Maternal high-fat diet alters angiotensin II receptors and causes changes in fetal and neonatal rats†.

Maternal high-fat diet (HFD) during pregnancy is linked to cardiovascular diseases in postnatal life. The current study tested the hypothesis that maternal HFD causes myocardial changes through angiotensin II receptor (AGTR) expression modulation in fetal and neonatal rat hearts. The control group of pregnant rats was fed a normal diet and the treatment group of pregnant rats was on a HFD (60% kcal fat). Hearts were isolated from embryonic day 21 fetuses (E21) and postnatal day 7 pups (PD7). Maternal HFD decreased the body weight of the offspring in both E21 and PD7. The ratio of heart weight to body weight was increased in E21, but not PD7, when compared to the control group. Transmission electron microscopy revealed disorganized myofibrils and effacement of mitochondria cristae in the treatment group. Maternal HFD decreased S-phase and increased G1-phase of the cellular cycle for fetal and neonatal cardiac cells. Molecular markers of cardiac hypertrophy, such as Nppa and Myh7, were found to be increased in the treatment group. There was an associated increase in Agtr2 mRNA and protein, whereas Agtr1a mRNA and AGTR1 protein were decreased in HFD fetal and neonatal hearts. Furthermore, maternal HFD decreased glucocorticoid receptors (GRs) binding to glucocorticoid response elements at the Agtr1a and Agtr2 promoter, which correlated with downregulation of GR in fetal and neonatal hearts. These findings suggest that maternal HFD may promote premature termination of fetal and neonatal cardiomyocyte proliferation and compensatory hypertrophy through intrauterine modulation of AGTR1 and AGTR2 expression via GR dependent mechanism.

Controversial ultrasound findings in mid trimester pregnancy. Evidence based approach.

Mid trimester fetal anatomy scan is a fundamental part of routine antenatal care. Some U/S soft markers or controversial U/S signs are seen during the scan and create some confusion regarding their relation to fetal chromosomal abnormalities. Example of these signs: echogenic focus in the heart, echogenic bowel, renal pyelectasis, ventriculomegaly, polydactely, club foot, choroid plexus cyst, single umbilical artery. We are presenting an evidence based approach from the literature for management of these controversial U/S signs.

Congenital heart disease in monochorionic twins with and without twin-to-twin transfusion syndrome.

OBJECTIVE: This study aims to evaluate the prevalence of congenital heart disease (CHD) in monochorionic (MC) twin pregnancies with and without twin-to-twin transfusion syndrome (TTTS) in an unselected cohort, which underwent prenatal and postnatal echocardiography. METHOD: This was a retrospective cohort study including 451 MC twin pregnancies between 2002 and 2012. Complete outcome data were available for 381 pregnancies. All patients had prenatal echocardiography, and postnatal echocardiography was performed in all newborns with symptoms or to follow-up on prenatal findings. Data from prenatal and postnatal echocardiography and autopsy were analyzed. The classification of Houyel et al. was used for structural CHD. RESULTS: Structural CHD was diagnosed in 5.5% of all MC twins (42/762). Twins with TTTS showed a significant higher rate of CHD than unaffected twins (9.3% vs 4.7%; p = 0.03). Prenatal detection rate of CHD was 48%. Most common abnormalities were ventricular septal defects (VSD) (2.1%) followed by anomalies of the ventricular outflow tracts (1.3%) in the overall population and VSD (2.9%) and anomalies of the great arteries (2.9%) in the group with TTTS. CONCLUSION: MC twin pregnancies show a high prevalence of structural CHD (5.5%), especially those affected by TTTS. A detailed prenatal and postnatal echocardiography could be considered in these pregnancies.

42 years old male with single atrium.

Single atrium (SA) is a rare congenital anomaly characterized by absence or virtual absence of atrial septum, vestigial remnant of which occasionally remain. We report here such a case of SA who presents his symptoms in different way of its natural course of presentation.

[Ebstein's malformation in the fetus with cardiomegaly. To treat or to observe?--a case report]. / Zespól Ebsteina z kardiomegalia plodu. Leczyc czy obserwowac?--opis przypadku.

Ebstein's malformation is a rare congenital cardiac defect characterized by an abnormal formation and/or displacement of the leaflets of the tricuspid valve. Prognosis for a neonate is poor in case of cardiomegaly due to coexistence of lung hypoplasia. This paper presents a case of a fetus with Ebstein's malformation with massive cardiomegaly (HA/CA = 0.62) in a 27-year-old patient in her first pregnancy. The cardiac defect was diagnosed in the 22nd week of pregnancy. Due to the fact that the patient decided to continue her pregnancy, and taking into consideration single reports of transplacental Digoxin therapy an attempt to apply Digoxin therapy was made. The mother and the fetus were monitored in two centers, in Rzeszów and in Lódz. In the course of a 12-week transplacental therapy, 8 fetal echocardiography examinations were performed and the following parameters improved: HA/CA (0.62-0.5), CVPS (5/10-7/10) SF RA (0%-11%), SF RV (18%-28%). There was also a conversion of the oxygen test from negative to positive, which seems to document that prevention of the lung hypoplasia was achieved. The neonate died on the 8th day of postnatal life before a cardiac surgery attempt.

Bilateral radial hemimelia, polydactyly and cardiomegaly in two cats.

CASE DESCRIPTION: Two feline littermates were presented to the Auburn University Small Animal Clinic at the age of approximately 10 weeks. Both cats had varus thoracic limb deformities bilaterally and pelvic limb polydactyly. CLINICAL FINDINGS: Radiographs revealed bilateral radial hypoplasia (hemimelia), generalised cardiomegaly, and pelvic limb polydactyly. TREATMENT AND OUTCOME: No treatment was instituted. Cardiopulmonary changes will be monitored periodically. CLINICAL RELEVANCE: The heritability of radial hemimelia has been suggested, but has yet to be proven. In utero environmental causes (teratogens) are another possible cause of congenital radial hemimelia. The presence of bilateral pelvic limb polydactyly, bilateral radial hemimelia, and generalised cardiomegaly in feline littermates may offer more information on the origins of this orthopaedic disorder and the potential undesirable results that can occur when breeding polydactyl cats or cats affected by radial hemimelia.

Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin.

Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopX(Tg)), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX(Tg), HopX(Tg) mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopX(Tg) mice (48 episodes in 13 of 15 HopX(Tg) mice versus 5 episodes in 2 of 15 TSA-HopX mice, P<0.001; versus 9 episodes in 2 of 15 WT mice, P<0.001; versus no episodes in any TSA-WT mice, P<0.001). TSA reduced atrial arrhythmia duration in HopX(Tg) mice (1307+/-289 ms versus 148+/-110 ms, P<0.01) and atrial fibrosis (8.1+/-1.5% versus 3.9+/-0.4%, P<0.001). Atrial connexin40 was lower in HopX(Tg) compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopX(Tg) mice (76.3+/-26.0 versus 69.7+/-16.6 pg/mg protein, P=NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy.

Autopsy case of the neonatal form of carnitine palmitoyltransferase-II deficiency triggered by a novel disease-causing mutation del1737C.

Carnitine palmitoyltransferase-II (CPT-II) deficiency is an autosomal recessive disease involving mitochondrial long-chain fatty acid oxidation that results in a distinct clinical phenotype. Reported herein is an autopsy case of the neonatal form of CPT-II deficiency in a 2-day-old Japanese boy who died due to a severe hepatocardiomuscular disease with an extremely early onset. Autopsy examination indicated massive pulmonary atelectasis with intra-alveolar hemorrhage, and the patient had marked cardiomegaly and hepatomegaly, both of which demonstrated the presence of abundant intracytoplasmic steatosis. Three years after the autopsy examination, CPT-II deficiency was suggested by acylcarnitine analysis of dried-blood on filter paper from the patient's younger sister at the age of 1. The younger sister also died due to sudden onset of cardiopulmonary arrest; a remarkable increase of long-chain (C16-18) acylcarnitines was detected on tandem mass spectrometry (TMS). Decreased CPT-II expression was detected in the liver, heart and kidney of the patient. Furthermore, del1737C, a novel mutation of the CPT-II gene, was detected as well as a known GA transition at codon 174. Eventually, laboratory and autopsy findings led to diagnosis of the neonatal form of CPT-II deficiency. TMS can be expected to be widely used to detect metabolic disorders in neonates.

[Effective transplacental therapy in fetal cardiomegaly to prevent lung hypoplasia--case report]. / Próba zahamowania progresji kardiomegalii i grozacej hipoplazji pluc udokumentowana w badaniach echokardiograficznych--opis przypadku.

In our referral center, 14,481 fetal echocardiography examinations were performed in 10,077 fetuses, in years 1994-2006. Fifty four fetuses presented cardiomegaly HA/CA > 0.6. There was one single survivor whose medical history is presented. Fetal cardiomegaly was detected by obstetrical ultrasound screening. In tertiary center HA/CA was evaluated as the following: 0.5 at 32 wks and 0.65 at 36 wks. In addition to cardiomegaly, pulmonary stenosis/atresia, dysplastic tricuspid valve with massive regurgitation were diagnosed. Digoxin was administered transplacentally for 33 days and, additionally, 30 min. oxygen was provided by mask for pregnant woman, 3 times per day. Spontaneous labour took place at 38 wks, with 3100 birth weight and 9 Apgar score. The newborn baby had only temporary tachypnoe, had a planned postdelivery therapy including prostin and cardiacsurgery and was discharged home at the age of 4 weeks in a good clinical condition. This is the first case in our institution of such massive cardiomegaly who did survived the neonatal period. The possible beneficial effects of transplacental digoxin and oxygen therapy are discussed, as well as fetal echocardiography monitoring using HA/CA and pulmonary venous Doppler flow.

Copy Number Variations with Isolated Fetal Ventriculomegaly.

BACKGROUND: Copy Number Variations (CNVs) are an important genetic cause of a number of neurodevelopmental disorders (NDs). However, the association between CNVs and the development and prognosis of fetal isolated mild ventriculomegaly (IMV) is unclear. OBJECTIVES: To investigate possible associations between CNVs and the development of fetal IMV. METHODS: This retrospective study recruited 154 subjects with ultrasound-confirmed fetal IMV and 190 subjects in a control cohort who underwent a high-risk prenatal serum screening program. The exclusion criteria included fetus G-banding chromosomal abnormality or positive fetus TORCH infection. DNA samples from all 344 fetuses were examined by an SNP-array. Developmental outcomes were assessed during postnatal follow-up. RESULTS: Fourteen pathogenic CNVs (pCNVs) were identified in 13 out of 154 IMV fetuses. Three pCNVs were found in 3 out of 190 subjects in the prenatal screening high-risk cohort, with a significant difference (P value=0.016, X2 test). Notably, the 14 pCNVs detected in the IMV cohort were all associated with neurodevelopmental disorders (NDs), including autism, intellectual disability. Among the 13 IMV fetuses carrying pCNVs, five subjects were found in the postnatal follow-up to manifest NDs, including two with autism and three with mild neurodevelopmental delay. The other 8 subjects consisted of three normal infants younger than 12-months old, two lost in the follow-up, and three with the termination of pregnancy. Out of 141 IMV subjects without detectable pCNVs, 123 subjects showed normal development, 16 were lost in the follow-up, 2 subjects terminated the pregnancy due to fetal hydrocephalus or congenital heart disease in the late fetus development. CONCLUSIONS: This study suggests an association between pCNVs and fetal IMV. pCNVs may be involved in the pathological process of fetal IMV and postnatal NDs. Identifying specific genomic alterations may provide an insight into pathogenetic mechanism and aid better diagnosis and prognosis of neurodevelopmental outcomes in fetal IMV.

The unique expression profile of the androgen receptor gene in a rat model of neonatal cardiac hypertrophy.

UNLABELLED: Gender can influence many cardiovascular events, including cardiac hypertrophy. The presence of and dynamic changes involving androgen receptor (AR) gene expression are important confirmatory findings for androgen modulation in the pathogenesis of cardiac hypertrophy. AIMS: To determine AR expression profile during neonatal hypertrophy and its regression process using a rat model. METHODS: Relative mRNA levels of the AR gene were quantified at postnatal days 1, 7, 14, 21 and 28 using real time PCR. RESULTS: A significant 10.6-fold decrease in AR transcription levels was observed at birth in neonates with cardiac hypertrophy (p < 0.05). Our analysis also showed a significant increase in AR mRNA levels at day 28, corresponding with regression of cardiac hypertrophy. DISCUSSION: The AR gene demonstrated a noteworthy trend in its expression pattern. The initial down-regulation was most likely the result of increased testosterone levels induced by hyperinsulinaemia and hypoglycaemia, which were present in neonates from diabetic mothers during pregnancy. The paradoxical increase in AR at day 28 suggested a potential long term-effect of the in utero diabetic environment.

Production of cardiac muscle abnormalities in offspring of rats receiving triiodothyroacetic acid (triac) and the effect of beta adrenergic blockade.

As a part of a continuing study on the effects of thyroid hormones on heart muscle, triiodothyroacetic acid (triac), either alone or concurrently with propranolol, has been administered to rats during pregnancy. Control groups received either buffer or propranolol. Offspring, which were given no further treatment, were killed at intervals after birth and their hearts examined histologically, histochemically, and electron microscopically. At 2, 6, and 14 days, offspring of triac-treated rats showed cardiac hypertrophy and, at ultrastructural level, marked disarray of the myofibrils was present. By 28 days, arrangement of the myofibrils had become regular but hypertrophy persisted and was still found in rats examined at 56 days of age, after which time the myocardium was normal. Offspring of rats which had received propranolol at the same time as triac showed a similar pattern of hypertrophy but myofibrillar disarray was not found. Propranolol alone produced no abnormalities. These findings provide further evidence that thyroid hormone analogues can adversely affect heart muscle. When considered in conjunction with previous experiments which showed that thyroxine or triac cause severe hypertrophy but not disarray when given directly to growing rats, they suggest that thyroid hormones can produce a spectrum of abnormalities, thought to depend on the stage of myocardial development at which the stimulus is administered. In the present experiment, the triac-induced myofibrillar disarray but not the hypertrophy was prevented by propranolol, indicating that beta-adrenergic blockade or some other action of propranolol protects the developing myofibrils. Possible mechanisms for the adverse effects of thyroid hormones and the protective action of propranolol are discussed.

The relationship between the oxidative stress and the cardiac hypertrophy in infants of diabetic mothers.

Recently, oxidative stress was suggested to play a role in maternal and fetal complications of diabetic pregnancies. The aim of this study is to evaluate the global oxidant and antioxidant status in infants of diabetic mothers (IDM) via measurement of total antioxidant capacity (TAC) and total oxidant status (TOS) and to determine their association with the clinical and cardiac manifestations of gestational diabetes on infants. Forty five infants constituted the IDM group, 51 infants born to non diabetic mothers served as the control group. Umbilical cord blood was drawn from IDM and controls for TAC and TOS measurement. Echocardiographic measurements were performed in the first three days of life. Infants of diabetic mother had significantly higher TAC (p=0.024), TOS (p=0.03) and oxidative stress index (OSI, p=0.04) levels compared to controls. Hemoglobin values were correlated to TOS (r=0.310, p=0.03) and OSI (r=0.310, p=0.03). Maternal HbA1c values were also correlated to TOS (r=0.576, p=0.001) and OSI (r=0.606, p<0.001). Systolic and diastolic interventicular septum measurements, and left ventricular mass were also correlated with TOS (r=0.330, p=0.02; r=0.453, p=0.002; r=0.404, p=0.006, respectively) and OSI (r=0.330, p=0.02; r=0.300, p=0.04, r=0.300; p=0.04, respectively). Oxidant-antioxidant balance is disturbed in favor of oxidants in IDM despite compensatory increase in TAC. The degree of oxidative stress is related to the severity of myocardial and hematological involvement in IDM in the first days of life and maternal glycemic control.

Congenital aneurysmal dilatation of the left auricle demonstrated by sequential cardiac blood-pool scintiscanning.

Congenital aneurysmal dilatation of the left auricle is a rare condition often associated with cardiac arrhythmias and systemic emboli. The diagnosis is made often by surgical exploration or presurgically by contrast angiography. A case is reported in which the dilated left auricle did not fill during contrast angiography but was demonstrated by sequential cardiac blood-pool scintiscanning.

Echocardiographic pulsed Doppler features of absent pulmonary valve syndrome in the neonate.

M mode echocardiography was used to evaluate nine neonates with absent pulmonary valve syndrome. Six were also studied with two dimensional echocardiography and two with pulsed Doppler echocardiography. M mode echocardiography demonstrated a large, overriding great artery and right ventricular dilation in all nine patients and abnormal septal motion in eight. Two dimensional echocardiography demonstrated aneurysmal dilation of the main pulmonary artery in all six patients studied. Pulsed Doppler echocardiography in the two infants studied demonstrated anterograde systolic and retrograde diastolic flow in the main pulmonary artery and right ventricular outflow tract. The echocardiographic features of absent pulmonary valve syndrome appear to be unique and allow the diagnosis to be made noninvasively, thus obviating or delaying the need for potentially high risk cardiac catheterization.

Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Cantú syndrome.

Cantú syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare condition, previously reported in 13 patients. We report on two additional patients with this disorder. One of the patients had pulmonary hypertension of unknown cause which was responsive to steroid therapy. She also had unusual, deep plantar creases, not reported previously in Cantú syndrome. Autosomal recessive inheritance has been suggested previously on the basis of sib recurrence in one family and consanguinity in another. We have performed a segregation analysis based on all reported families to date; the data indicate autosomal recessive inheritance is unlikely. A new dominant mutation or microdeletion syndrome are more likely possibilities, sib recurrence possibly representing gonadal mosaicism.

Congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia (Cantú syndrome): a new case with unusual radiological findings.

We report on a new case of a syndrome first described by Cantú et al. [1982: Hum Genet 60:36-41] comprising congenital hypertrichosis, "coarse" facial appearance, and mild osteochondrodysplasia. Our case has some unusual radiological findings, namely proximal and distal megaepiphyses of long bones and advanced bone age.

Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: further delineation of a new genetic syndrome.

The hypertrichosis and osteochondrodysplasia syndrome is a rare entity with clinical findings including macrosomia at birth cardiomegaly. Autosomal recessive inheritance is presumed based on the report of two affected sibs born to healthy parents. Here we report on four new patients with their follow-up data, as well as on one of the four cases from the original report. Comparison of all eight cases indicates that they share 50% of clinical and radiological changes. This report contributes to the further delineation of this newly recognized syndrome.

Congenital hypertrichosis, cardiomegaly and mild osteochondrodysplasia.

We report on a boy with congenital hypertrichosis, cardiomegaly and a mild osteochondrodysplasia, a rare syndrome of which there is only one previous report [Cantú et al., Hum Genet 60:36-41, 1982]. In all, five patients now are known to have this syndrome (2 females, 3 males). As the syndrome has been described in males and females and also in two sibs, inheritance is probably autosomal recessive.