Common genetic variants in selected Ca²⁺ signaling genes and the risk of appropriate ICD interventions in patients with heart failure.
OBJECTIVE
Defective Ca²⁺ handling in failing cardiomyocites predisposes patients with heart failure (HF) to ventricular arrhythmia. We investigated whether gene variants of Ca²⁺ handling proteins are associated with the occurrence of ventricular tachycardia/fibrillation (VT/VF) in HF patients implanted with a primary prevention implantable cardioverter-defibrillator (ICD).


METHODS
One hundred thirty-six patients with HF were followed from ICD implantation to the time of first appropriate ICD intervention for VT > 170 bpm. The following polymorphisms were genotyped: ATP2A2 rs1860561 and rs56243033; RYR2 rs4142933; CASQ2 rs4074536; SLC8A1 g.-23449C > A; PLN rs12198461; FKBP1B rs7568163. Hazard ratios (HR) were derived from Cox proportional-hazards regression analysis.


RESULTS
After a mean follow-up of 879 days (IQ range, 327 to 1,459), 34 patients (25%) had appropriate ICD intervention. Non-sustained VT (HR, 2.12; 95%CI, 0.87-5.19; p = 0.09) and atrial fibrillation (AF) at ICD implantation (HR, 2.33; 95%CI, 0.89-6.10; p = 0.08) predicted appropriate ICD interventions with borderline statistical significance. Prevalence of ATP2A2 rs1860561 variant was 17% in patients without VT/VF and 4% in those with ventricular arrhythmia (p = 0.009). After adjustment for AF and NSVT, the rs1860561 A mutant allele independently predicted lower incidence of VT/VF (HR, 0.29; 95%CI, 0.09-0.98; p = 0.04).


CONCLUSIONS
The observation that ATP2A2 rs1860561 gene variant associated with lower risk of life-threatening arrhythmia in HF patients suggests that selected calcium gene variants may modify the risk of SD even within the complex and polygenic pathological condition of HF. Combining traditional risk factors and genetic profiling could reveal helpful to identify HF patients who will benefit most from ICD implantation.
Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome Sant'Andrea Hospital, Via di Grottarossa, 00189, Rome, Italy, pietro.francia@uniroma1.it.
Pietro
P
Francia
Carmen
C
Adduci
Agnese
A
Ricotta
Rosita
R
Stanzione
Isabella
I
Sensini
Arianna
A
Uccellini
Alessandra
A
Frattari
Cristina
C
Balla
Maria
M
Cotugno
Riccardo
R
Cappato
Speranza
S
Rubattu
Massimo
M
Volpe
D000368:Aged; D015220:Calcium Channels / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000453:epidemiology* / Q000517:prevention & control*; D017147:Defibrillators, Implantable / Q000706:statistics & numerical data*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006333:Heart Failure / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors
D015220:Calcium Channels; D005819:Genetic Markers