Genetic-Inflammatory Cardiomyopathy Overlap: The role of multimodality imaging in guiding diagnosis and therapy in a TTN Variant Carrier

Description of Clinical Presentation: A 44-year-old athletic male presented with recurrent episodes of acute onset of chest pain and dyspnea. His initial workup included a normal coronary angiogram and an echocardiogram showing mitral valve prolapse and mild mitral regurgitation. Over three years, he developed supraventricular tachycardia and underwent ablation. His clinical course was marked by recurrent symptom flares following viral-like illnesses. A family history of cardiomyopathy in his brother prompted genetic testing and CMR.

Diagnostic Techniques and Their Most Important Findings: Genetic testing identified a pathogenic heterozygous truncating variant in the TTN gene (c.96206T >A). CMR demonstrated mild reduction in left ventricular systolic fraction (LVEF 48-49%) with globally elevated T1 and T2 values and subepicardial late gadolinium enhancement (LGE) in the basal inferolateral wall. Additionally, he was noted to have mitral annular disjunction with bi-leaflet mitral valve prolapse and mild mitral regurgitation. An Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed avid myocardial inflammation corresponding with the regions of LGE. Guideline-directed medical therapy (GDMT) provided no symptomatic relief, but a trial of corticosteroids resulted in rapid and dramatic improvement.

Learning Points from this Case: This case illustrates the critical overlap between genetic and inflammatory cardiomyopathies. A pathogenic TTN variant provided the susceptibility ("first hit"), while environmental triggers like viral illness acted as a disease accelerator ("second hit"). CMR revealed evidence of inflammation and the pattern of LGE suggested an underlying genetic cardiomyopathy versus myocarditis. FDG-PET confirmed ongoing inflammation. The dramatic response to corticosteroid therapy, with symptoms refractory to standard heart failure GDMT, challenges traditional diagnostic and therapeutic paradigms in genetic cardiomyopathy. Genetic testing should be integrated into the evaluation of inflammatory presentations with atypical features. Imaging is crucial for guiding personalized management.

T1 and T2 maps and corresponding polar plots
LGE
FDG-PET