# Increased epicardial adipose tissue is part of the phenotype of LMNA-associated partial lipodystrophy and could contribute to increased cardiovascular risk

Sophie Lamothe, Patricia Ancel, Inès Belalem, Leïla Boubekeur-Lecaque, Joris Fournel, Alexis Jacquier, Zouhair Houhou, Jean-Baptiste Julla, Jean-François Gautier, Corinne Vigouroux, et al.

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Sophie Lamothe, Patricia Ancel, Inès Belalem, Leïla Boubekeur-Lecaque, Joris Fournel, et al. In-creased epicardial adipose tissue is part of the phenotype of LMNA-associated partial lipodystrophy and could contribute to increased cardiovascular risk. Diabetes & Metabolism, 2025, 51 (6), pp.101710. 10.1016/j.diabet.2025.101710. hal-05396420

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# Increased epicardial adipose tissue is part of the phenotype of LMNA-associated partial lipodystrophy and could contribute to increased cardiovascular risk

Sophie Lamothe<sup>a,†,*</sup> <u>&#x20DD;</u>, Patricia Ancel<sup>b,†</sup>, Inès Belalem<sup>a</sup>, Leïla Lecaque<sup>a</sup>, Joris Fournel<sup>c</sup>, Alexis Jacquier<sup>c,d</sup>, Zouhair Houhou<sup>c</sup>, Jean-Baptiste Julla<sup>e,f</sup>, Jean-François Gautier<sup>e,f</sup>, Corinne Vigouroux<sup>a,g</sup>, Bénédicte Gaborit<sup>b,h</sup>, Camille Vatier<sup>a,g</sup>

## ARTICLE INFO

### Keywords:

CAC score

Cardiac computed tomography

Cardiovascular diseases

Deep learning

Diabetes type 2

Epicardial adipose tissue

Lipodystrophy

## ABSTRACT

LMNA-associated familial partial lipodystrophy (FPLD2) is characterized by limb lipoatrophy, cervicofacial and visceral abdominal lipohypertrophy, insulin resistance-related complications and early coronary artery disease (CAD), but epicardial adipose tissue (EAT) is poorly described. We aimed to characterize EAT as a potential new marker of cardiovascular risk in patients with FPLD2. Using a validated deep-learning algorithm, we measured EAT volume from cardiac CT-scans routinely performed for coronary artery calcium (CAC) scoring in patients with FPLD2 (n = 26, 24 women, 65 % with diabetes, median age 49 [32;57] years) compared to patients with type-2 diabetes (T2D) (n = 44, 40 women, age 49 [41;59], p = 0.18). Although lower BMI (23.3 [21;26.6] vs. 27.2 [24.7;29.6], P = 0.03) and HbA1c (6.5 [5.8;7.7] vs. 7.8 [7;8.5] %, P = 0.003) in patients with FPLD2 vs. T2D, EAT volume (110 [72;150] vs. 60 [42;78] ml, P < 0.001) and prevalence of CAD (19 vs. 2 %, P = 0.003) were higher. EAT was positively related to CAC score in the FPLD2 group. Our findings support that EAT is increased in patients with FPLD2 and represents a specific ectopic adipose tissue which could contribute to the increased cardiovascular risk.

## Introduction

Lipodystrophy syndromes (LD) are rare disorders characterized by anatomical and functional defects of adipose tissue, with severe insulin resistance, dyslipidemia, hepatic steatosis and an increased risk of cardiovascular disease [1,2]. LMNA-associated familial partial lipodystrophy (Dunnigan disease, FPLD2) is characterized by lipoatrophy of limbs, contrasting with cervicofacial and abdominal visceral fat

accumulation [3,4]. FPLD2 is associated with early atherosclerosis which could result from metabolic risk factors, including ectopic fat storage, and direct deleterious effects of LMNA variants on the arterial wall [5,6].

Although epicardial adipose tissue (EAT), a visceral adipose tissue depot adjacent to the myocardium, was shown to contribute to the risk of cardiovascular diseases [7], it was previously evaluated in only a few patients with FPLD2, by transthoracic echocardiography [8].

<footnote><sup>a</sup> Endocrinology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Antoine University Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France</footnote>

<footnote><sup>b</sup> Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France</footnote>

<footnote><sup>c</sup> Aix Marseille Univ, CNRS, CRMBM, Marseille, France</footnote>

<footnote><sup>d</sup> Department of Radiology, Hôpital de la Timone, AP-HM, Marseille, France</footnote>

<footnote><sup>e</sup> IMMEDIAB Laboratory, Institut Necker Enfants Malades (INEM), CNRS UMR 8253, INSERM U1151, Université Paris Cité, 75015, Paris, France</footnote>

<footnote><sup>f</sup> Diabetology and Endocrinology Department, Fédération de Diabétologie, Université Paris Cité, Lariboisière Hospital, APHP, 75015, Paris, France</footnote>

<footnote><sup>g</sup> Sorbonne University, Inserm UMR S 938, Saint-Antoine Research Centre, Cardiometabolism and Nutrition University Hospital Institute (ICAN), Paris, France</footnote>

<footnote><sup>h</sup> Department of Endocrinology, Metabolic Diseases and Nutrition, Pôle ENDO, Chemin des Bourrely, APHM, Hôpital Nord, 13915 Marseille Cedex 20, Marseille, France</footnote>

<footnote>* Corresponding author at: Endocrinology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Antoine University Hospital, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), European Reference Network for Rare Endocrine Conditions (Endo-ERN Assistance-Publique Consortium), Paris, France.</footnote>

<footnote>E-mail address: sophie.lamothe@aphp.fr (S. Lamothe).</footnote>

<footnote>† S.L and P.A. contributed equally to this work and are joint first authors.</footnote>
Since echography does not allow to precisely measure the total amount of EAT, we aimed at quantifying the total epicardial fat volume in patients with FPLD2 using a previously validated semi-automated method, based on an algorithm trained on low-dose cardio-centric chest computed tomography (CT) images originally intended for coronary artery calcium (CAC) score assessment [9].

EAT volume, measured in a series of patients with FPLD2 recruited through a national rare disease center and screened for macrovascular disease with CAC scoring, was compared to patients with type 2 diabetes (T2D) of similar age and gender included in the EPIDIAB study, a post-hoc analysis of the Angiosafe-T2D study (NCT02671864). We also evaluated whether epicardial fat volume correlates with total body fat, cardiovascular and metabolic markers, and CAC scoring in patients with FPLD2.

## Methods

### Patients and data

This retrospective study included 26 consecutive patients with FPLD2 (24 women) who underwent non-contrast cardiac CT for CAC scoring in the coordinating Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), AP-HP Saint-Antoine Hospital, France.

Patients' data were included in the BNDMR French National Rare Disease Database (CNIL # 2211,418). The study adhered to the principles of the Declaration of Helsinki, and informed consent was obtained from all patients for data collection.

We collected demographic (age, sex) and cardiometabolic data: smoking status, body mass index (BMI), presence of hypertension (>140/90 mmHg or antihypertensive treatment) and of coronary artery disease (CAD), glycated hemoglobin (HbA1c), fasting HDL- and LDL-cholesterol, triglycerides, liver enzymes, and high-sensitivity C-reactive protein (hsCRP). Imaging of body fat percentage using dual-energy X-ray absorptiometry (DEXA), vibration-controlled hepatic transient elastography (VCTE) and controlled attenuation parameter (CAP) using FibroScan® (Echosens, France) were acquired.

The results were compared to those of 44 patients (40 women) with T2D from the previously described AngiosafeDT2 cohort (NCT02671864), who had undergone CAC scoring for primary prevention of atherosclerotic cardiovascular disease [9,10], with non-statistically different sex and gender.

### Quantification of EAT volume

We used a previously described deep-learning-based method for quantifying EAT volume using non-contrast cardiac CT performed for CAC scoring in patients without coronary stents to avoid any misinterpretation. EAT was defined as the intra-pericardial volume with fat density between -190 and -30 HU [9,11].

### Statistical analyses

Descriptive statistics included median [25th – 75th percentile] for continuous variables and frequencies for categorical variables. Unpaired t-tests or Mann-Whitney tests (non-parametric) and Pearson or Spearman (non-parametric) correlations were used to compare the FPLD2 and T2D groups. For categorical data, Fischer's tests were used. Multivariate analyses were performed using a linear regression model. Values were considered statistically significant when *P* < 0.05. Statistical analyses were performed using GraphPad Prism and RStudio.

## Results

A total of 26 patients with FPLD2 (median age 49 [32;57] years; 92% female) and 44 patients with T2D (median age 49 [41;59] years; 91%

female) were included. Anthropometric, and cardiometabolic characteristics are depicted in Table S1 (see supplementary materials associated with this article on line). The patients with FPLD2 carried the heterozygous LMNA variants p.(Arg482Trp)(n = 8), p.(Arg482Gln)(n = 6), p.(Arg482Leu)(n = 3), p.(His506Asp)(n = 3), p.(Arg28Trp)(n = 2), p. (Asn466Asp)(n = 2), p.(Arg60Pro)(n = 1), or p.(Arg527Pro)(n = 1).

Patients with FPLD2 had a median BMI of 23.3 kg/m² [IQR 21–26.6] with a low amount of total fat mass (20.7 % [14.9–25.6]). Despite their young age, 35 % of the patients with FPLD2 (n = 9) already experienced cardiac events, including 4 patients with arrhythmic heart disease and 5 patients with CAD, including patients with coronary stents or bypass grafts, or regional wall motion abnormalities on echocardiography. Among the 3 patients with coronary stents: 2 of them had undergone CAC scoring before stent placement and one patient had inconclusive CAC scoring results due to the stents.

There were no significant differences in age, gender, smoking exposure, prevalence of hypertension, LDL-cholesterol values, hsCRP and liver enzymes between the two groups (Table S1; see supplementary materials associated with this article on line). Transient elastography, performed in 11 patients with FPLD2 and 25 patients with T2D revealed a median score of 5.6 kPa [5.1–9.5] and 5.3 kPa [4.4–5.8] respectively, in favour of a low risk of advanced liver fibrosis in both groups. Significant liver steatosis, defined as CAP values ≥ 250 dB/min, similarly affected patients with FPLD2 (9 among 10) or T2D (19 among 25, *P* = 0.64).

As compared to patients with T2D, patients with FPLD2 had lower BMI (23.3 [21–26.6] vs. 27.2 kg/m², *P* = 0.003), lower diabetes prevalence (65 vs. 100 %, *P* < 0.001), and lower HbA1c levels (6.5 [5.8;7.7] vs. 7.8 [7;8.5] %, *P* = 0.003). However, they had significantly higher triglycerides (2.64 [1.71;4.02] vs. 1.41 [0.88;2.03] mmol/l, *P* < 0.001) and higher median EAT volume (110 [72;150] vs. 60 [42;78] ml, *P* < 0.001) (Fig. 1). EAT volume was positively correlated with BMI (*r* = 0.62; *P* = 0.001) and with CAC score in patients with FPLD2 (*r* = 0.42; *P* = 0.04). In patients with T2D, but not with those with FPLD2, EAT was positively correlated with triglycerides (*r* = 0.31, *P* = 0.04 and *r* = -0.05; *P* = 0.81, respectively). Multivariate analysis adjusting for potential confounders (hypertension, triglycerides, HDL-cholesterol and smoking status) confirmed the association between EAT and CAC score (*P* = 0.003).

We did not find any association between EAT and age (*r* = 0.31; *P* = 0.13), body fat mass (*r* = 0.20; *P* = 0.45), nor with leptin levels (*r* = 0.03; *P* = 0.91), adiponectin levels (*r* = -0.48; *P* = 0.14) or CAP (*r* = -0.18 *P* = 0.63) in patients with FPLD2.

## Discussion

This study demonstrated that increased EAT volume is part of the phenotype of LMNA-associated partial lipodystrophy. Despite their lower BMI, patients with LMNA-associated partial lipodystrophy have a greater EAT volume than patients with T2D of similar age and gender. A previous study also pointed an increased EAT in FPLD2 [8], but only 6 patients were investigated and EAT thickness was assessed with thoracic echocardiography. Our study involved a significant number of patients, given the rarity of the disease, and our high-resolution deep-learning-based validated method allowed us to measure with precision the total volume of epicardial fat, providing a more relevant quantification of the epicardial adipose tissue compared to echocardiography [12].

Our findings also demonstrate that EAT volume is correlated with CAC scoring and BMI in patients with FPLD2. Although patients with FPLD2 presented with a higher prevalence of CAD, no significant difference in the CAC score was observed between the two groups. Therefore, EAT volume may represent a better marker of cardiovascular risk than the CAC score in this population with lipodystrophy.

EAT is distinct from other visceral fat depots. Its direct contacts with the myocardium and coronary arteries enable bidirectional crosstalks,
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Measurement of epicardial adipose tissue volume in patients with FPLD2 or type 2 diabetes from the EPIDIAB study (T2D). Measurements were performed using a previously validated automated algorithm analyzing non-contrast cardiac CT performed for CAC scoring. Values are expressed as median [25th-75th percentile]. Representative images showing the increased EAT volume in patients with FPLD2 as compared with patients with T2D are shown. A, anterior; P, posterior; L, left; R, right; S, superior; I, inferior. *** P 0.001.</figcaption></figure>

facilitating paracrine and vasocrine interactions between adipocytes, cardiomyocytes, and cells of the vascular wall [12]. EAT is an essential effector of innate immunity, producing both pro-inflammatory and regulatory cytokines [13].

The present study characterized EAT in patients with FPLD2 compared with patients living with T2D. Although a positive correlation between EAT volume and CAC scoring was observed in patients with FPLD2, we did not find any significant associations between EAT volume and other FPLD2-associated specific metabolic parameters such as total fat mass, leptin, or adiponectin.

Similarly, Brown et al. previously found that visceral adipose tissue did not correlate with metabolic disturbances in patients with generalized, but also partial, lipodystrophy [14].

It was previously shown in the general population that increased EAT is an independent risk factor for CAD [7]. As suggested by the positive correlation between EAT and CAC score identified in patients with FPLD2 from this study, increased EAT volume could contribute to the early coronary atherosclerotic disease described in the disease [5,6].

In addition, in patients with the phospholamban PLN p.(Arg14del) pathogenic variant, ventricular EAT accumulation was confirmed to be associated with a higher incidence of malignant ventricular arrhythmias [15]. Although it is not possible from our data to know whether increased EAT could contribute to FPLD2-associated specific cardiac rhythm disturbances, it would be of interest to measure EAT in larger cohorts of patients with FPLD2 and/or in patients with LMNA-associated cardiomyopathy to explore this hypothesis.

Our new findings suggest that the measurement of EAT from CAC-based cardiac CT-scans, adaptable in routine, could be considered by clinicians in order to better evaluate the lipodystrophy phenotype and the risk of coronary artery disease. In addition, the observed correlation between EAT and BMI underscores the critical importance of effective weight management in patients with FPLD2.

## Funding

This work was supported by the French Ministry of Solidarity and Health, Assistance Publique-Hôpitaux de Paris and Sorbonne University, France.

## CRediT authorship contribution statement

**Sophie Lamothe:** Writing – review & editing, Writing – original draft, Visualization, Validation, Investigation, Data curation, Conceptualization.
**Patricia Ancel:** Validation, Supervision, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization.
**Inès Belalem:** Formal analysis.
**Leïla Lecaque:** Validation.
**Joris Fournel:** Validation.
**Alexis Jacquier:** Validation.
**Zouhair Houhou:**

**Conceptualization.** **Jean-Baptiste Julla:** Validation. **Jean-François Gautier:** Validation. **Corinne Vigouroux:** Validation, Supervision.
**Bénédicte Gaborit:** Validation, Supervision, Project administration, Conceptualization. **Camille Vatier:** Visualization, Validation, Supervision.

## Declaration of competing interest

No potential conflict of interest relevant to this article was reported.

## Acknowledgements

We thank the patients who participated in this study, Pr Jean-Philippe Bastard and Dr Soraya Fellahli for adiponectin and leptin measurements in patients with FPLD2.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.diabet.2025.101710.

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