Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

Effect of anti-heart failure therapy on diastolic function in children with single-ventricle circulations.

BACKGROUND: Children with functionally univentricular circulations have chronic volume loading of the systemic ventricle, potentially affecting ventricular function. Medications including angiotensin-converting enzyme inhibitors and ß-blockers are used to treat ventricular dysfunction, despite limited evidence of their efficacy in this population. OBJECTIVE: To determine the effects of angiotensin-converting enzyme inhibitors on elevated filling pressures in children with single ventricle physiology. METHODS: We performed a single-centre, retrospective review of patients with single ventricle physiology who underwent multiple cardiac catheterisations between 1991 and 2013. Study population comprised of patients who commenced or had optimised dosing of angiotensin-converting enzyme inhibitors between assessments in response to high ventricular filling pressures. Patients undergoing interventions influencing loading conditions between assessments were excluded. RESULTS: A total of 17 patients were identified, with dominant morphologic right ventricle in eight patients (47.1%). Among them, 11 (64.7%) were pre-Fontan and six (35.3%) were post-Fontan completion. Median inter-assessment interval was 9.4 months (range 7.3-19.1). There was a reduction in end-diastolic pressure from 13 to 10 mmHg (p=0.002), mean pulmonary artery pressure from 16 to 13 mmHg (p=0.049), and mean atrial pressure from 12 to 9 mmHg (p=0.001). There was one cardiac transplant, and there were no patient deaths at median follow-up after 31 months. CONCLUSIONS: We observed a reduction in ventricular end-diastolic pressure, pulmonary artery pressure, and mean atrial pressure following treatment with angiotensin-converting enzyme inhibitors in patients with single ventricle physiology. Our study provides insights into the potential impact of anti-heart failure therapy in single ventricle circulations and calls for larger, controlled studies to assess for a therapeutic response.

Safety and feasibility of adjunct autologous cord blood stem cell therapy during the Norwood heart operation.

BACKGROUND: We conducted this phase I, open-label safety and feasibility trial of autologous cord blood (CB) stem cell (CBSC) therapy via a novel blood cardioplegia-based intracoronary infusion technique during the Norwood procedure in neonates with an antenatal diagnosis of hypoplastic left heart syndrome (HLHS). CBSC therapy may support early cardiac remodeling with enhancement of right ventricle (RV) function during the critical interstage period. METHODS: Clinical grade CB mononucleated cells (CBMNCs) were processed to NetCord-FACT International Standards. To maximize yield, CBSCs were not isolated from CBMNCs. CBMNCs were stored at 4 °C (no cryopreservation) for use within 3 days and delivered after each cardioplegia dose (4 × 15 mL). RESULTS: Of 16 patients with antenatal diagnosis, 13 were recruited; of these 13 patients, 3 were not treated due to placental abruption (n = 1) or conditions delaying the Norwood for >4 days (n = 2) and 10 received 644.9 ± 134 × 106 CBMNCs, representing 1.5 ± 1.1 × 106 (CD34+) CBSCs. Interstage mortality was 30% (n = 3; on days 7, 25, and 62). None of the 36 serious adverse events (53% linked to 3 deaths) were related to CBMNC therapy. Cardiac magnetic resonance imaging before stage 2 (n = 5) found an RV mass index comparable to that in an exact-matched historical cohort (n = 22), with a mean RV ejection fraction of 66.2 ± 4.5% and mean indexed stroke volume of 47.4 ± 6.2 mL/m2 versus 53.5 ± 11.6% and 37.2 ± 10.3 mL/m2, respectively. All 7 survivors completed stage 2 and are alive with normal RV function (6 with ≤mild and 1 with moderate tricuspid regurgitation). CONCLUSIONS: This trial demonstrated that autologous CBMNCs delivered in large numbers without prior cryopreservation via a novel intracoronary infusion technique at cardioplegic arrest during Norwood palliation on days 2 to 3 of life is feasible and safe.

Anterior mediastinal lymphangioma in an infant: diagnosis and surgical management.

Cystic lymphangioma is a rare lesion of the mediastinum. We present a patient with an antenatally detected mediastinal mass that appeared to regress during foetal life and was not demonstrated on early postnatal imaging. Acute severe respiratory distress at two months of age precipitated surgery with subsequent diagnosis of lymphangioma.

Myocarditis and myopericarditis cases following COVID-19 mRNA vaccines administered to 12-17-year olds in Victoria, Australia.

IMPORTANCE: COVID-19 mRNA vaccine-associated myocarditis has previously been described; however specific features in the adolescent population are currently not well understood. OBJECTIVE: To describe myocarditis adverse events following immunisation reported following any COVID-19 mRNA vaccines in the adolescent population in Victoria, Australia. DESIGN: Statewide, population-based study. SETTING: Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC) is the vaccine-safety service for Victoria, Australia. PARTICIPANTS: All SAEFVIC reports of myocarditis and myopericarditis in 12-17-year-old COVID-19 mRNA vaccinees submitted between 22 February 2021 and 22 February 2022, as well as accompanying diagnostic investigation results where available, were assessed using Brighton Collaboration criteria for diagnostic certainty. EXPOSURES: Any mRNA COVID-19 vaccine. MAIN OUTCOMES/MMEASURE: Confirmed myocarditis as per Brighton Collaboration criteria (levels 1-3). RESULTS: Clinical review demonstrated definitive (Brighton level 1) or probable (level 2) diagnoses in 75 cases. Confirmed myocarditis reporting rates were 8.3 per 100 000 doses in this age group. Cases were predominantly male (n=62, 82.7%) and post dose 2 (n=61, 81.3%). Rates peaked in the 16-17-year-old age group and were higher in males than females (17.7 vs 3.9 per 100 000, p=<0.001).The most common presenting symptoms were chest pain, dyspnoea and palpitations. A large majority of cases who had a cardiac MRI had abnormalities (n=33, 91.7%). Females were more likely to have ongoing clinical symptoms at 1-month follow-up (p=0.02). CONCLUSION: Accurate evaluation and confirmation of episodes of COVID-19 mRNA vaccine-associated myocarditis enabled understanding of clinical phenotypes in the adolescent age group. Any potential vaccination and safety surveillance policies needs to consider age and gender differences.

Augmentation of Pulmonary Arterial Growth in Single Ventricle Patients by Interim Selective Shunts.

Stenosis or diffuse hypoplasia of central pulmonary arteries (PA) is common in patients with single ventricle physiology, often requiring surgical patching. Such repairs are prone to failure, particularly with low pressure venous flow (bidirectional cavopulmonary connection or Fontan). We describe our experience of disconnection of central PA and selective systemic-PA shunt to the hypoplastic vessel. Single ventricle patients (n = 12) with diffuse left pulmonary artery (LPA) hypoplasia (LPA:right pulmonary artery diameter <0.7) underwent PA disconnection (ligation clip) and selective arterial shunt to the LPA. Patients with ≤mild atrioventricular valve regurgitation, and no more than mild systolic dysfunction on echocardiogram were considered. Following systemic-LPA shunt, patients were reassessed by cardiac catheterization prior to further surgery, with follow-up catheterization later performed and description of changes observed. Increased volume loading was well tolerated with no greater than mild atrioventricular valve regurgitation and preserved systolic function (normal or mildly reduced). Selective arterial shunting increased the caliber of the LPA from 4.1 mm (1.2-5.6) to 6.5 mm (1.7-11.9) and this increase was preserved post-Fontan (6.7 mm [1.3-8.0]) (median [range]). Ventricular end diastolic pressure increased with arterial shunting but resolved after shunt takedown and Fontan completion (median +3 and -4 mm Hg respectively). Post-Fontan hospital length of stay was not prolonged (median 11 days, range 7-14). No deaths occurred. In univentricular hearts and PA hypoplasia, selective systemic-PA shunting physiologically increases the caliber of the distal vessels. In selected patients this can be done safely with maintenance of PA growth and resolution of the elevated end diastolic pressure with Fontan completion.

Cardiac magnetic resonance imaging prior to bidirectional cavopulmonary connection in hypoplastic left heart syndrome.

BACKGROUND: Recent evidence has suggested that haemodynamic information obtained from cardiac catheterisation is not essential in pre-operative assessment of children with hypoplastic left heart syndrome (HLHS) undergoing Bidirectional Cavopulmonary Connection (BCPC). Therefore our unit changed to cardiac Magnetic Resonance Imaging (MRI) in 2006. We aimed to compare peri-operative outcomes before and after this change. METHODS: Children with HLHS who underwent BCPC between 2004 and 2008 were identified. Data were collected regarding pre-operative findings and peri-operative outcomes. RESULTS: Forty patients were identified-catheterisation (n=21), MRI (n=19). Catheterisation patients were older at the time of BCPC (114.9+/-22.7 days vs. 95.4+/-11 days: p value 0.002), with no other differences in baseline data. Two patients required cardiopulmonary resuscitation during catheterisation; with no adverse events during MRI. Cardiopulmonary bypass time, ventilation time, inotrope score, and intensive care unit stay were similar. Length of hospital stay and oxygen saturations at discharge were also not significantly different. CONCLUSIONS: We have demonstrated that post-operative course and outcomes are similar in patients with HLHS who had MRI or catheterisation as their pre-BCPC investigation. Additionally the complementary data provided by echocardiography and MRI safely provides sufficient anatomic and functional information with which to plan the BCPC.

Abnormal left ventricular diastolic function at late follow-up after repair of total anomalous pulmonary venous drainage: the impact of altered ventricular loading in utero.

BACKGROUND: Assessment of diastolic function has not been described after repair of total anomalous pulmonary venous drainage (TAPVD), but studies of exercise capacity demonstrate impaired performance in this population despite normal systolic function. We postulated that diastolic impairment might contribute to this finding. METHODS: We analyzed echocardiographic variables from 28 patients with repaired TAPVD and compared these with data from 32 healthy controls (normals) and 21 subjects with repaired transposition of the great arteries (TGA). RESULTS: Left ventricular (LV) end-diastolic volumes were smaller in the TAPVD group (median, 50 mL/m(2) compared with a median of 64 mL/m(2) in TGA and 67 mL/m(2) in normals; P < .001 in each case). LV diastolic function in the TAPVD group was impaired. Mitral early to late ratio was increased (median, 2.7 in TAPVD compared with a median of 1.9 in TGA [P = .047] and 2.1 in normals [P = .021]). LV isovolumic relaxation time was reduced (median, 50 milliseconds in TAPVD compared with a median of 70 milliseconds in both TGA and normals; P < .001 in each case). Late diastolic and systolic tissue Doppler velocities were lower and the E/e' ratio was higher in the TAPVD group. CONCLUSIONS: Patients with repaired TAPVD are usually regarded as having excellent outcomes, but the finding of LV diastolic dysfunction in this population warrants more careful follow-up. We postulate that the diastolic impairment in these patients is the result of relative unloading of the LV during early cardiac development. These findings may also have implications in considering therapeutic approaches for hypoplastic ventricles in attempting to achieve biventricular repair.

Remote ischemic preconditioning in cyanosed neonates undergoing cardiopulmonary bypass: a randomized controlled trial.

OBJECTIVE: The myocardial protective effect of remote ischemic preconditioning has been demonstrated in heterogeneous groups of patients undergoing cardiac surgery. No studies have examined this technique in neonates. The present study was performed to examine the remote ischemic preconditioning efficacy in this high-risk patient group. METHODS: A preliminary, randomized, controlled trial was conducted to investigate whether remote ischemic preconditioning in cyanosed neonates undergoing cardiac surgery confers protection against cardiopulmonary bypass. Two groups of neonates undergoing cardiac surgery were recruited for the present study: patients with transposition of the great arteries undergoing the arterial switch procedure and patients with hypoplastic left heart syndrome undergoing the Norwood procedure. The subjects were randomized to the remote ischemic preconditioning or sham control groups. Remote ischemic preconditioning was induced by four 5-minute cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Troponin I and the biomarkers for renal and cerebral injury were measured pre- and postoperatively. RESULTS: A total of 39 neonates were recruited-20 with transposition of the great arteries and 19 with hypoplastic left heart syndrome. Of the 39 neonates, 20 were randomized to remote ischemic preconditioning and 19 to the sham control group. The baseline demographics appeared similar between the randomized groups. The cardiopulmonary bypass and crossclamp times were not significantly different between the 2 groups. The troponin I levels were not significantly different at 6 hours after cardiopulmonary bypass nor were the postoperative inotrope requirements. Markers of renal (neutrophil gelatinase-associated lipocalin) and cerebral injury (S100b, neuron-specific enolase) were not significantly different between the 2 groups. CONCLUSIONS: Our data suggest that remote ischemic preconditioning in hypoxic neonates undergoing cardiopulmonary bypass surgery does not provide myocardial, renal, or neuronal protection. Additional studies are needed to examine the relationships among developmental age, hypoxia, and the molecular mechanisms of ischemic preconditioning.

Cardiac re-synchronization therapy in a child with severe anthracycline-induced congestive heart failure and normal QRS duration.

We report the case of a 9-year-old girl who developed acute anthracycline-induced cardiotoxicity with severe, refractory congestive heart failure. Rescue treatment with cardiac re-synchronization therapy was initiated, resulting in rapid improvement in left ventricular function and clinical status.