Cardiac Anxiety

Abstract

Constitutive Ca2+-calmodulin activated adenylyl cyclase Type 8 (AC8) is crucial for pacemaker cell automaticity (1). When human AC8 is overexpressed in mice (TGAC8), in vivo heart rate measured using telemetry devices at 3 months age was more than 30% higher throughout the 24 hour period compared to wildtype (WT)(2). In other words, the heart appears to perpetuate exercise in the absence of corporal exertion. The goal of the present study was to measure ventricular contractility and heart rate to determine how long an increased workload on the heart can be sustained and whether it is associated with reduced longevity. We performed echocardiography under light anesthesia on TGAC8 and WT littermates at 3, 10, 14, and 19 months. Linear mixed effects models assessed the changes in the repeated measurements of the cardiac markers from the echocardiogram. Tukey's post-hoc test evaluated the pair-wise comparisons of the mean values in the cardiac markers at 3 and 19 months old. The rate of change of heart rate decreases with age in TGAC8 mice, while the rate of change of heart rate increases with age in WT mice (p<0.0005). The TGAC8 heart rate is significantly higher than WT at 3 months of age (p<0.0003). This difference disappears, however, at 19 months of age. The rate of change in ejection fraction (EF) decreases with age in TGAC8 mice, while the rate of change of EF stays constant with age in WT mice (p<0.0001). The TGAC8 EF is significantly higher than WT at 3 months of age (p<0.0001). At 19 months of age, the opposite is observed, the TGAC8 EF is lower than the EF of the WT (p<0.07). The rate of change in posterior wall thickness (PWT) increases with age in TGAC8 mice and WT (p<0.005). The TGAC8 PWT is significantly higher than WT at 3 months of age (p<0.005). However, the difference was not statistically different at 19 months of age. The rate of change in end-diastolic volume (EDV) increases with age in TGAC8 mice, while the rate of change of EDV stays constant with age in WT mice (p<0.0001). The TGAC8 EDV is significantly lower than WT at 3 months (p<0.0002), but significantly higher at 19 months of age (p<0.05). The median lifespan of the TGAC8 was observed to be approximately at 19 months of age, while the WT median lifespan was approximately at 27 months of age. The longevity of the TGAC8 mouse is significantly shorter than the WT (p<0.0001). The changes observed in echocardiography reveal progressive decline in cardiac performance in TGAC8 over time that is accompanied by reduced longevity. However, until approximately 14 months cardiac performance was maintained without any excess mortality. Our study demonstrates how long-term hypercontractility and chronotropic stress leads to accelerated deterioration in cardiac function and reduced longevity. Further study will investigate the molecular mechanisms that undermine the maintenance of this chronic hyperfunctional heart while ensuring survival up to 14 months, and mechanisms that lead to reduced longevity. Support or Funding Information Research was supported by the National Institutes of Health/National Institute on Aging Intramural Research Training Program. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.