Ventricular Defect Research Articles

A cavalpulmonary assist device utilising impedance pumping enhanced by peristaltic effect.

Fontan procedure, the standard surgical palliation to treat children with single ventricular defects, causes systemic complications over years due to lack of pumping at cavopulmonary junction. A device developed specifically for cavopulmonary support is thus considered, while current commercial ventricular assist devices (VAD) induce high shear rates to blood, and have issues with paediatric suitability. To demonstrate the feasibility of a small, valveless, non-invasive to blood and pulsatile rotary pump, which integrates impedance and peristaltic effects. A prototype pump was designed and fabricated in-house without any effort to optimise its specification. It was then tested in vitro, in terms of effect of pumping frequency, background pressure differences and pump size on output performance. Net flow rate (NFR) and maximum pressure head delivery are both reasonably linearly dependent on pumping frequency within normal physiological range. Positive linearity is also observed between NFR and the extent of asymmetric pumping. The device regulates NFR in favourable pressure head difference and overcomes significant adverse pressure head difference. Additionally, performance is shown to be insensitive to device size. The feasibility of the novel rotary pump integrating impedance and peristaltic effects is demonstrated to perform in normal physiological conditions without any optimisation effort. It provides promising results for possible future paediatric cavopulmonary support and warrants further investigation of miniaturisation and possible haemolysis.

Patterns and Complications of Congenital Heart Disease in Adolescents and Adults in Ethiopia.

Congenital heart disease (CHD) encompasses morphofunctional anomalies in the heart and circulatory system present at birth, which may not become apparent until later in life. In Ethiopia, there needs to be more understanding of the prevalence, patterns, and associated complications of CHD malformations. This study aimed to investigate the patterns and complications of CHDs among patients receiving follow-up care at a specialized university referral hospital in Ethiopia. A hospital-based cross-sectional study was conducted on 199 patients with CHDs to assess the patterns and complications of defects. Retrospective data were collected from 16,972 patients who had follow-ups at a cardiac clinic in 2021 using medical records, and a statistical analysis was performed with SPSS version 24. The most prevalent types of CHDs in our study population were atrial septal defects (ASDs) at 41.2% (82 cases), ventricular septal defects (VSDs) at 26.6% (53 cases), and patent ductus arteriosus (PDAs) at 9.5% (19 cases). Complications related to CHDs were observed in 69.3% (138) of patients, with 30.7% (61) experiencing a single complication and 39.2% (87) experiencing multiple complications. This study found a higher prevalence of CHDs in females (77.8%) compared to males, a trend consistent across various atrial and ventricular defect types. Individuals aged 15 to 25 years exhibited the highest incidence of ASD and VSD. Moreover, CHD-related anomalies were present in 69.3% of the patients studied.

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna Δ9/Δ9 zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.

Sox7-positive endothelial progenitors establish coronary arteries and govern ventricular compaction.

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.

P53 DOUBLE OUTLET RIGHT VENTRICLE IN PATIENT WITH XP11.23 DUPLICATION AND SYNDROMIC PHENOTYPE: BROADENING OF THE CLINICAL SPECTRUM

Abstract DORV accounts for 2–3% of congenital heart disease (prevalence of 1/10,000). It is a cono–truncal anomaly with variable clinic. In 25–42.5% of cases there are chromosomal anomalies such as trisomy 13, 18, 22q11 microdeletion and possible associated anomalies such as facial and skeletal dysmorphisms, brain anomalies and renal agenesis. duplication Xp11.22–p11.23 was described in 2009 by Giorda and is characterized by intellectual disabilities, speech delay, epilepsy, and EEG abnormalities. We report the case of a patient with dupXp11.23 and major anomalies not reported in the literature. C.B. born from 1st pregnancy at 32+4 w, by cesarean section for fetal bradycardia and polyamnios; At first trimester screening, finding of large ventricular defect and high risk for trisomy 18 and 13. Non–resolving fetal DNA and normal 46XY karyotype. At birth weighing 1750 g, APGAR 1‘:3, 5‘:7,10‘: 8, he was intubated and transferred to intensive care. On physical examination: prominent frontal bumps, facial asymmetry with right hypoplasia, anterior plagiocephaly, microphthalmia, low–set left ear, large both pinnae, macroglossia, hypospadias. He underwent surgery for duodenal atresia and Meckel‘s diverticulum. In the following days poor clinical conditions, poor growth and manifestations of heart decompensation. On auscultation II tone of increased intensity, meso–pulmonary systolic murmur, hepatomegaly. The electrocardiogram showed normal sinus rhythm and signs of left ventricular hypertrophy. On echocardiogram Situs solitus –D loop Levocardia. Patent foramen ovale with middle left–right shunt, dilated left atrium, globular left ventricle, preserved systolic function. Poorly aligned arterial outflows emerging from the right ventricle. Large subpulmonary interventricular defect. Hyperflow flowmetry. Aortic arch dilated in the proximal tract. He therefore started therapy with furosemide. Subsequent monitoring showed poor growth for which cardiac surgery was indicated. This case report contributes to broadening the clinical spectrum of duplication syndrome Xp11.22–p11.23.

Laubry-Pezzi syndrome: three case reports and review of the literature.

We reported three cases of Laubry-Pezzi syndrome diagnosed in our department of cardiology on a cohort of more than 3000 cases of congenital heart disease. A 13-year-old patient presented a Laubry-Pezzi syndrome with severe AR and significant volumetric left ventricle overload and was operated on in time to allow a good evolution of his condition. A 43-year-old patient, followed for congenital cardiac pathology, presented with severe dyspnea. The echocardiogram found global dysfunction of the left ventricle with an ejection fraction of 35%, a perimembranous ventricular septal defect (VSD) almost completely closed by the prolapse of the noncoronary cusp, and severe eccentric aortic insufficiency due to the prolapse of the noncoronary cusp. Aortic valve replacement and VSD closure were indicated. The third patient is a 21-year-old patient with Down syndrome, in whom a grade 2/6 systolic murmur was detected. Transthoracic echocardiography revealed a perimembranous VSD measuring 4mm without any hemodynamic repercussions and a moderate aortic insufficiency due to the prolapse of the noncoronary cusp. Clinical and echocardiographic monitoring with Osler prevention was indicated as a modality of management. The pathophysiology is explained by the Venturi effect, the restrictive shunt of the VSD creates an area of low pressure that sucks the adjacent cusp resulting in aortic prolapse and regurgitation. The diagnosis is essentially based on transthoracic echocardiography; it must be conducted before the emergence of AR. The management of this rare syndrome still remains nonconsensual, whether it is through timing or operative techniques. Management must be early by closing the VSD with or without aortic valve intervention to prevent the onset or worsening of AR.

Decellularized Porcine Pericardium Enhances Autologous Vascularized Matrix as a Prosthesis for Left Ventricular Full-Wall Myocardial Reconstruction

Regenerative grafts for myocardial reconstruction are often mechanically not stable enough to withstand the left ventricle’s high blood pressure. Hence, decellularized pericardium may serve as a stabilizing structure for biological myocardium prostheses. The efficacy of detergent- and enzyme-based protocols to decellularize porcine pericardium was compared. Then, the decellularized pericardium was employed for a primary cover of a transmural left ventricular defect in minipigs (n = 9). This pericardium patch was applied to mitigate the high-pressure load on an autologous stomach tissue, which was utilized as a regenerative tissue prosthesis. Decellularization of the porcine pericardium with deoxycholic acid (DOA)- and enzyme-based protocols (trypsin/EDTA) removed 90% of the original cells (p < 0.001). The trypsin/EDTA protocol significantly altered the matrix architecture compared to the DOA protocol. There were no infections or clinical signs of graft rejection following the transplantation of the decellularized pericardium and the autologous segment of the stomach in the surviving animals (n = 7). A good left ventricular function could be detected via MRI six months following surgery. The biological integration of the graft into the host’s tissue was found histologically. The stabilization of initially fragile grafts with decellularized pericardium facilitates the application of regenerative myocardial prostheses even on the left ventricle.

Young Man With Syncope

A 29-year–old man presented to the emergency department with chest pain, dyspnea, and 4 episodes of nonexertional syncope, with the last episode being witnessed by emergency physicians. He had congenital aortic stenosis and a mechanical aortic valve and was anticoagulated. Two weeks prior, he had undergone repair of a right ventricular defect and pulmonic valve replacement. On examination, his blood pressure was 74/47 mmHg, his pulse rate was 130 beats/min with diminished peripheral pulses, and his respiratory rate was 40 breaths/min while speaking in full sentences.

Three centers experience with device closure of congenital Gerbode-type perimembranous ventricular septal defects.

We aim to evaluate our experience with interventional closure of Gerbode-type perimembranous ventricular septal defects (pmVSDs). We performed three-center retrospective data review of patients with congenital indirect Gerbode-type pmVSDs treated percutaneously between August 2017 and May 2021. Standard safety and latest follow-up outcomes were assessed. Ten patients (six females) were identified with a median age of 6.8 years (range: 2.5-54) and a median weight of 26.5 kg (range: 12-88). The median left ventricular defect size was 10 mm (range: 3-15.5). On baseline ultrasound, 6 patients had absent subaortic rim , 6 patients had trivial aortic regurgitation, and 3 patients had tear-drop-type (small) aortic cusp prolapse. The tricuspid regurgitation was graded II (n = 5)and III (n = 5). Five Lifetech Konar-Multifunctional occluders, four Amplatzer duct occluders II and one Amplatzer duct occluder I were implanted. The median fluoroscopy time was 10.4 min (range: 4.3-20.2). Pre-existing aortic regurgitations remained identical. One new aortic regurgitation was identified before discharge and remained trivial after 48 months of follow-up. No heart block or tricuspid stenosis was observed on a median follow-up of 17 months (range: 3-48). All patients are symptom-free with complete shunt closure and significant regression or resolution of tricuspid regurgitation. Despite anatomical challenges, interventional closure of congenital indirect Gerbode-type pmVSD appears to be feasible, safe, and most importantly clinically effective using different commercially available devices. Amplatzer duct occluder II and Lifetech Konar-Multifunctional occluder offer interesting specifications to retrogradely target this specific defect with success.

Computational profiling of hiPSC-derived heart organoids reveals chamber defects associated with NKX2-5 deficiency

Heart organoids have the potential to generate primary heart-like anatomical structures and hold great promise as in vitro models for cardiac disease. However, their properties have not yet been fully studied, which hinders their wide spread application. Here we report the development of differentiation systems for ventricular and atrial heart organoids, enabling the study of heart diseases with chamber defects. We show that our systems generate chamber-specific organoids comprising of the major cardiac cell types, and we use single cell RNA sequencing together with sample multiplexing to characterize the cells we generate. To that end, we developed a machine learning label transfer approach leveraging cell type, chamber, and laterality annotations available for primary human fetal heart cells. We then used this model to analyze organoid cells from an isogeneic line carrying an Ebstein’s anomaly associated genetic variant in NKX2-5, and we successfully recapitulated the disease’s atrialized ventricular defects. In summary, we have established a workflow integrating heart organoids and computational analysis to model heart development in normal and disease states.

Comparison of transient and permanent LAD ligation in mice using 18F-FDG PET imaging

ObjectiveAnimal models for myocardial injuries represent important cornerstones in cardiovascular research to monitor the pathological processes and therapeutic approaches. We investigated the association of 18F-FDG derived left ventricular metabolic volume (LVMV), defect area and cardiac function in mice after permanent or transient ligation of the left anterior descending artery (LAD).MethodsSerial non-invasive ECG-gated 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (18F-FDG PET) after permanent or transient LAD ligation enabled a longitudinal in vivo correlation of 18F-FDG derived left ventricular metabolic volume to functional parameters and myocardial defect.ResultsThe LVMV shows a more prominent drop after permanent than transient LAD ligation and recovers after 30 days. The loss of LVMV correlates with the defect area assessed by QPS software. Cardiac function parameters (e.g., EDV, ESV, SV) by the QGS software positively correlate with LVMV after permanent and transient LAD ligation.ConclusionsThis study provides novel insight into 18F-FDG derived LVMV after permanent and transient LAD ligation by longitudinal in 18F-FDG PET imaging and underlines the associations of the FDG derived parameter and cardiac function.

Endothelial-to-Mesenchymal Transition as Underlying Mechanism for the Formation of Double-Chambered Right Ventricle

Double-chambered right ventricle (DCRV) is a progressive division of the right ventricular outflow tract (RVOT) often associated with a subaortic ventricular defect (VSD). The septation is caused by a mixture of hypertrophied muscle bundles and fibrous tissue, whereof the latter is of unclear pathogenesis. Our group has previously reported that flow disturbances lead to formation of fibroelastic tissue through a process called endothelial-to-mesenchymal transition (EndMT) but it is unclear whether the same mechanism exists in the RV. Tissue from patients undergoing repair of DCRV was examined to identify the histomorphological substrate of this tissue. Demographic and pre-/post-operative echocardiographic data were collected from nine patients undergoing surgery for DCRV. RVOTO tissue samples were histologically analyzed for myocardial hypertrophy, fibrosis, elastin content, and active EndMT (immunohistochemical double-staining for endothelial and mesenchymal markers and transcription factors Slug/Snail) and compared to four healthy controls. Indication for surgery were symptoms and progressive RVOT gradients. A highly turbulent flow jet through the RVOTO and VSD was observed in all patients with a preoperative median RVOT peak gradient of 77 mmHg (IQR 55.0–91.5), improved to 6 mmHg (IQR 4.5–17) postoperatively. Histological analysis revealed muscle and thick infiltratively growing fibroelastic tissue. EndMT was confirmed as underlying patho-mechanism of this fibroelastic tissue but the degree of myocardial hypertrophy was not different compared to controls (P = 0.08). This study shows for the first time that an invasive fibroelastic remodeling processes of the endocardium into the underlying myocardium through activation of EndMT contributes to the septation of the RVOT.

Right Ventricular Outflow Tract Surgical Resection in Young, Large Animal Model for the Study of Alternative Cardiovascular Patches.

Tetralogy of Fallot (ToF) is a severe congenital heart defect (CHD) that requires surgical reconstruction soon after birth. Reconstructive surgery involves the implantation of synthetic cardiovascular patches to widen the right ventricular outflow tract (RVOT) and repair defects in the septal wall. However, synthetic patches can cause complications for these patients later in life as they do not integrate or adapt in the tissue of a growing patient; a limitation that could be solved with the development of a patch fabricated from a degradable biomaterial. Unfortunately, the lack of appropriate pre-clinical models has hindered the development of novel patch materials. Currently, most studies use rodent models to study the efficacy of new patch materials; however, large animal models are necessary to develop realistically sized patches in a clinically relevant growing heart where gradients in diffusion and length scales for cell migration are more similar to the human. Here, we describe a novel method by which a Satinsky vascular clamp is used to isolate RVOT muscle for resection followed by implantation of a cardiovascular patch in an appropriately young, rapidly growing porcine model.

Teratogenic effect of alcohol on the myocardium of laboratory animals at the stages of prenatal ontogenesis (literature review)

Background. To date, close attention is paid to the problems of formation and development of the myocardium in general and in particular its structural components. This phenomenon is associated with an increase in cardiovascular malformations in both adults and infants. These defects can be caused by genetic factors, as well as various teratogenic substances. One such substance is alcohol. Despite the risks, many women still drink alcohol during pregnancy. The main problem is that almost half of pregnancies are unplanned, so a woman may continue to consume alcohol for several weeks before learning about her condition. Especially in young women, fertilization can occur in a state of intoxication. In addition, under the influence of ethanol, cardiac function may be impaired in the absence of structural abnormalities. Chronic alcohol intoxication causes changes in the myocardium at all levels of its structural organization. First of all, teratogenic changes caused by the action of ethanol affect the development of cardiomyocytes in the process of embryogenesis, which contributes to the underdevelopment of the structure or function of heart cells. Although the effect of maternal alcohol consumption on the fetus has been studied for decades, there are still conflicting conclusions about the severity of myocardial morphological changes depending on the time, frequency and duration of alcohol consumption. Objective: to conduct a retrospective analysis of literature sources devoted to the study of adverse effects on the fetus caused by alcohol. Methods. The paper conducted a retrospective analysis of literature references and formed an understanding of the changes in the structure of the myocardium caused by teratogenic effects of alcohol. Results and conclusion. Analysis of literature sources showed a high level of adverse effects observed in offspring born to alcoholic mothers. Detrimental effects of alcohol cause changes in the myocardium at all levels of structural organization, including its ultrastructure. It was studied that prenatal exposure to ethanol induces significant changes in relative heart weight, left ventricular wall thickness and cardiomyocyte size. Exposure to high concentrations of alcohol in experimental animals during gestation can lead to congenital heart defects, such as atrial, ventricular, and septal defects. The main manifestation of the prenatal effect of alcohol after birth is the fetal alcohol syndrome, which combines various degrees of deviation in the development of the child.

Zebrafish Foxc1a controls ventricular chamber maturation by directly regulating wwtr1 and nkx2.5 expression

Chamber maturation is a significant process in cardiac development. Disorders of this crucial process lead to a range of congenital heart defects. Foxc1a is a critical transcription factor reported to regulate the specification of cardiac progenitor cells. However, little is known about the role of Foxc1a in modulating chamber maturation. Previously, we reported that foxc1a-null zebrafish embryos exhibit disrupted heart structures and functions. In this study, we observe that ventricle structure and cardiomyocyte proliferation are abolished during chamber maturation in foxc1a-null zebrafish embryos. To observe the endogenous localization of Foxc1a in the hearts of living embryos, we insert eyfp at the foxc1a genomic locus using TALEN. Analysis of the knockin zebrafish show that foxc1a is widely expressed in ventricular cardiomyocytes during chamber development. Cardiac RNA sequencing analysis reveals the downregulated expression of the Hippo signaling effector wwtr1. Dual-luciferase and chromatin immunoprecipitation assays reveal that Foxc1a can bind directly to three sites in the wwtr1 promoter region. Furthermore, wwtr1 mRNA overexpression is sufficient to reverse the ventricle defects during chamber maturation. Conditional overexpression of nkx2.5 also partially rescues the ventricular defects during chamber development. These findings demonstrate that wwtr1 and nkx2.5 are direct targets of Foxc1a during ventricular chamber maturation.

Cormatrix® for vessel reconstruction in paediatric cardiac surgery-a word of caution.

OBJECTIVESThe aim of this retrospective study was to determine if Cormatrix® (CM) represents a safe alternative to conventional patch materials used in congenital heart surgery.METHODSA total of 57 paediatric patients who underwent cardiac surgery using an Extracellular Matrix Bioscaffold (CM) were categorized into 4 groups according to the patch implant location. Patch-related complications and reintervention rates were analysed. A subgroup of 18 patients was subsequently compared to a matched group of 36 patients who underwent similar surgical procedures with autologous pericardium as patch material.RESULTSNo patient died during hospitalization. There were 2 late deaths, not related to the implanted CM patch. Fourteen (66.7%) out of 21 patients with arterial patch plasty developed progressive vessel/right ventricular outflow tract stenosis or aneurysm. All 3 patients with a valved CM conduit developed haemodynamically relevant valve stenosis or regurgitation. A total of 18 (31.5%) patients needed reintervention and 12 (21.1%) related to CM. Four (7%) patients needed surgical treatment with operative removal of the stenosis. Redo valve replacement was performed on 2 (3.5%) patients. Six (10.5%) patients required an interventional cardiology procedure at a median interval of 5 months from surgery. The subgroup analysis revealed a significantly lower patch-related reintervention rate in patients treated with autologous pericardium when compared to CM (P = 0.006).CONCLUSIONSCM is safe for atrial and ventricular defect closure. The use of CM for arterial vessel reconstruction is associated with higher reintervention rates when compared to autologous pericardium.

Childhood bradycardia associates with atrioventricular conduction defects in older age: a longitudinal birth cohort study

Abstract Background A high resting heart rate (RHR) has been associated with cardiovascular morbidity and mortality. However, little is known about the long-term effects of childhood bradycardia. Purpose This study aimed to explore the association between childhood bradycardia and later-life cardiac phenotype using longitudinal data from the 1946 Medical Research Council National Survey of Health and Development (NSHD) birth cohort. Methods RHR was recorded at ages 6 and 7 to provide the bradycardia exposure defined as a childhood RHR<75. Three outcomes were studied: i) echocardiographic data at 60–64 consisting of ejection fraction (EF), left ventricular mass index (LVmassi), myocardial contraction fraction index (MCFi) and E/e'; ii) electrocardiographic (ECG) evidence of atrio-ventricular (AV) conduction defects (Minnesota categories: 6-1, 6-2-1, 6-2-2, 6-2-3, 6-3, 6-8, 8-5-1, 8-5-2, 8-6-1, 8-6-2, 8-6-3 and 8-6-4) or ventricular conduction defects (any Minnesota group 7) by age 60–64; and iii) all-cause and cardiovascular mortality. Generalized linear models (glm) with gamma distribution were used for echocardiographic analyses, glms with binomial distribution for ECG analyses and Cox proportional hazards models for mortality. Adjustment was made for relevant demographic and health-related covariates, and for multiple testing. In order to account for within-subject correlated repeated measures at 6 and 7 years of age, mixed glms (glmms) were used as a sensitivity analysis. To explore any nonlinear relationships, we modeled each outcome as a sum of best fitting fractional polynomials of RHR at 6 and 7 (as continuous variables) and covariates using a “closed test procedure” with backward elimination. Results The number of participants included was: 4381 for mortality, 1631 for ECG and 1617 for echocardiography analyses. Childhood bradycardia was associated with male sex (p<0.0001) and higher BMI (p=0.009). In fully adjusted models, childhood bradycardia was associated with 2.91 higher odds of AV conduction defects (95% confidence interval [CI] 1.59–5.31, p=0.0005), even at a false discovery rate of 0.05. Associations persisted in random coefficients glmm models (odds ratio 2.50, 95% CI 1.01–4.31). The fractional polynomials analyses revealed that the log odds of AV conduction defects at 60–64 years of age were linearly associated with RHR at 7 years. There was no association between bradycardia in childhood and ventricular conduction defects, echocardiographic parameters or mortality outcomes. Conclusions Longitudinal data indicate that childhood bradycardia trebles the odds of having AV conduction defects, but does not influence mortality or heart size and function in older age. As one in three older adults with AV conduction defects will have been bradycardic in childhood, future research should concentrate on identifying children at risk, the potential mechanisms involved and whether AV blocking drugs accelerate nodal dysfunction. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation (MyoFit46 Special Programme Grant SP/20/2/34841)

Specific actin (ACTC1) missense variants are associated with different overlapping clinical phenotypes and outcomes

Abstract Introduction Pathogenic variants in ACTC1 have been associated with hypertrophic (HCM), dilated (DCM), and left ventricular non-compaction (LVNC) cardiomyopathies. Phenotypes often overlap and atrial septal defects have also been reported. Prognostic data on carriers of these variants are scarce. Methods and results The proprietary database of a cardiovascular genetic laboratory was examined to assess penetrance and survival in the 438 carriers (191 families) of 75 missense variants in ACTC1 associated with disease. Their mean age at diagnosis was 32.4 (±18.7) years; 52% were male. The diagnosis was isolated HCM in 47%, LVNC in 17%, and DCM in 9%. LVNC with either HCM or DCM was present in an additional 8%; 13% had an atrial septal defect. Among carriers with echocardiographic information, left ventricular dilatation and dysfunction were described in 13% and 16%, respectively. Ventricular arrhythmias and conduction defects were reported in 94 and 93 carriers. Percentages have not been calculated for the latter, as we cannot ensure a denominator in whom cardiac conduction defects and arrhythmias were certainly discarded. Overall, 50% of carriers were diagnosed by age 45, and 10% had experienced a major cardiac event. The p.Leu10Met and p.His90Tyr variants (23% of all carriers) demonstrated lower penetrance and a better prognosis than the p.Glu101Lys variant and the other missense variants. Conclusions Missense variants in ACTC1 are associated with a range of phenotypes that often overlap. Overall, penetrance and outcomes are age-dependent with a moderate rate of major cardiac events, which are highly dependent on the specific disease-causing variant Funding Acknowledgement Type of funding sources: None. Figure 1. The graph shows the percentage of carriers of pathogenic or likely pathogenic missense variants in the ACTC1 gene diagnosed at different ages. Considering all the missense variants in ACTC (in red), 50% of carriers had been diagnosed by age 45. It is worth highlighting the percentage of diagnosis (>15%) in the first 15 years of life, which is higher than the figure usually observed in sarcomeric hypertrophic cardiomyopathy.Figure 2. The graph shows the survival free of major cardiovascular events (sudden, heart failure, stroke-related death, appropriate ICD therapy and heart transplant) in individuals with missense variants in ACTC1. Carriers and affected relatives without genetic study were included. Events were infrequent in two of the most informative variants (p.Leu10Met and p.His90Tyr), and significantly different compared with carriers of the other missense variants (p=0.036 for p.Leu10Met and p=0.015 for p.His90Tyr).

Right Ventricular Free Wall Rupture After Myocardial Infarction

This paper describes the case of a 68-year-old man who presented in cardiac tamponade due to a right ventricular free wall rupture after a recent ST-segment elevation myocardial infarction. After a pericardiocentesis, the ventricular defect resolved spontaneously. The patient was managed medically and avoided surgical intervention. (Level of Difficulty: Intermediate.)

Implantation of Carmustine wafers after resection of malignant glioma with and without opening of the ventricular system.

Implantation of biodegradable Carmustine wafers in patients with malignant glioma is not generally recommended when the ventricular system is opened during tumor resection. Thrombin/fibrinogenn-covered collagen fleeces showed promising results in sufficiently closing ventricular defects. The aim of this study was to evaluate the postoperative morbidity in patients with implanted Carmustine wafers either with opened or intact ventricular system. A consecutive series of patients who underwent resection of malignant glioma with implantation of Carmustine wafers was analyzed. In case of opening of the ventricular system, the defect in the ventricle wall was sealed using a collagen sponge coated with fibrinogen and thrombin prior to the implantation of the wafers. Postoperative adverse events (AE) and Karnofsky performance status scale (KPS) at follow up were compared between both groups. Fifty-four patients were included. The ventricular system was opened in 33 patients and remained intact in 21 patients. Both groups were comparable in terms of age, rate of primary and recurrent glioma, preoperative KPS, rate of gross total resection and number of implanted wafers. Postoperative AEs occurred in 9/33 patients (27.3%) with opened and in 5/21 patients (23.8%) with intact ventricular system (p = 0.13). At follow-up assessments, KPS was not significantly different between both groups (p = 0.18). Opened ventricular system was not associated with a higher incidence of postoperative AEs (p = 0.98). Appropriate closure of opened ventricular system during resection of malignant glioma allows for a safe implantation of Carmustine wafers and is not associated with a higher incidence of postoperative AEs.