Risk stratification of sudden cardiac death in asymptomatic female Brugada syndrome patients: A literature review

Background and Objectives Risk stratification in Brugada syndrome remains a difficult problem. Given the male predominance of this disease and their elevated risks of arrhythmic events, affected females have received less attention. It is widely known that symptomatic patients are at increased risk of sudden cardiac death (SCD) than asymptomatic patients, while this might be true in the male population; recent studies have shown that this association might not be significant in females. Over the past few decades, numerous markers involving clinical symptoms, electrocardiographic (ECG) indices, and genetic tests have been explored, with several risk-scoring models developed so far. The objective of this study is to review the current evidence of clinical and ECG markers as well as risk scores on asymptomatic females with Brugada syndrome. Findings Gender differences in ECG markers, the yield of genetic findings, and the applicability of risk scores are highlighted. Conclusions Various clinical, electrocardiographic, and genetic risk factors are available for assessing SCD risk amongst asymptomatic female BrS patients. However, due to the significant gender discrepancy in BrS, the SCD risk amongst females is often underestimated, and there is a lack of research on female-specific risk factors and multiparametric risk scores. Therefore, multinational studies pooling female BrS patients are needed for the development of a gender-specific risk stratification approach amongst asymptomatic BrS patients

Attendance-related healthcare resource utilisation and costs in patients with Brugada Syndrome in Hong Kong: A retrospective cohort study.

Understanding healthcare resource utilisation and its associated costs are important for identifying areas of improvement regarding resource allocations. However, there is limited research exploring this issue in the setting of Brugada syndrome (BrS). This was a retrospective territory-wide study of BrS patients from Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and specialist outpatient attendances were analysed over a 19-year period, with their associated costs presented in US dollars. A total of 507 BrS patients with a mean presentation age of 49.9 ± 16.3 years old were included. Of these, 384 patients displayed spontaneous type 1 electrocardiographic (ECG) Brugada pattern and 77 patients had presented with ventricular tachycardia/ventricular fibrillation (VT/VF). At the individual patient level, the median annualised costs were 110 (52-224) at the (A&E) setting, 6812 (1982-32414) at the inpatient setting and $557 (326-1001) for specialist outpatient attendances. Patients with initial VT/VF presentation had overall greater costs in inpatient ($20161 [9147-189215] vs. $5290 [1613-24937],p<0.0001) and specialist outpatient setting ($776 [438-1076] vs. $542 [293-972],p=0.015) compared to those who did not present VT. In addition, patients without Type 1 ECG pattern had greater median costs in the specialist outpatient setting ($7036 [3136-14378] vs. $4895 [2409-10554],p=0.019). There is a greater healthcare demand in the inpatient and specialist outpatient settings for BrS patients. The most expensive attendance type was inpatient setting stay at$6812 per year. The total median annualised cost of BrS patients without VT/VF presentation was 78% lower compared to patients with VT/VF presentation. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

COVID-19 vaccination and carditis in children and adolescents: a systematic review and meta-analysis

BACKGROUND: Coronavirus Disease-2019 (COVID-19) vaccination has been associated with the development of carditis, especially in children and adolescent males. However, the rates of these events in the global setting have not been explored in a systematic manner. The aim of this systematic review and meta-analysis is to investigate the rates of carditis in children and adolescents receiving COVID-19 vaccines. METHODS: PubMed, Embase and several Latin American databases were searched for studies. The number of events, and where available, at-risk populations were extracted. Rate ratios were calculated and expressed as a rate per million doses received. Subgroup analysis based on the dose administered was performed. Subjects ≤ 19 years old who developed pericarditis or myocarditis following COVID-19 vaccination were included. RESULTS: A total of 369 entries were retrieved. After screening, 39 articles were included. Our meta-analysis found that 343 patients developed carditis after the administration of 12,602,625 COVID-19 vaccination doses (pooled rate per million: 37.76; 95% confidence interval [CI] 23.57, 59.19). The rate of carditis was higher amongst male patients (pooled rate ratio: 5.04; 95% CI 1.40, 18.19) and after the second vaccination dose (pooled rate ratio: 5.60; 95% CI 1.97, 15.89). In 301 cases of carditis (281 male; mean age: 15.90 (standard deviation [SD] 1.52) years old) reported amongst the case series/reports, 261 patients were reported to have received treatment. 97.34% of the patients presented with chest pain. The common findings include ST elevation and T wave abnormalities on electrocardiography. Oedema and late gadolinium enhancement in the myocardium were frequently observed in cardiac magnetic resonance imaging (CMR). The mean length of hospital stay was 3.91 days (SD 1.75). In 298 out of 299 patients (99.67%) the carditis resolved with or without treatment. CONCLUSIONS: Carditis is a rare complication after COVID-19 vaccination across the globe, but the vast majority of episodes are self-limiting with rapid resolution of symptoms within days. Central illustration. Balancing the benefits of vaccines on COVID-19-caused carditis and post-vaccination carditis

Risk stratification of sudden cardiac death in asymptomatic female Brugada syndrome patients: A literature review

Background and Objectives: Risk stratification in Brugada syndrome remains a difficult problem. Given the male predominance of this disease and their elevated risks of arrhythmic events, affected females have received less attention. It is widely known that symptomatic patients are at increased risk of sudden cardiac death (SCD) than asymptomatic patients, while this might be true in the male population; recent studies have shown that this association might not be significant in females. Over the past few decades, numerous markers involving clinical symptoms, electrocardiographic (ECG) indices, and genetic tests have been explored, with several risk-scoring models developed so far. The objective of this study is to review the current evidence of clinical and ECG markers as well as risk scores on asymptomatic females with Brugada syndrome. Findings: Gender differences in ECG markers, the yield of genetic findings, and the applicability of risk scores are highlighted. Conclusions: Various clinical, electrocardiographic, and genetic risk factors are available for assessing SCD risk amongst asymptomatic female BrS patients. However, due to the significant gender discrepancy in BrS, the SCD risk amongst females is often underestimated, and there is a lack of research on female-specific risk factors and multiparametric risk scores. Therefore, multinational studies pooling female BrS patients are needed for the development of a gender-specific risk stratification approach amongst asymptomatic BrS patients

Historical perspective and recent progress in cardiac ion channelopathies research and clinical practice in Hong Kong

Cardiac ion channelopathies encompass a set of inherited or acquired conditions that are due to dysfunction in ion channels or their associated proteins, typically in the presence of structurally normal hearts. They are associated with the development of ventricular arrhythmias and sudden cardiac death. The aim of this review is to provide a historical perspective and recent advances in the research of the cardiac ion channelopathies, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, in Hong Kong, China. In particular, recent works on the development of novel predictive models incorporating machine learning techniques to improve risk stratification are outlined. The availability of linked records of affected patients with good longitudinal data in the public sector, together with multidisciplinary collaborations, implies that ion channelopathy research efforts have advanced significantly

Secular trends of health care resource utilization and costs between Brugada syndrome and congenital long QT syndrome: A territory‐wide study

Background Health care resource utilization (HCRU) and costs are important metrics of health care burden, but they have rarely been explored in the setting of cardiac ion channelopathies. Hypothesis This study tested the hypothesis that attendance-related HCRUs and costs differed between patients with Brugada syndrome (BrS) and congenital long QT syndrome (LQTS). Methods This was a retrospective cohort study of consecutive BrS and LQTS patients at public hospitals or clinics in Hong Kong, China. HCRUs and costs (in USD) for Accident and Emergency (A&E), inpatient, general outpatient and specialist outpatient attendances were analyzed between 2001 and 2019 at the cohort level. Comparisons were made using incidence rate ratios (IRRs [95% confidence intervals]). Results Over the 19-year period, 516 BrS (median age of initial presentation: 51 [interquartile range: 38−61] years, 92% male) and 134 LQTS (median age of initial presentation: 21 [9−44] years, 32% male) patients were included. Compared to LQTS patients, BrS patients had lower total costs (2 008 126 [2 007 622−2 008 629] vs. 2 343 864 [2 342 828−2 344 900]; IRR: 0.857 [0.855−0.858]), higher costs for A&E attendances (83 113 [83 048−83 177] vs. 70 604 [70 487−70 721]; IRR: 1.177 [1.165−1.189]) and general outpatient services (2,176 [2,166−2,187] vs. 921 [908−935]; IRR: 2.363 [2.187−2.552]), but lower costs for inpatient stay (1 391 624 [1 391 359−1 391 889] vs. 1 713 742 [1 713 166−1 714 319]; IRR: 0.812 [0.810−0.814]) and lower costs for specialist outpatient services (531 213 [531 049−531 376] vs. 558 597 [558268−558926]; IRR: 0.951 [0.947−0.9550]). Conclusions Overall, BrS patients consume 14% less health care resources compared to LQTS patients in terms of attendance costs. BrS patients require more A&E and general outpatient services, but less inpatient and specialist outpatient services than LQTS patients

COVID-19 vaccination and carditis in children and adolescents: a systematic review and meta-analysis

BackgroundCoronavirus Disease-2019 (COVID-19) vaccination has been associated with the development of carditis, especially in children and adolescent males. However, the rates of these events in the global setting have not been explored in a systematic manner. The aim of this systematic review and meta-analysis is to investigate the rates of carditis in children and adolescents receiving COVID-19 vaccines.MethodsPubMed, Embase and several Latin American databases were searched for studies. The number of events, and where available, at-risk populations were extracted. Rate ratios were calculated and expressed as a rate per million doses received. Subgroup analysis based on the dose administered was performed. Subjects ≤ 19 years old who developed pericarditis or myocarditis following COVID-19 vaccination were included.ResultsA total of 369 entries were retrieved. After screening, 39 articles were included. Our meta-analysis found that 343 patients developed carditis after the administration of 12,602,625 COVID-19 vaccination doses (pooled rate per million: 37.76; 95% confidence interval [CI] 23.57, 59.19). The rate of carditis was higher amongst male patients (pooled rate ratio: 5.04; 95% CI 1.40, 18.19) and after the second vaccination dose (pooled rate ratio: 5.60; 95% CI 1.97, 15.89). In 301 cases of carditis (281 male; mean age: 15.90 (standard deviation [SD] 1.52) years old) reported amongst the case series/reports, 261 patients were reported to have received treatment. 97.34% of the patients presented with chest pain. The common findings include ST elevation and T wave abnormalities on electrocardiography. Oedema and late gadolinium enhancement in the myocardium were frequently observed in cardiac magnetic resonance imaging (CMR). The mean length of hospital stay was 3.91 days (SD 1.75). In 298 out of 299 patients (99.67%) the carditis resolved with or without treatment.ConclusionsCarditis is a rare complication after COVID-19 vaccination across the globe, but the vast majority of episodes are self-limiting with rapid resolution of symptoms within days. Central illustration. Balancing the benefits of vaccines on COVID-19-caused carditis and post-vaccination carditis

Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution

The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden