Unveiling Myocardial Microstructure Shifts: Exploring the Impact of Diabetes in Stable CAD Patients through CMR T1 Mapping

doi:10.21203/rs.3.rs-4287075/v1

Background: This study investigates myocardial structural changes in stable coronary artery disease (CAD) patients with type 2 diabetes using cardiac magnetic resonance (CMR) strain and T1 mapping.

Methods: A total of 155 stable CAD patients underwent CMR examination, including LV morphology and function assessment, late gadolinium enhancement (LGE), and feature tracking (CMR-FT) for LV global longitudinal, circumferential, and radial strain. T1 mapping with extracellular volume (ECV) evaluation was also performed.

Results: Among the enrolled patients, 67 had type 2 diabetes. Diabetic patients exhibited impaired LV strain and higher ECV compared to non-diabetics. Multivariate analysis identified type 2 diabetes as an independent predictor of increased ECV and decreased strain.

Conclusions: CMR-based T1 mapping highlights impaired myocardial contractility, elevated ECV, and potential interstitial fibrosis in diabetic patients with stable CAD. This suggests a significant impact of diabetes on myocardial health beyond CAD, emphasizing the importance of comprehensive assessment in these individuals.

Type 2 Diabetes Mellitus

Coronary Artery Disease

T1 mapping

Cardiac Magnetic Resonance - Feature Tracking

Extracellular Volume

Type 2 diabetes (T2D) is a robust independent cardiovascular risk factor for major cardiac events and significantly increases the likelihood of developing heart failure (HF) (1, 2). While coronary artery disease (CAD) and ischemic cardiomyopathy remain the primary causes of HF in T2D, other pathophysiological processes contribute to myocardial structural derangements (3, 4, 5). Hyperglycemia, insulin resistance, neurohormonal dysregulation, autonomic neuropathy, and cellular metabolic disorders collectively form a complex mechanism underlying diabetic cardiomyopathy (23). Early recognition of this disease enables timely implementation of therapeutic strategies for improved clinical management and potential intervention to slow its progression.

Cardiac magnetic resonance (CMR), with recent advancements, allows detailed characterization of cardiac structures through both anatomical and functional analysis. CMR tissue-tracking technology, compared to echocardiography, offers access to deformation parameters in post-processed cine images with simpler application and improved image quality (17, 18). Furthermore, T1 relaxation time mapping provides a non-invasive approach to assess both cellular and interstitial compartments, enabling unique pathological correlation (19). Extracellular volume (ECV) evaluation can detect early myocardial tissue changes, reflecting potential interstitial matrix alterations or diffuse fibrosis (6, 7, 8). Studies evaluating tissue changes in T2D have shown impaired global longitudinal strain (GLS) in non-ischemic diabetic patients compared to controls (20, 21). However, findings regarding native T1 and ECV values in diabetic patients with preserved left ventricle ejection fraction (LVEF) compared to normal controls remain inconsistent, particularly due to the lack of comprehensive CAD assessment (9, 10, 11, 22).

We hypothesize that T2D, independent of CAD, is associated with structural myocardial changes, and that CMR strain and T1 mapping can identify these alterations. Therefore, we aim to study patients with stable coronary artery disease with and without type 2 diabetes .

Patient Selection

This subanalysis delves into the comprehensive dataset generated by the prospective trial titled "Accuracy of Myocardial Biomarkers in the Diagnosis of Myocardial Infarction After Revascularization as Assessed by Cardiac Resonance: The Medicine, Angioplasty, Surgery Study V (MASS-V)". Details on study design and protocol are published elsewhere (12). In summary, a total of 202 patients were enrolled, meeting the criteria of having multivessel coronary artery disease (CAD) with normal left ventricular ejection fraction (LVEF), and an indication for coronary artery bypass grafting (CABG) or percutaneous coronary intervention. Individuals with recent (<6 months) myocardial infarction, overt or suspected infections, active rheumatologic diseases, chronic renal failure (creatinine > 2.0 mg/dL), recent (<6 months) pulmonary embolism or venous thromboembolism, and contraindications to cardiac magnetic resonance (CMR) such as pacemaker implantation or severe claustrophobia were excluded from the study. All enrolled patients underwent CMR within six days of the revascularization procedure. The study was conducted in accordance with the principles outlined in the Helsinki Declaration and received approval from the institutional ethics committee at the Heart Institute of the University of São Paulo Medical School, São Paulo, Brazil. Informed consent was obtained from all participants. Out of the original 202 patients, a subset of 155 individuals qualified for this subanalysis, with 35 excluded due to incomplete T1 mapping phases acquisition and 12 experiencing CMR image artifacts hindering proper analysis.

CMR, Strain, and T1 Mapping CMR examinations were conducted using a 1.5 Tesla Philips Achieva® scanner equipped with a dedicated 5-element phased-array cardiac surface coil, ensuring high-quality imaging. Electrocardiogram (ECG) synchronization was employed throughout the imaging process. Standard steady-state free precession (SSFP) cine sequences were acquired in both short and long axes of the left ventricle, capturing 30 cardiac phases to achieve sub-50 ms temporal resolution. Parameters such as left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and left ventricular mass (LVM) were measured and indexed to body surface area (BSA) (16). Late gadolinium enhancement (LGE) imaging was performed using phase-sensitive inversion recovery (PSIR) (15). CMR feature tracking (CMR-FT) was conducted using short-axis cine images and 2- and 4-chamber long-axis images. Manual delineation of end-diastolic left ventricular endocardial and epicardial contours in all images was followed by automated tracking, enabling the calculation of left ventricular global longitudinal strain (LVGLS), left ventricular global circumferential strain (LVGCS), and left ventricular global radial strain (LVGRS) (Figure 1). T1 mapping images were acquired utilizing the short modified Look-Locker inversion recovery (shMOLLI) technique in three short-axis slices (basal, middle, and apical). These images provided native T1, post-contrast T1, and extracellular volume (ECV) measurements (Figure 2) (13, 14). Native T1 was obtained before the administration of gadolinium-based contrast, while post-contrast T1 was acquired 15-20 minutes after intravenous injection of gadoterate meglumine (0.1 mmol/kg body weight). ECV was calculated using the formula: ECV = λ x (1-hematocrit [HT]). The partition coefficient (λ) was determined as λ = ΔR1myocardium/ΔR1blood, where ΔR1 represents the difference in relaxation rates (1/T1) before and after contrast administration. Notably, only segments without LGE were included in native T1, post-contrast T1, and ECV assessment. Trabeculae and papillary muscles were excluded from myocardial evaluation. All analyses were performed offline using dedicated commercial software (Cvi42) by two blinded observers. Discrepancies were resolved through consensus, or consultation with a third blinded observer if necessary.

Statistical Analysis

Continuous variables were described using means and standard deviations (SD) for normally distributed data or medians and interquartile ranges (IQR) for non-normal data. Categorical variables were presented as frequencies and percentages.

Comparisons between groups for categorical variables were performed using chi-squared tests, Fisher's exact tests, or likelihood ratio tests, depending on the number of expected cells per category. The Shapiro-Wilk test assessed normality of distribution for continuous variables. Normally distributed data were compared using Student's t-tests, while Mann-Whitney U tests were used for non-normal data. Univariate associations were evaluated with Pearson or Spearman correlation coefficients, depending on data normality.

Multivariate linear regression analysis explored the relationship between native T1, ECV, LVGLS, LVGCS, LVGRS, and the presence of T2D, additionally considering other relevant factors. Variables included in the model were clinically relevant or demonstrated statistical significance (p < 0.2 in univariate analysis).

All analyses were conducted using R software (version 3.6.2), with statistical significance set at p < 0.05.

Baseline Characteristics of the 155 patients are summarized in Table 1. Patients were classified as either T2D (n=67) or control (n=88). While clinical, laboratory, and angiographic data were generally similar between groups, T2D patients had a lower prevalence of current or past smoking (20% vs. 33%, p=0.03) and significantly higher hemoglobin A1c levels (7.7 ± 1.2% vs. 5.3 ± 0.7%, p<0.01). CMR Analysis Left ventricular volumes, mass, and LVEF did not differ between T2D and control groups (Table 2). However, T2D patients exhibited significantly lower global longitudinal strain (LVGLS), circumferential strain (LVGCS), and radial strain (LVGRS) compared to controls (-16.5% ± 2.3% vs. -17.5% ± 2.7%, p=0.03; -16.4% ± 2.6% vs. -17.4% ± 3.0%, p=0.04; 26.9% ± 5.9% vs. 29.5% ± 7.2%, p=0.02, respectively) (see Figure 3 for illustration). Despite similar native T1 and post-contrast T1 values between groups, T2D patients had significantly higher extracellular volume (ECV) (25.7% ± 2.6% vs. 23.5% ± 2.3%, p<0.01) (see Figure 4 for illustration). Relationship Between CMR Parameters and T2D Univariate analysis revealed no significant associations between native T1 or ECV and LVGLS, LVGCS, or LVGRS. Multivariate linear regression analysis, adjusting for clinically relevant covariates (age, sex, BMI, hypertension) and statistically significant covariates (heart rate, smoking status, creatinine, LVEF), confirmed that T2D was an independent predictor increased ECV (β=2.24, P<0.01), impaired LVGLS (β=0.72, P=0.02), impaired LVGCS (β=0.82, P=0.01), and impaired LVGRS (β=-2.22, P<0.01) were observed. As expected, LVEF was also correlated with reduced LVGLS (β=-0.19, P<0.01), LVGCS (β=-0.23, P<0.01), and LVGRS (β=0.52, P<0.01).

The present study demonstrated that patients with Type 2 Diabetes (T2D) exhibit decreased strain and higher extracellular volume (ECV) values in a stable coronary artery disease (CAD) setting, compared to controls, without notable differences in left ventricular (LV) structural parameters assessed by cardiac magnetic resonance (CMR). This association persisted even after adjusting for potential covariates. These findings may have implications for understanding and detecting diabetic cardiomyopathy.

In T2D, myocardial tissue is susceptible to higher rates of myocyte necrosis, collagen deposition, and interstitial fibrosis. Multiple factors contribute to the development of progressive myocardial damage and subsequent fibrosis, including hyperglycemia, increased oxidative stress, fatty acid availability, and activation of the renin-angiotensin-aldosterone system (4, 20). By utilizing CMR feature tracking and T1 mapping, we explored potential and accessible techniques for identifying patients at risk for adverse LV remodeling.

It is widely demonstrated that diabetes causes interstitial fibrosis and microvascular rarefaction and microvascular dysfunction. A general understanding is that these are the underlying factors causing diastolic dysfunction, which is highly prevalent in patients with type 2 diabetes. (30)

Our results revealed impaired LV global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS), and LV global radial strain (LVGRS) in diabetic patients, with no significant differences in mass or volumes, independently of T1 mapping analysis. These abnormalities in myocardial contractility may indicate a higher risk of future heart failure development, as LV strain can be employed to detect early subclinical myocardial dysfunction. The lack of association with ECV may suggest potential confounders, given that subtle differences in left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) are known to reduce LV strain (24, 25).

Although not statistically significant, there was a trend toward higher native T1 and lower post-contrast T1 in the myocardium of diabetic patients. As ECV depends on pre- and post-contrast T1 in the tissue, hematocrit, and pre- and post-contrast T1 in the blood, it can amalgamate slight differences in T1 values and better reflect changes in the extracellular matrix. Notably, higher ECV is associated with increased collagen volume fraction and myocardial fibrosis in histological comparison (17, 18, 19). LGE areas were excluded in the ECV analysis in this CAD patient study to assess only interstitial fibrosis in otherwise normal tissue. Furthermore, stable CAD is not known to affect the interstitial matrix in the absence of infarct. Our results emphasize that T2D patients have increased myocardial interstitial fibrosis compared to matched controls.

However, our study has limitations. Firstly, it was a single-center study with 155 subjects, a substantial number for CMR studies but possibly considered small for certain statistical analyses. Secondly, CMR has undergone extensive study in recent years, but differences in magnetic strengths, acquisition protocols, and standardized methods can yield varied results. We attempted to mitigate these limitations by selecting a homogeneous study sample. Thirdly, regional strain could be used to evaluate non-LGE segments, but significant overlap areas may occur, and the percentage of transmurality can yield different strain values. Furthermore, while the inclusion criteria specifically targeted patients with preserved ventricular function, it's crucial to acknowledge the limitation posed by the absence of specific data on diastolic dysfunction from echocardiography. Finally, being a cross-sectional study, inherent limitations are present, and a prospective study with clinical follow-up could provide additional data to support the development of diabetic cardiomyopathy following our results.

In this study, diabetic patients, when compared to control subjects with stable coronary artery disease, presented impaired myocardial contractility, with decreased left ventricular global strain (longitudinal, circumferential, and radial), as well as increased myocardial interstitial fibrosis assessed by T1 mapping ECV.

CMR - cardiac magnetic resonance

T1 mapping - T1 mapping

CMR-FT - cardiac magnetic resonance - feature tracking

ECV - extracellular volume

GLS - global longitudinal strain

LVEF - left ventricle ejection fraction

LVEDV - left ventricular end-diastolic volume

LVESV - left ventricular end-systolic volume

LGE - Late gadolinium enhancement

LVGLS - left ventricular global longitudinal strain

LVGCS - left ventricular global circumferential strain

LVGRS - left ventricular global radial strain

Authors' contributions

Each of the authors has made substantial contributions to this manuscript, either in conception and design or in the drafting of the article and critical revision for important intellectual content. G.A.B.B., W.H., and R M.R.G. researched data, contributed to discussion, and wrote the first draft of the manuscript. P.C.R., M.O.L.R., A.R.D. reviewed and edited the manuscript, E.G.L., C.H.N., and C.E.R. researched data and reviewed and edited the manuscript. J.A.F.R., R.K.F., contributed to discussion and reviewed and edited the manuscript. All authors approved the final version of the manuscript.

Acknowledgements

Medical writing support was provided by Ann Conti Morcos of MorcosMedia during the preparation of this paper, supported by the Zerbini Foundation.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Disclosures

None.

Ethics approval and consent to participate

The Ethics Committee of the Heart Institute of the University of São Paulo— Medical School, in São Paulo Brazil, approved the trial, and all procedures were performed in accordance with the Helsinki Declaration. All subjects gave informed consent.

Funding

Funding Financial support for the present study was provided by the Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP) under Nº 2011/20876-2. and, in part, by a research grant from the Zerbini Foundation, São Paulo, Brazil. Medical writing support was provided by Ann Conti Morcos during the preparation of this paper, supported by the Zerbini Foundation.

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Table 1. Baseline characteristics of the study population.

	T2D patients (n= 67)	Controls (n= 88)	*P value*
Age, yrs	62 ± 9	62 ± 10	0.57
Male, %	48 (72)	58 (66)	0.45
BMI, kg/m2	28.8 ± 4.2	27.4 ± 4.1	0.05
BSA, m2	1.8 ± 0.4	1.8 ± 0.2	0.57
Heart Rate, bpm	60 ± 8	57 ± 7	0.01
Current or past smoker, (%)	12 (20)	29 (33)	0.03
Hypertension, (%)	59 (88)	73 (83)	0.38
Previous myocardial infarct, (%)	23 (34)	30 (34)	0.97
3-vessel CAD, (%)	48 (72)	55 (63)	0.23
SYNTAX score	20 ± 8	20 ± 9	0.77
LABORATORY
Hematocrit , %	43 ± 4	43 ± 4	0.80
Creatinine, mg/dl	1.07 ± 0.2	1.02 ± 0.2	0.17
Cholesterol, mg/dl	171 ± 47	175 ± 48	0.55
LDL, mg/dl	99 ± 36	105 ± 39	0.42
HDL, mg/dl	38 ± 11	38 ± 13	0.86
Triglyceride, mg/dl	167 ± 110	167 ± 103	0.99
Hemoglobin A1C	7.7 ± 1.2	5.3 ± 0.7	< 0.01
MEDICATIONS
Acetylsalicylic acid, (%)	67 (100)	88 (100)	1
Statin, (%)	66 (98)	84 (95)	0.77
Other hypolipidemic drug, (%)	7 (10)	9 (10)	0.97
Beta blocker, (%)	60 (89)	80 (90)	0.86
ACE inhibitor, (%)	37 (55)	44 (50)	0.22
Angiotensin receptor blocker, %)	23 (34)	28 (32)	0.42
Calcium channel blocker, (%)	20 (30)	30 (34)	0.38
Metformin, (%)	54 (81)	4 (4)	< 0.01
Sulfonylurea, (%)	29 (43)	-
Insulin, (%)	22 (33)	-

Abbreviations: BMI, body mass index; BSA, body surface area; CCS, Canadian Cardiovascular Society; CAD, coronary artery disease; LDL low density lipoprotein; HDL, high density lipoprotein; ACE, angiotensin-converting enzyme.

Table 2. Cardiac magnetic resonance findings

	T2D (n= 67)	Controls (n= 88)	*P value*
LVEDVi, ml/m2	74.3 ± 16.0	73.0 ± 16.3	0.45
LVESVi, ml/m2	39.9 ± 8.3	40.9 ± 9.9	0.54
LVEF, %	54.9 ± 9.6	56.2 ± 9.0	0.42
LVMi, g/m2	53.4 ± 11.4	51.7 ± 11.8	0.40
LVGLS, %	-16.5 ± 2.3	-17.5 ± 2.7	0.03
LVGCS, %	-16.4 ± 2.6	- 17.4 ± 3.0	0.04
LVGRS, %	26.9 ± 5.9	29.5 ± 7.2	0.02
Native T1, ms	1015.5 ± 46.0	1003.8 ± 42.8	0.10
Post-contrast T1, ms	507.3 ± 35.9	516.8 ± 44.5	0.15
ECV, %	25.7 ± 2.6	23.5 ± 2.3	< 0.01

Abbreviations: LVEDV, left ventricular end-diastolic volume indexed to body surface area; LVESVi, left ventricular endsystolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVMi, left ventricular mass indexed to body surface area; LVGLS, left ventricle global longitudinal strain; LVGCS, left ventricle global circumferential strain; ECV, extracellular volume

Table 3. Multivariate adjusted analysis of T1 mapping and strain

	Native T1		Post-contrast T1		ECV		LVGLS		LVGCS		LVGRS
	β	P value	β	P value	β	P value	β	P value	β	P value	β	P value
T2D	11.47	0.13	-11.57	0.09	2.24	<0.01	0.72	0.02	0.82	0.01	-2.22	<0.01
Age	0.27	0.52	-0.03	0.94	0.02	0.36	0.00	0.88	-0.01	0.39	0.07	0.13
Sex	-8.59	0.33	20.52	<0.01	-1.17	0.02	0.50	0.16	0.64	0.07	-1.68	0.06
BMI	-1.05	0.25	-2.06	0.01	-0.08	0.12	0.07	0.06	-0.01	0.70	0.04	0.65
Hypertension	-5.24	0.62	1.68	0.86	0.34	0.57	0.08	0.86	-0.28	0.51	1.13	0.29
Heart Rate	0,70	0.16	1.10	0.01	0.02	0.56	-0.04	0.06	0.00	0.83	0.01	0.81
Current or past smoker	4.46	0.60	0.22	0.98	0.07	0.88	0.24	0.49	0.51	0.13	-1.25	0.15
Creatinine	12.95	0.44	-40.59	<0.01	0.31	0.74	0.46	0.50	-0.04	0.95	-0.48	0.78
LVEF	0.21	0.60	-0.37	0.31	-0.02	0.51	-0.19	<0.01	-0.23	<0.01	0.52	<0.01

Abbreviations: ECV, extracellular volume; LVGLS, left ventricle global longitudinal strain; LVGCS, left ventricle global circumferential strain; T2D, type 2 diabetes ; BMI, body mass index; LVEF, left ventricular ejection fraction.

No competing interests reported.

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Unveiling Myocardial Microstructure Shifts: Exploring the Impact of Diabetes in Stable CAD Patients through CMR T1 Mapping

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