Abstract 2725: Cardiac Function and Calcium Handling in Mouse Hearts: Taking Genetic Strain Variability Into Account
Genetic background is an important factor in determining disease progression and response to therapy. However, this factor is rarely considered in studies using transgenic mice, where strain-specific physiological differences may influence susceptibility, modify the phenotype and alter progression of the disease under study. The influence of genetic variability on cardiac function and Ca2+ handling in mice has not been systematically investigated. We studied 8 –10 weeks old males C57BL/6, BALB/C, FVB and SV129 mice, which account for up to 99% of inbred strains used in cardiac research. Echocardiography and radiotelemetry were used to assess cardiac function in vivo. LV ejection fraction was significantly lower in SV129 ((%): SV129: 49.4±2.6 (n = 9), C57BL/C: 59.2±4.1 (n = 9) P < 0.05, FVB: 73.9±1.9 (n = 10) P < 0.01). FVB had significantly faster heart rate (700±26 bpm (n = 6) vs BALB/C (590±20 bpm (n = 6) P < 0.01), but shorter PR interval. There were no strain differences in QT interval. Confocal microscopy, sarcomere length tracking and epifluorescence were used to investigate cell volume, t-tubule density, contractility and Ca2+ handling in isolated ventricular myocytes. Cell volume was larger in C57BL/6 and BALB/C (cell volume (μm3): C57BL/C: 30089±1430 (n = 66) P < 0.01, BALB/C: 33377±1574 (n = 62) P < 0.001, FVB: 28662±1241 (n = 69) P < 0.05 vs SV129: 23201±1185 (n = 60)). Sarcomere relaxation and Ca2+ transient time-to-peak were prolonged in BALB/C only. There were no strain differences in the contribution to Ca2+ extrusion by SERCA and NCX. SV129 had an elevated SR Ca2+ content (P < 0.001 vs C57BL/6 and BALB/C, P < 0.01 vs FVB), but Ca2+ sparks in BALB/C were more frequent, of larger amplitude and width, and of prolonged duration. Hence, SR Ca2+ leak was significantly higher in BALB/C (109.9±22.6 a.u. (n = 42)) vs FVB (23.9±6.1 a.u. (n = 44) P < 0.01) and vs SV129 (44.2±9.2 a.u. (n = 60) P < 0.05). We have demonstrated that genetic variation is associated with physiological differences in cardiac function in vivo and differences in contractility and Ca2+ handling at the cellular level. This should be considered in studies involving transgenic technology and is relevant for the assessment of the individual susceptibility to disease and response to therapy.