Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus.

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.

Reversible severe pulmonary hypertension related to scurvy in children.

BACKGROUND: Severe pulmonary hypertension (PH) in childhood is rare and can manifest as a life-threatening episode. We present 2 children with restrictive dietary habits with severe pulmonary hypertension secondary to scurvy and iron deficiency anemia with treatment and outcome. CASE PRESENTATION: The first case is a 2-year-old boy who presented with vomiting, diarrhea, and fever. After rehydration, he had recurrent episodes of hypotension with intermittent abdominal pain. Fluid resuscitation and inotropic medication were given. Then he suddenly collapsed. After 4-min cardiopulmonary resuscitation, his hemodynamic was stabilized. Most of the medical workup was unremarkable except for PH from the echocardiogram with estimated systolic pulmonary artery pressure (PAP) at 67 mmHg. Transient PH was diagnosed, and milrinone was prescribed. Since he had restrictive dietary habits and sclerotic rim at epiphysis in chest films, his vitamin C level was tested and reported low-level result. The second case is a 6-year-old boy with acute dyspnea, a month of low-grade fever, mild cyanosis, and a swollen left knee. Echocardiogram indicated moderate TR with estimated systolic PAP at 56 mmHg (systolic blood pressure 90 mmHg). Milrinone was given. Right cardiac catheterization showed PAP 66/38 (mean 50) mmHg and PVRi 5.7 WU.m2. Other medical conditions causing PH were excluded. With a history of improper dietary intake and clinical suspicion of scurvy, vitamin C was tested and reported undetectable level. Administration of vitamin C in both cases rapidly reversed pulmonary hypertension. CONCLUSION: Pediatric PH related to vitamin C deficiency can manifest with a wide range of symptoms, varying from mild and nonspecific to severe life-threatening episodes characterized by pulmonary hypertensive crises. PH associated with scurvy is entirely reversible with appropriate investigation, diagnosis, and treatment. Our report highlights the importance of considering nutritional deficiencies as potential confounding factors in pediatric PH, emphasizing the need for comprehensive evaluation and management of these patients.

Melody transcatheter pulmonary valve replacement: a single-center case series in Southeast Asia.

BACKGROUND: Studies of transcatheter pulmonary valve replacement (TPVR) with the Melody valve have demonstrated good clinical and hemodynamic outcomes. Our study analyzes the midterm clinical and hemodynamic outcomes for patients who underwent Melody valve implantation in Southeast Asia. METHODS: Patients with circumferential conduits or bioprosthetic valves and experiencing post-operative right ventricular outflow tract (RVOT) dysfunction were recruited for Melody TPVR. RESULTS: Our cohort (n = 14) was evenly divided between pediatric and adult patients. The median age was 19 years (8-38 years), a male-to-female ratio of 6:1 with a median follow-up period of 48 months (16-79 months), and the smallest patient was an 8-year-old boy weighing 18 kg. All TPVR procedures were uneventful and successful with no immediate mortality or conduit rupture. The primary implant indication was combined stenosis and regurgitation. The average conduit diameter was 21 ± 2.3 mm. Concomitant pre-stenting was done in 71.4% of the patients without Melody valve stent fractures (MSFs). Implanted valve size included 22-mm (64.3%), 20-mm (14.3%), and 18-mm (21.4%). After TPVR, the mean gradient across the RVOT was significantly reduced from 41 mmHg (10-48 mmHg) to 16 mmHg (6-35 mmHg) at discharge, p < 0.01. Late follow-up infective endocarditis (IE) was diagnosed in 2 patients (14.3%). Overall freedom from IE was 86% at 79 months follow-up. Three patients (21.4%) developed progressive RVOT gradients. CONCLUSION: For patients in Southeast Asia with RVOT dysfunction, Melody TPVR outcomes are similar to those reported for patients in the US in terms of hemodynamic and clinical improvements. A pre-stenting strategy was adopted and no MSFs were observed. Post-implantation residual stenosis and progressive stenosis of the RVOT require long term monitoring and reintervention. Lastly, IE remained a concern despite vigorous prevention and peri-procedural bacterial endocarditis prophylaxis.

Ischemic stroke in Kawasaki disease.

Pediatric stroke is considered to be rare. Stroke resulting from cerebral vasculitis is also uncommon in young children. With the increasing prevalence of Kawasaki disease (KD) diagnosis, this acquired vasculitis has been reported with various clinical presentations including neurological symptoms. Herein we describe the case of a KD patient presenting with stroke. A 15-month-old boy was referred due to stroke that occurred on the fifth day of febrile illness. He was initially admitted to another hospital due to fever and diarrhea. He was discharged and re-admitted 2 days afterward due to left hemiplegia. During the 10 days of the second hospitalization, he had a presumptive diagnosis of encephalomeningitis. Upon referral to the present hospital, he was found to have right middle cerebral artery branch stenosis and fusiform aneurysms of the coronary arteries. Retrospectively, the patient had the full clinical criteria for KD diagnosis. Therefore, stroke could be considered as one of the uncommon clinical manifestations of KD.

Low cardiac output thyroid storm in a girl with Graves' disease.

A 15-year-old girl with Graves' disease presented with hypotension after methimazole and propranolol were re-started for hyperthyroidism. She was found to have pulmonary artery hypertension resulting in obstructive shock. Thyroid storm was diagnosed according to Burch and Wartofsky score. She was promptly treated with anti-thyroid drugs, inorganic iodide, corticosteroid, and respiratory support. Pulmonary hypertension was treated with inhaled nitric oxide until the clinical status improved. Propranolol was withdrawn due to poor cardiac function. We herein present a unique case of a difficult-to-treat Graves' disease presenting with severe pulmonary hypertension resulting in low cardiac output thyroid storm.

5'UTR repeat polymorphisms of the BMPR2 gene in children with pulmonary hypertension associated with congenital heart disease.

UNLABELLED: The mutations of bone morphogenetic protein receptor type 2 (BMPR2) in patients with idiopathic pulmonary hypertension has been well defined. We investigated the occurrence of BMPR2 mutation and genetic polymorphisms in children with pulmonary hypertension associated with congenital heart disease (aPH/CHD) and correlated with the pulmonary haemodynamic and vasoreactivity. METHODS: BMPR2 mutation/polymorphisms were determined in 30 aPH/CHD children. All children underwent cardiac catheterisation to obtain baseline haemodynamic data. The 5'UTR containing promoter region and all the exons [1-13] of BMPR2 gene were genotyped for possible genetic variants that may be related to the aPH/CHD. RESULTS: None of our 30 patients (median-age 90 months) with aPH/CHD (mean PAP 48±17mmHg, PVR 6.7±4.2WUm(2)) has had any BMPR2 mutation. Fifteen of them had single nucleotide polymorphism, rs1061157 and/or 5'UTR-polymorphism, specifically GGC repeat variant in seven patients; AGC repeat variant in one patient; and nine base pairs duplication (CTTCTTCGG) in one patient. The GGC repeat ≥13 was found in three out of six of children with aPH/CHD with normal PVR vs. two out of 24 children with aPH/CHD with high PVR. The odd ratio between these two subgroups of aPH/CHD is 0.09 (95% CI 0.02-0.34). CONCLUSIONS: In our cohort, there was no BMPR2 mutation in children with aPH/CHD while nine out of 30 of them have 5'UTR repeat polymorphisms. Our data suggests the occurrence of GGC repeat ≥13 at the 5'UTR region may have some protective effect towards pulmonary vasculopathy in children who have been exposed to high pulmonary blood flow due to CHD.

Reversible course of pulmonary arterial hypertension related to bone marrow transplantation.

Pulmonary arterial hypertension (PAH) is considered to be a rare but serious complication of bone marrow transplantation (BMT). The majority of the reports demonstrated a potential fatal outcome, while treatments are postulated to require an indefinite duration. Our objective is to describe cases of reversible PAH related to BMT in two patients. Two patients with PAH after BMT were investigated for the common secondary causes of PAH. Both results were negative. The first patient was a 19-year-old male. He was diagnosed with relapse acute lymphoblastic leukemia, underwent BMT, and developed PAH 10 months after transplantation. He was initially treated with iloprost and sildenafil. His functional class gradually improved while his medication was titrated down and switched to amlodipine. His pulmonary arterial pressure has been normalized. The second patient is a 20-year-old female, with a confirmed case of chronic myeloid leukemia, who underwent BMT and developed PAH 4 months after BMT. She was treated with sildenafil and beraprost. With improvement of her symptoms and normal exercise test, her medication was discontinued after 4 months of therapy while her pulmonary pressure currently remains normal. BMT was considered to be an uncommon cause of PAH, which is amenable to reversibility.

Branch Pulmonary Artery Regurgitation in Repaired Tetralogy of Fallot: Correlation with Pulmonary Artery Morphology, Distensibility, and Right Ventricular Function.

BACKGROUND: The aim was to determine the effect of pulmonary artery (PA) morphology on the branch pulmonary artery-regurgitation fraction (BPA-RF), the relationship of pulmonary insufficiency (PI) to BPA-RF and PA-distensibility, and factors (BPA-RF and PA-distensibility) associated with right ventricular function (RVF) in repaired tetralogy of Fallot (rTOF). METHODS: A total of 182 rTOF patients (median age 17.1 years) were analyzed for length, angle of PA, BPA-RF, PI, and PA-distensibility, using magnetic resonance imaging. RESULTS: The left PA had a significant greater RF than the right PA (median (interquartile range)): LPA 43.1% (32.6-51.5) and RPA 35.2% (24.7-44.7), p < 0.001. The LPA was shorter with a narrower angle than the RPA (p < 0.001). The anatomy of the branch-PA was not a factor for the greater LPA-RF (odds ratio, 95% confidence interval: CI, p-value): length 0.44 (0.95-2.00), p = 0.28; angle 0.63 (0.13-2.99), p = 0.56. There was a strong positive correlation between PI and BPA-RF-coefficients (95% CI), p-value: LPA 0.78% (0.70-0.86), p < 0.001; RPA 0.78% (0.71-0.84), p < 0.001 and between BPA-RF and distensibility-coefficients (95%CI), p-value: LPA 0.73% (0.37-1.09), p < 0.001; RPA 1.63% (1.22-2.03), p < 0.001, respectively. The adjusted BPA-RF did not predict RVF, RPA (p = 0.434), LPA (p = 0.268). CONCLUSIONS: PA morphology is not a significant factor for the differential BPA-RF. The vascular wall in rTOF patients responds to chronic increased intravascular volume by increasing distensibility. BPA-RF is not a determinant of RVF.

Aerosolized iloprost for pulmonary vasoreactivity testing in children with long-standing pulmonary hypertension related to congenital heart disease.

BACKGROUND: In congenital heart disease with increased pulmonary blood flow and pressure, progressive changes in the vascular structure can lead to irreversible pulmonary hypertension (PH). Pulmonary hemodynamic parameters are used to determine whether surgical correction is no longer indicated. In this study, aerosolized iloprost was used to assess pulmonary vasoreactivity in children with long-standing PH related to congenital heart disease. METHODS: Children with long-standing and severe PH secondary to congenital heart disease were included in this study. Various hemodynamic parameters were measured before and after iloprost inhalation (0.5 microg/kg), and vascular resistance was determined. Responders to the iloprost test were defined as those with a decrease in both pulmonary vascular resistance (PVR) and pulmonary-to-systemic vascular resistance ratio (R(p)/R(s)) of >10%. RESULTS: Eighteen children aged between 7 months and 13 years with long-standing and severe PH secondary to congenital heart disease were studied. Thirteen children had a positive response, resulting in a mean (+/- SD) decrease of PVR from 9.3 +/- 4.6 to 4.6 +/- 2.7 Wood U x m(2) (P < 0.001), and a mean decrease of R(p)/R(s) from 0.54 +/- 0.37 to 0.24 +/- 0.14 (P = 0.005). CONCLUSIONS: Iloprost-induced pulmonary vasodilator responses vary among children with PH related to congenital heart disease. The use of inhaled iloprost in the cardiac catheterization laboratory results in pulmonary vasoreactivity for some of these children particularly a reduction in PVR and the pulmonary-to-systemic vascular resistance ratio.

Assessment of pulmonary vasoreactivity in children with pulmonary hypertension.

PURPOSE OF REVIEW: With the current advance in understanding and treatment of pulmonary arterial hypertension in children, pulmonary vasoreactivity testing would navigate the treatment option. An inclusive review of the milestone studies and also recent literature over the last few years on the pulmonary vasoreactivity testing in children will provide the update on various available pulmonary vasodilator agents, markers related to vasoreactivity response, the implication of the testing result on child management and outlook for the long-term outcome. RECENT FINDINGS: There continue to be emerging data regarding pulmonary vasodilators for vasoreactivity testing in children and the genetic predictor of pulmonary vasoreactivity response, particularly in children with idiopathic and familial pulmonary hypertension. Despite a recent advance in pulmonary hypertension therapy leading to improved prognosis in children, the novel knowledge on standardized pulmonary vasoreactivity testing in children and its interpretation remain limited and controversial. SUMMARY: The precise definition of pulmonary vasoreactivity testing remains debatable, particularly in children with pulmonary hypertension related to congenital heart defect. Defining the responder, in order to navigate the treatment option, is frequently dictated by institutional experience and facilities. Meanwhile, the criteria for responder in children with idiopathic pulmonary artery hypertension are reasonably consistent. In general, responders seem to have less severe disease and better prognosis.

Comparison of vascular complications between conventional treatment and bone marrow transplantation for children with beta-thalassemia disease.

Patients with ss-thalassemia may be predisposed to premature atherosclerosis due to vascular dysfunction. This is observed in adults. Whether atherosclerosis changes in ss-thalassemia disease (BTD) occur early in childhood is not clear. To prevent cardiovascular complications, this needs evaluation. Moreover, it remains uncertain whether curative treatment with bone marrow transplantation (BMT) would improve this vascular alteration. For this study, 37 ss-thalassemia children age 10.1 +/- 2.7 years were classified into group 1 (25 children with BTD treated conventionally) and group 2 (12 children with BTD who underwent BMT). A control group of 29 age-matched healthy children were studied simultaneously. The carotid stiffness index and intima-media thickness (IMT) were measured. Group1 had a greater arterial stiffness index than the control subjects (4.57 +/- 1.78 vs. 2.87 +/- 1.07; p < 0.001). The carotid IMT was significantly greater in both BTD groups than in the control group (group 1: 0.45 +/- 0.03 vs. 0.34 +/- 0.04 mm; p < 0.001; group 2: 0.43 +/- 0.03 vs. 0.34 +/- 0.04 mm; p < 0.001). Carotid IMT and arterial stiffness are increased in conventionally treated children with ss-thalassemia, suggesting an early atherosclerotic change in these children, whereas children with BTD who underwent BMT had an increased carotid IMT but normal arterial stiffness.

Transcoronary bone marrow-derived progenitor cells in a child with myocardial infarction: first pediatric experience.

BACKGROUND: Recent advances in stem cell therapy to restore cardiac function have great promise for patients with congestive heart failure after myocardial infarction in an adult population. OBJECTIVE: We examined the benefits of bone marrow-derived progenitor cells treatment modality for the pediatric patient. METHODS AND RESULTS: We present our first case of transcoronary autologous stem cell transplantation in a 9-year-old girl with refractory congestive heart failure secondary to myocardial infarction 1 year after transcatheter revascularization. The child received daily injections of granulocyte colony-stimulating factor for 3 days prior to the bone marrow aspiration. The bone marrow cells were isolated to constitute CD133+/CD34+ more than 90% of the total number. Subsequently, the progenitor cell suspension was injected via a transcoronary catheter without any complication. Three months after stem cell therapy, her cardiac function, assessed by both cardiac magnetic resonance and echocardiogram, has been improved with the left ventricular ejection fraction at 47% compared to the baseline of 30%. CONCLUSION: This is the first reported pediatric case of successful transcoronary injection of bone marrow-derived progenitor cells for end-stage heart disease. The procedure is considered safe and feasible for the pediatric population.

Aerosolized iloprost for postoperative pulmonary hypertensive crisis in children with congenital heart disease.

INTRODUCTION: Pulmonary hypertensive crisis (PHC) is a significant contributor to the morbidity and mortality of surgery for congenital heart defect. Management of such a potentially fatal complication has been evolving for the past decades. Inhaled iloprost has been reported as an alternative treatment for this condition. We evaluated the use of aerosolized iloprost as a rescue therapy for PHC in children undergoing congenital heart surgery. METHODS: In this clinical study, 12 high risk children were monitored in order to identify postoperative PHC after congenital heart repair. Factors being monitored included pulmonary artery pressure, systemic blood pressure, left atrial pressure, transcutaneous oximetry and heart rate. PHC was defined as an acute rise in pulmonary pressure which causes cardiopulmonary compromise as reflected by desaturation and hypotension. Despite conventional medical treatment to prevent postoperative PHC, children with PHC were therefore administered with aerosolized iloprost (0.5 microg/kg). RESULT: Eight of the 12 children had one or more episodes of PHC, secondary to the pulmonary vasoreactivity. All responded to the aerosolized iloprost treatment, as demonstrated by a fall in their mean pulmonary pressure from 47.9 + or - 14.9 to 30.2 + or - 7.9 mmHg (p=0.012) and a rise in the arterial saturation from 82.2 + or - 16.7 to 93.4 + or - 11.5 % (p=0.012) while mean systemic blood pressure tended to increase from 59.4 + or - 12.1 to 64 + or - 10.3 mmHg (p=0.16). CONCLUSION: In medical setting with limited access to the nitric oxide, inhaled iloprost is consider to be an effective alternative treatment for postoperative PHC in children undergoing congenital heart surgery.

Single-stage versus two-stage modified Fontan procedure.

We compared surgical outcomes of the single-stage and two-stage modified Fontan procedures to clarify clinical superiority. Of 28 children undergoing a modified Fontan procedure from October 1995 to October 2005, 15 had a 1-stage and 13 had a 2-stage operation. In the 2-stage group, pulmonary artery growth was evaluated before and after the first stage. Operative mortality was 26.6% in the 1-stage group and 0% in the 2-stage group. The benefits of a previous bidirectional Glenn shunt were decreased cyanosis and volume overload, but there was no significant difference in pulmonary artery growth reflected in pulmonary artery indices before and after the bidirectional Glenn procedure. Older children underwent a 2-stage modified Fontan procedure and had better outcomes in terms of lower mortality, improved oxygen saturation, decreased volume load, and less deterioration of atrioventricular valve regurgitation.

Pulmonary arterial hypertension after childhood cancer therapy and bone marrow transplantation.

According to the Third World Symposium on Pulmonary Arterial Hypertension (PAH), chemotherapy is considered to be one of the possible risk factors for patients developing PAH. However, to date, no literature has sufficiently addressed the risk, natural history, and effective treatment of this condition. We report our experience on how early diagnosis, detailed monitoring of disease course, and appropriate treatment application have led to a successful outcome of PAH management in childhood after cancer therapy. Our report reaffirmed the fact that PAH is now a recognized complication of chemotherapy and bone marrow transplantation for leukemia. Combined pulmonary vasodilator treatment has a beneficial effect in improving the patient's condition and functional status as suggested by initial acute pulmonary vasodilator testing.