PO41 When the genes lead the way: a case of biventricular disfunction

Cardiomyopathies are a heterogeneous group of myocardial disorders with overlapping phenotypic expressions, making diagnosis challenging as some patients transition between phenotypes over time. We present a 49-year-old female with cardiovascular risk factors (dyslipidemia, smoking) and systemic lupus erythematosus (SLE) diagnosed at 18. At 38, she was hospitalized for complete atrioventricular block, requiring a permanent pacemaker (PM), attributed to autoimmunity without structural heart disease or further study. She also had persistent recurrent symptomatic atrial flutter (AFL), documented three months post-PM, undergoing four ablations over time (2013 typical AFL; 2020 atypical AFL, right atrial circuit; 2022 typical and atypical AFL, left atrial circuit). No family history of cardiovascular disease. In March 2023, she suffered an out-of-hospital cardiac arrest due to ventricular fibrillation and was successfully resuscitated. Echocardiography showed moderate le ventricular (LV) dilation, an ejection fraction (EF) of 50-55%, and preserved right ventricular (RV) function. High-sensitivity troponin T (hs-TnT) peaked at 130 pg/mL (ref: 0-14 pg/mL). Coronary angiography showed no epicardial disease. Cardiac MRI revealed severe LV and atrial dilation, moderate RV dilation, LV EF of 38%, and RV EF of 44%. Transmural late gadolinium enhancement (LGE) was seen in the mid-basal inferolateral wall and all distal segments, with a small apical aneurysm. Given the unexplained dilated cardiomyopathy, subclinical inflammation was considered, but SLE was deemed unlikely. Antiphospholipid syndrome was suspected due to the LGE pattern and inadequate anticoagulation but was later ruled out. Her treatment was optimized with prognostic-modifying and immunosuppressive therapy, and a CRT-D was implanted. Genetic testing (October 2023) revealed a TMEM43 variant of uncertain significance [c.625T>G p.(Ser209Ala)], which predictive methods did not classify as deleterious. At 12-month follow-up, echocardiography showed worsening right heart dilation, segmental contractility abnormalities, apical bulging, and declining RV function. The combination of biventricular abnormalities, LGE pattern, ventricular arrhythmias, and genetic findings suggested arrhythmogenic cardiomyopathy, initially affecting the LV and progressing to the RV. Arrhythmogenic cardiomyopathy involves fibro-fatty myocardial replacement. Once linked primarily to RV involvement, recent advances have identified LV and biventricular phenotypes. TMEM43 variants are associated with this condition, often affecting the LV (inferolateral wall) or both ventricles simultaneously, where a worse prognosis is seen when LGE is present. Although the TMEM43 variant in this patient was not classified as deleterious, it appears to behave similarly to pathogenic variants described in the literature.