Cardiac calsequestrin and ageing

Cardiac calsequestrin (CSQ2) is the main Ca2+ binding protein of the mammalian heart. Patients with deletion of CSQ2 are susceptible to lethal catecholamine‐induced arrhythmias but in the absence of systolic heart failure. To further characterize the role of CSQ2 for regulation of cardiac contractility we generated CSQ2‐null (CSQ2−/−) mice by targeted deletion of the first exon (heterozygous: CSQ2+/−; wild type: CSQ2+/+). In the targeted CSQ2 allele, the coding region of exon 1 is replaced by a loxP site leading to a nonsense mutation. Chimeric mice were crossed into a C57BL/6 background to get CSQ2+/− mice for further breeding. Successful targeting of the CSQ2 allele was confirmed by Western blotting. CSQ2−/− mice were viable. Ventricular function as assessed by Langendorff perfusion in mice six months of age was already altered: basal contractility in CSQ2−/− mice was higher (possibly a compensatory mechanism) than in CSQ2+/− and CSQ2+/+ mice. Additionally, at six months gross morphology of the heart as well as absolute and relative heart weight were not different in CSQ2−/− mice compared to CSQ2+/+ or CSQ2+/−. However, in 20–22 months old mice we measured systolic heart failure (possibly as a result of breakdown of compensatory mechanisms) as assessed by decreases in ejection fraction (in echocardiography using a Vevo system and isoflurane anesthesia) in CSQ2−/− mice (29 ± 6.1%, n= 4) compared to six month old CSQ2−/− mice and to 20–22 months old CSQ2+/− mice (68 ± 6.4% n=5) and CSQ2+/+ (65 % ± 6.8%, n=4, p< 0.05). In summary, we present evidence that deletion of CSQ2 can lead to cardiac failure upon ageing, which might be relevant for human carriers of CSQ2 mutations.