Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography

Background

Elevated plasma level of asymmetric dimethylarginine (ADMA) was reported to be associated with endothelial dysfunction and atherosclerotic risk factors. We assessed the prognostic value of plasma ADMA levels in 997 consecutive individuals referred for coronary angiography from July 2006 to June 2009.

Methods

ADMA was measured by high performance liquid chromatography. All subjects were followed for a median period of 2.4 years for the occurrence of all-cause mortality, major adverse cardiovascular events (MACE, defined as cardiovascular death, non-fatal myocardial infarction and stroke), and MACE plus clinically-driven target vessel revascularization (TVR).

Results

Plasma ADMA levels were significantly higher in patients with significant coronary artery disease (CAD) (≥ 50% stenosis, n = 655) than those with insignificant CAD (20-50% stenosis, n = 272) and normal coronary artery (< 20% stenosis, n = 70) (0.47 ± 0.10 μmol/l vs 0.44 ± 0.10 μmol/l vs 0.42 ± 0.08 μmol/l, p < 0.001). By multivariate analysis, plasma ADMA level was identified as a significant independent risk factor of significant CAD (OR: 1.29, 95% CI: 1.10−1.50; p = 0.002). Moreover, multivariate Cox regression analysis showed that, comparing with the ADMA tertile I, the highest ADMA tertile was a significant independent predictor for all adverse long-term clinical outcomes. Notably, plasma ADMA level remained associated with the long-term outcomes in non-diabetic individuals, but not in those with diabetes (interaction p = 0.04 for MACE plus TVR).

Conclusions

Our findings suggest that elevated plasma ADMA level might be a risk factor of significant CAD, and might predict worse long-term clinical outcomes in subjects referred for cardiac catheterization, especially in non-diabetic individuals.     

Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events.

AIMS: We investigated the role of asymmetric dimethylarginine (ADMA) for clinical outcome of patients with unstable angina. METHODS AND RESULTS: Forty-five patients with stable angina, 36 patients with unstable angina, and 40 healthy controls were included in this study. Coronary artery disease (CAD) patients were prospectively followed for 1 year. ADMA levels were measured at baseline and after 6 weeks using a validated ELISA. Baseline ADMA concentration in controls was significantly lower than in patients with CAD (0.59+/-0.23 vs. 0.76+/-0.17 micromol/L; P<0.001). Patients with unstable angina had significantly higher baseline ADMA levels than patients with stable angina (0.82+/-0.18 vs. 0.73+/-0.15 micromol/L; P=0.01). There was a significant reduction of ADMA levels at 6 weeks after percutaneous coronary intervention (PCI) in patients with unstable angina who experienced no recurrent cardiovascular event (from 0.81+/-0.14 to 0.73+/-0.19 micromol/L; P<0.05). In contrast, patients with unstable angina who had an event showed no significant decrease in ADMA at 6 weeks. Actuarial survival analysis showed a significantly higher event rate in patients with persistently elevated ADMA plasma concentrations. CONCLUSION: ADMA is significantly elevated in patients with unstable angina. A reduced ADMA level at 6 weeks after PCI may indicate a decreased risk of recurrent cardiovascular events.     

不对称二甲基精氨酸对体外培养内皮祖细胞数量和功能的影响

目的:观察不对称二甲基精氨酸(ADMA)对体外培养内皮祖细胞(EPCs)数量和功能的影响。方法:密度梯度离心法获取外周血单个核细胞,培养6d后,收集贴壁细胞并分别加入ADMA1、5、10μmol/L干预培养72h。激光共聚焦显微镜和流式细胞仪鉴定EPCs,分别观察EPCs的数量、增殖及黏附和产生一氧化氮的能力。结果:与对照组相比,不同浓度的ADMA可显著抑制外周血EPCs扩增、黏附增殖能力和产生NO的能力。结论:ADMA可抑制培养EPCs的数量和功能。     

Haemoglobin-related mortality in patients undergoing percutaneous coronary interventions.

AIMS: It has recently been proposed that anaemia is an independent risk factor for development of cardiovascular disease in the general population. The impact of anaemia on long-term survival of patients with manifest coronary heart disease (CHD) has not been assessed so far. In this study, we examined the influence of haemoglobin concentrations on the outcome after percutaneous coronary interventions (PCI). METHODS AND RESULTS: In a retrospective cohort study, we analysed in-hospital and long-term mortality in all male patients admitted to our institution for elective PCI from 1998 to 1999. In 689 cases, complete follow-up information could be obtained (98.4%). Depending on their baseline haemoglobin, patients were divided in quintiles. In all subgroups, angiographic success after PCI (90-94%) was comparably high and in-hospital mortality was low (0-0.7%). During follow-up (median 697 days), patients in the lowest haemoglobin quintile (相似文献   

中性粒细胞/淋巴细胞比值与急性心肌梗死患者行急诊经皮冠状动脉介入治疗术后对比剂肾病发生的相关性

目的 探讨中性粒细胞/淋巴细胞比值（neutrophil/lymphocyte ratio,NLR）与急性ST段抬高心肌梗死（STEMI）患者行急诊经皮冠状动脉介入治疗（PCI）术后发生对比剂肾病（contrastinduced nephropathy,CIN）的相关性.方法 入选500例行急诊PCI的患者,CIN定义为使用对比剂后48～72 h内血肌酸酐（肌酐）值较基线值升高超过44.2 μmol/L或者较原基础值升高25％以上.比较CIN组与非CIN组之间的基线资料及院内不良临床事件发生率.采用受试者工作特征（ROC）曲线及Logistics回归分析评估NLR与CIN风险的相关性.结果 500例患者中,85例（17％）患者发生CIN.CIN组在院内死亡、需要肾脏替代治疗、需使用主动脉内球囊反搏、围术期低血压、急性心力衰竭、新发心律失常等院内不良事件的发生率均较非CIN组明显升高,差异有统计学意义.ROC曲线显示：NLR界值为6.03时,其预测CIN的敏感度为80.1％,特异度为73.7％,曲线下面积0.764.单因素Logistics回归分析显示,NLR水平与CIN发病率明显相关（OR 1.2,95％ CI 1.1～1.3,P＜ 0,01）.多因素Logistic回归分析显示,NLR＞6.03是CIN的独立危险因素（OR 1.3,95％ CI1.2～1.3,P＜0.001）;此外,女性、基础肾功能不全及围术期低血压也是CIN的独立危险因素（P＜0.05）.结论 急性STEMI患者行急诊PCI术前NLR水平与CIN相关,NLR升高的患者发生CIN的风险明显增高.     

CYP2C19 genotype-directed P2Y12 inhibitor antiplatelet therapy normalizes risk for major adverse cardiovascular events after percutaneous coronary intervention

ObjectiveTo study the use of CYP2C19 genotyping to guide P2Y₁₂ inhibitor selection to maximize efficacy, and attenuate risk in appropriate patients who underwent PCI for CAD.MethodsWe performed a retrospective analysis of 868 patients with CAD who received CYP2C19 genotyping after PCI and changed P2Y₁₂ inhibitor based on the results. Patients were divided into two groups based on clopidogrel metabolizer status. Group I: Intermediate (IM) and poor metabolizers (PM). Group II: Ultra-rapid (UM), rapid (RM) and normal metabolizers (NM). Each group was then categorized to one of two treatment arms guided by CYP2C19 genotype. Category 1: IM/PM started on clopidogrel, switched to ticagrelor or prasugrel; 2:IM/PM started on ticagrelor/prasugrel, continued these medications; 3: UM/RM/NM started on ticagrelor/prasugrel, switched to clopidogrel; 4: UM/RM/NM started on clopidogrel, continued clopidogrel. Death due to cardiac causes, bleeding events, non-fatal MI, target vessel revascularization (TVR), and MACE in all four categories were considered at 1, 6 and 12 months.ResultsWe did not observe significant difference between phenotypes for MACE at 1 (p = 0.274), 6 (p = 0.387), and 12 months (p = 0.083). Death due to cardiac causes, MI, and bleeding events were not significant at 1, 6, and 12 months. There was no significant difference in TVR at 6 (p = 0.491), and 12 months (p = 0.423) except at 1 month (p = 0.012).ConclusionCYP2C19 genotype-based intervention can be implemented effectively and reliably to guide selection of P2Y₁₂ inhibitor to optimize patient quality and safety when appropriate in post PCI patients.     

非对称性二甲基精氨酸和胱氨酸蛋白酶抑制剂C与冠心病

目的 探讨冠状动脉疾病中血浆非对称性二甲基精氨酸(ADMA)与胱氨酸蛋白酶抑制剂C(Cystatin C)之间的关系.方法 选取冠心病患者87例(其中急性心肌梗死39例,不稳定性心绞痛48例),健康对照组51例;同时,依据Cystatin C水平将冠心病患者分为Cystatin C升高组(51例)与无Cystatin C升高组(36例),采用高效液相色谱法测定血浆中ADMA、对称性二甲基精氨酸(SDMA)、左旋精氨酸(L-Arg)的含量,采用德国BNProSpec全自动速率散色比浊仪测定血浆Cystatin C的含量.结果 冠心病患者血浆ADMA[(0.47±0.15)μmol/L比(0.37±0.15)μmol/L]、SDMA[(0.39±0.19)μmol/L比(0.28±0.12)μmol/L]和Cystatin C浓度[(1.16±0.32)mg/L比(0.73±0.16)mg/L]均高于正常对照组(P均<0.05),L-Arg浓度低于正常对照组[(59.4±19.4)μmol/L比(83.7±19.6)μmol/L,P<0.05];对冠心病组的亚组分析显示血浆ADMA、L-Arg和Cystatin C浓度在心肌梗死组较心绞痛组差异无统计学意义.在Cystatin C<1 mg/L的冠心病患者中血浆ADMA与正常对照组比较,差异无统计学意义;而在Cystatin C>1 mg/L的冠心病患者血浆ADMA高于正常对照组[(0.50±0.17)μmol/L比(0.39±0.15)μmol/L,P<0.05].结论 只有在血浆Cystatin C水平升高的冠心病患者血浆ADMA水平才明显升高,提示冠心病患者血浆ADMA水平的升高并不与冠心病直接相关,可能与冠心病患者伴随轻微肾损害有关.     

Plasma fibrinogen levels and restenosis after primary percutaneous coronary intervention

Plasma fibrinogen levels influence restenosis following elective percutaneous coronary intervention (PCI) for stable angina. It is unknown whether the same is true in the setting of primary PCI. The aim of the study was therefore to assess whether fibrinogen levels were associated to 6-month in-stent restenosis (ISR) in STEMI patients undergoing successful primary PCI. From January 2003 to October 2004, 267 patients were admitted to our Institution for STEMI and treated by primary PCI. Of these, 171 patients met the inclusion criteria and were enrolled in our study. Fibrinogen levels were assessed at admission, 12 h, 24 h, 48 h, 72 h following PCI and at discharge. Six-month angiographic follow-up was 100% complete. Subjects with 6-month ISR showed higher fibrinogen levels than patients without ISR. Patients in the upper fibrinogen tertile showed a higher 6-month incidence of symptoms and/or inducible myocardial ischemia (27.1% vs. 7.1%, P = 0.006) and a larger late lumen loss (1.3 ± 0.8 vs. 1.0 ± 0.9 mm, P = 0.049). Logistic regression analysis demonstrated a significant and independent association between fibrinogen levels and ISR. Our study suggests that increased plasma fibrinogen levels are related to ISR in STEMI patients undergoing primary PCI. Larger studies are warranted to assess the prognostic value of fibrinogen over harder end-points.     

Relation of asymmetrical dimethylarginine levels with renal outcomes in hypertensive patients with and without type 2 diabetes mellitus

Aim

The aim of the study was to evaluate the association between high plasma ADMA levels, a biomarker of endothelial dysfunction, with the progression of albuminuria and chronic kidney disease (CKD) in hypertensive patients, with and without type 2 diabetes mellitus.

内脏脂肪素与冠心病的相关性及PCI术后变化

目的探讨内脏脂肪素与冠心病的相关性及 PCI 术后变化的意义。方法:90 例冠心病患者分为急性心肌梗死组 30 例、不稳定心绞痛组 30 例、稳定心绞痛组 30 例,均行冠脉造影确诊,其中 52 例患者行 PCI术。另选正常对照组 30 例 . 用酶联免疫法检测各组及PCI 术后血浆内脏脂肪素(visfatin)水平,于生化室检测肝功、肾功、血糖、血脂、高敏 C 反应蛋白(hs-CRP), 对行 PCI 术患者记录病变支数,植入支架个数及长度,最大球囊扩张压力,术后 TIMI 血流分级。结果:冠心病组 visfatin 和 hs-CRP 高于对照组,且 AMI 组和UAP 组较 SAP 组升高更明显,各组间有显著性差异(p<0.05), 冠心病组 visfatin 与 hs-CRP 水平的独立相关 (p<0.001), PCI 术后 visfatin 水平高于术前(p<0.01),且与最长支架长度和植入支架个数相关(p<0.05)。结论:血浆 visfatin 的水平反应斑块的不稳定程度,其参与冠脉硬化发生发展的过程,另外 PCI 术后 visfatin 较术前升高,可能参与术后再狭窄。     

芪参益气滴丸对冠状动脉介入术后炎症因子及心脏不良事件的影响

目的 观察芪参益气滴丸对急性冠脉综合征（ACS）患者经皮冠状动脉介入术（PCI）后炎症因子及主要不良心脏事件（MACE,包括复发心绞痛、急性心肌梗死、严重心律失常、心力衰竭、冠心病死亡）影响.方法纳入60例行PCI的ACS患者,随机分为常规治疗组（n=30）和芪参益气滴丸联合常规治疗组（芪参组,n=30）,采用酶联反应吸附法（ELISA法）比较两组术后24h和术后6个月血清高敏C反应蛋白（hs-CRP）、可溶性CD40配体（sCD40L）及基质金属蛋白酶-9（MMP-9）水平变化,并比较两组6个月MACE事件发生率.结果术后24h两组血清hs-CRP、sCD40L和MMP-9水平均无统计学差异（P＞0.05）;6个月后,两组hs-CRP、sCD40L和MMP-9水平分别是3.18±0.71mg/l、5.86±2.01 ng/dl和240.56±60.6 ng/dl.与对照组相比,芪参组血清hs-CRP、sCD40L及MMP-9均明显降低,差异有统计学意义（P＜0.05）,随访6个月,芪参组MACE发生率较对照组更低（13.33% vs.26.67%,P＜0.05）,且差异有统计学意义.结论 芪参益气滴丸可降低介入术后炎症因子hs-CRP、SCD40L和MMP-9的水平,同时降低MACE近期发生率.     

Effect of insurance type on adverse cardiac events after percutaneous coronary intervention

Previous studies have documented disparities in both access to invasive cardiovascular procedures and outcomes in patients with Medicaid, Medicare, or no insurance. Outcomes by insurance have yet not been examined in a percutaneous coronary intervention (PCI) population. Data from patients undergoing PCI from June 2000 to June 2009 were retrospectively analyzed. Insurance was categorized as private, Medicare, Medicaid, and uninsured, according to the primary insurance at discharge. The outcome variable of interest was major adverse cardiac events (a composite of death, Q-wave myocardial infarction, and target vessel revascularization) at 1 year. Multivariable Cox regression analysis was stratified according to age <65 and ≥65 years. Of the 13,573 patients who had undergone PCI, 6,653 (49.0%) had private insurance, 6,150 (45.3%) had Medicare, 486 (3.6%) had Medicaid, and 284 (2.1%) were uninsured. Of the patients <65 years old, Medicaid (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.04 to 2.43), Medicare (HR 2.18, 95% CI 1.58 to 2.99), and no insurance (HR 2.41, 95% CI 1.36 to 4.27) were associated with greater rates of adjusted major adverse cardiac events at 1 year compared with private insurance. Of the patients ≥65 years old, only Medicaid (HR 3.07, 95% CI 1.09 to 8.61) was associated with a greater rate of adjusted major adverse cardiac events at 1 year. In conclusion, patients with government-sponsored insurance and no insurance have worse cardiovascular outcomes than patients with private insurance after PCI at 1 year. This implies that the provision of health insurance alone might not have a dramatic effect on cardiovascular outcomes after PCI.     

Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes.

AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). METHODS AND RESULTS: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017). CONCLUSIONS: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.     

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease

In recent years an important role has been ascribed to a reduced nitric oxide (NO) availability in the pathophysiology of sickle cell disease (SCD). Endogenously produced inhibitors of NO synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various vascular disease states characterized by reduced NO availability. We determined ADMA levels in plasma of 12 adult sickle cell patients (eight HbSS and four HbSC), and compared these to plasma levels in race- and age-matched controls. Sickle cell patients were characterized by strongly elevated levels of ADMA [HbSS: median 0.63 mol/l (interquartile range 0.54–0.85), HbSC: 0.43 mol/l (0.40–0.46), HbAA: 0.33 mol/l (0.32–0.35) p<0.001]. ADMA levels were highest in HbSS patients with lowest hemoglobin levels and highest leukocyte counts, and in HbSS patients ADMA levels were positively associated with serum levels of soluble vascular cell adhesion molecule-1. These results suggest an important role of ADMA in limiting NO availability in SCD, and its role in the pathophysiology of SCD should be further investigated.This article was written on behalf of the CURAMA study group.The CURAMA study group is a collaborative effort studying sickle cell disease in the Netherlands and the Netherlands Antilles. Participating centers: the Department of Internal Medicine, Slotervaart Hospital, Amsterdam, the Netherlands; the Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; the Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands; the Department of Pathology, Groningen University Hospital, the Netherlands; the Department of Internal Medicine, the Laboratory of Clinical Thrombosis and Hemostasis and the Cardiovascular Research Institute, Academic Hospital Maastricht, the Netherlands; the Red Cross Blood Bank Foundation, Curaçao, Netherlands Antilles; the Antillean Institute for Health Research, Curaçao, Netherlands Antilles     

Relationship of serum adiponectin level to adverse cardiovascular events in patients who undergo percutaneous coronary intervention.

BACKGROUND: Hypoadiponectinemia has been reported to indicate an increased risk of cardiovascular disease, so the present study investigated the significance of serum adiponectin (APN) levels for predicting clinical outcomes after percutaneous coronary intervention (PCI). METHODS AND RESULTS: The APN levels were evaluated in 184 consecutive patients who underwent PCI. The patients were divided into Group A [the lowest quartile of APN levels (APN < or =4.5 microg/ml), n=46] and Group B [the upper 3 quartiles of APN levels (APN >4.5 microg/ml), n=138]. During a mean follow-up period of 27.3 months, the rate of major adverse cardiac and cerebrovascular events (MACCE: death from any cause, re-infarction, repeat coronary revascularization, hospitalization because of congestive heart failure, and cerebral infarction) was higher in Group A (58.7%) than in Group B (37.0%, p=0.0101). Moreover, when the APN levels were calculated by adjusting for sex, age, body mass index, and triglyceride levels, patients in the lowest quartile of residual APN levels had a higher risk of MACCE (p=0.0405). Multiple logistic analyses showed that hypoadiponectinemia (APN < or =4.5 microg/ml) was independently correlated with MACCE. Kaplan-Meier analysis demonstrated a higher MACCE rate in Group A than in Group B (Log-rank chi(2)=7.89, p=0.0050). CONCLUSION: The APN level may be helpful for predicting clinical outcomes after PCI.     

Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis

AIM To evaluate the effects of asymmetric dimethylarginine(ADMA) in renal arteries from portal hypertensive and cirrhotic rats.METHODS Rat renal arteries from Sham(n = 15), pre-hepatic portal hypertension(PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis(BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA(10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide(NO) synthase. Concentration-response curves to acetylcholine(1 × 10-9~(-3) × 10~(-6) mol/L) were determined in precontractedrenal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase(DDAH), an enzyme that catabolizes ADMA. RESULTS In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD 2 values to ADMA were similar in the Sham and PPVL groups(4.20 ± 0.08 and 4.11 ± 0.09, P 0.05, respectively), but were lower than those of the BDL group(4.79 ± 0.16, P 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of p D2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA(3 × 10~(-4) mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher(P 0.05) in the BDL group compared with that for the Sham and PPVL groups. The m RNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased(P 0.05) in PPVL and further enhanced(P 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group. CONCLUSION Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.