The relationship between abnormal myocardial alterations and glycemic control validated by cardiac magnetic resonance in a pig model of diabetes mellitus

doi:10.21203/rs.3.rs-2577924/v1

Aims

To investigate the relationship between hemoglobin (HbAlc) and abnormal myocardial alterations as determined by cardiac magnetic resonance (CMR) T1 mapping and feature tracking in a pig model of diabetes mellitus (DM).

Methods

Eight DM models were successfully established and were divided into two groups based on their HbAlc median value (high HbAlc ≥ 6.07%, n = 5; low HbAlc < 6.07%, n = 3). As controls, five healthy age-matched pigs were used. Over the diabetic course of 16 months, CMR cine, T1 mapping, and late enhancement gadolinium (LGE) were performed. Afterward, three pigs were then sacrificed and stained with masson trichrome and advanced glycation end products (AGEs) from control, high, and low HbAlc groups, respectively.

Results

Diabetes and control groups did not differ in terms of left ventricular ejection fraction (p = 0.784) and showed no evidence of LGE. However, when compared to controls, pigs with high HbAlc had higher native T1 and ECV as well as lower longitudinal strain and strain rate (all p < 0.05). Furthermore, HbAlc correlated well with native T1, ECV, longitudinal strain, and diastolic strain rate (R² = 0.470 to 0.849, all p < 0.05). Histological staining showed more significant deposition of myocardial interstitial fibrosis and AGEs in the pig with high HbAlc than in the other two pigs.

Conclusions

High HbAlc was associated with increased myocardial native T1 and ECV and decreased longitudinal myocardial deformation in DM pigs.

Diabetes mellitus

T1 mapping

glycemic control

myocardial fibrosis

cardiac deformation

Despite improvements in average glycemic control achieved by intensive diabetes therapy over 20–25 years in patients with diabetes mellitus (DM), the high incidence of diabetes complications has caused a large burden in terms of disability and death, quality of life, and health care costs [1]. As a chronic metabolic disorder characterized by long-term exposure to hyperglycemia, the persistent poor glycemic control significantly enhances the increase in glucose toxicity, leading to cumulative, persistent, and largely glycemic damage effects on the cardiovascular system [2–4]. In further, DM patients have been shown to predispose affected individuals to diabetic heart disease, which is associated with higher rates of heart failure [5]. However, the specific impact of different extent of glycemic control on cardiac alterations is still unclear. Hemoglobin (HbAlc) has been demonstrated as a potential clinical evaluation index of glycemic control. Additionally, the advanced glycation end products (AGEs), a marker of HbAlc, have an adverse impact on extra- and intracellular protein modification, promoting cardiomyocyte apoptosis and the formation of myocardial fibrosis, which might drive the decrease in cardiac compliance in diabetic heart disease [6–8].

Previous studies have confirmed that early abnormal cardiac changes in individuals with DM were detectable using cardiac magnetic resonance (CMR) [9–10]. Native T1 and extracellular volume (ECV) based on CMR T1 mapping has been considered as a surrogate of myocardial fibrosis superior to late enhancement gadolinium (LGE) [11–15]. Furthermore, magnetic resonance feature tracking (FT) technology can detect subtle early cardiac deformation damage in patients with heart disease [9, 16–18]. Therefore, this study aimed to investigate the relationship between HbAlc, myocardial fibrosis, and cardiac deformation based on CMR T1 mapping and FT in a DM pig model and validated by histopathology.

2.1 Animals

Thirteen Bama mini female pigs were used at 3 months at the beginning of the experiments and then were grouped randomly into the control group (n = 5) and the diabetes group (n = 8). The age and weight of the experimental group and the control group were matched. After fasting for 16 hours, a DM pig model was established by injection of streptozotocin (STZ, Sigma) at a dose of 150 mg/kg. Fasting and 2-hour postprandial blood glucose measurements were taken three times a week for the next 2 months. To ensure the survival of the animals, 12 U protamine zinc insulin was injected subcutaneously for hypoglycemic treatment when the blood glucose was higher than 20 mmol/L or 25 mmol/L. If the fasting blood glucose of the pigs continued to be higher than 7 mmol/L for 1 month after injection of STZ, the diabetes model was considered successful. Body weight and vital signs were monitored routinely.

2.2 Preparation For Cardiovascular Magnetic Resonance

The pigs were anesthetized by intramuscular injection of Zoletil 50 (10–15 mg/kg) and atropine before MRI. After an intravenous channel was established in the auricular vein, continuous intravenous infusion of propofol A (10 mg/ml, propofol emulsion injection, Xi 'an Labon Pharmaceutical Co., LTD) was used to maintain anesthesia at a rate of 2–4 mg/kg/h. A blood sample was collected from the superior vena cava under anesthesia using a sterile syringe for biochemical testing, including hematocrit (hct), fasting blood glucose (FBG), HbAlc, cardiac enzyme, liver, and renal function. Airway intubation was then performed using a 4.5-6.0mm trachea connected to a special animal ventilator. Mechanical ventilation was performed, and anesthesia was maintained with a gas mixture of isoflurane and oxygen with a tidal volume of 8–15 ml/kg, a respiratory rate of 10–30 beats/min, and an inhalation/breathing ratio of 1:2. During the whole scanning process, the animals were kept warm and stable, and their vital signs were closely monitored by electrocardiogram equipment.

2.3 Mri Protocol

All pigs were imaged using a 3.0 T magnetic resonance scanner (Magnetom Skyra, Siemens, Erlangen, Germany) with a commercial 18-channel receiver coil. ECG and respiratory gating were connected during image acquisition. A steady-state free precession sequence was used to obtain cardiac short-axis cine images. The scanning area was from the mitral valve to the apical myocardium. The parameters included echo time (TE), 1.36 ms; repetition time (TR), 3.15 ms; flip angle, 35°; slice thickness, 6.5 mm; matrix, 154 × 192 pixels; and field of view, 400 × 320 mm². Three planes of T1 mapping images (basis, mid-ventricular, and apex) were acquired from a modified Look-Locker inversion sequence in cardiac diastole before and 10–15 minutes after bolus injection of gadolinium (Magnevist; Bayer Healthcare Pharmaceuticals, Wayne, NJ, 0.2 ml/kg) at a rate of 2 ml/s. The parameters included TE, 1.07 ms; TR, 2.52 ms; flip angle, 35°; slice thickness, 6.5 mm; matrix, 154 × 192 pixels; and FOV, 258 × 322 mm². Phase sensitivity inversion recovery was performed to collect LGE images. The parameters included TE, 1.15 ms; TR, 2.75 ms; flip angle, 45°; slice thickness, 5 mm; matrix, 160 × 120 pixels; and FOV, 360 × 270 mm².

2.4 Imaging Analysis

For offline analysis, all CMR images were uploaded to dedicated postprocessing software (CVI42, Circle Cardiovascular Imaging, Calgary, Canada). According to the postprocessing standards of the Society for CMR [19], cine short-axis images were transferred into the short-3D module. After identifying the end-diastolic and end-systolic phases, endocardial, and epicardial boundaries were manually delineated, avoiding artifacts. Cardiac functional parameters were automatically calculated, including left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), left ventricular stroke volume (LVSV), and left ventricular cardiac output (LV CO).

Cardiac deformation, T1 maps, and ECV measurements were obtained according to the American Heart Association recommended myocardial 17-segment model with the exclusion of the apical segments. After segmentation, global myocardial T1, ECV and cardiac deformation values were averaged over the entire myocardium. The average values for the basal, mid, and apical myocardium were AHA 1 to 6, AHA 7 to 12, and AHA 13 to 16, respectively. The strain and strain rate were analyzed on cine short-axis and long-chamber views using a 2D module. Radial peak strain (RS), radial peak systolic strain rate (RSSR), and peak diastolic strain rate (RDSR); circumferential peak strain (CS), circumferential peak systolic strain rate (CSSR), and peak diastolic strain rate (CDSR); and longitudinal peak strain (LS), longitudinal peak systolic strain rate (LSSR), and peak diastolic strain rate (LDSR) were analyzed.

Native T1 and post T1 times were measured by delineation of endocardial and epicardial outline with edges excluded very carefully to reduce partial-voluming effects at the myocardial-blood interface. The region of interest was placed in the blood pool, and ECV was then automatically calculated after inputting the hct value according to the established formula [19].

ECV = (1 -Hct)*(myocardialΔR1 - blood poolΔR1)

ΔR1 = 1/T1 pre-1/T1 post

2.5 Histological Analysis

Three pigs (one from high HbAlc; one from low HbAlc; one from control) were sacrificed under deep anesthesia (defined as no pedal reflex, no blink reflex, and no response to painful stimulation) via the injection of potassium chloride through an auricular vein until cardiac arrest. After being removed from the chest, the heart was rinsed immediately with 4°C PBS or normal saline. The myocardial tissue was fixed with formalin for 24–48 h and then embedded in paraffin. Masson trichrome and AGEs (ab23722, Abcam) staining was then performed.

2.6 Inter- And Intraobserver Reproducibility

To assess intra- and interobserver reliability, 96 segments (48 from ECV, 48 from native T1) were randomly selected by Bland‒Altman plots. Intraobserver reproducibility was determined from the repeated measurement by one radiologist (Z.L.) with an interval of 2 weeks. Two experienced radiologists independently assessed interobserver reproducibility (Y.WF. and Z.L.) blinded to each participant's measurements.

2.7 Statistical Analysis

Statistical analyses were performed using SPSS software version 19.0 for Windows (SPSS, Chicago, IL). The results are expressed as the mean ± standard deviation or median with range, as appropriate. One-way analysis of variance was utilized to assess the differences among the control, high, and low HbAlc groups. The correlations between CMR parameters and HbAlc values were assessed using univariate linear regression. The intraobserver and interobserver reliability were derived using intraclass correlation coefficients (ICCs).

3.1 General and Biochemical Information

The eight diabetic pigs were successfully established, and each diabetic pig survived for more than a year post-DM. Diabetic pigs were divided into two groups based on the median HbAlc value: pigs with low HbAlc (HbAlc value < 6.07%, n = 3) and high HbAlc (HbAlc value ≥ 6.07%, n = 5). Cardiac injury biomarker was not significantly different between the diabetes and control groups (p = 0.406). Pigs with high HbAlc had greater fasting blood glucose than pigs with low HbAlc (p = 0.005) and controls (p < 0.001) (Table 1). Additionally, alanine aminotransferase and total cholesterol were higher in pigs with high HbAlc compared to controls (p = 0.043 and 0.017, respectively).

Table 1

Basic characteristics.
	Controls	Diabetic pigs		P
	Controls	Low HbAlc	High HbAlc	P
FPG (mmol/L)	4.8 ± 1.4	12.9 ± 0.7^*	16.2 ± 1.5^*#	< 0 .001
HbAlc, mmol/L	3.9 ± 0.5	5.3 ± 0.5^*	6.5 ± 0.6^*#	< 0 .001
TC (µmol/L)	1.2 ± 0.3	1.5 ± 0.5	2.2 ± 0.7^*	0.043
HDL-c (mmol/L)	0.5 ± 0.04	0.4 ± 0.1	0.6 ± 0.3	0.522
LDL-c (mmol/L)	0.7 ± 0.2	0.9 ± 0.5	1.3 ± 0.4	0.076
ADA (U/l)	2.3 ± 0.2	2.9 ± 1.0	3.9 ±2.6	0.433
ALT (IU/L)	30.7 ± 5.4	43.3 ± 1.5	56.4 ± 20.7^*	0.03
AST(IU/L)	27.2 ± 3.4	31.3 ± 8.0	27.2 ± 10.1	0.737
Urea	3.8 ± 0.9	5.00 ± 1.1	5.8 ± 1.3^*	0.034
Creatinine	99.8 ± 4.6	61.0 ± 16.5^*	50.8 ± 18.5^*	0.002
CK-MB	1.2 ± 0.6	1.9 ± 1.2	3.4 ± 2.6	0.517
HCT (%)	43.0 ± 3.3	41.9 ± 8.2	38.1 ± 2.2	0.241
FBG, fasting blood glucose; HbAlc, glycosylated hemoglobin; Hct, hematocrit; TC, total cholesterol; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; ADA, adenosine dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK-MB, creatine kinase-MB; HCT, hematocrit.
*p < 0.05 compared with control.
#p < 0.05 compared with the pigs with low HbAlc.

3.2 Myocardial Fibrosis, Cardiac Deformation, And Histopathological Staining

There was no LGE detected in any of the diabetic pigs. However, pigs with high HbAlc had higher native T1 in the global and basal myocardium (p = 0.022 and 0.016, respectively) compared with controls (Table 2). In pigs with low HbAlc, native T1 in the global or regional myocardium showed no differences from controls and pigs with high HbAlc (all p > 0.05). Both pigs with low and high HbAlc had higher ECV than the controls in the mid myocardium (p = 0.019 and 0.005, respectively) (Fig. 1). In the pigs with high HbAlc and controls, there was no statistically significant change in either native T1 in the mid and apical myocardium or ECV in the global, basal, and apical myocardium (all p > 0.05). Representative CMR images of LGE, native T1, ECV maps, and AGEs and Masson staining from the control and diabetes groups are shown in Fig. 2. Histopathologically, collagen fibers were stained with aniline blue, and cardiomyocytes were stained red. Under light microscopy, the pig with high HbAlc had more myocardial interstitial collagen fibrosis and AGEs staining than the pig with low HbAlc and control.

Table 2

Cardiac magnetic resonance imaging parameters.
	Controls	Diabetic pigs		p
	Controls	Low HbAlc	High HbAlc	p
LV EDV (ml)	55.4 ± 20.8	30.3 ± 16.9	27.3 ± 10.0	0.104
LV ESV (ml)	17.7 ± 9.0	7.1 ± 1.3	7.8 ± 4.0	0.168
LV EF (%)	69.1 ± 8.6	65.6 ± 19.0	61.2 ± 4.2	0.784
LV CO	3.7 ± 0.3	2.3 ± 1.5^*	1.6 ± 0.3^*	0.017
LV SV (ml)	37.7 ± 12.6	23.2 ± 15.6	19.5 ± 6.0	0.112
LV diastolic mass (g)	72.9 ± 10.2	66.5 ± 11.6	52.7 ± 7.7^*	0.02
Left ventricular ejection fraction (LVEF); left ventricular end-systolic volume (LVESV); left ventricle end-diastolic volume (LVEDV); left ventricular stroke volume (LVSV); left ventricular cardiac output (LV CO).
*p < 0.05 compared with controls.
#p < 0.05 compared with the pigs with low HbAlc.

Table 3

Native T1, ECV and longitudinal deformation parameters.
	Controls	Diabetic pigs		p
	Controls	Low HbAlc	High HbAlc	p
Global LS (%)	-14.6 ± 1.7	-9.6 ± 3.5	-6.4 ± 3.0^*	0.021
Basal LS (%)	-14.5 ± 1.5	-13.3 ± 3.9	-10.2 ± 2.9	0.298
Mid LS (%)	-14.8 ± 4.7	-9.0 ± 2.7	-6.6 ± 1.9^*	0.044
Apical LS (%)	-10.4 ± 3.2	-9.0 ± 1.8	-11.0 ± 6.2	0.716
Global LSSR (1/s)	-1.2 ± 0.2	-1.0 ± 0.3	-0.5 ± 0.1^*	0.044
Basal LSSR (1/s)	-1.1 ± 0.2	-1.3 ± 0.7	-0.6 ± 0.6	0.77
Mid LSSR (1/s)	-1.3 ± 0.1	-0.8 ± 0.01	-0.6 ± 0.1^*	0.024
Apical LSSR (1/s)	-0.6 ± 0.1	-0.9 ± 0.3	-0.8 ± 0.1	0.24
Global LDSR (1/s)	1.3 ± 0.5	0.7 ± 0.3	0.5 ± 0.2	0.052
Basal LDSR (1/s)	1.5 ± 0.9	0.7 ± 0.3	0.5 ± 0.2	0.239
Mid LDSR (1/s)	1.4 ± 0.4	0.7 ± 0.0	0.5 ± 0.2^*	0.037
Apical LDSR (1/s)	1.2 ± 0.7	1.0 ± 0.4	0.7 ± 0.4	0.513
Global Native T1 (ms)	1156 ± 11	1194 ± 28	1220 ± 43^*	0.024
Basal Native T1 (ms)	1143 ± 14	1170 ± 21	1213 ± 40^*	0.02
Mid Native T1 (ms)	1166 ± 13	1210 ± 36	1225 ± 46	0.064
Apical Native T1 (ms)	1160 ± 15	1206 ± 37	1225 ± 56	0.154
Global ECV (%)	21.6 ± 2.7	22.8 ± 2.8	26.7 ± 3.2	0.077
Basal ECV (%)	21.9 ± 1.5	22.5 ± 3.2	24.7 ± 2.8	0.361
Mid ECV (%)	21.3 ± 2.8	22.3 ± 2.6^*	27.6 ± 2.4^*	0.011
Apical ECV (%)	21.8 ± 4.4	23.3 ± 2.5	28.2 ± 6.5	0.271
Longitudinal peak strain (LS); longitudinal peak systolic strain rate (LSSR); peak diastolic strain rate (LDSR); ECV, extracellular volume.
*p < 0.05 compared with controls.
#p < 0.05 compared with the pigs with low HbAlc.

There was no statistically significant difference in left ventricular EF between the diabetes and control groups (p = 0.784). However, when compared to controls, pigs with high HbAlc showed lower LS and LSSR in the global myocardium (LS, p = 0.007; LSSR, p = 0.039) (Fig. 1). Furthermore, pigs with high HbAlc had lower LS, LSSR, and LDSR in the mid myocardium than controls (LS, p = 0.019; LSSR, p = 0.023; LDSR, p = 0.013) but not in the basal or apical myocardium (all p > 0.05). The strain and strain rate from the radial and circumferential directions either in global or regional myocardium did not differ between the control and the diabetic groups (all p > 0.05) (S1).

3.3 Associations Between Hbalc, Myocardial Fibrosis, And Cardiac Deformation

In the global, basal, mid, and apical myocardium, HbAlc demonstrated good correlations with native T1 (R² = 0.555 to 0.649, all p < 0.05) (Fig. 3); HbAlc also demonstrated good correlations with ECV (R² = 0.470 to 0.720, all p < 0.05), but not with ECV in the basal myocardium (p = 0.059). In the mid myocardium, we discovered that HbAlc significantly correlated with both LSSR and LDSR (R² = 0.849 and 0.810).

3.4 Intra- And Interobserver Reliability

In a subgroup of 96 segments, the ICCs for intra- and interobserver variability in native T1 were 0.926 and 0.944, respectively. The ICCs for intra- and interobserver variability in ECV were 0.906 and 0.929, respectively.

Based on measures of CMR strain and T1 mapping in a long-term large animal model, this study aimed to investigate the impact of HbAlc on DM-related specific cardiac impairments. Pigs with high HbAlc exhibited higher native T1, higher ECV, and lower longitudinal strain and strain rates, according to our research. Also, our study discovered good correlations between HbAlc and native T1, ECV, LSSR, and LDSR.

Even in pigs with long-lasting diabetes, we did not find any indication of LGE indicative of replacement fibrosis or focal necrosis in the current animal study. But our data demonstrated that both ECV and native T1 were higher in pigs with poor glycemic control. ECV indicates the proportion of extracellular matrix occupied mostly by the interstitium, whereas native T1 measurement characteristics represent combined effects in intra- and extracellular components [20]. Both parameters can quantitatively assess the severity of interstitial collagen fibrosis in the absence of a reference value [20]. Because of these characteristics, the CMR T1 mapping technique outperforms LGE in the assessment of diffuse interstitial fibrosis. Additionally, ECV in pigs with low HbAlc was still higher than in controls prior to the significant alterations in LV cardiac deformation and LVEF. Long-term fibrosis accumulation can lead to myocardial ischemia and hypoxia, and further, impair cardiac dysfunction [21]. CMR T1 mapping might be an effective approach to detect early and subtle subclinical myocardial tissue changes.

Our findings of impaired longitudinal strain and strain rate in the diabetic pig model prior to reduced LV EF are consistent with previous findings of cardiac strain changes in DM animal models [22], children [23, 24], and adults [25] with DM. We here further examined myocardial deformation alterations at the regional level and discovered that the mid myocardium had decreased longitudinal strain and strain rate but not the basal or apical myocardium. This might be attributed to the differences in hemodynamics and myocardial mechanic structure. It needs to be further studied if this may be due in part to a unique pattern in diabetic heart disease of sparing of longitudinal strain in basal and apical segments, while mid segments have depressed regional strain. Longitudinal strain is primarily affected by subendocardial longitudinal myofibers, which are most vulnerable to the deposition of myocardial fibrosis and impairment in the microcirculation [26]. The circumferential and radial strains of the myocardium, respectively, serve as the primary indicators of the changes in the length of the subepicardial myocardium and the thickness of the myocardium from the epicardium to the endocardium in the axial, which typically occur during the further progression of the diseases [27]. In our study, significant alterations did not be observed in circumferential and radial strain. These results suggested that the subclinical impairment in longitudinal deformation in DM pigs might represent an early sign of cardiac dysfunction and improve the risk prediction of major adverse cardiovascular events in patients with DM [28].

In recent years, a large human cohort study has reported that AGEs, which are derived from skin collagen glycation, had significant associations with the risk of subclinical cardiovascular disease [29]. Here, we used pig myocardial tissue for histological Masson and AGEs staining. We found that the diabetic pig with poor glycemic control had more myocardial interstitial fibrosis and AGEs deposition which was consistent with the CMR findings. Excess glycemic exposure may lead to reduced production of ATP and impairment in the uptake of Ca + + by the sarcoplasmic reticulum of cardiomyocytes as well as the formation of interstitial fibrosis, which thereby interfere with diastole and contraction [30–33]. We could speculate that the poor glycemic control caused greater accumulating AGEs, which is closely related to cumulative glycemic damage, which might be responsible for myocardial impairment in DM.

It has been shown that HbAlc could be used as a clinical evaluation index for glycemic control [3] and offered guidance for clinical management by facilitating greater ease of interpretation for patients and clinicians of the risk and development of diabetes complications [3]. The expanding interest in our study linking HbAlc to cardiac abnormal changes emphasizes the need for tight glycemic control to lessen the harmful effects of excess glucose, especially on the myocardial impairment.

Our study has several limitations. First, this was a relatively small study. However, this exploratory research was the first to create a large and long-duration animal model of the adverse impact of HbAlc on myocardial alterations and still provided some positive findings for further research. Thus, future studies should include more subjects to avoid possible type 1 errors and validate the results, especially in human beings with large cohorts. Second, in consideration of the maintenance of the model for exploring more findings regarding DCM, we only sacrificed three pigs for microscopic observation. Although myocardial changes, as expected, were observed in this study, quantitative measurements of these biomarkers in larger samples also need to be determined.

In conclusion, pigs with high HbAlc correlated well with higher native T1 and ECV and lower longitudinal deformation in DM pigs. T1 mapping and FT technique CMR-based assessment of myocardial fibrosis and cardiac deformation may have the potential as a non-invasive tool for the evaluation of subclinical myocardial alterations. Furthermore, HbAlc might have great potential as a clinical marker in the assessment of myocardial impairment in DM.

DM, Diabetes mellitums; HbAlc, Hemoglobin;AGEs, advanced glycation end products; CMR, cardiac magnetic resonance; ECV, extracellular volume; LGE, late enhancement gadolinium; FT, feature tracking; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVEDV, left ventricle end-diastolic volume; LVSV, left ventricular stroke volume; LVCO, left ventricular cardiac output; RS, Radial peak strain; RSSR, radial peak systolic strain rate; RDSR, peak diastolic strain rate; CS, circumferential peak strain; CSSR, circumferential peak systolic strain rate; CSDR, peak diastolic strain rate; LS, longitudinal peak strain; LSSR, longitudinal peak systolic strain rate; LDSR, peak diastolic strain rate; ICC, intraclass correlation coefficients.

Ethics approval and consent to participate

The Animal Ethics Committee at West China Hospital, Sichuan University, approve all animal experimentation methods, which were followed in full. All animal experiments were executed conforming to the “Guide for the Care and Use of Laboratory Animals” and in compliance with the ARRIVE guidelines.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Finding

This work was supported by the National Natural Science Foundation of China (82120108015, 81971586, 81771897, 82102020, 82071874, 81901712, 82271981 and 81771887); Sichuan Science and Technology Program (2020YFS0050, 2020YJ0029, 2017TD0005, 21ZDYF1967 and 2021YFS0175); Fundamental Research Funds for the Central Universities (SCU2020D4132); Clinical Research Finding of Chinese Society of Cardiovascular Disease (CSC) of 2019 (No. HFCSC2019B01) and “1•3•5 project for disciplines of excellence, West China Hospital, Sichuan University” (ZYGD18019).

Authors' contributions

Authors' contributions: Zl: Conceptualization, Methodology, Data analysis and interpretation, Original draft; GYK: Conceptualization, Methodology, Review & Editing; YZG: Resources, Methodology; JL: Methodology, Editing, Data analysis, and interpretation; YWF: Methodology; XHY: Supervision, Project administration, Review & Editing. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

Supplementarytable1.docx

The relationship between abnormal myocardial alterations and glycemic control validated by cardiac magnetic resonance in a pig model of diabetes mellitus

Status:

Version 1

Abstract

Aims

Methods

Results

Conclusions

Figures

Introduction

Subjects, Materials, And Methods

2.1 Animals

2.2 Preparation For Cardiovascular Magnetic Resonance

Results

3.1 General and Biochemical Information

3.3 Associations Between Hbalc, Myocardial Fibrosis, And Cardiac Deformation

3.4 Intra- And Interobserver Reliability

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1