Discussion:
This case underscores the intricate relationship between genetic factors and dilated cardiomyopathy (DCM), particularly the role of Titin (TTN) truncating variants (TTNtvs). TTN, the largest known human protein, is crucial in maintaining cardiac structure and function. Truncations in the TTN gene are a significant cause of DCM, as evidenced by Herman et al. (2012) (1)​​. These TTNtvs, while not uniformly leading to DCM, significantly increase the risk.
The pathophysiology of TTNtvs in DCM involves a disrupted sarcomere structure, which impairs cardiac muscle contractility and leads to heart failure (1). Research by Schafer et al. (2015)​​ indicates that TTNtvs are prevalent in both familial and sporadic cases of DCM, highlighting their importance in the disease’s genetic architecture (4). Furthermore, the haploinsufficiency model suggests that a loss of one functional allele of TTN can lead to insufficient protein production, contributing to DCM pathogenesis.
However, not all TTNtvs result in DCM, indicating a variable penetrance and expressivity. This variability, as explored by Roberts et al. (2015)​​, is influenced by additional genetic modifiers and environmental factors (3). Consequently, the clinical presentation of DCM in individuals with TTNtvs can range from asymptomatic to severe heart failure, underscoring the complexity of predicting disease progression and the necessity for personalized approaches to patient care.
In the presented case, the patient’s history of substance abuse complicates the clinical picture. Amphetamines and cocaine are known to have cardiotoxic effects, potentially exacerbating the underlying genetic predisposition to DCM. This emphasizes the need for a comprehensive approach to diagnosis and management, considering both genetic and environmental factors.
The discovery of TTNtv in our patient not only guided the clinical management but also highlighted the importance of genetic counseling for at-risk family members (4,5). Genetic testing for TTNtvs has become a vital tool in the diagnosis and management of DCM, aiding in the identification of familial cases and guiding therapeutic decisions.
In conclusion, this case report illustrates the multifaceted nature of DCM, where genetic predisposition interplays with environmental factors, such as substance abuse, to manifest the disease. It reinforces the need for genetic evaluation in unexplained cardiomyopathies and personalized patient care, considering both genetic background and lifestyle factors.