Newborn Heart Research Articles

Expression of HIF-1α, VEGF and EPO in peripheral blood from patients with two cardiac abnormalities associated with hypoxia

Objectives HIF-1α (hypoxia-inducible factor-1 alpha) mediates the responses of mammalian cells to hypoxia/ischemia by inducing the expression of adaptive gene products (e.g., vascular endothelial growth factor (VEGF) and erythropoietin (EPO)). Persistent pulmonary hypertension of the newborn (PPHN) and cyanotic congenital heart disease (CCHD) are common neonatal diseases considered as paradigms of hypoxemia. Since the expression HIF-1α, VEGF and EPO in newborns diagnosed with these diseases has yet to be studied, we set out to define the expression of these genes in peripheral blood from newborn infants diagnosed with PPHN and CCHD. Design and methods The mRNA transcripts encoding HIF-1α, VEGF and EPO were measured by RT-PCR in healthy newborn infants and infants diagnosed with PPHN and CCHD. Results An important increase in HIF-1α expression was observed in both pathological conditions, accompanied by significant increases in VEGF and EPO expression when compared to healthy infants. Conclusions HIF-1α mRNA expression increases in newborn infants with PPHN or CCHD, as does the expression of its target genes VEGF and EPO.

Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node

In rabbit, sodium current ( I Na) contributes to newborn sinoatrial node (SAN) automaticity but is absent in adult SAN, where heart rate is slower. In contrast, heart rate is high and I Na is functional in adult mouse SAN. Given the slower heart rates of large mammals, we asked if I Na is functionally active in SAN of newborn or adult canine heart. SAN cells were isolated from newborn (6–10 days), young (40–43 days) and adult mongrels. I Na was observed in > 80% of cells from each age. However, current density was markedly greater in newborn, decreasing with age. At all ages, I Na was sensitive to nanomolar tetrodotoxin (TTX); 100 nmol/L inhibited I Na by 46.7%, 59.9% and 90.7% in newborn, young and adult cells, respectively. While high TTX sensitivity suggested the presence of non-cardiac isoforms, steady-state inactivation was relatively negative (midpoints − 89.7 ± 0.7 mV, − 95.1 ± 1.2 mV and − 93.4 ± 1.9 mV from newborn to adult). Consequently, I Na should be unavailable at physiological potentials under normal conditions, and 100 nmol/L TTX did not change cycle length or action potential parameters of spontaneous adult SAN cells. However, computer modeling predicts the large newborn I Na protects against excess rate slowing from strong vagal stimulation. The results show that canine SAN cells have TTX-sensitive I Na which decreases with post-natal age. The current does not contribute to normal automaticity in isolated adult cells but can be recruited to sustain excitability if nodal cells are hyperpolarized. This is particularly relevant in newborn, where I Na is large and parasympathetic/sympathetic balance favors vagal tone.

Product News

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Heart Failure in Children

Why is heart failure in children important? If we just consider the number of individuals affected, adult heart failure is clearly a more compelling public health problem. However, the relatively small numbers belie the overall economic and social impact of pediatric heart failure. When a child is admitted to the hospital for heart failure, the costs are considerably higher for children than adults because of the frequent need for surgical or catheter-based intervention. The demands of medical care can fray the family structure and adversely affect parental economic productivity. When a child dies of heart failure, the economic impact is magnified enormously because of the number of potentially productive years lost per death. For these and other reasons, heart failure in children is a serious public health concern. In addition, growing numbers of children with heart failure are reaching adulthood because of the successful application of medical and surgical heart failure therapies and the improved outcomes of congenital heart surgery. A greater understanding of the pathophysiology of heart failure in childhood may help inform therapeutic strategies once these children become adults. Furthermore, given the recent explosion of research in the impact of cardiac development and cardiogenetics on pediatric cardiovascular disease, it is not outside the realm of possibility for a pediatric discovery to be made that will also benefit adults with heart failure. We may not yet be able to agree on a definition of heart failure, but the cardinal symptoms, dyspnea, anasarca (“dropsy”), and cachexia, were well recognized in antiquity.1 These symptoms were not specific for cardiac pathology, and it was not until the 17th century, when William Harvey definitively identified the heart as an organ that pumped blood rather than generating heat, that the heart could begin to be understood as a source of dyspnea, edema, and …

Ontogenetic development of cardiac tolerance to oxygen deprivation – possible mechanisms

Our present focus on the hypoxic immature heart is driven by clinical urgency: cyanotic congenital cardiac malformations remain the single largest cause of mortality from congenital defects and ischemic heart disease is no more the disease of the fifth and older decades but its origin as well as risk factors are present already during early ontogeny. Moreover, the number of adult patients operated for cyanotic congenital heart disease during infancy steadily increases. This group approaches the age of the rising risk of serious cardiovascular diseases, particularly ischemic heart disease. Experimental results have clearly shown that the immature heart is significantly more tolerant to oxygen deficiency than the adult myocardium. However, the mechanisms of this difference have not yet been satisfactorily clarified; they are likely the result of developmental changes in cardiac energy metabolism, including mitochondrial function. The high resistance of the newborn heart cannot be further increased by ischemic preconditioning or adaptation to chronic hypoxia; these protective mechanisms appear only with decreasing tolerance during development. Resistance of the adult myocardium to acute oxygen deprivation may be significantly influenced by perinatal hypoxia. These results suggest that the developmental approach offers new possibilities in the studies of pathogenesis, prevention and therapy of critical cardiovascular diseases.

Myocardial Hypertrophy and the Maturation of Fatty Acid Oxidation in the Newborn Human Heart

After birth dramatic decreases in cardiac malonyl CoA levels result in the rapid maturation of fatty acid oxidation. We have previously demonstrated that the decrease in malonyl CoA is due to increased activity of malonyl CoA decarboxylase (MCD), and decreased activity of acetyl CoA carboxylase (ACC), enzymes which degrade and synthesize malonyl CoA, respectively. Decreased ACC activity corresponds to an increase in the activity of 5'-AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. These alterations are delayed by myocardial hypertrophy. As rates of fatty acid oxidation can influence the ability of the heart to withstand an ischemic insult, we examined the expression of MCD, ACC, and AMPK in the newborn human heart. Ventricular biopsies were obtained from infants undergoing cardiac surgery. Immunoblot analysis showed a positive correlation between MCD expression and age. In contrast, a negative correlation in both ACC and AMPK expression and age was observed. All ventricular samples displayed some degree of hypertrophy, however, no differences in enzyme expression were found between moderate and severe hypertrophy. This indicates that increased expression of MCD, and the decreased expression of ACC and AMPK are important regulators of the maturation of fatty acid oxidation in the newborn human heart.

Age-related changes in parvalbumin in the heart of female rats

Changes of parvalbumin protein levels and immunolocalisation during the postnatal development of the female rat heart were investigated in order to determine if they were correlated with age-related changes in cardiac function. Hearts from newborn, 3-month-old (young), 6-month-old (young adult) and 12-month-old (adult) female Wistar rats were processed for immunohistochemical localization of parvalbumin and for Western blotting assay. Parvalbumin was detected by both methods in all age groups from newborn to 12-month-old rats. In the newborn rat heart, parvalbumin immunoreactivity did not fully fill the sarcoplasm of the cardiac myocytes and the amount of parvalbumin was low compared to the adult levels. In contrast, in 3-12-month-old rats, strong parvalbumin immunoreactivity was detected throughout the sarcoplasm of all cardiac myocytes and the amount of parvalbumin increased with increasing age (from newborn to adult). Our study indicates that an increase of parvalbumin levels in the female rat heart with increasing age may be associated with maintenance of proper relaxation of the cardiac myocytes needed to cope with the increasing workload of the heart during postnatal growth.

Transgenic Overexpression of Hdac3 in the Heart Produces Increased Postnatal Cardiac Myocyte Proliferation but Does Not Induce Hypertrophy

Class I and II histone deacetylases (HDACs) play vital roles in regulating cardiac development, morphogenesis, and hypertrophic responses. Although the roles of Hdac1 and Hdac2, class I HDACs, in cardiac hyperplasia, growth, and hypertrophic responsiveness have been reported, the role in the heart of Hdac3, another class I HDAC, has been less well explored. Here we report that myocyte-specific overexpression of Hdac3 in mice results in cardiac abnormalities at birth. Hdac3 overexpression produces thickening of ventricular myocardium, especially the interventricular septum, and reduction of both ventricular cavities in newborn hearts. Our data suggest that increased thickness of myocardium in Hdac3-transgenic (Hdac3-Tg) mice is due to increased cardiomyocyte hyperplasia without hypertrophy. Hdac3 overexpression inhibits several cyclin-dependent kinase inhibitors, including Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, and Cdkn2c. Hdac3-Tg mice did not develop cardiac hypertrophy at 3 months of age, unlike previously reported Hdac2-Tg mice. Further, Hdac3 overexpression did not augment isoproterenol-induced cardiac hypertrophy when compared with wild-type littermates. These findings identify Hdac3 as a novel regulator of cardiac myocyte proliferation during cardiac development.

Pharmacological regulation of the cardiomyocyte growth in tissue culture

Norepinephrine, blockers of beta-adrenoreceptors, angiotensin-converting enzyme inhibitors and angiotensin I receptor blocker were investigated in organotypic tissue culture of cardiomyocytes of 10-12-day-old chicken embryos and newborn rat heart in a wide range of concentrations. The data obtained show that low concentration of norepinephrine led to the cardiomyocyte growth control. The application of beta-adrenoblockers metoprolol and atenolol prevented stimulating effect of norepinephrine. Zofenopril inhibited the growth of cardiomyocytes but enalapril had no effect on this process. The effect of angiotensin I receptor blocker depended on concentration - low concentrations resulted in activation of cardiomyocyte growth; and high concentrations led to the decrease of their growth.

Pulmonary Arterial Hypertension from a Pediatric Perspective

This review of pediatric pulmonary arterial hypertension provides a framework within which to view pulmonary hypertension in children. Classification schemes, including the latest recommendations from the World Health Organization, are discussed, and the histopathology of severe pulmonary hypertension is reviewed. New information is provided regarding idiopathic and familial forms of the disease. Specific childhood etiologies, including persistent pulmonary hypertension of the newborn and congenital heart disease, are reviewed. Additionally, we examine the role of collagen vascular diseases, portal hypertension, and viruses in the pathogenesis of severe pulmonary arterial hypertension.

Multiple signaling pathways coordinately mediate reactive oxygen species dependent cardiomyocyte hypertrophy

The heart responds to an increased demand arising due to physiological stimuli or pathological insults by hypertrophy of myocytes. Reactive oxygen species (ROS) have recently been identified as the molecular intermediates in the translation of mechanical stimuli to cellular response. Different signal transduction pathways have been implicated with cardiac hypertrophy, prominent among them being, mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and calcineurin. It remains unclear whether the ROS induced hypertrophy is mediated through one or more of these pathways. This study was taken up with the objective to affirm the role of ROS in the induction of cardiomyocyte hypertrophy and examine the contribution of specific pathways in the mediation of the hypertrophic response. The cellular response to enzyme-generated reactive oxygen species was examined in cultured cells from newborn rat heart. Pathway specific inhibitors were used to identify the role of each pathway in the mediation of cellular hypertrophy. Cellular hypertrophy in response to hypoxanthine-xanthine oxidase was prevented by inhibition of any one of the pathways; leading to the inference that oxidative stress induced hypertrophy is mediated by coordinative regulation of the three major pathways.

Cardiac PPARα Protein Expression is Constant as Alternate Nuclear Receptors and PGC‐1 Coordinately Increase During the Postnatal Metabolic Transition

Gene expression data obtained in mouse heart indicate that increased expression for the nuclear receptor, peroxisomal proliferator activated receptor (PPAR), prompts the postnatal transition from predominantly carbohydrate to fatty acid oxidation preference. However, no phenotypic or proteomic data are available to confirm downstream signaling and metabolic transition in mice. We studied the hypothesis that shifts in nuclear receptor expression trigger the newborn metabolic switch in a newborn sheep. This species is well characterized with regards to developmental changes in substrate oxidative metabolism. Heart tissues from fetal (130 days gestation), newborn 24 hours, and 30-day old lambs were evaluated for protein expression from multiple enzymes controlling oxidative metabolism as well as principal nuclear receptors and coactivators. Although muscle and liver type carnitine palmitoyl transferases I showed no significant changes to correspond to the metabolic transition, hexokinase II protein content showed a profound transient drop, and pyruvate dehydrogenase kinase steadily increased. PPAR showed no increases preceding or during the transition, while peroxisomal proliferator activated receptor gamma coactivator-1 (PGC-1) increased approximately 20-fold transiently in newborn heart in conjunction with significant increases in thyroid hormone receptor 1 and retinoid-activated receptor . These data challenge the paradigm that increases in PPAR prompt the postnatal metabolic switch, and suggest that other nuclear receptors play a major role. As thyroid hormone (TH) modulates PGC-1 expression in sheep during development, these data further suggest that well-characterized perinatal TH surge in sheep contributes to this metabolic switch.

Cardiac angiotensin receptor expression in hypothyroidism: back to fetal gene programme?

Cardiac angiotensin receptor expression in hypothyroidism: back to fetal gene programme?

Ventricle-Specific Metabolic Differences in the Newborn Piglet Myocardium In Vivo and During Arrested Global Ischemia

Ventricular dysfunction is reported greater in the left (LV) versus right ventricle (RV) in infants following surgically induced ischemia. Ventricle-specific differences in baseline metabolism may alter response to ischemia thus affecting postischemic functional recovery. This study identifies ventricle-specific metabolic differences in the newborn (piglet) heart at baseline (working) and during ischemia (arrested). Baseline LV citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HAD) activities were 15% and 18% lower (p < 0.02), whereas creatine kinase (CK) and phosphofructokinase (PFK) activities were 40% and 23% higher (p < 0.04) than the RV. Baseline LV glycogen reserves were also 55% higher (p = 0.004). By 15 min of ischemia, LV ATP was 20% lower (p < 0.05), lactate was 51% higher (p = 0.001), and hydrogen ions (H) were 43% higher (p = 0.03) compared with the RV. These differences persisted for the entire ischemic period (p < 0.02). After 45 min of ischemia, the LV used 58% less (p < 0.05) glycogen than the RV. These findings demonstrate that the enhanced glycolytic capacity of the newborn LV was accompanied by greater anaerobic end-product accumulation and lower energy levels during ischemia. This profile may offer one explanation for greater LV-dysfunction relative to the RV in children following ischemia.

Choosing private hospital care

When I look at my pictures of my newborn boys my heart instantly fills with the happiest of memories. That cold night in February and that hot August morning are the greatest days of my life. I truly look forward to adding another amazing day, maybe two, to all our lives, but for now I'll enjoy my 19-month-old and 7- week-old. After all, having a baby is not an easy task. The nine months leading up to that moment are fraught with worry, attempts at the healthiest of diets, and, like the rest of motherhood, total selflessness. We were married in October and by May we were hoping to start trying for a family.

Cardioplégie au sang, cardioplégie cristalloïde en pédiatrie: Myocardial protective effect of blood and crystalloid cardioplegia in cardiac paediatric surgery

Most of heart operations in new-borns and children need a heart arrest period. This necessary heart arrest would permit the right reconstruction and the appropriate solutions for many congenital cardiac diseases. The heart protection during this ischemic period is a matter of important considerations and many studies are done in this subject. They concern usually the adult heart. But there is many differences between the immature new-born heart and the adult well developed heart. The aim of this paper is to describe the particularities of the children's heart and to review interesting information from the international literature on the subject of the children heart protection in paediatric heart surgery.

Functional arginine vasopressin system in early heart maturation

Since the neurohypophyseal hormone 8-arginine vasopressin (AVP) is involved in cardiovascular tissue hypertrophy and myocyte differentiation, it is possible that local AVP plays a role in heart maturation. AVP-specific RIA, RT-PCR, and immunoblot measurement of AVP receptors (VR) were used to investigate heart tissues from newborn and adult rats. To test AVP's role in differentiation and specialization into ventricle-like cardiomyocytes, we studied GFP-P19Cl6 stem cells, which express green fluorescence protein (GFP) reporter under transcriptional control of the myosin light chain-2v promoter. VR(1) transcripts and proteins were higher in adult than in newborn rat hearts. In contrast, VR(2) increased from postnatal day 1 to 5 and was barely detected in the adult rat heart. In cardiomyocytes expressing troponin C, immunofluorescence revealed VR(2) and VR(1). Intracellular cAMP increased 6.5- and 8.9-fold in response to the selective VR(2) agonist 1-desamino-8-D-AVP (DDAVP) after 1 and 24 h, respectively. Cardiac AVP was high in 1- and 5-day-old (330 +/- 26 and 276 +/- 53 pg/mg protein, respectively) but low in 66-day-old (98 +/- 15 pg/mg protein) rats. AVP immunostaining was detected in the tunica adventitia and endothelium of the coronary vessels. The possible role of AVP in cardiomyogenesis was indicated by DDAVP-AVP-dependent differentiation of GFP-P19Cl6 stem cells into contracting cells displaying GATA-4, a cardiac-specific marker, and ventricle-specific myosin light chain. Together, it is suggested that the AVP system is implicated in postnatal cardiac maturation.

Newborn hearts are at greater ‘metabolic risk’ during global ischemia – advantages of continuous coronary washout

Altered metabolic responses of the newborn heart to ischemia, which may increase irreversible injury, may at least partially explain the greater morbidity and mortality experienced by some children undergoing congenital cardiac repair. The present study compared newborn heart metabolic responses to global ischemia with those of adult, and evaluated whether continuous coronary artery washout in the newborn heart during 'ischemia' could favourably affect these responses. Adult (n=12) and newborn (n=12) pigs were anesthetized, and right ventricular biopsies were taken before global ischemia and at set intervals during ischemia. Another 12 newborns were subdivided into groups of nonperfused hearts and hearts receiving continuous perfusion. Time to onset of and time to peak of ischemic contracture were recorded. Biopsies were assayed for lactate, myocardial glycogen, glucose-6-phosphate and ATP. Newborn hearts were more sensitive to global ischemia than adult hearts, based on shorter time to onset of and time to peak of ischemic contracture, and had a significantly greater rate of ATP decline (P<0.01). This was due in part to a more rapid accumulation of lactate (P<0.05) and only a 50% use of glycogen, compared with 93% by adult hearts. Continuous washout of newborn hearts prevented lactate accumulation, allowing a 90% use of glycogen and delaying time to ischemic contracture by twofold. This was accompanied by lower levels of glucose-6-phosphate accumulation (P<0.05) and a threefold reduction in the rate of ATP decline. Significant differences in myocardial metabolism during ischemia in newborns compared with adults could predispose them to earlier ischemic injury, which can be eliminated by the removal of end products. Perfusion strategies taking these differences into account may further optimize pediatric myocardial protection and improve outcomes in newborn children undergoing cardiac procedures.

Phospholemman expression is high in the newborn rabbit heart and declines with postnatal maturation

Phospholemman (PLM) is a small sarcolemmal protein that modulates the activities of Na +/K +-ATPase and the Na +/Ca 2+ exchanger (NCX), thus contributing to the maintenance of intracellular Na + and Ca 2+ homeostasis. We characterized the expression and subcellular localization of PLM, NCX, and the Na +/K +-ATPase α1-subunit during perinatal development. Western blotting demonstrates that PLM (15 kDa), NCX (120 kDa), and Na +/K +-ATPase α-1 (∼100 kDa) proteins are all more than 2-fold higher in ventricular membrane fractions from newborn rabbit hearts (1–4-day old) compared to adult hearts. Our immunocytochemistry data demonstrate that PLM, NCX, and Na +/K +-ATPase are all expressed at the sarcolemma of newborn ventricular myocytes. Taken together, our data indicate that PLM, NCX, and Na +/K +-ATPase α-1 proteins have similar developmental expression patterns in rabbit ventricular myocardium. Thus, PLM may have an important regulatory role in maintaining cardiac Na + and Ca 2+ homeostasis during perinatal maturation.

Neonatal Murine Heart Slices. A Robust Model to Study Ventricular Isometric Contractions

Background/Aims: Cardiac function is increasingly studied using murine models. However, current multicellular preparations to investigate contractile properties have substantial technical and biological limitations and are especially difficult to apply to the developing murine heart. Methods: Newborn murine hearts were cut with a vibratome into viable tissue slices. The structural and functional integrity of the tissue was shown by histology, ATP content and sharp electrode recordings. Results: Within the first 48 hours after slicing structure remained intact without induction of apoptosis. ATP concentrations and action potential parameters were comparable to those of physiological tissue. Isometric force measurements demonstrated a physiological force-frequency relationship with a ‘primary-phase’ negative force-frequency relationship up to 1-2 Hz and a ‘secondary-phase’ positive force-frequency relationship up to 8 Hz. (-)-Isoproterenol (10^-6 mol/l) increased active force to 251±35% (n=15) of baseline values and shortened relaxation times indicating a preserved beta-adrenergic regulation of contraction. Changes of the force-frequency relationship after application of ryanodine and nifedipine indicated functionality of calcium release from the sarcoplasmic reticulum and of L-type calcium channels. Conclusion: Generation of viable, physiological intact ventricular slices from neonatal hearts is feasible and provides a robust model to study loaded contractions.