Abstract 3639: Enhanced Contractility but Reduced Excitation-contraction Coupling Efficiency and Adrenergic Reserve in Hearts With Increased Cav1.2 Activities
Hypercontractility has been proposed to for hearts under stresses to maintain the perfusion of the body, which is brought about by the activation of the adrenergic system and molecular remodeling, causing sustained increase in Cav1.2 activities. The effects of enhanced Cav1.2 activities on the EC coupling (ECC) process and adrenergic response are not clear.
Methods: To recapitulate increased Cav1.2 activities, transgenic (TG) mice with Cav1.2β2a overexpression of at the age of 4m were used. ECC and its response to an adrenergic agonist, isoproterenol (ISO), were studied. The cardiac response to ISO was also evaluated with echocardiography (ECHO) and invasive hemodynamic measurements.
TG VMs had increased ICa-L density (24.2±2.1pA/pF, n=15 vs. CTR 13.6±0.6pA/pF, n=11; p<0.05) and consequently greater fractional shortening (FS) (11.9±1.1%, n=11 vs. CTR 8.0±0.5%, n=16) and peak Ca transient (Fluo-3) (3.37±1.58, n=11 vs. CTR 2.25±0.08%, n=19);
TG VMs had enhanced SR Ca content (caffeine-spritz with Fluo-3 (F/F0): 4.7±0.4 vs. CTR 3.2±0.3);
In TG mice, ECHO showed greater ejection fraction (74.4±1.3%, n=34 vs. CTR 68.9±1.3%, n=33, p<0.05), FS (42.6±1.2%, n=34 vs. CTR 38.2±1.0%, n=33, p<0.001);
TG LV developed pressure (dp/dt) significantly faster (8266.0±14.4mmHg/s vs. CTR 6229.3±11.8mmHg/s). However,
the ECC gain ((F/F0)/∫ ICa-L) was significantly lower in TG than in CTR VMs;
ISO (1μM) did not increase ICa-L in TG VMs (↑8.2±0.5%, NS in 7 cells) but significantly by 74.5±9.5% in CTR VMs;
The FS of TG VMs had blunted response to ISO (5X10−8M) stimulation (↑20.2±1.4%, n=14 vs. in CTR VMs ↑50.4±4.5%, n=14).
, the SR Ca content was only increased by 15.3±2.2% in TG VMs but by 35.4±4.2% in CTR VMs.
Thr17 phosphorylation in the phospholamban was already higher in TG hearts than in CTR hearts and ISO could not further increase this phosphorylation;
ISO injection (2ug/g BW, ip) increased EF by 37.5±4.6% in CTR mice while only by 20.7±4.2% in TG mice; (7) ISO injection increased dp/dt in WT mice by 75.2±8.1% but only by 11.3±2.5% in TG.
Conclusion: Increasing Cav1.2 activities by promoting its high activity modes enhances cardiac contractility but decreases the ECC gain and the adrenergic reserve of the heart.
This research has received full or partial funding support from the American Heart Association, National Center.