New insight into titin cardiomyopathy

Comment

Approximately 15–20% of DCM patients have a truncating variant in the titin gene (TTNtv),¹ largely enriched in the titin region located in the sarcomeric A-band.^2,3 Furthermore, TTNtv located in constitutive exons (spliced in >90% of transcripts) are strongly associated with DCM, irrespective of their position in TTN.³ As the pathogenicity of these TTNtv becomes increasingly evident, the non-genetic factors determining their penetrance remain largely unknown. Recently, chemotherapy was reported as a potential factor uncovering TTNtv effects.⁴ Also, peripartum changes can be a factor uncovering the underlying genetic mutation as TTNtv are prevalent in patients with peripartum cardiomyopathy.⁵ A recent translational study by Verdonschot et al. from Maastricht (NL) identifies unique histological, molecular and functional alterations in patients with a dilated cardiomyopathy (DCM) caused by truncating titin mutations.  Titin DCM patients have increased cardiac fibrosis and obvious metabolic/mitochondrial alterations related to oxidative phosphorylation, with clear overexpression of genes related to electron transport chain complexes. These patients have improved functional recovery and lower cardiac mass as compared to other genetic DCM, but paradoxically increased atrial and ventricular arrhythmias at baseline and long-term follow-up. The latter mainly occurred in those patients with additional cardiac triggers such as chemotherapy, alcohol or cardiac virus presence. Thus, titin truncating mutations result in unique mitochondrial and structural alterations in the heart. These findings may help to develop titin-DCM targeted therapies.