Comparison of outcomes of self-expanding versus balloon-expandable valves for transcatheter aortic valve replacement: a meta-analysis of randomized and propensity-matched studies.

BACKGROUND: The postoperative outcomes of transcatheter aortic valve replacement (TAVR) with the new generation of self-expanding valves (SEV) and balloon-expandable valves (BEV) remain uncertain. METHODS: We conducted a meta-analysis based on randomized controlled trials (RCTs) and propensity score-matched (PSM) studies to evaluate the performance of the new generation TAVR devices, with a focus on Edwards SAPIEN 3/Ultra BEV, Medtronic Evolut R/PRO SEV, and Boston ACURATE neo SEV. Our primary endpoints were mortality and complications at both 30 days and one year post-operation. RESULTS: A total of 4 RCTs and 14 PSM studies were included. Our findings showed no significant difference between SEV and BEV regarding 30-day and 1-year mortality rates. ACURATE SEV required less permanent pacemaker implantation (PPI) at 30-day as compared to SAPIEN BEV, while Evolut SEV required a higher rate of PPI than SAPIEN BEV. The incidence of stroke, major or life-threatening bleeding (MLTB), major vascular complications (MVC), coronary artery obstruction (CAO) and acute kidney injury (AKI) did not differ significantly between the two groups. SEV had a larger effective orifice area (EOA) and lower mean transvalvular gradients (MPG) compared to BEV. However, there was an increased risk of paravalvular leakage (PVL) associated with SEV. CONCLUSIONS: In terms of 30-day mortality, stroke, bleeding, MVC, AKI, CAO, and one-year mortality, there was comparability between the two valve types following TAVR. SEV was associated with better hemodynamic outcomes, except for a higher incidence of PVL. Compared to SAPIEN BEV, ACURATE SEV had a lower risk of PPI at 30 days, while Evolut SEV was associated with a higher risk of PPI. These findings underscore the importance of personalized valve selection.

S-Nitrosylation of Akt by organic nitrate delays revascularization and the recovery of cardiac function in mice following myocardial infarction.

The effects of long-term nitrate therapy are compromised due to protein S-Nitrosylation, which is mediated by nitric oxide (NO). This study is to determine the role of Akt S-Nitrosylation in the recovery of heart functions after ischaemia. In recombinant Akt protein and in HEK293 cells, NO donor decreased Akt activity and induced Akt S-Nitrosylation, but was abolished if Akt protein was mutated by replacing cysteine 296/344 with alanine (Akt-C296/344A). In endothelial cells, NO induced Akt S-Nitrosylation, reduced Akt activity and damaged multiple cellular functions including proliferation, migration and tube formation. These alterations were ablated if cells expressed Akt-C296/344A mutant. In Apoe-/- mice, nitroglycerine infusion increased both Akt S-Nitrosylation and infarct size, reduced Akt activity and capillary density, and delayed the recovery of cardiac function in ischaemic hearts, compared with mice infused with vehicle. Importantly, these in vivo effects of nitroglycerine in Apoe-/- mice were remarkably prevented by adenovirus-mediated enforced expression of Akt-C296/344A mutant. In conclusion, long-term usage of organic nitrate may inactivate Akt to delay ischaemia-induced revascularization and the recovery of cardiac function through NO-mediated S-Nitrosylation.

Intracoronary application of nicorandil regulates the inflammatory response induced by percutaneous coronary intervention.

Intracoronary application of nicorandil can effectively reduce the myocardial no-reflow (MNR) after percutaneous coronary intervention (PCI). We sought to investigate the mechanisms of nicorandil in preventing MNR, besides that of dilating the coronary microvasculature. A total of 60 patients undergoing PCI were enrolled and randomly divided into a nicorandil group and a control group. Before PCI, 2 mg of nicorandil or an equal volume of normal saline was injected into the coronary artery. Blood samples were collected before, 24 hours and 1 week after PCI and inflammatory cytokines were tested. In the control group, the expression of pro-inflammatory cytokines was significantly increased, while the anti-inflammatory cytokines were decreased 24 hours after PCI. In contrast, these changes were reversed in the nicorandil group, indicating that nicorandil regulated the inflammatory response induced by PCI. Then, proteomic analysis was performed to further elucidate the potential mechanisms. A total of 53 differentially expressed proteins (DEPs) were found 24 hours after PCI in the control group, and the changes of these relevant genes were reversed in the nicorandil group. These DEPs were significantly enriched in the inflammatory pathways. In conclusion, the intracoronary application of nicorandil before PCI can regulate the inflammatory responses induced by PCI, which might be an important mechanism of nicorandil in preventing MNR.

Regulatory T cells protected against abdominal aortic aneurysm by suppression of the COX-2 expression.

CD4+ CD25+ regulatory T cells (Tregs) have been shown to protect against the development of abdominal aortic aneurysm (AAA). Cyclooxygenase-2 (COX-2), a pro-inflammatory protein, can convert arachidonic acid into prostaglandins (PGs). The present study was aimed to investigate the effect of Tregs on COX-2 expression in angiotension II (Ang II)-induced AAA in ApoE-/- mice. Tregs were injected via tail vein in every 2 weeks. Ang II was continuously infused by a micropump for 28 days to induce AAA. In vivo, compared with the control group, adoptive transfer of Tregs significantly reduced the incidence of AAA, maximal diameter, and the mRNA and protein expression of COX-2 in mice. Immunofluorescence showed that Tregs treatment reduced COX-2 expression both in smooth muscle cells (SMCs) and macrophages in AAA. In vitro, the Western blot analysis showed that Tregs reduced Ang II-induced COX-2 expression in macrophages and SMCs. Meanwhile, ELISA showed that Tregs reduced Ang II-induced prostaglandin E2 (PGE2 ) secretion. Moreover, Tregs increased SMC viability and induced transition of macrophages phenotype from M1 to M2. In conclusion, Tregs treatment dramatically decreased the expression of COX-2 in vivo and in vitro, suggesting that Tregs could protect against AAA through inhibition of COX-2. The study may shed light on the immune treatment of AAA.

Enhanced atherosclerosis in TIPE2-deficient mice is associated with increased macrophage responses to oxidized low-density lipoprotein.

Atherosclerosis has been widely recognized as an inflammatory disease of the arterial wall in which macrophages play a major role. Yet, how macrophage-mediated pathology is regulated during atherosclerosis is poorly understood. TNF-α-induced protein 8-like 2 (TIPE2, also known as TNFAIP8L2) is highly expressed in resting macrophages and can negatively regulate inflammation through inhibiting immune receptor signaling. We report in this article that TIPE2 plays a crucial atheroprotective role likely by regulating macrophage responses to oxidized low-density lipoprotein (ox-LDL). TIPE2-deficient macrophages treated with ox-LDL produced more oxidative stress and proinflammatory cytokines, and exhibited heightened activation of the JNK, NF-κB, and p38 signaling pathways. As a consequence, TIPE2 deficiency in bone marrow-derived cells exacerbated atherosclerosis development in Ldlr(-/-) mice fed a high-fat diet. Importantly, ox-LDL markedly downregulated TIPE2 mRNA and protein levels in macrophages, suggesting that ox-LDL mediates atherosclerosis by TIPE2 inhibition. These results indicate that TIPE2 is a new inhibitor of atherosclerosis and a potential drug target for treating the disease.

Risk factors for long-term outcome of drug-eluting stenting in adults with early-onset coronary artery disease.

OBJECTIVE: We lack data on the long-term outcome of drug-eluting stenting in patients with early-onset coronary artery disease (CAD). Here, we investigated the association of traditional risk factors and major adverse cardiovascular events (MACEs) after drug-eluting stenting in patients with CAD who were < 50 years old. METHODS: We enrolled 437 consecutive CAD patients < 50 years old who underwent drug-eluting stenting and 132 subjects who were age- and sex-matched and angiographically shown to be disease free as controls. MACEs were analyzed in CAD patients for a median of 24 months [interquartile range 14-34 months]. RESULTS: Male patients accounted for 90.4% of cases. As compared with controls, patients with early-onset CAD had higher body mass index and rates of smoking, family history of CAD, and diabetes and hypercholesterolemia. During the hospital stay, 1 patient died, and the incidence of MACEs was 1.1%. At the end of follow-up, the overall death rate was 0.7%. MACEs were observed in 54 patients (12.4%). On Cox proportional hazard analyses, positive family history and diabetes were independent risk factors of MACEs (HR 2.61, 95% confidence interval 1.29-4.00, p = 0.002; and HR 2.48, 95% confidence interval 0.86-3.14, p = 0.004, respectively). CONCLUSIONS: Drug-eluting stenting is a reliable treatment for patients with early-onset CAD. Positive family history of CAD and diabetes are independent risk factors of adverse cardiovascular events in this subgroup of patients after drug-eluting stent implantation.

Association of lactate/albumin ratio with 3-month readmission risk in heart failure patients: a retrospective study.

AIMS: The predictive value of the lactate/albumin ratio (LAR) in mortality is established in various conditions, yet its relevance to 3-month readmission risk in Chinese adults with heart failure (HF) remains unclear. METHOD AND RESULTS: Analysing data from 957 patients with HF at Zigong Fourth People's Hospital, Sichuan, China (December 2016 to June 2019), we assessed baseline characteristics, vital signs, comorbidities, and prescriptions. LAR demonstrated a linear correlation with 3-month readmission risk (HR = 1.60, 95% CI: 1.19-2.16). Tertile 3 (≥-0.48) exhibited higher risk than tertile 1 (<-0.83) and tertile 2 [-0.83, -0.48), with HRs and 95% CI of 1.49 (1.06-2.10), 1.43 (1.01-2.02), 1.48 (1.03-2.12), respectively. Subgroup and sensitivity analyses affirmed consistent influence of LAR on 3-month readmission risk for HF. CONCLUSIONS: Higher LAR significantly correlates with increased 3-month readmission risk in Chinese adult patients with HF, suggesting LAR is a valuable predictor for early readmission.

Generation of KCNH2 heterozygous knockout induced pluripotent stem cell (iPSC) line (Long and Short QT Syndrome).

KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member) encodes a voltage-activated potassium channel role as rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential. Mutations in this gene can cause long QT syndrome and short QT syndrome. Transcript variants encoding distinct isoforms were also identified. In this study, we generated induced pluripotent stem cells (iPSC) from a healthy individual by electroporation of peripheral blood mononuclear cells and generated a KCNH2 heterozygous knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had a normal karyotype, were free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Lentivirus-mediated RNA interference of chymase increases the plaque stability in atherosclerosis in vivo.

Chymase activity was proved to be closely related with plaque vulnerability in a hamster model of atherosclerosis with chymase inhibitors. Considering that chymase inhibitors are nonspecific, here we further investigated the role of chymase in atherosclerosis in vivo through injection of lentivirus containing chymase shRNA or chymase cDNA. Our results revealed that silencing of the chymase gene by shRNA remarkably enhanced atherosclerosis plaque stability without alterations in body weight or serum lipid levels. Lentiviral expression of a gain-of-function chymase gene promoted the formation of vulnerable plaque in hamsters. Mechanistically, chymase functions as an activator of MMP9 in atherosclerotic lesions that induces plaque instability.

Case Report: Hypereosinophilic syndrome vs. patent foramen ovale as etiopathogenetic contributors to stroke.

Hypereosinophilic syndrome (HES), characterized by an increased number of eosinophils in tissues and/or blood, presents with heterogeneous clinical manifestations. Studies have shown that HES can affect the nervous system and may be associated with cerebral infarction. Patent foramen ovale (PFO) is the most common congenital intracardiac defect that can cause right-to-left shunting and contribute to the paradoxical embolization of venous emboli, and even lead to stroke. We report the case of a young man who presented with cerebral infarction accompanied by both HES and PFO. The patient underwent thorough evaluation to determine the source of emboli and the potential pathogenesis. In this case, HES was confirmed and glucocorticoid treatment was conducted. Direct imaging using optical coherence tomography (OCT) confirmed that the embolus originated from the PFO. Therefore, we performed PFO occlusion. The patient recovered well, and no new cerebral infarction was observed at 6-month follow-up. Based on the results of our study, we conclude that it is important to consider unusual etiologies of cerebral infarction, particularly in younger patients.

Statins induce the accumulation of regulatory T cells in atherosclerotic plaque.

CD4⁺CD25⁺ regulatory T cells (Tregs) mediate immune suppression and prevent autoimmune disorders. Recently, Tregs were found to present in atherosclerotic lesions and play an important role in the progression of atherosclerosis. Statins have immunomodulatory properties, and the effect of statins on atherosclerosis depends in part on their immunomodulatory mechanisms. We sought to determine whether statins exhibit an effect on Tregs in atherosclerotic plaques and in peripheral circulation of patients with acute coronary syndrome (ACS). In an in vivo experiment, we induced atherosclerotic plaques in apolipoprotein E-deficient (ApoE⁻/⁻) mice. The mice were randomly divided into two groups for 6-wk treatment: simvastatin (50 mg/kg/d) or vehicle (control). Simvastatin significantly increased the number of Tregs and the expression of Treg marker Foxp3 (Forkhead/winged helix transcription factor), transforming growth factor (TGF)-ß and interleukin (IL)-10 in atherosclerotic plaques. Moreover, simvastatin played an important role in modulating the balance between antiinflammatory (Tregs and Th2 cells) and proinflammatory (Th17 and Th1 cells) subsets of T cells. In an in vitro experiment, peripheral blood mononuclear cells (PBMCs) were isolated from patients with ACS and incubated with simvastatin. After an incubation for 96 h, simvastatin significantly enhanced the frequency and functional suppressive properties of Tregs. Therefore, statin treatment may influence Tregs in atherosclerotic lesions. Furthermore, statins improved the quantity and suppressive function of Tregs in ACS patients.

Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway.

AIM: Glycyrrhizin (GL) has been found to inhibit extracellular HMGB1 cytokine's activity, and protect spinal cord, liver and brain against I/R-induced injury in experimental animals. The purpose of this study was to investigate the protective effect of GL in rat myocardial I/R-induced injury and to elucidate the underlying mechanisms. METHODS: Male adult Sprague-Dawley rats underwent a 30-min left coronary artery occlusion followed by a 24-h reperfusion. The rats were treated with glycyrrhizin or glycyrrhizin plus recombinant HMGB1 after 30 min of ischemia and before reperfusion. Serum HMGB1, TNF-α and IL-6 levels, and hemodynamic parameters were measured at the onset and different time points of reperfusion. At the end of the experiment, the heart was excised, and the infarct size and histological changes were examined. The levels of Bcl2, Bax and cytochrome c, as well as phospho-ERK1/2, phospho-JNK and phospho-P38 in the heart tissue were evaluated using Western blot analysis, and myocardial caspase-3 activity was measured colorimetrically using BD pharmingen caspase 3 assay kit. RESULTS: Intravenous administration of GL (10 mg/kg) significantly reduced the infarct size, but did not change the hemodynamic parameters at different time points during reperfusion. GL significantly decreased the levels of serum HMGB1, TNF-α and IL-6. GL changed the distribution of Bax and cytochrome c expression between the mitochondrial and cytosolic fractions in the heart tissue, resulting in inhibition of myocardial apoptosis. Moreover, expression of phospho-JNK, but not ERK1/2 and P38 was decreased by GL in the heart tissue. All of the effects produced by GL treatment were reversed by co-administration with the recombinant HMGB1 (100 µg). Intravenous administration of SP600125, a selective phospho-JNK inhibitor (0.5 mg/kg), attenuated HMGB1-dependent Bax translocation and the subsequent apoptosis. CONCLUSION: These results demonstrate that GL alleviates rat myocardial I/R-induced injury via directly inhibiting extracellular HMGB1 cytokine activity and blocking the phospho-JNK/Bax pathway.

Generation of TSC1 knockout induced pluripotent stem cell (iPSC) line.

The TSC1 gene is a tumor suppressor gene that encodes for the growth inhibitory protein hamartin. It was founded clinically relevant to tuberous sclerosis complex (TSC) and related epilepsy. Variants in TSC1 resulted in tuberous sclerosis, focal cortical dysplasia (FCD) Type II, pulmonary lymphangioleiomyomatosis and change in everolimus sensitivity. Here, we generated induced pluripotent stem cells (iPSC) from a normal individual by electroporation of peripheral blood mononuclear cells (PBMC), and further generated TSC1-knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had normal karyotype, free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Global magnitude and temporal trend of infective endocarditis, 1990-2019: results from the Global Burden of Disease Study.

AIMS: To estimate the spatiotemporal patterns in infective endocarditis (IE) burden along with its attributable risk factors at the national, regional, and global levels, which is essential to optimize the targeted prevention, clinical practice, and research. METHODS AND RESULTS: Based on all available data sources, the incidence, mortality, and disability-adjusted life years (DALYs) of IE in 204 countries and regions from 1990 to 2019 were reconstructed by Global Burden of Disease Study 2019 using the Cause of Death Ensemble model, spatiotemporal Gaussian process regression, and DisMod-MR 2.1. We depicted the epidemiological characteristics of IE in detail by gender, region, and age. Globally, 1 090 527 incident cases, 66 322 deaths, and 1 723 594 DALYs of IE were estimated in 2019. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) increased from 9.91 and 0.73 to 13.80 and 0.87 per 100 000 person-years over the past 30 years, respectively. ASIR were consistently more pronounced in higher socio-demographic index (SDI) regions. The leading ASMR in 2019 appeared in the High SDI region, with the largest increase in the past three decades. The age-specific burden rate of IE among people over 25 years old usually increased with age, and the annual increasing trend was more obvious for people over 60 years of age, especially in higher SDI regions. CONCLUSION: The incidence and mortality of IE have continued to rise in the past 30 years, especially in higher SDI regions. The patient population was gradually shifting from the young to the elderly.

PTX3, a key component of innate immunity, is induced by SAA via FPRL1-mediated signaling in HAECs.

Serum amyloid A (SAA) is regarded as an important acute phase protein in coronary artery diseases. However, its involvement in the immune response of atherosclerosis is poorly understood. The present study was designed to investigate the influence of SAA on the secretion of long pentraxin 3 (PTX3), a key component of innate immunity, in human aortic endothelial cells (HAECs). Our study revealed that recombinant SAA up-regulated PTX3 production in a remarkable dose- and time-dependent manner and the activation of formyl peptide receptor-like 1 (FPRL1) was crucial for SAA-induced expression of PTX3 in HAECs. Meanwhile, SAA-induced PTX3 production could be significantly down-regulated by using the specific siRNA sequences for Jun N-terminal kinases (JNK). Furthermore, the activation of activator protein-1 (AP-1) was necessary for the up-regulation of PTX3 expression. We also found that the activation of nuclear factor-kappa B (NF-κB) played an important role in this process. Our findings demonstrate that SAA up-regulates PTX3 production via FPRL1 significantly, and thus, contributes to the inflammatory pathogenesis of atherosclerosis.

[Roles of monocyte chemoattractant protein-1, RANTES and Fractalkine on promoting vulnerability of atherosclerotic plaques].

OBJECTIVE: To elucidate the roles of monocyte chemotactic factors (MCP-1, RANTES and Fractalkine) on the vulnerability of atherosclerotic plaques in patients with stable (SAP) and unstable angina pectoris (UAP). METHODS: Patients with SAP (n = 50) and UAP (n = 50) underwent coronary angiography (CAG) and intravenous ultrasound (IVUS) were included in the study. Monocyte chemotaxis was assayed by the transwell chamber. Concentrations of hs-CRP, MCP-1, RANTES and Fractalkine were measured by Enzyme-linked-immunosorbent assay (ELISA). mRNA expression of MCP-1, RANTES and Fractalkine in the monocytes was detected by RT-PCR. RESULTS: IVUS evidenced soft lipid plaques in 48% UAP patients and in 16% SAP patients (P < 0.05). SAP patients had mainly fibrous and mixed plaques. Plaque burden and vascular remodeling index were significantly higher in UAP patients than in SAP patients (P < 0.01). The averaged number of migrated monocytes in the UAP patients were higher than that in patients with SAP (P < 0.01). Concentration of hs-CRP, MCP-1, RANTES and Fractalkine were significantly higher in UAP patients than those of SAP patients (P < 0.05 or P < 0.01). mRNA expression of MCP-1, RANTES and Fractalkine in patients with UAP was significantly higher than those of SAP patients (P < 0.05). CONCLUSION: Upregulated monocyte chemotactic factors (MCP-1, RANTES and Fractalkine) might promote coronary plaque vulnerability in UAP patients.

Generation of SCN1B knock out induced pluripotent stem cell (iPSC) line (refractory epilepsy syndrome and Brugada syndrome related cell line).

The SCN1B gene, encoding the voltage-gated Na+ channel beta subunit Nav1.1, was founded as the most clinically relevant epilepsy and Brugadasyndrome gene. Variants in SCN1B resulted in genetic epilepsy with febrile seizures plus, severe Dravet Syndrome (DS), Brugadasyndrome, Atrial Arrhythmias, and Long QT-Syndrome. Here, we generated induced pluripotent stem cells (iPSC) from a normal individual by electroporation of peripheral blood mononuclear cells (PBMC), and further generated a SCN1B-knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had normal karyotype, free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Regulatory T Cells and Diabetes Mellitus.

Immune system dysfunction causes dysregulation of immune homeostasis, which in turn leads to autoimmune diseases. Regulatory T cells (Tregs) are a specialized T cell subpopulation that maintain peripheral tolerance and immune homeostasis. Diabetic patients are at an increased risk of developing cardiovascular diseases; thus, in terms of coronary risk, diabetes mellitus (DM) is considered coronary heart disease equivalent. Accumulating evidence indicates that Tregs play an important role in protecting against the development of various cardiovascular diseases. In this review, we provide an overview of the role of Tregs in the pathogenesis of DM, including type 1 DM, type 2 DM, latent autoimmune diabetes of adults, and gestational DM. In addition, we discuss the role of Tregs in diabetic complications, including cardiovascular diseases, nephropathy, neuropathy, and retinopathy. Tregs play a beneficial role in the pathogenesis of DM and diabetic complications, although the precise molecular mechanisms underlying the protective effect of Tregs against DM are still obscure. Collectively, modification of Tregs may provide a promising and novel future strategy for the prevention and therapy of DM and diabetic complications.

Association Between Stent Implantation and Progression of Nontarget Lesions in a Rabbit Model of Atherosclerosis.

BACKGROUND: Progression of nontarget lesions (NTLs) after percutaneous coronary intervention (PCI) has been reported. However, it remains unknown whether progression of NTLs was causally related to stenting. This study was undertaken to test the hypothesis that stent implantation triggers acute phase response and systemic inflammation which may be associated with progression of NTLs. METHODS: Thirty New Zealand rabbits receiving endothelial denudation and atherogenic diet were randomly divided into stenting, sham, and control groups. Angiography and intravascular ultrasonography were performed in the stenting and sham groups, and stent implantation performed only in the stenting group. Histopathologic study was conducted and serum levels of APPs (acute phase proteins) measured in all rabbits. Proteomics analysis was performed to screen the potential proteins related to NTLs progression after stent implantation. The serum levels of APPs and inflammatory cytokines were measured in 147 patients undergoing coronary angiography or PCI. RESULTS: Plaque burden in the NTLs was significantly increased 12 weeks after stent implantation in the stenting group versus sham group. Serum levels of APPs and their protein expression in NTLs were significantly increased and responsible for stenting-triggered inflammation. In patients receiving PCI, serum levels of SAA-1 (serum amyloid A protein 1), CRP (C-reactive protein), TNF (tumor necrosis factor)-α, and IL (interleukin)-6 were substantially elevated up to 1 month post-PCI. CONCLUSIONS: In a rabbit model of atherosclerosis, stent implantation triggered acute phase response and systemic inflammation, which was associated with increased plaque burden and pathological features of unstable plaque in NTLs. The potential mechanism involved vessel injury-triggered acute phase response manifested as increased serum levels of SAA-1, CRP, and LBP (lipopolysaccharide-binding protein) and their protein expression in NTLs. These findings provided a new insight into the relation between stent implantation and progression of NTLs, and further studies are warranted to clarify the detailed mechanism and clinical significance of these preliminary results. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900026393. Graphic Abstract: A graphic abstract is available for this article.

[Two novel mutations of GLA gene in Chinese patients with Fabry disease].

OBJECTIVE: To observe the disease-causing GLA gene mutations in Chinese patients with Fabry disease and the correlation between the genotype and phenotype. METHODS: DNA from 2 Chinese patients with Fabry disease and their relatives were collected. The seven exons and nonjunctional regions of GLA gene were amplified with polymerase chain reaction and the products were sequenced. The correlation between the genotype and phenotype was analyzed. RESULTS: Two mutations, G1168A and G1170A, located in 5' untranslated regions (5'UTR) were identified in the two probands and the two mutations were absent in normal controls. Three patients with the same genotype were found in the pedigree with G1168A mutation and there was no gene mutation carrier in the pedigree with G1170A mutation. Symptoms of the disease are less in female patients than that in male patients. CONCLUSION: GLA gene mutation in 5'UTR may also be involved in the disease process of patients with Fabry disease and the phenotype is partly affected by gender.