Identification of 6-methyladenosine sites using novel feature encoding methods and ensemble models.

N6-methyladenosine (6 mA) is the most common internal modification in eukaryotic mRNA. Mass spectrometry and site-directed mutagenesis, two of the most common conventional approaches, have been shown to be laborious and challenging. In recent years, there has been a rising interest in analyzing RNA sequences to systematically investigate mutated locations. Using novel methods for feature development, the current work aimed to identify 6 mA locations in RNA sequences. Following the generation of these novel features, they were used to train an ensemble of models using methods such as stacking, boosting, and bagging. The trained ensemble models were assessed using an independent test set and k-fold cross validation. When compared to baseline predictors, the suggested model performed better and showed improved ratings across the board for key measures of accuracy.

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.

Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients.

OBJECTIVES: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.

Role of mitochondrial DNA in diabetes Mellitus Type I and Type II.

Morbidity and mortality from diabetes mellitus and associated illnesses is a major problem across the globe. Anti-diabetic medicines must be improved despite existing breakthroughs in treatment approaches. Diabetes has been linked to mitochondrial dysfunction. As a result, particular mitochondrial diabetes kinds like MIDD (maternally inherited diabetes & deafness) and DAD (diabetic autonomic dysfunction) have been identified and studied (diabetes and Deafness). Some mutations as in mitochondrial DNA (mtDNA), that encodes for a significant portion of mitochondrial proteins as well as mitochondrial tRNA essential for mitochondrial protein biosynthesis, are responsible for hereditary mitochondrial diseases. Tissue-specificity and heteroplasmy have a role in the harmful phenotype of mtDNA mutations, making it difficult to generalise findings from one study to another. There are a huge increase in the number for mtDNA mutations related with human illnesses that have been identified using current sequencing technologies. In this study, we make a list on mtDNA mutations linked with diseases and diabetic illnesses and explore the methods by which they contribute to the pathology's emergence.

Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients.

OBJECTIVES: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. METHODS: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. RESULTS: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. CONCLUSIONS: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.

Long-term reverse remodeling and clinical improvement by MultiPoint Pacing in a randomized, international, Middle Eastern heart failure study.

PURPOSE: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing, MPP) has been shown to improve CRT response, although MPP response using automated pacing vector programming has not been demonstrated in the Middle East. The purpose of this study was to compare the impact of MPP to conventional biventricular pacing (BiV) using echocardiographic and clinical changes at 6-month post-implant. METHODS: This prospective, randomized study was conducted at 13 Middle Eastern centers. After de novo CRT-D implant (Abbott Unify Quadra MP™ or Quadra Assura MP™) with quadripolar LV lead (Abbott Quartet™), patients were randomized to either BiV or MPP therapy. In BiV patients, the LV pacing vector was selected per standard practice; in MPP patients, the two LV pacing vectors were selected automatically using VectSelect. CRT response was defined at 6-month post-implant by a reduction in LV end-systolic volume (ESV) ≥ 15%. RESULTS: One hundred and forty-two patients (61 years old, 68% male, NYHA class II/III/IV 19%/75%/6%, 33% ischemic, 57% hypertension, 52% diabetes, 158 ms QRS, 25.8% ejection fraction [EF]) were randomized to either BiV (N = 69) or MPP (N = 73). After 6 months, MPP vs. BiV patients experienced greater ESV reduction (25.0% vs. 15.3%, P = 0.08), greater EF improvement (11.9% vs. 8.6%, P = 0.36), significantly greater ESV response rate (68.5% vs. 50.7%, P = 0.04), and significantly greater NYHA class improvement rate (80.8% vs. 60.3%, P = 0.01). CONCLUSIONS: With MPP and automatic LV vector selection, more CRT patients in the Middle East experienced reverse remodeling and clinical improvement relative to conventional BiV pacing.

A novel homozygous SCN5A variant detected in sick sinus syndrome.

Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been reported in SSS, however, homozygosity of SCN5A is exceedingly rare. Here, we report a consanguineous family with four affected children with SSS. Symptomatic bradycardia necessitated implanting a pacemaker in all of them. Sequencing SCN5A revealed a novel homozygous variant (p.Cys1850Arg), which was predicted to interfere with protein folding. Our report describes the phenotype of a novel homozygous SCN5A variant and contributes to the compendium of molecular pathology of inherited arrhythmias in consanguineous populations.

Nonbacterial thrombotic endocarditis as an initial presentation of advanced cholangiocarcinoma in a young patient: A case report.

Nonbacterial thrombotic endocarditis, a form of noninfectious thrombotic endocarditis, is mainly characterized by deposition of sterile platelet thrombi on heart valves. Usually, it is observed in advanced malignancy. Herein, we report a case of a previously healthy male with recent unprovoked deep vein thrombosis presented with acute ischemic stroke. The echocardiogram revealed aortic and mitral valve masses. Eventually, he was discovered to have advanced cholangiocarcinoma. The present case, apart from being the youngest reported case, is among the few reported cases which manifest the association between cholangiocarcinoma and nonbacterial thrombotic endocarditis.

Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome.

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.

Ventricular arrhythmia and tachycardia-induced cardiomyopathy in Gitelman syndrome, hypokalaemia is not the only culpable.

Gitelman syndrome (GS) is an autosomal recessive tubulopathy recently implicated in cases with ventricular arrhythmias (VAs), the latter being considered linked to electrolytes' imbalance. However, a direct causal relationship is considered to be an oversimplification for a complex molecular dysfunction. Recent work has suggested a degree of microvascular dysfunction in patients with GS that might be attributed as a mechanism of arrhythmia. We report a case of GS presenting with VAs complicated by cardiomyopathy. The high load of premature ventricular contractions that were attributed to the hypokalaemia has masked the presence of the left ventricular (LV) outflow tract tachycardia. Her LV systolic function recovered after successful electrophysiology ablation procedure. Atrioventricular nodal re-entry tachycardia was discovered incidentally during the study and was ablated successfully.

Effect of Long-Term Allopurinol Therapy on Left Ventricular Mass Index in Patients with Ischemic Heart Disease; A Cross-Sectional Study.

BACKGROUND: Left ventricular hypertrophy (LVH), as assessed by measurement of left ventricular mass (LVM), is one of the most important cardiovascular risk factors. It is commonly present in patients with ischemic heart disease (IHD), irrespective of the level of blood pressure; recently, oxidative stress has been shown to be an important factor in its development. The question then arises: can this risk factor be modified by antioxidant treatment (e.g., with allopurinol, a xanthine oxidase inhibitor)? METHODS: This is an observational study with a cross-sectional design which explored the association between long-term (>12 months) allopurinol therapy and LV mass index (LVMI) as well as geometry in patients generally receiving standard treatments for IHD. The primary endpoint was LVMI measurement (by 2D-echocardiography) and secondary endpoints included the association of allopurinol use with LV function (ejection fraction), blood pressure, glycemic control, and lipid profile. RESULTS: Ninety-six patients on standard anti-ischemic drug treatment (control group) and 96 patients who were additionally taking allopurinol (minimum dose 100 mg/day) were enrolled. Both groups were matched for age, sex, height, and co-morbidities, but poorer kidney function in the allopurinol group required further sub-group analysis based on renal function. Allopurinol treatment was associated with the lowest LVMI in the patients with normal serum creatinine (median LVMI; 70.5 g/m2): corresponding values were 76.0 and 87.0 in the control group with, respectively, normal and elevated serum creatinine, and 89.5 in the allopurinol group with elevated serum creatinine (P=0.027). In addition, allopurinol was associated with better glycemic control (HbA1c) with a difference of 0.8% (95% CI; 1.3, 0.2) (P=0.004) as compared with control patients. CONCLUSION: In our population, treatment with allopurinol (presumably because of its anti-oxidant properties) has shown a tendency to be associated with smaller LVM in IHD patients with normal serum creatinine, along with better glycemic control.

Pulmonary and Paradoxical Embolism after Slow Pathway Ablation: A Thrombotic Disorder Unmasked by a Rare Complication.

Cardiac electrophysiology study (EPS) and catheter ablation procedure are established diagnostic and therapeutic procedures for cardiac arrhythmias. Pulmonary embolism (PE) is a relatively rare but potentially fatal complication of Cardiac electrophysiology study (EPS). The paradoxical embolism (PDE) occurs due to an intracardiac defect with a right to left shunt with patent foramen ovale (PFO) being the most common cause. The simultaneous occurrence of PE and PDE is rare. Here we present a case of PE and PDE after EPS and radiofrequency catheter ablation (RFCA) of the slow pathway in a patient with recurrent supraventricular tachycardia (SVT) due to atrioventricular nodal reentry tachycardia (AVNRT). To our knowledge, such a case of PE and PDE has not been reported after SVT ablation.

Right-Sided Subcutaneous Implantable Cardioverter Defibrillator System Implantation in a Patient with Complex Congenital Heart Disease and Dextrocardia: A Case Report and Literature Review.

Patients with complex congenital heart disease (CHD) and low left ventricular ejection fraction are at an increased risk of sudden cardiac death (SCD). Prevention of SCD by subcutaneous implantable cardioverter defibrillator (S-ICD) implantation may represent a valuable option in certain CHD patients. Patients with CHD and dextrocardia pose a challenge in S-ICD system implantation, and nonstandard device placement may be required. Furthermore, electrocardiogram (ECG) screening prior to S-ICD implantation in CHD patients has significant limitations. This case represents the placement of a S-ICD system on the right side of the chest in a 26-year-old male with severe biventricular failure and nonsustained ventricular tachycardia following multiple corrective surgeries of situs inversus totalis, double-outlet right ventricle with a ventricular septal defect, and pulmonary atresia. The use of S-ICDs in a CHD population and in particular CHD patients with dextrocardia and right-sided S-ICD implantation is briefly discussed.

Subcutaneous Implantable Cardioverter Defibrillators: An Overview of Implantation Techniques and Clinical Outcomes.

Sudden Cardiac Death (SCD) is a significant health problem worldwide. Multiple randomized controlled trials have shown that Implantable Cardioverter Defibrillators (ICDs) are effective life-saving management option for individuals at risk of SCD in both primary and secondary prevention. Although the conventional transvenous ICDs (TV-ICDs) are safe and effective, there are potential complications associated with its use, including localized pocket or wound infection or systematic infection, a vascular access related complication such as pneumothorax, and venous thrombosis, and lead related complications such as dislodgement, malfunction, and perforation. Furthermore, transvenous leads placement may not be feasible in certain patients like those with venous anomaly or occlusion, or with the presence of intracardiac shunts. Transvenous leads extraction, when needed, is associated with considerable morbidity & mortality and requires significant skills and costs. Totally subcutaneous ICD (S-ICD) is designed to afford the same life-saving benefit of the conventional TV-ICDs while avoiding the shortcomings of the TV-leads and to simplify the implant techniques and hence expand the use of ICDs in clinical practice. It becomes commercially available after receiving CE mark in 2009, and its use increased significantly after its FDA approval in 2012. This review aims to give an overview of the S-ICD system components, implantation procedure, clinical indications, safety, efficacy, and future directions.

Bioprosthetic tricuspid valve dysfunction in patients with transvalvular or epicardial pacing leads.

BACKGROUND: Dysfunction of native tricuspid valves due to transvenous pacing leads is well described. Patients with bioprosthetic tricuspid valve (BTV) who need ventricular pacing are often advised epicardial lead placement to avoid potential damage to the BTV although there are no data to support this. OBJECTIVE: The aim of the study was to assess the frequency of BTV dysfunction in patients with permanent transvenous right ventricular pacemaker lead and compare it to patients with epicardial leads. METHODS: A retrospective review of patients with BTV with ventricular pacing lead was conducted. Demographics, lead, BTV, and echocardiographic data were collected. Frequency of BTV dysfunction (moderate or severe) regurgitation or stenosis was compared between epicardial and transvalvular lead groups. RESULTS: Forty-six patients with BTV and ventricular pacing lead (20 transvalvular and 26 epicardial leads) were identified. Mean age was 46 years with the majority being female (85%) and with rheumatic heart disease (87%). Both groups were similar in age, sex, and indications for BTV. Mean echocardiographic follow-up was for 5.5 years (±4.1 years). BTV dysfunction was similar between the transvalvular group with six (30%) patients and the epicardial group with five (19.2%) patients. The incidence of BTV dysfunction was greater in patients in sinus rhythm compared to patients in atrial fibrillation (50% vs 10%, P  =  0.004). CONCLUSION: Development of BTV dysfunction is similar in patients with transvalvular ventricular leads and epicardial leads. The incidence of BTV dysfunction was higher in patients with sinus rhythm compared to atrial fibrillation.

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.

Increases in Heart Rate Variability Signal Improved Outcomes in Rapid Response Team Consultations: A Cohort Study.

BACKGROUND: Reduced heart rate variability (HRV) indicates dominance of the sympathetic system and a state of "physiologic stress." We postulated that, in patients with critical illness, increases in HRV might signal successful resuscitation and improved prognosis. METHODS: We carried out a prospective observational study of HRV on all patients referred to the rapid response team (RRT) and correlated with serial vital signs, lactate clearance, ICU admission, and mortality. RESULTS: Ninety-one patients were studied. Significantly higher HRV was observed in patients who achieved physiological stability and did not need ICU admission: ASDNN 19 versus 34.5, p=0.032; rMSSD 13.5 versus 25, p=0.046; mean VLF 9.4 versus 17, p=0.021; mean LF 5.8 versus 12.4, p=0.018; and mean HF 4.7 versus 10.5, p=0.017. ROC curves confirmed the change in very low frequencies at 2 hours as a strong predictor for ICU admission with an AUC of 0.772 (95% CI 0.633, 0.911, p=0.001) and a cutoff value of -0.65 associated with a sensitivity of 78.6% and a specificity of 61%. CONCLUSIONS: Reduced HRV, specifically VLF, appears closely related to greater severity of critical illness, identifies unsuccessful resuscitation, and can be used to identify consultations that need early ICU admission.

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.