Phenotype and Clinical Outcomes of Titin Cardiomyopathy

Abstract

Background: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification.

Objectives: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM.

Methods: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events.

Results: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m² reduction; p_adjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv^+/- groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82).

Conclusions: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.

Keywords: CMR; DCM; genetics; titin.

Graphical abstract

Figure 1

Position of TTNtv Variants According to Protein Domains and PSI Orange indicates Z disc; blue indicates I band; green indicates A band; and purple indicates M line. DCM = dilated cardiomyopathy; PSI = percentage spliced in; TTNtv = truncating variants in the titin gene.

Figure 2

LV Hypertrophy in TTNtv DCM Beeswarm and boxplot (black bars indicate median, pink shaded boxes indicate interquartile range) of indexed left ventricular (LV) mass, mean septal wall thickness (WT), and indexed LV end-diastolic volume (LVEDVi) stratified by titin status, showing that patients with TTNtv have lower indexed LV mass and thinner LV walls in the absence of evidence of differences in LV dilatation. Between-group comparisons are made using the Mann-Whitney test. NEG = negative; POS = positive; other abbreviations as in Figure 1.

Figure 3

Relationship Between LVMi and LVEDVi in Patients With and Without TTNtv Orange circles are patients with TTNtv. Blue circles are patients without TTNtv. The regression slope of indexed left ventricular mass (LVMi) ∼ LVEDVi (LVMi increase per 1-ml/m² increase in LVEDVi) is shown for patients with TTNtv (orange line: 0.26g/m²) and without TTNtv (blue line: 0.42g/m²). Typically, LVMi increases in line with increasing LVEDVi, but this effect is reduced in TTNtv DCM (p = 0.006). Abbreviations as in Figures 1 and 2.

Figure 4

Relationship Between TTNtv Location and Cardiac Endophenotypes Assessed by CMR in the Cohort The TTNtv location, defined by the complementary deoxyribonucleic acid (cDNA) position, is plotted on the x-axis (units = base pairs). A regression line with 95% confidence intervals is shown for each variable, and the slope and p value of the regression is shown above each plot. Only variants in constitutive exons are plotted. The dashed lines indicate the expected position of the Cronos promoter (upstream of exon 240, numbered according to the LRG391_t1 meta-transcript). CMR = cardiovascular magnetic resonance; LVEF = left ventricular ejection fraction; LVESVi = left ventricular indexed end-systolic volume; LVSVi = left ventricular indexed stroke volume; RVEDVi = right ventricular indexed end-diastolic volume; RVEF = right ventricular ejection fraction; RVESVi = right ventricular indexed end-systolic volume; RVSVi = right ventricular indexed stroke volume; other abbreviations as in Figures 1, 2, and 3.

Figure 5

Survival Curves Comparing Freedom From the Primary Endpoint in Patients With and Without TTNtv Curves are compared using the log-rank test. Confidence intervals are shown as dashed lines. Follow-up time is shown as years since study enrollment. There is no significant difference between the 2 groups for the primary endpoint on unadjusted analysis. TTNtv = truncating variants in the titin gene.

Central Illustration

Genotype, Phenotype, and Outcome Study of Titin DCM Truncating variants in the titin gene (TTNtv) are the largest single genetic contributor to dilated cardiomyopathy (DCM). In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic indicators for all-cause DCM also predict outcomes in TTNtv DCM, and that TTNtv DCM does not appear to be associated with a substantially worse medium-term prognosis, despite patients presenting at a younger age. CVS = cardiovascular; MRI = magnetic resonance imaging.