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Importance of improving tissue perfusion during treatment of hypertension. 高血压治疗中改善组织灌注的重要性。
Bernard Lévy

Experimental and clinical studies have established a link between end-organ damage in hypertensive patients and the severe impairment of tissue perfusion and microcirculation structure and function. Microvascular rarefaction is constantly observed in hypertension, and probably contributes to higher systemic resistance and lower tissue perfusion. Endothelial dysfunction leading to impaired arteriolar reactivity is also characteristic of the microvascular dysfunction in hypertensive patients. The effective lowering of blood pressure while maintaining optimal tissue perfusion is therefore one of the major goals of antihypertensive therapy, in order to improve the cardiovascular prognosis of hypertensive patients.

实验和临床研究已经证实了高血压患者终末器官损伤与组织灌注和微循环结构功能严重受损之间的联系。高血压患者经常观察到微血管稀疏,这可能导致更高的全身阻力和更低的组织灌注。内皮功能障碍导致小动脉反应性受损也是高血压患者微血管功能障碍的特征。因此,在保持最佳组织灌注的同时有效降低血压是降压治疗的主要目标之一,以改善高血压患者的心血管预后。
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引用次数: 4
ADVANCE: breaking new ground in type 2 diabetes. 进展:2型糖尿病的新突破。
John Chalmers, Vlado Perkovic, Rohina Joshi, Anushka Patel

Objective and rationale: ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) is a large-scale trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes, and to address a number of unresolved issues: whether blood pressure-lowering therapy and intensive glucose control therapy will reduce the risk of major vascular disease regardless of initial blood pressure or glucose concentration; whether more intensive glucose control targeting a haemoglobin A1c (HbA1c) level of 6.5% or less will confer greater protection against microvascular disease; and whether the benefits of the two interventions are additive.

Design and methods: ADVANCE is a 2 x 2 factorial randomized clinical trial evaluating the risks and benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based glucose control regimen, targeting an HbA1c of 6.5% or less versus standard guidelines based therapy for glucose control. There are two primary outcomes: a composite macrovascular endpoint and a composite microvascular endpoint.

Results: A total of 12 878 participants from 215 centres in 20 countries entered a 6-week run-in phase between June 2001 and January 2003, and 11 140 patients were randomly assigned by March 2003. The average (SD) systolic and diastolic blood pressure fell from 145 (22)/81 (11) to 137 (20)/78 (10) mmHg during the 6-week run-in phase, during which participants received one tablet of open-labelled perindopril 2 mg/indapamide 0.625 mg. Of the 12 878 patients who entered the run-in, only 3.6% withdrew because of suspected intolerance to perindopril/indapamide. The study is half way through follow-up and both the study medications (perindopril 2 mg/indapamide 0.625 mg and gliclazide-MR) continue to be well tolerated. Completion is expected in 2007.

Conclusion: Safe and effective blood pressure lowering with the fixed low-dose combination of perindopril and indapamide was confirmed during the run-in phase in 11 140 patients with type 2 diabetes, who were subsequently randomly assigned. Post-randomization study treatments have been well tolerated, and the completion of follow-up is scheduled in 2007.

目的和理由:ADVANCE(在糖尿病和血管疾病中的作用:preterAx和diamicon - mr对照评估)是一项大型试验,旨在研究2型糖尿病患者降压和强化血糖控制的益处,并解决一些未解决的问题:无论初始血压或血糖浓度如何,降压治疗和强化血糖控制治疗是否会降低主要血管疾病的风险;将糖化血红蛋白(HbA1c)控制在6.5%或更低水平是否能更好地预防微血管疾病;以及这两种干预措施的益处是否具有叠加性。设计和方法:ADVANCE是一项2 × 2因子随机临床试验,评估低剂量培哚普利和吲达帕胺固定联合与安慰剂相比降低血压的风险和益处,以及基于格列齐德mr的强化血糖控制方案,目标HbA1c为6.5%或更低,与基于标准指南的血糖控制治疗相比。有两个主要结局:复合大血管终点和复合微血管终点。结果:从2001年6月到2003年1月,共有来自20个国家215个中心的12878名参与者进入了为期6周的磨合阶段,到2003年3月,随机分配了11140名患者。在为期6周的磨合阶段,平均(SD)收缩压和舒张压从145(22)/81(11)降至137 (20)/78 (10)mmHg,在此期间,参与者接受一片开放标签perindopril 2mg /indapamide 0.625 mg。在12 878名患者中,只有3.6%的患者因疑似对培哚普利/吲达帕胺不耐受而退出试验。该研究已经进行了一半的随访,两种研究药物(培哚普利2mg /吲达帕胺0.625 mg和格列齐特- mr)的耐受性仍然良好。项目预计于2007年完成。结论:在11 140例2型糖尿病患者的磨合期,培哚普利与吲达帕胺固定低剂量联合降压安全有效。随机化后的治疗耐受性良好,随访计划于2007年完成。
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引用次数: 22
Is hypertension a tissue perfusion disorder? Implications for renal and myocardial perfusion. 高血压是组织灌注紊乱吗?对肾脏和心肌灌注的影响。
Jean-Jacques Mourad, Maurice Laville

Structural alterations in the microcirculation form a major link between hypertension and target organ damage. More than 60% of the overall peripheral resistance of the circulatory system arises at the level of the microcirculation. The primary function of the microcirculation is to supply oxygen and nutrients to tissues. In hypertension, remodelling of the microvascular vessels occurs, leading to an early, functional then anatomical reduction in the number of arterioles or capillaries in a given vascular bed. Such changes have been seen in the structure and density of the microvasculature of different target organs such as the myocardium and the kidneys. In hypertension, capillary rarefaction induces an increase in blood pressure, a relative decrease in tissue perfusion and an increased cardiovascular risk. Recent in-vivo non-invasive techniques for exploring the human microcirculation have allowed the detection of myocardial and renal microvascular impairment in hypertensive patients. In comparative therapeutic studies, antihypertensive drugs have been shown to have different capacities for preventing or reversing changes to the microvasculature of affected organs.

微循环结构改变是高血压和靶器官损伤之间的主要联系。循环系统总外周阻力的60%以上产生于微循环水平。微循环的主要功能是为组织提供氧气和营养。在高血压患者中,微血管发生重构,导致给定血管床中小动脉或毛细血管数量的早期、功能性和解剖学上的减少。这种变化在不同靶器官如心肌和肾脏的微血管的结构和密度中已被观察到。在高血压中,毛细血管稀疏导致血压升高、组织灌注相对减少和心血管风险增加。最近的体内无创技术用于探索人体微循环,可以检测高血压患者的心肌和肾脏微血管损伤。在比较治疗研究中,降压药物已被证明在预防或逆转受影响器官微血管变化方面具有不同的能力。
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引用次数: 22
Arteries, inflammation and insulin resistance. 动脉,炎症和胰岛素抵抗。
Jacques Amar, Laurence Perez, Rémi Burcelin, Bernard Chamontin

Inflammation plays a role in all stages of atherosclerosis from the formation to the rupture of the plaque. Guided by inflammatory mediators, monocytes bind to an endothelium damaged by cardiovascular risk factors, and then migrate towards the intima where, after incorporating oxidized low-density lipoprotein particles, they are transformed into foam cells. The lipid streak forms and develops as an atherosclerotic plaque, which is susceptible to erosion and rupture. Inflammation fed by excess adipose tissue decreases insulin sensitivity, which is the central feature of the metabolic syndrome. Inflammation therefore appears to be a common factor of atherosclerosis and the metabolic syndrome. The factors triggering this inflammation have yet to be determined. One line of thought would appear to point to diet.

从斑块形成到破裂,炎症在动脉粥样硬化的各个阶段都起作用。在炎症介质的引导下,单核细胞与被心血管危险因素损伤的内皮结合,然后向内膜迁移,在内膜中加入氧化的低密度脂蛋白颗粒后,它们转化为泡沫细胞。脂质条纹形成并发展为动脉粥样硬化斑块,易发生侵蚀和破裂。过量脂肪组织引起的炎症降低了胰岛素敏感性,这是代谢综合征的主要特征。因此,炎症似乎是动脉粥样硬化和代谢综合征的共同因素。引发这种炎症的因素尚未确定。一种观点似乎指向饮食。
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引用次数: 12
Abstracts of the 16th European Meeting of Hypertension, Madrid, Spain, June 12-15, 2006. 第16届欧洲高血压会议,马德里,西班牙,2006年6月12-15日。
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引用次数: 0
Consequences of elevated pulse pressure on renal function. 脉压升高对肾功能的影响。
Albert Mimran

Peripheral pulse pressure (PP) is a marker of aging-associated arterial stiffening after the fifth decade. In addition, PP has emerged as a strong predictor of cardiovascular morbidity and mortality. A study of the relationship between renal function and aging of the arterial system using reliable methods of estimating renal haemodynamics (effective renal plasma flow) and function (glomerular filtration rate; GFR) was thus undertaken in a large number of never-treated individuals with essential hypertension. In 212 patients with isolated systolic hypertension, there was an inverse correlation between GFR and PP, but the correlation did not persist after adjustment for age. In fact, the deleterious effect of PP on GFR was observed, independent of age and mean arterial pressure, only in patients aged 60 years and over. In contrast, no clear influence of PP on GFR was detected in patients aged 40 years and over but less than 60 years and in those younger than 40 years. It is thus proposed that PP may have a detrimental influence on the age-related decline in GFR. Prospective studies on the influence of antihypertensive agents with possible effects on peripheral and central PP on the progressive decline of GFR are required.

外周脉压(PP)是五十年后与衰老相关的动脉硬化的标志。此外,PP已成为心血管发病率和死亡率的一个强有力的预测因子。用可靠的方法估计肾血流动力学(有效肾血浆流量)和功能(肾小球滤过率;因此,GFR是在大量从未治疗过的原发性高血压患者中进行的。在212例孤立性收缩期高血压患者中,GFR与PP呈负相关,但在调整年龄后相关性不存在。事实上,仅在60岁及以上的患者中观察到PP对GFR的有害影响,与年龄和平均动脉压无关。相比之下,在40岁及以上、60岁以下和40岁以下的患者中,未发现PP对GFR的明显影响。因此,我们提出PP可能对GFR的年龄相关性下降有不利影响。需要对可能影响外周和中枢PP的降压药对GFR进行性下降的影响进行前瞻性研究。
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引用次数: 11
Pulse pressure reduction and cardiovascular protection. 降低脉压,保护心血管。
Stéphane Laurent, Anne-Isabelle Tropeano, Pierre Boutouyrie

Brachial pulse pressure (PP) is now a well-established cardiovascular risk factor. Central rather than peripheral PP should be measured to determine the 'true' haemodynamic effects of antihypertensive agents on target organs. Peripheral PP, measured at the brachial artery, does not reflect central PP (either carotid or ascending aorta), because their determinants are different and pathophysiological conditions and drugs may change central PP without changing peripheral PP. Central PP (i.e. carotid artery or ascending aorta) has shown an independent predictive value for all-cause mortality in patients with end-stage renal disease and in the hypertensive patients of the CAFE study. Antihypertensive treatment has repeatedly demonstrated its ability to prevent cardiovascular events. Whether the effect on cardiovascular events in clinical trials comparing two pharmacological classes or two therapeutic strategies is, at least partly, the result of differential effects on PP remains to be demonstrated. It is therefore of major importance to determine which therapeutic strategies may differentially lower central PP, and in turn reduce cardiovascular events. In clinical practice, lowering PP is often a difficult task, particularly in diabetic hypertensive individuals. In the PARADIS study, we aimed to determine, in a population of hypertensive patients with both type 2 diabetes and PP greater than 60 mmHg, which clinical characteristics predict the fall in PP on treatment and a reduction in cardiovascular events. The reinforcement of therapeutic measures, including a fixed low-dose perindopril/indapamide combination, made possible the effective lowering of PP and cardiovascular events in type 2 diabetic hypertensive patients, under conditions of usual care by general practitioners and specialists.

肱脉压(PP)是目前公认的心血管危险因素。为了确定降压药对靶器官的“真正”血流动力学影响,应该测量中央而不是周围的PP。在肱动脉测量的外周PP不能反映中枢性PP(颈动脉或升主动脉),因为它们的决定因素不同,病理生理条件和药物可能改变中枢性PP而不改变外周PP。中枢性PP(即颈动脉或升主动脉)对终末期肾病患者和高血压患者的全因死亡率具有独立的预测价值。降压治疗已多次证明其预防心血管事件的能力。在比较两种药物类别或两种治疗策略的临床试验中,对心血管事件的影响是否至少部分是对PP的不同影响的结果,仍有待证明。因此,确定哪些治疗策略可能会降低中枢性PP,从而减少心血管事件是非常重要的。在临床实践中,降低PP通常是一项艰巨的任务,特别是在糖尿病高血压患者中。在PARADIS研究中,我们旨在确定,在2型糖尿病和PP大于60 mmHg的高血压患者人群中,哪些临床特征预测治疗后PP的下降和心血管事件的减少。加强治疗措施,包括固定的低剂量培哚普利/吲达帕胺联合治疗,在全科医生和专科医生的常规护理条件下,可以有效降低2型糖尿病高血压患者的PP和心血管事件。
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引用次数: 32
Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials. 高危患者高血压管理:STRATHE和ADVANCE试验的经验教训和前景
Bernard Waeber

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

高血压的药物治疗是预防心血管和肾脏并发症的一种经济有效的方法。为了最大限度地从降压治疗中获益,每位高血压患者的血压应降至140/90 mmHg以下,如果同时存在糖尿病或肾脏疾病,则应降至更低(< 130/80 mmHg)。使用单一疗法通常无法达到这些目标。对于心血管风险高的患者尤其如此。两种作用机制不同的药物联合用药可显著提高血压控制率。这样的组合不仅有效,而且耐受性良好,一些固定的低剂量组合甚至具有类似安慰剂的耐受性。含有血管紧张素转换酶抑制剂培哚普利(2mg)和利尿剂吲达帕胺(0.625 mg)的制剂就是这种情况,这是一种固定的低剂量组合,在对照试验中显示,在减少蛋白尿、缓解心脏肥厚和改善大动脉僵硬方面比单一疗法更有效。一项双盲试验(高血压治疗策略:评价;使血压(< 140/90 mmHg)正常化的患者(62%)明显多于基于阿替洛尔、氯沙坦和氨氯地平的序贯单药治疗方法(49%)和基于缬沙坦和氢氯噻嗪的分步治疗策略(47%),三个组在耐受性方面没有差异。一项正在进行的随机试验(糖尿病和血管疾病的作用:Preterax和Diamicron修饰的释放控制评价;ADVANCE)是一项2 × 2因子设计的研究,评估了固定剂量培哚普利-吲达帕胺联合治疗和强化格列齐特改良释放型血糖控制方案对伴有或不伴有高血压的2型糖尿病患者的影响。随机抽取11 140例患者。在治疗的前6周(磨合期),perindopril-indapamide联合用药将血压从145/81 +/- 22/11 mmHg(平均+/- SD)降至137/78 +/- 20/10 mmHg。固定剂量联合用药在高血压治疗中越来越受欢迎,甚至被高血压指南列为治疗高血压患者的一线选择。
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引用次数: 11
Renal protection in diabetic patients: benefits of a first-line combination of perindopril-indapamide (Preterax). 糖尿病患者的肾脏保护:perindopril-indapamide (Preterax)一线联合治疗的益处
Luis M Ruilope, Julian Segura

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.

2型糖尿病(T2DM)通常伴有高血压(BP)和几种心血管危险因素的聚集,是终末期肾脏疾病的最常见原因。T2DM患者显性肾病的发展阶段从最初的肾功能改变(GFR升高),随后发展为微量白蛋白尿和大量白蛋白尿或蛋白尿,以确定的糖尿病肾病为特征,最终发展为终末期肾病。预防糖尿病肾病的发展需要早期干预,需要有效控制不同的危险因素,特别是高血压。在疾病的初期,严格控制血压对于防止肾脏和血管损害的发展至关重要。在T2DM患者中,适当的血压控制尤其困难,在大多数情况下需要使用联合治疗。Preterax是一种perindopril 2 mg和indapamide 0.625 mg的固定剂量组合,与传统策略相比,可以显著降低BP;当需要进一步控制血压时,可以将该组合升级为BiPreterax。在为期12个月的T2DM PREMIER研究中,与依那普利单药治疗相比,培哚普利/吲达帕胺联合治疗除了能很好地控制血压外,还能显著减少尿白蛋白排泄。对于更严重程度的肾损害,必须考虑更高剂量的固定组合。培哚普利/吲达帕胺的肾保护作用的药理学基础是,该组合可以独立于血压控制,预防肥胖Zucker大鼠的肾病和蛋白尿。从肾病初期开始严格控制血压,同时抑制肾素-血管紧张素系统,是预防蛋白尿的必要措施。培哚普利/吲达帕胺的固定联合用药,在肾病早期使用Preterax,在肾病晚期使用BiPreterax,可以极大地帮助临床医生实现上述目标。
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引用次数: 0
Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? 内皮功能障碍:如何在心血管连续体开始时进行干预?
Roland E Schmieder

Endothelial dysfunction, characterized by impaired nitric oxide activity, constitutes an early step in the pathogenesis of atherosclerotic disease. Prospective studies have shown that impaired endothelium-dependent vasorelaxation and the vasodilatory response of coronary arteries to acetylcholine predict cardiovascular events. Microalbuminuria and estimated glomerular filtration rate, which are both deeply influenced by renal nitric oxide activity, are predictors of cardiovascular outcome and total mortality but develop at a later stage of renal impairment. Endothelial dysfunction reflects early stage renal involvement in the atherosclerotic processes. The Telmisartan versus Ramipril in renal ENdothelium DYsfunction (TRENDY) trial examined endothelial function of the renal vasculature as a therapeutic target in patients with hypertension and type 2 diabetes, but without albuminuria. The rationale was that blockade of the renin-angiotensin system (RAS) is cardio- and renoprotective at later stages of the disease, but the impact of blockade of the RAS at earlier stages of disease is unknown. The results of TRENDY indicate that the endothelial function, as assessed by basal nitric oxide activity, can be improved after RAS blockade. These data complement the results of the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, which demonstrated that telmisartan and enalapril similarly decelerate the progression of overt diabetic nephropathy. The results of TRENDY are in accordance with the observed changes in peripheral circulation. Endothelium-dependent vasorelaxation could be improved with angiotensin II receptor blockers, but not with diuretics or beta-blockers, in hypertensive patients. Intervention at the beginning of the renal and cardiovascular continuum offers the opportunity to prevent the fatal development towards renal and cardiac failure.

以一氧化氮活性受损为特征的内皮功能障碍是动脉粥样硬化疾病发病机制的早期步骤。前瞻性研究表明,内皮依赖性血管松弛受损和冠状动脉对乙酰胆碱的血管舒张反应可预测心血管事件。微量白蛋白尿和估计的肾小球滤过率都深受肾脏一氧化氮活性的影响,它们是心血管结局和总死亡率的预测因子,但在肾脏损害的后期才会出现。内皮功能障碍反映了动脉粥样硬化过程中早期肾脏受累。替米沙坦与雷米普利治疗肾内皮功能障碍(赫基)试验检测了肾血管内皮功能作为高血压和2型糖尿病患者的治疗靶点,但没有蛋白尿。其基本原理是,阻断肾素-血管紧张素系统(RAS)在疾病晚期对心脏和肾脏有保护作用,但在疾病早期阻断RAS的影响尚不清楚。新潮的结果表明,以基础一氧化氮活性评估的内皮功能可以在RAS阻断后得到改善。这些数据补充了替米沙坦和依那普利(DETAIL)试验的结果,该试验表明,替米沙坦和依那普利类似地减缓了显性糖尿病肾病的进展。新潮的结果与观察到的外周循环变化一致。血管紧张素受体阻滞剂可以改善高血压患者的内皮依赖性血管松弛,但利尿剂或受体阻滞剂不能改善。在肾脏和心血管连续体的开始进行干预提供了机会,以防止肾和心力衰竭的致命发展。
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引用次数: 42
期刊
Journal of hypertension. Supplement : official journal of the International Society of Hypertension
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