Value of arterial stiffness in predicting cardiovascular events and mortality






Piotr JANKOWSKI, MD, PhD
First Department of Cardiology and Hypertension, Institute of Cardiology, Jagiellonian
University Medical College, Kraków, Poland

Value of arterial stiffness in predicting cardiovascular events and mortality


by P. Jankowski, Poland



There is a considerable interest in refining cardiovascular risk prediction in order to better target preventive therapy. Arterial stiffness is a well-recognized predictor of cardiovascular morbidity and mortality. Several hypotheses that may explain the association between arterial stiffness and cardiovascular risk are described in the literature. Out of a number of studied parameters, aortic pulse wave velocity is the most validated method used to quantify arterial stiffness noninvasively and is considered today the gold standard index, given its strong prediction of cardiovascular events and mortality. The predictive value of pulse wave velocity has been shown in a broad range of patients, although current evidence suggests a stronger association with the risk of cardiovascular events in younger subjects and in high-risk patients. Current evidence also suggests that the estimation of arterial wall compliance (especially using pulse wave velocity) may improve risk stratification, which is especially important in subjects with intermediate risk.

Medicographia. 2015;37:399-403 (see French abstract on page 403)



There is a considerable interest in refining cardiovascular risk prediction in order to better target preventive therapy. Nowadays, this issue is especially important for individuals considered by current guidelines to be at low or moderate risk. A number of cardiovascular biomarkers have been identified, including C-reactive protein, carotid intima-media thickness, dysfunctional high-density lipoprotein, and a variety of genetic variants. However, there are doubts concerning the utility and cost-effectiveness of these biomarkers in everyday clinical practice.1 Recently, increasing interest has been shown in aortic stiffness, which has emerged as both a biomarker, potentially improving risk prediction, as well as a risk factor, contributing to the pathogenesis of cardiovascular disease.

Mechanism of arterial stiffness – cardiovascular risk association

Arterial stiffness and its hemodynamic consequences are established predictors of cardiovascular mortality and morbidity. Arterial stiffness is positively associated with systolic hypertension, coronary artery disease, stroke, and heart failure, which are the leading causes of mortality in the developed world. It is important to understand the mechanism of increased cardiovascular risk in subjects with increased arterial stiffness. The literature suggests several concepts to explain this mechanism.2 The first concept is the relation between arterial wall stiffness and lower diastolic and higher systolic blood pressure in the ascending aorta. Low diastolic blood pressure is related to low perfusion pressure through myocardium and, therefore, to reduced coronary perfusion. Indeed, it has been suggested that myocardial revascularization procedures may transform the “J” shape of the relation between diastolic pressure and cardiovascular risk into a more linear relation.3 On the other hand, higher systolic blood pressure increases afterload and the oxygen demand of the myocardium and contributes to left ventricular hypertrophy. The net effect is that an increase in arterial stiffness (higher pulse wave velocity [PWV] and higher central pulse pressure [PP]) leads to an imbalance between myocardial oxygen demand and supply, and hence ischemia. This has been proven invasively by Leung and colleagues, who observed a strong inverse relationship between coronary blood flow and PWV/central PP in patients following a coronary intervention.4 All these effects may increase cardiovascular risk.

The second concept is that increased stiffness is a symptom of “disease” of the arterial wall. Indeed, structural changes contributing to an increase in arterial stiffness include fragmentation of elastin, increased deposition of collagen, arterial calcification, glycation of both elastin and collagen fibers, and cross-linking of collagen molecules by advanced glycation end products.5,6 In line with this concept, atherosclerotic plaques develop more easily in diffusely “diseased” arterial walls, leading to coronary and cerebrovascular events. Indeed, it has been hypothesized that the high predictive value of PWV results from the cumulative influence/damage of cardiovascular risk factors on the arterial wall over long periods. This explanation could also elucidate why aortic stiffness is able to predict cardiovascular risk independently of classic risk factors. Indeed, the intensity of risk factors may change over time leading to diminution of the association between risk factors and cardiovascular risk in cross-sectional, and even observational, studies. Recently, a relation between arterial wall stiffness and carotid intraplaque hemorrhage was found, which was partly independent of PP.7

The third concept is that high arterial stiffness increases the pulsatile component of blood pressure, especially central pressure, which in turn leads to the development of atherosclerosis and its complications as well as to damage of microvasculature. The influence of cyclic stretch (due to cyclic changes in blood pressure) on the arterial wall has been documented at every stage in the development of atherosclerosis.6,8 Apart from mediating atherosclerosis progression and plaque instability, the pulsatile component of blood pressure is the main mechanism associated with plaque rupture and, consequently, with acute coronary syndromes and other vascular complications. Moreover, PP is the strongest determinant of intraplaque hemorrhages.9

The correlation between increased arterial wall stiffness and the presence of risk factors and diseases related to increased cardiovascular risk, eg, diabetes, chronic kidney disease, diffuse atherosclerosis, etc, is the fourth concept. It is not always possible to account for all these factors and diseases when performing multivariate analysis. Other explanations, including damage of microvasculature leading among other things to slow coronary flow10 as well as to kidney failure11 (and indirectly to progression of atherosclerosis and its complications), are also possible.

Although structural changes related to increased arterial wall stiffness may be quantified pathologically, the clinical evaluation of arterial mechanical properties is more complex and a complete description of the stress–strain relationship of arteries in vivo is not possible owing to uncertainties arising from nonlinear behavior, viscoelasticity, anisotropy, active tone, residual stresses, and tethering.12 Many parameters have been proposed to quantitatively represent arterial stiffness and distensibility, such as pressure-strain elastic modulus, stiffness index, PWV, and characteristic impedance.13 A number of studies have shown that various indices of arterial compliance are related to cardiovascular risk. Although arterial stiffness is a well-recognized predictor of cardiovascular events, the large number of parameters employed to define arterial stiffness and the differing modalities used to assess aortic mechanics have somewhat hampered the current clinical impact of these measures.

Arterial stiffness and cardiovascular risk

Because some studies suggest that the predictive value of aortic stiffness may be slightly better than local (eg, carotid artery) stiffness and because of the ease of measurement, aortic (carotid-femoral) PWV has been proposed as the best surrogate to evaluate arterial stiffness, especially in everyday clinical practice. Indeed, the predictive value of PWV has been demonstrated in a number of studies.14-17 Many devices measure arterial stiffness, but methodological limitations need to be borne in mind. Some devices measure PWV of an arterial segment in mixed elastic and muscular arteries, thereby weakening their predictive value. Only the compliance of elastic arteries, and not muscular arteries, has been shown to be predictive of cardiovascular morbidity and mortality.17 Others use methods other than PWV and are frequently and substantially confounded by other factors. Carotid-femoral (aortic) PWV is the most validated method to noninvasively quantify arterial stiffness and is today considered the gold standard index, given its strong prediction of cardiovascular events and mortality.





The first evidence for the predictive value of carotid-femoral PWV was published in 1999.14 Subsequently a number of prospective studies were published.18 Almost all of them major meta-analyses summarized the evidence on the relation between PWV and cardiovascular risk.19,20 The first was published by Vlachopoulos et al (Table I). The authors used the results of 17 studies involving 15 877 patients and calculated that an increase in PWV of 1.0 m/s increases the risk of cardiovascular events by 14% (Table I).19 A similar conclusion was drawn by Ben-Shlomo et al, who used the data of 17 635 patients from 16 studies and were able to show that a change in PWV of 1 m/s was associated with hazard ratio for cardiovascular events of 1.07 for a nonsmoking, normotensive 60-year-old male without diabetes, but with mild hyperlipidemia.20


Table I
Table I. Risk ratios (95% confidence intervals) from different studies
for total cardiovascular events for a 1 m/s increase in aortic
pulse wave velocity.

Based on reference 19: Vlachopoulos et al. J Am Coll Cardiol. 2010;55:1318-1327.
© 2010, American College of Cardiology Foundation.



The relationship between aortic PWV and cardiovascular risk is present in a variety of subjects, including those with the highest cardiovascular risk: patients with chronic kidney disease, or those with coronary artery disease.14,21 Choi et al showed that the risk of cardiovascular events increased by 118% in patients undergoing coronary angiography when PWV was higher than 12.5 m/s.21 Even more studies have been published involving patients with chronic kidney disease. For example, in the study by Blacher et al the risk of cardiovascular events increased by 17% when PWV increased by 1 m/s.14 High PWV seems to be related to greater excess risk in highrisk patients than in low-risk patients.19

Vlachopoulos et al showed that the predictive role of PWV in patients with end-stage renal disease decreased with age.19 However, they failed to show such an association when all included in the meta-analysis studies were analyzed. On the other hand, age was related to the predictive value of PWV in a broad range of patients in a more recent meta-analysis by Ben-Shlomo et al.20 In younger participants, PWV was more strongly related to the risk of coronary artery disease, stroke, and cardiovascular and all-cause mortality (Table II).20 It should, however, be underlined that the absolute risk increase with increasing PWV may be greater in older patients due to their much greater cardiovascular risk.

The median value of aortic PWV in healthy subjects varies from 6.1 m/s in persons aged <30 years to 10.6 m/s in subjects >70 years of age.22 Although the relationship between aortic compliance and the risk of cardiovascular events is continuous, a threshold of 10 m/s has been suggested for use in clinical practice as a sign of significant alteration of aortic function.23

Brachial-ankle PWV has also been studied extensively. Vlachopoulos et al summarized the results of 18 studies involving 8169 participants and showed that when brachial-ankle PWV increased by 1 m/s, the risk of total mortality, cardiovascular mortality, and total cardiovascular events increased by 6%, 13%, and 12%, respectively.24 As with aortic PWV, age was inversely related to the predictive value of brachial-ankle PWV in patients with end-stage renal disease.

The Mobil-O-Graph system uses a less direct way of estimating PWV. Recently, an association between PWV as determined using the Mobil-O-Graph system and total mortality in patients with chronic kidney disease was shown, although, probably due to small number of study participants, the association became nonsignificant after adjustment for age.25


Table II
Table II. Hazard ratios (95% confidence intervals) for cardiovascular
events related to pulse wave velocity in younger (<61 years) and older (≥61 years) subjects.

Based on reference 20: Ben-Shlomo et al. J Am Coll Cardiol. 2014;63:636-646.
© 2014, American College of Cardiology Foundation.



The authors of the most recent meta-analysis were also able to show that the use of aortic PWV measurements may improve risk stratification, especially in subjects with intermediate cardiovascular risk.20 However, the importance of choosing the method of aortic PWV measurement should be emphasized. In fact, cardiovascular risk stratification may change in up to 40% of patients depending on the choice of device.26 Many experts insist that the issue of device standardization needs to be resolved before the technique can be used widely in everyday clinical practice.27

Taking into account the predictive value of PWV, it should be mentioned that European Society of Hypertension/European Society of Cardiology experts have not recommended PWV measurement as a required test in patients with hypertension mainly due to the limited availability of PWV measurement outside research centers.28 It should also be noted that the methodology of PWV measurement has not yet been clearly standardized. The most commonly used techniques are operator- dependent, which limit the generalizability of findings derived from research studies. Additionally, some experts insist that the improvement in cardiovascular prediction obtained by determining PWV does not always justify the costs related to PWV measurement. Indeed, the American College of Cardiology and the American Heart Association do not recommend the use of arterial stiffness measures in clinical practice.29

As previously mentioned above, many parameters have been proposed to quantitatively represent arterial stiffness. Of these, PWV is the one that has been most frequently applied to clinical medicine. However, some experts insist that PWV is dependent on blood pressure at the time of measurement, and is therefore not appropriate as a parameter for the clinical evaluation of arterial stiffness. Against this particular backdrop of uncertainty, stiffness index is especially interesting.

Stiffness index is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter was used to develop a new arterial stiffness index, called the cardio- ankle vascular index (CAVI). Although this index is obtained from the PWV between the heart and the ankle, it is essentially similar to the stiffness index; blood pressure changes therefore influence CAVI to a much lesser extent than PWV. CAVI is being extensively used in clinical medicine as a measure for the evaluation of cardiovascular diseases and risk factors related to arteriosclerosis. Today, there are only a few published studies dealing with the relationship between cardiovascular risk and CAVI.30,31 It has also been shown that serial measurements of CAVI provide important prognostic information.31

Other methods, eg, the timing of Korotkoff sounds (QKD method),32 have also been proven to be related to the risk of cardiovascular events; however, the evidence base is much smaller compared to that for the methods described above.

Although it is known that reduction in arterial wall compliance has a negative impact on prognosis,31 an important issue is whether an improvement in arterial compliance translates into a reduction in cardiovascular events. There is only limited evidence on this issue. Lifestyle interventions can reduce arterial stiffness and/or wave reflections. Physical activity is especially effective in reducing arterial wall stiffness.2,33 Also, a low-salt diet improves arterial distensibility by reducing BP as well as by direct effects that are independent of BP changes.2,34 Direct beneficial effects of fish oils have been reported by several researchers.2,35 Weight loss has also been suggested to improve arterial wall compliance.2,36 Some researchers have proposed that one of the potential “antiaging” benefits of prolonged caloric restriction is a reduction in the rate at which arterial stiffness increases with age. Most of the mentioned lifestyle interventions are related to improved survival, but it is not known to what extent lifestyle changes decrease cardiovascular risk through reduction in arterial stiffness.

Another important, related question is whether drug-induced improvement in arterial compliance translates into improved prognosis. Although a lot of authors have claimed to have shown drug-induced improvement in arterial compliance, the truth is that in most of these cases, drug-induced blood pressure changes in these studies were not taken into account. Therefore, it is not possible to differentiate between blood pressure–dependent and blood pressure–independent effects. Nevertheless, Guerin et al have shown that a lack of decrease in PWV in response to blood pressure reduction was a strong independent predictor of mortality in patients with end-stage renal disease.37

Conclusions

Arterial stiffness is a well-recognized predictor of cardiovascular morbidity and mortality. Aortic PWV is the most validated method used to quantify arterial stiffness noninvasively and is today considered the gold standard index, given its strong prediction of cardiovascular events and mortality. The predictive value of PWV has been shown in a broad range of patients, although current evidence suggests a stronger association in younger subjects and high-risk patients. Estimation of arterial wall compliance, especially using PWV, may improve risk stratification, which is especially important in subjects with intermediate risk.


References
1. Vlachopoulos C, Xaplanteris P, Aboyans V, et al. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. Atherosclerosis. 2015;241:507-532.
2. Jankowski P, Blacher J, Weber T. Arterial stiffness, central blood pressure and coronary heart disease. In : Safar ME, O’Rourke MF, Frohlich ED, eds. Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases. London, UK: Springer-Verlag; 2014.
3. Denardo SJ, Messerli FH, Gaxiola E, et al. Coronary revascularization strategy and outcomes according to blood pressure (from the International Verapamil SR-Trandolapril Study [INVEST]). Am J Cardiol. 2010;106:498-503.
4. Leung MCH, Meredith IT, Cameron JD. Aortic stiffness affects the coronary blood flow response to percutaneous coronary intervention. Am J Physiol Heart Circ Physiol. 2006;290:H624-H630.
5. Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension. 2005;45:1050-1055.
6. Safar ME, Blacher J, Jankowski P. Arterial stiffness, pulse pressure, and cardiovascular disease-is it possible to break the vicious circle? Atherosclerosis. 2011; 218:263-271.
7. Selwaness M, van den Bouwhuijsen Q, Mattace-Raso FU, et al. Arterial stiffness is associated with carotid intraplaque hemorrhage in the general popula- tion: the Rotterdam study. Arterioscler Thromb Vasc Biol. 2014;34:927-932.
8. Jankowski P, Bilo G, Kawecka-Jaszcz K. The pulsatile component of blood pressure: its role in the pathogenesis of atherosclerosis. Blood Press. 2007;16: 238-245.
9. Selwaness M, van den Bouwhuijsen QJ, Verwoert GC, et al. Blood pressure parameters and carotid intraplaque hemorrhage as measured by magnetic resonance imaging: The Rotterdam Study. Hypertension. 2013;61:76-81.
10. Guray U, Guray Y, Yilmaz MB, et al. Aortic pulse pressure and aortic pulsatility in patients with coronary slow flow. Cardiology. 2007;107:233-238.
11. Ishikawa T, Hashimoto J, Morito RH, et al. Association of microalbuminuria with brachial-ankle pulse wave velocity: the Ohasama study. Am J Hypertens. 2008; 21:413-418.
12. Vito RP, Dixon SA. Blood vessel constitutive models: 1995–2002. Ann Rev Biomed Eng. 2003;5:413-439.
13. O’Rourke MF, O’Brien C, Weber T. Arterial stiffness, wave reflections, wave amplification: basic concepts, principles of measurement and analysis in humans. In : Safar ME, O’Rourke MF, Frohlich ED, eds. Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases. London, UK: Springer-Verlag; 2014.
14. Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99:2434-2439.
15. Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001;37:1236-1241.
16. Inoue N, Maeda R, Kawakami H, et al. Aortic pulse wave velocity predicts cardiovascular mortality in middle-age and elderly Japanese men. Circ J. 2009; 73:549-553.
17. Laurent S, Cockcroft J, Van Bortel L, et al; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;7:2588-2605.
18. Palatini P, Casiglia E, Gąsowski J, et al. Arterial stiffness, central hemodynamics, and cardiovascular risk in hypertension. Vasc Health Risk Manag. 2011;7: 725-739.
19. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and metaanalysis. J Am Coll Cardiol. 2010;55:1318-1327.
20. Ben-Shlomo Y, Spears M, Boustred C, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63:636-646.
21. Choi CU, Park EB, Suh SY, et al. Impact of Aortic Stiffness on Cardiovascular Disease in Patients With Chest Pain. Am J Hypertens. 2007;20:1163-1169.
22. Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31:2338-2350.
23. Van Bortel LM, Laurent S, Boutouyrie P, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30:445-448.
24. Vlachopoulos C, Aznaouridis K, Terentes-Printzios D, Ioakeimidis N, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with brachialankle elasticity index: a systematic review and meta-analysis. Hypertension. 2012;60:556-562.
25. Salvadé I, Schätti-Stählin S, Violetti E, et al. A prospective observational study comparing a non-operator dependent automatic PWV analyser to pulse pressure, in assessing arterial stiffness in hemodialysis. BMC Nephrol. 2015;16:62.
26. Pichler G, Martinez F, Vicente A, Solaz E, Calaforra O, Redon J. Carotid-femoral pulse wave velocity assessment by two different methods: implications for risk assessment. J Hypertens. 2015. Epub ahead of print.
27. Mihalcea DJ, Florescu M, Suran BM, et al. Comparison of pulse wave velocity assessed by three different techniques: Arteriograph, Complior, and Echo-tracking. Heart Vessels. 2015. Epub ahead of print.
28. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159-2219.
29. Greenland P, Alpert JS, Beller GA, et al; American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. 2010 ACCF/ AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122: e584-e636.
30. Kubota Y, Maebuchim D, Takei M, et al. Cardio-Ankle Vascular Index is a predictor of cardiovascular events. Artery Res. 2011;5:91-96.
31. Otsuka K, Fukuda S, Shimada K, et al. Serial assessment of arterial stiffness by cardio-ankle vascular index for prediction of future cardiovascular events in patients with coronary artery disease. Hypertens Res. 2014;37:1014-1020.
32. Gosse P, Cremer A, Papaioannou G, Yeim S. Arterial stiffness from monitoring of timing of Korotkoff sounds predicts the occurrence of cardiovascular events independently of left ventricular mass in hypertensive patients. Hypertension. 2013;62:161-167.
33. Collier SR, Kanaley JA, Carhart R Jr, et al. Effect of 4 weeks of aerobic or resistance exercise training on arterial stiffness, blood flow and blood pressure in pre- and stage-1 hypertensives. J Hum Hypertens. 2008;22:678-686.
34. Avolio AP, Clyde KM, Beard TC, et al. Improved arterial distensibility in normotensive subjects on a low salt diet. Arteriosclerosis. 1986;6:166-169.
35. Yamada T, Strong JP, Ishii T, et al. Atherosclerosis and omega-3 fatty acids in the populations of a fishing village and a farming village in Japan. Atherosclerosis. 2000;153:469-481.
36. Kingwell BA, Cameron JD. Nonpharmacological treatment for increased arterial stiffness and altered wave reflections. In: Safar ME, O’Rourke MF, eds. Arterial Stiffness in Hypertension. New York, NY: Elsevier; 2006.
37. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001;103:987-992.


Keywords: blood pressure; hypertension; atherosclerosis; coronary artery disease; cardiovascular risk; arterial stiffness; arterial compliance; risk factor; pulse pressure