Arrhythmic Mitral Valve Prolapse and Mitral Annulus Disjunction in Heritable Aortic Disease.

Patients with heritable aortic disease (HAD) have an increased risk of ventricular arrhythmias and sudden cardiac death. Although mitral valve prolapse is common in HAD, mitral annulus disjunction (MAD) has only recently been described in these patients. This under-recognized condition may be a contributing factor to otherwise unexplained ventricular arrhythmias and sudden cardiac death in patients with HAD. This case series describes 3 patients in an adult HAD clinic who have concomitant mitral valve prolapse, MAD, and malignant arrhythmias. These cases may represent a unique disease entity or overlap syndrome, and they introduce MAD as a potential arrhythmogenic risk marker in HAD.

Cases

Case 1 is a 26-year-old male with Marfanoid features (Ghent score: 5) and a negative aortopathy gene panel (Supplemental Appendix S1). Transthoracic echocardiography demonstrated bileaflet mitral valve prolapse (MVP) and mitral annulus disjunction (MAD; maximal distance 14 mm at the posterolateral wall; Fig. 1A, top). He had moderate mitral regurgitation with preserved left ventricle (LV) dimensions and ejection fraction. His aortic root measured 3.3 cm (z-score: 0.52). He developed exercise-induced ventricular tachycardia (VT; Fig. 2A) and received an implantable cardioverter defibrillator (ICD), which recorded several episodes of nonsustained VT and one episode of polymorphic VT. He is treated with nadolol. Due to device implantation, gadolinium-enhanced cardiac magnetic resonance (CMR) imaging could not be performed.

Figure 1

Imaging: (A-C) case 1 mitral annulus disjunction (MAD) seen in the posterolateral and anterolateral wall. (D-F) Case 2 MAD seen in the posterolateral and inferior wall. (G,H) Case 3 MAD seen in the inferior and inferolateral wall. Yellow arrows indicate areas of MAD.

Figure 2

Electrophysiology: (A) Case 1: Graded exercise stress test shows brief triplets of rapid polymorphic ventricular tachycardia (VT). (B, C) Case 2: 12-lead electrocardiogram shows a ventricular ectopic localizing to the mitral annulus (black arrow), and implantable cardioverter defibrillator (ICD) report shows discharge due to ventricular fibrillation (VF). (D) Case 3: 24-hour Holter monitor shows frequent ventricular ectopics.

MAD should be recognized and quantitatively assessed in patients with HAD.

Patients with HAD and concomitant MVP and MAD should be evaluated for arrhythmia.

More research is required to improve the yield of genetic testing and assist in arrhythmia risk stratification in patients with HAD.

Case 2 is a 19-year-old male with a clinical diagnosis and family history of Marfan syndrome (MFS, Ghent score: 8), and no genetic testing. Transthoracic echocardiography demonstrated bileaflet MVP and MAD (maximal distance 18 mm at the posterolateral wall), with moderate to severe mitral regurgitation (Fig. 1, D-F). His LV was dilated, with an end-diastolic diameter of 70 mm and an end-systolic diameter of 42 mm, with an ejection fraction of 57%. His aortic root was dilated at 4.5 cm (z-score: 4.76). He had atrial fibrillation and frequent ventricular ectopy (2523 premature ventricular contractions in 24 hours, 1.6% of total QRS complexes). An electrocardiogram showed ventricular ectopy originating from the mitral annulus (Fig. 2B). A VT stimulation study showed inducible ventricular fibrillation, prompting ICD insertion. His ICD subsequently recorded several brief episodes of VT and one discharge for VT/ventricular fibrillation (Fig. 2C). He is treated with digoxin, valsartan, sotalol, and aspirin. Due to device implantation, gadolinium-enhanced CMR imaging could not be performed.

Case 3 is a 45-year-old female with MASS syndrome (mitral valve prolapse, aortic root diameter at upper limits of normal for body size, stretch marks of the skin, and skeletal conditions similar to Marfan syndrome), a variant in the FBN1 gene (Supplemental Appendix S1), and a family history of sudden cardiac death (SCD). Transthoracic echocardiography revealed bileaflet MVP and suspected MAD with mild mitral regurgitation. Her LV dimensions and ejection fraction were normal. Her aortic root measured 3.0 cm (z-score: –0.83). CMR imaging (Fig. 1, G-H) confirmed the presence of MAD (maximal distance 12 mm) and no areas of delayed gadolinium enhancement. A 24-hour Holter monitor (Fig. 2D) revealed sinus rhythm with frequent ventricular ectopy (1018 [1.1%] in 24 hours). The patient is managed conservatively.

Discussion

This case series uniquely describes 3 patients with heritable aortic disease (HAD) and ventricular arrhythmias (VAs), in the setting of MVP and MAD, although all 3 patients display distinctly different clinical and genetic characteristics. MAD refers to the abnormal atrial displacement of the mitral valve leaflet hinge point and is common in the setting of MVP. MAD has been described as a risk factor for malignant MVP. Others include bileaflet prolapse, younger age, myocardial fibrosis, and enlarged cardiac chambers. Interestingly, MAD can occur without MVP, and arrhythmic MAD is associated with younger age, lower LV ejection fraction, and papillary muscle fibrosis. Although VA and SCD have been described in children and adults with MFS, the mechanism and associated risk markers are not well elucidated. VA in MFS is associated with MVP and previous aortic surgery, and it is correlated with mitral regurgitation severity, increasing LV dimensions, and increasing Ghent score. Up to 40% of patients with MFS and Loeys–Dietz syndrome demonstrate echocardiographic evidence of MAD, which is associated with aortic events at a younger age and a greater need for mitral surgery. Furthermore, MAD is more common in patients with documented VA.

With emerging clinical experience linking MAD and MVP to risk of SCD, this case series highlights 3 patients who present with features of malignant MVP and MAD with underlying HAD. As yet unclear is whether this case series highlights a unique disease entity with a common pathophysiologic substrate, represents unique patients with overlap syndromes, or introduces MAD as an arrhythmogenic risk marker in aortopathy syndromes. This report highlights the variability in clinical presentation and the current limitations in genetic testing in this subset of aortic patients. Arrythmia risk stratification in patients with HAD and complex structural heart disease can be challenging, emphasizing the need for more research in this area.

Limitations

Our case series has important limitations. All patients did not undergo the same genetic testing (Supplemental Appendix S1), and expanding the genes under investigation in this cohort may play a role in the future. Although cardiac fibrosis has been implicated as a risk factor for ventricular arrhythmias in related disorders, we were unable to quantitate fibrosis by CMR imaging, owing to ICD implantation in 2 patients. Finally, future research with large cohorts is required to delineate the arrhythmogenic risk related to MAD, and in patients with vs without HAD.

Funding Sources

This project received funding from the Cardiology Academic Practice Plan from the University of British Columbia (Z.L.). The other authors have no funding sources to declare.

Disclosures

The authors have no conflicts of interest to disclose.