Mitral Annular Disjunction Associated with Ventricular Dilation in Pediatric Marfan Syndrome: A Cardiovascular Magnetic Resonance Study

doi:10.21203/rs.3.rs-4970437/v1

Background

Mitral annular disjunction (MAD) has increasingly been recognized as a marker for adverse cardiovascular events in Marfan syndrome (MFS). As recent adult data links MFS with left ventricular (LV) dilation and reduced ejection fraction (LVEF), we hypothesized that MAD may be associated with LV dilation in pediatric MFS patients.

Methods

A retrospective analysis was performed among MFS patients < 19 years old at initial cardiac MRI (CMR). MAD and mitral valve prolapse (MVP) were assessed by CMR or most proximate echo. CMR-derived left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured. Indexed volumes, absolute and indexed z-scores, and LVEF were calculated. The combined volume load from mitral and aortic regurgitation was indexed to LV stroke volume, allowing exclusion of patients with greater than mild volume load or prior MV intervention. MAD association with LV volumes and z-scores was then assessed.

Results

Forty-two patients were analyzed (median age 13.5 years old, IQR [10.9, 15.3]). MAD was present in 28 patients (66.7%), and MVP was present in 13 patients (31.0%). Absolute LVEDV z-score was > 2 in 35.7% of patients, LVESV z-score was > 2 in 42.9%, and LVEF was < 55% in 45.2%. In multivariable analysis including MVP, MAD remained independently associated with elevated absolute LVESV z-score > 2 (RR 3.88, 95% CI: 1.02–14.69, p = 0.046).

Conclusion

MAD was associated with CMR-derived volume-load-independent LV dilation among pediatric MFS patients. Prospective studies are needed to further understand this association and its relationship with LV dilation over time.

Mitral annular disjunction

Marfan syndrome

Cardiomyopathy

Mitral valve prolapse

Marfan syndrome (MFS) is a heritable connective tissue disease which typically arises from autosomal dominant fibrillin-1 (FBN1) mutations and involves the cardiovascular, skeletal, and ocular organ systems.[1, 2] While MFS cardiovascular manifestations have traditionally been characterized by aortopathy and valvular abnormalities, recent studies have demonstrated that adults with MFS can also develop ventricular dilation and reduced left ventricular ejection fraction (LVEF).[3–6] Although the exact mechanism of these findings in relation to fibrillin dysfunction has not been fully elucidated, the ventricular dilation and dysfunction appear to be independent of volume loading from valvar regurgitation, suggesting the presence of a MFS-associated cardiomyopathy phenotype.[7] Mitral annular disjunction (MAD) is a structural feature involving atrial displacement of the posterior mitral valve leaflet hinge point which has recently drawn attention for its association with mitral valve prolapse (MVP) and concurrent cardiovascular disease in MFS, particularly ventricular arrhythmias and sudden cardiac death.[8] MAD has also previously garnered attention outside of the MFS population for its association with arrhythmic MVP syndrome.[9, 10] More recently, data from our institution has suggested that MAD is an important clinical biomarker within the pediatric MFS population, possibly representing a more severe MFS phenotype.[11] Consequently, we hypothesized that MAD may also be associated with the presence of MFS-associated dilation or dysfunction.

Study Population

This retrospective cohort study included patients with MFS identified on an electronic health record (EHR) query from January 1, 2003 to December 31, 2022. Chart review was performed to collect patient demographics, medication regimens, initial cardiac magnetic resonance imaging (CMR) referral indications, and report-derived echocardiographic parameters from the most proximate study as described below. We included patients with a confirmed diagnosis of MFS (meeting Ghent criteria[12] and pathogenic FBN1 variant or ectopia lentis) followed at our institution between 2003–2022 who had at least 1 CMR study prior to 19 years of age. Patients with prior mitral valve intervention or inadequate imaging views to assess MAD (CMR or most proximate echocardiogram) were excluded. To mitigate confounding of valvar regurgitation on LV volumetrics, patients with greater than mild CMR-derived LV volume load were also excluded (see methodology below). This study was approved by Baylor College of Medicine’s Institutional Review Board.

CMR Volumetrics

Evaluation of CMR studies was limited to initial imaging. All CMR studies were performed using a 1.5 T16 Achieva, 1.5 T Ingenia scanner (Philips Medical System, Best, the Netherlands) or a 1.5 T Aera 17 scanner (Siemens Healthineers, Erlangen, Germany). Standard institutional CMR sequence parameters for balanced steady state free precession (SSFP) sequences were utilized (see sequencing parameters in the Appendix). Left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) ventricular volumes for all studies were measured from short axis SSFP sequence contouring by one reader (J.W.). For 10 of these studies, LVEDV and LVESV were re-measured in a blinded fashion for interobserver reliability assessment (co-author S.S.). Haycock body surface area (BSA) at CMR was computed based on available weight and height measurements. Heart rate at the time of the CMR was documented[13]. Absolute and indexed volume z-scores were then calculated using standard BSA-based algorithms.[14, 15] Absolute and indexed z-scores first were described as continuous variables and, on statistical analyses, were dichotomized as described below. LVEF was calculated and considered abnormal if < 55%. Patients were considered to have evidence of MFS-cardiomyopathy for LVEDV or LVESV absolute or indexed z-score > 2 or LVEF < 55% (in the setting of mild or less LV volume loading).

LV Volume Load Assessment

To account for the combined effect of valvar regurgitation on LV size (aortic and mitral regurgitation), LV volume load was defined by calculating the difference between right and left ventricular stroke volumes and indexing the stroke volume difference to the LV stroke volume (stroke volume difference divided by LV stroke volume). LV volume load was then stratified by severity (< 20% mild, 20–39% moderate, and > 40% severe). Only patients with mild or less LV volume loading were included in the analysis. Furthermore, the most proximate echocardiogram for each initial CMR was reviewed for right heart valve regurgitation (tricuspid, pulmonary). Patients with moderate or greater tricuspid or pulmonary regurgitation by echocardiography were also excluded from the analysis due to the inability to accurately quantify LV volume load.

MAD and MVP Assessment

MAD was defined as atrial displacement of the posterior mitral valve leaflet hinge point > 2mm from the inferolateral left ventricular myocardium. We utilized a standardized methodology for MAD measurement involving review of the posterior mitral valve hinge point at end-systole during the CMR or echocardiographic frame aligned with the T-wave peak. MAD was measured using the sagittal 3-chamber LV outflow (LVOT) CMR view (see Fig. 1) or parasternal long-axis transthoracic echocardiography views. One line was drawn between the anterior and posterior mitral valve hinge points and another along the crest of the ventricular myocardium to its insertion in the inferolateral wall. The distance between the two lines was measured 3 times over separate cardiac cycles and then averaged to account for cardiac cycle variability. Particular care was taken to avoid MAD overestimation by erroneous inclusion of “pseudo-MAD”.[16] CMR-derived MVP was also evaluated, defined as atrial displacement of the leaflet > 2mm from the annular plane.

MAD distance measured between two lines, shown in green: 1) line tracing the anterior and posterior mitral valve hinge points and 2) line tracing the crest of the ventricular myocardium and the lateral wa

Statistical Analysis

Based on Shapiro-Wilk analyses used to evaluate the normality of continuous variables, median and interquartile range (IQR) for continuous variables were reported. To assess if imaging parameters were greater among those with MAD compared to those without, generalized linear modeling was used to evaluate for differences in distribution of continuous variables by presence of MAD. Log-binomial logistic regression was utilized to assess the association between presence of MAD and categorical variables. Inter- and intraobserver reliability of ventricular volume measurement between readers was reported using intraclass correlation coefficients (ICC). To identify a clinically relevant cutoff for indexed z-scores, receiver operating curves (ROC) were generated, with cutoffs selected based on optimal Youden index (sensitivity + specificity − 1)[17] and area under the curve (AUC). Conversely, absolute z-scores were evaluated as > 2 or ≤ 2 for clinical relevance. Using these cutoffs, univariable log-binomial regression was performed to evaluate the association between presence of MAD and MVP (exposure variables) and each dichotomized imaging parameter (outcome) on initial CMR. Multivariable log-binomial regression including MAD and MVP was then performed. A p-value < 0.05 was considered statistically significant. Analyses was performed using Stata software (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC).

Study Population

Of the 58 patients identified on our EHR query, 16 were excluded either due to inadequate imaging views to measure MAD, moderate pulmonary or tricuspid regurgitation, or greater than mild LV volume load (see Appendix). Of the 42 patients included in the analysis (59.5% male), 34 (81.0%) had a documented pathogenic FBN1 mutation and 8 patients (19.0%) had ectopia lentis (see Table 1). The median age at initial CMR was 13.6 years old (IQR 10.9-16.3). CMR indications were predominantly for aortic arch assessment (38/42, 90%), and only 1 CMR (2.4%) was ordered specifically for LV size and/or function assessment. Most patients were already on medication at their initial CMR (90.5%) with the most common regimen being beta-blocker monotherapy (38.1%). No patients had pre-CMR cardiac surgery, and no dissections or other aortic events occurred prior to an initial CMR. Two patients had tiny to small atrial septal defects (ASD), and one patient had a history of an ASD device closure with no residual intracardiac shunting. No patients were found to have a bicuspid aortic valve. One patient was tachycardic on CMR with a reduced LVEF (49.9%), although their LVEDV or LVESV z-scores were <2. By chart review, only two patients had documented arrhythmias at the time of analysis. One patient had a cardiac arrest (at 20 years of age, 12 years following CMR) with documented ventricular fibrillation requiring CPR and subsequently went on to undergo ICD implantation. The second patient had two short runs of non-sustained atrial tachycardia on a surveillance Holter monitor (at 15 years of age, 2 years following CMR) and was started on a beta-blocker. Surveillance Holter monitors were not routinely performed in our study group, as only 10 patients (24%) had a Holter within 1 year of CMR (none with documented arrhythmias).

MAD, MVP, and CMR Parameters

CMR LVOT views were available for MAD assessment among 40 patients (95.2%), with the remaining 2 patients requiring utilization of the most proximate echocardiogram for MAD measurement. Median time from echocardiogram to CMR was 171 days. Interobserver and intraobserver reliability for LVED and LVES volume measurements were excellent, with an ICC of 0.999 (95% CI [0.995-1.000]; p < 0.0001) and 0.967 (95% CI [0.881-0.992]; p < 0.0001), respectively. MAD was noted in 28 patients (66.7%, see Table 2). Median MAD distance was 5.1mm [IQR 4.3-5.8]. MVP was present in 13 patients (31.0%). Median absolute LVEDV z-score was 1.25 [IQR -0.35, 2.52] and median absolute LVESV z-score was 1.54 [IQR 0.32, 3.32]. Absolute LVEDV z-score was >2 in 15 patients (35.7%), LVESV z-score was >2 in 18 patients (42.9%), and LVEF was <55% in 19 patients (45.2%). Twenty-eight (66.7%) patients had any CMR parameter abnormality (any LV volumetric z-score >2 or depressed LVEF).

In univariable analysis comparing MAD associations with continuous volumetric variables, MAD was associated with higher absolute LVEDV z-score (p=0.008), absolute LVESV z-score (p=0.003), as well as indexed LVESV volume and z-score (p=0.043 and p=0.03 respectively, see Figure 3 and Table 2). MAD was not associated with absolute LV volumes. When dichotomizing the z-scores and LVEF, MAD was associated with absolute LVEDV z-score >2 (p=0.048), absolute LVESV z-score >2 (p=0.04), but not depressed LVEF. ROC analysis of indexed z-scores identified an optimal cutoff of 2 for the indexed LVEDV z-scores and 3 for the indexed LVESV z-scores, but MAD was not associated with either dichotomous indexed z-score. CMR-derived MVP was not associated with diastolic volumes or z-scores, but it was associated with elevated LVESV indexed volumes, LVESV absolute and indexed z-scores, and the presence of dysfunction in univariable analysis (see Table 3). MVP was also associated with LVEF >55% in univariable analysis (p=0.027), but it was not associated with any dichotomized z-score.

In multivariable log-binomial logistic regression assessing MAD and MVP association with dichotomized variables, MAD remained independently associated with absolute LVESV z-score > 2 (p=0.046) (see Table 3). MAD associations with absolute LVEDV z-score >2 (p=0.052) and indexed LVESV z-score >2 (p=0.085) lost significance when including MVP. However, in multivariable generalized linear regression assessing association with continuous volumetric variables, MAD remained associated with higher absolute LVEDV z-score (p=0.017) when accounting for MVP. MVP was associated with indexed LVEDV, absolute LVESV z-scores, and LVEF in multivariate analysis. However, MVP was not associated with any binomial z-score elevation or dysfunction in multivariate analysis.

Our study uniquely examines the frequency of MAD and its relationship with CMR-derived LV volumes in a sizable group of pediatric patients with MFS. Our most important finding is that, even among patients with mild or less LV volume load, MAD appears to be associated with LV dilation in MFS. Furthermore, MAD association with systolic dilation remained significant, even when accounting for MVP.

MAD and LV Dilation

MFS-associated cardiomyopathy is now a well-recognized phenotype in adult studies[3, 6] and has also been demonstrated in a FBN1-hypomorphic murine model.[18] Furthermore, data from our institution has demonstrated that signs of this cardiomyopathy can be detected in pediatric patients with MFS, although MFS-associated cardiomyopathy appears to be more common among adults.[19] Previously proposed hypothetical mechanisms for LV dilation and dysfunction in MFS have included a reduction in microfibril assemblies[18] and/or loss of microfibril binding to integrin receptors in the myocyte extracellular matrix.[20] Although the development of MAD is currently not well understood, the elevated prevalence of MAD in the MFS population raises the possibility of relation to disrupted fibrillin/TGF-β signaling. Murine MFS models studying the development of MVP have demonstrated increased cell proliferation, decreased apoptosis and excess TGF-β signaling within the valvar apparatus,[21] demonstrating that the severity of the MFS phenotype may manifest in both myocardial and valvular abnormalities.

However, defining MFS-associated cardiomyopathy remains a challenge, particularly among pediatric MFS patients with no disease-specific normative volumes. Furthermore, in our study group of patients with mild or less LV volume loading, evidence of dilation (either absolute or indexed volumetric z-score > 2) or depressed LVEF was quite common (31 out of 42 patients, ~ 74%). Consequently, we chose to analyze MAD association with both absolute and BSA-indexed z-scores. We suspect that stronger MAD association with absolute z-score elevation rather than indexed z-score elevation in our study group may represent a couple of limitations of the indexed z-scores. Indexed z-scores are unavailable for patients under 8 years old, and therefore, they were only available for 35 out of 42 patients in our study group. Furthermore, indexed z-scores can underestimate dilation in patients with large BSA, possibly playing a role in our study group where ~ 24% of patients had a BSA greater than 2.

MAD and MVP

The interaction of MAD and MVP and their association with ventricular dilation are also complex and not fully understood. MAD has increasingly been described as a spectrum of disease, as there remains a lack of consensus regarding what degree of MAD is truly pathologic.[22–26] We utilized a definition of ≥ 2mm atrial displacement of the posterior mitral valve leaflet hinge point, as prior adult studies have demonstrated association with cardiovascular clinical findings with as little as 1mm MAD.[22, 27]

LV dilation has been documented in patients with non-syndromic MAD/MVP, even in the absence of significant mitral regurgitation.[4, 28, 29] Verbeke et al. describe several possible explanations including the presence of underlying connective tissue disease (such as MFS), underestimation of mitral regurgitation, frequent unrecognized ectopy, or a separate myocardial disease.[30] Bui et al. have also previously described both LV dilation and more diffusely shortened postcontrast T1 times concerning for global fibrosis in a group of adults with non-syndromic MVP[31], and more recently, Karur et al. have demonstrated longer T1 times in a small cohort of pediatric MFS and Loeys-Dietz patients.[32] Although T1 mapping and late gadolinium enhancement (LGE) acquisitions were not routinely performed in our study group of pediatric patients with MFS, prior adult studies of MFS-cardiomyopathy have demonstrated prevalent dilation and dysfunction in the absence of LGE[3], possibly suggesting a different mechanism for dilation. As we controlled for LV volume load in our study group and there were very few documented arrhythmias, we suspect that the higher LV absolute z-scores among those with MAD may represent a link between MAD and a more severe MFS phenotype. Interestingly, while CMR-derived MVP was associated with elevated indexed LVESV z-scores in univariable analysis, the significance of this association was lost on multivariate analysis including MAD. This may be related to the close association of MAD and MVP, our exclusion of patients with significant LV volume loading, or the overall younger age of the study group.

Limitations

Firstly, this was a retrospective analysis at a single institution with limited sample size. Secondly, we are not able to account for any impact that occult arrhythmias or frequent ectopy had on LV size or function. At our institution, Holter and event monitors are not routinely ordered for surveillance and instead are typically symptom-directed. LV afterload was not consistently assessed with concurrent blood pressure at the time of CMR, although the vast majority of patients were on afterload-reducing medications. While our data had the potential to be affected by selection/referral bias, the impact of these biases was significantly diminished given that the vast majority of the CMR studies in our study population (> 90%) were obtained for aortic indications only. Future prospective studies are needed to validate these findings and elucidate the impact of MAD distance in pediatric MFS.

Our study underscores the high prevalence of MAD among pediatric patients with MFS and its association with volume load-independent LV dilation. MFS-associated cardiomyopathy was also present in a significant proportion of our pediatric MFS study population. Prospective studies are needed to better characterize the relationship of MAD with MFS-associated cardiomyopathy, as well as the progression of MAD and LV abnormalities over time.

Author Contribution

T.D. and J.W. conceived of the project. Measurements were performed by J.W. and S.S. Data analysis was conducted by R.B. and S.S., with chart review performed by A.I.C. R.B. wrote the entire manuscript text. All authors contributed to revising the manuscript and have approved the final version.

Data Availability Statement

Data available on request.

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Table 1: Study Population Demographics and Characteristics at Initial CMR

Demographics	Study Population (n=42)
Male	25 (59.5%)
Race/Ethnicity Black/African American, Non-Hispanic White, Hispanic or Latino White, Non-Hispanic or Latino Other	3 (7.1%) 15 (35.7%) 17 (40.5%) 7 (16.7%)
MFS Diagnosis FBN1 Variant Ectopia Lentis Both FBN1 and Ectopia Lentis	20 (47.6%) 8 (19.0%) 14 (33.4%)
Patient Characteristics at Initial CMR
Age, years	13.6 [10.9, 15.3]
Height, cm	176 [162, 185]
Weight, kg	56.7 [37.5, 73.6]
Haycock BSA, m²	1.65 [1.28, 1.98]
Indication for CMR Assess Aortic Dimensions Assess LV in setting of MVP/MR/LV Dysfunction Primarily Aorta, Also Known LV Dilation/Dysfunction	38 (90.5%) 1 (2.4%) 3 (7.2%)
Antihypertensive Medication None Beta blocker Angiotensin Receptor Antagonist (ARB) Beta blocker & ACE inhibitor or ARB	4 (9.5%) 16 (38.1%) 11 (26.2%) 11 (26.2%)
Tachycardic at CMR	1 (2.4%)
Imaging Parameters
MAD, CMR- or Echocardiogram-derived MAD Distance, mm	28 (66.7%) 5.1 [4.3-5.8]
MVP, CMR-derived	13 (31.0%)
LV Volume Load, CMR-derived (%)	8.8 [1.5-13]

All values expressed as either median [Q1, Q3] or n (%). MFS: Marfan syndrome, CMR: cardiac magnetic resonance imaging, BSA: body surface area

Table 2. Initial CMR Parameters

n

All Patients

(n=42)

MAD

(n=28)

No MAD

(n=14)

p-value

CMR Volumetric Parameters

LVEDV, absolute (mL)

LVEDV, indexed (mL/m2)

LVEDV, absolute z-score

LVEDV, indexed z-score

LVESV, absolute (mL)

LVESV, indexed (mL/m2)

LVESV, absolute z-score

LVESV, indexed z-score

LVEF (%)

42

35

42

35

42

167 [116, 213]

92.6 [85.1, 112]

1.25 [-0.35, 2.52]

1.75 [0.61, 3.28]

74.4 [47.2, 94.4]

42.2 [36.5, 50.0]

1.54 [0.32, 3.32]

2.81 [1.76, 5.12]

56.0 [50.3, 59.6]

174 [110, 213]

95.7 [87.8, 114]

1.97 [0.56, 3.02]

2.18 [1.06, 3.52]

78.8 [46.3, 95.6]

45.3 [38.4, 56.8]

2.30 [1.22, 3.75]

3.59 [2.10, 6.11]

54.7 [49.3, 57.9]

144 [121, 210]

87.9 [78.6, 100]

0.00 [-1.18, 1.30]

1.41 [0.23, 1.92]

70.2 [50.7, 82.7]

37.7 [34.7, 43.7]

0.48 [-0.03, 3.75]

2.15 [1.67, 2.76]

58.0 [55.1, 60.7]

0.783

0.136

0.008*

0.093

0.662

0.043*

0.003*

0.030*

0.071

CMR Parameter Abnormality

Absolute LVEDV elevated z-score (>2)

Indexed LVEDV elevated z-score (>2)

Absolute LVESV z-score elevated (>2)

Indexed LVESV z-score elevated (>2)

LVEF depressed (EF<55%)

Any CMR parameter abnormality

42

35

42

35

42

15 (35.7%)

15 (42.9%)

18 (42.9%)

24 (68.6%)

19 (45.2%)

31 (73.8%)

14 (50.0%)

12 (42.9%)

16 (57.1%)

17 (60.7%)

15 (53.6%)

23 (82.1%)

1 (7.1%)

3 (21.4%)

2 (14.3%)

7 (50.0%)

4 (28.6%)

8 (57.1%)

0.048*

0.173

0.040*

0.367

0.170

0.143

All values expressed as either median [Q1, Q3] or n (%). Z-scores represent Buechel CMR pooled LV volumetric z-scores. P-values for univariable MAD association by generalized linear modeling for continuous variables and log-binomial logistic regression for binomial variables. Bolded p-values with an asterisk are those that reached statistical significance. MAD: mitral annular disjunction, LV: left ventricle, MVP: mitral valve prolapse, LVEDV: LV end-diastolic volume, LVESV: LV end-systolic volume, LVEF: LV ejection fraction

Table 3: Relative Risk Ratios and Confidence Intervals for Univariable and Multivariable Generalized Linear Modeling

	UNIVARIABLE ANALYSIS		MULTIVARIABLE ANALYSIS
	Coefficient (95% CI)	p-value	Coefficient (95% CI)	p-value
LVEDV Volume (mL)
MAD MVP	-6.29 (-51.09-38.51) 16.85 (-28.58-62.28)	0.783 0.467	-11.24 (-57.76-35.29) 19.77 (-27.67-67.21)	0.636 0.414
Absolute LVEDV Z-score
MAD MVP	1.67 (0.44-2.90) 0.85 (-0.49-2.18)	0.008* 0.213	1.56 (0.28-2.84) 0.44 (-0.86-1.74)	0.017* 0.506
Indexed LVEDV Volume
MAD MVP	10.71 (-3.38-24.79) 13.32 (-0.86-27.48)	0.136 0.065	7.89 (-6.45-22.23) 11.27 (-3.35-25.89)	0.281 0.131
Indexed LVEDV Z-score
MAD MVP	1.09 (-0.18-2.38) 0.97 (-0.32-2.27)	0.093 0.141	0.90 (-0.43-2.23) 0.73 (-0.60-2.06)	0.183 0.281
LVESV Volume (mL)
MAD MVP	5.36 (-18.70-29.43) 17.86 (-6.11-41.82)	0.662 0.144	0.96 (-23.65-25.58) 17.61 (-7.50-42.71)	0.939 0.169
Absolute LVESV Z-score
MAD MVP	1.69 (0.58-2.79) 1.54 (0.39-2.69)	0.003* 0.009*	1.39 (0.30-2.49) 1.17 (0.056-2.29)	0.013* 0.040*
Indexed LVESV Volume
MAD MVP	9.61 (0.32-18.89) 12.90 (3.80-22.01)	0.043* 0.005*	6.83 (-2.28-15.93) 11.13 (1.85-20.41)	0.142 0.019*
Indexed LVESV Z-score
MAD MVP	1.90 (0.19-3.61) 2.05 (0.36-3.74)	0.030* 0.017*	1.45 (-0.25-3.16) 1.66 (-0.047-3.37)	0.095 0.057
Ejection Fraction (%)
MAD MVP	-0.042 (-0.088-0.0036) -0.068 (-0.11-0.023)	0.071 0.003*	-0.027 (-0.072-0.017) -0.060 (-0.11-0.014)	0.228 0.010*

Bolded p-values with an asterisk are those that reached statistical significance. LVEDV: LV end-diastolic volume, LVESV: LV end-systolic volume, LVEF: LV ejection fraction; MAD: Mitral annular disjunction; MVP: Mitral valve prolapse; CMR: Cardiac magnetic resonance study

No competing interests reported.

Appendix.docx

Mitral Annular Disjunction Associated with Ventricular Dilation in Pediatric Marfan Syndrome: A Cardiovascular Magnetic Resonance Study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Methods

Study Population

CMR Volumetrics

LV Volume Load Assessment

MAD and MVP Assessment

Statistical Analysis

Results

Study Population

MAD, MVP, and CMR Parameters

Discussion

MAD and LV Dilation

MAD and MVP

Limitations

Conclusion

Declarations

Author Contribution

Data Availability Statement

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1