Background: Dilated cardiomyopathy (DCM) affects up to 1 in 250 individuals and is the
leading global indication for heart transplantation, though a subset of patients can recover
myocardial function.
Aim: To integrate clinical, genetic, and advanced imaging data to generate new insights into
DCM pathobiology.
Methods and Results
1) Evaluation of the genetic architecture of DCM in 647 unrelated Caucasian patients
revealed that variants in only 5 of 57 putative DCM genes were significantly enriched
compared to >30,000 reference samples. Truncating variants in the titin gene (TTNtv)
accounted for the largest genetic contribution to DCM (excess burden 14.1%, p=6.4x10-82).
2) Cardiovascular magnetic resonance (CMR) phenotype study of 716 DCM patients
demonstrated that TTNtv DCM was associated with a blunted hypertrophic response (mean
indexed left ventricular mass, g/m2; TTNtv-/+ 91.3 vs 83.5, padjusted=0.007). Moderate alcohol
excess was an environmental modifier of the TTNtv phenotype (10.0% reduction in left
ventricular ejection fraction, 95% CI -16.3 to -3.8%, p=0.002).
3) In 29 patients with recent onset DCM, myocardial contractile reserve during low-dose
dobutamine stress CMR was an independent predictor of LV remodelling (p=0.007).
Contractile reserve assessed by a novel cine-DENSE strain CMR sequence and relative RV
contractile reserve were also predictive of LV remodeling.
4) Amongst 604 DCM patients, followed up for a median of 3.9 years for the primary
composite endpoint of cardiovascular mortality, major arrhythmic events and major heart
failure events, the presence of TTNtv did not influence the primary outcome (TTNtv
unadjusted hazard ratio 0.81 [95% CI 0.41-1.63], p=0.56). Further analyses showed no
evidence that gender or CMR mid-wall fibrosis status modified the effect of TTNtv.
Conclusion
These data improve our understanding of the genetic basis of DCM, provide mechanistic
insight and inform risk stratification in DCM.