Clinical Phenotype and Genotype Associations With Improvement in Left Ventricular Function in Dilated Cardiomyopathy.
BACKGROUND
Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters.


METHODS AND RESULTS
Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with β-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN, genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09-0.42]; P<0.0001). TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09-6.20]; P=0.038 and 0.11 [0.01-0.99]; P=0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24-0.91]; P=0.009 and 0.18 [0.04-0.82]; P=0.007, respectively), and LVRR is an independent predictor for event-free survival.


CONCLUSIONS
The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.
['Verdonschot|Job A J|JAJ|', 'Hazebroek|Mark R|MR|', 'Wang|Ping|P|', 'Sanders-van Wijk|Sandra|S|', 'Merken|Jort J|JJ|', 'Adriaansen|Yvonne A|YA|', 'van den Wijngaard|Arthur|A|', 'Krapels|Ingrid P C|IPC|', 'Brunner-La Rocca|Hans-Peter|HP|', 'Brunner|Han G|HG|', 'Heymans|Stephane R B|SRB|']
D000319:Adrenergic beta-Antagonists D000328:Adult D000368:Aged D002311:Cardiomyopathy, Dilated D005260:Female D005838:Genotype D006333:Heart Failure D006801:Humans D008297:Male D008875:Middle Aged D010641:Phenotype D013318:Stroke Volume D016277:Ventricular Function, Left D020257:Ventricular Remodeling
cardiomyopathy, dilated humans therapeutics ventricular remodeling