Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

Abstract

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95%CI, 1.04–3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95%CI, 1.30–2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy

“…The association between tTTN and sex becomes complicated in previous studies (11,16,18,19,28,29). Akhtar et al reported a large cohort of 537 DCM with tTTN, in which the male patients had worse outcomes than the female patients (29). In the present study, we have shown that there is no significant difference between male patients and female patients for clinical phenotypes and outcomes, which is consistent with the results reported by Tayal et al (28).…”

“…Although, there is a common theme that male DCM patients carrying tTTN would have worse prognosis than female DCM patients. The association between tTTN and sex becomes complicated in previous studies (11,16,18,19,28,29). Akhtar et al reported a large cohort of 537 DCM with tTTN, in which the male patients had worse outcomes than the female patients (29).…”

Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel TTN Frameshift Mutation

“…Truncating mutations in the gene encoding for the titin protein are the most common cause of inherited DCM [ 18 , 19 , 20 ] and can result in a quite severe form of DCM, including frequent arrhythmia [ 19 ] and even heart transplantation [ 20 ]. However, many truncating variants in the TTN gene are found in the general population, even in healthy controls, calling into question the clinical significance of those variants [ 1 ].…”

Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics

“…As such, genetic testing for TTN by NGS can be useful in all DCM patients to allow for earlier diagnosis and therapeutic intervention. Interestingly, most patients with DCM caused by TTNtv have a relatively mild disease course and respond well to treatment, although some studies have reported a higher burden of LTVA, irrespective of LVEF in these patients [ 44 , 45 , 46 , 47 , 48 ]. The significance of TTNtv , however, remains uncertain in unaffected relatives and individuals tested for a non-DCM disease.…”