AtbHLH29 of Arabidopsis thaliana is a functional ortholog of tomato FER involved in controlling iron acquisition in strategy I plants

AtbHLH29 of Arabidopsis, encoding a bHLH protein, reveals a high similarity to the tomato FER which is proposed as a transcriptional regulator involved in controlling the iron deficiency responses and the iron uptake in tomato. For identification of its biological functions, AtbHLH29 was introduced into the genome of the tomato FER mutant T3238fer mediated by Agrobacterium tumefaciencs. Transgenic plants were regenerated and the stable integration of AtbHLH29 into their genomes was confirmed by Southern hybridization. Molecular analysis demonstrated that expression of the exogenous AtbHLH29 of Arabidopsis in roots of the FER mutant T3238fer enabled to complement the defect functions of FER. The transgenic plants regained the ability to activate the whole iron deficiency responses and showed normal growth as the wild type under iron-limiting stress. Our transformation data demonstrate that AtbHLH29 is a functional ortholog of the tomato FER and can completely replace FER in controlling the effective iron acquisition in tomato. Except of iron, FER protein was directly or indirectly involved in manganese homeostasis due to that loss functions of FER in T3238fer resulted in strong reduction of Mn content in leaves and the defect function on Mn accumulation in leaves was complemented by expression of AtbHLH29 in the transgenic plants. Identification of the similar biological functions of FER and AtbHLH29, which isolated from two systematically wide-diverged “strategy I” plants, suggests that FER might be a universal gene presented in all strategy I plants in controlling effective iron acquisition system in roots.

Molecular and functional characterization of sulfiredoxin homologs from higher plants

由在氧化 peroxiredoxin 减少 cysteine-sulfinic 酸， sulfiredoxin (Srx ) 在酵母和人的房间在氧化压力抵抗起一个重要作用。这里，我们从更高的植物报导 Srx 相当或相同的事物的第一分子、功能的描述。生物信息的分析揭示了把序列编码为两张单音的简易窄床和 dicot 植物种类的潜在的 Srx 的存在。通常认为的植物 Srx 蛋白质从酵母和人展出了重要身份到他们的 orthologs，并且为催化作用包含了保存签名顺序和残余必需品。然而，植物 Srxs 不同于酵母和人的 orthologs，都被预言在他们的主要结构拥有叶绿体运输肽。从 Arabidopsis 和米饭的 Srx 蛋白质(指定了为 AtSrx 和 OsSrx，分别地) 在 SRX1 删除酵母房间的 Srx 的补充功能的缺乏。AtSrx 的 GFP 熔化蛋白质在 Arabidopsis 叶肉原物被指向到叶绿体。AtSrx 抄写在植物、繁殖的机关发生了，并且最高的抄本水平在叶子被检测。在氧化应力下面， AtSrx 抄本水平实质地被增加，哪个有在维持被发现必要的 2-Cys peroxiredoxins 的提高的抄写的 paralleled 叶绿体氧化还原作用平衡。除了氧化应力， osmotic/water 赤字或冷处理也提起了 AtSrx 抄本水平。与上面的调查结果一致， AtSrx 的猛烈异种是显著地，产生氧化的更多比野类型 Arabidopsis 强调植物。总起来说，这个工作的结果在是必要的让工厂应付氧化应力的更高的工厂显示功能的 Srx 相当或相同的事物的存在。

Identification of AtENT3 as the main transporter for uridine uptake in Arabidopsis roots

当在酵母细胞生产了，差别在 Arabidopsis 器官被表示时，以前的研究证明了 Arabidopsis equilibrative nucleoside 运输 ers (AtENTs ) 拥有运输活动。此处，我们在 nucleoside 运输活动和 AtENT 成员的 transcriptional 模式报导进一步的分析。AtENTs 3 的 recombinant 蛋白质， 6，和 7，然而并非那些 AtENTs 1， 2， 4，和 8，被发现与高亲密关系搬运 thymidine。与以前的建议相反，那 AtENT1 不能搬运 uridine，这个工作证明 recombinant AtENT1 是 uridine 的 pH 依赖、高亲密关系的 transporter。当在 MS 盘子上成长时， AtENT3 猛烈植物比野类型的植物和 AtENT1 或 AtENT6 的猛烈植物对细胞毒素的 uridine 类似物 5-fluorouridine 更容忍。与这观察一致， AtENT3 猛烈的线展出了一个显著地减少的能力收起[(3 ) H ] 经由根的 uridine 什么时候与有变异的 AtENT1 或 AtENT6 的野类型的植物和植物相比。这显示那 AtENT3，然而并非 AtENTs 1 并且 6，是为在 Arabidopsis 根的 uridine 举起的主要 transporter。AtENTs 1 的抄写， 3， 4， 6， 7，和 8 在叶开发和老朽期间以一种复杂方式被调整。相反，六个 AtENT 成员并列地在种子萌芽期间被劝诱。这个工作为未来研究在 recombinant AtENT 蛋白质和新线索的运输性质上提供新信息在里面 vivo 运输活动和在 Arabidopsis 工厂的不同 ENT 蛋白质的生理的功能。

Long-term modifications of blood pressure in normotensive and spontane-ously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adeno- associated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxy- lases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hyperten- sion by blocking expression of CYP 4A in kidneys.

Chinese Society of Cardiology guidelines on the diagnosis and treatment of adult fulminant myocarditis

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium.It is characterized by acute onset,rapid progress and high risk of death.Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm.According to China’s practical experience,the adoption of the“life support-based comprehensive treatment regimen”(with mechanical circulation support and immunomodulation therapy as the core)can significantly improve the survival rate and long-term prognosis.Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease:current knowledge and new insights

Phenylacetylglutamine(PAGln)is an amino acid derivate that comes from the amino acid phenylalanine.There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases.In this review,we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln.We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases,such as heart failure,coronary heart disease/atherosclerosis,and cardiac arrhythmia.The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors.Besides,other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln.Moreover,since PAGln is produced across different organs including the intestine,liver,and kidney,the cross-talk among multiple organs focused on the function of this uremic toxic metabolite.Finally,the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.

A Kaposi’s sarcoma-associated herpes virus-encoded microRNA contributes to dilated cardiomyopathy

Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up.

Myocardial injury and related mortality in hospitalized patients with COVID-19 during the Omicron pandemic:new perspectives and insights

Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients,and has poor prognosis.However,the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave.We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital.The results indicated that the myocardial injury accounted for 30.8%of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching(PSM)[adjusted hazard ratio(HR),10.61;95%confidence interval(CI),7.76–14.51;P<0.001;adjusted HR,2.70;95%CI,1.86–3.93;P<0.001;respectively].Further,the levels of cytokines(IL-1β,IL-6,IL-10,and TNF-α)in patients with myocardial injury were higher than those without injury,and the higher levels of cytokines in the myocardial injury group were associated with increased mortality.Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers(ACEI/ARB)could significantly reduce the mortality in patients with myocardial injury(adjusted HR,0.52;95%CI,0.38–0.71;P<0.001).Additionally,the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury.Collectively,the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China,and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.

Machine learning modeling identifies hypertrophic cardiomyopathy subtypes with genetic signature

Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics

Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).

Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19

In December 2019,an outbreak of novel coronavirus(2019-nCoV)occurred in Wuhan,Hubei Province,China.By February 14,2020,it has led to 66492 confirmed patients in China and high mortality up to^2.96%(1123/37914)in Wuhan.Here we report the first family case of coronavirus disease 2019(COVID-19)confirmed in Wuhan and treated using the combination of western medicine and Chinese traditional patent medicine Shuanghuanglian oral liquid(SHL).This report describes the identification,diagnosis,clinical course,and management of three cases from a family,suggests the expected therapeutic effects of SHL on COVID-19,and warrants further clinical trials.

Temporal echocardiography findings in patients with fulminant myocarditis: beyond ejection fraction decline

The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients.In this study,changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored.We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment.Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled.Conventional echocardiographic measurements were obtained,and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (> 50%).Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified,and their changes with time were monitored in 14 FM patients.All patients had severely impaired cardiac function.Steep improvement in LVEF and GLS were observed within 6 days.Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal.In conclusion,FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days.The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.

Impact of mechanical circulatory support and immunomodulation therapy on outcome of patients with fulminant myocarditis: Chinese registry of fulminant myocarditis

Dear Editor,Patients presenting with acute myocarditis and sudden hemodynamic instability (termed fulminant myocarditis [FM]) still have a high mortality and need for heart transplantation, up to 28% at 60 days.1,2,3 Recent scientific statements and expert opinion consensus suggests early use of temporary mechanical circulatory supports (t-MCS).3,4 Specifically, Chinese scientific statement proposed an extensive use of t-MCS combined with immunoregulatory therapy (IT),4 although formal trials are lacking. We present a multicenter, retrospective study to compare the outcome of patients who were treated with t-MCS and IT vs. patients who didn’t receive these treatments. We included patients with the diagnosis of FM based on the presence of viral prodromal signs/symptoms followed by acute onset of severe heart failure (HF) without other relevant differential diagnosis or pre-existing cardiac disorders. Patients who received both t-MCS and IT during hospitalization were classified as t-MCS+IT group.

Effects of Shuanghuanglian oral liquids on patients with COVID-19:a randomized,open-label,parallel-controlled,multicenter clinical trial

We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.

Metabolism pathways of arachidonic acids:mechanisms and potential therapeutic targets

The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2),which is in turn further metabolized by cyclooxygenases(COXs)and lipoxygenases(LOXs)and cytochrome P450(CYP)enzymes to a spectrum of bioactive mediators that includes prostanoids,leukotrienes(LTs),epoxyeicosatrienoic acids(EETs),dihydroxyeicosatetraenoic acid(diHETEs),eicosatetraenoic acids(ETEs),and lipoxins(LXs).Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases(CVD),cancers,and inflammatory diseases.This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer.progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2.Thus,we herein present a synopsis of AA metabolism in human health,cardiovascular and cancer biology,and the signaling pathways involved in these processes.To explore the role of the AA metabolism and potential therapies,we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.

Fulminant myocarditis:a comprehensive review from etiology to treatments and outcomes

Fulminant myocarditis(FM)is characterized by a rapid progressive decline in cardiac function and a high mortality rate.Since the first report of FM patients in the 1980s,several clinical trials and research studies have been published increasing our knowledge regarding FM.Currently,the diagnosis of FM depends on various techniques including electrocardiography,echocardiography,endomyocardial biopsy,and cardiac magnetic resonance.The development of mechanical circulation support(MCS)devices and progress in our understanding of the pathophysiological mechanisms underlying FM,treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach.The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm.This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology,pathophysiology,treatments,and outcomes.

Hyperglycemic memory in diabetic cardiomyopathy

Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.

The double face of miR-320:cardiomyocytes-derived miR-320 deteriorated while fibroblasts-derived miR-320 protected against heart failure induced by transverse aortic constriction

MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.

Poor adherence to P2Y12 antagonists increased cardiovascular risks in Chinese PCI-treated patients

到在急性冠的症候群(交流) 以后的病人的第二等的预防药(ATM ) 的低坚持与差的临床的结果被联系。然而，文学在对与交流在中国病人与穷人联系的 ATM 和风险的评价以后提供有限数据。在当前的工作， ATM 在 Tongji 与交流在连续地招募的病人被估计从 2013 年 11 月 5 日的医院到 2014 年 12 月 31 日。2126 个病人的一个总数在低坚持下面被分类(盖住的天(PDC ) 分配 C <50%) 并且高坚持(PDC >50%) 在分泌物以后基于他们的表演组织。所有病人被跟随在上面在第一，第 6，和第 12 月当记录 ATM 和主要不利心脏的事件(向) 时，排出。Bivariate 逻辑回归被用来识别与 ATM 联系的因素。考克斯回归被用来在分泌物以后在一年以内分析在 ATM 和向之间的协会。结果证明冠的动脉独自绕过 grafting (CABG ) 到 P2Y12 对手的高坚持的有的显著地更低的比例(83.0% 对 90.7% ， P < 0.01 ) 比仅仅与经皮的冠的干预(一种总线标准) 对待的病人。而且在经历一种总线标准的病人，到 P2Y12 对手的高坚持减少了向的风险(危险比率 = 0.172， 95% 信心间隔：0.039-0.763；P = 0.021 ) 。在结论，对待一种总线标准的病人是对比对待 CABG 的病人仍然是支持者到药敏感的更多。到 P2Y12 对手的高坚持与向的更低的风险被联系。

FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction:evidence from an Asian population

The association among plasma trimethylamine-N-oxide(TMAO),FMO3 polymorphisms,and chronic heart failure(CHF)remains to be elucidated.TMAO is a microbiota-dependent metabolite from dietary choline and carnitine.A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction,with the longest follow-up of 7 years.The concentrations of plasma TMAO and its precursors,namely,choline and carnitine,were determined by liquid chromatography-mass spectrometry,and the FMO3 E158K polymorphisms(rs2266782)were genotyped.The top tertile of plasma TMAO was associated with a significant increment in hazard ratio(HR)for the composite outcome of cardiovascular death or heart transplantation(HR=1.47,95%CI=1.13-1.91,P=0.004)compared with the lowest tertile.After adjustments of the potential confounders,higher TMAO could still be used to predict the risk of the primary endpoint(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).This result was also obtained after further adjustment for carnitine(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).The FM03 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort,and lower TMAO levels were found in the AA-genotype.Thus,higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders,and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.