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Title: Integrated genetic and phenotypic assessment of dilated cardiomyopathy
Author: Tayal, Upasana
ISNI:       0000 0004 7657 8570
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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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.
Supervisor: Prasad, Sanjay ; Cook, Stuart ; Ware, James Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral