Titin-Truncating Variants as Genetic Determinants of Chemotherapy-Induced Cardiomyopathy: A Review

Current risk-prediction models for Cancer Therapy–Related Cardiovascular Toxicity (CTR-CVT) rely predominantly on demographic, diagnostic, and treatment variables, lacking genetic determinants of individual susceptibility. Recent evidence suggests cardiomyopathy-associated genetic variants, particularly Titin-truncating variants (TTNtv), may be significant in CTR-CVT development. This review examines the occurrence and impact of TTNtv in CTR-CVT patients. We conducted a PRISMA-guided review analyzing TTNtv in patients with chemotherapy exposure who developed cardiomyopathy. Literature searches were performed in PubMed and Scopus using keywords: “(cardiomyopathy OR heart failure) AND (chemotherapy OR cancer therapy) AND (Titin OR TTNtv).” Quality assessment employed the Newcastle-Ottawa Scale (NOS) for observational studies and the Joanna Briggs Institute (JBI) criteria for case reports. We included 2 case-control studies and 2 case reports. TTNtv prevalence was significantly higher in chemotherapy-induced cardiomyopathy than in controls: 7.5% versus 0.6-1.1% (multicenter cohort), and 6.5% versus 0% (single-center cohort). There are conflicting results regarding symptom severity and prognosis among those with and without TTNtv mutation. One multicenter case-control study with animal model validation demonstrated that chemotherapy is poorly tolerated in TTNtv carriers. Chemotherapy-to-symptom onset ranged from 0.4 to 9 years and primarily involved anthracyclines. Among truncating variations found in the included literature, localization in the A-band of the titin protein predominated. TTNtv represents a predominant genetic determinant in CTR-CVT susceptibility, although its association with severity and recovery outcomes remains inconsistent across studies. Genetic screening could identify high-risk cancer patients benefiting from personalized cardioprotective strategies and enable assessment of prophylactic interventions. Future investigations will determine if early genetic risk recognition optimizes cancer and cardiovascular treatments, potentially transforming precision cardio-oncology care. However, cost-benefit analysis, validation in diverse populations, and comparison with non-anthracycline CTR-CVT groups are needed.