Variable phenotype of a null PPP1R13L allele in children with dilated cardiomyopathy.

Childhood-onset cardiomyopathy is a genetically heterogeneous group of conditions with several genes implicated. Recently, biallelic loss-of-function variants in PPP1R13L have been reported in association with a syndromic form of dilated cardiomyopathy (DCM). In addition, affected children manifest skin and hair abnormalities, cleft lip and palate (CLP), and eye findings. Here, we delineate the condition further by describing the phenotype associated with a homozygous frameshift variant (p.Arg330 ProfsTer76) in PPP1R13L detected in two sibships in a consanguineous family with six affected children. The index case had DCM and wooly hair, two of his siblings had DCM and CLP while three cousins had, in addition, glaucoma. Global developmental delay was observed in one child. All the children, except one, died during early childhood. Whole exome sequencing and whole genome sequencing did not reveal any other plausible variant. We provide further evidence that implicates PPP1R13L in a variable syndromic form of severe childhood-onset DCM and suggests expanding the spectrum of this condition to include glaucoma. Given the variability of the phenotype associated with PPP1R13-related DCM, a thorough evaluation of each case is highly recommended even in the presence of an apparently isolated DCM.

Clinical and Genetic Characteristics of Arrhythmogenic Right Ventricular Cardiomyopathy Patients: A Single-Center Experience.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited progressive cardiomyopathy. We aimed to define the long-term clinical outcome and genetic characteristics of patients and family members with positive genetic tests for ARVC in a single tertiary care cardiac center in Saudi Arabia. Methods: We enrolled 46 subjects in the study, including 23 index-patients (probands) with ARVC based on the revised 2010 ARVC Task Force Criteria (TFC) and 23 family members who underwent a genetic test for the ARVC between 2016 and 2020. Results: Of the probands, 17 (73.9%) were males with a mean age at presentation of 24.95 ± 13.9 years (7 to 55 years). Predominant symptoms were palpitations in 14 patients (60.9%), and syncope in 10 patients (43.47%). Sustained ventricular tachycardia (VT) was documented in 12 patients (52.2%). The mean left ventricular ejection fraction (LVEF) by echocardiogram was 52.81±6.311% (30-55%), and the mean right ventricular ejection fraction (RVEF) by cardiac MRI was 41.3±11.37% (23-64%). Implantable cardioverter-defibrillator (ICD) implantation was performed in 17 patients (73.9%), and over a mean follow-up of 13.65 ± 6.83 years, appropriate ICD therapy was noted in 12 patients (52.2%). Genetic variants were identified in 33 subjects (71.7%), 16 patients and 17 family members, with the most common variant of plakophilin 2 (PKP2) in 27 subjects (81.8%). Conclusions: ARVC occurs during early adulthood in Saudi patients. It is associated with a significant arrhythmia burden in these patients. The PKP2 gene is the most common gene defect in Saudi patients, consistent with what is observed in other nations. We reported in this study two novel variants in PKP2 and desmocollin 2 (DSC2) genes. Genetic counseling is needed to include all first-degree family members for early diagnosis and management of the disease in our country.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

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.

Outcomes of Routine Coronary Angiography in Asymptomatic Patients With End-Stage Renal Disease Prior to Kidney Transplantation.

We report the prevalence of coronary artery disease (CAD) in asymptomatic patients with end-stage kidney disease (ESKD) on hemodialysis and explore the best revascularization strategies prior to kidney transplantation. This is a retrospective single-center study, which included all patients who were candidates for kidney transplantation and underwent coronary angiography between 2003 and 2018. All included patients underwent coronary angiography without noninvasive testing and were asymptomatic cardiac-wise. Out of the 368 patients with ESRD, 45% had coronary vessel disease, 17% had 3-vessel disease, 11% had 2-vessel disease, 5.2% had significant left main artery narrowing, and 17% had single-vessel disease. Patients with 3-vessel disease had the worst survival rate at 5 and 10 years. The patients with significant 3-vessel disease or left main artery involvement underwent revascularization; 19% underwent coronary artery bypass grafting, 5% had stenting of the coronary arteries, and 4.7% were on maximal medical therapy. The patients who underwent stenting had a better survival than those on medical therapy, but the difference was not significant (P = .445). Our findings reflect a high prevalence of CAD in patients with ESKD. There is a need for further studies to evaluate benefits of cardiovascular screening in this patient population.

Appropriate and Inappropriate Implantable Cardioverter Defibrillators Therapies in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Patients.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized histologically by the replacement of ventricular myocardium with fibrous and fatty tissue, and clinically by ventricular tachycardia arrhythmias primarily of right ventricular (RV) origin. Implantable cardioverter defibrillator (ICD) is the only proven therapy to reduce mortality in ARVC/D patients. However, it has the risk of inappropriate anti-tachycardia pacing (ATP) or shocks. This study aimed to assess the occurrence of appropriate and inappropriate ICD therapies in ARVC/D patients who underwent ICD implantation in a single Cardiac Centre. METHODS: Retrospective analysis of the data of patients with the diagnosis of ARVC/D based on the 2010 revised Task Force Criteria, who underwent ICD implantation in the Heart Centre, at King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh between January 1997 and May 2016. The clinical data and information about appropriate and inappropriate ICD therapies were obtained from medical records with the review of the available intra-cardiac electrograms (EGMs). RESULTS: Twenty-two ARVC/D patients with ICD implantation (20 males (91%), mean age at ICD implantation: 32 ± 14 years). ICD was implanted for secondary prevention of sudden cardiac death (SCD) in 15 patients (68.2%), and for primary prevention in 7 patients (31.8%). At mean follow-up of 9.4 ± 4.8 years, 11 patients (50%) had appropriate ICD therapies, and five patients (22.7%) had inappropriate ICD therapies. Out of 950 ICD therapies, 865 (91%) were appropriate (586 episodes of VT/VF treated with ATP (61.3%), and 279 episodes treated with shocks (29.37%)) and 85 (9.4%) were inappropriate (45 episodes treated with ATP (4.73%), and 40 treated with shocks (4.21%)). CONCLUSION: ARVC/D patients are at risk of VT/VF arrhythmias. ICD therapy is the only proven life-saving therapy in those patients. Most of ICD therapies in our patient's population are appropriate, and ATP therapy is effective in terminating most of VT episodes. Although we do not have any patient with subcutaneous ICD, the high success rate of ATP suggests that transvenous ICD would be more appropriate in ARVC/D patients.

Use of beta blockers is associated with hearing loss.

OBJECTIVE: This study was conducted to investigate the hypothesis that patients using ß-blockers will develop hearing loss. DESIGN: A cross-sectional study. STUDY SAMPLE: A total of 125 patients completed the study. A total of 63 patients were on ß-blockers and 62 were not on ß-blockers. RESULTS: Carvedilol was significantly associated with hearing loss. Other beta-blockers including metoprolol and atenolol showed no association with hearing loss. Linear multiple regression analysis was run including variables of gender, age, ischaemic heart disease, cardiac failure/dilated cardiomyopathy, frusemide and carvedilol use as predictors for total hearing loss severity at all frequencies. Age and gender, as well as carvedilol, were found to be the only statistically significant predictors for hearing loss severity. CONCLUSION: Chronic use of carvedilol was associated with significant hearing loss. This may need to be taken into account when prescribing the drug. Further randomised controlled studies with baseline audiometric hearing tests before starting treatment, and periodic follow-up tests, would provide a better assessment of the effect of carvedilol on hearing.

Subcutaneous Implantable Cardioverter Defibrillators Implantation Without Defibrillation Threshold Testing: A Single Center Experience.

BACKGROUND: Subcutaneous implantable cardioverter defibrillator (S-ICD) system has been proven to be an effective therapy for prevention of sudden cardiac death (SCD) in selected patients. Although the Shockless IMPLant Evaluation (SIMPLE) trial has shown that defibrillation threshold (DFT) testing is not necessary for transvenous ICD (TV-ICD) systems, it is still recommended for S-ICD systems. We aimed to study the efficacy and safety of S-ICD implantation without DFT in our Heart Center with the comparison of S-ICD patients' outcome to those with a single chamber TV-ICD without DFT in the same period. METHODS: A retrospective analysis of patients underwent S-ICD without DFT from December 2014 to May 2016 with the comparison to single chamber TV-ICD patients implanted during the same period. RESULTS: Thirty consecutive patients (23 males (76.7%); mean age 41 ± 13 years; mean left ventricular ejection fraction 30±12%) received a S-ICD for primary (25 patients, 83.3%) or secondary prevention (five patients, 16.7%) of SCD. During a mean follow-up of 710.6 ± 190 days, three patients received 38 appropriate ICD shocks (90.5%), and two patients received four inappropriate shocks (9.5%). There were two mortalities (6.7%): one cardiac and one non-cardiac. When compared to 30 consecutive who received a single chamber TV-ICD during the same period, there was no significant difference in mortality. CONCLUSIONS: Implantation of S-ICD using intermuscular approach without DFT seems to be safe and effective. Data from large S-ICD registries with long-term follow-up, and preferably randomized controlled studies, are needed to confirm this finding.

Predictors of Permanent Pacemaker Implantation After Coronary Artery Bypass Grafting and Valve Surgery in Adult Patients in Current Surgical Era.

BACKGROUND: Permanent pacemaker (PPM) implantation after cardiac surgery is required in 0.4-6% of patients depending on cardiac surgery type. PPM implantation in the early postoperative period may reduce morbidity and postoperative hospital stay. We performed a retrospective review of electronic medical records of adult patients with coronary artery bypass grafting (CABG), valve surgery, or both, over a 3-year period. Our aim was to identify predictors of PPM requirements and PPM dependency on follow-up in the current surgical era. METHODS: After exclusion of patients with congenital heart disease, patients who already had a PPM or implantable cardioverter defibrillator (ICD), and patients with an indication for PPM or ICD before surgery, we identified 1,234 adult patients who underwent cardiac surgery between January 2007 and December 2009. A retrospective review of electronic medical records and pacemaker clinic data was performed. RESULTS: Patients' mean age was 46.65 ± 16 years, and 59% were males. CABG was performed in 575 (46.6%) cases, aortic valve replacement in 263 (21.3%), mitral valve replacement in 333 (27%), and tricuspid valve replacement in 76 patients (6.2%). Twenty patients (1.6%) required implantation of a PPM postoperatively. Indications for PPM implantation included complete atrioventricular (AV) block in 13 (65%), sick sinus syndrome in three (15%), and atrial fibrillation (AF) with a slow ventricular rate in four (20%). Predictors for PPM requirement by multivariate analysis were the presence of pulmonary hypertension (P-HTN), reoperation, and left bundle branch block (LBBB) (P < 0.05). Late follow-up was available in 18 patients, at 84.5 ± 30 months. Eleven patients (61%) were PPM dependent on long-term follow-up. CONCLUSIONS: Patients at high risk for PPM implantation after cardiac surgery include those with P-HTN, reoperation, and pre-existing LBBB. Of those receiving a PPM, about one-third will recover at least partially at long-term follow-up. We recommend preoperative assessment for risk of requiring postoperative PPM, to counsel patients about this risk and early PPM implantation in high-risk patients who are PPM dependent after surgery.