龚丁旭
中国医学科学院阜外医院 再生医学实验室
Familial PHEOs (pheochromocytomas) are inherited as an autosomal dominant trait, and inherited PHEOs can be one clinical phenotype of clinical syndromes, such as multiple endocrine neoplasia type 2A (MEN2A). In recent years, there has been a lot of controversy about the factors affecting the penetrance of PHEOs in MEN2A, of which the effects of RET (rearranged during transfection) proto-oncogene mutations are the primary concern. In this report, we performed genetic screening of patients in one family presenting with PHEOs and found they carried a RET c.1901G>A mutation. They were ultimately diagnosed with familial MEN2A. We found that MEN2A patients with the RET c.1901G>A mutation tended to have bilateral PHEOs that appeared earlier than medullary thyroid carcinoma. Genetic analysis showed that the patients also carried novel SLC12A3 (solute carrier family 12 member 3) variants, which are highly associated with Giteman syndrome. The results of protein structure prediction models suggest this SLC12A3 mutant has altered both the protein structure and the interaction with surrounding amino acids. Further studies of the phenotypes and related mechanisms of the gene mutations are required to guide individual assessment and treatment.
Genes 2022
OBJECTIVES:Aldehyde dehydrogenase 2 activity is associated with cardioprotection. Individuals carrying an East Asian variant of the ALDH2 genotype (ALDH2*2) have significantly reduced aldehyde dehydrogenase 2 activity. No previous studies have determined the effect of the ALDH2*2 genotype on cardioprotective results after coronary artery bypass grafting (CABG).METHODS:In total, 207 patients who underwent selective off-pump CABG were prospectively enrolled. Their baseline characteristics and clinical results were collected. Preoperative and postoperative circulating oxidative stress levels (serum malondialdehyde adducts and hydroxynonenal adducts) were measured. After genotyping, the oxidative stress levels and clinical results were compared between the ALDH2*2 carriers and non-carriers.RESULTS:ALDH2*2 carriers exhibited higher levels of malondialdehyde (P = 0.02) and hydroxynonenal (P = 0.03) adducts after CABG. ALDH2*2 carriers had higher postoperative troponin I levels (P = 0.01) and 24-h inotropic scores (P = 0.02). The intensive care unit time (P = 0.03) and postoperative length of stay (P = 0.03) were longer in ALDH2*2 carriers. The postoperative pulmonary infection rate was higher (P = 0.03) in ALDH2*2 carriers.CONCLUSIONS:Patients with the ALDH2*2 genotype had higher postoperative oxidative stress levels and poorer clinical results after CABG. Special cardioprotective techniques should be considered for patients with a history of 'facial flushing' when performing CABG.
Interactive cardiovascular and thoracic surgery 2019
BACKGROUND:Dysfunction of mechanical heart valve prostheses is an unusual but potentially lethal complication after mechanical prosthetic valve replacement. We seek to report our experience with mechanical valve dysfunction regarding etiology, surgical techniques and early outcomes.METHODS:Clinical data of 48 patients with mechanical valve dysfunction surgically treated between October 1996 and June 2011 were analyzed.RESULTS:Mean age was 43.7±10.9 years and 34 were female (70.8%). The median interval from primary valve implantation to dysfunction was 44.5 months (range, 1 hour to 20 years). There were 21 emergent and 27 elective reoperations. The etiology was thrombosis in 19 cases (39.6%), pannus in 12 (25%), thrombosis and pannus in 11 (22.9%), improper disc orientation in 2 (4.1%), missing leaflet in 1 (2.1%), excessively long knot end in 1 (2.1%), endogenous factor in 1 (2.1%) and unidentified in 1 (2.1%). Surgical procedure was mechanical valve replacement in 37 cases (77.1%), bioprosthetic valve replacement in 7 (14.9%), disc rotation in 2 (4.2%) and excision of excessive knot end in 1 (2.1%). Early deaths occurred in 7 patients (14.6%), due to low cardiac output in 3 (6.3%), multi-organ failure in 2 (4.2%) and refractory ventricular fibrillation in 2 (4.2%). Complications occurred in 10 patients (20.8%).CONCLUSIONS:Surgical management of mechanical valve dysfunction is associated with significant mortality and morbidity. Earlier identification and prompt reoperation are vital to achieving better clinical outcomes. The high incidence of thrombosis in this series highlights the need for adequate anticoagulation and regular follow-up after mechanical valve replacement.
Journal of thoracic disease 2015
Genetic variants may determine susceptibility of congenital heart disease (CHD). To evaluate the impact of transforming growth factor-β1 (TGFβ1), TGFβ receptor II (TGFβR2) and vascular endothelial growth factor (VEGF) polymorphisms on conotruncal heart defects susceptibility, we genotyped six functional polymorphisms TGFβ1 rs1800469 C>T, TGFβR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T in a hospital based case-control study of 244 conotruncal heart defects cases and 136 non-CHD controls in a Chinese population. Logistic regression analyses revealed that if the TGFβ1 rs1800469 CC homozygote genotype was used as the reference group, subjects carrying the CT variant heterozygote had a significant 0.48-fold decreased risk of conotruncal heart defects [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.30-0.88], subjects carrying the TT variant homozygote had a significant 0.47-fold decreased risk of conotruncal heart defects (OR 0.53; 95% CI 0.28-1.00). In stratification analyses, the TGFβ1 rs1800469 C>T genotype was associated with a decreased risk for tetralogy of fallot in homozygote comparisons (OR 0.47; 95% CI 0.22-0.99), a decreased risk for transposition of great artery in the dominant genetic model (OR 0.49; 95 % CI 0.28-0.87) and heterozygote comparisons (OR 0.45; 95% CI 0.24-0.83). Our findings suggest that TGFβ1 rs1800469 C>T polymorphism was significantly associated with decreased risk of conotruncal heart defects. TGFβR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T polymorphisms may not play a role in the susceptibility of conotruncal heart defects.
Molecular biology reports 2014
Cardiac ischemia and reperfusion promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. Mitochondrial aldehyde dehydrogenase 2 is emerging as a key cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. Mitochondrial aldehyde dehydrogenase 2 activity strongly correlates to a better cardioprotective effect, and mitochondrial aldehyde dehydrogenase 2 can be activated by several pathways. After phosphorylation, the active mitochondrial aldehyde dehydrogenase 2 can reduce the build-up of aldehydes, inhibit autophagy, inhibit opening of the mitochondrial permeability transition pore, and prevent reperfusion arrhythmias. Therefore, mitochondrial aldehyde dehydrogenase 2 activation by small molecule activators suggests a promising new direction in cardiovascular research and the development of novel cardioprotective strategies. This review will discuss the cardioprotective effects of mitochondrial aldehyde dehydrogenase 2 activation in detail. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
Journal of molecular and cellular cardiology 2013
Ischemia/reperfusion damage is common during open-heart surgery. Activation of aldehyde dehydrogenase-2 can significantly reduce ischemia/reperfusion damage. We hypothesized that adding aldehyde dehydrogenase-2 agonist to regular cardioplegia solution would further ameliorate ischemia/reperfusion damage. Alda-1 was used as an aldehyde dehydrogenase-2 agonist. Cardioprotection by histidine-tryptophan-ketoglutarate solution with and without Alda-1 was compared using an ex vivo perfused rat heart model of ischemia/reperfusion. Three groups of ex vivo rat hearts endured different treatments with variant ischemia or an ischemia/reperfusion time course: sham, no ischemia/reperfusion; histidine-tryptophan-ketoglutarate; and histidine-tryptophan-ketoglutarate plus Alda-1. Aldehyde dehydrogenase-2 expressions and activities, oxidative parameters (including 4-hydroxy-2-nonenal-His adducts, malondialdehyde levels, and glutathione/oxidized glutathione ratios), myocardial protein carbonyl levels, coronary effluents creatine kinase isoenzyme MB levels, and heart function parameters were measured and compared. Alda-1 significantly elevated myocardium aldehyde dehydrogenase-2 activity (P < .01). Increased aldehyde dehydrogenase-2 activity in turn attenuated ischemia/reperfusion-induced elevation in cardiac aldehydes, creatine kinase isoenzyme MB leakage, and protein carbonyl formation (P < .01). The Alda-1 group also obtained higher glutathione/oxidized glutathione ratios (P < .01). Aldehyde dehydrogenase-2 activation alleviated ischemia/reperfusion-induced cardiomyocyte contractile function impairment as evidenced by improved maximal velocity of pressure development and decline, left ventricular developed pressure, and heart rate (P < .01). Alda-1 supplementation can significantly improve the cardioprotection effect of cardioplegia solution, possibly through activation of aldehyde dehydrogenase-2, to remove toxic aldehydes. This may aid in the identification of novel cardioplegia solutions.
Cardiovascular toxicology 2012
BACKGROUND:Controversies exist among trials reporting the effects of statins on endothelial dysfunction in patients with diabetes mellitus (DM). Therefore, we performed a meta-analysis to determine whether statin therapy could improve endothelial dysfunction in patients with DM.METHODS:PubMed, Cochrane and Embase were searched for randomized controlled trials of statins. Only trials reporting changes in flow-mediated dilatation (FMD) were included in this analysis. A meta-analysis was performed to assess the relationship between statin therapy and improvements in endothelial dysfunction. Meta-regression and subgroup analyses were done to identify sources of heterogeneity.RESULTS:Ten statin studies (845 patients) were included in this analysis. Statin therapy significantly improved FMD in patients with DM [weighted mean difference (WMD): 0.94%; 95% CI: 0.38%, 1.5%; P<0.001]. Although heterogeneity among trials was found (I(2): 67%), no significant publication bias was detected. Subgroup analyses showed that patients did not benefit from statin therapy if their body mass index (BMI) was>27.6 kg/m(2) (four trials; I(2): 0%; WMD: 0.11%; 95% CI: -0.47%, 0.70%; P=0.70). However, FMD was significantly improved among patients with BMI ≤27.6 kg/m(2) (five trials; I(2): 14%; WMD: 1.52%; 95% CI: 1.19%, 1.85%; P<0.001). Type 1 diabetes, younger age, lower baseline blood lipid levels and blood pressure were all associated with improvements in FMD. The meta-regression analysis yielded similar results.CONCLUSION:Statins significantly improved the FMD only in patients with better endothelial functions. The use of FMD in evaluating therapeutic outcomes should be careful in populations at high risk.
Atherosclerosis 2012
Increased proliferation after low-level laser irradiation (LLLI) has been well demonstrated in many cell types including mesenchymal stem cells (MSCs), but the exact molecular mechanisms involved remain poorly understood. The aim of this study was to investigate the change in mRNA expression in rat MSCs after LLLI and to reveal the associated molecular mechanisms. MSCs were exposed to a diode laser (635 nm) as the irradiated group. Cells undergoing the same procedure without LLLI served as the control group. Proliferation was evaluated using the MTS assay. Differences in the gene expression profiles between irradiated and control MSCs at 4 days after LLLI were analyzed using a cDNA microarray. Gene ontology and pathway analysis were used to find the key regulating genes followed by real-time PCR to validate seven representative genes from the microarray assays. This procedure identified 119 differentially expressed genes. Real-time PCR confirmed that the expression levels of v-akt murine thymoma viral oncogene homolog 1 (Akt1), the cyclin D1 gene (Ccnd1) and the phosphatidylinositol 3-kinase, catalytic alpha polypeptide gene (Pik3ca) were upregulated after LLLI, whereas those of protein tyrosine phosphatase non-receptor type 6 (Ptpn6) and serine/threonine kinase 17b (Stk17b) were downregulated. cDNA microarray analysis revealed that after LLLI the expression levels of various genes involved in cell proliferation, apoptosis and the cell cycle were affected. Five genes, including Akt1, Ptpn6, Stk17b, Ccnd1 and Pik3ca, were confirmed and the PI3K/Akt/mTOR/eIF4E pathway was identified as possibly playing an important role in mediating the effects of LLLI on the proliferation of MSCs.
Lasers in medical science 2012
AIMS:About 40% of East Asians carry an aldehyde dehydrogenase-2*2 (ALDH2*2) allele, and the influence of the ALDH2*2 allele on human cardioprotection has not been studied. This study was designed to evaluate the effect of ALDH2*2 allele on cardioprotection of patients with congenital heart diseases after open-heart surgery.METHODS AND RESULTS:The right atrial appendage was harvested before performing cardiopulmonary bypass in cyanotic and acyanotic congenital heart disease groups (n = 20 per group). Tissues were assayed to determine the impact of cyanosis on metabolic remodelling. A prospective cohort of Tetralogy of Fallot (TOF) patients (n = 118) was recruited to investigate the influence of the ALDH2*2 allele on cardioprotection after surgical repair. Myocardium samples were dissected after cardioplegia. ALDH2 activity, oxidative stress and glutathione (GSH) levels, and activating transcription factor-4 (ATF4) were analysed. After genotyping and grouping, all of the experimental and clinical results were compared between ALDH2*2 carriers and non-carriers. Cyanosis inhibited ALDH2 activity and led to aldehyde accumulation in ALDH2*2 carriers. This accumulation in turn increased expression of ATF4 and resulted in larger myocardium GSH pools. The differences in ALDH2 activity and GSH level between carriers and non-carriers disappeared during cardioplegic arrest, and more aldehydes accumulated in the non-carriers. Consequently, ALDH2*2 carriers showed lower postoperative troponin I, inotrope score, and shorter postoperative length of ICU and hospital stay.CONCLUSIONS:ALDH2*2 carriers with cyanotic congenital heart disease were associated with an induced metabolic remodelling phenotype and a compensatory myocardium GSH pool. When ALDH2 activity was impaired during open-heart surgery, this larger GSH pool could lead to unexpectedly better cardioprotection. This may aid in the prediction of cardioprotection outcomes and identification of individualized cardioprotective strategies.
European heart journal 2012
BACKGROUND:Folic acid has an important role during embryologic development, particularly the development of the cardiovascular system.METHODS:We analyzed the involvement of eight polymorphisms in genes related to folic-acid metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD1), transcobalamin (TCN2), reduced folate carrier (RFC), nicotinamide-N-methyltransferase (NNMT) and natriuretic peptide precursor A (NPPA) as risk factors of conotruncal heart defects.RESULTS:In single-locus analyses, the genotype frequencies of MTHFR rs1801133 C>T were 18.4% (CC), 50.4% (CT), and 31.1% (TT) in the subjects with conotruncal heart defects and 31.6% (CC), 52.9% (CT), and 15.4% (TT) in control subjects, and the difference was significant (p=0.001). Logistic regression analyses revealed that, if the MTHFR rs1801133 CC homozygote genotype was used as the reference group, subjects carrying the TT variant homozygote had a significant 3.46-fold [odds ratio (OR) 3.46; 95% confidence interval (CI) 1.83-6.55] increased risk of conotruncal heart defects. If the RFC rs1051266 GG homozygote genotype was used as the reference group, subjects carrying the GA variant heterozygote had a significant 1.68-fold (OR 1.68; 95% CI 1.02-2.78) increased risk of conotruncal heart defects. In stratification analyses, the MTHFR rs1801133 C>T genotype was associated with an increased risk for tetralogy of Fallot (TOF) and transposition of great artery (TGA) in homozygote comparisons, the dominant genetic model, and the recessive genetic model. The RFC rs1051266 GA genotype was associated with an increased risk for TGA compared with wild-type homozygotes and, in the dominant genetic model, the RFC rs1051266 GA/AA genotype was also associated with a significantly increased risk of TGA compared with RFC rs1051266 GG genotypes.CONCLUSIONS:These data suggest that genotypes for the MTHFR C677T and RFC rs1051266 polymorphism might be associated with the risk of conotruncal heart defects.
Clinical chemistry and laboratory medicine 2012
