Alessandro Giardini

Great Ormond Street Hospital for Children NHS Foundation Trust | GOSH · Department of Cardiology

Background: Known genetic causes of congenital heart disease (CHD) explain <40% of CHD cases, and interpreting the clinical significance of variants with uncertain functional impact remains challenging. We aim to improve diagnostic classification of variants in patients with CHD by assessing the impact of noncanonical splice region variants on RNA...

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtD...

Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we...

Importance Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions. Objective To compare the frequency of damaging variants...

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction o...

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This appro...

Background Adenosine deaminases acting on RNA ( ADAR ) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes...

Background Survival with critical aortic valve stenosis (CAS) can be successfully achieved in the short term. Long-term outcome however remains uncertain. We sought to study the long-term survival and reinterventions; exercise capacity and myocardial performance in a subgroup of long-term survivors. Methods Retrospective over 40 years of all patie...

Objective: Diazoxide is first line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterise the incidence, and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH....

Motivation: Noncoding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity, and uncertainty about relevant noncoding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensi...

Hypoplastic left heart syndrome surgery in neonates has revolutionized survival in childhood. A new population with complex univentricular circulations has been created. Complex management problems can be anticipated for the adult survivors.

Lifetime care of congenital heart disease aims to achieve survival with the best possible functional outcomes, and objective assessment using functional testing is now a key part of clinical care and research. Exercise testing enables quantification of cardiac and ventilatory function and their interaction. Specific causes of exercise limitation ca...

Infantile haemangiomas (IH) are common birthmarks in babies consisting of dilated blood vessels. They are also known as strawberry naevi. Most of them grow for a few months, then gradually shrink spontaneously over a period of months or years. However, in about 15% of cases they can cause serious functional problems when they involve important stru...

婴幼儿血管瘤(IH)是婴儿常见的胎记,由扩张的血管组成。这些胎记也称为草莓痣。大多数草莓痣会生长几个月,然后在几个月或几年间自发地逐渐缩小。但是,在大约15%的病例中,它们会累及眼、耳、口、鼻和肛周等部位,造成严重的功能障碍。此外,它们有时能够消退,但造成毁容。2008年,有报告称,β‐受体阻滞药普萘洛尔经口服用(口服),能够非常有效地使这些胎记迅速缩小。本文旨在就如何最好地对IH儿童患者使用普萘洛尔为医生提供指南。制定指导涉及多个阶段:对八个欧洲国家/地区的现行实践开展国际性调查;系统性文献综述;从19个中心收集当地现行指南生成70项声明。然后由来自相关专科(皮肤科、儿科、儿科心脏病学和儿科ENT外科)的19名专家仔细审查这70项声明。使用既定的研究方案,经由这些专家就涵盖八个类别的47项...

Background Infantile haemangiomas (IH) are the most common vascular tumours of infancy. Despite their frequency and potential complications, there are currently no unified UK guidelines for the treatment of IH with propranolol. There are still uncertainties and diverse opinions regarding indications, pre‐treatment investigations, its use in PHACES...

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.,...

Type of congenital heart defect among cases with trisomy 21 or DiGeorge syndrome/Velocardiofacial syndrome/22q11.2 deletion in the Pediatric Cardiac Genetic Consortium Cohort. ASD—atrial septal defect, AVCD—atrioventricular canal defect, CTD—conotruncal heart defect, DGS—DiGeorge syndrome, LAT—laterality disorder, LVOT—left ventricular outflow trac...

Congenital heart defect (CHD) phenotypes within each type of CHD in nonsyndromica cases in the Pediatric Cardiac Genetic Consortium Cohort. ASD—atrial septal defect, AVCD—atrioventricular canal defect, CTD—conotruncal heart defect, LAT—laterality disorder, LVOT—left ventricular outflow tract, RVOT—right ventricular outflow tract. (DOCX)

Demographic, pregnancy, and birth history comparisons of nonsyndromica cases across major CTD and LVOT subtypes in the Pediatric Cardiac Genetic Consortium Cohort. AVD—aortic valve disease (aortic stenosis, bicuspid aortic valve), COA—coarctation of the aorta, CTD—conotruncal heart defect, DORV—double outlet right ventricle, D-TGA—D-transposition o...

Demographic, pregnancy, and birth history comparisons of nonsyndromica cases across major types of congenital heart defect for cases ≤ 1 year of age at recruitment in the Pediatric Cardiac Genetic Consortium Cohort. ASD—atrial septal defect, AVCD—atrioventricular canal defect, CTD—conotruncal heart defect, LAT—laterality disorder, LVOT—left ventric...

Anonymized data set for replicating the results from the Pediatric Cardiac Genetic Consortium cohort description. (XLSX)

Neurodevelopmental outcomes across major CTD and LVOT subtypes for nonsyndromica cases ≥5 years in the Pediatric Cardiac Genetic Consortium Cohort. AVD—aortic valve disease (aortic stenosis, bicuspid aortic valve), COA—coarctation of the aorta, CTD—conotruncal heart defect, DORV—double outlet right ventricle, D-TGA—D-transposition of the great arte...

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent–offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes...

Objective: Today's growing medical image databases call for novel processing tools to structure the bulk of data and extract clinically relevant information. Unsupervised hierarchical clustering may reveal clusters within anatomical shape data of patient populations as required for modern precision medicine strategies. Few studies have applied hie...

Recent literature focuses on positive aspects and resources in disease management. The aim of this observational cross-sectional study is to investigate the relationships between illness perception, dispositional optimism, anxiety and depressive symptoms in chronic heart failure patients. The consecutively enrolled patients (n = 120) compiled the f...

Background: Aortic arch reconstruction after hypoplastic left heart syndrome (HLHS) palliation can vary widely in shape and dimensions between patients. Arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch three-dimensional shape features with functional and short-term outcome data after tota...

Objectives: Even after successful aortic coarctaion (CoA) repair, there remains a significant incidence of late systemic hypertension and other morbidities. Independent of residual obstruction, aortic arch morphology alone may impact on cardiac function and outcome. We sought to uncover the relationship of arch three-dimensional (3D) shape features...

In Norwood physiology, shunt size and the occurrence of coarctation can affect hemodynamics significantly. The aim of the study was to validate an in vitro model of the Norwood circulation against clinical measurements for patients presenting differing aortic morphologies.The mock circulatory system used coupled a lumped parameter network of the ne...

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. Th...

Background: Cardiopulmonary exercise testing helps prognosticate and guide treatment in adults with pulmonary hypertension. Concerns regarding its feasibility and safety limit its use in children with pulmonary hypertension. We aimed to assess the feasibility and safety of cardiopulmonary exercise testing in a large paediatric pulmonary hypertensi...

INSPIRE-CF is an on-going 24-month physiotherapy RCT examining the effects of an individually prescribed and weekly supervised exercise programme for children with CF, in terms of lung function, exercise capacity and quality of life. Objectives This interim review evaluated participation in the exercise intervention group in the first year of the...

A cardiopulmonary exercise test (CPET) including ECG is performed to assess aerobic exercise capacity and monitor exercise induced limitations. ECG is not routinely performed at clinic or annual reviews in children with CF. Cardiac arrhythmias are reportedly rare in CF. Objectives This report highlights a previously undiagnosed abnormal ECG in a c...

Patients with repaired tetralogy of Fallot (ToF) have an increased long-term risk of cardiovascular morbidity and mortality. Risk stratification in this population is difficult. Initial evidence suggests that cardiopulmonary exercise testing (CPET) may be helpful to risk-stratify patients with repaired ToF. We studied 875 patients after surgical re...

Objectives To assess the communication potential of three-dimensional (3D) patient-specific models of congenital heart defects and their acceptability in clinical practice for cardiology consultations. Design This was a questionnaire-based study in which participants were randomised into two groups: the ‘model group’ received a 3D model of the card...

Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patie...

A left-to-right shunt lesion exists when blood from the left atrium, left ventricle, or aorta transits to the right atrium or its tributaries, the right ventricle, or the pulmonary artery. In these conditions blood from the systemic arterial circulation mixes with systemic venous blood. The presence of a left-to-right shunt results in a volume over...

To the Editor, We read with interest the article by Khiabani et al,1 where the authors examine the relationship between power loss in the total cavopulmonary connection (TCPC) and clinical exercise testing. Using an indexed power loss, ‘iPL’, they report that higher iPL correlates with worse minute oxygen consumption and exercise work at anaerobic...

Cone reconstruction is advocated to treat severe tricuspid valve (TV) regurgitation associated with Ebstein's anomaly. Data on postoperative clinical status, ventricular adaptation, and objective cardiopulmonary testing are lacking in these patients. The clinical characteristics, echocardiography, magnetic resonance imaging, and exercise data from...

Introduction: Communication in medical consultations is recognised as an important factor in optimising patient satisfaction and health outcomes. Patient-specific (PS) plastic models of congenital heart lesions may offer benefits for education and communication purposes. This study aimed to quantitatively test the translational potential of PS mode...

Although exercise stress echocardiography (ESE) is a well-validated technique in adult population, its use in children is quite limited. We aimed to assess the feasibility, the safety and the reproducibility of ESE, using on-line scanning in semi-supine cyclo-ergometer protocol in a large pediatric population. Between July 2008 and January 2013, 42...

The recovery of cardiopulmonary variables from peak exercise in patients with pulmonary stenosis (PS) or regurgitation (PR) is delayed, but the impact of treating PS or PR on exercise recovery kinetics is unknown. 43 patients (median age 14 years) with PS (n = 23) or PR (n = 20) after repair of congenital heart disease underwent successful percutan...

Objective To assess coupling efficiency in hypoplastic left heart syndrome (HLHS), considering the effect of surgical arch reconstruction and type of shunt received during the Norwood procedure. Methods Ventriculo-arterial (VA) coupling was assessed prior to Fontan completion in 32 HLHS patients (19 modified Blalock-Taussig (mBT) and 13 Sano shunt...

Reduced exercise capacity is nearly universal among Fontan patients. Although many factors have emerged as possible contributors, the degree to which each impacts the overall hemodynamics is largely unknown. Computational modeling provides a means to test hypotheses of causes of exercise intolerance via precisely controlled virtual experiments and...

Objective This study aims to compare atrial switch and arterial switch operations for repair of transposition of the great arteries (TGA), assessing cardiac function and ventriculo-arterial (VA) coupling based on cardiac magnetic resonance (CMR) data. Using CMR-derived wave intensity analysis, this study compares non-invasively the two systemic ven...

Background: Reliability of computational models for cardiovascular investigations strongly depends on their validation against physical data. This study aims to experimentally validate a computational model of complex congenital heart disease (i.e., surgically palliated hypoplastic left heart syndrome with aortic coarctation) thus demonstrating th...

Initial evidence suggests that total cavopulmonary connection (TCPC) completion during winter is associated with prolonged pleural effusion and hospitalization. This study was carried out to review the impact of season of operation on short-term outcome after TCPC procedure. We conducted a retrospective study on 104 consecutive patients who underwe...

Background: Reduced exercise capacity is nearly universal among Fontan patients, though its etiology is not yet fully understood. While previous computational studies have attempted to model Fontan exercise, they did not fully account for global physiologic mechanisms nor directly compare results against clinical and physiologic data. Methods: I...

Aortic arch geometry is linked to abnormal blood pressure (BP) response to maximum exercise. This study aims to quantitatively assess whether aortic arch geometry plays a role in blood pressure (BP) response to exercise. 60 age- and BSA-matched subjects -- 20 post-aortic coarctation (CoA) repair, 20 transposition of great arteries post arterial swi...

First stage palliation of hypoplastic left heart syndrome (HLHS), i.e. the Norwood operation, results in a complex physiological arrangement, involving different shunting options (modified Blalock-Taussig, RV-PA conduit, central shunt from the ascending aorta) and enlargement of the hypoplastic ascending aorta. Engineering techniques, both computat...

Pulmonary valve replacement (PVR) after repair of tetralogy of Fallot (ToF) is commonly required and is burdensome. Detailed anatomic and physiologic characteristics of survivors free from late PVR and with good exercise capacity are not well described in a literature focusing on the indications for PVR. In 1085 consecutive patients receiving stand...

A blunted heart rate recovery (HRR) from peak exercise is associated with adverse outcome in adults with ischemic heart disease. We assessed HRR after pediatric heart transplantation (HTx) and its prognostic use. Between 2004 and 2010 we performed 360 maximal exercise tests (median, 2 tests/patient; range, 1-7) in 128 children (66 men; age at test,...

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac...

Barth syndrome is an X-linked recessive disorder that is characterized by cardiomyopathy, variable neutropenia, skeletal myopathy, growth delay, and organic aciduria. The cardiac involvement typically results in a high risk of severe heart failure in infancy or early childhood. While Berlin Heart EXCOR is widely accepted as ventricular assistance i...

This study describes the implementation of an experimental model of the "Sano" variant (right-ventricle to pulmonary-artery shunt) of the Norwood operation used to treat hypoplastic left-heart syndrome (HLHS). The Sano operation is an alternative to the modified Blalock-Taussig shunt (innominate to pulmonary artery shunt). In the experimental setup...

The case report describes a 9-year-old boy who presented with an acute cerebrovascular accident and was found to have cardiac tamponade caused by cardiac rhabdomyosarcoma. Symptoms of rhabdomyosarcoma can be indolent and nonspecific, even with metastatic disease. Echocardiography and cardiac magnetic resonance imaging are explored as adjuncts to di...

All children have a natural need to move, play, and perform activities. Physical activity is necessary for optimal physical, emotional, and psychosocial development for healthy children as well as children with congenital heart disease (CHD). In this paper we provide recommendations for physical activity, recreational sport, and exercise training i...

Objective: To evaluate the aortic arch elastic properties and ventriculoarterial coupling efficiency in patients with single ventricle physiology, with and without a surgically reconstructed arch. Methods: We studied 21 children with single ventricle physiology after bidirectional superior cavopulmonary surgery: 10 with hypoplastic left heart sy...

The timing and indicators for surgical pulmonary valve replacement (PVR) in patients with pulmonary regurgitation (PR) after repair of tetralogy of Fallot (ToF) are controversial. In this study we tested the hypothesis that delaying PVR in patients with ToF and severe PR would lead to short-term progressive deterioration in right ventricular/left v...

Kawasaki disease is an important differential diagnosis when evaluating prolonged fever in childhood. Although the aetiology of this vasculitic disease process remains obscure, prompt recognition and treatment significantly reduces vascular complications such as coronary artery aneurysms. Patients presenting with atypical or incomplete diagnostic f...

Aims To assess the impact of relief of pulmonary stenosis (PS) and pulmonary regurgitation (PR) by percutaneous pulmonary valve implantation (PPVI) on biventricular function during exercise stress.Methods and resultsSeventeen patients, who underwent PPVI for PS or PR, were included. Magnetic resonance imaging was performed at rest and during supine...

Surgical palliation of hypoplastic left heart syndrome (HLHS) is performed in three stages, the first of which is known as the Norwood procedure [1]. Traditionally, this operation involves securing an unobstructed outlet for the systemic circulation in infants for whom the single right ventricle is the only pump in the system, with pulmonary flow s...