INTERNATIONAL JOURNAL OF CLINICAL AND MEDICAL CASES (ISSN:2517-7346)

We present the case of a 44-year-old woman who suffered an out of hospital cardiorespiratory arrest. After six direct current shocks and 10 minutes of cardiopulmonary resuscitation she had return of spontaneous circulation and regained consciousness. Transthoracic echocardiography showed normal left ventricular ejection fraction and a mildly dilated left atrium. The mitral valve was thickened with myxomatous degeneration (Barlow’s disease) and moderate regurgitation secondary to bileaflet prolapse. Cardiac catheterization showed no coronary artery disease while left ventriculography revealed a mildly dilated left ventricle with preserved systolic function and high-end diastolic pressures. Cardiac MRI revealed an enlarged left ventricle with mitral valve (MV) prolapse and moderate to severe mitral regurgitation (MR). There were no features suggestive of a specific cardiomyopathy other than her valvular heart disease. The patient had an uneventful hospitalization, received an implantable cardioverter defibrillator (ICD), and eventually had MV repair surgery. In this article we also review the literature regarding similar cases and record important data for the epidemiology of the disease and the important research that has been carried out in the identification of prognostic imaging factors and the genetic background of these patients. We emphasize once again that it is especially important to be able to timely identify patients with mitral regurgitation who are at increased risk of sudden cardiac death so that immediate and effective treatment can be offered.

Patient presentation

A 44-year-old patient was transferred to the Accident and Emergency Department of Nicosia General Hospital after suffering an out of hospital cardiorespiratory arrest during anaerobic exercise at the gym. The patient reported weakness and dizziness before she lost consciousness. A bystander nurse initiated cardiopulmonary resuscitation. Ventricular fibrillation was recorded as the initial rhythm upon connecting to an external defibrillator by the paramedics. After six direct current shocks, 10 minutes of CPR, the administration of 2mg adrenaline IV and 300mg amiodarone IV, the patient had return of spontaneous circulation (ROSC) and regained consciousness, upon arrival at the emergency department. She reported a past medical history of mitral valve prolapse and migraines with occasional use of analgesics. She is an active tobacco smoker. She denied any history of chest discomfort, palpitations, and shortness of breath, nausea or vomiting, either at stress or at rest. There was no recent febrile illness, gastroenteritis, or rashes. She is a mother of 5 children and has 1 previous miscarriage. There is no family history of heart disease or sudden cardiac death. On clinical examination she was afebrile; heart rate was 88 beats per minute, blood pressure 122/77mmHg and had oxygen saturation 92% on room air. Her cardiac examination revealed normal S1 and S2 with a mid-systolic click and a late systolic murmur best heard at the apex of the heart. There were normal breathing sounds, no peripheral edema, and normal peripheral pulses. Her neurologic examination was normal with GCS 15/15 and normal cranial nerve exam.

Initial work up

The electrocardiogram (ECG) revealed sinus rhythm, normal axis with normal QRS and QTc intervals with infrequent ventricular ectopic beats. Shallow negative T waves were noted in lead II, III and aVF(Figure 1). Blood tests were normal with normal arterial blood gasses while her chest X ray showed an increased cardiothoracic index. Inpatient Holter monitoring revealed a 2% burden of ventricular ectopy (singlets and couplets) of primarily a single morphology. A transthoracic cardiac ultrasound revealed an Ejection Fraction (EF) of 55-60%, a mildly dilated Left Atrium (LA), normal Right Atrium (RA) and a normal trileaflet Aortic Valve (AV). The mitral valve was thickened with myxomatous degeneration (Barlow’s disease) and a moderate Mitral Valve Regurgitation (MR) with a predominately anteriorly directed jet. Moderate bileaflet prolapse was also present. There were only traces of Tricuspid Regurgitation (TR) with normal right ventricular systolic pressure (RVSP). No pericardial effusion was noted (Figure 2). Due to her presentation with an out-of-hospital cardiac arrest, she had an emergency coronary angiogram which showed normal coronary tree anatomy and no coronary lesions of concern. Left ventriculography showed a mildly dilated ventricle with preserved systolic function and high-end diastolic pressures. There was angiographically severe mitral valve regurgitation and a large left atrium (Figure 3).

Diagnosis and Management

Transthoracic and transesophageal echocardiography confirmed that moderate MR was present. The regurgitant volume (Rvol) was 30ml with a Vena Contracta of 0,3cm and Effective Regurgitant Orifice (ERO) of 20mm2 . The mitral valve was myxomatous with bileaflet prolapse (Figure 4,5). For further evaluation of the MR, exercise treadmill testing was utilized using the standard Bruce protocol. The patient was exercised for 6 minutes achieving a maximum heart rate of 95 bpm, whist on b blocker therapy. There was normal heart rate and blood pressure response to exercise. The test was stopped at the patient’s request. There were multiple PVCs and couplets at peak stress. The echo images showed moderate to severe mitral valve insufficiency at peak exercise and RVSP increased to 50mmHg from 30mmHg at rest. The patient subsequently underwent a cardiac MRI which showed a severely enlarged left ventricle with normal wall thickness and a mildly affected systolic performance. Localized hypokinesia of the mid anterolateral wall segment of the left ventricle was present. The left atrium exhibited increased dimensions. There was leaflet mitral valve prolapse with moderate to severe MR (Barlow disease, Figure 6).

Follow up

The paient had an uneventful hospitalization, and following a multidisciplinary heart team discussion, an ICD was implanted. The decision for this was based on the circumstances of her presentation with a malignant arrhythmia and the fact that she was a survivor of an arrhythmogenic cardiac arrest. The patient was discharged 12 days after admission and referred for a surgical mitral valve repair. Metoprolol was also prescribed at discharge. The patient eventually had an MV repair surgery with exceptionally good results (Figures 7). With regards to recurrence of significant cardiac arrhythmias, the patient developed recurrent and highly symptomatic episodes of paroxysmal atrial fibrillation, which were successfully suppressed with a combination of bisoprolol and propafenone. There has been no documented recurrence of a notable ventricular arrhythmia following her surgery as seen on her scheduled and frequent ICD checks. Furthermore, her burden of ventricular ectopy remains low. The patient was genetically investigated with Next Generation Sequencing of a panel of 72 genes which are known to be implicated in inherited cardiac conditions (not shown). Two variants were of particular interest, which were further validated by Sanger sequencing (Table 1,2). In the MYPN gene, exon 19, variant c. 3793G>A, p. Ala1265Thr was detected. In Silico analysis shows it is extremely rare and classified as a variant of uncertain significance (VUS) in the Varsome and ClinVar databases. Importantly, a known pathogenic variant reported in the Human Gene Mutation Database (HGMD) affected the same amino acid residue, but substituting alanine with proline, in an Asian female patient with hypertrophic cardiomyopathy [1,2]. She was first diagnosed at age 28-yrs and was compound heterozygote for another variant in the second allele of the same gene, MYPN, thus suggesting recessive inheritance. A second variant in our patient was in the TMPO gene, exon 4, substituting aspartate with glycine, c. 1970A>G, p. Asp657Gly. Varsome classifies it as likely benign, and Mutation Taster is divided between classifications of polymorphism and disease causing. The mother of the patient carries only mutation in the TMPO gene, and she is healthy at age 68-yrs. Three children of the patient, a son from a first marriage and a son and daughter from a second marriage, aged 28, 21 and 10-yrs respectively, are mainly healthy, with the 21-yo son manifesting mild mitral valve regurgitation. Two other sons, one from each marriage aged 27 and 22-yo, are healthy and have inherited neither of the variants.

It is not easy to attribute causality to either of the two DNA variants, thus reiterating previous similar experience by many authors in this field. Reduced penetrance is certainly a likely explanation of the lack of obvious past family history. If only digenic inheritance is sufficient and necessary to produce a perceptible phenotype, might also explain this lack of past history while the three children who by chance co-inherited both linked variants, may be at increased risk and require close clinical monitoring. Overall, the genetics findings, although not conclusive, might suggest that digenic inheritance is responsible for the phenotype, implicating genes previously linked to dilated cardiomyopathy, thus expanding the phenotypic spectrum of variants and mutations in these genes. An alternative to digenicinheritance might be that the variant in the MYPN gene is pathogenic and the variant in the TMPO gene acts more like a genetic modifier. A genetic modifier is a DNA variant with no effect on its own, but which could exacerbate or even precipitate the phenotype when co-inherited on the background of another condition [3]. A limitation of this work is the absence of unequivocal segregation of the phenotype with the genetic findings, which may be resolved in the future if one or more of the younger members develop pathognomonic clinical features, hopefully not a fatal cardiac arrest. The literature is not particularly helpful in further resolving the genetic uncertainty, as many genes have been shown to be mutated in patients with MVP while incomplete penetrance, or age-dependent penetrance, is the norm. More genes that may play a role either following Mendelian inheritance or following digenic inheritance are to be discovered through contemporary parallel sequencing of panels of genes or through whole exome and whole genome sequencing.