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Effects of Fetal Hypoxia on Individuals that are Predisposed to Arrhythmia

CPVT mechanisms

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is defined by episodic syncope that occurs during intense emotion or exercise. Some people develop the disease, while others remain asymptomatic. The variation in CPVT severity among people with the same mutation may indicate that non-genetic factors influence the course of the disease. The potential contribution of intrauterine environmental factors to CPVT penetrance has not yet been taken into account. Unpublished data from the Galli Lab suggests that arrhythmia sensitivity can be programmed throughout fetal development by hypoxia. We hypothesize that fetal hypoxia may increase disease severity in individuals with CPVT.

METHODS:

 

RyR2-R2474S knock-in male mice were bred with wild type C57BL/6NRj female mice. Pregnant mice were either subjected to normoxic (21% O2) or hypoxic (13% O2) conditions from gestational day (GD) 6-18. From this, four experimental groups were established - (1) Wild Type Normoxia (WT-N), (2) RyR2 normoxia (RyR2-N), (3) Wild Type Hypoxia (WT-H) and (4) RyR2 Hypoxia (RyR2-H). Maternal food and water intake were monitored every 48 hours in both the conditions. Maternal weight was measured at GD 6 and 18, and the weights were used to calculate weight gain. Cumulative litter weight gain was measured on days 3, 7, 14, 21, 30, 60, 90 and 120 for 10 normoxic and 5 hypoxic pregnancies. Individual offspring body weight was monitored in males (n =42 offspring from 10 normoxic pregnancies and n=21 offspring from 5 hypoxic pregnancies) and in females (n = 38 offspring from 10 normoxic pregnancies and n=14 offspring from 5 hypoxic pregnancies at month 4 (adult). Additionally, litter size and sex split were also determined from each pregnancies (n=15 normoxic and n=11 hypoxic).

RESULTS SO FAR

The data showed that there were no significant differences in maternal body weight, food intake or water intake between the normoxic and hypoxic offspring. Furthermore, no significant relationship was found between litter size, sex split, individual offspring body weight, and litter weight. 

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CONCLUSION:

This study indicates that hypoxia had no significant effect on maternal parameters and that any programmed consequences in the offspring are exclusively due to hypoxiaIn future, picrosirius red staining will be utilised under brightfield and polarised light microscopy to determine the percentage of collagen fibres each group. Echocardiography will be carried out to measure the thickness of the heart in unconscious mice. In addition, electrical mapping with and without isoprenaline will be used to quantify the arrhythmia sensitivity utilising S1-S2 and S1-S11 pacing protocols in vitro. And, radiotelemetry will be used to evaluate the in vivo arrhythmia sensitivity to test our hypothesis.

Cardiac optical mapping
Cardiac optical mapping

Relevant Papers

Kashimura T, Briston SJ, Trafford AW, Napolitano C, Priori SG, Eisner DA, Venetucci LA. In the RyR2(R4496C) mouse model of CPVT, β-adrenergic stimulation induces Ca waves by increasing SR Ca content and not by decreasing the threshold for Ca waves. Circ Res. 2010 Dec 10;107(12):1483-9. doi: 10.1161/CIRCRESAHA.110.227744. Epub 2010 Oct 21. PMID: 20966392.

Kashimura T, Briston SJ, Trafford AW, Napolitano C, Priori SG, Eisner DA, Venetucci LA. In the RyR2(R4496C) mouse model of CPVT, β-adrenergic stimulation induces Ca waves by increasing SR Ca content and not by decreasing the threshold for Ca waves. Circ Res. 2010 Dec 10;107(12):1483-9. doi: 10.1161/CIRCRESAHA.110.227744. Epub 2010 Oct 21. PMID: 20966392.

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