Arterial stiffness and wave reflection: Biomarkers of cardiovascular risk

Arterial stiffness and excessive pressure pulsatility have emerged as important risk factors for cardiovascular disease. Arterial stiffness increases with age and in the presence of traditional cardiovascular disease risk factors, such as hypertension, diabetes and lipid disorders. Pathologic stiffening of large arteries with advancing age and risk factor exposure predominantly involves the elastic aorta and carotid arteries, whereas stiffness changes are relatively limited in muscular arteries. Aortic stiffening is associated with increased pulse wave velocity and pulse pressure, which are related but distinct measures of the pulsatile energy content of the pressure waveform. A dramatic increase in pulsatile energy content of pressure and flow waves in the arterial system places considerable pulsatile stress on the heart, large arteries and distal circulation. Large artery stiffening is associated with abnormalities in microvascular structure and function that may contribute to tissue damage, particularly in susceptible high flow organs such as the brain and kidneys. This brief review summarizes results of recent research on risk factors for and adverse effects of large artery stiffening.     

Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions.

AIMS: Increased arterial wave reflections are associated with the presence and extent of coronary atherosclerosis and with cardiovascular mortality in selected populations. We prospectively evaluated their prognostic value in the short- and long-term following percutaneous coronary interventions (PCIs). METHODS AND RESULTS: We non-invasively quantified wave reflections [expressed as augmentation index corrected for heart rate of 75 b.p.m. (AIx@75)] using applanation tonometry of the radial artery and a validated transfer function to obtain the corresponding aortic values in 262 patients undergoing PCI. During 2-year follow-up, 61 patients reached the primary endpoint [death, myocardial infarction (MI), and restenosis]. Increasing tertiles of Alx@75 were related to the rate of patients reaching the primary endpoint [15.2, 20 and 35.3%, respectively (P = 0.001)], as well as the secondary endpoints total mortality, myocardial infarction and death plus myocardial infarction (RR for the third vs. the first tertile 4.33, 3.25 and 3.46, respectively, P < 0.05). In a multivariable Cox-regression model, AIx@75 added prognostic value above and beyond clinical risk factors, angiographic variables, and medications (RR 1.8, 95%CI 1.18-2.76 per increasing AIx@75-tertile, P < 0.01). CONCLUSION: Increased arterial wave reflections are independently associated with an increased risk for severe short- and long-term cardiovascular events in patients undergoing PCI.     

大内皮素-1和动脉僵硬度在冠心病患者中的关系研究

目的 探讨冠心病患者大内皮素-1（big ET-1）与颈股动脉脉搏波传导速度（cf-PWV）的关系.方法 纳入95例冠心病患者,检测其大内皮素-1、颈股动脉脉搏波传导速度、血压、超敏C反应蛋白（hs-CRP）等指标.应用多因素回归方法分析大内皮素-1与颈股动脉脉搏波传导速度的关系.结果 在单因素分析中,血浆大内皮素-1水平与年龄、血压（收缩压、舒张压、平均动脉压和脉压差）、超敏C反应蛋白、腰围、空腹血糖、血尿素氮和低密度脂蛋白水平呈正相关.在单因素分析中,大内皮素-1与颈股动脉脉搏波传导速度没有显著的统计学关系（r=0.014,P＞0.05）;在多因素分析中,血浆大内皮素-1水平与颈股动脉脉搏波传导速度也没有显著的统计学关系（P＞0.05）.结论 本研究没有发现冠心病患者大内皮素-1与动脉僵硬度之间有着独立的显著性相关性,提示内皮素系统可能不是冠心病患者动脉僵硬度升高的重要因素.     

Blood pressure variability and arterial stiffness

Blood pressure variability (BPV) is defined by the standard deviation of a given sample of population of normotensive or hypertensive subjects. Recent studies have suggested that this parameter might constitute a cardiovascular risk factor. Reduction of blood pressure variability could be an important purpose of anti-hypertensive treatment, as suggested from experimental studies. In a double-blind controlled investigation, the thiazide compound indapamide was compared to placebo, to the angiotensin blocker candesartan and to the calcium-entry blocker amlodipine for 12 weeks treatment. The 3 drugs reduced significantly and identically blood pressure. Only indapamide and amlodipine reduced significantly BPV. This study was the first to demonstrate the interest of BPV in the setting of a double-blind, placebo controlled, trial.     

Inflammatory status, arterial stiffness and central hemodynamics in hypertensive patients with metabolic syndrome

Introduction

Inflammatory state is activated in metabolic syndrome and may explain part of the adverse prognosis of this entity. Arterial stiffness, central blood pressures and wave reflections are independent predictors of cardiovascular risk. This study investigates the relation between low-grade inflammation and arterial stiffness and central hemodynamics in patients with metabolic syndrome.

Methods

We studied 106 consecutive hypertensive patients with metabolic syndrome. Arterial stiffness was assessed by carotid-femoral (c-f) and carotid-radial (c-r) pulse wave velocity (PWV). Central blood pressures were evaluated by pulse wave analysis and heart rate corrected augmentation index (AIx₇₅) was used as a measure of wave reflections. White blood cell count (WBC), high sensitivity C-reactive protein (hsCRP) and fibrinogen were measured as inflammatory markers.

Results

In univariable analysis, PWVc-f correlated with both hsCRP (p < 0.01) and fibrinogen (p < 0.01), while PWVc-r correlated with hsCRP (p = 0.05). Regarding central blood pressures, aortic SBP correlated positively with hsCRP (p < 0.05) and marginally with fibrinogen (p = 0.06) and WBC (p = 0.08). Interestingly, no correlation was found between AIx₇₅ and any of these biomarkers. After adjustment for age, gender, smoking, mean arterial pressure, heart rate, waist circumference, glucose, total and HDL cholesterol, PWVc-f was independently related to hsCRP (p < 0.001) and fibrinogen (p < 0.01), while a marginal independent correlation was also found between PWVc-r and hsCRP (p = 0.06). Furthermore, aortic PP independently associated with fibrinogen (p < 0.05) whereas marginal associations demonstrated between aortic SBP and hsCRP and fibrinogen (p = 0.06 for both).

Conclusion

Inflammatory status is related to arterial stiffness and central blood pressures (but not to augmentation index) in hypertensives with metabolic syndrome. These findings may have implications for increased cardiovascular risk in these patients.     

维持性血液透析患者大动脉弹性的变化及临床意义

目的探讨维持性血液透析(MHD)患者大动脉弹性功能的改变及其影响因素。方法应用脉搏波速度(PWV)自动测量系统分别对96例MHD患者和28名健康人进行大动脉PWV测量,并行生化指标检测,记录一般状况,进行相关分析。结果 MHD患者的大动脉PWV显著高于健康人[(13.96±1.68)m/s比(10.12±1.48)m/s,P<0.01]。MHD患者的PWV与年龄(r=0.797)、收缩压(r=0.642)、脉压(r=0.627)、血肌酐(r=0.788)、血尿酸(r=0.763)、血糖(r=0.760)均呈正相关(均为P<0.05);MHD患者的PWV与体质指数、舒张压、血红蛋白、血浆白蛋白、TC、TG、HDL-C、LDL-C、血钙、血磷水平无相关性。多元逐步回归分析结果显示,PWV与年龄(B=0.031)、血肌酐(B=0.007)、收缩压(B=0.004)密切相关(均为P<0.05)。结论 MHD患者大动脉弹性减低,其PWV值与血肌酐相关。     

血压、脉压水平及高血压病程对高血压患者动脉僵硬度的影响

目的探讨血压、脉压水平及高血压病程对高血压患者动脉僵硬度的影响。方法从上海市宝山区6家社区卫生中心及本院入选1026例高血压患者,收集相关病史信息,检测其颈-股动脉(C-F)、颈-桡动脉(C-R)、颈-足背动脉(C-D)脉搏波传导速度(PWV),672例患者在随访1年后复测PWV。从血压、脉压、高血压病程3者的不同水平进行分组比较及随访前后对照分析。结果 (1)1、2、3级高血压患者的C-FPWV随血压水平的增高而增快,分别为(12.61±2.76)m/s,(14.35±3.41)m/s,(15.50±2.93)m/s(均为P<0.01)。1级高血压组较2级、3级高血压组C-FPWV差异有统计学意义(均为P<0.01)。(2)随访前后C-FPWV在1级和2级高血压组分别为(12.73±2.91)m/s和(13.39±3.25)m/s,(13.96±3.07)m/s和(14.75±4.10)m/s,差异有统计学意义,而在3级高血压组差异无统计学意义。(3)脉压<40 mm Hg,40～60 mm Hg,≥60 mm Hg 3组C-FPWV随脉压的增大而增快,分别为(11.95±2.60)m/s,(12.94±2.85)m/s,(14.89±3.22)m/s(均为P<0.01)。随访1年后3组的C-FPWV分别较前增快0.70 m/s,0.65 m/s,0.85 m/s,差异均有统计学意义。(4)高血压病程<5年、5～10年、≥10年3组C-FPWV分别为(12.77±2.75)m/s,(12.85±3.07)m/s,(13.76±3.05)m/s,3组比较差异有统计学意义(均为P<0.01),病程越长,C-FPWV越快。结论(1)C-FPWV较C-RPWV、C-DPWV更能反映动脉僵硬度的变化。(2)C-FPWV随血压、脉压水平的增高及高血压病程的延长而增快,3者均为动脉僵硬度的重要影响因素。     

Combination therapy in hypertension: From effect on arterial stiffness and central haemodynamics to cardiovascular benefits

Measures of arterial aging have the potential to improve risk prediction beyond traditional risk scores. Such biomarkers that fulfil most, or some of the strict criteria of a surrogate end-point are aortic stiffness (IIa level of recommendation in European Guidelines and Position Papers) and central haemodynamics (IIb level of recommendation). Early intervention towards improving aortic elastic properties acquires particular importance since evidence suggests that arterial stiffening may occur before the onset of hypertension. Part of the beneficial effects of antihypertensive treatment in risk reduction may be mediated through improvement in aortic stiffness and central haemodynamics. However, not all antihypertensive drugs affect aortic stiffness and central haemodynamics in a similar way. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) have beneficial effects on such parameters. Meta-analytical approaches have shown that ACE inhibitors reduce mortality in hypertension, whereas ARBs do not exhibit such a benefit. Furthermore, ACE inhibitors have been shown to reduce the risk of coronary artery disease, and CCBs to reduce the risk of stroke independently of blood pressure reduction. Combining an ACE inhibitor with a CCB has the potential to reduce cardiovascular risk (synergy at the clinical level) by reducing aortic stiffness and improving central haemodynamics (synergy at the vascular level).     

Limitations and pitfalls of non-invasive measurement of arterial pressure wave reflections and pulse wave velocity

In this paper, we briefly revise some of the most widely applied methods to non-invasively assess pressure wave reflection (augmentation index) and arterial stiffness (pulse wave velocity; PWV) in clinical vascular research. It is clear that the pressure waveform alone provides insufficient information to accurately quantify the magnitude of pressure wave reflection or to even fully interpret its nature. A major difficulty arises from the identification of timing of return of the reflected pressure wave, the “fiducial” point, and incorrect assessment of this point has an effect on all of the derived parameters. From our studies, it also follows that the use of an approximated flow waveform has little or no added value to assess magnitude of wave reflection. As for PWV, carotid–femoral pulse wave velocity is currently considered as the gold standard method, although accurate assessment of travel distance remains ambiguous. New methods have also been suggested for the assessment of PWV, relying on the concept that the pressure wave is composed of one single forward wave and one single reflected wave, originating from a single reflection site. This simple conceptual scheme is no more than a paradigm for a complex physical reality of wave transmission and continuous reflections in a complex branching network of elastic vessels and the accuracy of these methods is very limited. As such, the benefit of the ease of use of these methods should be weighted against the desired accuracy and reliability.     

汉族人群中血压与动脉硬化关系的研究

目的 :探讨汉族人群中家庭测量血压与动脉硬化的关系。方法 :将 471名受试者分为青年组 (n =2 3 5 )和中年组 (n =2 3 6) ,各组又分为血压正常者和高血压者。对受试者进行 2次家访 ,每次家访各测 5次血压 ,取其 10次读数的平均值作为血压值。应用动脉脉搏波分析 (PWA )仪记录受试者桡动脉脉搏波形 ,经计算机自动转化为中心动脉脉搏波 ,以反射波增强指数 (AIx)作为反映全身动脉硬化的参数。结果 :血压正常者PWA结果显示 ,中年组与青年组比较增强指数有极显著性差异 (P <0 .0 1) ,经年龄调整后两组间无显著性差异。两组中高血压者与血压正常者比较增强指数均升高 ,有极显著性差异 (P均 <0 .0 1)。即使在血压正常者中 ,血压正常高值者 (血压 13 0～ 13 9/ 85～ 89mmHg ,1mmHg =0 .13 3kPa)增强指数也显著高于血压正常值者 (血压 <13 0 / 85mmHg ,P <0 0 0 1)。将增强指数作为因变量 ,年龄、身高、心率、家访时的收缩压及舒张压作为自变量进行多元回归分析显示 ,受试者年龄及收缩压与增强指数呈显著的正相关。结论 :血压正常者中 ,增强指数随年龄的增加而升高。高血压者与血压正常者相比 ,增强指数显著升高 ,提示高血压患者动脉顺应性下降、动脉硬化 ;收缩压与动脉顺应性显著相关。即使血压正常高值者 ,增     

高血压病脉搏波速度与脉压关系的研究

目的　研究高血压病患者主动脉脉搏波速度 (PWV)与脉压的关系。方法　 3 15 6例高血压患者入选了我们的横断面研究 [平均年龄 ( 5 3 7± 11 6 )岁 ]。应用自动脉搏波速度测定仪测量颈动脉 股动脉PWV作为反映大动脉硬度的指标 ,血压测量采用标准水银柱血压计。结果　脉压≥ 6 0mmHg ( 1mmHg =0 133kPa)者PWV显著大于脉压 <6 0mmHg者 [( 12 4 6± 2 4 6 )比 ( 10 96± 1 79)m s ,P <0 0 1]。脉压和PWV与年龄显著正相关 (脉压r =0 396 ,P =0 0 0 0 ;PWVr =0 5 31,P =0 0 0 0 )。收缩压一定时 ,PWV随舒张压的降低显著升高 ;舒张压一定时 ,PWV随收缩压的升高显著升高。结论　PWV与脉压密切相关 ,PWV由高到低依次为单纯收缩期高血压、收缩舒张期高血压、单纯舒张期高血压和正常血压者。     

未治疗原发性高血压患者脉搏波速度与血浆同型半胱氨酸水平相关性分析

目的 研究未经治疗的原发性高血压患者各动脉节段脉搏波速度（PWV）变化及其相关因素.方法 选取未经治疗的原发性高血压患者97例,健康对照组97例.采用Complior分析仪测定颈-股动脉脉搏波传导速度（CF-PWV）、颈-桡动脉脉搏波传导速度（CR-PWV）和颈-踝动脉脉搏波传导速度（CA-PWV）.采用全自动生化分析仪检测血糖、血脂、尿酸、同型半胱氨酸、高敏C反应蛋白等血液生化指标.结果 与对照组比较,未治疗的原发性高血压患者CF-PWV、CR-PWV和CA-PWV、血压、心率、空腹血糖、总胆固醇、三酰甘油、低密度脂蛋白胆固醇、尿酸和同型半胱氨酸均显著增加（P＜0.05或P＜0.01）.高密度脂蛋白胆固醇、肌酐和高敏C反应蛋白无明显变化.多因素逐步回归分析显示,CF-PWV的独立相关因素是高血压（β=0.333,P＜0.01）、脉压差（β=0.269,P＜0.01）和同型半胱氨酸（β=0.124,P＜0.05）.CR-PWV的独立相关因素是高血压（β=0.376,P＜0.01）、心率（β=0.148,P＜0.05）和同型半胱氨酸（β=0.135,P＜0.05）.CA-PWV的独立相关因素是高血压（β=0.556,P＜0.01）、体质量指数（β=-0.163,P＜0.01）和同型半胱氨酸（β =0.145,P＜0.05）.结论 未治疗原发性高血压患者各动脉节段PWV增加,血浆同型半胱氨酸水平是其独立相关因素之一.     

Acute hyperglycaemia rapidly increases arterial stiffness in young patients with type 1 diabetes

Aims/hypothesis Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects. Methods Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured. Results At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (−5 ± 2.7 vs −20 ± 2.8%, p < 0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (−5 ± 2.7 vs 8 ± 2.5%, p < 0.001) and healthy volunteers (−20 ± 2.8 vs 6 ± 8.8%, p < 0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 ± 1.2 vs 8.0 ± 1.0 m/s, p < 0.001), but not in healthy men (7.4 ± 1.7 vs 7.3 ± 1.4 m/s, NS). Conclusions/interpretation Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

原发性高血压患者动脉僵硬度与心脏重构的相关性研究

目的 探讨原发性高血压患者动脉僵硬度与左心功能的相关性.方法 纳入原发性高血压患者79例,根据颈桡脉搏波传导速度（PWV）将患者分为对照组（PWV＜0.9m/s,n=42）和观察组（PWV≥0.9m/s,n=37）,两组患者均行心脏彩超检查比较心功能参数差异.结果 两组患者间左室舒张末期内径（LVEDd）、左室射血分数（LVEF）、左室质量指数（LVMI）、二尖瓣舒张早期血流峰速（E）、舒张晚期血流峰速（A）及二者比值（E/A）差异具有统计学意义（P＜0.05）;Pearson相关分析显示PWV与LVMI存在显著的相关性（r=0.347,P＜0.05）.结论 原发性高血压患者动脉僵硬度与左心重构存在显著的相关性,在临床上检测动脉弹性对于评价高血压患者心脏重构具有显著的临床意义.     

Allometric Hemodynamic Analysis of Isolated Systolic Hypertension and Aging

Isolated systolic hypertension (ISH) is prevalent in the elderly and the contributing factors are predominantly vascular in origin. We previously showed that the hemodynamic manifestation of ISH is the result of a concurrently mild increase in peripheral resistance with a large reduction in arterial compliance or greatly increased vascular stiffness. Such elastic mismatching can lead to increased wave reflections. Therefore, we hypothesize that significantly increased pulse wave reflections associated with a drastically reduced arterial compliance beyond normal aging is a principle contributing factor to the production of ISH. To investigate this, we developed a new allometric hemodynamic model that can account for the arterial compliance and peripheral resistance changes during the progression of aging. This model also affords the time domain analysis of forward and reflected waves during aging and ISH. Results show that a further and much greater reduction in arterial compliance beyond normal aging is necessary to produce ISH. Comparison of ISH with normal aging at 60-year old showed that in ISH the amount of wave reflections is much more pronounced, with a greater amplitude and earlier arrival in systole. The increased wave reflections in ISH further amplify the cyclic stress on the already stiffened blood vessels. Therefore, therapies to treat ISH patients need to focus on reducing pulse wave reflections as well as on improving large vessel compliance.     

Central haemodynamics reveal significant potential for prevention in Black hypertensive patients born and living in sub-Saharan Africa

Background

Few studies assessed arterial stiffness in Black hypertensive patients born and living in sub-Saharan Africa, where cardiovascular disease reaches epidemic proportions.

Methods

The Newer versus Older Antihypertensive Agents in African Hypertensive Patients (NOAAH) trial is currently recruiting native African patients to compare the efficacy of various antihypertensive drugs given once daily as single-pill combinations. Two centres engaged in pulse wave analysis and measured carotid-femoral pulse wave velocity (PWV). Statistical methods included single and multiple linear regressions.

Results

Of 172 patients screened, 116 entered the ancillary study on central haemodynamics (51.3% women; mean age 52.7 years; untreated blood pressure 147.6/87.1 mm Hg). The augmentation indexes were higher (p < 0.0001) in women than men, both peripherally (pAI, 11.1 vs. −10.6%) and centrally (cAI, 39.0 vs. 28.0%). PWV (8.91 m/s) and central pulse pressure (cPP, 48.7 mm Hg) were similar (p > 0.844) in both sexes. pAI and cAI increased with female sex and mean arterial pressure, but decreased with heart rate and body mass index. cPP increased with age and mean arterial pressure. PWV increased with age and mean arterial pressure. Patients with measurements above the age-specific thresholds determined in healthy Black South Africans amounted to 0 for cAI, 1 (1.2%) for cPP, and 11 (18.3%) for PWV.

Conclusion

NOAAH patients have measures of arterial stiffness similar to those of a healthy Black reference population with determinants as reported in the literature. Our observations highlight the potential for the prevention of irreversible arterial damage by timely treating sub-Saharan hypertensive patients to target blood pressure levels.     

“Inflammation and arterial stiffness in humans”

Arterial stiffness is an established marker of cardiovascular morbidity and mortality and a potential therapeutic target. While hypertension and aging are established factors contributing to arterial stiffness, the role of inflammation in stiffening of the arteries is less well understood. We summarize existing literature regarding inflammation and arterial stiffness, including a discussion of the potential mechanisms by which inflammation may lead to arterial stiffening and studies assessing: (1) The association between subclinical inflammation and arterial stiffness in the general population; (2) The presence of increased arterial stiffness in primary inflammatory diseases; (3) The effect of anti-inflammatory therapy on arterial stiffness in primary inflammatory disease including the effect of statins; (4) Experimental evidence of immunization-induced arterial stiffening in normal adults. We discuss potential opportunities to assess the impact of anti-inflammatory interventions on arterial stiffness in subjects without primary inflammatory conditions. We also review the effect of inflammation on wave reflections.