John O'Sullivan

Survival with congenital heart disease and need for follow up in adult life

OBJECTIVE To predict the growth in demand for long term follow up of adults with congenital heart disease. DESIGN Observed diagnoses of congenital heart disease in infancy and childhood were adjusted for observed infant survival, predicted further survival to age 16 years, underascertainment in older childhood, and predicted need for long term follow up. SETTING The resident population of one health region in the UK. PATIENTS All confirmed cardiovascular malformations diagnosed in 1985 to 1999 in children born in 1985 to 1994. RESULTS 1942 cases of congenital heart disease were diagnosed in infancy in a population of 377 310 live births (5.2/1000). 1588 (82%) survived to 1 year and 1514 were predicted to survive to age 16. 605 further diagnoses were made in childhood—678 when adjusted for underascertainment. Thus, 2192 children were predicted to reach age 16, of whom 784 would require long term follow up in adult life. The adult population would comprise 28% complex, 54% significant, and 18% minor congenital heart disease. These figures predict the need for adult follow up of congenital heart disease of over 200 extra cases per 100 000 live births each year or over 1600 extra cases a year every year in the UK. CONCLUSIONS The need for follow up of congenital heart disease in adult life is likely to grow linearly, with increasing complexity and increasing need for reinvestigation and reintervention with time. Appropriate provision should be made for adequate manpower, resources, and facilities for care of these patients.

Prevalence of hypertension in children after early repair of coarctation of the aorta: a cohort study using casual and 24 hour blood pressure measurement

Objective: To study the prevalence of hypertension in a cohort of patients using the current strategy of repair in early childhood. Patients: The cohort of patients with coarctation of the aorta born between 1983 and 1992. Intervention: Casual (mean of three resting readings) and 24 hour blood pressure were measured in 119 children and compared with data from 1034 normal controls. The arch repair and left ventricular parameters were assessed using Doppler echocardiography. Results: Median ages at first intervention and at blood pressure measurement were 0.2 years (interquartile range 0.04–2.0) and 12.0 years (9.0–14.5), respectively. Doppler velocity in the descending aorta was significantly associated with blood pressure (r = 0.28, p = 0.002 for casual systolic blood pressure (SBP); r = 0.26, p = 0.005 for mean 24 hour SBP). Patients were classified as having “no” (n = 70) or “mild” (n = 49) arch obstruction. Casual SBP was > 95th centile in 28% (34 of 119) overall and in 21% (15 of 70) of the no arch obstruction group. Mean 24 hour SBP was > 95th centile in 30% (36 of 119) overall and in 19% (13 of 70) of the no obstruction group. The sensitivity and specificity of casual SBP in detecting increased 24 hour SBP were 66% and 88%, respectively. Conclusions: This unique study of a large cohort of patients treated for coarctation in early childhood showed that a disappointingly high prevalence of hypertension is already apparent in children aged 7–16 years in the absence of significant arch obstruction, whether assessed by 24 hour or by casual blood pressure measurement.

Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome

Background: Although severe T cell immunodeficiency in DiGeorge anomaly is rare, previous studies of humoral function in these patients have found no antibody abnormalities but have not examined the response to polysaccharide antigens. Isolated cases of autoimmunity have been reported. Several patients with 22q11.2 deletion attending our immunology clinic suffered recurrent sinopulmonary infection or autoimmune phenomena. Aims: To investigate humoral immunodeficiency, particularly pneumococcal polysaccharide antibody deficiency, and autoimmune phenomena in a cohort of patients with 22q11.2 deletion. Methods: A history of severe or recurrent infection and autoimmune symptoms were noted. Lymphocyte subsets, immunoglobulins, IgG subclasses, specific vaccine antibodies, and autoantibodies were measured. Subjects were vaccinated with appropriate antigens as indicated. Results: Of 32 patients identified, 26 (81%) had severe or recurrent infection, of which 13 (50%) had abnormal serum immunoglobulin measurements and 11/20 ≥4 years old (55%) had an abnormal response to pneumococcal polysaccharide. Ten of 30 patients (33%) had autoimmune phenomena; six (20%) were symptomatic. Conclusions: Humoral immunodeficiency is more common than previously recognised in patients with 22q11.2 deletion. Normal T cell function and immunoglobulin levels do not exclude poor specific antibody responses. Patients should be referred for formal immunological assessment of cellular and humoral immune function.

Parental recall of birth weight: how accurate is it?

OBJECTIVE To assess the accuracy of parental recall of birth weight in a British population and to investigate whether social class and age of the child significantly influence the accuracy of recalled birth weight. METHODS A questionnaire was given to parents whose children were participating in a blood pressure study and the hospital records were retrieved to check the birth weight data. RESULTS At the time of the study, the children (n = 649) ranged in age from 6 to 15 years. Seventy five per cent of the recalled birth weights were within 50 g of that recorded in the hospital records. No significant associations were found between the difference in birth weights (recalled birth weight minus hospital record) and social class of the parents or age of the child at time of data collection. CONCLUSION This large study shows that parental recall of birth weight is good across the social classes and up to 16 years after delivery. There was no evidence of systematic bias, which would prejudice results of studies on the relation of birth weight to adult hypertension.

Cardiac transplantation in adults with congenital heart disease

Background Due to increasing success with repair or palliation in childhood, there is a rapidly growing population of adult patients with complex congenital heart disease who may require transplantation. There remains little data on outcomes of cardiac transplantation in this group. Methods 38 orthotopic cardiac transplants were performed in 37 patients (18 men) ≥18 years of age with congenital heart disease (CHD) from 1988 to 2009 in our institution. Outcomes were reviewed using medical records and transplant databases. Results 15 patients (41%) had univentricular and 22 (59%) biventricular physiology. The biggest group was transposition of the great arteries following atrial switch in eight patients (22%). Six (16%) had no previous surgical intervention. Mean age at transplant was 33.5 years (range 19.1–59.9 years). 11 patients (30%) required additional surgical procedures at transplant. 16 (43%) died, 12 early and 4 late deaths (1.8, 2.4, 2.7 and 7 years). Survival was 70% at 30 days, 68% at 1 year, 58% at 5 years and 53% at 10 and 15 years. Outcome improved in later eras with reduction in 30-day mortality from 50% to 18% and increase in 5-year survival from 50% to 69%. Two patients developed post-transplant lymphoproliferative disease. None required long-term renal replacement therapy. One patient was re-transplanted for cardiac allograft vasculopathy. Conclusions While operative mortality following cardiac transplantation for adult congenital heart disease is higher than for other diagnostic groups, long-term survival is good and comparable to patients without CHD. Disappointing early results are improved with increasing experience.

Ambulatory blood pressure in schoolchildren

OBJECTIVE To define the range and variability of ambulatory blood pressure in normal schoolchildren. DESIGN Prospective study. METHODS Resting blood pressure of 1121 schoolchildren from Newcastle upon Tyne was recorded. An ambulatory blood pressure device, which uses both auscultatory (Korotkoff) and oscillometric methods of blood pressure measurement, was then put in place for 24 hours. RESULTS The day was divided into three time periods: school, home, and night time. Normal centiles for blood pressure for each of these time periods were obtained and many daytime readings were outside reported normal resting levels. The normal variation of blood pressure was quantified by comparing each of these time periods with the resting readings. Resting systolic blood pressure did not predict 24 hour mean systolic blood pressure. CONCLUSIONS The availability of normal ambulatory blood pressure data on the level and variation of blood pressure in children may facilitate the early identification of hypertension in this age group.

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10−7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10−5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19–1.65; combined P = 2.6 × 10−10). Genotype accounted for ∼9% of the population-attributable risk of ASD.

Natural and unnatural history of pulmonary atresia

OBJECTIVE To investigate mortality, cause of death, survival, and quality of life in all types of cardiac malformation with congenital pulmonary atresia. DESIGN Retrospective analysis. SETTING The resident population of one health region with a single tertiary referral centre. PATIENTS All babies with pulmonary atresia live born in 1980 to 1995. MAIN OUTCOME MEASURES Anatomical classification, total mortality, cause of death, duration of survival, exercise ability. All cases were classified as pulmonary atresia with intact septum (PA-IVS), pulmonary atresia with ventricular septal defect (PA-VSD), or pulmonary atresia with complex cardiac malformation (complex pulmonary atresia). RESULTS 129 cardiac malformations with congenital pulmonary atresia were identified from 601 635 live births (21.4/100 000): 29 had PA-IVS, 60 had PA-VSD, and 40 had complex pulmonary atresia. Total mortality was 72/129 (56%), with 15 deaths in the first week and 49 in the first year. There were 23 surgical deaths, 33 hospital deaths (not related to surgery), and 16 sudden deaths, 12 of which remained unexplained. The sudden death rate was 29/1000 patient years of follow up. Of the 57 survivors, 39% have exercise ability I or II and 61% III or IV. Definitive surgical repair produced better exercise ability. CONCLUSIONS Early mortality is high in all types of pulmonary atresia, although survival has improved in recent years. Most children who have not undergone definitive repair have significant exercise limitation.

Multicenter Experience of ABO‐Incompatible Pediatric Cardiac Transplantation

Although ABO blood group incompatible cardiac transplantation in neonates and infants reduces waiting list mortality without compromising outcome, the technique has not been adopted by all centers, and to date Toronto remains the only center to have published results from a large case series. We present a review of ABO‐incompatible heart transplantation in the United Kingdom (UK) where current recipient selection criteria differ somewhat from those used in the United States (US) and Canada. Between February 2000 and November 2006, 21 ABO‐incompatible cardiac transplants were performed in children aged 2–40 months (median 10.0). Immunosuppression followed standard regimens. Pretransplant donor‐specific isohemagglutinins of >1:4, (the UNOS cutoff), were present in five patients and reduced by plasma exchange. After transplantation, 19/21 recipients demonstrated persisting deficiency of donor‐specific isohemagglutinins. Significant donor‐specific isohemagglutinins levels were detected repeatedly in 2/21 recipients who have shown no clinical or biopsy evidence of rejection. All recipients survive without retransplantation and there have been no episodes of humoral rejection. We conclude it is possible for other centers to replicate the excellent results achieved in Toronto and that ABO‐incompatible transplantation may be performed successfully in some patients beyond infancy with established isohemagglutinin production providing preoperative antibody removing strategies are used.

Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation

Congenital cardiovascular malformation (CVM) exhibits familial predisposition, but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants. Exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One nonsynonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 domain of SMAD6, an intracellular inhibitor of BMP signaling. Sequencing this domain in an additional 346 cases of CVM yielded two further nonsynonymous variants (p.P415L and p.A325T). Functional effects of all three SMAD6 mutations were investigated using BMP signaling assays in vitro. Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild‐type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay. In addition, the p.C484F variant had a significantly (P < 0.05) lower capacity to inhibit an osteogenic response to BMP signaling. We conclude that low‐frequency deleterious variants in SMAD6 predispose to CVM. This is the first report of a human disease phenotype related to genetic variation in SMAD6. Hum Mutat 33:720–727, 2012.