Initial Angiotensin Receptor Blocker Response in Young Marfan Patients Decreases After 3 Years of Treatment.

Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.

Aortic elasticity deterioration proves intrinsic abnormality of the ascending aorta in pediatric Turner syndrome unrelated to the aortic valve morphology.

Turner syndrome (TS) is a common genetic disorder in females with high incidence of ascending aortic dilatation and even dissection occurring as early as in the second decade. Known risk factors (RF) are bicuspid aortic valves (BAV), coarctation of the aorta (CoA), and arterial hypertension. Since 10% of dissections occur in patients without RF, an intrinsic aortic wall abnormality has been postulated. This study aimed to investigate the elasticity of the ascending aorta as a surrogate marker of aortic wall texture. Forty-six pediatric patients with genetically proven TS were prospectively examined for the morphology of their aortic valve, and size and elasticity indices of the adjacent aorta. Cohorts of 46 female subjects with tricuspid aortic valves (TAV) and ten non-syndromic females with BAV were investigated as separate control groups. Comparison of healthy controls with TS patients revealed significantly deteriorated elasticity indices in those with TS. Furthermore, normalized aortic dimensions were greater in TS patients, but dilatations of the ascending aorta with z-score levels above two were restricted to those with BAV (14/46). Deteriorated elasticity indices were measured in TS patients, independent of aortic dilatation, BAV, and CoA, and were comparable to those of patients with isolated, non-syndromic BAVs. By measuring elasticity levels as a surrogate for aortic wall texture, we were able to gather evidence that TS presents with an intrinsic abnormality of the ascending aorta even in patients without concomitant BAV, CoA or dilatations as early as in childhood.

Reference values of aortic flow velocity integral in 1193 healthy infants, children, and adolescents to quickly estimate cardiac stroke volume.

The aortic velocity time integral (VTI) is an echocardiographic tool used to estimate cardiac output (CO) by multiplying it with the aortic valve (AV) area and heart rate (HR). Inaccurate measurement of AV diameter will lead to squared miscalculation of CO. The aortic VTI itself can serve as a left-ventricular (LV) output parameter. The normal range of aortic VTI in adulthood is relatively stable, compared with childhood, but reference data are lacking. The aim of this study was to establish reference values of VTI in infants, children, and adolescents. A retrospective analysis of 1223 echocardiographic examinations of healthy children (age 0-20 years, body surface area [BSA] 0.11-2.23 m(2)) was performed. Data were correlated with age, BSA, and HR, and age subgroups with normal distribution were determined. Interobserver and intraobserver variability was calculated. Aortic VTI ranged from mean 13.8 cm (10.0-18.4 cm 5-95th percentile) in neonates to 25.1 cm (19.6-32.8 cm 5-95th percentile) in children >17 years of age and had a positive correlation with age (r = 0.685, p < 0.001), BSA (r = 0.645, p < 0.001) and a negative correlation with HR (r = -0.710, p < 0.001). Interobserver and intraobserver variability were excellent (3.9 ± 3.1 and 4.6 ± 3.7 %, respectively). Calculated mean values and percentile charts for the different age groups can serve as reference data to easily judge LV output in patients with or without congenital heart disease without enlargement or dysfunction of the AV.

Evaluation of bone mineral density and bone turnover in children on anticoagulation.

Background: Childhood and adolescence are critical periods of bone mineral acquisition. Children on anticoagulation (AC) might have an increased risk for reduced bone mineral density (BMD). Risk factors for impaired bone accumulation include chronic diseases, immobility, and medication. Vitamin K (VK) deficiency reflected by undercarboxylated osteocalcin levels (ucOC) has been identified as a predictor of osteoporosis and fractures. Data on bone health in children under AC are sparse. Aims: To evaluate BMD in children on AC and characterize the risk factors of low BMD, including VK and Vitamin D (VD) status. Methods: Single-center cross-sectional study of clinical, biochemical, and densitometric parameters. Assessment of VK surrogate parameters included ucOC and matrix gla protein (MGP). Results: A total of 39 children (4-18 years; 12 females) receiving AC were included, 31 (79%) on VK antagonists and 8 (21%) on direct oral anticoagulants. Overall, BMD was decreased for both the lumbar spine (LS; -0.7SDS) and total body less head (TBLH; -1.32SDS) compared with pediatric reference data. Significant associations were found between early pubertal development and TBLH-BMD, and between BMI and LS-BMD. VK surrogate parameters were highly related to patients' age and pubertal development. Neither serum parameters nor AC-related factors predicted BMD. VD was detected in 10/39 patients with lower values during puberty. Conclusion: Our data indicate BMD reduction in pediatric patients on AC. Although AC-related factors did not predict reduced BMD, low BMI and pubertal stages represented important risk factors. Awareness of risk factors for low BMD and high prevalence of VD deficiency during puberty could contribute to the improvement of bone health in this vulnerable patient group.

Autosomal recessive cutis laxa type Ib-Successful redo aortic root and arch replacement.

We present an adolescent girl with a highly stenotic ascending aortic conduit of her former during infancy corrected giant aneurysm. Genetic testing determined autosomal recessive cutis laxa type-Ib as the underlying connective tissue disorder. Re-do valve sparing root and arch replacement gained excellent restoration of the aorta; 1-year-follow-up was uneventful.

Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K+ Channel) Channel Function.

BACKGROUND: Inherited forms of sinus node dysfunction (SND) clinically include bradycardia, sinus arrest, and chronotropic incompetence and may serve as disease models to understand sinus node physiology and impulse generation. Recently, a gain-of-function mutation in the G-protein gene GNB2 led to enhanced activation of the GIRK (G-protein activated inwardly rectifying K+ channel). Thus, human cardiac GIRK channels are important for heart rate regulation and subsequently, genes encoding their subunits Kir3.1 and Kir3.4 ( KCNJ3 and KCNJ5) are potential candidates for inherited SND in human. METHODS: We performed a combined approach of targeted sequencing of KCNJ3 and KCNJ5 in 52 patients with idiopathic SND and subsequent whole exome sequencing of additional family members in a genetically affected patient. A putative novel disease-associated gene variant was functionally analyzed by voltage-clamp experiments using various heterologous cell expression systems (Xenopus oocytes, CHO cells, and rat atrial cardiomyocytes). RESULTS: In a 3-generation family with SND we identified a novel variant in KCNJ5 which leads to an amino acid substitution (p.Trp101Cys) in the first transmembrane domain of the Kir3.4 subunit of the cardiac GIRK channel. The identified variant cosegregated with the disease in the family and was absent in the Exome Variant Server and Exome Aggregation Consortium databases. Expression of mutant Kir3.4 (±native Kir3.1) in different heterologous cell expression systems resulted in increased GIRK currents ( IK,ACh) and a reduced inward rectification which was not compensated by intracellular spermidine. Moreover, in silico modeling of heterotetrameric mutant GIRK channels indicates a structurally altered binding site for spermine. CONCLUSIONS: For the first time, an inherited gain-of-function mutation in the human GIRK3.4 causes familial human SND. The increased activity of GIRK channels is likely to lead to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate. Modulation of human GIRK channels may pave a way for further treatment of cardiac pacemaking.

Effect of angiotensin AT2 receptor stimulation on vascular cyclic GMP production in normotensive Wistar Kyoto rats.

In the present study in normotensive Wistar Kyoto rats (WKY), we investigated whether any angiotensin II (ANG II) increases in vascular cyclic GMP production were via stimulation of AT(2) receptors. Adult WKY were infused for 4h with ANG II (30 ng/kg per min, i.v.) or vehicle (0.9% NaCl, i.v.) after pretreatment with (1) vehicle, (2) losartan (100 mg/kg p.o.), (3) PD 123319 (30 mg/kg i.v.), (4) losartan+PD 123319, (5) icatibant (500 microg/kg i.v.), (6) L-NAME (1 mg/kg i.v.), (7) minoxidil (3 mg/kg i.v.). Mean arterial blood pressure (MAP) was continuously monitored, and plasma ANG II and aortic cyclic GMP were measured at the end of the study. ANG II infusion over 4h raised MAP by a mean of 13 mmHg. This effect was completely prevented by AT(1) receptor blockade. PD 123319 slightly attenuated the pressor effect induced by ANG II alone (123.4+/-0.8 versus 130.6+/-0.6) but did not alter MAP in rats treated simultaneously with ANG II + losartan (113+/-0.6 versus 114.3+/-0.8). Plasma levels of ANG II were increased 2.2-3.7-fold by ANG II infusion alone or ANG II in combination with the various drugs. The increase in plasma ANG II levels was most pronounced after ANG II+losartan treatment but absent in rats treated with losartan alone. Aortic cyclic GMP levels were not significantly changed by either treatment. Our results demonstrate that the AT(2) receptor did not contribute to the cyclic GMP production in the vascular wall of normotensive WKY.

Doppler-derived parameters of diastolic left ventricular function in preterm infants with a birth weight <1500 g: reference values and differences to term infants.

Transmitral flow parameters in preterm and term infants were compared in order to study differences in signal expression and temporal dynamics of left ventricular diastolic function. In 63 preterm infants between 26 and 33 weeks of gestation and 102 term infants, a Doppler survey was performed during 6 months after birth. Early and atrial filling-time velocity integrals and peak velocities were significantly lower in the preterm neonates. Atrial filling parameters reached the level observed in term infants by 2 months of age. Peak early filling velocity was still lower for 2-month-old preterms and attained the term infants' level by 3 months of age. Preterm infants continued having high atrial filling fraction (AFF) (0.51+/-0.07) during 2 months after birth, while in term infants the fraction decreased continuously from 0.41+/-0.06 to 0.37+/-0.05. Isovolumic relaxation time (IVRT) was the only parameter without differences between preterm and term infants, and it decreased from 54+/-7 ms in neonates to 41+/-4 ms over 3 months. Stroke volume passing the mitral valve doubled in preterm (4+/-1 to 7.9+/-1.5 ml/cm2), but increased by only 37% (6.9+/-1.6 to 9.5+/-2.2 ml/cm2) in term infants. Our observations show that the maturational period of diastolic function appears prolonged in preterm infants. As preterm infants have to cope with a higher physiologic preload augmentation during growth, part of the delay in parameter changes might be caused by preload stress rather than by persistence of functional impairment. Although doing well under physiological conditions, preterm neonates may be at higher risk for diastolic dysfunction than term infants when an additional preload challenge is encountered.

A single-center experience with the ross procedure over 20 years.

BACKGROUND: The Ross procedure offers several potential advantages in a young patient population. The widespread use of the procedure is still limited due to the technical challenge. Pulmonary homograft stenosis and autograft dilatation remain a matter of concern. We present the long-term outcome in a single center with special emphasis on mortality and need for valvular reintervention. METHODS: All patients who received a Ross procedure as freestanding root replacement (modified Yacoub technique) at our institution between 1991 and 2011 were followed. Descriptive statistical methods and Kaplan-Meier analyses were performed. RESULTS: A total of 246 patients (191 males, 55 females) underwent the Ross procedure during the study period. There were 176 adults and 70 pediatric patients with an average age of 36 ± 10 and 10 ± 5 years, respectively. The median follow-up was 10 years. Twelve (4.9%) subjects were lost to follow-up. Early mortality was 1.6%. Overall mortality was comparable with an age and sex matched population for adult patients. The linearized risk for reoperation per patient-year was 0.6% for the autograft and 0.6% for the right ventricular outflow tract, with a mean time to surgery of 6.4 ± 4.9 years. Overall freedom from reintervention was 95% at 5 years, 88% at 10 years, and 81% at 15 years. CONCLUSIONS: The Ross procedure provides good early results and an excellent long-term survival. It represents an excellent method of aortic valve replacement in children and young adults. Root reinforcement techniques and aortic reduction plasty may be beneficial, especially in adult patients with native aortic valve regurgitation.

Similarities and differences of the aortic root after arterial switch and ross operation in children.

Pulmonary root dilation and valve regurgitation if translocated into the aortic position is frequently seen in children with transposition of the great arteries (TGA) after an arterial switch operation, as well as in patients after the Ross procedure. Many mechanisms are thought to be responsible for the progressive dilation. Despite the differences between the 2 groups, the similarity of having the pulmonary valve and its adjacent tissue working in the systemic circulation might have a comparable effect on the neoaortic root dimensions and elasticity. We prospectively recruited 52 patients with TGA, 23 Ross patients, and 48 healthy subjects for echocardiographic assessment of their aortic valve, root, sinutubular junction, and ascending aortic dimensions and elasticity. The data were compared, stratified by patient age at investigation and the duration of follow-up postoperatively. In relation to the healthy subjects, the neoaortic root dimensions were significantly larger and the tissue stiffer and less distensible in those with TGA and those who had undergone the Ross procedure. Although the pulmonary valve of the Ross patients had been under systemic pressure load for a significantly shorter period (4.4 ± 3.6 vs 10.1 ± 5.5 years), the dimensions and elasticity values had deteriorated more. These differences could neither be clearly attributed to the age differences at surgery or to an auxiliary congenital ventricular septal defect in those with TGA or the aortic valve phenotype before the Ross operation. In conclusion, the worse outcome of the neoaortic root dimensions and elasticity in the Ross patients should at least be partly related to the different predefined pulmonary artery structures and the different development of the normal and transposed pulmonary arteries.

Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome.

Since 2008, when angiotensin II type I receptor blockade with losartan was introduced in the prevention of cardiovascular manifestation of Marfan syndrome (MFS), a specific treatment to address the cardiovascular lesions became available. The present study aimed to compare the response of such in an unselected cohort of patients with genotyped MFS. At a tertiary university children's hospital, 20 pediatric and adolescent patients aged 1.7 to 21.6 years with genetically proven MFS were enrolled in a prospective treatment study of losartan for evaluation of the aortic dimensions and elasticity indexes. The mean follow-up period was 33 ± 11 months. A significant reduction in the normalized aortic dimensions with losartan was observed in the valve, root, sinotubular junction, and ascending aortic segments (p = 0.008, p <0.001, p = 0.012, and p = 0.001, respectively). No correlation between elasticity behavior and the decrease in the aortic dimension with losartan therapy was detectable. A significant correlation between stronger improvement and younger age at onset (r = 0.643, p = 0.002) and a longer therapy duration (r = -0.532, p = 0.016) was verifiable. However, no correlation between improvement with therapy and the type of mutation or presentation of clinical forms was remarkable. Elasticity also seemed to improve but not significantly. In conclusion, in our cohort of young patients with MFS, a significant improvement with losartan monotherapy was proved in all affected proximal aortic segments, with a better response to therapy when started at an earlier age and with a longer therapy duration.

Morphology of the bicuspid aortic valve and elasticity of the adjacent aorta in children.

Bicuspid aortic valve (BAV) is a common congenital malformation with the known sequela of ascending aortic dilation. The morphology of the BAV and the elasticity of the adjacent ascending aorta appear to influence the outcome. We prospectively examined 48 pediatric patients with an isolated, native BAV for the morphology and size of the aortic valve, aortic root, sinotubular junction, and ascending aorta and their elasticity indexes. A cohort of 48 matching subjects with tricuspid aortic valves was investigated as controls. A comparison of the aortic valve subtypes showed normal-size aortic dimensions in the tricuspid aortic valves. In contrast, in the BAVs, the ascending aorta and aortic valve itself tended to dilate with age and aortic elasticity deteriorated. In the BAVs, the stiffness was significantly greater (4.43 ± 1.82 vs 3.43 ± 0.81 in the tricuspid aortic valves; p = 0.001). The distensibility indexes decreased inversely in the BAVs (6.57 ± 2.83 vs 7.84 ± 2.04 cm(2) × dynes(-1) × 10(-6), p = 0.013; and 53.5 ± 26.0 versus 64.3 ± 17.9 kPa(-1) × 10(-3), p = 0.020). The anteroposterior-oriented phenotype of BAVs showed significantly stiffer and less distensible elasticity even after correction for congenital valve dysfunction, which was more frequent in the left-right-oriented phenotype. In conclusion, the morphology of the BAV seems to play a major role in the outcome of BAV disease, although the left-right phenotype is more prone to congenital valve dysfunction, the anteroposterior phenotype showed worse elasticity quality.

Noninvasive measurement of atrial contribution to the cardiac output in children and adolescents with congenital complete atrioventricular block treated with dual-chamber pacemakers.

The contribution of atrial contraction to cardiac output (CO) has been the subject of extensive research but has yet to be quantified adequately in children and adolescents. Patients with third-degree atrioventricular (AV) block treated with pacemakers (PMs) are ideal candidates to assess the atrial contribution to CO by repeated measurements in single-chamber pacing mode (VVIR) and dual-chamber pacing mode (DDD/VDD). Hemodynamic measurements in children are often complicated by technical restrictions, but more recently a noninvasive method involving inert gas rebreathing has become available, which is an excellent tool for this age group. We examined 10 patients (6 female patients, mean age 14.5 ± 2.5 years, range 11 to 18) with congenital complete AV block treated with dual-chamber PM. Using an inert gas rebreathing device (Innocor) we measured CO in DDD/VDD with optimized AV delays. Devices were subsequently set to VVIR with matched heart rates and after 20 minutes the CO measurement was repeated. Mean CO of 6.4 ± 1.8 L/min was significantly higher in DDD/VDD than in VVIR, where it averaged 5.2 ± 1.4 L/min (p <0.001). Fractional increase of CO gained through sequential ventricular contraction was 18% (p <0.001). In VVIR, 8 patients reported PM-related symptoms. In conclusion, our data strongly suggest that pediatric patients with congenital complete AV block may benefit from AV synchrony with respect to hemodynamics and tolerability. Therefore, preferred use of DDD/VDD with optimized AV conduction delays should be considered.

Echocardiography predicts closure of patent ductus arteriosus in response to ibuprofen in infants less than 28 week gestational age.

BACKGROUND: Patent ductus arteriosus (PDA) is a frequent problem in preterm infants, and its incidence is inversely correlated with gestational age. The efficacy of medical treatment decreases with decreasing gestational age (GA), and failure rates as well as ductus ligation rates of 40% have been reported in <28 week GA newborns. The aim of this study was to determine whether echocardiographic parameters can predict response to ibuprofen treatment of PDA. STUDY DESIGN: In a longitudinal study, 29 infants born <28 week GA were screened for a significant PDA (left atrial to aortic root ratio>1.4, anterior cerebral artery resistance index>0.8, and oxygen requirement>35%) at 24-72 h of life and, if a PDA was found, treated with 10-5-5mg/kg ibuprofen intravenously every 24h. Ductal parameters were monitored by serial echocardiography. Infant neurodevelopmental outcomes were assessed at 24 month corrected age. RESULTS: All 15 infants with significant PDA responded to the ibuprofen loading dose indicated by reduced PDA diameters or increased PDA maximum flow velocities (PDA V(max)), and 7 patients showed an ongoing response resulting in a closed PDA after the 1st cycle (47%). Of the 8 non-responders, 7 received a 2nd cycle with 2 further responders (29%). All non-responders to the 2nd course had a PDA V(max)

Cardiac troponin I is increased after interventional closure of atrial septal defects.

This study was designed to assess possible myocardial injury caused by interventional closure of atrial septal defects (ASDs) compared to diagnostic catheterization by measuring cardiac troponin I (cTn-I). Forty patients were enrolled; in 33 ASDs were successfully closed, while in 7 a diagnostic balloon sizing of the defect was performed only. Total cTn-I increased significantly from 0.1 to 1.9 microg/l at the end of the intervention and 2.23 at 4 hr and decreased to 1.35 at 15 hr. No significant increase could be detected in patients with diagnostic balloon sizing only or of CK/CK-MB levels either. Following interventional closure of ASDs with Amplatzer septum/PFO occluders, increased cTn-I levels for several hours indicate some transient, reversible myocardial membrane instability due to the device. Discrimination of ventricular myocardial infarction might be possible by estimating less sensitive CK and CK-MB levels only.