Assessment of Myocardial Fibrosis in Marfan Syndrome Using Cardiac Magnetic Resonance Imaging

ABSTRACT

Background

Impaired myocardial function and arrhythmia are important manifestations of Marfan syndrome (MFS). Studies assessing myocardial fibrosis in relation to these manifestations are scarce.

Methods

This cross‐sectional, single‐center study assessed ventricular volumes, ventricular function, and myocardial fibrosis by cardiac magnetic resonance imaging (CMR) in patients with MFS harboring a (likely) pathogenic FBN1 variant. The presence and extent of fibrosis were assessed by late gadolinium enhancement (LGE) and extracellular volume measurement (ECV). Data on 24‐h Holter monitoring and clinical data were extracted from electronic patient records.

Results

The study included 32 unselected patients with MFS (median age 38 years [range 10–69], 41% women). No focal myocardial fibrosis was detected. Six patients (21%) had diffuse fibrosis (ECV > 29%). No association was found between the presence of diffuse fibrosis and clinically relevant myocardial dysfunction. Five patients (16%) had reduced left ventricular ejection fraction (LVEF < 55%). While all of these exhibited mitral annular disjunction (MAD), only two had ECV > 29%. Patients with MAD had increased indexed LV volumes (median end‐diastolic volume, 92 mL/m² [IQR, 78–100] vs. 78 mL/m² [IQR, 71–87]; median end‐systolic volume, 31 mL/m² [IQR, 23–46] vs. 22 mL/m² [IQR, 21–28]), also after adjusting for the presence of mitral and aortic valve regurgitation. No differences in ECV were seen between patients with and without MAD.

Conclusions

In this cohort of patients with MFS, focal myocardial fibrosis was not detected using CMR. Although diffuse fibrosis was observed in 21% of patients, no evident connection to clinically relevant myocardial dysfunction was found. Further studies should evaluate the impact of diffuse fibrosis on clinical outcome prediction.

In Marfan syndrome patients, cardiac magnetic resonance imaging revealed no focal myocardial fibrosis but detected diffuse fibrosis in 21%. This hints towards an overlooked aspect of cardiac involvement, highlighting the need for further research into its clinical significance.

1. Introduction

Marfan syndrome (MFS) (OMIM #154700, ORPHA #284963) is a heritable connective tissue disorder affecting the cardiovascular, skeletal, and ocular systems. In the majority of patients, a (likely) pathogenic variant in the fibrillin‐1 (FBN1) gene encoding the extracellular matrix glycoprotein fibrillin‐1 can be found (Loeys et al. 2010). Well‐known cardiovascular manifestations of MFS include aortic root dilatation, aortic dissection, and mitral valve prolapse. In recent years, less well‐studied aspects of MFS have received increasing awareness (von Kodolitsch et al. 2019), including (mostly mild) myocardial dysfunction and (supra)ventricular arrhythmia (Demolder et al. 2020). These features may manifest as reduced ejection fraction (EF), which can be either asymptomatic or symptomatic, impaired diastolic function, atrial fibrillation, non‐sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), or sudden cardiac death (SCD) (Demolder et al. 2020). Prediction of outcome in MFS is key, yet remains challenging. In our previous work, we determined that mitral annular disjunction (MAD) is a useful marker of adverse outcomes, encouraging research toward a better understanding of the underlying mechanism of the disease (Demolder et al. 2021). Cardiac magnetic resonance (CMR) imaging can provide valuable information in this context through assessment of myocardial structure and biventricular function. Furthermore, due to its non‐invasive nature, CMR is the first‐line technique for cardiac fibrosis assessment (Gupta et al. 2021). Studies reporting myocardial fibrosis detected by late gadolinium enhancement (LGE, typically used for detection of focal fibrosis) and extracellular volume measurement (ECV, indicating diffuse fibrosis) have shown associations between fibrosis and clinically relevant outcomes, including arrhythmic risk, in a patient with dilated cardiomyopathy (DCMP) (Gupta et al. 2021; Alba et al. 2020; Rubiś et al. 2021). Recent studies have suggested that MAD is associated with LGE in the basal segments of the LV. Together with elevated myocardial ECV, these are established early indicators of clinically relevant myocardial involvement in patients with mitral valve prolapse (Gupta et al. 2021; Alba et al. 2020; Rubiś et al. 2021; Dejgaard et al. 2018; Pavon et al. 2021). However, studies reporting on focal or diffuse myocardial fibrosis in MFS are scarce. In this study, we used CMR to evaluate cardiac fibrosis and study whether it correlated with ventricular function, the presence of MAD, and the occurrence of arrhythmia in patients with MFS.

2. Methods

2.1. Study Design

We conducted a cross‐sectional, single‐center study with retrospective analysis at the Ghent University Hospital in patients with a diagnosis of MFS based on the revised Ghent criteria (Loeys et al. 2010) who underwent regular follow‐up. Patients with a (likely) pathogenic FBN1 gene variant planned for aortic screening by CMR from February 1, 2020 to July 31, 2022 were eligible for inclusion. Pediatric patients were defined as < 16 years old; patients with neonatal MFS or previous mitral valve surgery were excluded. Patients were included consecutively and unselected without additional inclusion criteria other than a diagnosis of Marfan syndrome. Cardiovascular follow‐up, including echocardiography, was performed annually in patients with an aortic root diameter < 45 mm and those who previously underwent aortic root replacement and semi‐annually in those with diameters between 45 and 50 mm with no indication for surgery. Data on 24‐h Holter monitoring were collected. Clinical data were extracted from electronic patient records. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee.

2.2. Objectives and Endpoints Definitions

The main objective of the study was to assess the ventricular volume and the severity of myocardial fibrosis (extent of LGE, pre‐contrast T1 relaxation time, and ECV) in patients with MFS. As a secondary objective, we assessed the relation between myocardial fibrosis and clinically relevant myocardial dysfunction, including left ventricular ejection fraction (LVEF) less than 55%, the incidence of NSVT using 24‐h Holter monitoring, and the presence and extent of MAD.

2.3. 24‐Hour Holter Monitoring

Twenty‐four‐hour Holter monitoring was performed as clinically indicated or annually within a research context since 2016. Data were analyzed using 2 semiautomatic software packages (Philips DigiTrak XT; Philips and Trillium Platinum; Forest Medical). Premature atrial complexes (PACs), premature ventricular complexes (PVCs), and other arrhythmias were automatically identified and manually overread. Atrial ectopy was defined as more than 10 PACs per hour, and ventricular ectopy was defined as more than 10 PVCs per hour. Atrial runs were defined as 3 or more consecutive premature atrial beats at a rate of more than 100 beats per minute, and NSVT was defined as 3 or more consecutive premature ventricular beats at a rate of more than 100 beats per minute. All 24‐h Holter monitoring reports were examined; the numbers of PACs, PVCs, atrial runs, and NSVT episodes observed were noted for each 24‐h Holter monitoring report, and the highest number was considered for analysis.

2.4. Cardiovascular Magnetic Resonance Protocol

Electrocardiogram (ECG)‐gated CMR imaging was performed using a 1.5T CMR system (MAGNETOM Avanto, Siemens Healthineers, Erlangen‐Germany) with a 32‐channel phased‐array surface receiver coil. Cine images were acquired using a breath‐hold balanced steady‐state free precession sequence (bSSFP) in long‐axis (2‐chamber, 3‐chamber, and 4‐chamber) and short‐axis views (7 mm slices 3 mm gap, ±10 slices). For pre‐contrast T1 mapping, we used the ECG‐triggered modified LookLocker inversion recovery (MOLLI) sequence using the scheme 5(3)3(0) in the three long‐axis orientations. Seven to 15 min after the administration of a 0.2 mmol/kg intravenous bolus of Gadobutrol (Gadovist, Bayer Healthcare, Berlin, Germany), LGE images were acquired using a 2D breath‐hold phase‐sensitive segmented inversion‐recovery gradient echo pulse sequence in the same orientations as cine images, long axis, short axis and then long axis again. Inversion time was individually optimized to null the signal from the normal myocardium. Post‐contrast T1‐mapping was acquired following LGE imaging (typically 15–20 min after Gadobutrol bolus injection) using a MOLLI sequence (5(3)3(0)scheme). As previously reported in the literature (Muiño‐Mosquera and De Backer 2021), pre‐ and post‐contrast T1 mappings were optimized to improve the precision of the measurement; in particular, pre‐contrast T1 mapping was optimized for measuring long T1s of the order of 1000 ms while the post‐contrast sequence was optimized for short T1s of the order of 200 ms.

2.5. Image Analysis

All CMR examinations were analyzed using the Argus software (Siemens Healthineers) to calculate LV volumes, LV mass, and LVEF by delineating endocardial and epicardial borders in the stack of short‐axis cine images. The presence of myocardial LGE was visually evaluated and its extent was semi‐quantitatively reported according to the American Heart Association 17 segments model [22].

MAD was considered as both a qualitative and a quantitative trait: present or absent based on the presence or absence of an apparent systolic separation (≥ 3 mm) between the left atrial wall–mitral valve junction and the base of the LV wall (Figure 1). The presence of MAD was assessed in 3 different views (LVOT view, 4 chamber view, and vertical long‐axis view) and the extent was measured from the apparent LA wall‐posterior mitral leaflet junction to the top of the basal LV inferolateral wall during systole (Figure 1) (Dejgaard et al. 2018).

FIGURE 1.

Cardiovascular magnetic resonance imaging views for measuring mitral annular disjunction. The red arrow represents the measured mitral annular disjunction (MAD) length in three views: (A) vertical long‐axis (VLA), (B) four‐chamber (4CH), and (C) left ventricular outflow tract (LVOT). These views provide key reference planes for evaluating the displacement of the mitral annulus relative to the left ventricular myocardium. 4CH, four‐chamber view; LVOT, left ventricular outflow tract; VLA, vertical long axis.

2.6. T1 Mapping

Pre‐ and post‐contrast T1 mapping images were first visually reviewed to assess quality, and myocardial T1 relaxation times were then measured by drawing a region of interest (ROI) in the different parts of the myocardium, using the viewing software of the Siemens MR workstation (Figure 2). After manual tracing of the endocardial and epicardial borders, the bull's eye diagram was filled in with the corresponding values. Hematocrit sampling was used in the calculation of ECV following the formula: ECV = (1‐hct) [(1/pT1my—1/nT1my)/(1/pT1bp—1/nT1bp)], where nT1 = native T1, pT1 = postcontrast T1, my = myocardium, bp = blood pool, and hct = hematocrit (Kellman et al. 2012). An ECV greater than 29% was considered to be significant (Sado et al. 2012; Dabir et al. 2014).

FIGURE 2.

Cardiovascular magnetic resonance imaging views and extracellular volume (ECV) maps. The panels display pre‐contrast ECV, native images, and post‐contrast ECV maps. Regions of interest (ROIs) are demarcated for quantifying myocardial ECV. These maps illustrate tissue characterization before and after contrast administration. 4CH, four‐chamber view; ECV, extracellular volume; LVOT, left ventricular outflow tract.

2.7. Echocardiography

All patients underwent transthoracic echocardiographic examination (GE Vivid systems; GE Healthcare), performed annually for those with an aortic root diameter < 45 mm or who previously underwent aortic root replacement, and semi‐annually for those with diameters between 45 and 50 mm without an indication for surgery. Image acquisitions and standard measurements were carried out by experienced echocardiographers in accordance with the guidelines of the American Society of Echocardiography and the European Association of Cardiovascular Imaging (Lang et al. 2015). Echocardiographic data were collected from the most recent patient visits.

2.8. Statistical Analysis

Continuous data are reported as mean and standard deviation (SD) values or median values with interquartile ranges (IQR). The Shapiro–Wilk test was used to determine if the data are normally distributed. Categorical data are reported as proportions or percentages (n, %), and comparisons between groups were performed using the chi‐squared test or the Fisher exact test, where appropriate. Comparisons of continuous variables between groups were performed using either the t test or the Mann–Whitney test depending on the distribution of the data. Correlation analysis was performed using Spearman's correlation. Considering the inhomogeneous distribution of pre‐contrast T1 relaxation times and ECV, the average values of the regional segments were used for analyses. Statistical tests were 2‐tailed, and p < 0.05 was considered statistically significant. Analyses were conducted using SPSS, version 28.0 (IBM Corp).

3. Results

For this study, 32 patients (13 females (41%); median age at CMR examination, 38 years [range, 10–69 years]) were evaluated. Data on baseline characteristics are shown in Table 1. The median time since diagnosis at the moment of the CMR was 14 years (IQR, 10.4–17.3 years). Eleven patients (34%) had an aortic event prior to inclusion: 4 had aortic dissection with subsequent surgery (3 type A dissection each with subsequent Bentall procedure, 1 type B dissection after prior aortic surgery) and 7 had prophylactic aortic root surgery (5 David procedure, 2 Bentall procedure).

TABLE 1.

Characteristics of patients.

	Median (IQR)
	Total (n = 32)
Baseline characteristics
Age, median (IQR), years	38 (24–52)
Pediatric patients, no. (%)	2 (6)
Female, no. (%)	13 (41)
CMR data
Aortic root, median (IQR), mm a	40 (37–43)
Mechanical aortic valve, no. (%)	5 (16)
ECV, % b	26.3 (25–28.8)
Global ECV > 29%, no. (%) b	6 (21)
VLA anterior wall ECV	26.5 (24.7–30.4)
VLA inferior wall ECV	26.8 (23.9–29.6)
Four‐chamber anterolateral ECV	26.2 (24.4–27.7)
Four‐chamber posteroseptal ECV	26.2 (24.6–28.3)
LVOT anteroseptal ECV	26.6 (25.4–28.8)
LVOT posterolateral ECV	25.5 (23.6–28)
Presence of LGE, no. (%)	0 (0)
LVEDVi, mL/m2	86 (75–98)
LVESVi, mL/m2	27 (21–35)
LVEF, %	68 (62–73)
LVEF < 55%, no. (%)	5 (16)
LVmassi, g/m2	59 (49–69)
RVEDVi, mL/m2	82 (65–92)
RVESVi, mL/m2	32 (25–39)
RVEF, %	61 (53–66)
RVEF < 55%, no. (%)	10 (31)
MAD, no. (%)	19 (59)
MAD distance, median (IQR), mm	6 (4–10)
Echocardiographic data
MR severity, no. (%)
Mild	12 (38)
Mild–moderate	5 (16)
Moderate	1 (3)
Severe	0 (0)
AR severity, no. (%)
Mild	8 (25)
Mild–moderate	0 (0)
Moderate	0 (0)
Severe	0 (0)
Cardiovascular history
Aortic event, no. (%)	11 (34)
Prophylactic aortic root surgery, no. (%)	7 (22)
Aortic dissection, no. (%)	4 (13)
Type A dissection, no. (%)	3 (9)
Type B dissection, no. (%)	1 (3)
Antihypertensive medication, no. (%)
β‐blocker	25 (78)
ARB	13 (41)
Other	2 (6)

Abbreviations: AR, aortic regurgitation; ARB, angiotensin receptor blocker; CMR, Cardiovascular magnetic resonance imaging; ECV, extracellular volume; IQR, interquartile range; LGE, late gadolinium enhancement; LVEDVi, left ventricular end‐diastolic volume indexed; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end‐systolic volume indexed; LVmassi, left ventricular mass indexed; LVOT, left ventricular outflow tract; MAD, mitral annular disjunction; MR, mitral regurgitation; MVP, mitral valve prolapse; RVEDVi, right ventricular end‐diastolic volume indexed; RVEF, right ventricular ejection fraction; RVESDi, right ventricular end‐systolic volume indexed; VLA, vertical long axis.

^a In patients without previous aortic root replacement.

^b 3 patients without ECV values due to missing hematocrit (1 in the MAD(−) and 2 in the MAD(+)group).

Mitral valve regurgitation (MR) assessed by echocardiography, was absent in 14 patients (44%), mild in 12 patients (38%), mild–moderate in 5 patients (16%), and moderate in 1 (3%). MAD was present in 19 patients (59%). Aortic valve regurgitation (AR) assessed by echocardiography, was absent in 24 patients (75%), mild in 8 (25%), and no patients had mild–moderate, moderate, or severe AR. In CMR, median LVEDVi was 86 mL/m² (IQR 75–98) and median LVEF was 68% (IQR 62–73). Five patients had decreased LVEF below 55%.

In the present study cohort, 28 patients (88%) received at least one Holter recording (median of 3 Holters/patient). The median absolute time interval between Holter monitoring and the CMR was 15 [7–30] days. The results are summarized in Tables S1 and S2. Atrial ectopy and atrial runs were observed in 18% and 39%, respectively. Ventricular ectopy and NSVT were noted in 39% and 32%, respectively.

3.1. Tissue Characterization

LGE was not observed in any of the included patients. The median ECV in our cohort was 26.3% [IQR 25–28.8]. Interestingly, 6 patients (21%) had an ECV above the upper limit of normal. The clinical characteristics of these patients can be found in Table 2. ECV did not correlate with LVESVi (p = 0.656), LVEDVi (p = 0.710), LVEF (p = 0.561), aortic root diameter (p = 0.403), ventricular ectopic burden (p = 0.168), or atrial ectopic burden (p = 0.192). Patients with any MR present had significantly higher ECV values compared to those without (27.6% [25.5–30.1] vs. 25.1% [23.3–27.1], p = 0.008). Similarly, patients with any AR present also had significantly higher ECV values compared to those without (28.1% [26.3–31.4] vs. 25.5 [24.5–27.9], p = 0.042). No significant differences in ECV were observed between patients with vs. without aortic events (p = 0.417), or between patients receiving anti‐hypertensive medication and the three patients who were not (p = 0.516). While comparing ECV values between patient groups with and without MAD or NSVT, no significant differences were observed, neither globally nor in specific regions of the left ventricle.

TABLE 2.

Characteristics of patients with ECV above the upper normal limit.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Age, years	59	69	37	49	10	44
Sex	Female	Female	Male	Male	Male	Female
Aortic root, mm	—	33	—	—	28	32
ECV, %	30.1	30	31.4	29.7	32	36.8
VLA anterior wall ECV	30.7	29.3	32.7	32.9	32.3	39.1
VLA inferior wall ECV	32.1	29.2	30.4	31.3	27.5	37.1
Four‐chamber anterolateral ECV	31.3	26.2	29.4	26.8	31.5	37.1
Four‐chamber posteroseptal ECV	31.6	28.3	29.1	28.9	33.1	35.3
LVOT anteroseptal ECV	33.4	28.9	30.8	28.5	32.7	38
LVOT posterolateral ECV	22.8	30.5	31.6	30.2	32.7	34.7
LVEDVi, mL/m2	66	97	69	73	148	98
LVESVi, mL/m2	27	49	29	20	70	28
LVEF, %	59	49	58	75	53	72
MR severity	Mild	Mild	Mild	Mild–moderate	Moderate	Mild–moderate
AR severity	—	Mild	Mild	—	None	Mild
RVEDVi, mL/m2	62	62	69	99	104	79
RVESVi, mL/m2	29	21	28	35	60	30
RVEF, %	53	66	60	65	42	62
MAD	No	Yes	Yes	Yes	Yes	Yes
MAD distance, mm	—	6	3	7	11	5
Aortic event	Bentall procedure	—	Prior aortic root replacement + subsequent Type B dissection	Type A dissection, received Bentall procedure	—	—
AF/AFL/AT	AF	No	No	No	No	No
Atrial ectopy	Yes	No	No	Yes	No	No
Ventricular ectopy	Yes	Yes	No	Yes	No	No
NSVT episodes	2	0	0	0	0	0
Longest NSVT	4 beats	—	—	—	—	—

Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AR, aortic regurgitation; AT, atrial tachycardia; ECV, extracellular volume; IQR, interquartile range; LVEDVi, left ventricular end‐diastolic volume indexed; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end‐systolic volume indexed; LVSVi, left ventricular stroke volume indexed; LVOT, left ventricular outflow tract; MAD, mitral annular disjunction; MR, mitral regurgitation; NSVT, non‐sustained ventricular tachycardia; RVEDVi, right ventricular end‐diastolic volume indexed; RVEF, right ventricular ejection fraction; RVESDi, right ventricular end‐systolic volume indexed; RVSVi, right ventricular stroke volume indexed; VLA, vertical long axis.

3.2. Myocardial and Valvular Function in Patients With vs. Without MAD

Patients with MAD had increased median indexed LV volumes (end‐diastolic volume, 92 mL/m² [IQR, 78–100 mL/m²] vs. 78 mL/m² [IQR, 71–87 mL/m²], p = 0.030; end‐systolic volume, 31 mL/m² [IQR, 23–46 mL/m²] vs. 22 mL/m² [IQR, 21–28 mL/m²], p = 0.016), also after adjusting for the presence of MR and AR (p = 0.021 for indexed LV end‐diastolic volume and p = 0.009 for indexed LV end‐systolic volume). We observed a trend towards lower median LVEF in patients with MAD (65% [IQR, 53%–71%] vs. 71% [IQR, 65%–75%], p = 0.071), which became significant after adjusting for the presence of MR and AR (p = 0.006). Five patients (16%) had reduced EF (< 55%), and all of these had MAD. A moderate to strong correlation was seen between MAD distance and left ventricular volume (LVESVi, Spearman r = 0.617, p = 0.005; LVEDVi, Spearman r = 0.572, p = 0.010). There was no significant difference in median ECV values between patients with vs. without MAD (26.3% [IQR, 25.1%–29.9%] vs. 26.6% [IQR, 23.6%–28.3%], p = 0.347).

4. Discussion

In this study, we assessed the presence and extent of focal and diffuse fibrosis in an unselected cohort of patients with MFS and correlated the findings to ventricular function, arrhythmia, and the presence of MAD. We found no LGE indicating that these patients do not seem to have focal cardiac fibrosis. 21% of patients presented ECV values above the upper limit of normal. Factors associated with increased ECV were mitral‐ and aortic valve regurgitation. No differences in ECV were seen between patients with and without MAD or patients with and without atrial or ventricular arrhythmia.

To the best of our knowledge, this is the largest CMR study assessing cardiac fibrosis in patients with MFS to date. LGE has been a useful tool in identifying areas of replacement fibrosis (Gupta et al. 2021). However, its limitations in accurately measuring interstitial fibrosis have inspired the use of T1 mapping and ECV as a more robust method (Rubiś et al. 2021; Pavon et al. 2021). Only one similar smaller study by Karur et al. (2018). assessed fibrotic and functional remodeling in 14 and 21 pediatric patients with MFS and Loeys–Dietz syndrome (LDS), respectively. The authors observed elevated myocardial T1 and ECV values in patients with MFS and LDS compared to healthy controls. Of note, the reported ECV values, which were similar to ours, were on average below the upper normal limit of 29% for adults (Karur et al. 2018). Together with our findings, this aligns with previous reports of mild biventricular dysfunction in patients with MFS, suggesting that the fibrosis detected in these patients is mostly mild with still unclear clinical implications. ECV did not correlate with ventricular volumes, EF, aortic events, or aortic root size, which was also corroborated in the study by Karur et al. (2018). The median ECV value of our studied cohort is within the normal range, and lower than those reported in patients with hypertrophic cardiomyopathy (29.1% ± 0.5% [1.5T]) and dilated cardiomyopathy (28% ± 0.4% [1.5T]) (Haaf et al. 2016); however, ours is an unselected cohort of patients with MFS with very variable phenotype and in general mild clinically relevant myocardial dysfunction. Further studies are needed to demonstrate if the inclusion of MFS patients with more overt cardiomyopathy or clinically relevant arrhythmia may show higher ECV values.

In our study, the most notable association was observed between increased ECV values and the presence of mitral or aortic regurgitation. This finding is clinically significant and warrants further exploration. High ECV is indicative of myocardial tissue remodeling, characterized by extracellular expansion due to either edema or fibrosis (Haaf et al. 2016; Kong, Christia, and Frangogiannis 2014). This remodeling can be a response to chronic volume overload (in the context of valvular regurgitations) or pressure overload (in the context of hypertension, aortic stiffness, or others) (Haaf et al. 2016). Chronic volume overload results in ventricular dilation and increased wall stress, promoting myocardial fibrosis and extracellular matrix expansion (Kong, Christia, and Frangogiannis 2014). Findings from fbn1 mouse model studies also support a link to volume and pressure overload. These studies indicate that mechanical factors such as volume‐ or pressure overload are not correctly compensated, leading to myocardial dysfunction. For instance, partial ligation of the aortic arch in fbn1 ^C1039G/+ mice resulted in cardiomyopathy due to pressure overload. Similarly, volume overload caused by valvular regurgitation (both mitral and aortic valve) led to dilated cardiomyopathy in the same mouse model (Muiño‐Mosquera and De Backer 2021). The increased ECV observed in our study aligns with this pathophysiological mechanism. Specifically, the elevated ECV in patients with mitral or aortic regurgitation likely reflects diffuse myocardial fibrosis rather than localized fibrosis, the latter being more characteristic of pressure overload conditions. Examining patients 5 and 6 from Table 2, both of whom exhibited higher ECV values and significant regurgitant volumes, further supports this hypothesis.

Future longitudinal studies should aim to investigate the progression of ECV changes over time in patients with valvular regurgitations and other volume overload conditions. These could provide valuable insights into the temporal relationship between regurgitation severity and myocardial fibrosis.

In our cohort, no significant differences in ECV values between patients with and without MAD could be detected. These findings are in contrast with the study by Pavon et al. (2021). which compared LGE and ECV between non‐MFS patients with MAD vs. without MAD. The discrepancy may be explained by a number of factors. First, in their study, a short axis view was chosen, allowing to divide the basal slice of the LV into 6 equal segments and calculate the corresponding T1 relaxation times. Whereas in our study, regional average T1 values were obtained from different long‐axis views, resulting in different areas of assessment. Second, the small sample size of our study may have prevented statistically robust conclusions. Out of the 6 patients who displayed elevated ECV, 5 also exhibited MAD. Although this finding suggests a potential association, a larger number of cases would be required to justify this conclusion. Further research with a larger sample size may help to better elucidate the relationship between ECV and MAD. Third, the arrhythmic burden of our studied cohort may not have been sufficiently high to detect a substrate correlate via CMR techniques (Rubiś et al. 2021). Indeed, only a subset of patients experienced (rare) NSVT episodes, mainly of short duration, whereas no patients with sustained VT were included. Alternatively, it is possible that the presence of MAD does not significantly affect ECV in patients with MFS. Further research is needed to better understand the long‐term consequences of MAD and associated altered mitral annular dynamics in relation to fibrosis, especially in regions of interest such as the papillary muscles. Despite the lack of difference in ECV, we did find that patients with MAD had larger left ventricular end‐diastolic and end‐systolic volumes (also after adjusting for valvular regurgitation), consistent with previous research (Essayagh et al. 2021; Luyten et al. 2022; Drescher et al. 2022). Studies have shown that MAD imposes an added volume load upon the left ventricle in the form of the prolapsing volume, leading to increased end‐diastolic and end‐systolic volumes (El‐Tallawi et al. 2020). Cardiac remodeling, such as LV dilatation leading to repolarization alterations, and fibrosis provide a substrate for the development of ventricular arrhythmias. However, in our cohort, these features appeared to be either absent or in their early stages, suggesting the need for continued longitudinal follow‐up studies.

5. Limitations

Our work is best understood in the context of its limitations. A notable limitation of this study is the small sample size, which may hinder the ability to draw definitive, statistically robust conclusions. Second, the lack of a control group required us to rely on reference values for ECV. We did not have institution‐specific reference values for T1 and ECV, relying instead on established literature to determine the cut‐off values (Sado et al. 2012; Dabir et al. 2014). Third, specific regions of interest such as the papillary muscles or short axis views of the basal LV regions were not evaluated in our CMR protocol. Additionally, T1 mapping was performed on long‐axis views instead of the short‐axis plane due to the manual nature of the analysis at the study's inception, which may affect the comparability of our results with other studies using automated short‐axis T1 mapping. Lastly, MR severity was not systematically evaluated during CMR examinations and therefore the influence of MR was estimated by echocardiography.

6. Conclusion

In conclusion, our assessment of cardiac fibrosis in a small and unselected cohort of patients with MFS revealed that the vast majority did not exhibit focal or diffuse fibrosis. A subgroup, however, had ECV values above the upper normal limit. No clear correlation between arrhythmia or reduced EF and diffuse fibrosis could be established.

Author Contributions

The author takes full responsibility for this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1.

Table S2.

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.