Mystery of Isolated Right Atrial Hypertrophy: Story of Two Sisters

Priya Chudgar, MD FSCMR^*; Nitin Burkule, MD DM FASE FSCMR^*; Srinivas Lakshmivenkateshiah MD

Department of Cardiology and Radiology, Jupiter Hospital, Mumbai, India

Clinical History:

A 14-year-old female presented with two episodes of syncope. The first episode of syncope occurred on the school playground, with the immediate recovery of consciousness without tonic-clonic convulsions or bowel/bladder incontinence. Another episode was at home while performing simple household chores. Her systemic and clinical examination was normal. Her family history revealed sudden cardiac death (SCD) in her elder sister at the age of 17 years with premortem clinical and imaging diagnosis of hypertrophic cardiomyopathy (HCM).

The electrocardiogram (ECG) of this patient (index case) showed an ultra-short PR interval and an undulating upstroke of QRS that was suggestive of a delta wave (pre-excitation) (Figure 1A). Routine blood tests were unremarkable. The two-dimensional (2D) echocardiography study showed normal biventricular size and function, no valvular pathology but isolated right atrial (RA) free wall severe thickening (Movie 1). Due to her symptoms, family history of SCD, and RA free wall thickening she underwent cardiac magnetic resonance imaging (CMR).

The older sister with HCM had an ECG with an identical ultra-short PR interval, pre-excitation and additionally down-sloping ST depression and T wave inversion in inferolateral leads (Figure 1B). Her 2D echocardiography showed HCM with asymmetric septal hypertrophy.

Figure 1. (A) An electrocardiogram of the index case shows ultra-short PR and pre-excitation. (B) Electrocardiogram of older sister with HCM showing ultra-short PR and pre-excitation with ST depression and T wave inversion in infero-lateral leads.

Movie 1. 2D Echocardiography right ventricle focused 4 chamber view of the index case showing severe right atrial free wall thickening.

CMR Findings:

The CMR (performed on Siemens 3T, Verio) of the index case revealed isolated RA free wall hypertrophy, measuring 9 mm in maximum thickness. The RA free wall was isointense compared to the left ventricular (LV) myocardium on steady state free precession (SSFP) images and there was no LV hypertrophy (Movie 2).

Movie 2. Four chamber stack cine steady-state free precession of the index case show isolated right atrial free wall hypertrophy which is isointense compared to left ventricular myocardium.

The T1 values of the thick RA free wall, on both native and post-contrast T1 maps, were similar to the LV myocardium (Figure 2).

Figure 2. (A) Pre-contrast native T1 map and (B) post-contrast T1 map of the index case showing right atrial free wall T1 values similar to the LV myocardium.

The RA free wall showed isointense enhancement compared to LV myocardium on the gadolinium first-pass perfusion sequence (Movie 3) and no evidence of late gadolinium enhancement (Figure 3).

Movie 3. The sequential gadolinium first pass perfusion images of index case showing RA free wall isointense enhancement compared to LV myocardium.

Figure 3. Segmented, inversion recovery, gradient echo post-contrast images of the index case showed no evidence of late gadolinium enhancement of the RA free wall (arrow).

The CMR imaging proved that the RA free wall thickening was atrial myocardial hypertrophy and not a layered clot, epicardial fat, focal infiltrative pathology or neoplasm. Other cardiac chambers revealed normal morphology, volume, and function and no late gadolinium enhancement.

The CMR (performed on Siemens 3T Skyra) of the older sister with HCM (now diseased) revealed non-obstructive LV asymmetric septal hypertrophy with a maximum septal thickness of 22 mm (Movie 4).

Movie 4. Cine steady-state free precession short axis stack of the older sister with HCM shows non-obstructive LV asymmetric septal hypertrophy.

There was patchy mid-myocardial late gadolinium enhancement of the basal to apical septal wall with involvement of the inferior RV insertion site in the older sister with HCM (Figure 4).

Figure 4. Segmented, inversion recovery, gradient echo post contrast images of the older sister with HCM showed patchy mid myocardial late gadolinium enhancement in the basal to apical septum with involvement of inferior RV insertion site.

Conclusion:

In view of conduction abnormality on both ECGs, rare phenotypic expression of isolated RA hypertrophy in the index case, and premature SCD in the sibling with HCM phenotype, further workup with genetic testing was performed. It revealed PRKAG2 mutation with a pathogenic variant (heterozygous missense variant c.1589A>G: p.H530R, chr7-151257699 T>C) and autosomal dominant inheritance. No genetic testing was performed on the diseased elder sister with HCM phenocopy. The patient was advised of dual-chamber implantable cardioverter defibrillator (ICD) device implantation with close clinical follow-up for monitoring arrhythmias.

Perspective:

The γ2 regulatory subunit of the PRKAG2 gene on chromosome 7q31 encodes the enzyme Adenosine Monophosphate-activated protein kinase (AMP-K). AMP-K enhances glucose and lipid metabolism to elevate intracellular ATP and regulates the CPK to reduce ATP depletion.[1]
PRKAG2 mutation is a rare autosomal dominant disease with a myocardial intracellular, non-lysosomal, accumulation of glycogen and amylopectin. These patients present with ventricular pre-excitation, supraventricular arrhythmias, atrioventricular block, and non-sarcomeric familial hypertrophic cardiomyopathy. [2,3] PRKAG2 mutation presenting as isolated RA hypertrophy is not described in the medical literature as per our literature search. This case is a classic example of a pathological genotype, associated with a cardiomyopathy, presenting with different phenotypic expressions in different family members.

This clinical case of the 14-year-old girl with isolated RA-free wall hypertrophy is an unreported phenotypic expression of PRKAG2 pathological mutation. Morphologic assessment and muti-parametric tissue characterization of RA-free wall thickening with CMR helped in differentiating likely atrial myocardial hypertrophy from focal infiltrative disease, epicardial fat, and cardiovascular masses.
We stress the importance of a comprehensive evaluation of cardiomyopathy which should include: family history of SCD, detection of conduction abnormality in ECG, review of clinical and imaging data of affected first-degree relatives, high index of suspicion for HCM phenocopies in symptomatic young patients, low threshold for muti-parametric CMR imaging, cardiomyopathy gene panel testing in appropriate patients. This clinical approach has the potential to prevent future risk of SCD in the index case.

*The first two authors (PC and NB) have equal contributions to the patient’s diagnostic workup and preparing the manuscript.