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Concept: Tetralogy of Fallot


OBJECTIVE: To evaluate the scale and clinical importance of loss to follow-up of past patients with serious congenital heart disease, using a common malformation as an example. To better understand the antecedents of loss to specialist follow-up and patients' attitudes to returning. DESIGN: Cohort study using NHS number functionality. Content and thematic analysis of telephone interviews of subset contacted after loss to follow-up. PATIENTS, INTERVENTION AND SETTING: Longitudinal follow-up of complete consecutive list of all 1085 UK patients with repair of tetralogy of Fallot from single institution 1964-2009. MAIN OUTCOME MEASURES: Survival, freedom from late pulmonary valve replacement, loss to specialist follow-up, shortfall in late surgical revisions related to loss to follow-up. Patients' narrative about loss to follow-up. RESULTS: 216 (24%) of patients known to be currently alive appear not to be registered with specialist clinics; some are seen in general cardiology clinics. Their median age is 32 years and median duration of loss to follow-up is 22 years; most had been lost before Adult Congenital services had been consolidated in their present form. 48% of the late deaths to date have occurred in patients not under specialist follow-up. None of those lost to specialist follow-up has had secondary pulmonary valve replacement while 188 patients under specialist care have. Patients lost to specialist follow-up who were contacted by telephone had no knowledge of its availability. CONCLUSIONS: Loss to specialist follow-up, typically originating many years ago, impacts patient management.

Concepts: Cohort study, Longitudinal study, Hospital, Heart, Congenital disorder, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot


Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.

Concepts: DNA, Gene, Genetics, Genetic disorder, Copy number variation, Human genome, Congenital heart disease, Tetralogy of Fallot


The aim of this study was to describe gender differences in patients operated on for TOF and to define the impact of pregnancy in late post-surgical follow-up in women.

Concepts: Gender, Gender role, Gender identity, Tetralogy of Fallot, Gender differences


The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

Concepts: Gene, Heart, Hypertrophic cardiomyopathy, Down syndrome, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot, Hypoplastic left heart syndrome


The association of tetralogy of Fallot with a partial anomalous pulmonary vein is rare. Although this combination is generally treated with surgery, in this paper we present the case of an 8-year-old boy whose anomalous venous drainage was successfully closed with an Amplatzer vascular plug after a total correction of a tetralogy of Fallot. The patient was asymptomatic at his last follow-up.

Concepts: Blood, Lung, Heart, Blood vessel, The Association, Vein, Tetralogy of Fallot, Total anomalous pulmonary venous connection


OBJECTIVE: We sought to investigate the impact of 22q11.2 deletion on perioperative outcome in tetralogy of Fallot. METHODS: We conducted a retrospective review of patients with tetralogy of Fallot who underwent complete surgical reconstruction at The Children’s Hospital of Philadelphia between 1995 and 2006. Inclusion criteria included diagnosis of tetralogy of Fallot and known genotype. Fisher exact and Mann-Whitney tests were used for categoric and continuous variables, respectively. Regression analysis was used to determine whether deletion status predicts outcome. RESULTS: We studied 208 subjects with tetralogy of Fallot, 164 (79%) without and 44 (20%) with 22q11.2 deletion syndrome. There were no differences in sex, race, gestational age, age at diagnosis, admission weight, and duration of mechanical ventilation. Presenting anatomy, survival, complications and reoperations were also comparable between patients with and without 22q11.2 deletion syndrome. Those with 22q11.2 deletion syndrome had more aortopulmonary shunts preceding complete surgical repair (21% vs 7%, P = .02). This association was present after adjustment for presenting anatomy (stenosis, atresia, or absence of pulmonary valve and common atrioventricular canal) and surgical era. In addition, those with 22q11.2 deletion syndrome had longer cardiopulmonary bypass time (84 vs 72 minutes, P = .02) and duration of intensive care (6 vs 4 days, P = .007). CONCLUSIONS: Genotype affects early operative outcomes in tetralogy of Fallot resulting, in particular, in longer duration of intensive care. Future studies are required to determine factors contributing to such differences in this susceptible population.

Concepts: Regression analysis, Hospital, Syndromes, Genetic disorders, Outcome, Tetralogy of Fallot, DiGeorge syndrome, Children's Hospital of Philadelphia


OBJECTIVES: Timing of primary repair of tetralogy of Fallot (TOF) remains controversial. We evaluated the long-term outcome of early primary treatment strategy in a patient cohort with TOF less than eight months of age. METHODS: A group of 120 patients with TOF less than eight months of age (5 ± 2.4 months) underwent early primary repair of TOF between October 1998 and August 2009. Sixty-one patients received a transanular (TAN) repair, and 59 patients received a right ventricular outflow tract (RVOT) + main pulmonary artery (MPA) double patch repair with concomitant pulmonary valve reconstruction. RESULT: There was no early or late mortality. The follow-up was 100% completed. There were eight reoperations and eight patients underwent catheter intervention for severe pulmonary valve insufficiency or stenosis, obstruction of right ventricular outflow tract, and stenosis of pulmonary arteries. Actuarial survival was 100% at ten years. At latest follow-up 80 patients were in NYHA Class I without any antiarrhythmic medications. On latest echocardiography, 90 (75%) patients had mild to moderate pulmonary regurgitation, and 10 had a right ventricular outflow tract gradient more than 40 mmHg. CONCLUSIONS: These data strongly support the concept of early primary repair of TOF in patients with well developed pulmonary arteries. Early primary repair is associated with an excellent early and late outcomes, an acceptable risk of reoperation and re-intervention, and a low incidence of significant right ventricular dysfunction.

Concepts: Blood, Lung, Heart, Artery, Pulmonary artery, Right ventricle, Tetralogy of Fallot, Pulmonary vein


We investigated intermodality agreements of strains from two-dimensional echocardiography (2DE) and cardiac magnetic resonance (CMR) feature tracking (FT) in the assessment of right (RV) and left ventricular (LV) mechanics in tetralogy of Fallot (TOF). Patients were prospectively studied with 2DE and CMR performed contiguously. LV and RV strains were computed separately using 2DE and CMR-FT. Segmental and global longitudinal strains (GLS) for the LV and RV were measured from four-chamber views; LV radial (global radial strain [GRS]) and circumferential strains (GCS) measured from short-axis views. Intermodality and interobserver agreements were examined. In 40 patients (20 TOF, mean age 23 years and 20 adult controls), LV, GCS showed narrowest intermodality limits of agreement (mean percentage error 9.5%), followed by GLS (16.4%). RV GLS had mean intermodality difference of 25.7%. GLS and GCS had acceptable interobserver agreement for the LV and RV with both 2DE and CMR-FT, whereas GRS had high interobserver and intermodality variability. In conclusion, myocardial strains for the RV and LV derived using currently available 2DE and CMR-FT software are subject to considerable intermodality variability. For both modalities, LV GCS, LV GLS, and RV GLS are reproducible enough to warrant further investigation of incremental clinical merit.

Concepts: Heart, Tetralogy of Fallot, Mean absolute percentage error


Context:Paragangliomas are a type of neuroendocrine tumor that has been reported to be present in patients with cyanotic congenital heart disease. This report documents the first case of a patient with successful resection of a sympathetic paraganglioma in the setting of unrepaired tetralogy of Fallot, the most common cause of cyanotic heart disease, with pulmonary atresia.Objective:We present a 33-yr-old woman with hypertensive crises from a paraganglioma who presented for surgical resection.Patient and Methods:The patient’s preoperative workup was consistent with a functioning sympathetic paraganglioma. Preoperative transesophageal echocardiogram displayed normal ventricular function, moderate-severe right ventricular hypertrophy, severe right ventricular hypertension, an overriding aorta, bidirectional shunting, pulmonary atresia, and aortopulmonary collaterals.Results:The patient underwent a successful laparoscopic resection of a functioning 7-cm paraganglioma after careful preoperative preparation and intraoperative monitoring. Pathology returned as a well-defined, partially hemorrhagic mass measuring 7.0 × 4.5 × 4.5 cm adjacent to and compressing the adrenal gland.Conclusion:Surgical resection of paraganglioma tumors in rare patients such as this one is appropriate; however, surgery requires meticulous perioperative management with a multidisciplinary approach. Future studies are needed to determine whether there is a link between neuroendocrine tumors and cyanotic congenital heart disease.

Concepts: Oncology, Hypertension, Cardiology, Heart, Blood pressure, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot


BACKGROUND: Many adults with repaired tetralogy of Fallot have had prior Blalock-Taussig shunts. These shunts may theoretically hinder growth and development of the ipsilateral arm. METHODS: We prospectively enrolled consecutive patients with tetralogy of Fallot in a cross-sectional study to measure arm length and assess handgrip strength. Bilateral handgrip strength was quantified by a dynamometer in a standing position after instructing patients to clench each hand tightly in succession. The maximum force achieved, in kilograms, was measured. RESULTS: A total of 80 consecutive adults with tetralogy of Fallot, aged 36.0±12.5years, 49% female, were prospectively enrolled. Thirty-eight (47.5%) patients had prior Blalock-Taussig shunts at a median age of 1.0year. Twenty-one (55.3%) were left-sided and 23 (60.5%) were classic shunts. All but six patients with right-sided shunts and one without a prior shunt were right-handed. The shunts were present for a median of 4.0years prior to takedown during corrective surgery. The arm ipsilateral to the shunt was significantly shorter than the contralateral arm (71.5±6.1 versus 73.6±5.6cm, P<0.0001). Handgrip strength was significantly weaker on the ipsilateral versus contralateral side (median [IQR], 26.5 [14.0-41.5] versus 31.0 [18.0-46.0] kg, P<0.0001) and the ipsilateral-to-contralateral handgrip ratio was lower with classic versus modified shunts (median [IQR], 1.05 [1.02-1.14] versus 1.19 [1.07-1.33] kg, P=0.0541). CONCLUSION: In patients with tetralogy of Fallot, Blalock-Taussig shunts may impair normal development of the ipsilateral arm with repercussions in adulthood that include shorter limb length and reduced handgrip strength. These changes are most pronounced in patients with classic end-to-side anastomoses.

Concepts: Measurement, Mass, Tetralogy of Fallot, International System of Units, Kilogram, Adult, SI base unit, Shunt