Reversed Remodeling Unveils Mitral Annular Disjunction

Abstract

Background

Mitral annular disjunction (MAD) is a structural abnormality increasingly recognized in association with mitral valve prolapse (MVP) and cardiomyopathy. Its clinical significance in nonischemic cardiomyopathy (NICM) is less understood.

Case Summary

A 60-year-old man with NICM presented with progressive dyspnea and atrial fibrillation. Initial cardiac magnetic resonance imaging (CMR) showed severe left ventricular (LV) dilation, reduced ejection fraction (16%), and mild MVP without MAD. After 18 months of guideline-directed medical therapy, LV function normalized, but severe mitral regurgitation and significant MAD became more apparent. Surgical repair with a quadrangular resection and annuloplasty was successful, resolving symptoms.

Discussion

This case highlights the role of CMR in identifying MAD in NICM, and demonstrates how reverse LV remodeling can unmask MAD and MVP. Reduced tethering forces on mitral chordae after LV size reduction likely contributed to revealing the underlying pathology of bi-leaflet redundancy and prolapse.

Visual Summary

History of Presentation

A 60-year-old man with no significant cardiac history presented with 3 months of progressive dyspnea on exertion, palpitations, and orthopnea. Physical examination revealed bilateral lower-extremity edema and crackles at both lung bases with irregular and fast radial pulse.

Take-Home Messages

• •This case highlights a patient with worsening mitral valve disease paradoxically alongside myocardial reversed remodeling.
• •The clinical implications of incidentally detected MAD in patients with NICM are uncertain, because MAD may confer an increased risk of ventricular arrhythmias in MVP patients.

Past Medical History

The patient had a history of hyperlipidemia, obstructive sleep apnea, and Covid-19 pneumonia.

Differential diagnosis

The differential diagnosis for a new presentation of progressive dyspnea on exertion is broad but includes heart failure, pulmonary hypertension, valvular heart disease, arrhythmia, and anemia.

Investigations

Electrocardiography displayed coarse atrial fibrillation, minimal voltage criteria for left ventricular hypertrophy, and premature ventricular complexes. Transthoracic echocardiography and subsequent transesophageal echocardiography revealed a severely reduced left ventricular ejection fraction (LVEF) (10%), moderately enlarged left ventricle (LV), and significantly dilated left atrium with associated thrombus. Mitral regurgitation was minimal, and the mitral valve showed no structural abnormalities (Figures 1 and 2). Coronary angiography revealed nonobstructive epicardial coronary arteries. Atrial fibrillation did not respond to cardioversion, and the etiology of nonischemic cardiomyopathy (NICM) was attributed to likely tachycardia-induced cardiomyopathy. To help solidify the etiology of NICM, the patient was referred for cardiac resonance imaging (CMR), which demonstrated severe left ventricular enlargement (indexed left ventricular end-diastolic volume [LVEDVi] 155 mL/m²), severe systolic dysfunction (LVEF 16%), mild mitral valve prolapse (MVP), mild mitral regurgitation (MR), and global hypokinesis (Figure 3). On the baseline CMR, late gadolinium enhancement (LGE) imaging revealed mid-myocardial enhancement in the inferoseptal region, which was consistent with a nonischemic pattern. This focal area of mid-wall LGE was thought to represent focal replacement fibrosis rather than a septal perforator, because the width of the LGE was beyond the typical linear pattern for a septal perforator on the short-axis image. Fibrosis did not involve the papillary muscles or the periannular region (Figure 4). The mitral annulus was dilated secondary to LV dilation, and the mitral valve appeared thickened but without significant MR (Figure 3). The patient reported no family history of cardiomyopathy, heart failure, or sudden cardiac death (SCD), and genetic testing was not performed.

Figure 1.

Serial TTE

The initial transthoracic echocardiography (TTE) and the follow-up TTE after 1 year on guideline-directed medical therapy. Initial TTE shows parasternal long-axis (PLAX) view of a dilated left ventricle (LV) with an end-diastolic dimension (EDD) of 6.2 cm (mitral valve not well visualized). PLAX and apical 4-chamber (A4C) views, respectively, show severely depressed LV systolic function, LV ejection fraction of 15%, and redundant mitral valve leaflets with minimal leaflet billowing and trivial mitral regurgitation. Follow-up TTE: PLAX view with reduction in LVEDD to 5 cm. PLAX and A4C views now show normalization of LV systolic function, with interval development of mitral annular systolic curling and disjunction (red star) and moderately severe late-systolic mitral regurgitation caused by bi-leaflet billowing and prolapse. Postoperative TTE: PLAX view shows consistent reduction in LVEDD to 5 cm. Moderately severe late-systolic mitral regurgitation improved, as shown by the PLAX and A4C views.

Figure 2.

Serial TEE at Different Stages

Initial TEE was performed before electrical cardioversion during the patient’s initial admission. The mid-esophageal 4-chamber view shows minimal leaflet billowing, the bi-commissural view shows minimal MR, and 3-dimensional reconstruction of the mitral valve underscores leaflet redundancy. Preoperative TEE was performed during surgical planning for mitral valve repair (MVr). It shows leaflet billowing and prolapse (red arrows) in the mid-esophageal 120-degree view, significant mitral regurgitation (yellow arrow depicting the proximal isovelocity surface area) in the mid-esophageal 4-chamber view, and leaflet redundancy and prolapse in the 3D reconstruction. Postoperative TEE performed after MVr shows a normally functioning mitral valve after ring implantation.

Figure 3.

Serial Magnetic Resonance Imaging

Comparison between end-systolic cine steady-state free-precession images (A, B) before guideline-directed medical therapy (GDMT) optimization and (C, D) 3 months after GDMT initiation, demonstrating mitral annular disjunction after remodeling. (A) Mitral valve thickening and mild posterior mitral valve prolapse. (B) Severe left ventricular enlargement. (C, D) Interval development of mitral annular disjunction (blue arrow) and bi-leaflet mitral valve prolapse without left ventricular dilation.

Figure 4.

Sequential LGE Imaging

Comparison of mid-slice LGE sequences from initial and follow-up magnetic resonance imaging (MRI) scans, aimed at evaluating the presence and potential progression of myocardial fibrosis. Initial MRI: (A) Late gadolinium enhancement phase sensitive inversion recovery (PSIR) short axis image. (B) PSIR left ventricular outflow tract (LVOT) image displays areas of suspected mid-myocardial LGE in the mid-inferoseptum (arrows), which may represent possible fibrosis or a septal perforator branch due to its typical localization and appearance. Follow-up MRI: (C) PSIR short asix stack image and (D) PSIR LVOT demonstrate basal inferoseptal midwall enhancement (arrows) and possible additional LGE in the basal inferolateral wall (noted on the 3-chamber view but less clear on the short-axis slice), possibly indicating myocardial fibrosis progression.

Management

The patient was started on guideline-directed medical therapy (GDMT) including sacubitril-valsartan, metoprolol, and spironolactone, and a wearable cardioverter-defibrillator (Lifevest) was also recommended for SCD prevention; no malignant arrhythmias were detected while it was worn. Eight months after heart failure diagnosis, he underwent catheter ablation for permanent atrial fibrillation and remained on anticoagulation with subsequent reduction in atrial fibrillation burden to 10% as determined by means of Life Vest interrogation during his follow-up.

Outcome and Follow-Up

After 18 months on GDMT, transthoracic echocardiography revealed an increase in LVEF from 10% to 54%, with interval improvement in LV dilation. However, the degree of MVP-related MR worsened to the severe range, and mitral annular disjunction (MAD) was identified (Figures 1 and 2). At this time, the patient was experiencing symptomatic MR including orthopnea and dyspnea. Subsequently, the patient was referred for follow-up CMR to evaluate the MR further and plan a possible mitral valve repair. CMR demonstrated normalized LV size (LVEDVi 102 mL/m²), LVEF 54%, regional LGE in the basal and inferolateral walls, and significant bi-leaflet MVP with mitral valve regurgitant fraction of 38% (Figures 3 and 4). Significant MAD was identified, which was not previously present to that degree. Figure 3 shows baseline CMR with LV dilation with mild MVP and no evidence of MAD, compared with the follow-up CMR with normalized LV size but with significant MVP and MAD. LGE progressed from a mild mid-myocardial enhancement of the mid-inferoseptum to mid-myocardial enhancement of the basal septum and the basal inferolateral wall (Figure 4). Myocardial extracellular volume fraction was elevated, at 38% ± 5%, in both initial and final CMR with no significant change (Figure 5). All measurements are presented in Table 1. Owing to the worsening severity of MR and high degree of symptom burden, the patient was referred for mitral valve repair surgery and left atrial appendage ligation. The procedure was scheduled 3 months later, with close follow-up by an advanced imaging cardiologist. Preoperative imaging confirmed severe MR secondary to Barlow disease, with a redundant P2 leaflet (Figure 2B). The mitral valve was successfully repaired with the use of a P2 quadrangular resection with sliding valvuloplasty, along with implantation of a 35-mm Duran annuloplasty ring. Postoperative transesophageal echocardiography demonstrated excellent results, with no residual MR (Figure 2).

Figure 5.

Cardiac Magnetic Resonance Imaging Showing Progression of T1 Mapping and ECV

ECV maps at 2 time points: (A) ECV at time point 1, with a global ECV of 95.1 mm; (B) ECV at time point 2, with a global ECV of 93.3 mm. The bullseye plots depict regional ECV percentages across the myocardium according to the 17-segment American Heart Association model.

Table 1.

Sequential Measurements of LV, MVP, and MAD

	Initial Imaging	1 y on GDMT	2 y on GDMT
Echocardiographic parameters
LV systolic function	Severely reduced	Mildly reduced	Normal
LVEF (≥54%)	15%	49%	58%
LVEDD (<56 mm)	65 mm	62 mm	50 mm
LVEDVi (≤74 mL/m2)	78 mL/m2	66 mL/m2	59 mL/m2
LAVi (≤34 mL/m2)	62 mL/m2	54 mL/m2	55 mL/m2
MR duration	Holosystolic	Late-Systolic	Late-Systolic
MR severity	Trivial to Mild (1+)	Mild to Moderate (1+-2+)	Moderately Severe (3+)
MAD appearance	Absent	Present	Present
MAD length	Absent	7 mm	10 mm
CMR parameters
LVEF (≥57%)	15%		54%
LVEDVi (60-100 mL/m2)	155 mL/m2		102 mL/m2
Delayed enhancement imaging (LGE)	Mid-myocardial, mid-inferior septum		Mid-myocardial, basal-septal, basal-inferolateral
SVi (40-50 mL/m2)	24 mL/m2		55 mL/m2
MR severity	Trivial		Moderately severe
MR reg. volume (mL)/reg. fraction (%)	8%		42 mL (48%)
MAD appearance	Absent		Present

This table outlines the changes in echocardiographic and cardiac magnetic resonance (CMR) parameters for the patient over time. Parameters were assessed at 3 time points: 1) initial encounter; 2) 1 year after initiation of guideline-directed medical therapy (GDMT); and 3) 2 years on GDMT. Improvements in LVEF and stroke volume and reductions in LVEDVi and are shown, reflecting positive remodeling and response to GDMT. In addition, interval appearance of MAD is present on both imaging modalities. CMR was performed only at time points 1 and 3. Normal imaging reference ranges are shown in parentheses, as obtained from the major societal guidelines, including the 2015 American Society of Echocardiography chamber quantification guidelines and the 2021 Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance imaging.^17,18

LAVi = indexed left atrial volume; LGE = late gadolinium enhancement; LVEDD = left ventricular end-diastolic diameter; LVEDVi = indexed left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; MAD = mitral annular disjunction; MR = mitral regurgitation; SVi = indexed stroke volume.

Discussion

This case exemplifies the intricacies of NICM, which initially obscured the presence of MAD, which was subsequently unveiled through impressive reverse remodeling and normalization of LV dimensions and function. CMR alongside echocardiography allowed for identifying scar by means of LGE features and allowed us to look at the mitral valve in more detail as part of the preparation for mitral valve repair. With GDMT, our patient demonstrated a notable decrease in LVEDVi from 152 mL/m² to 102 mL/m², correlating with a substantial reduction in LV dilation. This alteration likely modified the tensile forces within the mitral valve apparatus, revealing the previously hidden MAD.¹ Mitral valve repair in this patient aimed to decrease the tensile forces on the mitral valve and apparatus, improve hemodynamics, and reduce subsequent remodeling.

Correlation with cardiomyopathy

This clinical scenario outlines the pivotal association between NICM and MAD/MVP. Symptomatic MVP patients displayed a range of myocardial abnormalities such as stress in the basal inferior/inferolateral wall and papillary muscles, which leads to myocardial fibrosis and resultant hypertrophy after reverse LV remodeling on GDMT. We speculate that the association between underlying cardiomyopathy and the concurrent worsening of mitral disease in this patient was also potentially complicated by tachycardic induced cardiomyopathy. Symptomatic MVP patients exhibit mechanical stress in the basal inferior/inferolateral wall and papillary muscles which can lead to myocardial fibrosis and resultant remodeling.² The relationship between MVP/MAD and cardiomyopathy can be hypothesized through various mechanisms: mitral valve–mediated LV dilation, myocardial fibrosis, and primary genetic processes.

MR progression exacerbates the mitral annular pathology, leading to further leaflet displacement and billowing.³ MVP may trigger myocardial fibrosis due to significant MR.⁴ A study analyzing LV biopsies from peripapillary regions, basal inferior/inferolateral LV wall, and apex in surgical MVP revealed localized fibrosis in the peripapillary myocardium, accompanied by increased macrophages and myofibroblasts.⁵ Fibrosis is potentially mediated by increases in transforming growth factor (TGF)-β2 through the canonic SMAD pathway. Increased TGF-β1 expression in mitral valves from patients with MVP is associated with elevated levels of connective tissue growth factor and matrix metalloproteinase 2, which are involved in fibrosis and matrix remodeling.⁶ Cardiomyopathy can also develop simultaneously with progression of MR.

Severe MR–related volume overload is commonly considered the main cause of LV dilation in MVP. However, substantial LV remodeling has also been noted in patients with minimal or mild MR, particularly in those with bi-leaflet MVP or Barlow disease, suggesting that genetic predisposition to can lead myocardial fibrosis.⁷ The hypothesis of genetic predisposition as the primary driver considers a genetic predisposition that drives simultaneous mitral valve pathology and myocardial disease progression, marked by the co-development of myocardial fibrosis, which could stem from genetic factors, a “second hit” scenario (eg, an underlying genetic predisposition), or frequent ventricular beats.⁸

MVP can present as part of syndromic conditions such as Marfan syndrome, but it is most often nonsyndromic and occurs in isolated or familial forms, predominantly following an autosomal dominant inheritance pattern. MVP is classified into myxomatous degeneration (Barlow), fibroelastic deficiency (FED), and filamin A–related MVP (FlnA-MVP), with myxomatous and FlnA-MVP considered to be familial, and FED linked to aging. Recent genetic studies have identified FLNA, DCHS1, and DZIP1 as causative genes in myxomatous forms, though they account for only a small proportion of cases; genome-wide association studies reveal a significant role of common genetic variants, aligning with MVP’s high prevalence.⁸ Notably, the present patient continued to experience MR/MVP progression despite reverse ventricular remodeling, indicating possible ongoing development of cardiomyopathy, thus supporting the genetic hypotheses (Figure 6).

Figure 6.

Structural Abnormalities Associated With MAD

This figure highlights the structural abnormalities associated with MAD. Late gadolinium enhancement (LGE) shows myocardial fibrosis localized to the papillary muscles and mitral annular region, reflecting expanded extracellular volume. The progression of disease often includes severe mitral regurgitation (MR) and heart failure with reduced ejection fraction (HFrEF), with tachycardia-induced cardiomyopathy linked to high premature ventricular contraction (PVC) burden. Genetic features and structural changes, such as variable leaflet billowing, progressive MR, and the hallmark abnormal displacement of the mitral valve annulus, are depicted in the yellow-highlighted region. MVP = mitral valve prolapse; VF = ventricular fibrillation; VT = ventricular tachychardia.

Arrhythmogenic potential

Interestingly, significant reverse remodeling in this patient was accompanied by possible progressive LGE, although the extracellular volume remained elevated and stable, pointing to an increased risk of adverse cardiac events and necessitating vigilant follow-up.⁹ The prevalence of myocardial fibrosis in MVP patients is as high as 36.7%, in stark contrast to the 6.7% observed in non-MVP individuals with MAD.⁴ In MVP patients, MR often arises from myxomatous degeneration and prolapse of the mitral leaflets, contributing to a higher prevalence of myocardial fibrosis. In contrast, in non-MVP patients with MAD, MR is still primary but results from the structural disjunction of the annulus, which disrupts the normal annular-ventricular continuity and impairs proper leaflet coaptation. This leads to MR without the myxomatous changes seen in MVP. Consequently, the myocardial fibrosis prevalence in non-MVP patients is lower, likely due to the absence of the severe myxomatous degeneration that characterizes MVP.¹⁰ The development of LGE as seen from initial to follow-up MRI raises the risk of malignant arrhythmias and highlights MAD’s role in arrhythmogenic mitral valve disease.¹¹ In the absence of moderate-to-severe MR or LV dysfunction, the presence of LGE confers a hazard ratio of 4.2 for adverse outcomes, such as sustained ventricular tachycardia, SCD, or unexplained syncope.⁹ In addition, in nonischemic dilated cardiomyopathy, LGE presence predicts implantable cardioverter-defibrillator shock and cardiac mortality, with a 13% LV mass cutoff by LGE conferring a 7-fold higher risk compared with those without LGE or with <13% LGE.¹²

MAD has been implicated in ventricular arrhythmias and SCD, particularly when the disjunction exceeds 8.5 mm.¹³ A CMR study looking at 116 patients with MAD (median longitudinal MAD distance of 3.0 mm) showed that most (71%) experienced palpitations and 12% had severe arrhythmic events. MVP was present in 78% of the patients but was not linked to arrhythmias, suggesting that MAD itself is a distinct arrhythmogenic condition.¹⁴

Although MAD correlates with a heightened risk of arrhythmic events, it does not predict increased mortality within the first decade after diagnosis.¹⁵ MAD and LGE are pivotal in cardiac remodeling and hold substantial prognostic significance in MVP management. These insights reinforce the critical role of cardiac imaging in risk stratification and management, aiming to identify patients at increased risk for arrhythmias and SCD.¹⁶

Conclusions

This case report highlights the emergence of MAD in a patient with NICM after GDMT and the conversion of atrial fibrillation to sinus rhythm. Continued CMR surveillance in treated NICM patients is warranted to evaluate the recurrence of this phenomenon.

Visual Summary.

Sequential Echocardiographic and CMR Findings Over 2 Years of GDMT

Echocardiographic and CMR measurements at baseline, 1 year, and 2 years following initiation of GDMT. Parameters include left ventricular size and function, mitral regurgitation severity, mitral annular disjunction appearance and length, delayed enhancement imaging findings, and indexed chamber volumes. Reference ranges are included in parentheses. CMR was performed at initial and 2-year time points. The visual summary includes 3 image panels corresponding to each time point; the yellow arrow in the center panel denotes MAD. CMR = cardiac magnetic resonance; GDMT = guideline-directed medical therapy.

Funding Support and Author Disclosures

Dr Calcagno has received funding from the National Heart, Lung, and Blood Institute of the National Institutes of Health under 1R01HL170090-02; has a research agreement with Circle cvi42 and Myocardial Solutions; and has received consulting fees from Pfizer for conducting an educational session on Cardiac MRI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.