Precision medicine in catecholaminergic polymorphic ventricular tachycardia: Recent advances toward personalized care

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy where the initial disease presentation is during childhood or adolescent stages, leading to increased risks of sudden cardiac death. Despite advances in medical science and technology, several gaps remain in the understanding of the molecular mechanisms, risk prediction, and therapeutic management of patients with CPVT. Recent studies have identified and validated seven sets of genes responsible for various CPVT phenotypes, including RyR2, CASQ-2, TRDN, CALM1, 2, and 3, and TECRL, providing novel insights into the molecular mechanisms. However, more data on atypical CPVT genotypes are required to investigate the underlying mechanisms further. The complexities of the underlying genetics contribute to challenges in risk stratification as well as the uncertainty surrounding nongenetic modifiers. Therapeutically, although medical management involving beta-blockers and flecainide, or insertion of an implantable cardioverter defibrillator remains the mainstay of treatment, animal and stem cell studies on gene therapy for CPVT have shown promising results. However, its clinical applicability remains unclear. Current gene therapy studies have primarily focused on the RyR2 and CASQ-2 variants, which constitute 75% of all CPVT cases. Alternative approaches that target a broader population, such as CaMKII inhibition, could be more feasible for clinical implementation. Together, this review provides an update on recent research on CPVT, highlighting the need for further investigation of the molecular mechanisms, risk stratification, and therapeutic management of this potentially lethal condition

Precision medicine in catecholaminergic polymorphic ventricular tachycardia:Recent advances toward personalized care

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy where the initial disease presentation is during childhood or adolescent stages, leading to increased risks of sudden cardiac death. Despite advances in medical science and technology, several gaps remain in the understanding of the molecular mechanisms, risk prediction, and therapeutic management of patients with CPVT. Recent studies have identified and validated seven sets of genes responsible for various CPVT phenotypes, including RyR2, CASQ-2, TRDN, CALM1, 2, and 3, and TECRL, providing novel insights into the molecular mechanisms. However, more data on atypical CPVT genotypes are required to investigate the underlying mechanisms further. The complexities of the underlying genetics contribute to challenges in risk stratification as well as the uncertainty surrounding nongenetic modifiers. Therapeutically, although medical management involving beta-blockers and flecainide, or insertion of an implantable cardioverter defibrillator remains the mainstay of treatment, animal and stem cell studies on gene therapy for CPVT have shown promising results. However, its clinical applicability remains unclear. Current gene therapy studies have primarily focused on the RyR2 and CASQ-2 variants, which constitute 75% of all CPVT cases. Alternative approaches that target a broader population, such as CaMKII inhibition, could be more feasible for clinical implementation. Together, this review provides an update on recent research on CPVT, highlighting the need for further investigation of the molecular mechanisms, risk stratification, and therapeutic management of this potentially lethal condition

Clinical characteristics, genetic basis and healthcare resource utilisation and costs in patients with catecholaminergic polymorphic ventricular tachycardia: A retrospective cohort study

Background: This study examined the clinical characteristics, genetic basis, healthcare utilisation and costs of catecholaminergic ventricular tachycardia (CPVT) patients from a Chinese city. Methods: This was a territory-wide retrospective cohort study of consecutive CPVT patients at public hospitals or clinics in Hong Kong. Healthcare resource utilisation for accident and emergency (A&E), inpatient and outpatient attendances were analysed over 19 years (2001–2019) followed by calculations of annualised costs (in USD). Results: Sixteen patients with a median presentation age (interquartile range (IQR) of 11 (9–14) years old) were included. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and ventricular tachycardia/fibrillation (VT/VF). One patient had PVCs without VT/VF. Genetic tests were performed on 14 patients (87.5%). Eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2) gene. Seven variants have been described elsewhere (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A).c.14861C>G is a novel RyR2 variant not been reported outside this cohort. Patients were treated with beta-blockers (n = 16), amiodarone (n = 3) and verapamil (n = 2). Sympathectomy (n = 8) and implantable-cardioverter defibrillator implantation (n = 3) were performed. Over a median follow-up of 13.3 years (IQR: 8.4–18.1) years, six patients exhibited incident VT/VF. At the patient level, the median (IQR) annualised costs for A&E, inpatient and outpatient attendances were $66 (40–95),$10521 (5240–66887) and $791 (546–1105), respectively. Conclusions: All patients presented before the age of 19. The yield of genetic testing was 57%. The most expensive attendance type was inpatient stays, followed by outpatients and A&E attendances

Cardiovascular risks of chemo-immunotherapy for lung cancer: A population-based cohort study.

Despite their proven efficacy for treating lung cancer, the cardiovascular risks associated with programmed cell death protein 1 (PD-1) inhibitors and their combinations with chemotherapy (chemo-immunotherapy) are unclear. This study aimed to investigate these associations. This retrospective cohort study included Hong Kong patients with lung cancer receiving PD-1 inhibitors during 2013-2021. Patients with non-concurrent use of PD-1 inhibitors and chemotherapy, any use of tyrosine kinase inhibitors or other immunotherapy agents, and those with prior stroke, heart failure, or myocardial infarction were excluded. PD-1 inhibitors and chemo-immunotherapy were compared for major adverse cardiovascular events (MACE), a composite of cardiovascular mortality, heart failure, stroke, and myocardial infarction. All patients were followed up until the end of 2021. Inverse probability of treatment weighting was used to balance covariates between the two treatment groups. In total, 713 patients (333 PD-1 inhibitors users and 380 chemo-immunotherapy users) were analysed. Over a mean follow-up of 1.4 ± 1.3 years, 24 had MACE, with an observed incidence of 2.8 [1.6-4.8] events per 100 person-year for patients on PD-1 inhibitors, and 2.1 [1.2-3.8] per 100 person-year for patients on chemo-immunotherapy. No significant between-group difference in MACE incidence was observed (log-rank p = 0.641). The cardiovascular risks associated with PD-1 inhibitors and chemo-immunotherapy may not be significantly different amongst patients with lung cancer. Cardiovascular events associated with either regimen may be uncommon. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

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.

The role of cardiac magnetic resonance in identifying appropriate candidates for cardiac resynchronization therapy - a systematic review of the literature

Despite the strict indications for cardiac resynchronization therapy (CRT) implantation, a significant proportion of patients will fail to adequately respond to the treatment. This systematic review aims to present the existing evidence about the role of cardiac magnetic resonance (CMR) in identifying patients who are likely to respond better to the CRT. A systematic search in the MedLine database and Cochrane Library from their inception to August 2021 was performed, without any limitations, by two independent investigators. We considered eligible observational studies or randomized clinical trials (RCTs) that enrolled patients > 18 years old with heart failure (HF) of ischaemic or non-ischaemic aetiology and provided data about the association of baseline CMR variables with clinical or echocardiographic response to CRT for at least 3 months. This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement). Following our search strategy, 47 studies were finally included in our review. CMR appears to have an additive role in identifying the subgroup of patients who will respond better to CRT. Specifically, the presence and the extent of myocardial scar were associated with increased non-response rates, while those with no scar respond better. Furthermore, existing data show that scar location can be associated with CRT response rates. CMR-derived markers of mechanical desynchrony can also be used as predictors of CRT response. CMR data can be used to optimize the position of the left ventricular lead during the CRT implantation procedure. Specifically, positioning the left ventricular lead in a branch of the coronary sinus that feeds an area with transmural scar was associated with poorer response to CRT. CMR can be used as a non-invasive optimization tool to identify patients who are more likely to achieve better clinical and echocardiographic response following CRT implantation. [Abstract copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Comparing sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors on new-onset depression: a propensity score-matched study in Hong Kong.

The risk of new onset depression associated with sodium-glucose co-transporter 2 inhibitor (SGLT2I) use in patients with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the risk of new onset depression between SGLT2I and dipeptidyl peptidase 4 inhibitor (DPP4I) users. This was a population-based cohort study of T2DM patients in Hong Kong between January 1st, 2015, and December 31st, 2019. T2DM patients over 18 with either SGLT2I or DPP4I use were included. 1:1 propensity-score matching using the nearest-neighbour method was conducted based on demographics, past comorbidities and non-DPP4I/SGLT2I medication use. Cox regression analysis models were used to identify significant predictors for new onset depression. The study cohort included a total of 18,309 SGLT2I users and 37,269 DPP4I users (55.57% male, mean age: 63.5 ± 12.9 years) with a median follow-up duration of 5.56 (IQR: 5.23-5.8) years. After propensity score matching, SGLT2I use was associated with a lower risk of new onset depression compared to DPP4I use (HR: 0.52, 95% CI: [0.35, 0.77], P = 0.0011). These findings were confirmed by Cox multivariable analysis and sensitive analyses. SGLT2I use is associated with significantly lower risk of depression compared to DPP4 use in T2DM patients using propensity score matching and Cox regression analyses. [Abstract copyright: © 2023. The Author(s).

Risk factors of pancreatic cancer in patients with type 2 diabetes mellitus: The Hong Kong Diabetes Study

Context Diabetes mellitus (DM) is associated with the development of pancreatic cancer (PaC), but few large-scale studies have examined its predictive risk factors. Objective The present study aims to examine the predictors for PaC in patients with type 2 diabetes mellitus (T2DM) in a territory-wide, retrospective cohort study. Methods This was a territory-wide, retrospective cohort study of patients with T2DM mellitus older than 40 years with no prior history of PaC. Baseline demographics, use of antidiabetic medications, comorbidities, and biochemical parameters were extracted. Cox regression was used to calculate hazard ratios (HR) with 95% CI. Subgroup analyses based on chronic kidney disease (CKD) stages were performed. Results This study consisted of 273 738 patients (age = 65.4 ± 12.7 years, male = 48.2%, follow-up duration = 3547 ± 1207 days, disease duration = 4.8 ± 2.3 years), of whom 1148 developed PaC. The number of antidiabetic medications prescribed (HR: 1.20; 95% CI, 1.01-1.42; P = .040), diabetic microvascular complications (HR: 1.91; 95% CI, 1.30-2.81; P < .001), chronic kidney disease (HR: 1.81; 95% CI, 1.25-2.64; P = .002), use of acarbose (HR: 2.24; 95% CI, 1.35-3.74; P = .002), and use of glucagon-like peptide-1 receptor agonist (HR: 4.00; 95% CI: 1.28-12.53, P = .017) were associated with PaC development on multivariable Cox regression adjusting for the duration of DM, mean glycated hemoglobin A1c, and history of pancreatic diseases. Stage 3A CKD or below was associated with PaC but not stage 3B or beyond. Conclusion Diabetic microvascular complications, especially stage 1, 2, and 3A CKD, were associated with PaCs

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

Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors vs. Dipeptidyl Peptidase-4 (DPP4) inhibitors for new-onset dementia: A propensity score-matched population-based study with competing risk analysis

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset cognitive dysfunction in type 2 diabetes mellitus remain unknown. This study aimed to evaluate the effects of the two novel antidiabetic agents on cognitive dysfunction by comparing the rates of dementia between SGLT2I and DPP4I users. This was a population-based cohort study of type 2 diabetes mellitus patients treated with SGLT2I and DPP4I between January 1, 2015 and December 31, 2019 in Hong Kong. Exclusion criteria were <1-month exposure or exposure to both medication classes, or prior diagnosis of dementia or major neurological/psychiatric diseases. Primary outcomes were new-onset dementia, Alzheimer's, and Parkinson's. Secondary outcomes were all-cause, cardiovascular, and cerebrovascular mortality. A total of 13,276 SGLT2I and 36,544 DPP4I users (total = 51,460; median age: 66.3 years old [interquartile range (IQR): 58-76], 55.65% men) were studied (follow-up: 472 [120-792] days). After 1:2 matching (SGLT2I: = 13,283; DPP4I: = 26,545), SGLT2I users had lower incidences of dementia (0.19 vs. 0.78%, < 0.0001), Alzheimer's (0.01 vs. 0.1%, = 0.0047), Parkinson's disease (0.02 vs. 0.14%, = 0.0006), all-cause (5.48 vs. 12.69%, < 0.0001), cerebrovascular (0.88 vs. 3.88%, < 0.0001), and cardiovascular mortality (0.49 vs. 3.75%, < 0.0001). Cox regression showed that SGLT2I use was associated with lower risks of dementia (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: [0.27-0.61], < 0.0001), Parkinson's (HR:0.28, 95% CI: [0.09-0.91], = 0.0349), all-cause (HR:0.84, 95% CI: [0.77-0.91], < 0.0001), cardiovascular (HR:0.64, 95% CI: [0.49-0.85], = 0.0017), and cerebrovascular (HR:0.36, 95% CI: [0.3-0.43], < 0.0001) mortality. The use of SGLT2I is associated with lower risks of dementia, Parkinson's disease, and cerebrovascular mortality compared with DPP4I use after 1:2 ratio propensity score matching. [Abstract copyright: Copyright © 2021 Mui, Zhou, Lee, Leung, Lee, Chou, Tsang, Wai, Liu, Wong, Chang, Tse and Zhang.