Distinct non-ischemic myocardial late gadolinium enhancement lesions in patients with type 2 diabetes

Standard 2D echocardiography was performed using a Vivid S5 probe on a GE healthcare Vivid E9 cardiovascular ultrasound system. The GE EchoPAC workstation was used for analysis. Peak early mitral inflow (E) was measured in the 4-chamber view using pulsed-wave Doppler with the sample volume placed between the tips of the mitral valve leaflets. Also, in the 4-chamber view, the early diastolic myocardial velocity (e′) was measured using pulsed-wave tissue velocity Doppler with the sample volume placed in the septal and lateral mitral annulus.

CMR studies were performed on a 1.5 T scanner (Siemens Avanto, n = 247 patients and all healthy controls or GE healthcare Optima 450w, n = 19 patients) with patients in a supine position on the back using a surface- and spine cardiac coil with ECG gating. Cardiac short-axis steady-state free precession cine sequences were acquired during end-expiratory breath-holds in 25 phases (covering the whole heart; slice thickness 8 mm, no gap) and in 2-, 3- and 4-chamber views. Sequence settings were TE 1.16–1.25 ms, TR 46.24–49.98 ms, Matrix 210 × 208, FoV 258 × 320–485 × 481. Myocardial perfusion images were obtained at the basal, mid-ventricular and apical cardiac short-axis level during rest and pharmacological stress (adenosine 140 µg/kg/min) using an iv. dose of 0.075 mmol/kg of gadobutrol (Gadovist®, Bayer AG, Germany) for each sequence as previously described [11]. LGE imaging was performed using a phase-sensitive segmentation gradient echo inversion recovery sequence following selection of the appropriate TI time based on a Look-Locker sequence. Approximately 5 min after the last contrast dose, a short axis LGE stack of the LV was performed (slice thickness 8 mm, no gap, TE 3.16–3.20 ms, TR 537-748 ms, Matrix 224 × 256–256 × 256, FoV 318 × 340–443 × 458). This was followed by LGE images in the 2-, 3- and 4-chamber views. A trained physician reviewed LGE images during the scan and any LGE lesions seen in the short axis images were confirmed from perpendicular slices through the lesion in question. Additionally, native and post-contrast T₁-mapping were performed as previously described [11] (not performed in the 19 patients scanned with the GE healthcare Optima 450w).

CMR images were analysed using cvi42^© (Circle Cardiovascular Imaging Inc., Calgary Canada, v. 5.5.1). LV volumes and mass were determined by semi-automatic tracing of the endo- and epicardial contours in end-diastolic and end-systolic phases. Papillary muscles were excluded. LA maximum volume was measured by manual tracing in the LV end-systolic frame. For all CMR parameters we chose to report both the absolute values and indexed to body surface area because the majority of our patients were severe obese, which could bias the indexed results. A LGE lesion was considered to be present if seen in at least two perpendicular slices. Blinded to each other, two observers analysed all LGE images (AB and MS). Blinded to clinical data, the analyses were reviewed and finalized by a third observer with 10 years of CMR experience (PLvM). A LGE lesion was classified as ischemic if subendocardial or transmural and respecting the perfusion territory of a coronary artery [12], otherwise, the lesion was considered to be non-ischemic. Hinge-point fibrosis was not included, and these patients were categorised as patients without LGE lesion. A semi-automatic toll marking LGE lesions with increased myocardial signal intensity 5SD above remote myocardium was used to quantify lesion mass. Myocardial mass and mass of myocardial LGE lesions were determined from end-diastolic volumes applying a density of 1.05 g mL⁻¹. On native and post-contrast T₁-maps endocardial and epicardial borders were traced semi-automatically, and the average ECV was calculated from areas outside LGE lesions [13]. For determination of the ECV within a LGE lesion, care was taken to exclude any myocardium without LGE in the segment. Myocardial perfusion scans before and after adenosine infusion were visually inspected for perfusion defects. Using a five-point linear fit model of signal intensity vs. time myocardial perfusion up-slopes were calculated and normalized to the arterial input function. Regions with infarcts, sub-endocardial perfusion defects and dark-rim artefacts were excluded. Myocardial perfusion reserve index (MPRI) was defined as the ratio between normalized stress and rest perfusion [12].

296 T2DM patients and 25 sex-matched controls were included. Twenty-five T2DM patients did not complete the CMR scan, and in 6 patients the scan was performed without gadolinium contrast. In one patient, the LGE images could not be analysed because of poor image quality leaving 264 T2DM patients for final analysis. None of the 25 control subjects had any LGE lesions. In patients with T2DM, 207 (78.4%) did not have LGE lesions; 29 (11.0%) had ischemic LGE lesions only; 25 (9.5%) had non-ischemic LGE lesions only, and 3 (1.1%) patients had both an ischemic and a non-ischemic lesion. Six T2DM patients (2.3%) with ischemic LGE lesions had no prior history of ischemic heart disease. None of the patients without LGE lesions or with non-ischemic lesions had any hypoperfused areas on the adenosine stress perfusion scan indicative of significant coronary artery disease.

In all 28 patients with non-ischemic LGE lesions, these were located mid-myocardial in the basal lateral or the basal inferolateral part of the LV myocardium (Figs. 1, 2). Two patients had two non-ischemic LGE lesions, with the additional lesion located in the middle part of the interventricular septum. Non-ischemic LGE lesions appeared grey compared to ischemic LGE lesions that were well-demarcated and bright white (Figs. 1, 2). Myocardial segments of patients with ischemic lesions were to a variable degree thinned with hypo- or akinesia on cine images, whereas myocardial segments with non-ischemic LGE lesions were thick and did not present abnormal wall motion. The median mass of a non-ischemic lesion was smaller than that of an ischemic lesion (2.8 (IQR1.5–4.4) g (1.8 (IQR1.0–3.0) % of total myocardium vs. 11.7 (IQR6.9–16.1) g (7.4 (IQR5.8–9.8) % of total myocardium (P < 0.0001 for both)). At least one T₁ mapping slice passed through the LGE lesion in 11 patients with non-ischemic and in 18 patients with ischemic LGE lesions: Without difference between non-affected remote myocardium (31.4 (IQR29.0–33.9) % vs. 33.0 (IQR31.5–35.8) %, P = 0.11), the median ECV value for a non-ischemic lesion was lower than what was seen in an ischemic lesion (40.6 IQR37.0–44.7 vs. 51.7 IQR44.9–60.8%; P = 0.004).

Patient demographics including clinical characteristics and laboratory values are presented in Table 1. In comparison with T2DM patients without LGE lesions, T2DM patients with non-ischemic LGE lesions demonstrated a trend towards higher age (P = 0.06), but though numerically higher diabetes duration there was no significant difference between any three T2DM groups. Further, patients with non-ischemic LGE lesions as compared to those without LGE had a trend towards increased systolic blood pressure (P = 0.06) but had the same diastolic blood pressure and the overall prevalence of hypertension (P = 0.11). No differences were noted between groups with respect to the number of patients in NYHA class II/III or in the number of patients treated with insulin. NT-proBNP (P = 0.02) and hs-TNT (P = 0.007) concentrations were higher in patients with non-ischemic LGE lesions than in patients without LGE.

The cardiac structural and functional characteristics of the four groups are presented in Table 2. T2DM patients without ischemic LGE had smaller LV volumes than controls. Further, patients with non-ischemic lesions had significantly higher LV mass than both controls and T2DM patients without LGE (P = 0.02). In comparison with controls, all T2DM groups had increased myocardial ECV, and patients with non-ischemic LGE lesions had higher ECV than patients without any LGE lesions (P = 0.01). All patients with T2DM had lower MPRI compared with controls, but we observed no significant difference in MPRI between patients with non-ischemic LGE compared to patients without LGE lesions. Compared to controls, both groups with LGE lesions had lower lateral and septal e′ and increased average E/e′. In comparison with T2DM patients without LGE, patients with non-ischemic lesions had decreased lateral e′ (P = 0.0496) and increased average E/e′ (P = 0.04) and also a higher maximal LA volume (P = 0.049).

Association of DM complications between the three groups of T2DM patients is shown in Table 3. Having any type of LGE lesion was associated with a higher prevalence of retinopathy and autonomic neuropathy. The increased prevalence of autonomic neuropathy was driven by a lowered beat-to-beat variation. Patients with non-ischemic lesions more often had retinopathy (P = 0.009) and autonomic neuropathy (P = 0.005) than patients without LGE.

Previous LGE CMR studies in T2DM populations have focused on ischemic heart disease with ischemic LGE lesions from myocardial infarctions [14‐16]. Of interest, we found a lower prevalence of unrecognised myocardial infarcts than in previously examined T2DM cohorts [16] This could be due to different study populations but it is also likely that due to modern treatment of risk factors for ischemic heart disease in T2DM, T2DM populations now reach higher age. Perhaps therefore the non-ischemic fibrotic lesions were more prevalent than unrecognised myocardial infarcts. Small autopsy studies from the 1970–1980s have however described localised confluent fibrotic lesions in patients, who had died from diabetic cardiomyopathy without signs of coronary sclerosis and without infarction [17, 18]. Similar to ours, the non-ischemic fibrosis in these autopsy studies was placed mid-myocardial, although unfortunately no information of their anatomical localization in the left ventricle was given. In a study by Stroz et al. cardiovascular magnetic resonance imaging including LGE was performed in a smaller T2DM population of 47, all free of known cardiovascular disease [19]. Out of the 47 patients 3 patients (4.2%) had LGE lesions but unfortunately the type of LGE lesions found was not described in the study. In this study the mean duration of diabetes at 8.4 ± 5.7 was lower than in our study, which could be a possible explanation for the lower LGE prevalence found in the study. Further, the prevalence of hypertension was similar to ours. Another study by Bizino et al. performed CMR in 47 patients with T2DM without known cardiovascular disease [20]. They reported one patient with LGE in the inferoposterior basal segment, the patient had no sign of cardiac ischemia, and hence this LGE element could be of the same nature as the ones presented in this study. However, the authors did not report if the LGE lesion was sub-endocardial, transmural or mid-wall.

Patients with non-ischemic LGE lesions had increased ECV, which has previously been shown to correlate well with the levels of diffuse interstitial myocardial fibrosis [21]. Thus, one possible explanation for our findings could be that the non-ischemic LGE lesions represent an exceedingly high local concentration of fibrosis becoming so high as to be seen with the conventional LGE technique. This could be a possible explanation for the increase in LV mass seen in the group. Compared to controls all patients with T2DM had increased LV mass consistent with previous studies [22], but LV mass was further increased in patients with non-ischemic LGE indicating that this group had more pronounced cardiac involvement. The non-ischemic LGE lesions, may also be related to microvascular complications as the lesions were statistically associated with retinopathy and autonomic neuropathy. This increased prevalence of these complications of diabetes indicates that non-ischemic LGE lesions could be a result of poorly treated DM. However, further research is needed to determine the aetiology and mechanisms leading to these lesions.

Non-ischemic LGE lesions are well-known in patients with other non-ischemic cardiomyopathies such as hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, myocarditis, Chagas disease, sarcoidosis, Anderson-Fabry or cardiac amyloidosis [23]. In all cases, the LGE pattern differs from the quite specific pattern in patients with T2DM found in our study. Only few and smaller CMR studies have been done in other patients populations known to develop heart failure. But LGE patterns have been described in patients with uraemia (of whom some also had DM) [24, 25], hypertensive cardiomyopathy [26], aortic stenosis [26], atrial fibrillation [27] and exercise-induced hypertrophy [28]. In none of the studies a typical pattern of LGE was described. Further, unfortunately most of these studies did not report prevalence of diabetes. In our study, it was not possible to isolate the effect of DM from that of hypertension often seen in T2DM. The prevalence of hypertension was not higher in patients with non-ischemic LGE lesions, however, there was a trend towards higher measured systolic blood pressure, but non-ischemic LGE lesions could be seen despite normal blood pressure.

In other cardiomyopathies, the finding of non-ischemic LGE lesions is associated with prognosis, and if such is the case in T2DM this now has to be established. Non-ischemic LGE lesions have in other patient groups been correlated to heart failure, arrhythmias, and sudden cardiac death [27, 29, 30]. The non-ischemic LGE lesions found in our study were related to parameters associated with impaired diastolic function, in itself an important prognostic factor. Further, non-ischemic LGE lesions were related to increments in prognostic important biomarkers. Thus, increased NT-pro-BNP relates to cardiac remodeling [31] and hs-TNT with cardiac myocyte damage [32] and, hence, these findings suggest that the non-ischemic LGE is associated with the adverse structural remodelling shown in the group.