Metabolic and Molecular Imaging of the Diabetic Cardiomyopathy

Abstract

The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.

Keywords: diabetes mellitus; diabetic cardiomyopathies; fibrosis; metabolism; molecular imaging.

Figure. 1.

Myocardial metabolic remodeling – beyond substrate flux. Several processes are modulated by metabolic perturbations, such as those that occur with obesity, DM and inborn errors of metabolism. Among these are shown clockwise from upper left: 1) Lipid accumulation. Lipid droplets within the myocardium are shown on this electron micrograph (reproduced with permission)(133); 2) Energetic abnormalities: ³¹P spectra from a normal control (left) and a patient with Barth syndrome (right) (reproduced with permission) (134); 3) Oxidative stress: Increased hydrogen peroxide production in the myocardium of wild type diabetic (streptozotocin [WT/STZ]-treated) animals as compared with wild type controls (WT/C); 4) Inflammation: CD68 tissue levels in rat heart induced by high fat feeding (HFD); 5) Apoptosis: Increased caspase-3 levels in hyperglycemic (HG) conditions compared with normoglycemic (NG) and osmotic control (OSM) conditions, and with treatment with liraglutide + HG. (reproduced with permission)(135); 6) Infarct size: Infarction/necrosis in human heart; 7) Fibrosis: Fibrosis in human heart; 8) Gene expression: Increased mRNA expression of acyl-CoA accentuated by fasting in mice that overexpress PPARα in mouse heart. Center) A global longitudinal strain map showing diminished (less negative) strain in a patient with decreased LV function. Normal strain is depicted by dark red; lighter pink = lower, less negative strain, and blue indicates dyskinesis.

Figure 2:

Myocardial FA utilization measurements. (A) Myocardial FA utilization uptake rate (MFAU_UpR), (B) Myocardial FA esterification uptake rate (MFAE_UpR) and (C) Myocardial FA oxidation uptake rate (MFAO_UpR) in untreated (ZDF; N=6), Metformin-treated (ZDF+MET; N=6) and Rosiglitazone-treated (ZDF+ROSI; N=6) ZDF rats at week 14 (W14) and week 19 (W14). MFAE_UpR, MFAO_UpR and MFAU_UpR represents the intrinsic capacity of the heart to oxidize and utilize FAs, respectively, independent of the concentration of free FAs in plasma ([FFA]_P) while MFAO is derived by the relation MFAO=MFAO_UpR*[FFA]_P. *, denotes that the treatment is significantly better than no treatment; †, denotes that the Rosiglitazone treatment is significantly better than Metformin treatment. A P<.05 was considered significant. All resulted are presented as mean ± 1 SD. Reproduced with permission.(93) Illustration credit: Ben Smith.

Figure 3:

Myocardial ketone body utilization in GK rats. The detection of [3-¹³C]acetoacetate, [1-¹³C]acetoacetate, [5-¹³C]glutamate, and [1-¹³C]acetylcarnitine over 2 minutes upon [3-¹³C]acetoacetate injection in (a) controls and (b) GK rats. (c) Representative cardiac ¹³C MR spectra from a control and a GK rat. The quantification of (d) [5-¹³C]glutamate + [1-¹³C]acetylcarnitine, (e) [5-¹³C]glutamate, (f) [1-¹³C]acetylcarnitine, and (g) [3-¹³C]β-OHB. Metabolic conversion rates for (h) [3-¹³C]acetoacetate to [5-¹³C]glutamate exchange and (i) [3-¹³C]acetoacetate to [1-¹³C]acetylcarnitine exchange. Data are means ± SD (except for (a) and (b): mean ± SEM), and normalized to [3-¹³C]acetoacetate (controls n = 10, GK n = 9; except for (i) GK n = 8). AcAc: acetoacetate, acc: acetylcarnitine, cit: citrate, glu: glutamate. *P < 0.05, **P < .01, ***P < .001 vs. controls. Reproduced with permission.(98)

Figure 4:

(Left) Representative examples of hyperpolarized MR spectra from both a healthy control and a subject with T2DM in both the fasted and fed states (Control; A & C, T2DM; D & F), with ¹³C containing downstream metabolites labelled (A). The 1-¹³C- bicarbonate resonance is visibly reduced in the subject with T2DM with increases seen during feeding in both controls and subjects with T2DM. Time courses of the normalized signal amplitudes of downstream ¹³C-labelled metabolic products of administered 1-¹³C-pyruvate (shown in blue), in both a control and a subject with T2DM are also shown (B & E). (Right) Plots of flux data for each metabolic product of administered 1-¹³C-pyruvate. Controls (Fasted (blue); N=5 and Fed (red); N=2) and T2DM (Fasted; N=5 and Fed; N=3). Flux through PDH (Bicarbonate) is reduced in the fasted subjects with T2DM (N=5) (p=.013, A), with increases seen during feeding (N=3) (p<.001, E). Levels of 1-¹³C-lactate were significantly higher in the hearts of people with T2DM (p<.001, B) with no change observed upon feeding (F). The ratio of bicarbonate and lactate was significantly lower in the subjects with T2DM (p<.001, C) and was elevated by feeding (p<.001, G). No significant differences in 1-¹³C-alanine were seen across all injections (D and H). ‘x’ indicates the data point excluded as an outlier. † p<.05 in subjects with T2DM vs. controls, * p<.05 in fasted subjects vs. fed, ‘x’ indicates the data point excluded as an outlier. Reproduced with permission.(81)

Figure 5:

Sexual dimorphism in myocardial metabolism. A, Impact of sex and DM on myocardial FA oxidation, esterification, and %oxidation suggesting more pronounced effects in women. Obese men (N=10), obese women (N=29), T2DM men (N=12) and T2DM women (N=21). After adjustment for age, ^aP=NS, ^bP=.0060 and ^cP=.03. Subgroup analyses not significantly different for FA oxidation; for FA esterification, ^dP<.06 for diabetic men vs. women. Measurements of myocardial glucose utilization, glycogen deposition, glycolysis, and oxidation measured by PET with 1-¹¹C-glucose in (B) lean, obese, and T2DM men (N=4, 9 and 32, respectively) and (C) women (N=6, 17 and 40, respectively). Data suggest that men exhibit a greater decline in glucose metabolism compared with women as one transitions from lean to obese to T2DM. Reproduced with permission. (107, 113)

Figure 6:

Kaplan-Meier Curves for 231 individuals with diabetes and 945 individuals without T2DM. Extracellular matrix expansion in myocardium quantified by extracellular volume (ECV) fraction is associated with increased risks of: death or heart failure admission (top panel); heart failure admission ignoring or censoring for death (middle panel); or all-cause mortality (lower panel). Event rates were higher for those with T2DM. Reproduced with permission.(130)