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Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-beta protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-beta signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm(TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8(-/-) mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-beta signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8(-/-) mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-beta signaling pathway in TAA development. Because importin 8 is the most downstream TGF-beta-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

Background: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. Methods: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. Results: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1 ). Conclusions: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

Objectives Transcatheter closure is the treatment of choice for most patent ductus arteriosus (PDA) in infants, children, and adults. However, there is a controversy regarding transcatheter closure of clinically silent PDAs. Some authors favor device closure to eliminate the lifelong risk of infective endarteritis while others recommend avoiding PDA closure in such patients. The study describes our experience of closing the silent PDAs using the Amplatzer duct occluder II-additional size (ADO II-AS) (St. Jude Medical Corp, St. Paul, MN). Materials and methods From April 2018 through March 2021, 52 consecutive pediatric patients aged 18 years and less with clinically silent PDA who had transcatheter closure at our center were enrolled. Patients were excluded if they had clinically detected PDAs; had surgical ligation of PDA with no residual shunt; had left heart dilatation on echocardiography; or moderate-sized PDAs closed with ADO II-AS. In addition, patients with an innocent murmur or murmur due to an associated lesion were included. This study was retrospective, and all of the 52 patients underwent PDA device closure using ADO II-AS. Results Fifty-two consecutive patients were enrolled with a median age of 17 months, range (97-2.5) 94.5 months. Mean weight was 11.29 kilogram, range (24.8-3.5) 21.3 kilogram, and mean follow-up was 13.5 months, range (29-0) 29 months. Thirty-one (59.6%) were females, and 21 (40.4%) were males. The mean procedure time was 30.6 min, range (60-10) 50 min, and mean fluoroscopic time was 5.5 min, range (28-1.7) 26.3 min. The mean volume of contrast given was 9.1 milliliter, range (30-4) 26 milliliter. Forty-five (45; 88.2%) patients had immediate closure of PDA. No patients had anesthetic or vascular complications; however, two patients had procedural complications. Device placement was unsuccessful in one patient with Downs syndrome. The mean follow-up for our patients was 13.5 months, range (29-0) 29 months; the patients were asymptomatic at the follow-up, and none of the patients had any residual leak. None of the patients showed coarctation or left pulmonary artery stenosis at the latest follow-up. Conclusion The usefulness of catheter-based therapy for silent PDA is less well-established by current evidence. Further studies are needed to justify the intervention solely based on the premise that the silent duct is a substrate for infective endarteritis; however, our reason to close silent PDA was to do so primarily because of social reasons. This study found that device closure of silent PDA is safe and effective using an ADO II-AS device with minimal risk of embolization and a low residual shunt rate. Coils have been used to close small PDAs, however, with higher rates of embolization and device malpositioning. We believe ADO-II AS offers an advantage of safety and efficacy over coils. In addition, the study highlights the advantage of using an ADO II-AS device, which can be delivered via a four French delivery system with no arterial complications.

Background Pulmonary arteriovenous malformations (PAVMs) are rare pulmonary vascular anomalies. They can result in right-to-left shunt and, if significant, low systemic saturation, cyanosis, polycythaemia, and paradoxical systemic embolization. Case summary Eighteen months old female child was referred to our centre due to unexplained central and peripheral cyanosis. Based on the agitated saline contrast echocardiography study, computed tomography scan confirmed the presence of abnormal vasculature at the left lower lobe. Percutaneous closure of the PAVM was performed using Amplatzer Duct Occluder type 1 device. The genetic study revealed a pathogenic mutation in the endoglin gene, which is a known cause of hereditary haemorrhagic telangiectasia (HHT) inhered in an autosomal dominance pattern. Discussion PAVM could be the first manifestation of HHT. Closing the malformation percutaneously is feasible, which can eliminate the right to left shunt and improves the saturation. Genetic study is warranted in these cases, as well as long-term follow-up.

Background: Congenital severe tricuspid valve (TV) insufficiency secondary to ruptured papillary muscle or ruptured chordae tendineae is very uncommon. Ruptured chordae and/or papillary muscle will lead to flail leaflet and tricuspid insufficiency, the severity of which depends upon the severity of the affected leaflet(s). The neonatal presentation might simulate that of severe Ebstein anomaly of the TV, with severe cyanosis due to reduced pulmonary blood flow. Compared to Ebstein anomaly, there is no apical displacement of the tricuspid valve leaflets. Case presentation: We are presenting a neonate with refractory neonatal cyanosis immediately after birth due to congenital flail TV leaflets. A successful surgical repair of the TV improved the TV function with excellent immediate, short and midterm outcomes. Conclusions: TV repair is the best surgical option for TV dysplasia with ruptured chordae and flail leaflets, with good immediate as well as short and mid-term outcomes.

Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is one type under group 1 PH. Undiagnosed or delayed diagnosis of significant CHD might lead to significant PAH and at the end might lead to Eisenmenger syndrome. We could expect the degree of PAH in patients with CHD by proper clinical assessment as well as by the basic assessment tools including the chest x-ray (CXR), ECG, and transthoracic echocardiography (TTE). We are presenting a three and half years old child with a delayed/missed diagnosis of large patent ductus arteries (PDA) who present with significant PAH. Clinical evaluation, CXR, ECG, TTE, as well as cardiac catheterization data are presented, with a review of the current guidelines regarding the management of pediatric patients with PAH-CHD.

Introduction Pediatric cardiac catheterization interventions become an established way of care for selected patients with congenital heart diseases. Cardiac catheterization for neonates and small infants can be challenging. The indications for diagnostic cardiac catheterization have decreased with the advent of advanced non-invasive imaging modalities. Patients and method Between June 2012 and July 2017 patients less than three months who had cardiac catheterization in two centers were reviewed. Results During the study period, 174 patients underwent interventional cardiac catheterization,83.3% of them had CHD with two-ventricle circulation and 29 patients (16.7%) had single ventricle pathophysiology. Procedures include diagnostic cath, BAS, balloon pulmonary and aortic valvuloplasty, coarctation angioplasty, and stenting procedures. The vascular access depends upon the type of procedure. All except one had general anesthesia. ICU admission was required on 106 patients (62%). Patients were divided according to the type of cardiac lesion (single versus biventricular pathology) as well as according to the type of intervention (stenting and non-stenting procedures). Comparing these groups revealed that: stent procedures and procedures for patients with single ventricle pathologies were performed at an earlier age, with more contrast, fluoro and procedure time than for non-stent procedures and procedures for patients with biventricular pathologies. Complications include transient arrhythmias in most patients, perforation of the RVOT in one and lower limb hypoperfusion in 12 patients. ICU complications include low cardiac output symptoms (LCOS) in 10 (7%), and sepsis in 8. No intra-procedure mortality. The overall survival was 94%. Ten patients died, with one early and 9 late mortality. 60% of the dead patients had PDA stenting. Reintervention varies according to the patient's diagnosis. Conclusion Cardiac catheterization intervention an important modality in the management of neonates and infants with critical CHD. Well planned procedures and team expertise are essential. Stenting procedures and procedures for patients with single ventricles carries higher morbidity and mortality.

Although infective endocarditis is an uncommon condition, it can be fatal if not treated. The new era of infective endocarditis in children with structurally normal heart has become apparent entity. Duke criteria has been established for a long time and gives clear guidelines for diagnosis; however, surgical indication in pediatric population needs to be tailored to individual patients. Keywords: Endocarditis, Infective, Pediatric, Surgical management

BACKGROUND: Red blood cell transfusion is common in critically ill children after cardiac surgery. Since the threshold for hemoglobin (Hb) transfusion need is not well defined, the threshold Hb level at which dependent critical oxygen uptake-to-delivery (VO2-DO2) status compensation is uncertain. OBJECTIVES: To assess the effects of blood transfusion on the oxygen extraction ratio (O2ER) and central venous oxygen saturation (ScvO2) to identify a critical O2ER value that could help us determine the critical need for blood transfusion. DESIGN: Prospective, observational cohort study. SETTING: Cardiac Surgical Intensive Care Unit at Prince Sultan Cardiac Center in Qassim, Saudi Arabia. PATIENTS AND METHODS: Between January 2013 and December 2015, we included all children with cardiac disease who underwent surgery and needed a blood transfusion. Demographic and laboratory data with physiological parameters before and 1 and 6 hours after transfusion were recorded and O2ER before and 6 hours after transfusion was computed. Cases were divided into two groups based on O2ER: Patients with increased O2ER (O2ER >40%) and normal patients without increased O2ER (O2ER ≤40%) before transfusion. MAIN OUTCOME MEASURE(S): Changes in O2ER and ScvO2 following blood transfusion. RESULTS: Of 103 patients who had blood transfusion, 75 cases had normal O2ER before transfusion while 28 cases had increased O2ER before transfusion. Following blood transfusion, O2ER and ScvO2 improved in the group that had increased O2ER before transfusion, but not in the group that had normal O2ER before transfusion. CONCLUSIONS: The clinical and hemodynamic indicators O2ER and ScvO2 may be considered as markers that can indicate a need for blood transfusion. LIMITATIONS: The limitation of this study is the small number of patients that had increased O2ER before transfusion. There were few available variables to assess oxygen consumption.

Transcatheter closure of secondum atrial septal defect (ASD) is an alternative option to open heart surgery with good short and long-term outcomes. For this purpose, the Amplatzer septal occluder (ASO) device is widely used. Arrhythmias are known complications of ASD device closure including atrial ectopy and heart block.We report a seven-year-old female patient who developed second degree atrioventricular block (AVB) within few hours after ASD device closure using ASO device. At the seventh post-procedure day; while under close observation; patient regained sinus rhythm which was maintained thereafter. A 3-day course of prednisolone was given.

Background: PDA device closure can be performed without an arterial access. We are presenting our experience in closing the PDA with and without arterial access. Methods: From February 2012 till August 2014, all patients underwent transcatheter PDA closure were included. Detailed echocardiographic evaluation of the heart with hemodynamic doppler assessment was performed. Results: During the period, 45 patients underwent PDA device closure. All have venous access, 14 patients (31%) have additional arterial access. Since 2013 our protocol is to do PDA device closure without an arterial access except in selected patients when arterial access was considered necessary. Pre-procedure angiograms were performed in tow projections by the venous catheter positioned at the PDA descending aorta junction in 32 patients (71%), and by the arterial accessed catheter in 13 patients (29%). PDA was closed by ado1 device in 25 patients (56%), Oculotech PDA device in 18 patients (40%), and by coils in 2 patients (4.4%). Post PDA device angiograms were performed through the side port of the long delivery sheath. Detailed echocardiographic assessment was performed 2 hrs to 4 hrs after intervention as well as in the next day. No major immediate complications. One patient developed mild pericardial effusion 24 hrs after the procedure. Comparing the differences between those with and without arterial access revealed that the procedure time, the fluoroscopic time as well as the amount of the contrast dose used were less in those with no arterial access. Conclusion: PDA device closure without an arterial access can be performed safely and effectively by experienced interventionist. Patient selection and appropriate pre-intervention detailed echocardiography and procedure planning are essential for accomplishing device closure of PDA. The procedure is simplified and many patients can be discharged on the day of the procedure.

Worldwide, congenital heart defects (CHD) are the leading cause of infant deaths owing to congenital anomalies. Knowing the actual incidence of severe CHD is important for defining the requirement for resources and the burden of disease within the total population. Objectives. The aim of the study is to estimate the incidence of severe CHD at the province of Al-Qassim as a reflection of that in the Kingdom of Saudi Arabia. Study Design. A retrospective database review of all cases diagnosed to have severe CHD at Prince Sultan Cardiac Center-Qassim during a 3-year period from January 2008 to December 2010. Results. During the study period, 316 patients were diagnosed to have severe CHD. During the 3-year study period, the total live birth at the province of Al-Qassim was 58 908. The incidence of severe CHD is 5.4/1000 live birth/year. Sixty-five percent of cases were diagnosed at less than 2 months of age, with a median age at diagnosis of 45 days (range of 1 day to 1 year). Ventricular septal defect was the most common lesion diagnosed (22.5%). Collectively, prostaglandin-dependent lesions constitute 38% of cases. Fifteen percent of patients were proved to have a syndrome. The most common syndrome was Down syndrome. Conclusion. Severe CHD is a major health problem at the Kingdom of Saudi Arabia and worldwide. The incidence of severe CHD likely to require intervention in infancy, in the province of Al-Qassim, Saudi Arabia, is 5.4 per 1000 live births.

We present a very rare cardiac lesion where we found a combination of abnormal pulmonary venous drainage and left-sided obstructive lesions. This case gives new insight into the complex malformation of the heart, raising questions about cardiac embryology and timing of interfering events. Here we describe the lesion for the first time and review the related literature. To the best of our knowledge, this combination has never been reported.

Objective: To evaluate the knowledge of basic life support (BLS) among students and health providers in Medicine, Pharmacy, Dentistry, and Allied Health Science Colleges at Qassim University. Methodology: A cross sectional study was performed using an online BLS survey that was completed by 139 individuals. Results: Ninety-three responders were medical students, 7 were medical interns, 6 were dental students, 7 were pharmacy students, 11 were medical science students and 15 were clinical practitioners. No responder scored 100% on the BLS survey. Only two out of the 139 responders (1.4%) scored 90–99%. Both of these individuals were fifth year medical students. Six responders (4.3%) scored 80–89%. Of these, 5 were fifth year medical students, and one was fourth-year medical student. Eleven responders (7.9%) scored 70–79%. Of these, eight were fifth year medical students, two were medical interns and one was a pharmacist. Twenty-three responders (16.5%) scored 60–69%. Of these, 11 were fifth year medical students, 1 was a fourth-year medical student, 3 were medical interns, 2 were medical science students, 1 was a dentistry student, and 5 were pharmacists. Twenty-eight responders (20.1%) scored 50–59%. Of these, 11 were fifth year medical students, 3 were fourthyear medical students, 1 was a third-year medical student, 1 was a second-year medical student, 2 were first-year medical students, 1 was a pharmacy student, 3 were dental students, 1 was a allied health science student, 2 were doctors, and 3 were pharmacists. The remaining 69 responders (49.6%) scored less than 50%. Conclusion: Knowledge of BLS among medicine, pharmacy, dentistry, and allied health science students and health providers at Qassim University is poor and needs to be improved. We suggest that inclusion of a BLS course in the undergraduate curriculum with regular reassessment would increase awareness and application of this valuable life-saving skill set.

Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 30 genes have been identified in familial cases; mostly inherited as autosomal dominant. Defective genes in isolated recessive DCM are rarely observed. Recently, heterozygous mutations in NEXN gene, which encodes a cardiac Z-disc protein, have been identified in patients with dominantly inherited dilated and hypertrophic forms of cardiomyopathy. Through our Cardiovascular Genetics Program, we have conducted genome-wide analysis in 43 consanguineous Saudi families with recessive forms of cardiomyopathy. The analysis detected a region of homozygosity (ROH) on chromosome 1p31 in one family who has two affected infants with severe DCM. The index case presented at the age of 1 month with severely dilated left ventricle with ejection fraction of 21%. The identified ROH in this family was found to be shared by the 2 affected siblings and was not found in their parents and unaffected sibling. Direct sequencing of 6 candidate genes within the identified ROH revealed a novel homozygous deletion (c.1582-1584delGAA) in NEXN gene in both affected siblings. This mutation leads to a deletion of glutamate, at position 528, which is a highly conserved amino acid. To our knowledge, this is the first study identifying a homozygous mutation in NEXN gene in association with recessive cardiomyaopthy. This finding could be utilized to prevent the recurrence of DCM through preimplantation genetic diagnosis and carrier screening for at-risk family members. Our work also illustrates the importance of homozygosity analysis in identifying genetic causes of familial cardiovascular disorders in our highly consanguineous population.

Introduction Chronic illness may result in a variety of stressful outcomes, families of children with congenital heart disease are not exception. In Saudi Arabia, many public supporting groups for families with chronically ill children like diabetics or cancer patients are active and giving a great deal of help but unfortunately, non are available for families of children with severe congenital heart disease. Our study is an effort to put this issue in focus. Objective To evaluate the social impact on families of patients with of congenital heart disease. Design Cross sectional survey. Setting Pediatric cardiology outpatient department at Prince Sultan Cardiac Center – Qassim. Patients Parents of 71 randomly selected children with CHD of different severity. Main outcome measures The social impact on family score. Methods The impact on family questionnaire of Stein and Riessman was instituted. This questionnaire, which determines the effects of a chronic illness on parents and families, has been used to assess the impact of CHD. It is based on four subscales assessing perceived (1) financial burden; (2) familial/social impact; (3) personal strain; and (4) mastery. The first subscale contains four statements. The second subscale contains nine statements assessing social effects of CHD. The third subscale has six statements relating to the personal stress imposed by CHD on the parent. The third subscale has six statements relating to the personal stress imposed by CHD on the parent. The final subscale contains positively phrased statements to assess the positive effects of the child’s CHD on the parent’s feelings of control in his or her life. The parent’s response is given as a number from 1 to 4, where 1 represents strong agreement, 2 predominant agreement, 3 weak partial agreement, and 4 strong disagreement. The fourth subscale is reverse coded, so that it is compatible with the other subscales to calculate a final score where a low score corresponds to a high impact. This score is then inverted so that a high score is equivalent to a high impact. The questionnaire was administered by a two Researchers. Patients were divided into three groups according to the severity of the CHD they do have (Mild, Moderate and Sever). Mild CHD was defined as any CHD with no need for medical or surgical management. Moderate CHD was defined as a CHD which required surgical or cath intervention. Severe CHD was defined as CHD with single ventricle physiology who underwent Glenn or Fontan procedure, as well as patients with dilated CMP taking more than two cardiovascular medications. The mean impact on family scores was compared among the different groups by two sample t test analysis. Results Families of 71 children with severe CHD were interrogated. The main age was 3.76 ± 3 years. 23 were males (32.4%) and 48 (67.6%) were females. Mild CHD constitute 36.6%, moderate 29.6% and severe 33.8%. Families of children with severe CHD had a significantly higher impact on family score (mean of 62) than families with mild and moderate CHD (mean of 48) P value > .005. Conclusion Families of patients with severe CHD have significant social impact because of their child illness. Supporting public groups in Saudi Arabia should be initiated and encouraged.

Study Objective: The aim of the study was to assess the level of risk for cardiovascular diseases (CVD) among young Saudi women living in Al-Qassim, Saudi Arabia. Methods: As part of “The Heart Protection Campaign” in the Al-Qassim region, data were collected from Saudi women using questionnaires as well as objective measurement of height, weight, blood pressure, and blood glucose. Data were analyzed using descriptive statistics. Results: Only 15% of the sample were free of risk factors, the majority had either one (57.5%) or two (20.8%) risk factors. Additionally, 6.7% were considered to be at high-risk with three or more risk factors. The most common risk factors were physical inactivity (74%) and overweight/obesity, (25% / 29%). There was a significant increase in the number of risk factors across age groups. Women over the age of 30 were more likely to have a higher number of risk factors than the younger women (20-24 years). Conclusions: Young women in Al-Qassim, Saudi Arabia have an unusually high risk for CVD. Since the number of risk factors increases substantially between the ages of 20 and 35, there is a need to develop prevention programs to lower the CVD risk through diet and exercise. Keywords: cardiovascular risk factors, diabetes mellitus, hypertension, obesity, young women, Saudi Arabia. Â