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Background: Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves., Methods and Results: To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2-/- embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos., Conclusions: From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.

Background: Cardiogram signal amplitude is a key index of hypertrophy but has not been investigated extensively in utero. In this study, magnetocardiography was used to assess P and QRS amplitude in normal subjects and subjects with fetal arrhythmia., Methods and Results: The study cohort consisted of 68 normal fetuses and 25 with various arrhythmias: 9 reentrant supraventricular tachycardia (SVT), 2 ventricular tachycardia (VT), 2 sinus tachycardia, 2 blocked atrial bigeminy, 2 congenital second-degree atrioventricular (AV) block, and 8 congenital complete AV block. Subjects with congenital AV block, all presenting with bradycardia, showed large QRS amplitude, exceedingly large P-wave amplitude, and long P-wave duration. The 2 subjects with VT, both with poor ventricular function, also exhibited large P waves. SVT was associated with only moderate signal amplitude elevation., Conclusions: The data imply that AV block in utero is accompanied by hypertrophy, which is more pronounced for the atria than the ventricles. We hypothesize that the hypertrophy results from a compensatory response associated with regulation of cardiac output and is likely to be observable in other arrhythmias and disease states. Magnetocardiography may be more sensitive than fetal echocardiography for detection of atrial hypertrophy in utero.

Background: Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system., Methods and Results: Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery., Conclusions: Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.

Objective: To correlate the presence of baseline variability and the duration of a prolonged deceleration/bradycardia in intrapartum fetal heart rate (FHR) tracings with the development of neonatal acidemia., Methods: We identified 186 patients with term gestations who had continuous electronic fetal monitoring for at least 2 hours before delivery, with an identified bradycardia during that period. Each patient had umbilical artery cord analysis done and delivery within 30 minutes of that bradycardia. One investigator blinded to the cord gas outcome reviewed the last 2 hours of the tracing using the National Institute of Child Health and Human Development guidelines for FHR monitoring. We assessed the presence or absence of variability before the bradycardia and recovery or no recovery of the bradycardia and placed the patients into four groups. Group 1 (128 patients) with normal variability and recovery, group 2 (40 patients) with normal variability and no recovery, group 3 (nine patients) with decreased variability and recovery, and group 4 (nine patients) with decreased variability and no recovery. We compared the incidence of neonatal acidosis defined as a pH of less than 7.0 at birth among the four groups. The relationship between the various groups was assessed using analysis of variance and the chi(2) test. In addition, a multiple logistic regression model was developed with the parameters of amplitude and recovery used to predict pH at birth., Results: The presence of decreased variability and no recovery of the FHR of a bradycardia was associated with the lowest pH 6.83 +/- 0.16 and a 78% incidence of significant acidosis. Decreased variability before FHR bradycardia was the FHR parameter significantly correlated with low pH., Conclusion: The most significant factor predicting the development of pathologic neonatal acidemia and indicating the need for urgent delivery in the presence of a bradycardia is decreased variability before the bradycardia.