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Gee2023 - Central and intrinsic cardiac circuits

ABSTRACT: Model Context: Model of neural control of cardiovascular behavior and its interaction with respiratory behavior Primary goal of the model: The primary objective of the modeling study was to evaluate the role of neural signals in controlling the dynamic behavior of the heart, particularly in regulating cardiovascular metrics such as heart rate and blood pressure. We also seek to understand neural control of respiratory sinus arrhythmia, a natural acceleration and deceleration of heart rate in synchronization with respiration, which is characteristic of good cardiovascular health. Our model builds on a previously developed model of neural control of the heart.1 We extended this model by integrating the “little brain of the heart”, the intrinsic cardiac nervous system (ICN), to study its contributions to cardiovascular control. This newly developed model with the ICN also integrates modeling of the cardiac phase-dependent effect of parasympathetic activity on heart rate deceleration and gating of signals in the brainstem in based on respiratory phase to represent a possible mechanism of respiratory sinus arrhythmia (RSA). Our expanded model can be utilized to explore the role of the ICN on beat-to-beat cardiovascular behavior, specifically RSA. Simulations can be performed to explore regulation of cardiovascular behavior in response to changes in lung tidal volume and electrical stimulation of the vagus nerve, which connects the brain and the heart.

SUBMITTER: Michelle M Gee

PROVIDER: MODEL2402270001 | BioModels | 2024-02-27

REPOSITORIES: BioModels

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			Action	DRS
	MODEL2402270001?filename=Aff1_Eff0_5.mat	Other
	MODEL2402270001?filename=AfferentOnly.mat	Other
	MODEL2402270001?filename=Analysis_Rajendran2019.m	Other
	MODEL2402270001?filename=Both1Hz.mat	Other
	MODEL2402270001?filename=DARWIN_BatchRunParallel_1558902.m	Other

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Project description:Rationale: 22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages but not in the Wnt1+ neural crest or Mef2c+ second heart field lineages. Microarray analysis revealed increased expression of BMP10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome. The aim of this microarray experiment was to compare gene expression changes in the E13.5 mouse heart in a conditional knockout of Hic2 (Mesp1Cre/+; Hic2FL/FL) against control. All samples represent pools of isolated hearts from E13.5 mouse embryos. 3 replicates of each genotype were assayed. The genotypes are: 'WT' (Hic2FL/FL) 'KO' (Mesp1Cre/+; Hic2 FL/FL)

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Gee2023 - Central and intrinsic cardiac circuits

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