Newborn Heart Research Articles

The epidemiology and risk factors for postnatal complications among postpartum women and newborns in southwestern Uganda: A prospective cohort study.

Sub-Saharan Africa accounts for two-thirds of the global burden of maternal and newborn deaths. Adverse outcomes among postpartum women and newborns occurring in the first six weeks of life are often related, though data co-examining patients are limited. This study is an exploratory analysis describing the epidemiology of postnatal complications among postpartum women and newborns following facility birth and discharge in Mbarara, Uganda. This single-site prospective cohort observational study enrolled postpartum women following facility-based delivery. To capture health information about both the postpartum women and newborns, data was collected and categorized according to domains within the continuum of care including (1) social and demographic, (2) pregnancy history and antenatal care, (3) delivery, (4) maternal discharge, and (5) newborn discharge. The primary outcomes were readmission and mortality within the six-week postnatal period as defined by the WHO. Multivariable logistic regression was used to identify risk factors. Among 2930 discharged dyads, 2.8% and 9.0% of women and newborns received three or more postnatal visits respectively. Readmission and deaths occurred among 108(3.6%) and 25(0.8%) newborns and in 80(2.7%) and 0(0%) women, respectively. Readmissions were related to sepsis/infection in 70(88%) women and 68(63%) newborns. Adjusted analysis found that caesarean delivery (OR:2.91; 95%CI:1.5-6.04), longer travel time to the facility (OR:1.54; 95%CI:1.24-1.91) and higher maternal heart rate at discharge (OR:1.02; 95%CI:1.00-1.01) were significantly associated with maternal readmission. Discharge taken on all patients including maternal haemoglobin (per g/dL) (OR:0.90; 95%CI:0.82-0.99), maternal symptoms (OR:1.76; 95%CI:1.02-2.91), newborn temperature (OR:1.66; 95%CI:1.28-2.13) and newborn heart rate at (OR:1.94; 95%CI:1.19-3.09) were risk factors among newborns. Readmission and death following delivery and discharge from healthcare facilities is still a problem in settings with low rates of postnatal care visits for both women and newborns. Strategies to identify vulnerable dyads and provide better access to follow-up care, are urgently required.

Sensitivity and activation of endoplasmic reticulum stress response and apoptosis in the perinatal sheep heart.

Although the unfolded protein response (UPR) contributes to survival by removing misfolded proteins, endoplasmic reticulum (ER) stress also activates proapoptotic pathways. Changed sensitivity to normal developmental stimuli may underlie observed cardiomyocyte apoptosis in the healthy perinatal heart. We determined in vitro sensitivity to thapsigargin in sheep cardiomyocytes from four perinatal ages. In utero cardiac activation of ER stress and apoptotic pathways was determined at these same ages. Thapsigargin-induced phosphorylation of eukaryotic initiation factor 2 (EIF2A) was decreased by 72% between 135 and 143 dGA (P = 0.0096) and remained low at 1 dPN (P = 0.0080). Conversely, thapsigargin-induced caspase cleavage was highest around the time of birth: cleaved caspase 3 was highest at 1 dPN (3.8-fold vs. 135 dGA, P = 0.0380; 7.8-fold vs. 5 dPN, P = 0.0118), cleaved caspase 7 and cleaved caspase 12 both increased between 135 and 143 dGA (25-fold and 6.9-fold respectively, both P < 0.0001) and remained elevated at 1 dPN. Induced apoptosis, measured by TdT-mediated dUTP nick-end labeling (TUNEL) assay, was highest around the time of birth (P < 0.0001). There were changes in myocardial ER stress pathway components in utero. Glucose (78 kDa)-regulated protein (GRP78) protein levels were high in the fetus and declined after birth (P < 0.0001). EIF2A phosphorylation was profoundly depressed at 1 dPN (vs. 143 dGA, P = 0.0113). In conclusion, there is dynamic regulation of ER proteostasis, ER stress, and apoptosis cascade in the perinatal heart. Apoptotic signaling is more readily activated in fetal cardiomyocytes near birth, leading to widespread caspase cleavage in the newborn heart. These pathways are important for the regulation of normal maturation in the healthy perinatal heart.NEW & NOTEWORTHY Cardiomyocyte apoptosis occurs even in the healthy, normally developing perinatal myocardium. As cardiomyocyte number is a critical contributor to heart health, the sensitivity of cardiomyocytes to endoplasmic reticulum stress leading to apoptosis is an important consideration. This study suggests that the heart has less robust protective mechanisms in response to endoplasmic reticulum stress immediately before and after birth, and that more cardiomyocyte death can be induced by stress in this period.

MicroRNA205: A Key Regulator of Cardiomyocyte Transition from Proliferative to Hypertrophic Growth in the Neonatal Heart.

The mammalian myocardium grows rapidly during early development due to cardiomyocyte proliferation, which later transitions to cell hypertrophy to sustain the heart's postnatal growth. Although this cell transition in the postnatal heart is consistently preserved in mammalian biology, little is known about the regulatory mechanisms that link proliferation suppression with hypertrophy induction. We reasoned that the production of a micro-RNA(s) could serve as a key bridge to permit changes in gene expression that control the changed cell fate of postnatal cardiomyocytes. We used sequential expression analysis to identify miR205 as a micro-RNA that was uniquely expressed at the cessation of cardiomyocyte growth. Cardiomyocyte-specific miR205 deletion animals showed a 35% increase in heart mass by 3 months of age, with commensurate changes in cell cycle and Hippo pathway activity, confirming miR205's potential role in controlling cardiomyocyte proliferation. In contrast, overexpression of miR205 in newborn hearts had little effect on heart size or function, indicating a complex, probably redundant regulatory system. These findings highlight miR205's role in controlling the shift from cardiomyocyte proliferation to hypertrophic development in the postnatal period.

Impact of maternal age and body mass index on the structure and function of the heart in newborns: a Copenhagen Baby Heart Study

BackgroundMaternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn.MethodsInfants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2) < 18.5; 18.5–24.9 (reference); 25–29.9; 30–34.9 and ≥ 35 and maternal age (years) < 25; 25–29; 30–34 (reference); 35–39 and ≥ 40. Outcomes were LV parameters ascertained by 2D-echocardiography. Associations between each maternal factor and infant LV parameters were analysed with either a linear model adjusted for the child’s weight and length at birth, gestational age, sex, age at TTE, and maternal smoking, or a linear mixed model, further adjusted for random effects of analyst and month of analysis. Analyses investigating impact of maternal BMI were adjusted for maternal age, and vice versa.ResultsThe study cohort included 24,294 infants. Compared with infants in the BMI reference group, infants born to women with a BMI ≥ 25 kg/m2 generally had smaller measures of LV internal diameters in end-diastole, reaching statistical significance for BMI 30–34.9 kg/m2 [-0.11 ± 0.04 mm, p = 0.01]. All groups of infants born to women with a BMI ≥ 25 kg/m2 had significantly smaller LV internal diameters in end-systole: BMI 25–29.9 kg/m2 [-0.04 ± 0.02 mm, p = 0.04], BMI 30–34.9 kg/m2 [-0.12 ± 0.03 mm, p = 0.001] and BMI ≥ 35 kg/m2 [-0.11 ± 0.05 mm, p = 0.03].Compared with infants in the age reference group, infants born to women ≥ 40 years had significantly smaller LV internal diameters in end-diastole [-0.15 ± 0.04 mm, p = 0.001] and end-systole [-0.09 ± 0.04 mm, p = 0.009].ConclusionsSystematic population-based echocardiography of infants showed that a maternal prepregnancy BMI ≥ 25 kg/m2 and maternal age ≥ 40 years were associated with smaller systolic and diastolic LV diameters. The long-term effects are unknown.Clinical trial registrationApril 2016, Copenhagen Baby Heart, NCT02753348.

RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.

Maturation of lipid metabolism in the fetal and newborn sheep heart.

At birth, the fetus experiences a dramatic change in environment that is accompanied by a shift in myocardial fuel preference from lactate and glucose in fetal life to fatty acid oxidation after birth. We hypothesized that fatty acid metabolic machinery would mature during fetal life in preparation for this extreme metabolic transformation at birth. We quantified the pre- (94-day and 135-day gestation, term ∼147 days) and postnatal (5 ± 4 days postnatal) gene expression and protein levels for fatty acid transporters and enzymes in hearts from a precocial species, the sheep. Gene expression of fatty acid translocase (CD36), acyl-CoA synthetase long-chain 1 (ACSL1), carnitine palmitoyltransferase 1 (CPT1), hydroxy-acyl dehydrogenase (HADH), acetyl-CoA acetyltransferase (ACAT1), isocitrate dehydrogenase (IDH), and glycerol phosphate acyltransferase (GPAT) progressively increased through the perinatal period, whereas several genes [fatty acid transport protein 6 (FATP6), acyl-CoA synthetase long chain 3 (ACSL3), long-chain acyl-CoA dehydrogenase (LCAD), very long-chain acyl-CoA dehydrogenase (VLCAD), pyruvate dehydrogenase kinase (PDK4), phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT)] were stable in fetal hearts and had high expression after birth. Protein expression of CD36 and ACSL1 progressively increased throughout the perinatal period, whereas protein expression of carnitine palmitoyltransferase 1a (fetal isoform) (CPT1a) decreased and carnitine palmitoyltransferase 1b (adult isoform) (CPT1b) remained constitutively expressed. Using fluorescent-tagged long-chain fatty acids (BODIPY-C12), we demonstrated that fetal (125 ± 1 days gestation) cardiomyocytes produce 59% larger lipid droplets (P < 0.05) compared with newborn (8 ± 1 day) cardiomyocytes. These results provide novel insights into the perinatal maturation of cardiac fatty acid metabolism in a precocial species.NEW & NOTEWORTHY This study characterized the previously unknown expression patterns of genes that regulate the metabolism of free fatty acids in the perinatal sheep myocardium. This study shows that the prenatal myocardium prepares for the dramatic switch from carbohydrate metabolism to near complete reliance on free fatty acids postnatally. Fetal and neonatal cardiomyocytes also demonstrate differing lipid storage mechanisms where fetal cardiomyocytes form larger lipid droplets compared with newborn cardiomyocytes.

Proteomic analysis of neonatal mouse hearts shows PKA functions as a cardiomyocyte replication regulator

The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.

Evaluation of Mean “R” Wave Amplitude in Lead V1 of Electrocardiogram among Term Newborn Infants in Tertiary Care Institution in South India

Background: The changes in the left ventricle to right ventricle muscle mass ratio account for the majority of the age-related changes in pediatric electrocardiograms (ECGs). A newborn's right ventricle muscle mass is more than the newborn's left ventricle. Physiologically, newborn infants have a dominant right ventricle. Race differences in QRS voltage normal values exist. Compared to Euro-Americans, African-Americans have a higher upper normal limit of QRS voltages. Typically, right ventricular hypertrophy is seen in newborns. To distinguish between pathological and physiological newborn hypertrophy, it is critical to measure the mean QRS amplitude in healthy newborns. This is the first study on the Indian population, with previous ones being conducted among African-Americans. Methodology: Between 2015 and 2016, this prospective observational study was carried out in the pediatrics department of a tertiary care facility in India. The study included 76 term newborns who were under 3 days old. In Chennai's Kilpauk Medical College and Hospital, the newborn infants underwent clinical examinations as well as echocardiography before receiving their ECGs. A baseline questionnaire that had been previously created was used for data collection. Results: For the Indian population, the mean R wave amplitude was 11.56 mm, with a standard deviation of 2.96 mm, and the 5th and 95th percentiles were 6.85 mm and 16.15 mm, respectively. The Fridericia formula for the mean QTc interval gives a value of 357.14 ms, a standard deviation of 34.072 ms, and a 95% confidence interval of 349.36–364.93 ms. Since a newborn's heart rate typically exceeds 100 beats/min, the measurement of QTc using the Fridericia formula more accurately predicts QTc in the newborn. The mean heart rate was 125.75 beats/min, with a standard deviation of 15.44 beats/min, and the 5th and 95th percentiles were 93.7 and 149 beats/min, respectively. Conclusions: The “R” wave mean amplitude in lead V1 was 11.56 mm, with a 2.96 mm standard deviation; the fifth and ninety-fifth percentiles, respectively, were 6.85 mm and 16.15 mm. The population's “R” wave in the lead V1 exhibits racial differences in amplitude.

Use of Suctioning during Newborn Resuscitation and Its Effects on Heart Rate in a Low-Resource Setting, Tanzania.

Suctioning of newborns immediately after birth, as part of delivery room resuscitation, is only recommended if the airway is obstructed. The aim of this study was to describe the use of suctioning during newborn resuscitation among survivors versus those who died within 3 days and potential suction-related heart rate responses and associations to newborn characteristics. This was a retrospective observational study from July 2013 to July 2016 in a referral hospital in rural Tanzania. Research assistants observed and documented all deliveries, newborn resuscitations were video-recorded, and newborn heart rates were captured with a dry-electrode electrocardiogram. Liveborn infants ≥34 weeks gestation who received ventilation and with complete datasets were eligible. All 30 newborns who died were included, and a total of 46 survivors were selected as controls. Videos were annotated and heart rate patterns were observed before and after the suction events. Suctioning was performed more frequently than recommended. No differences were found in suctioning characteristics between newborns who died versus those who survived. In 13% of suction events, a significant heart rate change (i.e., arrhythmia or brief/sustained >15% fall in heart rate) was observed in relation to suctioning. This represents a potential additional harm to already depressed newborns undergoing resuscitation.

Commentary on “Brain Injury During Transition in the Newborn With Congenital Heart Disease: Hazards of the Preoperative Period”

BRAIN INJURY DURING TRANSITION IN THE NEWBORN WITH CONGENITAL HEART DISEASE: HAZARDS OF THE PREOPERATIVE PERIOD: Jennifer M. Lynch, J. William Gaynor, Daniel J. Licht Seminars in Pediatric Neurology Volume 28, December 2018, Pages 60-65 Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population.

The newborn heart GLAdly benefits from maternal milk.

The newborn heart GLAdly benefits from maternal milk.

Cardiac Fibrosis and Innervation State in Uncorrected and Corrected Transposition of the Great Arteries: A Postmortem Histological Analysis and Systematic Review

In the transposition of the great arteries (TGA), alterations in hemodynamics and oxygen saturation could result in fibrotic remodeling, but histological studies are scarce. We aimed to investigate fibrosis and innervation state in the full spectrum of TGA and correlate findings to clinical literature. Twenty-two human postmortem TGA hearts, including TGA without surgical correction (n = 8), after Mustard/Senning (n = 6), and arterial switch operation (ASO, n = 8), were studied. In newborn uncorrected TGA specimens (1 day-1.5 months), significantly more interstitial fibrosis (8.6% ± 3.0) was observed compared to control hearts (5.4% ± 0.8, p = 0.016). After the Mustard/Senning procedure, the amount of interstitial fibrosis was significantly higher (19.8% ± 5.1, p = 0.002), remarkably more in the subpulmonary left ventricle (LV) than in the systemic right ventricle (RV). In TGA-ASO, an increased amount of fibrosis was found in one adult specimen. The amount of innervation was diminished from 3 days after ASO (0.034% ± 0.017) compared to uncorrected TGA (0.082% ± 0.026, p = 0.036). In conclusion, in these selected postmortem TGA specimens, diffuse interstitial fibrosis was already present in newborn hearts, suggesting that altered oxygen saturations may already impact myocardial structure in the fetal phase. TGA-Mustard/Senning specimens showed diffuse myocardial fibrosis in the systemic RV and, remarkably, in the LV. Post-ASO, decreased uptake of nerve staining was observed, implicating (partial) myocardial denervation after ASO.

Comparing Strategies for Critical Congenital Heart Disease Newborn Screening.

An extended newborn critical congenital heart disease (CCHD) screening program using oximetry has been implemented in Taipei, Taiwan since April 2014. This study was conducted to investigate the test accuracy and efficiency of this screening protocol. This study analyzed data from 30 birthing facilities representing 87.9% of live births in Taipei. Positive screening was defined as oxygen saturation <95% in either extremity or a preductal-postductal oxygen saturation difference of >3%. This study cohort was used to retrospectively estimate outcomes on the basis of different CCHD screening protocols. During the study period, 93 058 of 94 204 (98.8%) infants who had no prenatal suspicion were screened. The referral rate was 0.17% (156/93 058), and up to 90% of test-positive infants were referred within 48 hours of life. Forty-two CCHD cases without prenatal suspicion were detected and 97.6% were diagnosed within 72 hours of life. Of the screened newborns, 4 CCHD cases passed the screening. The false positive and false negative rates were 0.12% and 0.04%, respectively. In addition, applying our database to Spanish and updated American Academy of Pediatrics screening strategies led to more CCHD case detection. The Taipei protocol provided an efficient and effective screening referral system in a community setting. For optimal efficiency, we advocated the updated American Academy of Pediatrics algorithm/Spanish recommendation with a modification of immediate referral if oxygen saturation ≤90% in either extremity. The updated protocol would be practicable for nationwide screening in Taiwan and could also be applied to other regions with similar medical care systems.

Measuring respiratory and heart rate using a fiber optic interferometer: A pilot study in a neonate model.

The study aim was to test the safety and efficacy of a pad with optic fibers developed for monitoring newborn respiratory rate (RR) and heart rate (HR). Thirty New Zealand White rabbits were included, divided by weight into three groups. RR and HR were measured using two methods for each rabbit: ECG electrodes as the reference method and a newly developed pad with an experimental fiber optic system (EFOS) as the experimental method. Analysis was performed on data for 29 rabbits (10 female, 34%; 19 male, 66%). EFOS performed better at measuring RR compared with HR. RR values did not differ significantly between the methods for the whole group (p = 0.151) or within each sex (female: p > 0.999; male: p = 0.075). Values for HR, however, did differ between methods for the whole group of animals (p < 0.001) and also within groups by sex (female: p < 0.001; male: p = 0.006). The results of this preclinical study demonstrate the potential of this non-invasive method using a fiber optic pad to measure HR and RR.

The Laryngeal Mask: Empowering Nurses to Rescue Newborns.

Since 2005, the Neonatal Resuscitation Program (NRP) has recommended the laryngeal mask (LM) as an alternative airway when positive-pressure ventilation (PPV) is unsuccessful and intubation is unsuccessful or unfeasible. There is a paucity of literature regarding LM use in high-resource countries; however, anecdotal information and recent studies suggest low implementation. This article increases awareness of LM safety and efficacy, provides guidance for determining nursing scope of practice, and includes suggestions for developing a training program. Methods include considering NRP customers' questions, recent systematic reviews of the literature, how NRP recommendations are developed, how to determine nursing scope of practice, and how to develop a training program. Recent studies support the NRP recommendation to use the LM as a rescue airway when PPV fails and intubation is not feasible. The LM provides more effective PPV than face-mask ventilation. The LM may be effective as the initial PPV device for infants of at least 34 weeks' gestation. To use the LM, nurses may require training, which may include a simulation-based curriculum. Nurses can increase their awareness of the advantages of LM use, determine their scope of practice, and develop a training program. When face-mask ventilation is unsuccessful and intubation is unfeasible, LM insertion will likely increase the newborn's heart rate and avoid intubation. Future research should determine training requirements, efficacy of the LM as the initial PPV device in high-resource settings, and LM use during complex resuscitation and in preterm newborns.

Impact of maternal risk factors on the structure and function of the heart in newborns

Abstract Introduction Maternal factors such as smoking during pregnancy, advanced age, and obesity are associated with increased risk of complex congenital heart defects in the offspring. It is unknown whether maternal risk factors may also cause subtle abnormalities in cardiac structure and function. Purpose To investigate whether the following maternal factors: advanced age, high body mass index (BMI), and smoking during pregnancy are associated with changes in left ventricle (LV) dimensions and systolic function in the newborn child. Methods Data was obtained as part of a population-based cohort study with prenatal inclusion and postnatal transthoracic echocardiography (TTE) of newborns within 60 days of birth. The TTE protocol included measurements of: Interventricular septal thickness at end-diastole (IVSd), LV posterior wall thickness at end-diastole (LVPWd), LV internal diameter at end-diastole (LVIDd) and LV internal diameter at end-systole (LVIDs). Fractional shortening (FS) was calculated by use of Teicholz's formula. Children of mothers with data available on age, BMI, and smoking status, respectively, were divided into the following groups depending on whether their mothers were: of young age &amp;lt;25 years, 25–29 years, 30–34 years (reference group), 35–39 years, and advanced age ≥40 years; underweight BMI &amp;lt;18.5, normal range BMI 18.5–24.9 (reference group), preobese BMI 25–29.9, and obese BMI ≥30; smoking or nonsmoking (reference group). Associations between different groups with each maternal risk factor and newborn LV parameters were analysed using a multiple linear regression model. Results Children of mothers with advanced age at the time of childbirth (n=1,411) had significantly smaller LVIDd and LVIDs (Table 1) compared to children of mothers in their early thirties (n=10,045). Children of preobese (n=4,707) and obese mothers (n=2,138) had significantly smaller LVIDd and LVIDs than children of mothers in the normal BMI range (n=17,654). Children of mothers who smoked during pregnancy (n=808) had significantly larger LVPWd than children of non-smoking mothers (n=24,072). A significant difference in FS was only seen in children of obese mothers. Subanalyses of the quantity of maternal smoking (available data in n=548 [67.8%] of mothers who smoked during pregnancy) showed that children of heavy smoking mothers (≥15 cigarettes/day, n=101), had significantly thicker IVSd and LVPWd compared with children of nonsmoking mothers, whereas no significant effect was identified in newborns of mothers smoking less than 15 cigarettes per day (Table 2). Conclusions Systematic population-based echocardiography of newborns showed that an increased maternal BMI and maternal age above 40 years were associated with smaller LV cavity dimensions in the offspring and that heavy smoking during pregnancy was associated with increased LV myocardial thickness. FS was only affected in children of obese mothers. The long-term effects of these novel findings are unknown. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Herlev-Gentofte Hospital Internal Funding for Cardiological Research andThe Novo Nordisk Foundation

Comparative gross anatomy of epicardiac ganglionated nerve plexi on the human and sheep cardiac ventricles.

This study aimed to examine the distribution and quantitative parameters of the epicardiac ventricular neural ganglionated plexus in the hearts of humans and sheep, highlighting the differences of this plexus in humans and large models. Five non-sectioned pressure distended whole hearts of the human newborns and 10 hearts of newborn German black-faced lambs were investigated applying a histochemical method for acetylcholinesterase to stain epicardiac neural structures with their subsequent stereomicroscopic examination. In humans, the ventricular nerves are spread by four epicardiac nerve subplexuses, that is, the left and right coronary as well as the left and middle dorsal. In sheep, the ventricular nerves are spread by five epicardiac nerve subplexuses, that is, the left and right coronary, the left and middle dorsal and the right ventral ones. The ventricular epicardium involved up to 129 ganglia in humans and up to 198-in sheep. The largest number of the ventricular ganglionic cells in humans were located on the ventral side, in front of the conus arteriosus, while on sheep ventricles, the most numerous neurons distributed on the dorsal wall of the left ventricle. This comparative study of the morphological patterns of the human and sheep ventricles demonstrates that the sheep heart is neuroanatomically distinct from the human one and this must be taking into consideration using the sheep model for the heart physiology experiments.

Modeling propofol-induced cardiotoxicity in the isolated-perfused newborn mouse heart.

Infants and children are vulnerable to developing propofol infusion syndrome (PRIS) and young age is a risk factor. Cardiac involvement is often prominent and associated with death. However, the mechanisms of pediatric PRIS are poorly understood because of the paucity of investigation and lack of a gold standard animal model. Unfortunately, in vivo modeling of PRIS in a newborn mouse is not feasible and would be complicated by confounders. Thus, we focused on propofol‐induced cardiotoxicity and aimed to develop an ex‐vivo model in the isolated‐perfused newborn mouse heart. We hypothesized that the model would recapitulate the key cardiac features of PRIS seen in infants and children and would corroborate prior in vitro observations. Isolated perfused newborn mouse hearts were exposed to a toxic dose of propofol or intralipid for 30‐min. Surface electrocardiogram, ventricular contractile force, and oxygen extraction were measured over time. Real‐time multiphoton laser imaging was utilized to quantify calcein and tetramethylrhodamine ethyl ester fluorescence. Propidium iodide uptake was assessed following drug exposure. A toxic dose of propofol rapidly induced dysrhythmias, depressed ventricular contractile function, impaired the mitochondrial membrane potential, and increased open probability of the permeability transition pore in propofol‐exposed hearts without causing cell death. These features mimicked the hallmarks of pediatric PRIS and corroborated prior observations made in isolated newborn cardiomyocyte mitochondria. Thus, acute propofol‐induced cardiotoxicity in the isolated‐perfused developing mouse heart may serve as a relevant ex‐vivo model for pediatric PRIS.

Models are useful, but they are still only the models ….

Dr. Peer with colleagues [1] verifies the hypothesis that mechanical assistance of the pulmonary blood flow in a Norwood circulation can increase systemic blood flow and oxygen delivery. The verification of this hypothesis was not performed in vivo but using a circulatory lumped parameter model, which was developed to simulate a Norwood circulation with 3.5-mm Blalock–Taussig (BT) shunt in a neonate. Irrespective of the topic of the study, the idea to test the physiologic consequences of our surgical procedures using a computational model is not new but still a very attractive concept. The obvious advantage is the avoidance of the patients suffering in the case of a wrong idea, but the main disadvantage (and I think the main limitation of such studies) is underestimation of the biology complexity. Nevertheless, I admire the efforts of the authors to construct such a computational model as well as the new idea alone. One of the 2 key findings of the study is that the mechanical support of the pulmonary blood flow increases the systemic cardiac output. The increase of the systemic blood flow almost equals the decrease of the BT-shunt flow. This means that the effect of better systemic perfusion is caused only by the reduction of the BT-shunt flow due to competitive flow from the pump (effect of the redistribution of the blood flow). The model does not assess the effect of the reduction of the preload and filling of the ventricle on the systemic cardiac output (relative hypovolaemia in the systemic circulation). The authors analyze 4 different amount of assisted pulmonary blood flow: 200, 400, 600 and 800 ml/min and in each case the systemic blood flow increases linearly. If we take 800 ml/min from the right atrium of a newborn heart (even if we assume that there is an additional inflow bladder with a volume of 25 ml as designed in the presented model) and pump to the pulmonary circulation, the question is, if there is still enough blood to fill the single ventricle? The model should predict when the filling of the ventricle (preload) would be a limiting factor for the systemic blood flow and even a cause for a reversal flow through the BT shunt.

Modified Technique for the Use of Neonatal Murine Hearts in the Langendorff Preparation

The use of the ex-vivo retrograde perfused heart has long been a cornerstone of ischemia-reperfusion investigation since its development by Oskar Langendorff over a century ago. Although this technique has been applied to mice over the last 25 years, its use in this species has been limited to adult animals. Development of a successful method to consistently cannulate the neonatal murine aorta would allow for the systematic study of the isolated retrograde perfused heart during a critical period of cardiac development in a genetically modifiable and low-cost species. Modification of the Langendorff preparation enables cannulation and establishment of reperfusion in the neonatal murine heart while minimizing ischemic time. Optimization requires a two-person technique to permit successful cannulation of the newborn mouse aorta using a dissecting microscope and a modified commercially available needle. The use of this approach will reliably establish retrograde perfusion within 3 min. Because the fragility of the neonatal mouse heart and ventricular cavity size prevents direct measurement of intraventricular pressure generated using a balloon, use of a force transducer connected by a suture to the apex of the left ventricle to quantify longitudinal contractile tension is necessary. This method allows investigators to successfully establish an isolated constant-flow retrograde-perfused newborn murine heart preparation, permitting the study of developmental cardiac biology in an ex-vivo manner. Importantly, this model will be a powerful tool to investigate the physiological and pharmacological responses to ischemia-reperfusion in the neonatal heart.