Spontaneous resolution of an intrapericardial thrombus as a complication of pericardiocentesis in a neonate.

We present the case of a premature neonate with pericardial effusion secondary to extravasation of total parenteral nutrition from a mispositioned/migrated umbilical venous catheter. Emergency pericardiocentesis was complicated by an intrapericardial thrombus, which was managed conservatively with spontaneous resolution within 24 hours. This case illustrates that the rare complication of an intrapericardial thrombus after pericardiocentesis can be successfully managed conservatively with close monitoring in haemodynamically stable paediatric patients.

Evaluation of late cardiac effects after multisystem inflammatory syndrome in children.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is associated with important cardiovascular morbidity during the acute phase. Follow-up shows a swift recovery of cardiac abnormalities in most patients. However, a small portion of patients has persistent cardiac sequelae at mid-term. The goal of our study was to assess late cardiac outcomes of MIS-C. Methods: A prospective observational multicenter study was performed in children admitted with MIS-C and cardiac involvement between April 2020 and March 2022. A follow-up by NT-proBNP measurement, echocardiography, 24-h Holter monitoring, and cardiac MRI (CMR) was performed at least 6 months after MIS-C diagnosis. Results: We included 36 children with a median age of 10 (8.0-11.0) years, and among them, 21 (58%) were girls. At diagnosis, all patients had an elevated NT-proBNP, and 39% had a decreased left ventricular ejection fraction (LVEF) (<55%). ECG abnormalities were present in 13 (36%) patients, but none presented with arrhythmia. Almost two-thirds of patients (58%) had echocardiographic abnormalities such as coronary artery dilation (20%), pericardial effusion (17%), and mitral valve insufficiency (14%). A decreased echocardiographic systolic left ventricular (LV) function was detected in 14 (39%) patients. A follow-up visit was done at a mean time of 12.1 (±5.8) months (range 6-28 months). The ECG normalized in all except one, and no arrhythmias were detected on 24-h Holter monitoring. None had persistent coronary artery dilation or pericardial effusion. The NT-proBNP level and echocardiographic systolic LV function normalized in all patients, except for one, who had a severely reduced EF. The LV global longitudinal strain (GLS), as a marker of subclinical myocardial dysfunction, decreased (z < -2) in 35%. CMR identified one patient with severely reduced EF and extensive myocardial fibrosis requiring heart transplantation. None of the other patients had signs of myocardial scarring on CMR. Conclusion: Late cardiac outcomes after MIS-C, if treated according to the current guidelines, are excellent. CMR does not show any myocardial scarring in children with normal systolic LV function. However, a subgroup had a decreased GLS at follow-up, possibly as a reflection of persistent subclinical myocardial dysfunction.

Physical activity and physical fitness in children with heritable connective tissue disorders.

Objectives: Health problems in patients with heritable connective tissue disorders (HCTD) are diverse and complex and might lead to lower physical activity (PA) and physical fitness (PF). This study aimed to investigate the PA and PF of children with heritable connective tissue disorders (HCTD). Methods: PA was assessed using an accelerometer-based activity monitor (ActivPAL) and the mobility subscale of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). PF was measured in terms of cardiovascular endurance using the Fitkids Treadmill Test (FTT); maximal hand grip strength, using hand grip dynamometry (HGD) as an indicator of muscle strength; and motor proficiency, using the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOTMP-2). Results: A total of 56 children, with a median age of 11.6 (interquartile range [IQR], 8.8-15.8) years, diagnosed with Marfan syndrome (MFS), n = 37, Loeys-Dietz syndrome (LDS), n = 6, and genetically confirmed Ehlers-Danlos (EDS) syndromes, n = 13 (including classical EDS n = 10, vascular EDS n = 1, dermatosparaxis EDS n = 1, arthrochalasia EDS n = 1), participated. Regarding PA, children with HCTD were active for 4.5 (IQR 3.5-5.2) hours/day, spent 9.2 (IQR 7.6-10.4) hours/day sedentary, slept 11.2 (IQR 9.5-11.5) hours/day, and performed 8,351.7 (IQR 6,456.9-1,0484.6) steps/day. They scored below average (mean (standard deviation [SD]) z-score -1.4 (1.6)) on the PEDI-CAT mobility subscale. Regarding PF, children with HCTD scored well below average on the FFT (mean (SD) z-score -3.3 (3.2)) and below average on the HGD (mean (SD) z-score -1.1 (1.2)) compared to normative data. Contradictory, the BOTMP-2 score was classified as average (mean (SD) z-score.02 (.98)). Moderate positive correlations were found between PA and PF (r(39) = .378, p < .001). Moderately sized negative correlations were found between pain intensity and fatigue and time spent actively (r(35) = .408, p < .001 and r(24) = .395 p < .001, respectively). Conclusion: This study is the first to demonstrate reduced PA and PF in children with HCTD. PF was moderately positively correlated with PA and negatively correlated with pain intensity and fatigue. Reduced cardiovascular endurance, muscle strength, and deconditioning, combined with disorder-specific cardiovascular and musculoskeletal features, are hypothesized to be causal. Identifying the limitations in PA and PF provides a starting point for tailor-made interventions.

Generation of human induced pluripotent stem cell line UGENTi001-A from a patient with Marfan syndrome carrying a heterozygous c.7754 T > C variant in FBN1 and the isogenic control UGENT001-A-1 using CRISPR/Cas9 editing.

Marfan syndrome is an autosomal dominant genetic disorder resulting from pathogenic variants in FBN1 gene. FBN1 encodes for fibrillin-1, an important extracellular matrix protein. Impaired fibrillin-1 affects multiple organ systems, including the cardiovascular system. We generated an iPSC line carrying a heterozygous variant c.7754 T > C (p.Ile2585Thr, missense) in FBN1 from a patient with Marfan syndrome. Also, an isogenic control is generated, where the pathogenic variant is repaired using CRISPR-Cas9. This isogenic pair provides a valuable resource for in vitro disease modelling.

HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN.

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFß pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives.

EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA.

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Arrhythmia and impaired myocardial function in heritable thoracic aortic disease: An international retrospective cohort study.

BACKGROUND: Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-ß signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. METHODS: This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF<50%). Arrhythmias included atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (presumed arrhythmogenic) (SCD). RESULTS: Medical records of 3219 patients with HTAD were screened (2761, 385 and 73 carrying a PV/LPV in FBN1, in a TGF-ß signaling gene and in ACTA2 respectively). Non-aortic cardiac disease was reported 142 times in 101 patients (3.1%) (age 37 [range 12-77] years, 39% female): 88 patients carrying an FBN1 PV/LPV and 13 carrying a PV/LPV in one of the TGF-ß signaling genes. Neither impaired myocardial function nor arrhythmia was reported in screened patients carrying a PV/LPV in ACTA2. Among the 142 reported non-aortic cardiac diseases, 68 (48%) were impaired myocardial function, 47 (33%) were AF/AFL and 27 (19%) were VT/VF/SCD. Among the patients with non-aortic cardiac disease, prior cardiac surgery was noted in 80% and severe valvular disease (valvular surgery or severe valvular regurgitation) in 58%, while 18% of the patients developed non-aortic cardiac disease in the absence of any of the latter. CONCLUSIONS: In patients with HTAD, arrhythmia and impaired myocardial function was reported in patients with PV/LPVs in FBN1 and in the TGF-ß signaling genes and not in patients harboring PV/LPVs in ACTA2. Though infrequent, non-aortic cardiac disease should be acknowledged as potentially severe, also occurring in young patients with no underlying significant valvular or aortic disease.

Cardiomyopathy in Genetic Aortic Diseases.

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome.

Importance: Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored. Objective: To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS. Design, Setting, and Participants: This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019. Main Outcomes and Measures: The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery. Results: A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD. Conclusions and Relevance: This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.

A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations.

PURPOSE: The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data. METHODS: This study uses exome sequencing and corresponding phenotypic data from Mount Sinai's BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1. RESULTS: Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5). CONCLUSIONS: Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.

Analysis of the recovery phase after maximal exercise in children with repaired tetralogy of Fallot and the relationship with ventricular function.

BACKGROUND: Few studies demonstrate delayed recovery after exercise in children and adults with heart disease. We assess the recovery patterns of gas exchange parameters and heart rate (HR) in children with repaired Tetralogy of Fallot (rToF) compared to healthy peers and investigate the correlation with ventricular function and QRS duration. METHODS: 45 children after rToF and 45 controls performed a maximal incremental cardiopulmonary exercise test. In the subsequent recovery period, patterns of VO2, VCO2 and HR were analysed. Half-life time (T1/2) of the exponential decay and drop per minute (Recmin) were compared between groups. In the rToF group, correlations were examined between the recovery parameters and QRS-duration and ventricular function, described by fractional shortening (FS) and tricuspid annular plane systolic excursion (TAPSE) measured at baseline prior to exercise. RESULTS: Recovery of VO2 and VCO2 was delayed in rToF patients, half-life time values were higher compared to controls (T1/2VO2 52.51 ±11.29 s vs. 44.31 ± 10.47 s; p = 0.001 and T1/2VCO2 68.28 ± 13.84 s vs. 59.41 ± 12.06 s; p = 0.002) and percentage drop from maximal value was slower at each minute of recovery (p<0.05). Correlations were found with FS (T1/2VO2: r = -0.517; p<0.001; Rec1minVO2: r = -0.636, p<0.001; Rec1minVCO2: r = -0.373, p = 0.012) and TAPSE (T1/2VO2: r = -0.505; p<0.001; Rec1minVO2: r = -0.566, p<0.001; T1/2VCO2: r = -0.466; p = 0.001; Rec1minVCO2: r = -0.507, p<0.001), not with QRS-duration. No difference was found in HR recovery between patients and controls. CONCLUSIONS: Children after rToF show a delayed gas exchange recovery after exercise. This delay correlates to ventricular function, demonstrating its importance in recovery after physical activity.

Genética en la cardiopatía congénita: ¿estamos preparados? / Genetics in congenital heart disease. Are we ready for it?

En los últimos años, la genética ha adquirido merecidamente un lugar importante en casi todas las disciplinas médicas, y este también es el caso en el campo de las cardiopatías congénitas. Esto no solo ha llevado a una mejor comprensión de la fisiopatología de los defectos cardiacos congénitos, sino que también conlleva un impacto positivo en el tratamiento del paciente. La integración de la genética clínica en centros acreditados para el abordaje de las cardiopatías congénitas es sin duda una recomendación clara. Los cardiólogos pediátricos y de adultos tienen un papel crucial en el proceso de evaluación genética de los pacientes y sus familias, por lo que deben conocer las señales de alerta que justifiquen un estudio genético más o menos elaborado, así como el asesoramiento y la realización de otras pruebas. Para la correcta interpretación de los resultados de las pruebas genéticas, es esencial disponer de algunos conocimientos básicos. En este documento de revisión se proporciona una visión general práctica de lo que implica la evaluación genética, qué tipo de pruebas genéticas son posibles hoy y cómo se aplican al paciente individual en la práctica clínica

Genetics has rightly acquired an important place in almost all medical disciplines in recent years and this is certainly the case in the field of congenital cardiology. Not only has this led to greater insight into the pathophysiology of congenital heart defects but it also has a beneficial impact on patient management. Integration of clinical genetics in multidisciplinary centers of expertise for CHD is therefore a clear recommendation. Adult and pediatric cardiologists play a crucial role in the process of genetic evaluation of patients and families and should have be familiar with red flags for referral for further clinical genetic elaboration, counseling, and eventual testing. Some basic knowledge is also important for the correct interpretation of genetic testing results. In this review article, we provide a practical overview of what genetic evaluation entails, which type of genetic tests are possible today, and how this can be used in practice for the individual patient

Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study.

BACKGROUND: Aortic root dilatation and-dissection and mitral valve prolapse are established cardiovascular manifestations in Marfan syndrome (MFS). Heart failure and arrhythmic sudden cardiac death have emerged as additional causes of morbidity and mortality. METHODS: To characterize myocardial dysfunction and arrhythmia in MFS we conducted a prospective longitudinal case-control study including 86 patients with MFS (55.8% women, mean age 36.3 yr-range 13-70 yr-) and 40 age-and sex-matched healthy controls. Cardiac ultrasound, resting and ambulatory ECG (AECG) and NT-proBNP measurements were performed in all subjects at baseline. Additionally, patients with MFS underwent 2 extra evaluations during 30 ± 7 months follow-up. To study primary versus secondary myocardial involvement, patients with MFS were divided in 2 groups: without previous surgery and normal/mild valvular function (MFS-1; N = 55) and with previous surgery or valvular dysfunction (MFS-2; N = 31). RESULTS: Compared to controls, patients in MFS-1 showed mild myocardial disease reflected in a larger left ventricular end-diastolic diameter (LVEDD), lower TAPSE and higher amount of (supra) ventricular extrasystoles [(S)VES]. Patients in MFS-2 were more severely affected. Seven patients (five in MFS-2) presented decreased LV ejection fraction. Twenty patients (twelve in MFS-2) had non-sustained ventricular tachycardia (NSVT) in at least one AECG. Larger LVEDD and higher amount of VES were independently associated with NSVT. CONCLUSION: Our study shows mild but significant myocardial involvement in patients with MFS. Patients with previous surgery or valvular dysfunction are more severely affected. Evaluation of myocardial function with echocardiography and AECG should be considered in all patients with MFS, especially in those with valvular disease and a history of cardiac surgery.

Myocardial Function, Heart Failure and Arrhythmia in Marfan Syndrome: A Systematic Literature Review.

Marfan syndrome (MFS) is a heritable systemic connective tissue disease with important cardiovascular involvement, including aortic root dilatation and mitral valve prolapse. Life expectancy in patients with MFS is mainly determined by cardiovascular complications, among which aortic dissection or rupture are most dreaded. In recent years, heart failure and ventricular arrhythmia have drawn attention as extra-aortic cardiovascular manifestations and as additional reported causes of death. Imaging studies have provided data supporting a primary myocardial impairment in the absence of valvular disease or cardiovascular surgery, while studies using ambulatory ECG have demonstrated an increased susceptibility to ventricular arrhythmia. In this paper, current literature was reviewed in order to provide insights in characteristics, pathophysiology and evolution of myocardial function, heart failure and ventricular arrhythmia in MFS.

Genetics in congenital heart disease. Are we ready for it?

Genetics has rightly acquired an important place in almost all medical disciplines in recent years and this is certainly the case in the field of congenital cardiology. Not only has this led to greater insight into the pathophysiology of congenital heart defects but it also has a beneficial impact on patient management. Integration of clinical genetics in multidisciplinary centers of expertise for CHD is therefore a clear recommendation. Adult and pediatric cardiologists play a crucial role in the process of genetic evaluation of patients and families and should have be familiar with red flags for referral for further clinical genetic elaboration, counseling, and eventual testing. Some basic knowledge is also important for the correct interpretation of genetic testing results. In this review article, we provide a practical overview of what genetic evaluation entails, which type of genetic tests are possible today, and how this can be used in practice for the individual patient.