Dr. University Of Calgary Calgary, Alberta, Canada
Case background: Patient 1 History of presentation: A 42-year-old female presented to hospital with recurrent myopericarditis. She had pleuritic chest pain and elevated high-sensitivity troponin T (89 ng/L; normal < 14 ng/L).
A background history of episodic chest pain since adolescence was provided. At age 39 years, she was hospitalized with acute myopericarditis following a motor vehicle accident. Peak high-sensitivity troponin T was 480 ng/L and cardiac magnetic resonance imaging (MRI) showed normal ventricular function with myocardial edema and sub-epicardial pattern late gadolinium enhancement (LGE). The patient was treated with colchicine, non-steroidal anti-inflammatory drugs, and a proton-pump inhibitor. However, she had refractory symptoms requiring two additional hospitalizations leading to the incremental usage of glucocorticoids and anakinra.
Clinical examination showed: blood pressure 139/89 mmHg, heart rate 81 bpm, height 157 cm, and weight 84 kg. S1 and S2 heart sounds were normal. There were no extra heart sounds, friction rubs or murmurs. Palmoplantar keratoderma was observed. Hair was normal.
Past medical and family history: The patient had no other medical history. A family history of dilated cardiomyopathy with sudden death in her father, paternal uncle, and paternal aunt was elicited. Palmoplantar keratoderma had also been described in multiple relatives.
Differential diagnosis: The differential diagnosis of chronic, recurrent myocarditis includes infectious disease, autoimmune diseases, and genetic cardiomyopathies. Infectious causes include virus-induced, Lyme myocarditis and Chagas disease. Systemic and organ-specific autoimmune disorders such as systemic lupus erythematosus, sarcoidosis and inflammatory bowel disease have been described in association with chronic myocarditis. Genetic cardiomyopathies – such as desmoplakin cardiomyopathy – may also present in this manner.
Investigations: A 12-lead electrocardiogram showed normal sinus rhythm without any abnormalities.
Echocardiography showed normal left ventricle (LV) size and ejection fraction, normal right ventricle (RV) size and function, no significant valve disease, and no pericardial effusion.
Cardiac MRI showed normal biventricular volumes, global LV hypokinesis with mildly reduced systolic function (ejection fraction 52%), and normal RV function. There was no myocardial edema seen on T2 weighted imaging. Multifocal sub-epicardial LGE was seen without pericardial enhancement. The extent of LGE had progressed compared to the MRI performed three years prior with prominent involvement of the basal inferoseptal and anterolateral segments, the latter associated with wall thinning (Figure 1A).
Cardiac PET performed shortly thereafter showed intense, multifocal and circumferential fluorodeoxyglucose (FDG) uptake of the LV myocardium, most pronounced in the basal to mid septal and lateral walls, supporting the presence of an active myocardial inflammatory process (Figure 2A).
A cardiomyopathy gene panel identified a novel pathogenic heterozygous DSP c.123C>G (p.Tyr41*) truncating variant. This sequence change creates a premature translational stop signal in exon 1 of DSP and is predicted to result in nonsense mediated decay. Loss-of-function is a known mechanism of disease. This variant is not reported in population databases (gnomAD v4.1.0).
Patient 2
History of presentation: The 44-year-old female sister of patient 1 was identified as having the same heterozygous pathogenic DSP truncating variant through predictive testing. She had no other significant medical history.
Clinical examination disclosed the following: blood pressure 104/72 mm Hg, heart rate 61 beats / min, height 158 cm, and weight 48 kg. S1 and S2 heart sounds were normal. The chest was clear to auscultation. There was no jugular venous distension or peripheral edema. Palmoplantar keratoderma was present.
Differential diagnosis: Inherited cardiomyopathies may present with variable penetrance and expressivity. The presence of a likely pathogenic or pathogenic DSP variant warrants investigation for phenotypic expression. Common manifestations include myocarditis, ventricular myocardial fibrosis, arrhythmias, late-onset heart failure, and cutaneous abnormalities. Autosomal recessive diseases associated with DSP variants are Carvajal syndrome, characterized by dilated cardiomyopathy, woolly hair, and keratoderma, as well as lethal acantholytic epidermolysis bullosa, characterized by cardiomyopathy, rapidly progressive skin erosion, alopecia, and abnormalities of the teeth, ears, and skeleton.
Investigations: Variant testing identified the DSP c.123C>G (p.Tyr41*) variant.
A 12-lead electrocardiogram showed normal sinus rhythm with premature ventricular complexes of variable morphologies in a bigeminy pattern. Dominant R waves in V1-V2 and nonspecific T wave abnormality were also noted.
Echocardiography showed normal LV size with mild systolic dysfunction. There was grade 1 diastolic dysfunction with normal left atrial pressures. RV size and function were normal, and there were no significant valvopathies.
A cardiac MRI was performed and showed normal LV volumes with moderately reduced systolic function (ejection fraction 36%). There was prominent mid to apical trabeculation of the LV, with associated hypokinesis. The RV was normal in size with borderline systolic function (ejection fraction 47%). No myocardial edema was seen on T2 weighted imaging. There was a large burden of circumferential, sub-epicardial myocardial fibrosis on LGE imaging (Figure 1B).
Cardiac PET was subsequently performed to definitively exclude myocardial inflammation and to better inform decisions regarding immunosuppressive therapy. This did not show any abnormal myocardial hypermetabolism to suggest an active cardiac inflammatory process (Figure 2C).
Management Challenges: Patient 1 was treated with prednisone 1 mg / kg / day for 1 month, which was then decreased to 15mg daily. Mycophenolate mofetil 500 mg twice daily was also prescribed, with prophylaxis for bone health and opportunistic infections. We introduced quadruple guideline-directed medical therapy (GDMT) with beta-blocker, angiotensin-converting enzyme inhibitor, mineralocorticoid receptor antagonist and SGLT2 inhibitor. We implanted a primary prevention implantable cardioverter defibrillator (ICD) to mitigate against the elevated risk of sudden death given the presence of LV dysfunction and LGE. Finally, we arranged predictive testing of first-degree relatives. Patient 1 underwent repeat PET scan after 3 months of immunosuppression, which showed a significant improvement of myocardial inflammation (Figure 2B). We tapered steroids thereafter. No myocarditis recurrences have been reported since.
GDMT was progressively introduced in patient 2 given her LV systolic dysfunction. Considering her reduced ejection fraction and extensive myocardial fibrosis on MRI, her annual risk of sudden cardiac death was deemed to be elevated. No immunosuppression was offered given her negative PET scan. We arranged predictive testing of her first-degree relatives. She has remained free of myocarditis-like events. She was offered primary prevention ICD but opted to defer this procedure due to other ongoing psychosocial stressors.
