Background
Atrial arrhythmias, particularly atrioventricular nodal reentrant tachycardia, can coexist with drug‐induced type 1 Brugada electrocardiogram (ECG) pattern (DI‐Type1‐BrP). The present ...study was designed to determine the prevalence of DI‐Type1‐BrP in patients with atrioventricular accessory pathways (AV‐APs) and to investigate the clinical, electrocardiographic, electrophysiologic, and genetic characteristics of these patients.
Methods
One‐hundred twenty‐four consecutive cases of AV‐APs and 84 controls underwent an ajmaline challenge test to unmask DI‐Type1‐BrP. Genetic screening and analysis was performed in 55 of the cases (19 with and 36 without DI‐Type1‐BrP).
Results
Patients with AV‐APs were significantly more likely than controls to have a Type1‐BrP unmasked (16.1 vs 4.8%, P = 0.012). At baseline, patients with DI‐Type1‐BrP had higher prevalence of chest pain, QR/rSr’ pattern in V1 and QRS notching/slurring in V2 and aVL during preexcitation, rSr’ pattern in V1‐V2, and QRS notching/slurring in aVL during orthodromic atrioventricular reentrant tachycardia (AVRT) compared to patients without DI‐Type1‐BrP. Abnormal QRS configuration (QRS notching/slurring and/or fragmentation) in V2 during preexcitation was present in all patients with DI‐Type1 BrP. The prevalence of spontaneous preexcited atrial fibrillation (AF) and history of AF were similar (15% vs 18.3%, P = 0.726) in patients with and without DI‐Type1‐BrP, respectively. The prevalence of mutations in Brugada‐susceptibility genes was higher (36.8% vs 8.3%, P = 0.02) in patients with DI‐Type1‐BrP compared to patients without DI‐Type1‐BrP.
Conclusions
DI‐Type1‐BrP is relatively common in patients with AV‐APs. We identify 12‐lead ECG characteristics during preexcitation and orthodromic AVRT that point to an underlying type1‐BrP, portending an increased probability for development of malignant arrhythmias.
Abstract
Aims
Hypertrophic cardiomyopathy (HCM) is an inheritable disease that leads to sudden cardiac death and heart failure (HF). Sarcomere mutations (SMs) have been associated with HF. However, ...the differences in ventricular function between SM-positive and SM-negative HCM patients are poorly characterized.
Methods and results
Of the prospectively enrolled 374 unrelated HCM patients in Taiwan, 115 patients underwent both 91 cardiomyopathy-related gene screening and cardiovascular magnetic resonance (45.6 ± 10.6 years old, 76.5% were male). Forty pathogenic/likely pathogenic mutations were identified in 52 patients by next-generation sequencing. The SM-positive group were younger at first cardiovascular event (P = 0.04) and progression to diastolic HF (P = 0.02) with higher N-terminal pro-brain natriuretic peptide (NT-proBNP) New York Heart Association (NYHA) Class III/IV symptoms with left ventricular ejection fraction > 55% than the SM-negative group (P < 0.001). SM-positive patients had a greater extent of late gadolinium enhancement (P = 0.01), larger left atrial diameter (P = 0.03), higher normalized peak filling rate (PFR) and PFR ratio, and a greater reduction in global longitudinal strain than SM-negative patients (all P ≤ 0.01). During mean lifelong follow-up time (49.2 ± 15.6 years), SM-positive was a predictor of earlier HF (NYHA Class III/IV symptoms) after multivariate adjustment (hazard ratio 3.5; 95% confidence interval 1.3–9.7; P = 0.015).
Conclusion
SM-positive HCM patients had a higher extent of myocardial fibrosis and more severe ventricular diastolic dysfunction than those without, which may contribute to earlier onset of advanced HF, suggesting the importance of close surveillance and early treatment throughout life.
Graphical Abstract
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A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan.
We report the first whole genome ...sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine.
Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2.
We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting.
This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.
Homocysteine has been long considered a risk factor for atherosclerosis. However, cardiovascular events cannot be reduced through homocysteine lowering by B vitamin supplements. Although several ...association studies have reported an elevation of serum homocysteine levels in cardiovascular diseases, the relationship of homocysteine with ST-segment elevation myocardial infarction (STEMI) is not well established.
We prospectively enrolled STEMI patients who were consecutively admitted to an intensive care unit following coronary intervention in a single medical center in Taiwan. Control subjects were individuals who presented to the outpatient or emergency department with acute chest pain but subsequently revealed patent coronary arteries by coronary arteriography. The association between serum homocysteine levels and STEMI was investigated. A culture system using human coronary artery endothelial cells was also established to examine the toxic effects of homocysteine at the cellular level.
Patients with chest pain were divided into two groups. The STEMI group included 56 patients who underwent a primary percutaneous coronary intervention. The control group included 17 subjects with patent coronary arteries. There was no difference in serum homocysteine levels (8.4 ± 2.2 vs. 7.6 ± 1.9 μmol/L, p = 0.142). When stratifying STEMI patients by the Killip classification into higher (Killip III-IV) and lower (Killip I-II) grades, CRP (3.3 ± 4.1 vs. 1.4 ± 2.3 mg/L, p = 0.032), peak creatine kinase (3796 ± 2163 vs. 2305 ± 1822 IU/L, p = 0.023), and SYNTAX scores (20.4 ± 11.1 vs. 14.8 ± 7.6, p = 0.033) were significantly higher in the higher grades, while serum homocysteine levels were similar. Homocysteine was not correlated with WBCs, CRP, or the SYNTAX score in STEMI patients. In a culture system, homocysteine at even a supraphysiological level of 100 μmol/L did not reduce the cell viability of human coronary artery endothelial cells.
Homocysteine was not elevated in STEMI patients regardless of Killip severity, suggesting that homocysteine is a bystander instead of a causative factor of STEMI. Our study therefore supports the current notion that homocysteine-lowering strategies are not essential in preventing cardiovascular disease.
Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) ...is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications.
We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant.
A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P<0.001; OR: 1.76 (1.02–3.05), P = 0.04, respectively).
This GSTM3 deletion is frequently observed in BrS patients and is associated with reduced INa, pointing to this as a novel potential genetic modifier/risk predictor for the development of the electrocardiographic and arrhythmic manifestations of BrS.
This work was supported by the Ministry of Science and Technology (107-2314-B-002-261-MY3 to J.M.J. Juang), and by grants HL47678, HL138103 and HL152201 from the National Institutes of Health to CA.
The exact world-wide prevalence of Brugada electrocardiogram (ECG) pattern is still unclear, especially in adults aged 55 years and older.
The study was conducted as part of the Healthy Aging ...Longitudinal Study in Taiwan (HALST). Using a stratified random sampled method, a sample of community-dwelling subjects was recruited from seven community-based regions across Taiwan. All enrolled subjects were follow-up annually and cause of death was documented by citizen death records. A total of 5214 subjects were enrolled (male/female: 2530/2684) with a mean age of 69 ± 8 years. The overall prevalence of Brugada ECG patterns was 3.32%. Four subjects carried spontaneous Type 1 Brugada ECG pattern, 68 carried Type 2, and 101 carried Type 3. Compared with the world-wide average prevalence of Brugada ECG patterns, the prevalence of spontaneous Type 1 Brugada ECG pattern in subjects from the HALST cohort was similar (0.077 vs. 0.07%) and the combined prevalence of Types 2 and 3 Brugada ECG pattern was 10 times higher (3.24 vs. 0.28%) even the mean age of study subjects was significantly higher (69 ± 8 vs. 35 ± 8, P < 0.001). However, all-cause mortality and cardiac mortality rates were not significantly different between subjects with and without Brugada ECG patterns during the 4-year follow-up (log-rank test, P = 0.21, 0.32, respectively).
The prevalence of Brugada ECG pattern in adults aged 55 years and older in Taiwan was higher than the average world-wide prevalence but was not associated with increased mortality.
With an aging world population, risk stratification of community-based, elderly population is required for primary prevention. This study proposes a combined score developed using ...electrocardiographic (ECG) parameters and determines its long-term prognostic value for predicting risk of cardiovascular mortality. A cohort-study, conducted from December 2008 to April 2019, enrolled 5,380 subjects in Taiwan, who were examined, using three-serial-12-lead ECGs, and their health/demographic information were recorded. To understand the predictive effects of ECG parameters on overall-survival, Cox hazard regression analysis were performed. The mean age at enrollment was 69.04 ± 8.14 years, and 47.4% were males. ECG abnormalities, LVH hazard ratio (HR) = 1.39, 95% confidence intervals (CI) = (1.16–1.67),
P
= 0.0003, QTc HR = 1.31, CI = (1.07–1.61),
P
= 0.007 and PR interval HR = 1.40, CI = (1.01–1.95),
P
= 0.04, were significantly associated with primary outcome all-cause death. Furthermore, LVH HR = 2.37, CI = (1.48–3.79),
P
= 0.0003 was significantly associated with cardiovascular death, while PR interval HR = 2.63, CI = (1.24– 5.57),
P
= 0.01 with unexplained death. ECG abnormality (EA) score was defined based on the number of abnormal ECG parameters for each patient, which was used to divide all patients into sub-groups. Competing risk survival analysis using EA score were performed by using the Gray's test, which reported that high-risk EA groups showed significantly higher cumulative incidence for all three outcomes. Prognostic models using the EA score as predictor were developed and a 10-fold cross validation design was adopted to conduct calibration and discrimination analysis, to establish the efficacy of the proposed models. Overall, ECG model could successfully predict people, susceptible to all three death outcomes (
P
< 0.05), with high efficacy. Statistically significant (
P
< 0.001) improvement of the c-indices further demonstrated the robustness of the prediction model with ECG parameters, as opposed to a traditional model with no EA predictor. The EA score is highly associated with increased risk of mortality in elderly population and may be successfully used in clinical practice.
Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as ...benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%,
< 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%,
= 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-
variants, which may be pathogenic in some ancestries but only disease-predisposing in others.
Identifying Brugada electrocardiographic pattern (BrP) early is crucial to prevent sudden cardiac death. Two different diagnostic criteria proposed by International Society for Holter and Noninvasive ...Electrocardiography (ISHNE) and Heart Rhythm Society/European Heart Rhythm Association/Asia-Pacific Heart Rhythm Society (HRS/EHRA/APHRS) were widely used in clinical practice. The difference in prevalence and prognosis of BrP by applying the two different criteria was never studied before.
This study was prospectively conducted in a nationwide large-scale stratified random sampling community-based cohort (HALST) from Han Chinese population in Taiwan from December 2008 to December 2012. We compared the prevalence and prognosis of BrP defined by the two diagnostic criteria.
A total of 5214 adults were enrolled (2530 men) with mean age of 69.3 years. Four had spontaneous type 1 BrP (0.077%). By the HRS/EHRA/APHRS criteria, 68 individuals have type 2 BrP (1.30%) and 101 have type 3 BrP (1.94%) whereas by the ISHNE criteria, 46 individuals exhibited type 2 BrP (0.88%). When applying the ISHNE criteria, the number of individuals with BrP decreased by 71%. However, all-cause mortality and cardiovascular mortality were not different between individuals with or without BrP, irrespective of the criteria used.
The two different criteria may impact the diagnostic yield of individuals with BrP, but do not affect the prognosis of the individuals with BrP. Key messages Comparing with the use of HRS/EHRA/APHRS criteria, the number of individuals with Brugada ECG patterns was decreased by 71% when applying the ISHNE criteria. The prognosis of individuals with Brugada ECG patterns defined by 2012 ISHNE or 2013 HRS/EHRA/APHRS criteria were not different.
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