Characteristics and outcomes associated with sarcomere mutations in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that can lead to sudden cardiac death. Impact of genetic testing for the prognosis and treatment of patients with HCM needs to be improved. We conducted a systematic review and meta-analysis to investigate the characteristics and outcomes associated with sarcomere genotypes in index patients with HCM. METHODS: A systematic search was conducted in Medline, Embase, and Cochrane Library up to Dec 31, 2023. Data on clinical characteristics, morphological and imaging features, outcomes and interventions were collected from published studies and pooled using a random-effects meta-analysis. RESULTS: A total of 30 studies with 10,825 HCM index patients were included in the pooled analyses. The frequency of sarcomere genes in HCM patients was 41%. Sarcomere mutations were more frequent in women (p < 0.00001), and were associated with lower body mass index (26.1 ± 4.7 versus 27.5 ± 4.3; p = 0.003) and left ventricular ejection fraction (65.7% ± 10.1% vs. 67.1% ± 8.6%; p = 0.03), less apical hypertrophy (6.5% vs. 20.1%; p < 0.0001) and left ventricular outflow tract obstruction (29.1% vs. 33.2%; p = 0.03), greater left atrial volume index (43.6 ± 21.1 ml/m2 vs. 37.3 ± 13.0 ml/m2; p = 0.02). Higher risks of ventricular tachycardia (23.4% vs. 14.1%; p < 0.0001), syncope (18.3% vs. 10.9%; p = 0.01) and heart failure (17.3% vs. 14.6%; p = 0.002) were also associated with sarcomere mutations. CONCLUSIONS: Sarcomere mutations are more frequent in women, and are associated with worse clinical characteristics and poor outcomes.

Opportunities and challenges for anti-CD47 antibodies in hematological malignancies.

CD47 is a cell-surface ligand that is overexpressed in various malignancies and that binds to SIRPα on macrophages to promote tumor cell evasion of phagocytosis. Blocking the CD47-SIRPα axis can increase the phagocytosis of macrophages to exert antitumor effects. CD47-based immunotherapy is a current research focus. The combination of anti-CD47 antibodies with other drugs has shown encouraging response rates in patients with hematological tumors, but side effects also occur. Bispecific antibodies and SIRPα/Fc fusion proteins appear to balance the efficacy and safety of treatment. We review the latest clinical research advances and discuss the opportunities and challenges associated with CD47-based immunotherapy for hematological malignancies.

An ultra-compact promoter drives widespread neuronal expression in mouse and monkey brains.

Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.

Associations between blood inflammatory markers and bone mineral density and strength in the femoral neck: findings from the MIDUS II study.

Chronic and systematic inflammation have been related to increased risks of osteopenia and related fracture. However, studies concerning the association between low-grade inflammation and the bone mineral density (BMD) and strength of the femoral neck are still few and inconsistent. This study aimed to examine the relationships between blood inflammatory biomarkers and BMD and femoral neck strength in an adult-based cohort. We retrospectively analyzed a total of 767 participants included in the Midlife in the United States (MIDUS) study. The blood levels of inflammatory markers, including interleukin-6 (IL6), soluble IL-6 receptor, IL-8, IL-10, TNF-α and C-reactive protein (CRP), in these participants were measured, and their associations with the BMD and strength of the femoral neck were determined. We analyzed these 767 subjects with data concerning the BMD, bending strength index (BSI), compressive strength index (CSI), and impact strength index (ISI) in the femoral neck and inflammatory biomarkers. Importantly, our results suggest that strongly negative associations exist between the blood soluble IL6 receptor levels and the BMD (per SD change, Sß = -0.15; P < 0.001), CSI (per SD change, Sß = -0.07; P = 0.039), BSI (per SD change, Sß = -0.07; P = 0.026), and ISI (per SD change, Sß = -0.12; P < 0.001) in the femoral neck after adjusting for age, gender, smoked cigarettes regularly, number of years drinking, BMI and regular exercise. However, the inflammatory biomarkers, including blood IL-6 (per SD change, Sß = 0.00; P = 0.893), IL-8 (per SD change, Sß = -0.00; P = 0.950), IL-10 (per SD change, Sß = -0.01; P = 0.854), TNF-α (per SD change, Sß = 0.04; P = 0.260) and CRP (per SD change, Sß = 0.05; P = 0.137), were not strongly associated with the BMD in the femoral neck under the same conditions. Similarly, there was no significant difference in the relationships between the inflammatory biomarkers (IL-6, IL-8, IL-10, TNF-α and CRP) and the CSI, BSI, and ISI in the femoral neck. Interestingly, in concomitant inflammation-related chronic diseases, only arthritis affected the soluble IL-6 receptor and the CIS (interaction P = 0.030) and SIS (interaction P = 0.050) in the femoral neck. In this cross-sectional analysis, we only observed that high blood levels of soluble IL-6 receptor were strongly associated with reduced BMD and bone strength in the femoral neck. The independent associations between the other inflammatory indicators, including IL-6, IL-8, IL-10, TNF-α and CRP, and the BMD and femoral neck strength in an adult-based cohort were not significant.

Coronin 2B Regulates Neuronal Migration via Rac1-Dependent Multipolar-Bipolar Transition.

In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form functional circuitry. The shaping of neuronal morphologies by actin cytoskeleton dynamics is crucial for neuronal migration. However, it is largely unknown how the distribution and assembly of the F-actin cytoskeleton are coordinated. In the present study, we found that an actin regulatory protein, coronin 2B, is indispensable for the transition from a multipolar to bipolar morphology during neuronal migration in ICR mice of either sex. Loss of coronin 2B led to heterotopic accumulation of migrating neurons in the intermediate zone along with reduced dendritic complexity and aberrant neuronal activity in the cortical plate. This was accompanied by increased seizure susceptibility, suggesting the malfunction of cortical development in coronin 2B-deficient brains. Coronin 2B knockdown disrupted the distribution of the F-actin cytoskeleton at the leading processes, while the migration defect in coronin 2B-deficient neurons was partially rescued by overexpression of Rac1 and its downstream actin-severing protein, cofilin. Our results collectively reveal the physiological function of coronin 2B during neuronal migration whereby it maintains the proper distribution of activated Rac1 and the F-actin cytoskeleton.SIGNIFICANCE STATEMENT Deficits in neuronal migration during cortical development result in various neurodevelopmental disorders (e.g., focal cortical dysplasia, periventricular heterotopia, epilepsy, etc.). Most signaling pathways that control neuronal migration process converge to regulate actin cytoskeleton dynamics. Therefore, it is important to understand how actin dynamics is coordinated in the critical processes of neuronal migration. Herein, we report that coronin 2B is a key protein that regulates neuronal migration through its ability to control the distribution of the actin cytoskeleton and its regulatory signaling protein Rac1 during the multipolar-bipolar transition in the intermediate zone, providing insights into the molecular machinery that drives the migration process of newborn neurons.

Obesity difference on association blood malondialdehyde level and diastolic hypertension in the elderly population: a cross-sectional analysis.

AIMS: Although increased production of malondialdehyde (MDA), an end product of lipid oxidation caused by reactive oxygen species (ROS), has been found be elevated in hypertensive population, whether MDA contributed to a changed risk of hypertension is uncertain. We aimed to investigate whether elevated blood levels of MDA contribute to increased risk of hypertension and obesity has a modified effect on the association in an older Chinese population. METHODS: Data were obtained from 2011 to 2012 of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a national cohort of older adults in China. Associations between blood MDA level and systolic and diastolic blood pressure (BP) and risk of hypertension were performed by multivariable linear regression and logistic regression analysis. RESULTS: The results of smooth curve revealed a gradual upward trend on association of blood MDA level with diastolic BP (P < 0.001), but not with systolic BP (P > 0.05). Logistic regression analysis suggested that elevated blood MDA levels were associated with increased risk of diastolic hypertension (OR = 1.079, 95% CI 1.039-1.122, P < 0.001) rather than systolic hypertension (OR = 0.978, 95% CI 0.943-1.015, P = 0.247) after adjustments of related confounding factors were made. Furthermore, we found the significant modification effect of obesity on the association between MDA level and risk of diastolic hypertension evaluated by body mass index (BMI, interaction P = 0.015) and by waist circumference (interaction P = 0.016). CONCLUSION: Our results firstly identified that increased blood MDA levels were associated with elevated risk of diastolic hypertension, rather than systolic hypertension in the non-obese old population.

Low arterial oxygen partial pressure induces pulmonary thrombocytopenia in patients and a mouse model.

BACKGROUND: Recent basic studies demonstrate that the lung is a primary organ of platelet biogenesis. However, whether the pathophysiological state of the lung affect the platelets is little known. We aim to investigate the incidence of thrombocytopenia in patients with pulmonary infection (PIN) and risk factors associated with pulmonary thrombocytopenia. METHODS: In total, 11,941 patients with pulmonary infection (PIN) were enrolled, and patients with other three infectious diseases were collected as controls. The incidence of thrombocytopenia was compared, and the risk factors associated with thrombocytopenia in PIN patients were investigated by multivariate analysis. To explore the mechanism of thrombocytopenia, hypoxic model was constructed. Blood platelet counts from the angular vein (PLTs), left ventricle (PLTpost) and right ventricle (PLTpre) were determined. Megakaryocytes identified by anti-CD41 antibody were detected through flow cytometry and immunofluorescence. RESULTS: The incidence of thrombocytopenia in PIN was higher than that in other three infectious diseases (9.8% vs. 6.4% ~ 5.0%, P < 0.001). Low arterial oxygen partial pressure (PaO2) was an important risk factor for thrombocytopenia (OR = 0.88; P < 0.001). In a hypoxic mouse model, PLTs decreased (518.38 ± 127.92 vs 840.75 ± 77.30, P < 0.05), which showed that low PaO2 induced thrombocytopenia. The difference between the PLTpost and PLTpre (∆PLTpost-pre), representing the production of platelets in the lungs, was significantly attenuated in hypoxic mice when compared with normoxic mice (F = 25.47, P < 0.05). Additionally, proportions of CD41-positive megakaryocytes in the lungs, marrow, spleen all decreased in hypoxic mice. CONCLUSION: There is a high incidence for thrombocytopenia in PIN patients. Low PaO2-induced thrombocytopenia is associated with impaired generation of platelet in the lungs.

Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury.

Autophagy plays a deleterious role in ischemic myocardial injury. The deacetylase SIRT1 is a well-established regulator of autophagy that can be modified by the ubiquitin-like protein SUMO1. Our previous work demonstrated that another ubiquitin-like protein, FAT10, exerts cardioprotective effects against myocardial ischemia by stabilizing the caveolin-3 protein; however, the effects of FAT10 on autophagy through SIRT1 are unclear. Here, we constructed a Fat10-knockout rat model to evaluate the role of FAT10 in autophagy. In vivo and in vitro assays confirmed that FAT10 suppressed autophagy to protect the heart from ischemic myocardial injury. Mechanistically, FAT10 was mainly involved in the regulation of the autophagosome formation process. FAT10 affected autophagy through modulating SIRT1 degradation, which resulted in reduced SIRT1 nuclear translocation and inhibited SIRT1 activity via its C-terminal glycine residues. Notably, FAT10 competed with SUMO1 at the K734 modification site of SIRT1, which further reduced LC3 deacetylation and suppressed autophagy. Our findings suggest that FAT10 inhibits autophagy by antagonizing SIRT1 SUMOylation to protect the heart from ischemic myocardial injury. This is a novel mechanism through which FAT10 regulates autophagy as a cardiac protector.

Whole exome sequencing identifies three novel gene mutations in patients with the triad of diabetic ketoacidosis, hypertriglyceridemia, and acute pancreatitis.

BACKGROUND: This study aimed to analyze the genetics and treatments of the patients with the triad of diabetic ketoacidosis (DKA), hypertriglyceridemia, and acute pancreatitis (AP). METHODS: We conducted a retrospective study of six patients with the triad of AP, hypertriglyceridemia, and DKA at our hospital. All patients underwent plasmapheresis as part of their treatment. The clinical characteristics of the patients were obtained from the hospital information system and analyzed. Whole exome sequencing was performed using samples of one patient (case 6) and his family members. RESULTS: The average triglyceride level before plasmapheresis was 3282.17 ± 2975.43 mg/dL (range: 1646-9332 mg/dL). The triglyceride levels dropped by approximately 80% after plasmapheresis. None of the patients developed complications related from plasmapheresis. During follow-up, patients 5 and 6 developed recurrent pancreatitis for several times and showed the formation of pancreatic pseudocysts. We identified three novel heterozygous missense mutations in the family of patient 6, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD. CONCLUSIONS: Three novel heterozygous missense mutations, including c.12614C > T (p.Pro4205Leu) in APOB, c.160G > C (p.Glu54Gln) in CILP2, and c.1199C > A (p.Ala400Glu) in PEPD were first identified in a patient with the triad of DKA, hypertriglyceridemia, and AP. The combination of plasmapheresis, hydration, and insulin therapy may have the greatest clinical benefits for these patients.

The relationship between Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 12 (SNHG12) expression in solid malignant tumors and prognosis of tumor patients: A systematic review and meta-analysis.

BACKGROUND: Small nucleolar RNA host gene 12 (SNHG12) has been demonstrated to be a long noncoding RNA (lncRNA) that facilitates the progression of several solid malignant tumors. However, whether the expression level of SNHG12 in solid malignant tumors is associated with patients prognosis have not been investigated. METHODS: We systematically searched PubMed, EMBASE and Cochrane Library from Jan 1, 1950 to Mar 24, 2020 for randomized controlled trials published in English on SNHG12 expression in solid malignant tumors. We used the Newcastle-Ottawa Scale to assess the quality of articles. The HRs and 95%CI that extracted from Kaplan-Meier curves were used to perform the forest plot using a fixed-effects model. The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Thirteen articles containing 821 patients were included in this systematic review and meta-analysis. The result showed that high lncRNA SNHG12 expression is significantly associated with poor overall survival (OS) (HR = 1.94, 95% CI: 1.56-2.41, P < .001) and the studies are lack of statistically significant heterogeneity (P= .878, I = 0.0%). Beggs plot and Eggers test were applied to testify no publication bias existence in these studies. Subgroup analyses were performed and the result showed that TNM stage, lymph node metastasis and tumor type can influence the patients outcome, while there was no significantly correlation between SNHG12 expression and gender. CONCLUSIONS: The systematical review and meta-analysis synthetically analyzed 13 articles including 821 patients with ten types of solid malignant tumors, concluding that higher lncRNA SNHG12 expression is significantly associated with worse clinical prognosis.

Low deceleration capacity is associated with higher stroke risk in patients with paroxysmal atrial fibrillation.

BACKGROUND: Deceleration capacity (DC) is a non-invasive marker for cardiac autonomic dysfunction; however, few studies have shown that the influence factors of cardiac autonomic dysfunction and the correlations between DC and stroke risk in paroxysmal atrial fibrillation (AF). We aimed to explore the influencing factors of abnormal DC and the relationships between DC and stroke risk in patients with paroxysmal AF. METHODS: The study included hospitalized paroxysmal AF patients with DC measurements derived from 24-h Holter electrocardiography recordings taken between August 2015 and June 2016. Multivariable regression analysis was performed to evaluate the associations between correlated variables and abnormal DC values. The relationship between DC and ischemic stroke risk scores in patients with paroxysmal AF was analyzed. RESULTS: We studied 259 hospitalized patients with paroxysmal AF (143 [55.2%] male, mean age 66.4 ±â€Š12.0 years); 38 patients of them showed abnormal DC values. In the univariate analysis, age, hypertension, heart failure, and previous stroke/transient ischemic attack (TIA) were significantly associated with abnormal DC values. Among these factors, a history of previous stroke/TIA (odds ratio = 2.861, 95% confidence interval: 1.356-6.039) were independently associated with abnormal DC values in patients with paroxysmal AF. The abnormal DC group showed a higher stroke risk with the score of congestive heart failure, hypertension, age >75 years, diabetes mellitus, previous stroke and TIA (CHADS2) (2.25 ±â€Š1.48 vs. 1.40 ±â€Š1.34, t = -4.907, P = 0.001) and CHA2DS2-vascular disease, age 65-74 years and female category (VASc) (3.76 ±â€Š1.95 vs. 2.71 ±â€Š1.87, t = -4.847, P = 0.001) scores. Correlation analysis showed that DC was negatively correlated with CHADS2 scores (r = -0.290, P < 0.001) and CHA2DS2-VASc scores (r = -0.263, P < 0.001). CONCLUSIONS: Lower DC is closely associated with previous stroke/TIA, and is also correlated negatively with higher stroke risk scores in patients with paroxysmal AF. It could be a potential indicator of stroke risk in paroxysmal AF patients.

Decreased eGFR Is Associated With Ischemic Stroke in Patients With Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is increasingly indicated as a cause of cardioembolic syndrome, in particular, cardioembolic ischemia stroke. However, the potential risk factors for stroke among DCM patients remain under investigated. DCM patients hospitalized from June 2011 to June 2016 were included. The cases were defined as the group of DCM patients with stroke compared with those without stroke. Clinical characteristic data were collected and compared between the two groups including demographic data, complicated diseases, echocardiography index, and laboratory parameters and estimated glomerular filtration rate (eGFR). A multivariate logistic regression analysis model adjusted by sex and age was used to explore the related risk factors for stroke in DCM patients. A total of 779 hospitalized patients with DCM were included. Of these, 55 (7.1%) had experienced a stroke. Significantly lower eGFR levels (68.03 ± 26.22 vs 79.88 ± 24.25 mL/min/1.73 m2, P = .001) and larger left atrial diameters (45.32 ± 7.79 vs 43.25 ± 7.11 mm, P = .04) were found in the group of patients having DCM with stroke compared to those without stroke. When the eGFR was categorized as eGFR >60, 30

Spatiotemporal Regulation of Rho GTPases in Neuronal Migration.

Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar-bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in neuronal migration by regulating both actin and microtubule cytoskeletal components. This review focuses on the spatiotemporal-specific regulation of Rho GTPases as well as their regulators and effectors in distinct steps during the neuronal migration process. Their roles in bridging extracellular signals and cytoskeletal dynamics to provide optimal structural support to the migrating neurons will also be discussed.

FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3.

FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin-proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions.

Preparative expression and purification of a nacreous protein N16 and testing its effect on osteoporosis rat model.

N16, a nacreous protein isolated from Pinctada martensii, is related to nacreous layer formation. Our previous study indicated that N16 showed dual regulatory effects by inducing osteoblast biomineralization as well as inhibiting osteoclast formation. In order to obtain large quantity of N16 for animal experiment and clinical trial, a fermentation and preparative purification method was established. The N16 cDNA was cloned to a BL21(DE3)plysE-pET32a vector and grown in a 20 L fermenter. The medium, temperature, pH and dissolved oxygen (DO) were optimized. N16 was expressed in inclusion bodies. It was denatured and refolded in 8 M urea buffer and purified to 97% purity by passing through a gel filtration column. The glucocorticoid induced osteoporosis (GIO) rat model was used to investigate the anti-osteoporosis activity of N16 in vivo. Results showed that the decrease of the bone mineral density (BMD) and the ultimate load was significantly relieved after N16 treatment. N16 displayed dual regulatory effects by promoting osteogenesis as well as inhibiting bone resorption in vivo. Our work will contribute to further clinical studies on N16 for osteoporosis treatment.

Molecular mechanisms of Ellis­van Creveld gene variations in ventricular septal defect.

The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single­nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (P<0.007). A known mutation, c.343C>G, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B­cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti­apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD.

A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

BACKGROUND: Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory. METHODS AND RESULTS: We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. CONCLUSIONS: Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.

Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis.

The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1-3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1-3 leads and a strong family history of ARVC.

Meta-analysis of ATRIA versus CHA2DS2-VASc for predicting stroke and thromboembolism in patients with atrial fibrillation.

BACKGROUND: Several studies have compared the discriminative performances of CHA2DS2-VASc and ATRIA scores, but the results are still disputed. Therefore, we aimed to explore their predictive abilities regarding stroke and thromboembolism (TE) risk in AF patients. METHODS: We systematically searched the Cochrane Library, PubMed and ScienceDirect databases up to May 2016 for studies regarding CHA2DS2-VASc and ATRIA scores. The data were extracted and then pooled using Review Manager software version 5.30. RESULTS: Six cohort studies with 363,432 participants were included. Using the published cut-off points, the pooled C-statistics were 0.66 for ATRIA and 0.63 for CHA2DS2-VASc (Pdiff>0.05). Using the optimized cut-off points, the C-statistics were 0.66 for ATRIA and 0.65 for CHA2DS2-VASc (Pdiff>0.05). However, the ATRIA score presented a positive net reclassification improvement (NRI) value compared with the CHA2DS2-VASc score. In contrast, the CHA2DS2-VASc score classified fewer patients as low and moderate risk than the ATRIA score. The CHA2DS2-VASc score had lower event rates (either events per person or events per 100 person-years) in both the low and moderate risk categories compared with the ATRIA score. CONCLUSIONS: In combination with C-statistics and NRI values, the ATRIA score performed better than the CHA2DS2-VASc score for stroke risk prediction. In contrast, the CHA2DS2-VASc score was superior to the ATRIA score for identifying truly "low risk" AF patients.

Can ventricular tachycardia non-inducibility after ablation predict reduced ventricular tachycardia recurrence and mortality in patients with non-ischemic cardiomyopathy? A meta-analysis of twenty-four observational studies.

BACKGROUND: At present, the role of ventricular tachycardia (VT) non-inducibility after ablation in patients with non-ischemic cardiomyopathy (NICM) remains controversial. We conducted a meta-analysis of the published literature to assess whether VT non-inducibility after ablation could predict reduced VT recurrence and mortality in patients with NICM. METHODS: PubMed, ScienceDirect, and the Cochrane library were searched for studies evaluating the effects of VT non-inducibility after catheter ablation on the long-term outcome in NICM patients with sustained VT. Results were analyzed using a fixed-effect model, and the data were pooled using RevMan 5.3 software. RESULTS: Twenty-four observational studies were identified (736 participants, mean follow-up time: 22months). NICM patients with VT inducibility after ablation had a higher risk of VT recurrence (odds ratio [OR]=5.83, 95% confidence interval [CI] 4.07-8.37; P<0.00001) and all-cause mortality (OR=3.55, 95% CI 1.62-7.78; P=0.002) compared with VT non-inducibility. Similarly in the subgroup analysis, patients with VT inducibility showed a higher risk of VT recurrence from non-ischemic dilated cardiomyopathy (OR=3.92, 95% CI 2.36-6.50; P<0.00001) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (OR=5.37, 95% CI 2.20-13.10; P=0.0002). Additionally, meta-analysis also showed that combined endo-epicardial ablation significantly reduced the risk of VT recurrence compared with endocardial-only ablation (OR=2.02, 95% CI 1.19-3.44; P=0.009; mean follow-up time: 22months). CONCLUSION: Recent evidence has shown that VT non-inducibility after ablation is a predictor for reduced VT recurrence and mortality compared with VT inducibility in NICM patients with sustained VT. In addition, endocardial plus adjuvant epicardial ablation provides better long-term arrhythmia-free survival than endocardial ablation alone.