IFIH1 loss of function predisposes to inflammatory and SARS-CoV-2-related infectious diseases.

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole-exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2-related disorders.

Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease.

Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk genes, we collected 16,349 variants [single-nucleotide variants (SNVs) and Indels] impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using American College of Medical Genetics (ACMG) guidelines, we excluded the 0.1% of benign/likely benign variants and the resulting dataset consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six (GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19, and TTC36) were novel candidate CHD genes. Single-cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of the top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using the single-cell transcriptome revealed significant (P < 0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single-cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.NEW & NOTEWORTHY Congential heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. We present a comprehensive analysis combining genomics and CHD single-cell transcriptome. Our study identifies 90 potential candidate CHD risk genes of which 6 are novel. The risk genes have heterogenous expression suggestive of multiple genes contributing to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

Clinical learning environments across two different healthcare settings using the undergraduate clinical education environment measure.

BACKGROUND: The clinical placements of our medical students are almost equally distributed across private and public sectors. This study aims to assess medical students' perceptions of their Clinical learning Environment (CLE) across these two different healthcare settings, using the Undergraduate Clinical Education Environment Measure (UCEEM). METHODS: 76 undergraduate medical students (Year 5 and 6), were invited to participate. Data were collected using an online UCEEM with additional questions related to demographics and case load exposure. The UCEEM consists of two overarching domains of experiential learning and social participation, with four subdomains of learning opportunities, preparedness, workplace interaction, and inclusion. RESULTS: 38 questionnaires were received. Of 225 responses to the individual UCEEM items, 51 (22.6%) scored a mean of ≥ 4 (range 4-4.5, representing strong areas), 31 (13.7%) scored a mean of ≤ 3 (range 2.1-3, needing attention) and 143 (63.6%) scored a mean of 3.1-3.9 (areas that could be improved). The majority (63%) of the case load exposure responses scored a mean of ≥ 4 (range 4-4.5). Compared to the private sittings, there is a significant reduction in total UCEEM (p = 0.008), preparedness for student entry (p = 0.003), and overarching dimension of social participation (p = 0.000) scores for the public sector. Similarly, both workplace interaction patterns and student inclusion and equal treatment scored significantly lower for the public sector (p = 0.000 and p = 0.011 respectively). Two out of three case load exposure items scored significantly higher for the public sector (p = 0.000). DISCUSSION: The students' CLE perceptions were generally positive. The lower UCEEM ratings in the public sector items were related to student entry preparedness, workplace interactions, student inclusiveness and workforce equity of treatment. In contrast the students were exposed to more variety and larger number of patients in the public sector. These differences indicated some significantly different learning environments between the two sectors.

Computational Analysis of Short Linear Motifs in the Spike Protein of SARS-CoV-2 Variants Provides Possible Clues into the Immune Hijack and Evasion Mechanisms of Omicron Variant.

Short linear motifs (SLiMs) are short linear sequences that can mediate protein-protein interaction. Mimicking eukaryotic SLiMs to compete with extra- or intracellular binding partners, or to sequester host proteins is the crucial strategy of viruses to pervert the host system. Evolved proteins in viruses facilitate minimal protein-protein interactions that significantly affect intracellular signaling networks. Unfortunately, very little information about SARS-CoV-2 SLiMs is known, especially across SARS-CoV-2 variants. Through the ELM database-based sequence analysis of spike proteins from all the major SARS-CoV-2 variants, we identified four overriding SLiMs in the SARS-CoV-2 Omicron variant, namely, LIG_TRFH_1, LIG_REV1ctd_RIR_1, LIG_CaM_NSCaTE_8, and MOD_LATS_1. These SLiMs are highly likely to interfere with various immune functions, interact with host intracellular proteins, regulate cellular pathways, and lubricate viral infection and transmission. These cellular interactions possibly serve as potential therapeutic targets for these variants, and this approach can be further exploited to combat emerging SARS-CoV-2 variants.

Single-cell transcriptomics trajectory and molecular convergence of clinically relevant mutations in Brugada syndrome.

Brugada syndrome (BrS) is a rare, inherited arrhythmia with high risk of sudden cardiac death. To evaluate the molecular convergence of clinically relevant mutations and to identify developmental cardiac cell types that are associated with BrS etiology, we collected 733 mutations represented by 16 sodium, calcium, potassium channels, and regulatory and structural genes related to BrS. Among the clinically relevant mutations, 266 are unique singletons and 88 mutations are recurrent. We observed an over-representation of clinically relevant mutations (∼80%) in SCN5A gene and also identified several candidate genes, including GPD1L, TRPM4, and SCN10A. Furthermore, protein domain enrichment analysis revealed that a large proportion of the mutations impacted ion transport domains in multiple genes, including SCN5A, TRPM4, and SCN10A. A comparative protein domain analysis of SCN5A further established a significant (P = 0.04) enrichment of clinically relevant mutations within ion transport domain, including a significant (P = 0.02) mutation hotspot within 1321-1380 residue. The enrichment of clinically relevant mutations within SCN5A ion transport domain is stronger (P = 0.00003) among early onset of BrS. Our spatiotemporal cellular heart developmental (prenatal to adult) trajectory analysis applying single-cell transcriptome identified the most frequently BrS-mutated genes (SCN5A and GPD1L) are significantly upregulated in the prenatal cardiomyocytes. A more restrictive cellular expression trajectory is prominent in the adult heart ventricular cardiomyocytes compared to prenatal. Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS-associated cell type that provides insight into the complex genetic etiology of BrS.NEW & NOTEWORTHY Brugada syndrome is a rare inherited arrhythmia with high risk of sudden cardiac death. We present the findings for a molecular convergence of clinically relevant mutations and identification of a single-cell transcriptome-derived cardiac cell types that are associated with the etiology of BrS. Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS-associated cell type that provides insight into the complex genetic etiology of BrS.

Association of obesity indices with in-hospital and 1-year mortality following acute coronary syndrome.

BACKGROUND/OBJECTIVES: According to the "obesity paradox", adults with obesity have a survival advantage following acute coronary syndrome, compared with those without obesity. Previous studies focused on peripheral obesity and whether this advantage is conferred by central obesity is unknown. The objective of this study was to describe the association of peripheral and central obesity indices with risk of in-hospital and 1-year mortality following acute coronary syndrome (ACS). SUBJECTS/METHODS: Gulf COAST is a prospective ACS registry that enrolled 4044 patients age ≥18 years from January 2012 through January 2013, across 29 hospitals in four Middle Eastern countries. Associations of indices of peripheral obesity (body-mass index, [BMI]) and central obesity (waist circumference [WC] and waist-to-height ratio [WHtR]) with mortality following ACS were analyzed in logistic regression models (odds ratio, 95% CI) with and without adjustment for Global Registry of Acute Coronary Events risk score. RESULTS: Of 3882 patients analyzed (mean age: 60 years; 33.3% women [n = 1294]), the prevalence of obesity was 34.5% (BMI ≥ 30.0 kg/m2), 72.2% (WC ≥ 94.0 cm [men] or ≥80.0 cm [women]) and 90.0% (WHtR ≥ 0.5). In adjusted models, deciles of obesity indices showed higher risk of mortality at extreme versus intermediate deciles (U-shaped). When defined by conventional cut-offs, peripheral obesity (BMI ≥ 30.0 versus 18.5-29.9 kg/m2) showed inverse association with risk of in-hospital mortality (0.64; 95% CI, 0.42-0.99; P = 0.04; central obesity showed trend toward reduced mortality). In contrast, for risk of 1-year mortality, all indices showed inverse association. Obesity, defined by presence of all three indices, versus nonobesity showed inverse association with risk of 1-year mortality (0.52; 95% CI, 0.35-0.75; P = 0.001). Results were similar among men and women. CONCLUSION: The degree of obesity paradox following ACS depends on the obesity index and follow-up time. Obesity indices may aid in risk stratification of mortality following ACS.

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

Long-Read Sequencing Improves the Detection of Structural Variations Impacting Complex Non-Coding Elements of the Genome.

The advent of long-read sequencing offers a new assessment method of detecting genomic structural variation (SV) in numerous rare genetic diseases. For autism spectrum disorders (ASD) cases where pathogenic variants fail to be found in the protein-coding genic regions along chromosomes, we proposed a scalable workflow to characterize the risk factor of SVs impacting non-coding elements of the genome. We applied whole-genome sequencing on an Emirati family having three children with ASD using long and short-read sequencing technology. A series of analytical pipelines were established to identify a set of SVs with high sensitivity and specificity. At 15-fold coverage, we observed that long-read sequencing technology (987 variants) detected a significantly higher number of SVs when compared to variants detected using short-read technology (509 variants) (p-value < 1.1020 × 10-57). Further comparison showed 97.9% of long-read sequencing variants were spanning within the 1-100 kb size range (p-value < 9.080 × 10-67) and impacting over 5000 genes. Moreover, long-read variants detected 604 non-coding RNAs (p-value < 9.02 × 10-9), comprising 58% microRNA, 31.9% lncRNA, and 9.1% snoRNA. Even at low coverage, long-read sequencing has shown to be a reliable technology in detecting SVs impacting complex elements of the genome.

SARS-CoV-2 Whole Genome Amplification and Sequencing for Effective Population-Based Surveillance and Control of Viral Transmission.

BACKGROUND: With the gradual reopening of economies and resumption of social life, robust surveillance mechanisms should be implemented to control the ongoing COVID-19 pandemic. Unlike RT-qPCR, SARS-CoV-2 whole genome sequencing (cWGS) has the added advantage of identifying cryptic origins of the virus, and the extent of community-based transmissions versus new viral introductions, which can in turn influence public health policy decisions. However, the practical and cost considerations of cWGS should be addressed before it is widely implemented. METHODS: We performed shotgun transcriptome sequencing using RNA extracted from nasopharyngeal swabs of patients with COVID-19, and compared it to targeted SARS-CoV-2 genome amplification and sequencing with respect to virus detection, scalability, and cost-effectiveness. To track virus origin, we used open-source multiple sequence alignment and phylogenetic tools to compare the assembled SARS-CoV-2 genomes to publicly available sequences. RESULTS: We found considerable improvement in whole genome sequencing data quality and viral detection using amplicon-based target enrichment of SARS-CoV-2. With enrichment, more than 99% of the sequencing reads mapped to the viral genome, compared to an average of 0.63% without enrichment. Consequently, an increase in genome coverage was obtained using substantially less sequencing data, enabling higher scalability and sizable cost reductions. We also demonstrated how SARS-CoV-2 genome sequences can be used to determine their possible origin through phylogenetic analysis including other viral strains. CONCLUSIONS: SARS-CoV-2 whole genome sequencing is a practical, cost-effective, and powerful approach for population-based surveillance and control of viral transmission in the next phase of the COVID-19 pandemic.

Association of QRS narrowing with response to cardiac resynchronization therapy-a systematic review and meta-analysis of observational studies.

Prolonged QRS duration, which reflects a higher degree of mechanical dysynchrony, is a predictor of response to CRT. However, the association of QRS narrowing after biventricular pacing with CRT response rates is not clear. Our aim was to conduct a systematic review and meta-analysis on the association between QRS narrowing after cardiac resynchronization therapy (CRT) and clinical and echocardiographic response to CRT in patients with heart failure. Two independent investigators searched MedLine and EMBASE databases through July 2018 without any limitations. Studies providing estimates (continuous data) on the association of QRS shortening with either clinical (defined as New York Heart Association (NYHA) reduction ≥ 1) or echocardiographic (defined as left ventricular end-systolic volume (LVESV) reduction ≥ 15%) response to CRT were finally included in the quantitative synthesis. We included 32 studies (14 studies (1274 patients mean age 64 years old, males 79.3%) using clinical CRT response and 18 studies (1270 patients, mean age 64 years old, males 69.1%) using echocardiographic CRT response). A significant association between QRS narrowing and shorter attained QRS duration with clinical and echocardiographic CRT response was observed. The observed association was independent of the timing of QRS width measurement after CRT implantation. Acute and late improvement of electrical dysynchrony as depicted by QRS narrowing following biventricular pacing is associated with clinical and echocardiographic response to CRT. However, large prospective studies are needed to further examine our findings.

Physicians' perspective on shared decision-making in Dubai: a cross-sectional study.

BACKGROUND: Shared decision-making (SDM) is an integral part of patient-centered delivery of care. Maximizing the opportunity of patients to participate in decisions related to their health is an expectation in care delivery nowadays. The purpose of this study is to explore the perceptions of physicians in regard to SDM in a large private hospital network in Dubai, United Arab Emirates. METHODS: This study utilized a cross-sectional design, where a survey questionnaire was assembled to capture quantitative and qualitative data on the perception of physicians in relation to SDM. The survey instrument included three sections: the first solicited physicians' personal and professional information, the second entailed a 9-item SDM Questionnaire (SDM-Q-9), and the third included an open-ended section. Statistical analysis assessed whether the average SDM-Q-9 score differed significantly by gender, age, years of experience, professional status-generalist versus specialist, and work location-hospitals versus polyclinics. Non-parametric analysis (two independent variables) with the Mann-Whitney test was utilized. The qualitative data was thematically analyzed. RESULTS: Fifty physicians from various specialties participated in this study (25 of each gender-85% response rate). Although the quantitative data analysis revealed that most physicians (80%) rated themselves quite highly when it comes to SDM, qualitative analysis underscored a number of barriers that limited the opportunity for SDM. Analysis identified four themes that influence the acceptability of SDM, namely physician-specific (where the physicians' extent of adopting SDM is related to their own belief system and their perception that the presence of evidence negates the need for SDM), patient-related (e.g., patients' unwillingness to be involved in decisions concerning their health), contextual/environmental (e.g., sociocultural impediments), and relational (the information asymmetry and the power gradient that influence how the physician and patient relate to one another). CONCLUSIONS: SDM and evidence-based management (EBM) are not mutually exclusive. Professional learning and development programs targeting caregivers should focus on the consolidation of the two perspectives. We encourage healthcare managers and leaders to translate declared policies into actionable initiatives supporting patient-centered care. This could be achieved through the dedication of the necessary resources that would enable SDM, and the development of interventions that are designed both to improve health literacy and to educate patients on their rights.

Impact of Dual versus Single Antiplatelet Therapy on Major Cardiovascular Outcomes in Patients with Acute Coronary Syndrome in the Arabian Gulf.

OBJECTIVE: To evaluate the association of dual versus single antiplatelet therapy with major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) in the Arabian Gulf. SUBJECTS AND METHODS: Data were analyzed from 3,559 patients with a diagnosis of ACS admitted to 29 hospitals in 4 Arabian Gulf countries (Bahrain, Kuwait, Oman, and United Arab Emirates) from January 2012 to January 2013. Dual antiplatelet therapy (DAPT), consisting of aspirin and clopidogrel, was compared to aspirin alone. MACE included 12-months cumulative stroke/transient ischemic attack (TIA), myocardial infarction (MI), all-cause mortality, and readmissions for cardiac reasons, post discharge. Analyses were performed using multivariable logistic regression. RESULTS: A total of 74% (n = 2,634) of the patients were on DAPT. At 12-month follow-up, patients on DAPT were significantly less likely to experience MACE events (adjusted OR [aOR] 0.73; 95% CI: 0.61-0.86; p < 0.001). Lower cardiovascular (CV) event rates were also consistent across the following MACE components; MI (aOR 0.66; 95% CI: 0.49-0.88; p = 0.005), all-cause mortality (aOR 0.69; 95% CI: 0.51-0.94; p = 0.018), and readmissions for cardiac reasons (aOR 0.79; 95% CI: 0.66-0.95; p = 0.011). Conversely, DAPT was adversely associated with increased risk of stroke/TIA (aOR 1.68; 95% CI: 1.05-2.69; p = 0.030). CONCLUSIONS: DAPT, compared to aspirin therapy alone, was generally associated with better CV outcomes after an ACS event. However, DAPT was adversely associated with increased risk of stroke/TIA in ACS patients in the Arabian Gulf.

Precipitating Factors for Hospitalization with Heart Failure: Prevalence and Clinical Impact Observations from the Gulf CARE (Gulf aCute heArt failuRe rEgistry).

OBJECTIVE: Despite the expanding burden of heart failure (HF) worldwide, data on HF precipitating factors (PFs) in developing countries, particularly the Middle East, are very limited. We examined PFs in patients hospitalized with acute HF in a prospective multicenter HF registry from 7 countries in the Middle East. METHOD: Data were derived from the Gulf CARE (Gulf aCute heArt failuRe rEgistry) for a prospective, multinational, multicenter study of consecutive patients hospitalized with HF in 47 hospitals in 7 Middle Eastern countries between February 2012 and November 2012. PFs were determined by the treating physician from a predefined list at the time of hospitalization. RESULTS: The study included 5,005 patients hospitalized with acute HF, 2,276 of whom (45.5%) were hospitalized with acute new-onset HF (NOHF) and 2,729 of whom (54.5%) had acute decompensated chronic HF (DCHF). PFs were identified in 4,319 patients (86.3%). The most common PF in the NOHF group was acute coronary syndromes (ACS) (39.2%). In the DCHF group, it was noncompliance with medications (27.8%). Overall, noncompliance with medications was associated with a lower inhospital mortality (OR 0.47; 95% CI 0.28-0.80; p = 0.005) but a higher 1-year mortality (OR 1.43; 95% CI 1.1-1.85; p = 0.007). ACS was associated with higher inhospital mortality (OR 1.84; 95% CI 1.26-2.68; p = 0.002) and higher 1-year mortality (OR 1.62; 95% CI 1.27-2.06; p = 0.001). CONCLUSION: Preventive and therapeutic interventions specifically directed at noncompliance with medications and ACS are warranted in our region.

Increases in statin eligibility to reduce cardiovascular risk according to the 2013 ACC/AHA cholesterol guidelines in the Africa Middle East region: a sub-analysis of the Africa Middle East Cardiovascular Epidemiological (ACE) study.

BACKGROUND: With development of cholesterol management guidelines by the American College of Cardiology/American Heart Association (ACC/AHA), more individuals at risk of cardiovascular disease may be eligible for statin therapy. It is not known how this affects statin eligibility in the Africa and Middle East Region. METHODS: Data were used from the Africa Middle East Cardiovascular Epidemiological (ACE) study. The percentage of subjects eligible for statins per the ACC/AHA 2013 cholesterol guidelines and the 2002 National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP III) recommendations were compared. Analyses were carried out according to age, gender, community (urban/rural), and country income categories based on World Bank definitions. RESULTS: According to the ACC/AHA recommendations, 1695 out of 4378 subjects (39%; 95% confidence interval [CI], 37-40%) satisfied statin eligibility criteria vs. 1043/4378 (24%; 95% CI, 23-25%) per NCEP-ATP recommendations, representing a 63% increase in statin eligibility. Consistent increases in eligibility for statin therapy were seen according to the ACC/AHA vs. NCEP-ATP guidelines across sub-groups of age, gender, community, and country income. Notable increases for statin eligibility according to ACC/AHA vs. NCEP-ATP were seen, respectively, in subjects aged ≥65 years (86% vs. 39%), in males (46% vs. 25%), in low-income countries (28% vs. 14%), and rural communities (37% vs. 19%). CONCLUSION: An increase in statin eligibility was seen applying ACC/AHA cholesterol guidelines compared with previous NCEP-ATP recommendations in the Africa Middle East region. The economic consequences of these guideline recommendations will need further research. TRIAL REGISTRATION: The ACE trial is registered under NCT01243138 .

Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy and Defibrillators: Triggers, Treatment, and Implications.

INTRODUCTION: Triggers and ICD interventions of ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) offer insight into mechanisms and treatment. METHODS AND RESULTS: Intracardiac ICD electrograms from 71 HCM patients in the HCM I and II studies were analyzed by three individuals. Rhythms were defined as VF (polymorphic ventricular arrhythmia), VT (monomorphic ventricular tachycardia), and ventricular flutter (VFL; VT ≥ 240 bpm). Physical activity and rhythm preceding the arrhythmia were ascertained. Of 149 arrhythmias, VF was present in 74, VT in 57, and VFL in 18. In those whose activity was known, moderate or intense physical activity was associated with over 50% of the tachycardias (57 of 111). Rhythms preceding ventricular arrhythmias were often sinus tachycardia (49 of 149; 33%) or rapid atrial fibrillation (7 of 149; 5%). VF and VFL were more likely preceded by supraventricular rhythms >100 bpm (30 of 68 with VF; 44%; 12 of 16 with VFL 75%, vs. 14 of 50 with VT 28%; P = 0.001). Antitachycardia pacing (ATP) was successful in 39 of 53 (74%). Multiple shocks were more often required to terminate VFL (10 of 18; 56%) compared to VF (10 of 72; 14%) and VT (2 of 25; 8%; P < 0.0001). Of arrhythmias requiring more than one shock to terminate, 16 of 22 were preceded by sinus tachycardia and/or moderate or extreme physical activity. CONCLUSIONS: Rapid supraventricular rhythms, and at least moderate activity, frequently precede VT and VF, and when they occur in these situations often require multiple ICD shocks to restore sinus rhythm. ATP is successful in terminating VT and VFL, and should be a programmed in all HCM patients with ICDs.

Cardiac resynchronization therapy in patients with postero-lateral scar by cardiac magnetic resonance: A systematic review and meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in selected patients with heart failure, but up to one third of patients may not respond to CRT. A transmural postero-lateral (TMPL) wall scar in the left ventricle (LV) or over the LV pacing site may attenuate clinical and echocardiographic response to CRT. METHODS AND RESULTS: We systematically searched PubMed, EMBASE, and Cochrane databases for studies examining the association between Cardiac magnetic resonance (CMR)-determined postero-lateral or LV pacing site scar and clinical and echocardiographic response to CRT. Eleven prospective studies were included. The presence of TMPL scar on pre-implant CMR was associated with a 75% lower chance of echocardiographic response to CRT, and a similarly lower chance of clinical response. Significant scar over LV pacing site on pre-implant CMR was also associated with a 46% lower chance of echocardiographic response to CRT, and a 67% lower chance of clinical response. CONCLUSIONS: The presence of transmural postero-lateral scar or significant scar within the LV pacing site detected by pre-implant CMR is associated with a lower rate of clinical or echocardiographic response to CRT.

Effects of menstrual cycle on hemodynamic and autonomic responses to central hypovolemia.

Background: Estrogen and progesterone levels undergo changes throughout the menstrual cycle. Existing literature regarding the effect of menstrual phases on cardiovascular and autonomic regulation during central hypovolemia is contradictory. Aims and study: This study aims to explore the influence of menstrual phases on cardiovascular and autonomic responses in both resting and during the central hypovolemia induced by lower body negative pressure (LBNP). This is a companion paper, in which data across the menstrual phases from healthy young females, whose results are reported in Shankwar et al. (2023), were further analysed. Methods: The study protocol consisted of three phases: (1) 30 min of supine rest; (2) 16 min of four LBNP levels; and (3) 5 min of supine recovery. Hemodynamic and autonomic responses (assessed via heart rate variability, HRV) were measured before-, during-, and after-LBNP application using Task Force Monitor® (CNSystems, Graz, Austria). Blood was also collected to measure estrogen and progesterone levels. Results: In this companion paper, we have exclusively assessed 14 females from the previous study (Shankwar et al., 2023): 8 in the follicular phase of the menstrual cycle (mean age 23.38 ± 3.58 years, height 166.00 ± 5.78 cm, weight 57.63 ± 5.39 kg and BMI of 20.92 ± 1.96 25 kg/m2) and 6 in the luteal phase (mean age 22.17 ± 1.33 years, height 169.83 ± 5.53 cm, weight 62.00 ± 7.54 kg and BMI of 21.45 ± 2.63 kg/m2). Baseline estrogen levels were significantly different from the follicular phase as compared to the luteal phase: (33.59 pg/ml, 108.02 pg/ml, respectively, p < 0.01). Resting hemodynamic variables showed no difference across the menstrual phases. However, females in the follicular phase showed significantly lower resting values of low-frequency (LF) band power (41.38 ± 11.75 n.u. and 58.47 ± 14.37 n.u., p = 0.01), but higher resting values of high frequency (HF) band power (58.62 ± 11.75 n.u. and 41.53 ± 14.37 n.u., p = 0.01), as compared to females in the luteal phase. During hypovolemia, the LF and HF band powers changed only in the follicular phase F(1, 7) = 77.34, p < 0.0001 and F(1, 7) = 520.06, p < 0.0001, respectively. Conclusions: The menstrual phase had an influence on resting autonomic variables, with higher sympathetic activity being observed during the luteal phase. Central hypovolemia leads to increased cardiovascular and autonomic responses, particularly during the luteal phase of the menstrual cycle, likely due to higher estrogen levels and increased sympathetic activity.

Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations.

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal autosomal recessive disorder for which several treatment options, including a gene therapy, have become available. SMA incidence has not been well-characterized in most Arab countries where rates of consanguinity are high. Understanding SMA disease epidemiology has important implications for screening, prevention, and treatment in those populations. METHODS: We perform SMA diagnostic testing in a clinical multi-national patient cohort (N = 171) referred for hypotonia and/or muscle weakness. In addition, we carry out genetic newborn screening for SMA on 1502 healthy Emirati newborns to estimate the carrier frequency and incidence of the disease in the United Arab Emirates. RESULTS: Patients referred for SMA genetic testing are mostly Arabs (82%) representing 18 countries. The overall diagnostic yield is 33.9%, which is higher (>50%) for certain nationalities. Most patients (71%) has two SMN2 copies and earlier disease onset. For the first time, we estimate SMA carrier frequency (1.3%) and incidence of the disease (1 in 7122 live births) in the United Arab Emirates. Using birth and marriage rates in two Arab populations (United Arab Emirates and Saudi Arabia), as well as disease incidence in both countries, we show that, besides preventing new cases, premarital genetic screening could potentially result in around $8 to $324 million annual cost savings, respectively, relative to postnatal treatment. CONCLUSIONS: The SMA carrier frequency and incidence we document suggests high potential benefit for universal implementation of premarital genomic screening for a wide range of recessive disorders in Arab populations.

The occurrence of spinal muscular atrophy, a fatal genetic nerve and muscle disease, has been poorly studied in most Arab countries. Individuals who carry a single mutated gene copy (carriers) may be more likely to marry other carriers in regions where marriage rates amongst relatives, who share similar genetics, are high. Here we report the results of a newborn testing program for this disease in 1502 Emiratis and calculate the presence of carriers (1/79) and occurrence of disease (1/7122) in this population. Using this new information along with the annual birth and marriage rates in the United Arab Emirates and Saudi Arabia, we make the case that premarital genomic screening (carrier testing) is the best way to prevent this and other similarly inherited disorders in the Arab population.

Unintended Harm and Benefit of the Implantable Defibrillator in an Unfortunate 19-Year-Old Male: Featuring a Sequence of Rare Life-threatening Complications of Cardiac Procedures.

All procedures have inherent risk. Our patient endured a sequence of rare life-threatening complications from commonly preformed procedures. The sequence of these complications was; large pericardial effusion post implantable cardioverter-defibrillator (ICD) implantation with echocardiographic signs of tamponade, left main narrowing post radiofrequency ablation, and late stent thrombosis post coronary intervention with a bare metal stent. All these occurred to one unfortunate young man. Furthermore, our patient demonstrated an unintended benefit of ICD which saved his life.

Association of Late Potentials With Fatal Arrhythmic Events in Patients With Brugada Syndrome-A Meta-analysis.

Risk stratification of patients with Brugada syndrome (BrS) remains challenging. Signal-averaged electrocardiogram (SAECG) is a noninvasive tool that can be used to identify the electrophysiologic substrate potentially underlying fatal ventricular arrhythmias. The aim of this meta-analysis is to summarize the existing evidence about the role of late potentials (LP) as a predictor for arrhythmic events in patients with BrS. A systematic search in the MedLine database through to June 2022 without any limitations was performed. Ten studies were included in the quantitative synthesis (1431 patients with BrS, mean age 47.4 years, males 86%). Of these, 1220 patients underwent SAECG evaluation (53.2% had positive LP, and 20.6% had a fatal arrhythmic event). There was a nonsignificant association between positive LPs and fatal arrhythmic events [RR: 2.06 (0.98-4.36), P = 0.06, I2 = 82%]. By including only studies with patients without a history of fatal arrhythmia, the association between LP with arrhythmic events remained nonsignificant [RR: 1.29 (0.67-2.48), P = 0.44, I2 = 54%]. In conclusion, there is a possible association between LP and fatal arrhythmic events in patients with BrS, but the literature remains inconclusive. Large cohort studies using a multiparametric approach for risk stratification purposes are needed to improve the risk stratification of BrS and to optimize the selection of BrS patients that should be referred for implantable cardioverter-defibrillator.