Evidence and clinical relevance of maternal-fetal cardiac coupling:A scoping review

BACKGROUND: Researchers have long suspected a mutual interaction between maternal and fetal heart rhythms, referred to as maternal-fetal cardiac coupling (MFCC). While several studies have been published on this phenomenon, they vary in terms of methodologies, populations assessed, and definitions of coupling. Moreover, a clear discussion of the potential clinical implications is often lacking. Subsequently, we perform a scoping review to map the current state of the research in this field and, by doing so, form a foundation for future clinically oriented research on this topic.METHODS: A literature search was performed in PubMed, Embase, and Cochrane. Filters were only set for language (English, Dutch, and German literature were included) and not for year of publication. After screening for the title and the abstract, a full-text evaluation of eligibility followed. All studies on MFCC were included which described coupling between heart rate measurements in both the mother and fetus, regardless of the coupling method used, gestational age, or the maternal or fetal health condition.RESULTS: 23 studies remained after a systematic evaluation of 6,672 studies. Of these, 21 studies found at least occasional instances of MFCC. Methods used to capture MFCC are synchrograms and corresponding phase coherence indices, cross-correlation, joint symbolic dynamics, transfer entropy, bivariate phase rectified signal averaging, and deep coherence. Physiological pathways regulating MFCC are suggested to exist either via the autonomic nervous system or due to the vibroacoustic effect, though neither of these suggested pathways has been verified. The strength and direction of MFCC are found to change with gestational age and with the rate of maternal breathing, while also being further altered in fetuses with cardiac abnormalities and during labor.CONCLUSION: From the synthesis of the available literature on MFCC presented in this scoping review, it seems evident that MFCC does indeed exist and may have clinical relevance in tracking fetal well-being and development during pregnancy.</p

Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function

Objective: Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function. Methods: A genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography. Results: We identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals. Conclusions: Our study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.publishedVersio

Immunomodulation by maternal autoantibodies of the fetal serotoninergic 5-HT4 receptor and its consequences in early BALB/c mouse embryonic development

<p>Abstract</p> <p>Background</p> <p>The presence of functional 5-HT₄receptors in human and its involvement in neonatal lupus erythematosus (NLE) have prompted us to study the receptor expression and role during embryogenesis. Earlier we managed to demonstrate that female BALB/c mice immunized against the second extracellular loop (SEL) of the 5-HT₄receptor gave birth to pups with heart block. To explain this phenomenon we investigated the expression of 5-HT₄receptors during mouse embryogenesis. At the same time we looked whether the consequence of 5-HT₄receptor immunomodulation observed earlier is in relation to receptor expression.</p> <p>We studied the expression of 5-HT₄receptor at the mRNA level and its two isoforms 5-HT_4(a)and 5-HT_4(d)at the protein level in embryos from BALB/c mice, at 8^th, 12^th, 18^thgestation days (GD) and 1 day post natal (DPN). Simultaneously the receptor activity was inhibited by rising antibodies, in female mice against SEL of the receptor. The mice were mated and embryos were collected at 8^th, 12^th, 18^thGD and 1 DPN.</p> <p>Results</p> <p>5-HT₄receptor mRNA increased in brain from 12^thGD to 1 DPN. Its expression gradually decreased in heart and disappeared at birth. This was consistent with expression of the receptor isoforms 5-HT_{4(a) and (d)}. Abnormalities like decreased number of embryos, growth delay, spina bifida and sinus arrhythmia from 12^thGD were documented in pups of mice showing anti-5-HT₄receptor antibodies.</p> <p>Conclusion</p> <p>serotoninergic 5-HT₄receptor plays an important role in mouse foetal development. In BALB/c mice there is a direct relation between the expression of receptor and the deleterious effect of maternal anti-5-HT₄receptor autoantibodies in early embryogenesis.</p

Early-Life Supplementation of Omega-3 Polyunsaturated Fatty Acids Improved Growth and Skeletal Muscle Glucose Metabolism in the Heat Stress-Induced IUGR Neonatal Lamb

Our 1st study determined whether metabolic deficits of IUGR-born neonatal lambs can be improved by ameliorating elevated inflammatory tone. Supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFA) improved hindlimb insulin-stimulated glucose oxidation rates and basal lactate secretion. Ex vivo skeletal muscle-specific glucose oxidation rates were improved when heightened inflammatory tone was moderated. Pancreatic β cell function in response to hyperglycemia was improved by ω-3 PUFA supplementation. Tempered inflammatory tone also partially recovered skeletal muscle glycogen stores. Thus, we found that targeting heightened inflammatory tone inherent in IUGR-born neonatal lambs moderately improved glucose metabolism and pancreatic β cell responsiveness. Our 2nd study evaluated the efficacy of targeting heightened inflammatory tone of IUGR -born neonatal lambs with anti-inflammatory ω-3 PUFA on growth deficits. Growth metrics including rate of gain, bodyweight, and biometric measurements were partially or fully recovered by ω-3 PUFA supplementation. Muscle fat-to-protein ratios were not improved by ω-3 PUFA supplementation, but muscle carbohydrate content was. Myoblast populations were improved in IUGR-born neonates supplemented with ω-3 PUFA, but myoblast proliferation rates were not. From these findings, we can conclude that early-life treatment with ω-3 PUFAs is an effective strategy in recovering some growth deficits in IUGR-born lambs. Advisor: Dustin T. Yate

Mid-Gestation Maternofetal Inflammation Impacts Growth, Skeletal Muscle Glucose Metabolism, and Inflammatory Tone in the Ovine Fetus During Late Gestation

Our 1st and 2nd studies assessed the impact of mid-gestation maternofetal inflammation on growth, skeletal muscle glucose metabolism, and inflammatory tone in the late gestation ovine fetus. The objective was to determine if inducing maternofetal inflammation during peak placental growth would lead to more profound IUGR characteristics in the fetus. MI-IUGR fetuses exhibited reduced body and skeletal muscle weights and hallmark asymmetric growth at late gestations. Fetuses had higher baseline glucose:insulin ratios and reduced glucose-stimulated insulin secretion. Moreover, hindlimb glucose oxidation was impaired independent of glucose uptake. Skeletal muscle specific glucose uptake and oxidation was reduced in MI-IUGR fetuses. MI-IUGR fetuses also had increased circulating cytokines and cytokine receptor content in skeletal muscle. Therefore, targeting inflammation during mid- to late gestation is an area of interest for future IUGR therapeutic treatments. Our 3rd study examined the differentially expressed genes in neonatal skeletal muscle transcriptome in response to maternofetal inflammation (MI-IUGR) or maternal hyperthermia (PI-IUGR) during gestation. Although PI-IUGR lambs exhibited a more severe IUGR phenotypically, skeletal muscle of MI-IUGR exhibited showed more transcriptomic changes. Regardless of the source of maternal stress, a large percentage of genes and pathways impacted in the IUGR fetus were related to inflammation. These data further support the role of the inflammatory pathway in IUGR pathologies. Our final study examined the changes in tissue composition of the sheep hindlimb across different stages of development. We found that 40% of the tissue in the fetal hindlimb is skeletal muscle compared to 65% of the tissue in the juvenile lamb. This was an important gap in the literature not previously addressed, and could help us more accurately interpret the results of in vivo metabolic studies. Advisor: Dustin T. Yate

ヒトおよびマウスにおける母と胎児のRR間隔の類似性と胎児発達との関係

Tohoku University齋藤昌利課

ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward—How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe

Intrauterine growth restriction (IUGR) is the second leading cause of perinatal mortality and predisposes offspring to metabolic disorders at all stages of life. Muscle-centric fetal adaptations reduce growth and yield metabolic parsimony, beneficial for IUGR fetal survival but detrimental to metabolic health after birth. Epidemiological studies have reported that IUGRborn children experience greater prevalence of insulin resistance and obesity, which progresses to diabetes, hypertension, and other metabolic disorders in adulthood that reduce quality of life. Similar adaptive programming in livestock results in decreased birth weights, reduced and inefficient growth, decreased carcass merit, and substantially greater mortality rates prior to maturation. High rates of glucose consumption and metabolic plasticity make skeletal muscle a primary target for nutrient-sparing adaptations in the IUGR fetus, but at the cost of its contribution to proper glucose homeostasis after birth. Identifying the mechanisms underlying IUGR pathophysiology is a fundamental step in developing treatments and interventions to improve outcomes in IUGR-born humans and livestock. In this review, we outline the current knowledge regarding the adaptive restriction of muscle growth and alteration of glucose metabolism that develops in response to progressively exacerbating intrauterine conditions. In addition, we discuss the evidence implicating developmental changes in β adrenergic and inflammatory systems as key mechanisms for dysregulation of these processes. Lastly, we highlight the utility and importance of sheep models in developing this knowledge