BURGGREN, Warren W*; YAMADA-FISHER, Miho; Univ. of North Texas: CHRONIC BRADYCARDIA ACCELERATES DEVELOPMENT OF FRANK-STARLING MECHANISM DURING EARLY AVIAN EMBRYOGENESIS

Congenital bradycardia in embryos of human and other species may increase spontaneous embryonic death, suggesting that very early embryos may not be able to compensate hemodynamically for decreased heart rate. We hypothesize that abnormal heart rate in the early vertebrate embryo may, among other effects, alter length-tension relationships (i.e. Frank-Starling relationships) of the developing cardiac muscle. To alter heart rate in chicken embryos, we are introducing the bradycardic agent ZD7288, which blocks cardiac If channels and creates dose-dependent bradycardia without affecting cardiac contractility. We topically applied ZD7288 to HH stage 15-16 chicken embryos (50-56 h of incubation), and then assessed hemodynamic responses with a pulsed Doppler flowmeter before and 30 min after treatment with 5 μl of 500μM ZD7288. Mean heart rate (HR) following treatment (104+6.4 bpm, n=9) was significantly lower than control (138+4.8 bpm, n=7). Yet, stroke volume (SV) was unaffected at 0.17+0.01 ml in both groups. Cardiac output (CO) thus decreased from 24.0+3.5 to 17.9+1.7 ml following bradycardia induced by ZD7288 treatment. Thus, transient bradycardia reveals an immature Frank-Starling mechanism, as evident from lack of compensatory increases in SV that would maintain CO. Surprisingly, however, chronic bradycardia (76% of normal HR) produced by 24 h of continuous application of 30μM ZD7288 from onset of heartbeat had, by HH stage15-16, caused a significant increase in SV to 0.24+0.02 ml (n=6) from 0.17 +0.008 ml (n=6) in controls. Thus, chronic but not acute bradycardia is compensated for by an increase in SV, thus maintaining a normal CO. We conclude that cardiac muscle tissue remodeling associated with chronic bradycardia hastens onset of length-tension relationships in early avian embryos.