Relationship between Left Ventricular Structural and Metabolic Remodelling in Type 2 Diabetes Mellitus

Abstract

Concentric left ventricular (LV) remodelling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodelling in diabetes, per se, is unclear, but may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship amongst myocardial metabolic changes and LV remodelling in T2DM. Forty-six non-hypertensive T2DM patients and twenty matched controls underwent cardiovascular magnetic resonance to assess LV remodelling (LV mass to LV end diastolic volume ratio-LVMVR), function, pre- and post-contrast tissue characterisation using T1 mapping, ¹H-, ³¹P-magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine to ATP ratio (PCr/ATP) respectively. When compared to body mass index and blood pressure matched controls, diabetes was associated with: concentric LV remodelling, higher MTG, impaired myocardial energetics and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodelling and systolic strain. Extracellular volume fraction was unchanged, indicating absence of fibrosis. In conclusion, cardiac steatosis may contribute to LV concentric remodelling and contractile dysfunction in diabetes. As cardiac steatosis is modifiable, strategies aimed at reducing myocardial triglyceride may be beneficial in reversing concentric remodelling and improving contractile function in the diabetic heart.

Introduction

Diabetes mellitus (DM) is associated with an increased risk of both heart failure¹ and cardiovascular mortality², even in the absence of coronary artery disease (CAD). The reasons for this, are not clear, but one candidate mechanism that has emerged is concentric LV hypertrophy, which is frequently observed in patients with type 2 diabetes mellitus (T2DM)^{3, 4}, preceding the development of clinical heart failure⁵ and shown to be a strong predictor of adverse cardiovascular events⁶.

Concentric remodelling of the LV is characterised by an increased LV mass to LV end diastolic volume ratio (LVMVR) but normal LV mass index⁷. The precise underlying mechanism of concentric LV remodelling in patients with DM, in the absence of significant arterial hypertension, remain unclear. One potential driver of LV concentric remodelling in patients with T2DM is cardiac steatosis, where excess myocyte accumulation of triglyceride leads to hypertrophic signaling^{8, 9}. The link between lipotoxicity and concentric LV remodelling has been demonstrated in animal models of excess lipid accumulation^7,10 and in humans¹¹ and particularly patients with generalised lipodystrophy¹², who exhibit severe concentric LV hypertrophy and significant cardiac steatosis. Proton (¹H) magnetic resonance spectroscopy (MRS) allows for the non-invasive measurement of cardiac triglyceride content. Using this technique cardiac steatosis has been shown to be a prominent and early feature of diabetic cardiomyopathy¹³.

In addition, impaired myocardial high-energy phosphate metabolism is another important feature of diabetic cardiomyopathy¹⁴. ³¹Phosphorus magnetic resonance spectroscopy (³¹P-MRS) allows for cardiac energetics to be measured non-invasively. Whether a relationship between concentric LV remodelling and impaired myocardial energetics exists in T2DM is unknown, but given the link between PCr/ATP ratio and mortality¹⁵, this is worthy of investigation.

Interstitial fibrosis has also been implicated in the pathogenesis of LV hypertrophy ¹⁶ and has been identified in the more advanced stages of diabetic cardiomyopathy¹⁷. The role of interstitial fibrosis in the pathogenesis of LV hypertrophy in stable/early diabetic cardiomyopathy is much less clear as abnormal myocyte hypertrophy rather than fibrosis appears to predominate in the early stages ¹⁸. Cardiac magnetic resonance (CMR) T1 mapping for extracellular volume (ECV) quantification allows for non-invasive quantification of fibrosis¹⁹, correlating closely with collagen proportionate area on histology ²⁰.

Thus, we used CMR imaging, combined with ¹H-MRS and ³¹P-MRS, to assess the relationship amongst LV concentric remodelling, cardiac fibrosis, steatosis and myocardial energetics in T2DM, and compared the results to non-diabetic age, body mass index (BMI) and blood pressure matched controls.

Research Design and Methods

The study complies with the Declaration of Helsinki, it was approved by the National Research Ethics Committee (REC Ref 13/SW/0257) and informed written consent was obtained from each participant. All patients were recruited from the general practice surgeries in Oxfordshire, United Kingdom. Forty-six stable T2DM (diagnosed according to the World Health Organization criteria²¹) and 20 controls were recruited to the study.

Inclusion and Exclusion Criteria

The diabetes population assessed in this study is comprised of T2DM patients only, with stable disease and no known diabetes complications. Subjects were excluded if they had a history of cardiovascular disease, chest pain, smoking, hypertension (resting systolic blood pressure (BP) >140 mmHg and diastolic BP >90 mmHg), contraindications to MR imaging, ischemic changes on 12-lead ECG, or renal impairment (estimated glomerular filtration rate below 30 mL/min). T2DM participants were excluded if they had HBA1C >9% or were taking insulin.

Anthropometric Measurements

Height and weight were recorded and BMI calculated. Blood pressure was recorded as an average of 3 supine measures taken over 10 minutes (DINAMAP-1846-SX, Critikon Corp). Fasting venous blood was drawn for glucose, triglyceride, HBA1c, renal function and free fatty acids (FFA), full blood count tests as previously described²². Fasting insulin was also recorded in all diabetic patients. In agreement with the diabetes management guidelines²³ spot (random) urine sample albumin levels and the albumin: creatinine ratio was assessed in the majority of patients with T2DM, (~69%, n=32).

Coronary computed tomographic angiography

An optional scan of coronary computed tomographic angiography (CCTA) were offered to diabetic patients to exclude obstructive coronary artery disease (>50% of luminal stenosis). CCTA scans were performed on 64-slice CT scanner (GE Healthcare, Discovery 690) in accordance to performance guidelines from the Society of Cardiovascular Computed Tomography²⁴. Participants received beta-blockade (intravenous Metoprolol) and sublingual GTN (if necessary and safe) prior to the scan to achieve a heart rate of <65 beats per minute. During the CTCA acquisition, 80ml of iodinated contrast (Visipaque, GE Healthcare, Princeton, NJ) was injected followed by a 50ml saline flush.

Echocardiography

Transthoracic echocardiography was performed with the subjects at rest using commercially available ultrasound transducer and equipment (Philips iE33 Medical Systems, The Netherlands). All images were digitally stored on hard disks for offline analysis (EchoPAC version 108.1.5, GE-Vingmed). Measurements of LV diastolic function were performed according to the guidelines of the American Society of Echocardiography.²⁵ The following diastolic indices were obtained: transmitral early (E) and late (A) diastolic velocities and E/A ratio.

Cardiac Magnetic Resonance Protocol

All LV imaging were performed on a 3.0 Tesla MR system (Siemens, Germany). Images for LV volumes and diastolic function were acquired using a steady state free precession (SSFP) sequence and analysed using cmr42© (Circle Cardiovascular Imaging Inc, Canada) as previously described²⁶.

To determine mid-ventricular peak systolic circumferential strain and diastolic strain rate, myocardial tagging was performed as described previously^{27 28}. Tagged images were analysed using Cardiac Image Modeller software (CimTag2D v7 Auckland Medical Research, Auckland, New Zealand). Semi-automated analysis was performed by aligning a grid to the myocardial tagging planes at end-diastole.

T1 mapping and ECV quantification was performed using a Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) sequence²⁹. T1 maps were generated from the mid short-axis images as described previously²⁹. Consistent with earlier reports on ECV estimation^{19, 30}, we measured pre-contrast and post-contrast myocardial and blood T1 values, and the estimation of ECV and lambda was based on multipoint regression, incorporating all available pre-contrast and post-contrast points, to increase the robustness of the estimates by increasing the number of underlying data points. ECV was calculated as: (1 – hematocrit). For calculation of post-contrast T1 values, the post-contrast T1 map acquired at 15 min was utilized for ECV calculation. Baseline and 15 min post-contrast images were contoured by two observers (EL and SKP) in a blinded fashion, using dedicated software, as previously described³¹.

Late gadolinium enhancement (LGE) imaging was performed to exclude presence of previous silent myocardial infarction or regional fibrosis and it was acquired according to standard clinical protocols and analyzed qualitatively.

³¹P-MR Spectroscopy

³¹P MR spectroscopy was performed to obtain the rest PCr/ATP from a voxel placed in the mid-ventricular septum, with the subjects lying prone with their heart over the centre of the ³¹P heart/liver coil in the isocentre of the magnet as previously described³². ³¹P-MRS post processing analysis was performed using in house software within Matlab version R2012a (Mathworks, Natick, Massachusetts) as previously described³².

Cardiac ¹H-MRS

Myocardial ¹H-MR spectra were obtained from the mid-interventricular septum as previously described³³. Spectroscopic acquisitions were performed using ECG trigger at end-expiration to minimize motion artefacts. Water-suppressed spectra were acquired to measure myocardial lipid content, and spectra without water suppression were acquired as an internal standard. Spectra were analyzed using Matlab and the AMARES algorithm in Java-based Magnetic Resonance User Interface as previously described³³. Myocardial lipid content was calculated as a percentage relative to water: (signal amplitude of lipid/signal amplitude of water)×100.

Statistical Analysis

All statistical analysis was performed with commercially available software packages (IBM SPSS Statistics, version 20). All data were checked for normality using the Kolmogorov–Smirnov test and presented as mean ± standard deviations, and median (interquartile range) as appropriate. Normally distributed data sets were analysed with the independent Student t test. The chi-square test was used to compare discrete data as appropriate. Bivariate correlations were performed using Pearson’s or Spearman’s method as appropriate. To assess the associations concentric remodeling and metabolic parameters, linear regression across all subjects was performed. Linearity was assessed visually. Variables with P<0.05, and the strongest relationship with concentric remodelling were then included in multiple linear regression models by a stepwise selection method to assess the "best" subset in predicting cardiovascular remodelling. Significance was assumed at P < 0.05.

Results

Participant Characteristics

Demographic, clinical, and biochemical data are shown in Table 1.

Table 1. Clinical, Biochemical Characteristics and Echocardiographic Features.

Variable	Controls N=20	Type 2 DM patients N=46	P value
Age, y	54 ± 10	55 ± 9	0.583
BMI, kg/m2	28.6 ± 2.8	29.6 ± 5.7	0.463
Male,%	45	50	0.714
Diabetes duration, y	…	7[IQR:1-8]
Heart rate, beats per minute	66 ± 13	68 ± 8	0.377
Systolic blood pressure, mmHg	128 ± 12	129 ± 8	0.583
Diastolic blood pressure, mmHg	74 ± 8	76 ± 7	0.311
Plasma fasting glucose, mmol/L	4.9 ± 0.5	8.9 ± 3.1	<0.001
Glycated hemoglobin, %	5.4 ± 0.3	7.5 ± 0.2	<0.001
Glycated haemoglobin, mmol/mol	37 ± 3	57 ± 15	<0.001
Plasma triglycerides, mmol/L	1.59 ± 0.68	1.60 ± 0.78	0.931
Plasma free fatty acids, mmol/L	0.38 ± 0.23	0.61 ± 0.36	0.017
Total cholesterol, mmol/L	5.6 ± 0.9	3.9 ± 0.9	<0.001
HDL, mmol/L	1.53 ± 0.61	1.18 ± 0.29	0.005
LDL, mmol/L	3.41 ± 0.53	2.04 ± 0.74	<0.001
Creatinine, mmol/L	72 ± 19	65 ± 17	0.228
Hematocrit, %	41 ± 4	42 ± 3	0.501
Urine albumin, mg/L, (N=32)	…	16 ± 30
Urine albumin: creatinine ratio, mg/mmol, (N=32)	…	1.7 ± 3
Medications, n (%)
Metformin, n (%)	-	41 (89)
Sulphonylurea	-	14 (30)
Aspirin	-	5 (11)
Statin	-	34 (74)
ACE-I	-	12 (26)
Echocardiographic Features
Mitral in-flow E/A ratio	1.17 ±0.38	0.99 ±0.25	0.038

Values are mean ±standard deviations or percentages. T2DM indicates type 2 diabetes mellitus; BMI, body mass index; y, years; HDL, high density lipoprotein; LDL, low density lipoprotein; ACE-I angiotensin-converting enzyme inhibitors.

Forty-six patients (24 male, mean age 55 ± 9years, body mass index (BMI) 29.6 ± 5.7kg/m²) with T2DM, median diabetes duration 7 years [IQR: 1-8] and mean HBA1c of 7.5 ± 1.2%, and twenty controls (9 male, mean age 54 ± 10 years, BMI 28.6 ± 2.8kg/m²) were studied. Patients were of similar age, gender, weight, resting heart rate and blood pressure with controls. As expected, diabetes was associated with higher fasting blood glucose, HBA1c, free fatty acids (FFA), triglyceride levels and lower high-density lipoprotein cholesterol. About 74% of the diabetic patients were on statin therapy, hence the lower total cholesterol and low-density lipoprotein cholesterol levels were detected in patients compared to controls. Urine albumin: creatinine ratio and urine albumin results were recorded in 32 patients with T2DM in the study and all were within normal limits.

CCTA

Of the 46 patients with T2DM, in 76% significant CAD was excluded by CCTA and the remaining 11 did not consent to having CCTA.

The Effect of Diabetes on LV Geometry and Function

In agreement with previous reports, diabetes was associated with concentric LV remodelling. Although LV mass was not significantly different between T2DM and controls (P = 0.183), LV end-diastolic volume was 16% smaller in T2DM (P = 0.004). As a result, T2DM was associated with increased LV mass to volume ratio (LVMVR) by 31%, (0.97 ± 0.17, vs 0.74 ± 0.14g/ml, P < 0.001; Figure 1, A; Table 2), suggesting significant concentric remodelling. Importantly, this concentric remodelling was not correlated with blood pressure, which was within normal limits in both groups,(R = -0.002, P = 0.989).

Figure 1.

Differences in cardiac geometry and function between patients with T2DM and controls; (A) LV Mass: LV-EDV ratio (g/ml), (B) Systolic strain %, (C) Myocardial triglyceride content (%) and (D) Myocardial energetics (PCr/ATP ratio).

Table 2. LV Geometry and Function.

	Controls N=20	Type 2 DM N=46	P value
LV end-diastolic volume, ml	148 ± 34	124 ± 27	0.004
LV end-systolic volume (ESV), ml	43 ± 16	37 ± 13	0.351
LV stroke volume (SV), ml	104 ± 21	86 ± 21	0.055
LV ejection fraction, %	71 ± 5	70 ± 7	0.586
LV wall thickness, mm	9.6 ± 1.3	10.4 ± 1.8	0.047
LV mass, g	109 ± 31	120 ± 28	0.183
LV mass index, g/m2	53.1 ± 15.9	60.2 ± 11.6	0.05
LV mass to LV end-diastolic volume, g/ml	0.74 ± 0.14	0.97 ± 0.17	<0.001
Peak circumferential diastolic strain rate, s-1	65 ± 13	60 ± 24	0.057
Native myocardial T1 value, ms	1184 ± 28	1194 ± 32	0.23
Extra Cellular Volume fraction, %	29 ± 3	29 ± 2	0.773

Values are mean ±standard deviations or percentages. T2DM indicates type 2 diabetes mellitus; CMR, cardiac magnetic resonance; LV, left ventricular.

Despite normal LV ejection fraction (LVEF), mid-ventricular peak systolic circumferential strain was impaired in patients with T2DM (T2DM 14.5 ± 3.5%, vs controls 18.3 ± 2.6%, P < 0.001; Figure 1B), indicating subtle contractile dysfunction. The differences in diastolic strain rate between the T2DM patients and controls did not reach statistical significance, but there was a strong trend (T2DM 60 ± 24s^-1, vs controls 65 ± 13s^-1, P = 0.057). LVMVR showed a negative correlation with peak systolic circumferential strain (R = -0.430, P < 0.001), but not with diastolic strain rates (R= -0.121, P=0.341). The echocardiographic assessment of mitral inflow E/A ratio was significantly lower in T2DM patients (T2DM 0.99 ± 0.25, vs controls 1.17 ± 0.38, P = 0.038). In-keeping with the dissociation of diastolic strain rates and the myocardial triglycerides, there was no significant correlation between the mitral inflow E/A ratio and the myocardial triglyceride (R= -0.135, P= 0.393).

Cardiac Steatosis, Myocardial Energetics, Concentric Remodeling and Strain

As described before, diabetes was associated with an almost two-fold elevation of myocardial triglyceride (T2DM 1.13 ± 0.78, vs controls 0.64 ± 0.52, P = 0.017; Figure1, C) and was also associated with ~18% reduction in the myocardial PCr/ATP ratio (T2DM 1.68 ± 0.28, vs controls 2.05 ± 0.34, P < 0.001 ; Figure 1, D). When investigating all study subjects, there was a positive correlation between the MTG and concentric LV remodelling (R = 0.41, P = 0.003) and a negative correlation between myocardial energetics and LVMVR (R = -0.30, P < 0.020). Stepwise multivariable regression revealed myocardial triglyceride (β = 0.473, P = 0.001) to be the only independent predictor of concentric remodelling (overall R² of the model = 0.304, P = 0.001). Furthermore, myocardial triglyceride also negatively correlated with systolic strain (R = -0.40, P = 0.003), and it was also the only independent predictor of systolic strain (β = -0.400, P = 0.003) on stepwise multivariable regression analysis. However, there was no correlation between diastolic strain rate and steatosis (R = 0.158, P = 0.263). Figure 2 shows representative examples of cardiac ³¹P-MRS, ¹H-MRS and cine images in a control and a patient with T2DM.

Figure 2.

Representative examples of cardiac ³¹P-MRS, ¹H-MRS and cine imaging in a control and a patient with T2DM. Top panel: normal control ³¹P-MRS with PCr/ATP=2.16, vs patient with T2DM PCr/ATP= 1.54; Second panel: normal control 1H-MRS with myocardial lipid to water ratio=0.44%, vs patient with T2DM= 1.74%; Third panel: normal control cine image with LV mass : LV end-diastolic volume ratio=0.55 g/ml, vs patient with T2DM = 1.28g/ml.

T1 mapping , extracellular volume (ECV) quantification and late Gadolinium Enhancement

There was no significant difference in native myocardial T1 values between the T2DM patients and controls (T2DM 1194 ± 32 ms, vs controls 1184 ± 28 ms; P = 0.23). Similarly, ECV did not differ between the groups (T2DM 29 ± 2%, vs controls 29 ± 3%, P = 0.773), suggesting absence of interstitial fibrosis. On visual assessment of the LGE images, no areas of enhancement indicative of scarring in either ischaemic or non-ischaemic patterns were identified in any of the participants.

Discussion

Concentric LV remodelling is an adverse prognostic marker of cardiovascular events³⁴, and is linked to contractile dysfunction³⁵. Using CMR and MRS we show here that diabetes, in the absence of hypertension, is associated with concentric LV remodelling and we confirm the findings of previous studies, showing pronounced cardiac steatosis¹³ and decreased energetics^14,36 in patients with T2DM. We have also shown that despite normal LVEF, peak systolic strain was significantly impaired in diabetics, indicating a subtle contractile dysfunction, which was negatively correlated with both reduced myocardial energetics and concentric LV remodelling. Importantly, we have shown here for the first time, that the degree of myocardial triglyceride accumulation is predictive of concentric LV remodelling and cardiac contractile function in patients with T2DM. The correlation of myocardial concentric remodelling with myocardial triglyceride accumulation and peak systolic strain in diabetic hearts suggest a link between these; however, the causality of these relationships will need to be investigated in future studies. From these initial cross-sectional studies, we clearly cannot determine whether the observed correlations between myocardial triglyceride and LVMVR and function are causal. As myocardial steatosis has been shown to be modifiable^37,38 , this provides the potential for novel therapies aimed at reducing concentric LV remodelling and improving cardiac function in diabetes. Finally, as no significant difference in ECV and native (pre-contrast) T1 mapping was found between the patients with T2DM and controls, it is unlikely that interstitial fibrosis plays a significant role in the pathogenesis of concentric LV remodelling in this well controlled, stable T2DM population. This suggests that the process of concentric remodelling is not limited to poorly controlled diabetics, or those with renal dysfunction¹⁷, and occurs in the absence of significant systemic hypertension.

Microalbuminuria is strongly associated with risk for cardiovascular disease, but the nature of this link remains controversial and poorly understood ³⁹. In this study, in patients with stable T2DM, free of coronary artery disease, no association between the urine albumin excretion and the LV remodelling, contractile dysfunction, cardiac energetics or steatosis was observed.

The diabetes population assessed in this study is comprised of highly selected T2DM patients, with stable disease only and no other significant comorbidities. Although this has the advantage of better demonstrating the pathophysiological relationships between T2DM and cardiovascular remodelling it does reduce the broader applicability to "real world" populations where additional co-morbidities are commonplace. Given the fact we have shown significant abnormalities in myocardial energetics, myocardial triglyceride deposition, myocardial geometry and peak systolic strain in a stable diabetes population, similar or amplified findings may potentially be expected in diabetic patients with more advanced cardiovascular disease, or other significant comorbidities such as hypertension. Future studies are needed to confirm this. Furthermore, whether or not the subtle changes in cardiac geometry, energetics and lipid deposition will predict adverse cardiovascular outcomes in a diabetes cohort remains to be definitively demonstrated by longitudinal studies.

The LVMVR is calculated by dividing the left ventricular mass by the left ventricular end diastolic volume, as an index of wall thickness to cavity size. LVMVR lacks a well-defined normal reference range, therefore age and sex-matched healthy volunteers without co-existent coronary artery disease, hypertension, aortic stenosis or other forms of heart disease were recruited and scanned contemporaneously. LVMVR in this group was 0.74 ± 0.10 g/mL and consistent with previous larger studies of >700 healthy volunteers, carried out in our centre⁴⁰. The LVMVR in the control group in this small cross sectional study is however lower than the average demonstrated in a multi-ethnic study of atherosclerosis (MESA). This is likely the result of the fact that the MESA population study of >5000 participants did not exclude subjects with hypertension, impaired fasting glucose, diabetes, smoking and other causes of concentric hypertrophy ⁴¹. In addition, in MESA participants were on average 6-8 years older than the participants in our study, and only around 10% had diabetes, making comparisons with this larger population based study more difficult. ⁴¹

Relationship between LV Geometric Remodelling and Cardiac Steatosis in the Diabetic Heart

Ectopic lipid deposition in the diabetic heart is a well-documented process, and non-invasive studies using ¹H-MRS have reported elevated levels of cardiac triglyceride in human diabetes¹³. However, the link between cardiac steatosis and diabetes, above and beyond that observed in obesity, and its potential role in concentric LV remodelling within diabetes, has not been explored in humans. This study now demonstrates that diabetes per se is linked to significant cardiac steatosis, and we show a correlation between myocardial triglyceride and the concentric LV remodelling, suggesting a link between the two; however, the causality of this relationship will need to be investigated in future studies.

The importance of cardiac steatosis in the pathophysiology of concentric LV remodelling has been assessed in experimental models. In diabetes, where fatty acid supply exceeds the oxidative capacity of the heart, this leads to diversion of lipids away from oxidative processes and towards non oxidative processes with the production of lipotoxic intermediates such as ceramide and diacyl-glycerol⁴². These lipotoxic intermediates have been shown to activate signalling pathways affecting ATP production, insulin sensitivity, myo-cellular contractility, and apoptosis⁴². Recently, it has also been demonstrated that cardiac steatosis potentiates the effects of Angiotensin 2 on the heart⁴³. Given the fact that Angiotensin 2 is a potent hypertrophic stimulus and that both Angiotensin 2 receptor density and mRNA expression are elevated in the diabetic heart ⁴⁴, this is likely to be an important driver for hypertrophy. In addition, animal models of overexpression of fatty acid transporters and increases in triglyceride synthesis both result in severe cardiac steatosis and concentric LV hypertrophy^9,36. This provides a mechanistic link between cardiac steatosis, lipotoxicity and concentric LV remodelling in diseases of upregulated fatty acid metabolism such as diabetes. Importantly, successful reduction of myocardial steatosis with glucagon-like peptide-1 receptor (GLP-1) agonists ³⁷ and mineralocorticoid receptor blockers ³⁸ have both been shown to reverse concentric LV remodelling.

Here, we have demonstrated that myocardial steatosis is a predictor of concentric LV remodelling and subclinical contractile dysfunction in patients with T2DM. This supports the notion that the development of concentric LV remodelling in T2DM may be mechanistically linked to cardiac steatosis, and that cardiac lipotoxicity represents a component of this process, however an observational study such as ours cannot clearly identify the mechanisms responsible and future studies will need to investigate this. If a causal link is proven, this would suggest that therapies and interventions aimed at reducing myocardial triglyceride may promote beneficial reverse remodelling in humans.

LV Concentric Remodeling and Myocardial Energetics

A healthy heart is able to metabolise a range of substrates, to fulfil the demand for ATP production. Depending on the availability of substrates and the physiological conditions, the heart will switch its metabolic preference amongst substrates. This flexibility is lost in diabetes and myocardial substrate selection is shifted almost exclusively to fatty acid metabolism⁴⁴. This over utilisation of fatty acids results in a reduced ATP yield and a loss of mitochondrial efficiency⁴⁴. The interplay between myocardial energetic status and geometrical changes in diabetes has previously not been explored. Here we report that in the context of well controlled diabetes, myocardial energetics, in the form of PCr/ATP ratios, are impaired, and are linked to concentric remodelling.

Limitations

Of the 46 patients with T2DM, 11 patients (24%) did not consent to have CCTA performed and as such it is possible that occult coronary artery disease could be present in this minority of patients.

Insulin measurements were not taken in the control group. Although diabetes was excluded on fasting glucose measurements, this does preclude the investigation of the role of insulin resistance in the pathogenesis of cardiac steatosis.

Urine albumin levels were recorded only in ~69% (n=32) of the patients with T2DM.

Conclusions

When compared to BMI matched controls, patients with well controlled T2DM exhibit LV concentric remodelling in the absence of arterial hypertension. This concentric remodelling is associated with cardiac steatosis, myocardial energetic impairment and subclinical systolic dysfunction. As myocardial steatosis is independently predictive of concentric remodelling and cardiac systolic strain, it may play an important role in adverse geometric remodelling in T2DM. Importantly, as myocardial TG content is modifiable, strategies aimed at reversing myocardial steatosis may be beneficial in reversing LV remodelling, and potentially improve contractile function and prognosis in patients with diabetes.