Chronic Fetal IGF1 Administration Matches Coronary Growth to Myocardial Growth
Authors: Jonker Sonnet S , Giraud George D , Chang Eileen I , Louey Samantha 
Published: June 2021

Insulin‐like growth factor 1 (IGF1) increases fetal heart mass in late gestation by stimulating cardiomyocyte proliferation, and is thus a potential therapeutic intervention to increase cardiomyocyte endowment. However, how the fetal coronary vasculature grows in the context of IGF1 stimulation is unknown.

METHODS AND RESULTS

Fetal sheep had surgery at 120 days gestational age (dGA; term 147 d) to place catheters (ascending aorta, superior vena cava, coronary sinus), inflatable occluders (descending thoracic aorta, inferior vena cava), and a Transonic flow probe (circumflex artery). Fetuses received 6.6 ug/kg/hr IGF1 LR3 or vehicle from 127 dGA (day 0) until 134 dGA (day 7).

In order to understand how coronary reserve is regulated in IGF1‐treated fetuses, occluders were used to change perfusion pressure under autonomic blockade (~0.5mg/kg atropine, ~1mg/kg propranolol); coronary conductance was calculated as the slope relating pressure to flow. A maximally vasodilating dose of adenosine (with minimal systemic effects) was then infused into the right atrium to determine maximal conductance. Coronary conductance on day 7 at baseline (under conditions of autoregulation) was not different between Control and IGF1‐treated fetuses (0.06 ± 0.01 ml/min/g/mmHg). Although maximal conductance was higher than baseline (0.24 ± 0.02 ml/min/g/mmHg; P<0.0001), it was not different between treatments. This showed that in IGF1‐treated fetuses, coronary growth matched myocardial growth.

Fetuses at day 0 had a partial pressure of oxygen of 20 ± 1 mmHg, which at day 7 was maintained in Control fetuses (20 ± 1 mmHg), but not IGF1‐treated fetuses (17 ± 1 mmHg; P<0.02). As fetuses become hypoxic, coronary flow increases; therefore, as conductance was not different between groups at day 7, the effect of IGF1 treatment on coronary reserve was investigated. Coronary reserve, the difference between baseline and maximal conductance at a given pressure, was similar between Control and IGF1‐treated fetuses at day 0 (maximal flow 3.9 ± 0.4 fold baseline flow). Control fetuses maintained that relationship (2.8 ± 0.4 fold) at day 7, but in IGF‐1 treated fetuses reserve was relatively depleted (2.3 ± 0.4 fold; P<0.003). This was supported by coronary flow in fetuses without sedation or autonomic blockade. At day 0, circumflex coronary blood flow was regulated at 21 ± 3% of adenosine‐stimulated maximal blood flow. This remained unchanged in Control fetuses on day 7 (24 ± 3%), however, fetuses treated with IGF1 used a greater fraction of coronary reserve at rest on day 7 (41 ± 11%) than on day 0 (P<0.02).

CONCLUSIONS

When fetal cardiac growth is stimulated with an IGF1 analogue, coronary growth is matched to myocardial growth. This supports IGF1 as a potential therapeutic intervention to increase healthy fetal cardiomyocyte endowment. Due to the development of hypoxia, IGF1‐treated fetuses autoregulate at a higher resting blood flow, using a greater part of their coronary reserve.

Support or Funding Information

Supported by NIH R01HD071068, P01HD034430, and T32HL094294.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.