NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.

BackgroundThe molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and beta-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of beta-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes.Methodology/principal findingsUsing antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.ConclusionsThis study suggests that NKX2-5 modulates the beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes

Tricuspid valve disease with significant tricuspid insufficiency in the fetus: Diagnosis and outcome

AbstractThe echocardiographic studies and clinical course of 27 fetuses (mean gestationl age 26.9 weeks) diagnosed in utero with tricuspid valve disease and significant tricuspid regurgitation were reviewed. The diagnosis of Ebstein's anomaly was made in 17 of the fetuses, 7 had tricuspid valve dysplasia with poorly developed but normally attached leaflets and 2 had an unguarded tricuspid valve orifice with little or no identifiable tricuspid tissue. One fetus was excluded from data analysis because a more complex heart lesion was documented at autopsy. All fetuses had massive right atrial dilation and most who were serially studied had progressive right-sided cardiomegaly. Hydrops fetalis was found in six cases and atrial flutter in five.Associated cardiac lesions included pulmonary stenosis in five cases and pulmonary alresia in six. Four fetuses with normal forward pulmonary artery flow at the initial examination were found at subsequent study to have retrograde pulmonary artery and ductal flow in association with the development of pulmonary stenosis (n = 1) and pulmonary atresia (n = 3). On review of the clinical course of the 23 fetuses (excluding 3 with elective abortion), 48% of the fetuses died in utero and 35% who were liveborn died despite vigorous medical and, when necessary, surgical management, many of whom had severe congestive heart failure. Of the four infants who survived the neonatal period, three had a benign neonatal course, all of whom were diagnosed with mild to moderate Ebstein's anomaly; only one had pulmonary outflow obstruction. An additional finding at autopsy was significant lung hypoplasia documented in 10 of 19 autopsy reports.Tricuspid valve anomalies with tricuspid insufficiency can be identified echocardiographically in the fetus and should be searched for in the presence of right atrial enlargement. The prognosis for the fetus diagnosed in utero with significant tricuspid valve disease is extremely poor, with a prenatal course that includes progressive right heart dilation, with cardiac failure and lung hypoplasia in many and development of pulmonary stenose or pulmonary atresia later in gestation in some

Depressed Left and Right Ventricular Cardiac Output in Fetuses of Diabetic Mothers

INTRODUCTION: We compared right and left ventricular cardiac output (RVCO and LVCO) in fetuses of diabetic mothers (FDM) to a large normal cohort. METHODS: We prospectively enrolled 264 normal fetuses and 30 FDM. Fetal CO parameters: semilunar valve velocity time integrals (AVVTI, PVVTI), ventricular outflow diameters (LVOTD, RVOTD), stroke volumes (AVSV, PVSV) were measured, and LVCO and RVCO calculated. These were normalized using nonlinear regression to estimated fetal weight (EFW) to provide means and standard deviations. Among FDMs, mean Z-scores and 95% confidence limits (CL) were calculated, and compared to zero. RESULTS: LVCO, RVCO, and parameters they were calculated from, increased predictably and non-linearly with increasing EFW. In FDM, LVCO was depressed (mean Z -1.679, 95% CL -2.404, -0.955, p CONCLUSION: Normal biventricular stroke volumes and outputs follow a nonlinear regression with EFW. FDM have significantly lower right and left heart stroke volumes and outputs for weight than do normal fetuses

Persistent Aortic Stiffness and Left Ventricular Hypertrophy in Children of Diabetic Mothers

Publisher Copyright: © 2020 Canadian Cardiovascular SocietyBackground: Fetuses of diabetic mothers develop left ventricular (LV) hypertrophy and are at increased long-term risk of cardiovascular disease. In our previous longitudinal study from midgestation to late infancy we showed persistence of LV hypertrophy and increased aortic stiffness compared with infants of healthy mothers, the latter of which correlated with third trimester maternal hemoglobin A1c. In the present study, we reexamined the same cohort in early childhood to determine if these cardiovascular abnormalities persisted. Methods: Height, weight, and right arm blood pressure were recorded. A full functional and structural echocardiogram was performed with offline analysis of LV posterior wall and interventricular septal diastolic thickness (IVSd), systolic and diastolic function, and aortic pulse wave velocity. Vascular reactivity was assessed using digital thermal monitoring. Participants also completed a physical activity questionnaire. Results: Twenty-five children of diabetic mothers (CDMs) and 20 children from healthy pregnancies (mean age, 5.6 ± 1.7 and 5.3 ± 1.3 years, respectively; P = not significant) were assessed. Compared with controls, IVSd z score was increased in CDMs (1.2 ± 0.6 vs 0.5 ± 0.3, respectively; P = 0.006), with one-fifth having a z score of more than +2.0. Aortic pulse wave velocity was increased in CDMs (3.2 ± 0.6 m/s vs 2.2 ± 0.4 m/s; P = 0.001), and correlated with IVSd z score (R2 = 0.81; P = 0.001) and third trimester maternal A1c (R2 = 0.65; P < 0.0001). Body surface area, height, weight, blood pressure, vascular reactivity, and physical activity scores did not differ between groups. Our longitudinal analysis showed that individuals with greater IVSd, and aortic stiffness in utero, early and late infancy also tended to have greater measures in early childhood (P < 0.001 and P < 0.0001, respectively). Conclusions: CDMs show persistently increased interventricular septal thickness and aortic stiffness in early childhood.Peer reviewe

Intrauterine exposure to chronic hypoxia in the rat leads to progressive diastolic function and increased aortic stiffness from early postnatal developmental stages

Aim We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages. Methods Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2) from embryonic day E15‐21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro‐sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively. Results Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p \u3c .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1–2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E’/A’ tissue velocities compared to controls (p \u3c .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p \u3c .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p \u3c .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4. Conclusion Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages

Cardiovascular Health of Offspring of Diabetic Mothers From the Fetal Through Late-Infancy Stages

Non peer reviewe

Prenatal Diagnosis Improves the Postnatal Cardiac Function in a Population-Based Cohort of Infants with Hypoplastic Left Heart Syndrome

Background: Prenatal diagnosis of hypoplastic left heart syndrome (HLHS) enables planning of perinatal care and is known to be associated with more stable preoperative hemodynamics. The impact on postnatal myocardial function is poorly known. The aim of this study was to determine the impact of prenatal diagnosis of HLHS on postnatal myocardial function.Methods: A consecutively encountered cohort of 66 infants with HLHS born between 2003 and 2010 in Finland was retrospectively reviewed. Twenty-five infants had prenatal diagnoses. Postnatal global and segmental right ventricular fractional area change, strain rate, and myocardial velocity were analyzed from the apical four-chamber view using Velocity Vector Imaging. Preoperative hemodynamic status and end-organ damagemeasurements were the lowest arterial pH, highest lactate, alanine aminotransferase, and creatinine. Early mortality was studied until 30 days after Norwood procedure.Results: Prenatally diagnosed infants had better cardiac function (fractional area change, 27.9 &plusmn; 7.4% vs 21.1 &plusmn; 6.3%, P = .0004; strain rate, 1.1 &plusmn; 0.6/1.3 &plusmn; 1.0 vs 0.7 &plusmn; 0.2/0.7 &plusmn; 0.3 1/sec, P = .004/.003; myocardial velocity, 1.6 &plusmn; 0.6/2.0 &plusmn; 1.1 vs 1.3 &plusmn; 0.4/1.4 &plusmn; 0.4 cm/sec, P = .0035/.0009). Mechanical dyssynchrony was similar in both groups (P &gt; .30). Infants diagnosed prenatally had less acidosis (pH = 7.30 vs 7.25, P = .005) and end-organ dysfunction (alanine aminotransferase, 33 &plusmn; 38 vs 139 &plusmn; 174 U/L, P = .0001;creatinine, 78 &plusmn; 18 vs 81 &plusmn; 44 mmol/L, P = .05). No deaths occurred among the prenatally diagnosed infants, but four deaths were recorded among postnatally diagnosed infants (P = .15).Conclusions: A prenatal diagnosis of HLHS is associated with improved postnatal right ventricular function, reduced metabolic acidosis, and end-organ dysfunction. (J Am Soc Echocardiogr 2013;26:1073-9.)Keywords: Hypoplastic left heart syndrome, Prenatal diagnosis, Cardiac function, Velocity Vector Imaging<br /

Research campaign : macroscopic quantum resonators (MAQRO)

The objective of the proposed macroscopic quantum resonators (MAQRO) mission is to harness space for achieving long free-fall times, extreme vacuum, nano-gravity, and cryogenic temperatures to test the foundations of physics in macroscopic quantum experiments at the interface with gravity. Developing the necessary technologies, achieving the required sensitivities and providing the necessary isolation of macroscopic quantum systems from their environment will lay the path for developing novel quantum sensors. Earlier studies showed that the proposal is feasible but that several critical challenges remain, and key technologies need to be developed. Recent scientific and technological developments since the original proposal of MAQRO promise the potential for achieving additional science objectives. The proposed research campaign aims to advance the state of the art and to perform the first macroscopic quantum experiments in space. Experiments on the ground, in micro-gravity, and in space will drive the proposed research campaign during the current decade to enable the implementation of MAQRO within the subsequent decade

Echocardiographic assessment of fetal arrhythmias

See article on page 144