Case

A 15-year-old male with no significant past medical history presented to an outside emergency department after a vasovagal syncopal episode following a basketball practice characterised by light-headedness, nausea, shortness of breath, and pale appearance. Chest pain and discomfort were denied. He had received his second COVID-19 vaccination 4 days prior to the event. An elevated troponin of 0.11ng/mL (normal<0.01) prompted transfer to a quaternary children’s hospital for further evaluation. Initial vital signs included a blood pressure of 141/90 mmHg, heart rate of 76 beats per minute, respiratory rate of 16 breaths per min, oxygen saturation of 98%, and temperature of 36.4°C. An electrocardiogram demonstrated sinus rhythm and was within normal limits. No echocardiogram was done. The troponin leak was presumed secondary to vigorous exercise, and he was discharged home with return instructions and follow-up care with outpatient cardiology.

An echocardiogram was performed one week later demonstrating normal biventricular size and systolic function. High-sensitivity troponin was elevated at 128pg/mL (normal<45pg/mL). Based on the timing of his second COVID-19 vaccine and his elevated troponin level, he was diagnosed with COVID-19 vaccine myocarditis. He was restricted from sports for 4 months from presentation.

A month later, his high-sensitivity troponin level normalised (6pg/mL) and a cardiac MRI revealed mild dilation of his right ventricle with moderately decreased function, right ventricle ejection fraction of 37%, mildly depressed left ventricular function (left ventricle ejection fraction = 52%), and a large, near full thickness subepicardial focus of late gadolinium enhancement spanning between the mid-ventricular anterolateral and inferolateral segments. Elevated Native T2 values and extracellular volume were present, collectively suggesting oedema, inflammation, and fibrosis (Figure 1).^{Reference Ferreira, Schulz-Menger and Holmvang2}

Figure 1. Initial study. (a, b) Late gadolinium enhancement (LGE) sequences. To the right (arrows) there is near full thickness LGE predominantly along the mid inferolateral segment with some extension into the anterolateral segment. There was elevated T2 values at the base which would indicate inflammation. There was a mildy dilated right ventricle with moderately decreased function. Left ventricle is normal in size but with mildly decreased function. Arrows indicate LGE. (c) T2 map of the basal left ventricle segments. Elevated with global value of 60 ms.

Four months after presentation, his cardiac MRI again revealed a mildly dilated right ventricle with mild-moderately reduced function (right ventricle ejection fraction = 39%) and mildly depressed left ventricle (left ventricle ejection fraction = 51%) (Figure 2). In comparison to the previous cardiac MRI, both size and function of the right ventricle were improved while that of the left ventricle were not. His exercise stress test demonstrated frequent multiform premature ventricular contractions with one ventricular couplet.

Figure 2. Two months after presentation. Right ventricle was still moderately depressed, mildly dilated, with slight improvement in right ventricular ejection fraction. Left ventricle remained normal in size with mildly depressed function. T1, T2, and extracellular volume are all normal globally at this time. Arrows indicate LGE.

A cardiac MRI performed 16 months after presentation was unchanged (Figure 3), making the diagnosis of COVID-19 vaccine myocarditis less likely, and he was referred for genetic counselling. Family history is significant for atrial fibrillation and junctional rhythm with frequent premature ventricular contractions resulting in cardiac ablation in his maternal grandmother in her 40s. Genetic testing was recommended and included evaluation of 22 genes (ACTN2, BAG3, CDH2, DES, DSC2, DSG2, DSP, EMD, FLNC, JUP, LMNA, PKP2, PLN, PPA2, PRKAG2, RBM20, RYR2, SCN5A, TMEM43, TNNI3, TNNT2, TTN). He was found to have a pathogenic variant in the PKP2 gene (deletion of exons 2–4). This deletion is out-of-frame and creates a premature termination codon resulting in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic. The clinical course and genetic testing results led to a diagnosis of arrhythmogenic cardiomyopathy. Arrhythmogenic cardiomyopathy is a genetic heart condition that is associated with increased risk of ventricular arrhythmias. In the past, this condition was referred to as arrhythmogenic right ventricular cardiomyopathy. It is now known that individuals can have both left- and right-sided heart involvement which is referred to as arrhythmogenic cardiomyopathy. The prevalence of clinical arrhythmogenic cardiomyopathy is estimated at 1:1,000–1,250 in the general population. The initial diagnosis of COVID-19 vaccination myocarditis was no longer correct.

Figure 3. 16 months after presentation. Grey blood imaging demonstrating again the near thickness late gadolinium enhancement at the mid-inferolateral segment with extension into the anterolateral segment. Arrows indicate late gadolinium enhancement.

Heterozygous variants in the PKP2 gene can be inherited in an autosomal dominant pattern or occur de novo. Cascade genetic testing was recommended to inform family risk stratification and the PKP2 variant was found to be maternally inherited. His maternal grandmother was found to be PKP2 gene-positive. Her positive genetic testing results prompted additional cardiac imaging and she was found to also meet diagnostic criteria for arrhythmogenic cardiomyopathy. Multiple family members were found to be gene-positive and are receiving cardiac screening based on published guidelines. PKP2 gene mutations are known to have reduced and age-dependent penetrance. Among family members, testing positive for a PKP2 mutation first identified in an affected individual, approximately 30–35% will develop a positive phenotype consistent with arrhythmogenic cardiomyopathy. In general, there is wide variability even within families ranging from severe and early onset disease to individuals who remain asymptomatic late in life.^{Reference Dalal, James and Devanagondi3}