Alessandro Giardini

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Putting both heart and brain at risk For reasons that are unclear, newborns with congenital heart disease (CHD) have a high risk of neurodevelopmental disabilities. Homsy et al. performed exome sequence analysis of 1200 CHD patients and their parents to identify spontaneously arising (de novo) mutations. Patients with both CHD and neurodevelopmental disorders had a much higher burden of damaging de novo mutations, particularly in genes with likely roles in both heart and brain development. Thus, clinical genotyping of patients with CHD may help to identify those at greatest risk of neurodevelopmental disabilities, allowing surveillance and early intervention. Science, this issue p. 1262 Genotyping of children with congenital heart disease may identify those at high risk of neurodevelopmental disorders. 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. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients

AIMS We sought to assess the effects of sildenafil on exercise capacity and haemodynamic response to exercise in Fontan patients. METHODS AND RESULTS We prospectively studied 27 patients with Fontan circulation (age 22.8 +/- 4.9 years). All patients underwent a baseline exercise test with non-invasive measurement of cardiac index (CI) and pulmonary blood flow (PBF) index, and peak exercise oxygen uptake (VO(2)). After the baseline test, patients were randomly assigned to receive either a single 0.7 mg/kg body weight oral dose of sildenafil citrate (n = 18) or no treatment (control group, n = 9). After 1 h of rest, all patients performed a second exercise test. All patients completed the study protocol. The dose of sildenafil ranged from 25 to 50 mg. The change in peak VO(2), the primary endpoint, was greater in the sildenafil group (9.4 +/- 5.2%) than in the control group (0.3 +/- 4.1%, P < 0.05). Sildenafil increased rest and peak exercise PBF index (P < 0.01 and P < 0.05 vs. control group, respectively), as well as rest and peak exercise CI (P < 0.001 and P < 0.05 vs. control group, respectively), without altering rest or peak exercise transcutaneous arterial blood oxygen saturations (P > 0.05 vs. control group for both). No patient reported serious adverse events after sildenafil. CONCLUSION In Fontan patients, oral administration of a single dose of sildenafil improves exercise capacity and haemodynamic response to exercise.

Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients

AIMS previous studies have established an association between exercise intolerance and increased morbidity and mortality in congenital heart disease patients. We aimed to clarify if exercise intolerance is associated with poor outcome in Fontan patients and to identify risk factors for mortality, transplantation, and cardiac-related hospitalization. METHODS AND RESULTS a total of 321 Fontan patients (57% male, mean age 20.9 ± 8.6 years) who underwent cardiopulmonary exercise testing (CPET) at four major European centres between 1997 and 2008 were included. During a median follow-up of 21 months, 22 patients died and 6 patients underwent cardiac transplantation (8.7%), resulting in an estimated 5-year transplant-free survival of 86%. Parameters of CPET were strongly related to increased risk of hospitalization, but-with the exception of heart rate reserve-unrelated to risk of death or transplantation. In contrast, patients with clinically relevant arrhythmia had a 6.0-fold increased risk of death or transplantation (P < 0.001). Furthermore, patients with atriopulmonary/-ventricular Fontan had a 3.7-fold increased risk of death or transplantation compared with total cavopulmonary connection patients (P= 0.009). The combination of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and signs of symptomatic or decompensated heart failure was associated with a particularly poor outcome (3-year mortality 25%). CONCLUSION on short-term follow-up, most parameters of CPET are associated with increased risk of hospitalization but not death or transplantation in contemporary Fontan patients. Only decreased heart rate reserve and a history of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and/or heart failure requiring diuretic therapy are associated with poor prognosis, potentially identifying patients requiring medical and/or surgical attention.

Natural History of Exercise Capacity After the Fontan Operation: A Longitudinal Study

BACKGROUND Previous studies have shown that older Fontan patients and those with an underlying morphologically right ventricle have lower exercise capacity. We sought to assess the natural history of exercise capacity after the Fontan operation in individual patients, and to identify the factors influencing the rate of decrease of exercise capacity over time. METHODS We studied, longitudinally, 53 Fontan patients with cardiopulmonary exercise tests (average 3.2 +/- 1.1 tests for each patient). Age at the first test was 14 +/- 6 years. Time intervals between tests ranged from 1 to 16 years (average, 7.7 +/- 4.0 years). The morphology of the functionally single ventricle was left in 29 patients (55%) and right in 24 patients (45%). Twenty-two patients had undergone a total cavopulmonary connection (TCPC) at a mean age of 5.9 +/- 2.8 years. Thirty-one patients had undergone an atriopulmonary or an atrioventricular connection at an age of 6.9 +/- 4.4 years. Exercise capacity was expressed as percentage of predicted peak oxygen uptake (VO2). RESULTS Overall, peak VO2 decreased at a rate of -2.6 +/- 2.7%/year. Ventricular morphology (r = 0.525, p = 0.0001) and type of Fontan operation (r = 0.381, p = 0.0057) appeared as the only predictors of the rate of decrease of peak VO2 at multivariate analysis. Patients with an underlying left ventricular morphology (-1.7 +/- 2.0 vs -3.7 +/- 3.2%/year, p = 0.005), and those who underwent a TCPC (-1.9 +/- 1.8 vs -3.3 +/- 3.2%/year, p = 0.042), had the lowest rate of decrease in peak VO2. CONCLUSIONS Exercise capacity progressively declines in Fontan subjects. The decline of exercise capacity seems to be slower in patients with an underlying left ventricular morphology and in those who received a TCPC.

Recommendations for physical activity, recreation sport, and exercise training in paediatric patients with congenital heart disease: a report from the Exercise, Basic & Translational Research Section of the European Association of Cardiovascular Prevention and Rehabilitation, the European Congenital Heart and Lung Exercise Group, and the Association for European Paediatric Cardiology

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 in children and adolescents with CHD. In general, children with CHD should be advised to comply with public health recommendations of daily participation in 60 min or more of moderate-to-vigorous physical activity that is developmentally appropriate and enjoyable and involves a variety of activities. While all patients with CHD can participate and benefit from physical activity and exercise, those with specific lesions or complications may require counselling regarding precautions and recommendations.

Ventilatory Efficiency and Aerobic Capacity Predict Event-Free Survival in Adults With Atrial Repair for Complete Transposition of the Great Arteries

OBJECTIVES The goal of this study was to assess the prognostic value of the cardiopulmonary exercise test (CPET) in patients who received a Mustard and Senning (M/S) operation. BACKGROUND Patients who received an M/S operation have increased long-term risk of cardiovascular morbidity and mortality. Limited information is available on how to stratify risk in this population. METHODS Between 1996 and 2007, 274 adults (age 26.3 +/- 8.9 years, range 16 to 50 years) who had received a Mustard (n = 144) or Senning (n = 130) operation in infancy were studied with CPET. During a follow-up of 3.9 +/- 2.3 years (range 0.2 to 10.8 years), 12 patients died at an age of 36 +/- 14 years, and 46 patients required a cardiac-related emergency (<24 h from the onset of symptom/condition) hospital admission at an age of 30 +/- 11 years. RESULTS At multivariate Cox analysis, the slope of ventilation per unit of carbon dioxide output (VE/VCO(2) slope) (hazard ratio: 1.088, p < 0.0001) and percentage of predicted peak oxygen uptake (Vo(2)%) (hazard ratio: 0.979, p = 0.0136) were the strongest predictors of death/cardiac-related emergency hospital admission among demographic, clinical, and exercise variables. A VE/VCO(2) slope > or =35.4 (hazard ratio: 10.7, 95% confidence interval [CI]: 7.8 to 24.6), and a peak Vo(2)% < or =52.3% (hazard ratio: 3.4, 95% CI: 2.5 to 8.2) were associated with an increased 4-year risk of death/cardiac-related emergency hospital admission. Patients who had both a VE/VCO(2) slope > or =35.4 and a peak Vo(2)% < or =52.3% of predicted value were at highest risk (4-year event rate: 78.8%). CONCLUSIONS CPET provides important prognostic information in adults with M/S operation. Subjects with enhanced ventilatory response to exercise or those with poor exercise capacity have a substantially higher 4-year risk of death/cardiac-related emergency hospital admission.

Early Versus Late Functional Outcome After Successful Percutaneous Pulmonary Valve Implantation Are the Acute Effects of Altered Right Ventricular Loading All We Can Expect

OBJECTIVES The purpose of this study was to assess the potential of late positive functional remodeling after percutaneous pulmonary valve implantation (PPVI) in right ventricular outflow tract dysfunction. BACKGROUND PPVI has been shown to impact acutely on biventricular function and exercise performance, but the potential for further late functional remodeling remains unknown. METHODS Sixty-five patients with sustained hemodynamic effects of PPVI at 1 year were included. Patients were divided into 2 subgroups based on pre-procedural predominant pulmonary stenosis (PS) (n = 35) or predominant pulmonary regurgitation (PR) (n = 30). Data from magnetic resonance imaging and cardiopulmonary exercise testing were compared at 3 time points: before PPVI, within 1 month (early) and at 12 months (late) after PPVI. RESULTS There was a significant decrease in right ventricle end-diastolic volume early after PPVI in both subgroups of patients. Right ventricle ejection fraction improved early only in the PS group (51 ± 11% vs. 58 ± 11% and 51 ± 12% vs. 50 ± 11%, p < 0.001 for PS, p = 0.13 for PR). Late after intervention, there were no further changes in magnetic resonance parameters in either group (right ventricle ejection fraction, 58 ± 11% in the PS group and 52 ± 11% in the PR group, p = 1.00 and p = 0.13, respectively). In the PS group at cardiopulmonary exercise testing, there was a significant improvement in peak oxygen uptake early (24 ± 8 ml/kg/min vs. 27 ± 9 ml/kg/min, p = 0.008), with no further significant change late (27 ± 9 ml/kg/min, p = 1.00). In the PR group, no significant changes in peak oxygen uptake from early to late could be demonstrated (25 ± 8 ml/kg/min vs. 25 ± 8 ml/kg/min vs. 26 ± 9 ml/kg/min, p = 0.48). CONCLUSIONS In patients with a sustained hemodynamic result 1 year after PPVI, a prolonged phase of maintained cardiac function is observed. However, there is no evidence for further positive functional remodeling beyond the acute effects of PPVI.

A pilot study on the effects of carvedilol on right ventricular remodelling and exercise tolerance in patients with systemic right ventricle

BACKGROUND Patients with atrial repair for transposition of the great arteries and patients with congenitally corrected transposition have a right ventricle (RV) in the systemic position and they may develop RV dysfunction and exercise intolerance with advancing age. No data is available on the effect of carvedilol in patients with dysfunctional systemic RV. METHODS We studied with cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing, and standard 12-leads electrocardiogram, 8 adults (median age 26 years, range 18-31) with chronic stable heart failure and systemic RV dysfunction (6 patients with atrial repair and 2 patients with congenitally corrected transposition). Assessment was done before and after 12 months of carvedilol administration. The initial dose was 3.125 mg twice daily, and the target dose was 25 mg twice a day. RESULTS Carvedilol administration was safe and the target dose was achieved in 5/8 (62%) patients. Right ventricular end-diastolic (119 ± 31 vs. 112 ± 28 ml/m², p=0.01) and end-systolic volumes decreased (79 ± 17 vs. 65 ± 14 ml/m², p=0.006), and RV ejection fraction improved (34 ± 6 vs. 42 ± 7%, p=0.004). Left ventricular ejection fraction increased (44 ± 8 vs. 49 ± 9%, p=0.01), suggesting a positive biventricular remodelling. Peak oxygen uptake did not change with carvedilol (26.8 ± 5.3 vs. 27.3 ± 5.7 ml O₂/Kg/min, p=0.58), whereas exercise duration increased (13.4 ± 2.6 vs. 17.3 ± 3.1 min, p=0.008). CONCLUSIONS In this small cohort, carvedilol administration was safe and it was associated with positive RV remodelling as well as improved exercise duration.

The Congenital Heart Disease Genetic Network Study Rationale, Design, and Early Results

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 Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.

Prevalence and predictors of neoaortic regurgitation after arterial switch operation for transposition of the great arteries

BACKGROUND The fate of the native pulmonary valve after arterial switch operation is still unknown and may become a cause for a secondary aortic valve operation during adult life. We evaluated the prevalence and predictive factors associated with neoaortic valvular regurgitation by a retrospective study of children who underwent arterial switch operation for transposition of the great arteries. METHODS The onset of neoaortic valvular regurgitation was correlated with demographic data, cardiac anatomy, surgical technique, and postoperative ventricular function. The size of the neoaortic root and ascending aorta was measured in a selected subset of patients. RESULTS Among 253 survivors, 173 were eligible for the study. After a median follow-up time of 8.2 years, 61 patients showed echocardiographic or angiographic evidence of valvular incompetence, which was progressive in 14 cases; this led to surgical intervention in 2 patients, and there was 1 operative death. At multivariate analysis, the onset of valvular regurgitation was correlated with the trap-door technique for coronary reimplantation (P <.01). A smooth transition from the aortic sinus to the ascending aorta, with loss of the normal sinotubular junction geometry, may be associated with valvular incompetence. CONCLUSIONS After arterial switch operation, there is an increasing frequency of neoaortic regurgitation, which may lead to significant valvular dysfunction later in life. The trap-door type of coronary reimplantation is associated with an increased risk for valvular dysfunction, possibly because of a distortion of the sinotubular junction geometry. For this reason, we recommend the punch technique for repair in all but the most complicated coronary pattern.