysfunction in asymptomat-ic patients with diabetes who had preserved systolic function (46). They also determined that reduced longitudinal strain correlated with duration of diabetes, and they suggested 2D STE as a method for detecting subclinical disease in people with diabetes (46). Another study examining strain and SR confirmed abnormal functional patterns as assessed by STE (47). The authors found evidence of subclinical myocardial systolic and diastolic dysfunction with impaired LV longitu-dinal strain and SR, despite normal LV structure and systolic function (47), They concluded that a diagnosis of diabetes mellitus was an independent predictor of subclinical LV dysfunction (47). Further research is required to clarify the accuracy and clinical role of strain imaging in diabetes.

CMR can measure and evaluate similar markers for dia-stolic function and flow; parameters and analytical tools, however, have not been standardized. More recent CMR techniques have applied strain analysis for assessing dia-stolic function (48), but large data sets are even more rare than for echocardiography. CMR is also able to assess strain in the radial, circumferential and longitudinal motion axes, and to acquire 3D strain data (48,49). This is done with the use of myocardial “tagging,” a technique that magnetically imprints a grid or striped pattern on the myocardium at end-diastole and allows for quantitative evaluation of the subsequent deformation (41,49). In a study to assess LV function and SR in type 2 diabetes, echocardiography TDI

reproducible and, therefore, less valuable for follow-up studies (35,36). Standard techniques such as M-mode and 2-dimensional (2D) echocardiography calculate function and morphological parameters using geometric assumptions of ventricular shape (37). Three-dimensional (3D) echocar-diography, although more accurate and without geometric assumptions, remains less reproducible than CMR, with a limited acoustic window, poorer contrast and myocardial border definition (35,37).

CMR is considered the gold standard for the noninvasive assessment of LV mass and volumes. CMR does not rely on geometric assumptions for morphological and func-tional calculations, and it has high spatial resolution and myocardium-to-blood contrast (36,37). CMR uses 3D data of circumferential, longitudinal and radial planes through-out the cardiac cycle and at multiple levels of the heart (35,38). The low inter-observer variability, strong accuracy and reproducibility of CMR make it a practical option for follow-up studies (38).

CMR studies of LVH in a diabetes population are lim-ited, although CMR imaging has been used to visualize wall thickness and LV mass in the recent Framingham Offspring Study (39). The researchers found that insulin resistance and glycemic profile were both independently correlated with changes in cardiac structure and LV remodelling (39). The Multi-Ethnic Study of Atherosclerosis (MESA) found similar results using CMR, correlating glycemic category (normal, impaired fasting glucose, type 2 diabetes) with LV mass (40). Although LVH is considered one of the defin-ing manifestations of diabetic CMP, it has most often been associated with more advanced stages of disease and is dif-ficult to distinguish from other causes, such as hypertension (20,39). Therefore, although important to a diagnosis of diabetic CMP, the value of LV mass quantification for iden-tifying early, subclinical stages of diabetic CMP appears to be limited. Nevertheless, the prognostic significance of LVH has been well established, and LV mass remains an impor-tant endpoint in the evaluation of diabetic CMP (10,34).

Diastolic dysfunction The mechanisms and phenotypes of diastolic dysfunction are not well understood and depend on several factors, including atrial pressure, myocardial compliance and hemodynamic status (41). Well-accepted diagnostic targets have yet to be identified, but markers for diastolic dysfunction have been frequently identified in heart failure and may therefore be useful (42). In a 5 year follow-up study, patients with type 2 diabetes and preclinical diastolic dysfunction had a 37% probability of developing heart failure (42).

Echocardiography has been widely used for detecting abnormalities of diastolic function in patients with type 2 diabetes (9,43,44). Proposed markers target impaired LV



and SR imaging—as well as 3D SR imaging with CMR tag-ging—were used (50). The authors found that diastolic and systolic SRs were depressed in patients with diabetes and diastolic dysfunction, despite preserved LV ejection fraction (50). While promising, tagging has not become clinically routine, and analysis is time consuming; furthermore, long-term follow-up and outcome data are not yet available.

The progression from diabetic CMP to heart failure has been reported to occur secondary to diastolic dysfunction (42), although it is not clear whether such a transition or progression is inevitable or even frequent. Reduced systolic function, however, seems to be associated with later stages of diabetes, and is correlated with high glycated hemoglobin levels and poorer glycemic control (51). Although both CMR and echocardiography can accurately detect LV ejection frac-tion as an indicator of systolic function, CMR is considered the gold standard because of its more robust image quality and unrestricted image planes (35).

Interstitial fibrosis A notable and frequently observed pathological finding in diabetic CMP is interstitial fibrosis (11). The accumulation of extracellular matrix secondary to persistent hyperglyce-mia leads to reduced ventricular compliance and subsequent impairment of LV filling (29). Increased deposition of both type I and type III collagen have been detected in the myo-cardial tissue of patients diagnosed with diabetes (52). This accumulation of fibrotic tissue may contribute to diastolic dysfunction due to decreased compliance and myocardial stiffening (28,29).

Although biopsy studies have provided documentation of interstitial fibrosis in this patient group, they are not routinely used for clinical purposes due to their invasive nature (52,53). Echocardiography studies have employed calibrated integrated backscatter to estimate the degree of fibrosis, using transmitral Doppler and video densitometry to examine the magnitude of cyclic backscatter variations (54,55). These studies found increased myocardial reflectiv-ity in the myocardium of patients with diabetes, indicating an increase in myocardial collagen deposition (54,55). Accuracy and reproducibility, however, have not been stud-ied in sufficiently large samples, and the specificity of these findings appears to be limited (21,29).

The clinical utility of serologic assessment of collagen markers for assessing myocardial fibrosis appears promising, but these markers are not specific to the myocardium (56). Nevertheless, correlating systemic markers with imaging findings of myocardial changes in the early stages of diabetes may provide additional clinically useful information when screening patients.

CMR imaging methods used for the clinical assessment of myocardial fibrosis include late gadolinium enhancement

for focal regional fibrosis (57,58) and T1 mapping for diffuse

fibrosis (59,60). The delayed washout of interstitial contrast agents such as gadolinium complexes (due to the increased volume of distribution in fibrotic myocardium) is used to visualize regions of fibrosis in a variety of clinical popula-tions, with results closely matching histopathology findings (57,58). Both late gadolinium enhancement and T

1 have

also been used in patients with heart failure, and have been correlated with LV diastolic dysfunction (59,60). Prospective data with larger samples are lacking, however, and the sensi-tivity of T

1 mapping to detect early stages of diffuse myocar-

dial fibrosis in diabetes is presently unknown (29).

microvascular disease The development of CAD is pronounced in people with dia-betes (2). Importantly, microvascular dysfunction secondary to metabolic alterations precedes clinically significant CAD (31,61). These early manifestations of microvascular dys-function include endothelial dysfunction, reduced vasodila-tory capacity, capillary rarefication, autonomic neuropathy, increased vascular permeability and basal membrane thick-ening (31,32). Data are scarce for detecting microvascular dysfunction as an early manifestation of diabetic CMP, and diagnostic techniques are often insufficient to differentiate it from CAD.

Echocardiography can been used to measure myocar-dial blood flow and coronary flow reserve for the functional assessment of coronary circulation (62,63). Myocardial contrast echocardiography and Doppler flow measurements have shown that coronary flow reserve and vasodilatory capacity in response to stress are significantly reduced in patients with type 2 diabetes, even in the absence of coro-nary stenosis (63). The limited acoustic window often con-fines echocardiography studies of sufficient quality to the LAD territory, limiting their clinical applicability.

Myocardial perfusion imaging (MPI) uses exercise or pharmacological stress to assess for ischemia-induced ven-tricular dysfunction (64). Intravenous injection of vasoac-tive substances, such as adenosine, can be used to evaluate vasodilatory response (64). MPI has been used with various imaging modalities and applied in patients with diabetes (16). It is suitable for identifying regional perfusion deficits caused by severe coronary artery stenosis, which are visual-ized by a delayed or reduced inflow relative to normal myo-cardium during or immediately after physical exertion or pharmacological vasodilation (64,65). Microvascular disease in diabetes, however, would likely affect the myocardium more diffusely, and therefore, a method measuring absolute myocardial blood flow may be advantageous, although not used in clinical practice (31).

CMR stress perfusion studies with adenosine accurately detect regional ischemia as well as diffuse, subendocardial


perfusion deficits (65) (Figure 2). Although there are reports of the use of adenosine CMR to assess microvas-cular response in patients with syndrome X (66) and in patients with suspected small vessel disease (67), the utility of perfusion imaging for assessing microvascular function in patients with diabetes has yet to be established. It is important to keep in mind that adenosine primarily allows for the evaluation of smooth muscle vasodilatory capacity (64). However, perfusion defects in diabetes, as detected by a globally reduced hyperemic response to adenosine, may also be due to endothelial dysfunction and impaired nitric oxide production (31,61).

Single-positron emission computed tomography (SPECT) MPI has been used in patients with diabetes in several trials, including the recent DIAD trial (16). In this multicentre, randomized trial of over 1000 asymptomatic patients, the mean event rate of cardiac death or nonfatal myocardial infarction and the positive predictive value of a positive screening were low. Researchers concluded that without sig-nificant reduction of cardiac events, screening with MPI is seemingly unnecessary (16). Although the authors reported the results of each test to each patient’s primary care physi-cian, this trial did not include treatment and was also lim-ited by a low event rate. Therefore, the potential impact of screening methods on treatment and subsequent outcome remains to be studied further. Moreover, although SPECT is able to determine the presence and extent of perfusion defects (Figure 3), radiation exposure and a lower spatial resolution compared to CMR and computed tomography should be noted (64,65).

CMR has been applied for the quantitative assessment of vascular function using various contrast-enhanced and non-contrast approaches (67,69). So far, these applica-tions, however, have not addressed coronary vascular dysfunction in diabetes. More recently, blood oxygen-level dependent (BOLD)-CMR has been used to assess micro-vascular function, based on the paramagnetic properties of deoxyhemoglobin (69). Using the paramagnetic proper-ties of deoxyhemoglobin as an endogenous contrast agent, BOLD-CMR is able to directly assess myocardial oxygen-ation without the use of exogenous contrast agents or sur-rogate markers (69,70). This method has been shown to quantitatively assess myocardial perfusion and oxygenation, with results comparable to established positron emission tomography (PET) (71). Because oxygenation is altered by pharmacologically induced changes of blood flow, this approach may be suitable for assessing peripheral vascular function. Preclinical data assessing peripheral endothelial function with BOLD-sensitive CMR are promising (69) and may prove useful for assessing endothelial and vasodilatory function in the myocardium of patients with diabetes.

Figure 2. CMR adenosine stress perfusion image

CMR perfusion images at rest and stress. (A) Rest image of myocardium ofhealthycontroland(B)ofapatientdiagnosedwithtype2diabetes;(C) stress perfusion image of healthy control without visually discernible reductionsinsignalintensity;(D)stressperfusionimageofapatientwithdiabetes. The darker inner ring in the left ventricle during adenosine infu-sion shows circumferentially reduced contrast uptake, indicative of a sub-endocardial perfusion defect and non-ischemic microvascular disease.

CMR = cardiac magnetic resonance

Figure 3. SPECT myocardial perfusion imaging (68)

Perfusiondeficitinapatientdiagnosedwithtype2diabetesasassessedby adenosine Tc-99m Sestamibi SPECT myocardial perfusion imaging: anterior perfusion deficit (arrow) with spontaneous resolution

SPECT = single-positron emission computed tomography

Reproduced from (64) with kind permission from Springer Science+BusinessMedia.

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metabolic alterationsMetabolic imaging would provide valuable insight into the pathogenesis of diabetic CMP and contributions of meta-bolic alterations in glucose and fatty acid metabolism, as well as secondary changes due to repeated episodes of hyperg-lycemia. Metabolic imaging is possible with both PET and, though less well established, magnetic resonance imaging (72,73). Relevant diagnostic targets of metabolic imaging include glucose metabolism compounds, triglycerides and high-energy phosphates. For example, cardiac steatosis, although not clinically evaluated, represents an important area of research in diabetic CMP and may contribute to dia-stolic dysfunction (72,73).

In a recent study, abnormal metabolism was detected in insulin-naive men with diabetes (73). When compared to controls, patients showed a decreased rate of myocardial glu-cose uptake, increased fatty acid uptake and oxidation, and decreased fatty acid esterification (73), indicating myocardial insulin resistance and increased fatty acid metabolism. It remains to be studied how early during the course of diabetic CMP these changes occur and when they could be detected.

PET 18-fluorodeoxyglucose (18FDG) imaging is often used to assess myocardial viability based on glucose uptake and metabolism (74). However, in diabetes, myocyte glucose uptake is significantly reduced, and consistent and repro-ducible metabolic imaging becomes difficult (74). A general challenge to metabolic studies is the uncertainty caused by diurnal and day-to-day variability. Persistent alterations, such as structural changes of the myocardium, may be more suitable and robust as early disease markers.

CMR may use various nuclei as signal sources, includ-ing hyperpolarized 13C, which allows for assessing pyruvate metabolism. It has been suggested that combining 1H MR imag-ing with the 13C technique may provide valuable insight into alterations of cardiac energetics and metabolism, as associated with functional changes in heart failure (74). This approach could be used to identify metabolic alterations in the diabetic heart, and correlated with structural and functional changes discussed above. Published studies, however, are lacking.

Another imaging approach, magnetic resonance spectros-copy (MRS), has been used to quantify triglyceride accu-mulation in vivo in the myocardium (72,73), calculated as a percentage of the water content in the myocardium (75). Studies by McGavock and colleagues (72) and Rijzewijk and colleagues (76) have used 1H MRS to quantify triglyceride accumulation in diabetic cardiomyocytes, which may con-tribute to the diastolic dysfunction observed in diabetic CMP (75,76). This technique is nevertheless very demanding, acquisition times are long and spatial resolution is limited. As such, a widespread application of MRS for the study of diabetic CMP and cardiac steatosis appears unlikely for the near future.

CLINICAL POTENTIAL OF IMAGING MODALITIES IN DIABETIC CMP When considering the accelerated pathophysiological pro-cesses leading to heart failure and ischemic heart disease in diabetes, imaging becomes important for risk stratification and aggressive risk factor management (17,77). CMR imag-ing allows for identification of the structural and functional alterations in the heart secondary to diabetes, yet its specificity to diabetic CMP varies between diagnostic targets (Table 2). Markers for abnormal myocardial glucose metabolism and specific downstream structural changes appear to be useful for understanding the interaction between molecular and structural abnormalities. Advanced imaging modalities may provide valuable tools for assessing diabetic CMP, because regional distribution patterns of functional and structural abnormalities can be differentiated from infiltrative disor-ders and, most importantly, CAD. Such information, how-ever, will have to be put into the context of clinical history and serological markers. Clinical trials with prospective follow-up data will be required to test these approaches for their utility and effectiveness as primary prevention tools.

Echocardiography is the most widely used imaging modality and offers tools for assessing diastolic function as an early marker. However, its value in differentiating diabetes from other causes of functional abnormalities, and for detecting subclinical disease, is limited. Nuclear imaging provides accurate and precise information about metabolic imaging and perfusion defects. Nevertheless, in addition to the high cost of nuclear imaging, the exposure to ionizing radiation should be a deterring factor for its use as a screening tool.

CMR shows considerable promise, as it is able to evalu-ate the full spectrum morphologic, functional and meta-bolic changes in the diabetic heart. Although screening of all patients with type 2 diabetes is unrealistic, CMR may serve as a comprehensive and cost-effective tool to further research the progression of diabetic CMP, and is suitable for clinical application in well-defined subjects at risk for CVD. Specific protocols, however, have yet to be developed and tested.

SUMMARYAlthough of prognostic significance, diabetic CMP as a dis-tinct clinical entity is still poorly understood and escapes standard diagnostic approaches. Because of its increasing impact on cardiovascular health in our society, new and standard diagnostic approaches must be identified. Available imaging techniques for assessing the early stages of the disease include echocardiography, SPECT, PET and CMR. Whereas echocardiography is most suitable for assessing functional abnormalities, PET is more sensitive in detect-ing early metabolic markers. Although SPECT can be used


AUTHOR CONTRIBUTIONSAS was the lead author of this review, with MF in a supervi-sory role, contributing through edits and revisions.

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to assess perfusion abnormalities, CMR would—within a single scan—allow investigation of both functional and metabolic alterations. Additionally, it can be used to visual-ize structural changes of the myocardial tissue.

More clinical studies are required to clearly define the utility of these approaches for an individualized primary prevention strategy and to identify the early stages of dia-betic heart disease. In addition, comprehensive noninvasive imaging strategies such as CMR may also prove valuable in assessing the efficacy of therapy in patients with established end-organ dysfunction.

AUTHOR DISCLOSURESAnna Schmidt is a PhD candidate at the University of Calgary and has been supported by the Canadian Diabetes Association, Canadian Institutes of Health Research and Tomorrow’s Research Cardiovascular Health Professionals (TORCH) program of Alberta. Matthias G. Friedrich is scientific advisor and shareholder of Circle Cardiovascular Imaging Inc., Calgary, Alberta, Canada.

Table 2. Imaging modalities and techniques in diabetes mellitus

LVH

Diastolic dysfunction

Interstitial fibrosis

Microvascular disease

Relevant coronary artery stenosis

Limitations

Echo Standard2Decho•M-mode •

Transmitral •DopplerTDI•STE•Colour M-mode•Pulmonary venous •blood flow analysis

(Calibrated •integrated backscatter)

(First-pass •perfusion echo)

Physical or •pharmacological stress echo

Acoustic window•Inconsistent•image qualityInterobserver•variability

CMR Standard CMR • Flow-sensitive •CMRTagging•Tissue velocity •mapping

LGE for regional •fibrosis(T• 1 mapping for diffuse fibrosis)

(First-pass perfu-•sion CMR)BOLD-CMR•

First-pass •perfusion CMRPharmacological •stress CMR(Coronary MR •angiography)

Contraindications •(pacemakers, defibrillators, severe claustrophobia)Availability•

CT Standard CT• — (Contrast •enhancement)

(First-pass perfu-•sion CT)

CT coronary •angiography

Radiation•

SPECT — — — (Perfusion imaging)• Perfusion SPECT• Radioactive •tracersLimited spatial •resolution

PET — — (Perfusable tissue •index)

(Perfusion imaging)• FDG-PET• Radioactive •tracersLimited spatial •resolutionAvailability•Cost•

Bracketsareusedtoindicatethattheclinicalutilityofthespecifiedimagingapplicationhasnotbeenwidelydemonstrated

BOLD=blood-oxygenationleveldependentCMR = cardiac magnetic resonanceCT = computed tomographyEcho = echocardiography FDG=fluorodeoxyglucoseLGE = late gadolinium enhancement

LVH = left ventricular hypertrophyMR = magnetic resonancePET = positron emission tomographySPECT = single-photon emission computed tomographySTE = speckle tracking echocardiography TDI=tissueDopplerimaging



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Imaging Targets in Diabetic Cardiomyopathy: Current Status and Perspective