Recovery in Patients With Dilated Cardiomyopathy With Loss-of-Function Mutations in the Titin Gene

A high proportion of dilated cardiomyopathy (DCM) cases arise from loss-of-function mutations in the titin gene (TTN),¹ which codes for the sarcomeric protein Titin. Although TTN plays a fundamental role in maintaining cardiac contractility, it has recently been demonstrated that individuals with TTN mutations recover systolic function with left ventricular assist device support (in addition to standard medical therapy).² However, to our knowledge, it remains unknown whether standard medical therapy for systolic dysfunction is equally effective in these patients without left ventricular assist device support. Our objective was to compare the prevalence of TTN mutations in patients with DCM receiving standard pharmacological therapy with and without recovery of systolic function.

We recruited 141 patients with DCM referred to the Heart Failure Clinic of the McGill University Health Centre in Montreal, Quebec, Canada, an academic tertiary care heart failure clinic providing heart transplant and mechanical circulatory support, for medical therapy between April 2010 and January 2012 (mean [SD] age, 53.6 [11.9] years; range, 18-81 years). Dilated cardiomyopathy was defined as having a left ventricular ejection fraction of 45% or less. Patients with an ischemic etiology or other obvious structural abnormality (eg, congenital heart disease or noncompaction syndromes) were excluded. Recovery was defined as a left ventricular ejection fraction greater than 50% at follow-up after 1 or more years. Clinical characteristics of those who recovered are shown in the Table. All coding exons of TTN were sequenced using the MiSeq Reagent Kit version 2 (Illumina) after targeted capture using the Access Array system (Fluidigm). Sequence data were analyzed with the Genome Analysis Toolkit (Broad Institute) and Variant Effect Predictor (Ensembl), and variants were compared with the Exome Sequencing Aggregation Consortium database (http://exac.broadinstitute.org). The McGill University Health Centre Biomedical Research Ethics Board approved the protocol, and all participants provided written informed consent. Comparisons were performed using Fisher exact test, Student t test, or the Mann-Whitney test. Statistical significance was defined as P < .05. The median read depth of exonic base pairs was 421X, with 99.3% of identified variants having a read depth greater than 15X.

After excluding variants found in the I-band and those at greater than 0.0001 minor allele frequency in the Exome Sequencing Aggregation Consortium database, 26 TTN truncating variants were identified in the 128 successfully sequenced samples from our DCM cohort. All of these variants were heterozygous mutations causing truncation in the 2 TTN cardiac isoforms, N2BA and N2B. Thus, all 26 were considered to be pathogenic for DCM³ and represented 26 of 128 patients (20.3%) of our sample. Patients with recovery of systolic function with medical therapy were equally likely to have TTN mutations compared with those without recovery (14.3% vs 22.0%; P = .44) (Table).

We demonstrate that truncating TTN mutations are frequently observed in patients with DCM who recover systolic function with standard medical therapy alone. Our results suggest that despite the key role played by TTN in cardiac function, individuals with these mutations can recover systolic function and are equally likely to experience recovery as those with other causes of DCM. While it was recently shown that recovery is possible in patients with DCM who have a truncating mutation in TTN with mechanical unloading therapy support,^2,3 our findings that recovery is possible in those receiving medical therapy alone is consistent with another recently published study.⁴ However, not all patients with TTN mutations receiving medical therapy recovered. While the specific mutations that cause DCM and their penetrance are known to play a role in age at onset and prognosis,^5,6 to our knowledge, it remains unknown whether recovery from DCM also depends on the specific TTN mutation or penetrance. Because the recovery of left ventricular function in response to pharmacological therapy is variable, future studies should assess whether TTN mutations could affect the decision to continue medical therapy in patients with DCM who demonstrate sustained recovery.

Similar to other recent work,⁴ our results suggest that further understanding of the variables that affect recovery from DCM, including the effect of genetics and their possible interactions with medical therapy, may be important in identifying each patient’s long-term management.

Corresponding Author: James C. Engert, PhD, Division of Cardiology, Department of Medicine, Royal Victoria Hospital, McGill University Health Centre, MUHC-RI Room # EM1.2218, 1001 Decarie Blvd. Montreal, Quebec, H4A 3J1, Canada (jamie.engert@mcgill.ca).

Accepted for Publication: February 17, 2017.

Published Online: April 19, 2017. doi:10.1001/jamacardio.2017.0763

Author Contributions: Dr Engert had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mr Luk and Dr Bakhsh contributed equally to this work.

Study concept and design: Luk, Giannetti, Elstein, Lathrop, Thanassoulis, Engert.

Acquisition, analysis, or interpretation of data: Luk, Bakhsh, Thanassoulis, Engert.

Drafting of the manuscript: Luk, Bakhsh, Engert.

Critical revision of the manuscript for important intellectual content: Luk, Giannetti, Elstein, Lathrop, Thanassoulis, Engert.

Statistical analysis: Luk, Lathrop, Engert.

Obtained funding: Giannetti.

Administrative, technical, or material support: Luk, Giannetti, Thanassoulis.

Supervision: Thanassoulis, Engert.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: We thank all the patients who participated in this study, and Katia Desbiens, MSc (Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada), Line Dufresne, MSc (Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada), Nikolaus Yasui, PhD (McGill University, Montreal, Quebec, Canada), Joanna Pineda, PhD (McGill University, Montreal, Quebec, Canada), and Pierre Lepage, PhD (McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada), for technical support. These contributors received no compensation for their assistance.