Cardiac Drugs in ACHD Cardiovascular Medicine.

Adult congenital heart disease (ACHD) is a growing population that requires life-long care due to advances in pediatric care and surgical or catheter procedures. Despite this, drug therapy in ACHD remains largely empiric due to the lack of clinical data, and formalized guidelines on drug therapy are currently lacking. The aging ACHD population has led to an increase in late cardiovascular complications such as heart failure, arrhythmias, and pulmonary hypertension. Pharmacotherapy, with few exceptions, in ACHD is largely supportive, whereas significant structural abnormalities usually require interventional, surgical, or percutaneous treatment. Recent advances in ACHD have prolonged survival for these patients, but further research is needed to determine the most effective treatment options for these patients. A better understanding of the use of cardiac drugs in ACHD patients could lead to improved treatment outcomes and a better quality of life for these patients. This review aims to provide an overview of the current status of cardiac drugs in ACHD cardiovascular medicine, including the rationale, limited current evidence, and knowledge gaps in this growing area.

Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Diagnostic Value of 18F-Fluorodeoxyglucose Positron Emission Tomography Computed Tomography in Prosthetic Pulmonary Valve Infective Endocarditis.

OBJECTIVES: The aim of this study was to assess the diagnostic performances of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in congenital heart disease (CHD) patients with pulmonary prosthetic valve or conduit endocarditis (PPVE) suspicion. BACKGROUND: PPVE is a major issue in the growing CHD population. Diagnosis is challenging, and usual imaging tools are not always efficient or validated in this specific population. Particularly, the diagnostic yield of 18F-FDG PET/CT remains poorly studied in PPVE. METHODS: A retrospective multicenter study was conducted in 8 French tertiary centers. Children and adult CHD patients who underwent 18F-FDG PET/CT in the setting of PPVE suspicion between January 2010 and May 2020 were included. The cases were initially classified as definite, possible, or rejected PPVE regarding the modified Duke criteria and finally by the Endocarditis Team consensus. The result of 18F-FDG PET/CT had been compared with final diagnosis consensus used as gold-standard in our study. RESULTS: A total of 66 cases of PPVE suspicion involving 59 patients (median age 23 years, 73% men) were included. Sensitivity, specificity, positive predictive value, and negative predictive value of 18F-FDG PET/CT in PPVE suspicion were respectively: 79.1% (95% CI: 68.4%-91.4%), 72.7% (95% CI: 60.4%-85.0%), 91.9% (95% CI: 79.6%-100.0%), and 47.1% (95% CI: 34.8%-59.4%). 18F-FDG PET/CT findings would help to correctly reclassify 57% (4 of 7) of possible PPVE to definite PPVE. CONCLUSIONS: Using 18F-FDG PET/CT improves the diagnostic accuracy of the Duke criteria in CHD patients with suspected PPVE. Its high positive predictive value could be helpful in routine to shorten diagnosis and treatment delays and improve clinical outcomes.

Edwards SAPIEN XT transcatheter pulmonary valve implantation: 5-year follow-up in a French Registry.

OBJECTIVES: This study sought to investigate patient intermediate-term outcomes after transcatheter pulmonary valve replacement (TPVR) with Edwards SAPIEN valve. BACKGROUND: The Edwards SAPIEN valve, initially designed for percutaneous aortic valve replacement, has been approved for TPVR in patients with dysfunctional right ventricular outflow tracts (RVOT), but only short-term follow-up has been reported. METHODS: From 2011 to 2016, 62 patients undergoing successful TPVR using the SAPIEN XT valve were consecutively included into the study. Primary efficacy and safety endpoints were defined as freedom from valve-reintervention and freedom from infective endocarditis at last follow-up, respectively. RESULTS: The primary efficacy outcome was met for 87.1% patients after a mean follow-up of 4.6 ± 1.8 years, corresponding to a freedom of reintervention at 5 years of 89% (95% CI 74.8-95.6%). Reinterventions were exclusively due to recurrent obstruction, no significant valvular regurgitation was observed. One case of infective endocarditis was reported, corresponding to a rate of 0.35% per patient-year (95% CI 0.01-2.00%). At 5 years, freedom from infective endocarditis was 98.4% (95% CI 89.1-99.8%). Six patients died or were transplanted due to advanced cardiac failure, without relationship with TPVR. In univariate analysis, reintervention was associated with young age, a smaller tube-graft, a higher pulmonary valve gradient after the procedure and a ratio of largest implanted stent diameter to invasive balloon conduit diameter over 1.35. CONCLUSIONS: This study documents the mid-term safety and efficacy of the Edwards SAPIEN XT valve in patients with dysfunctional RVOT, and identifies a patient profile associated with an uncertain benefit-risk balance.

Measurement, consequences and determinants of time to diagnosis in children with new-onset heart failure: A population-based retrospective study (DIACARD study).

BACKGROUND: Time from first symptoms to diagnosis, called time to diagnosis, is related to prognosis in several diseases. The aim of this study was to assess time to diagnosis in children with new-onset heart failure (HF) and assess its consequences and determinants. METHODS: A retrospective population-based observational study was conducted between 2007 and 2016 in a French tertiary care center. We included all children under 16 years old with no known heart disease, and HF confirmed by echocardiography. With logistic regression used for outcomes and a Cox proportional-hazards model for determinants, analyses were stratified by HF etiology: congenital heart diseases (CHD) and cardiomyopathies/myocarditis (CM). RESULTS: A total of 117 children were included (median age [interquartile range (IQR)] 25 days (6-146), 50.4% were male, 60 had CHD and 57 had CM). Overall median (IQR) time to diagnosis was 3.3 days (1.0-21.2). The frequency of 1-year mortality was 17% and 1-year neuromotor sequel 18%. Death at 1 year was associated with low birth weight for all patients (adjusted odds ratio 0.24, 95% confidence interval [CI] 0.08-0.68) and time to diagnosis below the median with CM (0.09, 0.01-0.87) but not time to diagnosis above the median for all patients (0.59, 0.13-2.66). Short time to diagnosis was associated with clinical severity on the first day of symptoms for all patients (adjusted hazard ratio 3.39, 95% CI 2.01-5.72), and young age with CM (0.09, 0.02-0.41). CONCLUSIONS: In children with new-onset HF presenting in our region, median time to diagnosis was short. Long time to diagnosis was not associated with poor outcome.

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.

AIMS: Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear. METHODS AND RESULTS: Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed. Six families were included. Genetic analysis revealed a variant in desmosomal proteins genes in all the probands [five in desmoplakin (DSP) gene and one in desmoglein 2 gene]. In the five families identified with a DSP variant, genetic testing was triggered by the association of an acute myocarditis with a single case of apparently isolated dilated cardiomyopathy or sudden death. Familial screening identified 28 DSP variant carriers; 39% had an arrhythmogenic left ventricular (LV) cardiomyopathy phenotype. Familial histories of sudden death were frequent, and a remarkable phenotype of isolated LV late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance without any other structural abnormality was found in 38% of asymptomatic mutation carriers. None of the DSP variant carriers had imaging characteristics of right ventricle involvement meeting current Task Force criteria for arrhythmogenic right ventricular cardiomyopathy. CONCLUSIONS: Comprehensive familial screening including genetic testing in case of acute myocarditis associated with a family history of cardiomyopathy or sudden death revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that frequently evade arrhythmogenic right ventricular cardiomyopathy Task Force criteria. In view of our results, acute myocarditis should be considered as an additional criterion for arrhythmogenic cardiomyopathy, and genetic testing should be advised in patients who experience acute myocarditis and have a family history of cardiomyopathy or sudden death.

Pathophysiology and natural history of atrial septal defect.

Atrial septal defects are among the third most common types of congenital heart disease. This group of malformations includes several types of atrial communications allowing shunting of blood between the systemic and the pulmonary circulations. The nature of shunting across the defect in patients with atrial septal defect is of particular interest. Understanding the underlying mechanisms of interatrial shunts and their natural history will help selecting the best timing for closure, before irreversible cardiac and pulmonary injury occur. This review describes the different pathophysiologic mechanisms involved in the direction and magnitude of blood flow through atrial septal defects. The natural history of an individual born with an isolated atrial septal defect is then discussed, including the impact of a longstanding shunt on survival.

Edwards SAPIEN Transcatheter Pulmonary Valve Implantation: Results From a French Registry.

OBJECTIVES: The aim of this study was to describe and analyze data from patients treated in France with the Edwards SAPIEN transcatheter heart valve (Edwards Lifesciences LLC, Irvine, California) in the pulmonary position. BACKGROUND: The Edwards SAPIEN valve has recently been introduced for percutaneous pulmonary valve implantation (PPVI). METHODS: From April 2011 to May 2017, 71 patients undergoing PPVI were consecutively included. RESULTS: The median age at PPVI was 26.8 years (range 12.8 to 70.1 years). Primary underlying diagnoses were conotruncal malformations (common arterial trunk, tetralogy of Fallot and variants; n = 45), Ross procedure (n = 18), and other diagnoses (n = 8). PPVI indication was pure stenosis in 33.8% of patients, pure regurgitation in 28.1%, and mixed lesions in 38.1%. PPVI was successfully implemented in 68 patients (95.8%). Pre-stenting of the right ventricular outflow tract was performed in 70 patients (98.6%). Early major complications occurred in 4 subjects (5.6%), including 1 death, 1 coronary compression, and 2 pulmonary valve embolizations. Three of the 4 major complications occurred in the first 15 operated patients. No significant regurgitation was recorded after the procedure. Transpulmonary gradient was significantly reduced from 34.5 to 10.5 mm Hg (p < 0.0001). No patient died during a 1-month follow-up period. At 1-year follow-up, the death rate was 2.9%, and 3 patients had undergone surgical reintervention (44%). CONCLUSIONS: Early results with the Edwards SAPIEN valve in the pulmonary position demonstrate an ongoing high rate of procedural success.

Value of Image Fusion in Coronary Angiography for the Detection of Coronary Artery Bypass Grafts.

BACKGROUND: Coronary angiography is more complex in patients with coronary artery bypass grafts (CABG). Image fusion is a new technology that allows the overlay of a computed tomography (CT) three-dimension (3D) model with fluoroscopic images in real time. METHODS AND RESULTS: This single-center prospective study included 66 previous CABG patients undergoing coronary and bypass graft angiography. Image fusion coronary angiographies (fusion group, 20 patients) were compared to conventional coronary angiographies (control group, 46 patients). The fusion group included patients for whom a previous chest CT scan with contrast was available. For patients in this group, aorta and CABG were reconstructed in 3D from CT acquisitions and merged in real time with fluoroscopic images. The following parameters were compared: time needed to localize the CABG; procedure duration; air kerma (AK); dose area product (DAP); and volume of contrast media injected. Results are expressed as median. There were no significant differences between the 2 groups in patient demographics and procedure characteristics (access site, number of bypass to be found, and interventional cardiologist's experience). The time to localize CABG was significantly shorter in the fusion group (7.3 versus 12.4 minutes; P=0.002), as well as the procedure duration (20.6 versus 25.6 minutes; P=0.002), AK (610 versus 814 mGy; P=0.02), DAP (4390 versus 5922.5 cGy·cm(2); P=0.02), and volume of iodinated contrast media (85 versus 116 cc; P=0.002). CONCLUSIONS: 3D image fusion improves the CABG detection in coronary angiography and reduces the time necessary to localize CABG, total procedure time duration, radiation exposure, and volume of contrast media.

Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.

We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.

Transcatheter closure of coronary artery fistulas in infants and children: A French multicenter study.

OBJECTIVES: The short-term efficacy and safety of transcatheter closure (TCC) for the management of coronary artery fistulas (CAFs) was investigated in pediatric patients. BACKGROUND: CAFS are rare with potentially severe complications and their management is still a matter of debate. Percutaneous closure appears to be the treatment of choice in anatomically suitable vessels but limited data are available in the pediatric population. METHODS: This retrospective, observational, multicenter, national study included patients under 16 years of age who underwent TCC of a congenital CAF. Patients with additional congenital heart defect were excluded. RESULTS: 61 patients (36 girls, 25 boys) with a median age of 0.6 year [0-15.4] at diagnosis and 3.9 years [0-16] at procedure were included. The CAF was large in 48 patients (79%); it was distal in 23 (38%) and proximal in 22 (36%). Most patients (77%) were asymptomatic at diagnosis. Clinical signs of congestive heart failure were present in seven patients (11%). Perioperative complications included three cases of ST elevation myocardial infarction (exclusively during attempted closure of a distal CAF), three devices migrations, and one case of leg ischemia. One patient died after surgical closure of a large distal CAF that could not be closed by TCC. Follow-up data were collected for 43 patients (70%) for a median of 91 days [0-4,824]. The Kaplan-Meyer estimate for complete occlusion at 2 years was 73 ± 7.6%. CONCLUSION: TCC in the pediatric population appears to be effective and associated with few complications.

Maternal and fetal outcomes of pregnancy with Fontan circulation: A multicentric observational study.

BACKGROUND: Despite serious long-term sequel, women with Fontan palliation have reached childbearing age. However there is paucity of data on the pregnancy outcomes and management of this condition. We aimed to determine the maternal and fetal outcomes of pregnancy in women with Fontan palliation. METHODS: This multicentric, retrospective study included women with Fontan circulation followed in 13 French specialized centers from January 2000 to June 2014. All pregnancies were reviewed, including miscarriages, abortions, premature and term births. We reviewed maternal and fetal outcomes. RESULTS: Thirty-seven patients had 59 pregnancies. Mean age was 27 ± 5 years at first pregnancy. There were 16 miscarriages (27%) and 36 live births with 1 twin pregnancy. Cardiac events occurred in 6 (10%) pregnancies, with no maternal death. The most common cardiac complication was atrial arrhythmia, which occurred in 3 patients. Hematological complications including thromboembolic/hemorrhagic events (n=3/7) occurred in 5 women antepartum (n=2/3), and 4 women postpartum (n=1/4). Two of the 3 thromboembolic events occurred in patients without anticoagulation. There was a high incidence of prematurity (n=25/36, 69%). Anticoagulation was associated with adverse neonatal outcome (OR=10.0, 95% CI [1.5-91.4], p<0.01). After a median follow-up of 24 months, there was no significant worsening of clinical status and thromboembolic disease noted. CONCLUSIONS: Pre-selected women can successfully complete pregnancy with Fontan circulation. There is an increase in cardiac and neonatal morbidity during pregnancy. Because thromboembolism could have a severe consequence on Fontan circulation, anticoagulation should be indicated during pregnancy and postpartum period.

Late repair of tetralogy of Fallot during childhood in patients from developing countries.

OBJECTIVES: Although the current surgical approach of tetralogy of Fallot (TOF) is primary complete repair in infancy, late diagnosis and lack of surgical facilities in developing countries may delay surgical treatment. Some of these patients exposed to prolonged chronic hypoxaemia are transferred to more privileged countries to undergo surgical repair with the support of non-governmental organizations. The objective of this single-centre retrospective study was to compare the postoperative outcomes of these foreign patients undergoing delayed repair with those of patients born in France undergoing timely repair during the same time period. METHODS: The computer database of our institution was searched for all cases of TOF in foreign patients younger than 15 years, supported by two non-profit organizations, who underwent complete repair between January 2007 and December 2013. The control population consisted of the patients with TOF born in France, who underwent timely complete repair during the same period. RESULTS: The 47 foreign children were older (57.6 ± 38.4 vs 8.3 ± 9.1 months, P < 0.0001), more hypoxaemic (SaO2 79 ± 11 vs 91 ± 8%, P < 0.0001), more growth-retarded (body mass index Z-score -1.35 ± 1.5 vs -0.46 ± 1.3, P = 0.0034), and had higher haematocrit level (52.5 ± 11.7 vs 37.5 ± 6.1%, <0.0001) and worse left ventricular ejection fraction (LVEF 62 ± 8 vs 69 ± 3.8%, P < 0.0001) than the 90 French patients. Postoperative mortality and morbidity (sepsis, arrhythmia, bleeding and need for surgical revision) were similar in the two groups, except for a higher rate of pericardial and/or pleural effusion in foreign children (36 vs 17%, P = 0.02). Length of stay was shorter in foreign than in French patients (11 ± 6 vs 15 ± 15 days, P = 0.0012). CONCLUSIONS: In our experience, despite the presence of several risk factors (growth retardation, chronic hypoxaemia, polycythaemia and left ventricular dysfunction), late repair of TOF was undertaken during childhood in patients from developing countries with no difference in postoperative morbidity and mortality compared with that of timely repair during infancy. These older patients can be discharged sooner. However, patients undergoing late surgery may be at higher risk of complications of right ventricular failure, such as pleural and/or pericardial effusion.

Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations.

Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of sudden cardiac death. We have recently reported families with BrS and SCN5A mutations where some affected members do not carry the familial mutation. We evaluated the involvement of additional genetic determinants for BrS in an affected family. We identified three distinct gene variants within a family presenting BrS (5 individuals), cardiac conduction defects (CCD, 3 individuals) and shortened QT interval (4 individuals). The first mutation is nonsense, p.Q1695*, lying within the SCN5A gene, which encodes for NaV1.5, the α-subunit of the cardiac Na(+) channel. The second mutation is missense, p.N300D, and alters the CACNA1C gene, which encodes the α-subunit CaV1.2 of the L-type cardiac Ca(2+) channel. The SCN5A mutation strictly segregates with CCD. Four out of the 5 BrS patients carry the CACNA1C variant, and three of them present shortened QT interval. One of the BrS patients carries none of these mutations but a rare variant located in the ABCC9 gene as well as his asymptomatic mother. Patch-clamp studies identified a loss-of-function of the mutated CaV1.2 channel. Western-blot experiments showed a global expression defect while increased mobility of CaV1.2 channels on cell surface was revealed by FRAP experiments. Finally, computer simulations of the two mutations recapitulated patient phenotypes. We report a rare CACNA1C mutation as causing BrS and/or shortened QT interval in a family also carrying a SCN5A stop mutation, but which does not segregate with BrS. This study underlies the complexity of BrS inheritance and its pre-symptomatic genetic screening interpretation.

Aortic coarctation and the retinal microvasculature.

BACKGROUND: Aortic coarctation has been associated with generalized vascular disease, yet little is known about retinal vascular patterns and their changes over time. OBJECTIVES: The aim of this study is to characterize the nature and extent of retinal vascular disease in adults with aortic coarctation, and explore age-related effects and associations with cardiovascular outcomes. METHODS: A prospective cross-sectional seroepidemiological study was conducted on 60 consecutive adults with repaired aortic coarctation, age 42.4±14.1 years, 61.7% male. In addition to detailed questionnaires, imaging studies, and laboratory testing, high-quality retinal images were acquired by 45° nonmydriatic digital funduscopy. RESULTS: No patient had evidence of hypertensive retinopathy. A distinctive vascular pattern characterized by bilaterally symmetric tortuosity of retinal arteries and veins was observed. Arterial tortuosity was abnormal in 98.3% of patients and decreased with age (P=0.0005). In patients≥45 years, a 1-point increase in the arterial tortuosity score was associated with a 1.5-fold higher risk of cardiovascular complications (i.e., acute coronary syndrome, stroke, cerebral aneurysm, aortic dissection/rupture) [odds ratio 1.50, 95% CI (1.01, 2.24), P=0.0496]. Abnormal venous tortuosity was present in 75.0% of patients and non-significantly correlated with higher levels of serum inflammatory markers (C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-alpha). A higher venous tortuosity score was likewise associated with an increased risk of cardiovascular complications [odds ratio 1.86, 95% CI (1.03, 3.35), P=0.0392]. CONCLUSIONS: Adults with repaired aortic coarctation exhibit a unique retinal vascular pattern characterized by excessive arterial and venous tortuosity that regresses with age. Greater tortuosity is associated with adverse cardiovascular outcomes in patients≥45 years.