Impacts of gene variants on drug effects-the foundation of genotype-guided pharmacologic therapy for long QT syndrome and short QT syndrome.

The clinical significance of optimal pharmacotherapy for inherited arrhythmias such as short QT syndrome (SQTS) and long QT syndrome (LQTS) has been increasingly recognised. The advancement of gene technology has opened up new possibilities for identifying genetic variations and investigating the pathophysiological roles and mechanisms of genetic arrhythmias. Numerous variants in various genes have been proven to be causative in genetic arrhythmias. Studies have demonstrated that the effectiveness of certain drugs is specific to the patient or genotype, indicating the important role of gene-variants in drug response. This review aims to summarize the reported data on the impact of different gene-variants on drug response in SQTS and LQTS, as well as discuss the potential mechanisms by which gene-variants alter drug response. These findings may provide valuable information for future studies on the influence of gene variants on drug efficacy and the development of genotype-guided or precision treatment for these diseases.

Bilobalide Prevents Apoptosis and Improves Cardiac Function in Myocardial Infarction.

Myocardial infarction (MI) is an extremely severe cardiovascular disease, which ranks as the leading cause of sudden death worldwide. Studies have proved that cardiac injury following MI can cause cardiomyocyte apoptosis and myocardial fibrosis. Bilobalide (Bilo) from Ginkgo biloba leaves have been widely reported to possess excellent cardioprotective effects. However, concrete roles of Bilo in MI have not been investigated yet. We here designed both in vitro and in vivo experiments to explore the effects of Bilo on MI-induced cardiac injury and the underlying mechanisms of its action. We conducted in vitro experiments using oxygen-glucose deprivation (OGD)-treated H9c2 cells. Cell apoptosis in H9c2 cells was assessed by conducting flow cytometry assay and evaluating apoptosis-related proteins with western blotting. MI mouse model was established by performing left anterior descending artery (LAD) ligation. Cardiac function of MI mice was determined by assessing ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD). Histological changes were analyzed, infarct size and myocardial fibrosis were measured by hematoxylin and eosin (H&E) and Masson staining in cardiac tissues from the mice. The apoptosis of cardiomyocytes in MI mice was assessed by TUNEL staining. Western blotting was applied to detect the effect of Bilo on c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (p38 MAPK) signaling both in vitro and in vivo. Bilo inhibited OGD-induced cell apoptosis and lactate dehydrogenase (LDH) release in H9c2 cells. The protein levels of p-JNK and p-p38 were significantly downregulated by Bilo treatment. SB20358 (inhibitor of p38) and SP600125 (inhibitor of JNK) suppressed OGD-induced cell apoptosis as Bilo did. In MI mouse model, Bilo improved the cardiac function and significantly reduced the infarct size and myocardial fibrosis. Bilo inhibited MI-induced cardiomyocytes apoptosis in mice. Bilo suppressed the protein levels of p-JNK and p-p38 in cardiac tissues from MI mice. Bilo alleviated OGD-induced cell apoptosis in H9c2 cells and suppressed MI-induced cardiomyocyte apoptosis and myocardial fibrosis in mice via the inactivation of JNK/p38 MAPK signaling pathways. Thus, Bilo may be an effective anti-MI agent.

Evaluation of the Efficacy of Sacubitril/Valsartan on Radiofrequency Ablation in Patients with Hypertension and Persistent Atrial Fibrillation.

OBJECTIVE: To evaluate whether the effect of radiofrequency ablation can be improved by using sacubitril/valsartan (S/V) to control blood pressure in hypertensive patients with persistent atrial fibrillation. METHODS: A total of 63 and 67 hypertension patients with persistent atrial fibrillation were enrolled in an S/V group and ACEI/ARB group, respectively. All patients underwent radiofrequency catheter ablation (RFCA). The blood pressure of the two groups was controlled within the range of 100-140 mmHg (high pressure) and 60-90 mmHg (low pressure). The clinical outcomes of the two groups were observed after 12 months of follow-up. RESULTS: No significant differences in blood pressure were observed between the S/V and ACEI/ARB groups. In addition, the recurrence rate of atrial fibrillation between the two groups was not different. The left atrial diameter was an independent predictor of recurrence (HR = 1.063, P = 0.008). However, in the heart failure subgroup, the recurrence rate of S/V was significantly lower than that of the ACEI/ARB group (P = 0.005), and Cox regression analysis showed that the recurrence risk of atrial fibrillation of the S/V group was 0.302 lower than that of the ACEI/ARB group. NT-proBNP, LVEF, and LAD were significantly improved in hypertension patients with heart failure when comparing cases before and at the end of follow-up. CONCLUSIONS: S/V is better than ACEI/ARB in reducing the recurrence of persistent atrial fibrillation in patients with hypertension and heart failure after RFCA.

SHP-1 alleviates atrial fibrosis in atrial fibrillation by modulating STAT3 activation.

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has a well-established role in myocardial infarction, yet its involvement in atrial fibrosis and atrial fibrillation (AF) has not been elucidated. As cardiac arrhythmias caused by AF are a major global health concern, we investigated whether SHP-1 modulates AF development. The degree of atrial fibrosis was examined using Masson's trichrome staining, and SHP-1 expression in the human atrium was assessed using quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC), and western blotting (WB). We also examined SHP-1 expression in cardiac tissue from an AF mouse model, as well as in angiotensin II (Ang II)-treated mouse atrial myocytes and fibroblasts. We found that SHP-1 expression was reduced with the aggravation of atrial fibrosis in clinical samples of patients with AF. SHP-1 was also downregulated in the heart tissue of AF mice and Ang II-treated myocytes and fibroblasts, compared with that in the control groups. Next, we demonstrated that SHP-1 overexpression alleviated AF severity in mice by injecting a lentiviral vector into the pericardial space. In Ang II-treated myocytes and fibroblasts, we observed excessive extracellular matrix (ECM) deposition, reactive oxygen species (ROS) generation, and transforming growth factor beta 1 (TGF-ß1)/mothers against decapentaplegic homolog 2 (SMAD2) pathway activation, all of which were counteracted by the overexpression of SHP-1. Our WB data showed that STAT3 activation was inversely correlated with SHP-1 expression in samples from patients with AF, AF mice, and Ang II-treated cells. Furthermore, administration of colivelin, a STAT3 agonist, in SHP-1-overexpressing, Ang II-treated myocytes and fibroblasts resulted in higher levels of ECM deposition, ROS generation, and TGF-ß1/SMAD2 activation. These findings indicate that SHP-1 regulates AF fibrosis progression by modulating STAT3 activation and is thus a potential treatment target for atrial fibrosis and AF.

Evaluating Common NOS1AP Variants in Patients with Implantable Cardioverter Defibrillators for Secondary Prevention : Evaluating SNPs in NOS1AP.

BACKGROUND: Recent research has found that single nucleotide polymorphisms (SNPs) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with altered QT intervals and sudden cardiac death (SCD). However, the clinical utility and implications of NOS1AP SNPs remain unclear. Thus, this study aimed to explore the influence of NOS1AP SNPs in patients with implantable cardioverter defibrillator (ICD) for secondary prevention. METHODS: We conducted a case-control study to evaluate the most studied SNPs in NOS1AP (rs12143842, rs10494366, rs12567209, and rs16847548) in patients with ICD for secondary prevention. Patients were followed for up to 36 months from the time of ICD implantation. ICD interrogation data at 3 and 12 months, including rapid ventricular arrhythmia episodes and appropriate therapies, were then analyzed.  RESULTS: A significant association was observed between rs10494366 and ICD recipients who experienced appropriate therapies. After a mean follow-up time of 31.70 ± 9.15 months, we detected significant differences among the three rs10494366 genotype groups in the distribution of ICD shocks and appropriate therapies, as well as in the correlation of rs10494366 and ICD shocks. According to Kaplan-Meier and Cox regression analyses, patients with the TT genotype had a higher risk of SCD than those with the GG genotype. CONCLUSIONS: The present study revealed that NOS1AP SNP rs10494366 was associated with appropriate therapies. Specifically, the TT genotype increased ICD shocks and SCD risk in patients with ICD for secondary prevention for the first time.

TRIM7 promotes proliferation and migration of vascular smooth muscle cells in atherosclerosis through activating c-Jun/AP-1.

Atherosclerosis (AS), with associated risk of stroke or cerebrovascular disease, is one of the most common causes of death globally. It has been well established that tripartite motif-containing protein 7 Tripartite Motif-containing 7 (Trim7), as an E3 ubiquitin protein ligase, is involved in protein ubiquitination and thus regulating cellular proliferation. Moreover, TRIM7 is upregulated in advanced carotid AS. However, the detailed mechanism of TRIM7 on regulation of AS remains unclear. In the present study, we firstly discovered that TRIM7 expression was robustly induced in platelet-derived growth factor type BB-treated vascular smooth muscle cells (VSMCs) and human atherosclerotic plaques. Functional approaches established that knockdown of TRIM7 inhibited proliferation and migration of VSMCs, as well as arrested the cell cycle at G1-S, thus suppressing AS progression. Our results also identified that c-Jun/activator protein 1 (AP-1) signaling pathway was activated by TRIM7. Moreover, gain- and loss-of-function studies revealed that TRIM7 could promote proliferation and migration of VSMCs via activation of c-Jun/AP-1 signaling pathway. Finally, by using atherogenic apolipoprotein E-deficient (apoE-/-) C57BL/6 mice with high-fat diet AS model, we demonstrated that interference of TRIM7 could effectively mitigate in vivo AS via inactivation of c-Jun/AP-1 signaling pathway. In general, activation of c-Jun/AP-1 signaling pathway via TRIM7 could be an important mechanism in AS progression, thus shedding light on the development of novel therapeutics to the treatment of the disease.

Systematic Meta-Analysis of the Association Between a Common NOS1AP Genetic Polymorphism, the QTc Interval, and Sudden Death.

Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.

Protective effect of histone methyltransferase NSD3 on ISO-induced cardiac hypertrophy.

Nuclear receptor-binding SET domain 3 (NSD3) is a lysine methyltransferase that plays important roles in multiple biological activities; however; its potential roles in the cardiovascular system remain unknown. In this study, we found that NSD3 expression is reduced by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of NSD3 attenuates ISO-induced cardiomyocyte hypertrophy. Mechanistically, ISO treatment decreases H3K27me2/3 modifications on the atrial natriuretic factor (ANF) promoter by suppressing NSD3 and inhibits the association between NSD3 and bromodomain-containing protein 4 (BRD4), thus suppressing the BRD4-mediated H3K27ac modifications, which ultimately promote ANF transcription and cardiomyocyte hypertrophy. In conclusion, NSD3 decreases ANF expression and, thereby, attenuates ISO-induced cardiomyocyte hypertrophy.

SNP rs3825214 in TBX5 is associated with lone atrial fibrillation in Chinese Han population.

BACKGROUND: A prolonged PR interval is a sign of increased risk of cardiac arrhythmia. Recent genome-wide association studies found that the single-nucleotide polymorphism (SNP) rs3825214 in T-box 5 (TBX5) was positively associated with PR interval, QRS duration, QT interval, and common arrhythmia disorders such as atrial fibrillation (AF) and advanced atrioventricular block. However, other independent replication studies are required to validate the result. This study assessed associations between rs3825214 and ECG parameters, AF, and ventricular tachycardia (VT) in a Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: To assess the association between rs3825214 and AF and VT, we carried out case-control association studies with 692 AF patients (including 275 lone AF patients), 235 VT patients, and 856 controls. Genotyping was performed using a Rotor-Gene TM 6000 High Resolution Melt system. Statistical analyses of associations were adjusted for potential confounding factors. A moderate association was detected between rs3825214 and AF (P(adj) = 0.036, OR = 0.79) and a highly significant association was detected between the G allele of rs3825214 and lone AF (P(adj) = 0.001, OR = 0.65; genotypic P = 3.75×10⁻4 with a dominant model). We also found that rs3825214 showed a significant association with atrial-ventricular block (AVB; P = 0.028; P(adj) = 0.035, OR = 0.494). CONCLUSIONS: Our results indicate that rs3825214 conferred a significant risk of lone AF in this Chinese Han population.

[Predictive value of HATCH score on atrial fibrillation recurrence post radiofrequency catheter ablation].

OBJECTIVE: To determine the predictive value of HATCH score on recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). METHODS: The data of 123 consecutive AF patients (74 paroxysmal and 49 persistent AF) who underwent RFCA between April 2009 and December 2010 in our department were retrospectively analyzed. Of theses patients, 65 (52.9%) patients had HATCH score = 0, 41 (33.3%) patients had HATCH score = 1, and 17 (13.8%) patients had HATCH score ≥ 2 (HATCH = 2 in 11 patients, HATCH = 3 in 5 patients, HATCH = 4 in 1 patient). The recurrence was defined as atrial tachyarrhythmia lasting more than 30 seconds after 3 months post RFCA. The patients were divided into recurrence group and no recurrence group. Relationship between HATCH score and recurrence was observed. RESULTS: There were 43 cases in recurrence group and 80 cases in no recurrence group. After 12 months follow-up, HATCH score was significant higher in recurrence group than in non-recurrence group [(0.91 ± 0.94) score vs. (0.53 ± 0.80) score, P < 0.05]. The ratio of patients with HATCH ≥ 2 in recurrence group was higher than in non-recurrence group [23.3% (10/43) vs. 8.8% (7/80), P < 0.01]. The sensitivity and specificity of HATCH ≥ 2 to define the risk of recurrence was 25.0%, 92.4% respectively. Cumulative non-recurrence rate of patients with HATCH score ≥ 2 was lower than patients with HATCH score = 0 and 1 (P < 0.05). CONCLUSION: Higher HATCH score is associated with increased risk of AF recurrence post RFCA.