蔺亚晖
中国医学科学院阜外医院 实验诊断中心
BACKGROUND:Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.METHODS:Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.RESULTS:The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.CONCLUSIONS:The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.IMPACT:First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.
Pediatric research 2023
Background:Clopidogrel is a traditional P2Y12 receptor inhibitor that is widely used in clinical practice, but there are significant individual differences in its therapeutic effect. Carriers of the CYP2C19 deletion allele have a higher risk of adverse cardiovascular events than non-carriers.Methods:In this study, 170 patients diagnosed with coronary heart disease (CHD) and on regular oral clopidogrel or ticagrelor antiplatelet therapy in the Department of Cardiology of Wuxi Second People's Hospital from August to December 2019 were screened. Baseline patient data were collected, percutaneous coronary angiography (CAG) or coronary computed tomography angiography (CTA) results were recorded, CYP2C19 gene type was detected, and prognosis/outcome was assessed by telephone/outpatient/inpatient follow-up for 12 months.Results:(I) Of the 170 patients, 0.66% were the fast metabolic type, 41.45% were the normal metabolic type, 42.76% were the intermediate metabolic type, and 15.13% were the poor metabolic type. CYP2C19*2 mutation accounted for 89.29% of all mutations, CYP2C19*3 mutation accounted for 9.82%, and CYP2C19*17 mutation accounted for only 0.89%. (II) Among the patients with CHD who regularly took clopidogrel, the risk in the intermediate metabolic group was 5.208-fold higher than that of normal metabolic group, and that of the poor metabolic group was 3.75-fold higher than that of normal metabolic group; there was no significant difference between the intermediate and poor metabolic groups. (III) Prognosis was significantly associated with regular use of ticagrelor or clopidogrel by patients in the intermediate metabolic group. There was no significant correlation between poor metabolism (PM) and normal metabolism (NM). Prognosis was significantly associated with regular use of ticagrelor or clopidogrel in patients undergoing percutaneous coronary intervention (PCI), but not in patients who did not undergo PCI.Conclusions:CYP2C19 polymorphism was associated with the prognosis of patients with CHD administered antiplatelet therapy with oral clopidogrel. The incidence of poor prognosis was significantly increased with CYP2C19*2 and/or CYP2C19*3 mutations, and patients undergoing PCI or carrying a single CYP2C19 deletion allele had a better prognosis with ticagrelor as replacement therapy.
Journal of thoracic disease 2022
Background and aims: Our goals in the study were to (1) quantify the discordance in LDL-C levels between equations (the Friedewald, Sampson, and Martin/Hopkins equations) and compare them with direct LDL-C (dLDL-C); and (2) explore the proportion of misclassified patients by calculated LDL-C using these three different equations. Methods: A total of 30,349 consecutive patients with angiographically confirmed coronary artery disease (CAD) were prospectively enrolled. Concordance was defined as if the LDL-C was <1.8 mmol/L with each pairwise comparison of LDL-C equations. Estimated LDL-C that fell into the same category as dLDL-C at the following levels: <1.4, 1.4 to 1.7, 1.8 to 2.5, 2.6 to 2.9, and ≥3.0 mmol/L was considered to have been correctly categorized. Results: The concordance was 96.3% (Sampson vs. Martin/Hopkins), 95.0% (Friedewald vs. Sampson), and 91.4% (Friedewald vs. Martin/Hopkins), respectively. This proportion fell to 82.4% in those with hypertriglyceridemia (TG ≥ 1.7 mmol/L). With an accurate classification rate of 73.6%, the Martin/Hopkins equation outperformed the Sampson equation (69.5%) and the Friedewald equation (59.3%) by a wide margin. Conclusions: Comparing it to the validated Martin/Hopkins equation, the Friedewald equation produced the lowest levels of LDL-C, followed by the Sampson equation. In the classification of LDL-C, the Martin/Hopkins equation has also been shown to be more accurate. There is a significant difference between the equations and the direct measurement method, which may lead to overtreatment or undertreatment.
Journal of cardiovascular development and disease 2022
(1) Background: Apolipoprotein E(ApoE) plays a critical role in lipid transport. The specific allele of APOE being expressed is associated with the development of coronary heart disease (CHD), however the specific mechanisms by which ApoE drives disease are unclear. In this study, we investigated the relationship between APOE allele, lipoprotein metabolome, and CHD severity to provide evidence for the efficacy of clinical cholesterol-lowering therapy; (2) Methods: Blood samples were collected from 360 patients with CHD that were actively being treated with statins. The lipoprotein profile, including particle numbers, particle size, and lipoprotein composition concentrates, was measured by nuclear magnetic resonance (NMR) spectroscopy. The severity of CHD was determined by quantifying coronary angiography results using the Gensini scoring system; (3) Results: We found there was no significant difference in low-density lipoprotein cholesterol (LDL-C) levels among ε2+ (ε2 allele carriers, consisting of ε2/ε2 and ε2/ε3 genotypes), ε3 (consisting of ε3/ε3 and ε2/ε4 genotypes), and ε4+ (ε4 allele carriers, consisting of ε3/ε4 and ε4/ε4 genotypes) participants receiving statin treatment. Compared with the ε3 group, patients with the ε2+ genotype showed lower concentrations of total low-density lipoprotein (LDL), small-LDL, and middle-LDL particles, as well as a larger LDL size, higher very low-density lipoprotein (VLDL) composition concentrates, and higher intermediate density lipoprotein (IDL) composition concentrates. The ε4+ group showed higher concentrations of total LDL, small LDL particles, and LDL compositions with smaller LDL size. The higher level of small LDL concentration was associated with a high Gensini score (B = 0.058, p = 0.024). Compared with the ε3 group, the risk of increased branch lesions in the ε2+ group was lower (OR = 0.416, p = 0.027); (4) Conclusions: The specific allele of APOE being expressed can affect the severity of CHD by altering components of the lipoprotein profile, such as the concentration of small LDL and LDL size.
Molecules (Basel, Switzerland) 2022
OBJECTIVE:To determine the prognostic role of big endothelin-1 (ET-1) in left ventricular non-compaction cardiomyopathy (LVNC).METHODS:We prospectively enrolled patients whose LVNC was diagnosed by cardiac MRI and who had big ET-1 data available. Primary end point was a composite of all-cause mortality, heart transplantation, sustained ventricular tachycardia/fibrillation and implanted cardioverter defibrillator discharge. Secondary end point was cardiac death or heart transplantation.RESULTS:Altogether, 203 patients (median age 44 years; 70.9% male) were divided into high-level (≥0.42 pmol/L) and low-level (<0.42 pmol/L) big ET-1 groups according to the median value of plasma big ET-1 levels. Ln big ET-1 was positively associated with Ln N-terminal pro-brain natriuretic peptide, left ventricular diameter, but negatively related to age and Ln left ventricular ejection fraction. Median follow-up was 1.9 years (IQR 0.9-3.1 years). Kaplan-Meier analysis showed that, compared with patients with low levels of big ET-1, those with high levels were at greater risk for meeting both primary (p<0.001) and secondary (p<0.001) end points. The C-statistic estimation of Ln big ET-1 for predicting the primary outcome was 0.755 (95% CI 0.685 to 0.824, p<0.001). After adjusting for confounding factors, Ln big ET-1 was identified as an independent predictor of the composite primary outcome (HR 1.83, 95% CI 1.27 to 2.62, p=0.001) and secondary outcome (HR 1.93, 95% CI 1.32 to 2.83, p=0.001).CONCLUSIONS:Plasma big ET-1 may be a valuable index to predict the clinical adverse outcomes in patients with LVNC.
Heart (British Cardiac Society) 2021
BACKGROUND:High-sensitivity cardiac troponin (hs-cTn) assays provide high sensitivity detection of myocardial injury. Although an assay using whole blood can reduce turn-around-time and labour, hs-cTn assays using whole blood samples are novel requiring characterization of their analytical performance.METHODS:The imprecision of Pylon hs-cTnI assay was evaluated with whole blood, plasma and commercial quality control samples. The limit of quantitation (LOQ) of whole blood samples and plasma were determined for the Pylon hs-cTnI assay. The correlation between the Pylon hs-cTnI assay and the Abbott Architect hs-cTnI assay was evaluated using whole blood samples and plasma.RESULTS:The average concentrations of pooled patient plasma were 8.3, 15.0 and 396.9 ng/l, while the corresponding CVs of repeatability and within-laboratory CVs were calculated respectively as 7.6% and 9.9%, 4.3% and 4.5%, and 3.3% and 4.5%. LOQ (20% CV) was 1.2 ng/l in plasma and 2.0 ng/l in whole blood. The lowest concentrations to reach 10% CV were 4.8 ng/l with plasma and 9.4 ng/l with whole blood. Quantification of whole blood and corresponding plasma samples correlated with no effect by hematocrits ranging from 25 to 44%.CONCLUSION:The analytical performance of the Pylon hs-cTnI assay with whole blood is comparable to that of a clinical lab instrument.
Clinica chimica acta; international journal of clinical chemistry 2020
BACKGROUND:Point-of-care (POC) cTn assays are needed when the central laboratory is unable to provide timely results to the emergency department. Many POC devices are available. The prospect of choosing them is daunting. In order to provide a quick decision-making reference for POC cTn device selection comparing them to the central laboratory, seven POC devices commonly employed by emergency department were evaluated.METHODS:Firstly, we reviewed all devices package inserts. Secondly, we evaluated several POC cTn assays for imprecision, linearity, and correlation with central laboratory assays according to CLSI EP protocols. The linear regression analyses were performed only for the detectable concentrations. Five cTnI devices (Alere Triage, BioMerieux Vidas, Mitsubishi Pathfast, ReLIA TZ-301, and Radiometer AQT90) were evaluated against a contemporary cTnI assay (Beckman Access II Accu TnI). Two cTnT assays (Radiometer AQT90 and Roche Cobas h232) were compared to a high-sensitivity (hs) cTnT method (Roche Cobas e601).RESULTS:For cTn levels around the 99th percentile upper reference limits (URLs) of the comparator assays, imprecision could not be assessed for the Alere, BioMerieux, and Cobas h232 as they gave undetectable readings due to a lack of assay sensitivity. Imprecision (CV) was unacceptably high for the ReLIA (33.3%). On account of this precision metric, these four assays were deemed unsuitable. Regression analyses showed acceptable linearity for all the POC devices. The correlation coefficients for ReLIA, BioMerieux, Cobas h232, and Radiometer cTnT were >0.95. Unlike the cTnT devices, the cTnI assays employ different capture and detection antibodies leading to non-commutable results. The POC cTn results were concordant with their comparator-Radiometer cTnT 90%, Pathfast cTnI 85%, and Radiometer cTnI 75%.CONCLUSION:Our study provides the procedure and essential data to guide selection of a POC cTn device. Of the point-of-care devices, methods evaluated Radiometer AQT90 (cTnI and cTnT) and Pathfast might be considered.
Journal of clinical laboratory analysis 2020
AIM:ST2 plays important roles in diabetes and cardiovascular diseases. However, the distribution and changes in plasma soluble ST2 during the development of type 2 diabetes remain unclear.METHODS:In the present study, 525 subjects were recruited and divided into three groups: normal, prediabetic and diabetic subjects. The sST2 levels of all subjects were measured using a high-sensitivity assay.RESULTS:sST2 levels were modestly but significantly elevated in patients with diabetes (26.1ng/ml) compared with normal subjects (19.3ng/ml, P<0.001) and persons with prediabetes (20.3ng/ml, P<0.001). The third and fourth quartiles (21.3 and 29.1ng/ml, respectively) of the sST2 levels were associated with a 2.31- and 4.00-fold increased risk of having diabetes. With the prediabetic group as a reference population, patients with sST2 levels in the fourth quartiles had a higher increased risk of having diabetes mellitus (odds ratios=2.19, P<0.05). Furthermore, each SD log sST2 was associated with a 1.57-fold increased risk of atherosclerosis when all relevant variables was added to the multivariable logistic regression models. After adjustment for age and sex, all markers of liver and renal function, HDL-cholesterol, total cholesterol and smoking status showed a significant association with sST2 levels.CONCLUSION:Elevated sST2 levels were not only associated with metabolic characteristics of diabetes but also with a significantly increased risk of having diabetes.
Diabetes research and clinical practice 2016
OBJECTIVE:The calmodulin-binding transcription activator 2 (CAMTA2) promotes transcription of genes involved in cardiac hypertrophy through its interaction with Nkx2.5 and is an indispensable transcription coactivator for cardiac hypertrophy. We hypothesized that variants in the coding region of CAMTA2 would affect its function and confer a risk of cardiac hypertrophy.METHODS:The effects of the variant rs238234 on the activity of the atrial natriuretic factor promoter and on the cardiomyocytes hypertrophy were assessed in the H9C2 cell line and primary neonatal rat cardiomyocytes, respectively. Furthermore, the association of this variant with left ventricular hypertrophy (LVH) was tested in hypertensive patients with and without hypertrophy (N = 325 and 697), and this analysis was replicated in an independent population of 987 hypertensive patients without hypertrophy and 463 hypertensive patients with hypertrophy.RESULTS:We found that the G allele of rs238234 activated the atrial natriuretic factor promoter more strongly than the C allele. The cell size of cardiomyocytes was larger in the presence of the Ad-CAMTA2 G allele, and the G allele was associated with significantly increased susceptibility to LVH in hypertensive [odds ratio (OR), 1.29; P = 0.009]. In the discovery cohort, after adjusting for age and sex, the GG genotype was significantly associated with increased LVH risk (OR, 1.75; P = 0.015). There was little attenuation of the ORs (1.62; P < 0.05) when adjusting for BMI, heart rate, blood pressure, smoking, and drinking and further adjusting all covariates including lipid levels and other major risk factors. However, the GC genotype did not show any association with LVH using three regressive models. Replication in the second study yielded similar results.CONCLUSION:Our results provide evidence that the rs238234 GG genotype in the coding region of CAMTA2 may increase the risk of LVH by affecting the activation of Nkx2.5-dependent transcription.
Journal of hypertension 2016
The present study aims to test whether Lycium barbarum L. has anti-hypertensive effect through regulating expression of lncRNA sONE in a rat model of salt-sensitive hypertension. Nine weeks old borderline hypertensive rats (BHRs) were divided into 4 groups receiving high (8% NaCl), medium (0.25% NaCl, as control group), and low salt diet (0.015% NaCl) for 16 weeks, respectively, while the fourth group (high salt + L. barbarum group) fed with high salt diet for 12 weeks, then followed by 8% NaCl and L. barbarum treatment for 4 weeks. Body weight and blood pressure were recorded biweekly. Salt-sensitive hypertension was successfully induced by 12-week high salt diet in BHR model. Blood pressure was significantly increased in the model (P < 0.05), and L. barbarum treatment reversed the elevated blood pressure to normal level. Expression of lncRNA sONE was significantly reduced and eNOS expression level was dramatically improved in the hypertension model rats with the L. barbarum compared with that receiving high salt diet. Our results indicated that L. barbarum L. had anti-hypertensive effect and might lower blood pressure by suppressing the expression of lncRNA sONE in BHR model.
International journal of clinical and experimental pathology 2015
