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Vascular Stiffness Is a Biomarker of Global Cardiovascular Risk

Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biologic or pathogenic processes and of responses to therapeutic interventions, because, to be useful to clinicians, biomarkers must add predictive information in addition to that of established risk markers; hence, new and novel biomarkers are rare. However, vascular stiffness, particularly as measured as aortic pulse wave velocity (PWV), fulfills this requirement as demonstrated by a report of the results of an international meta-analysis of prospective observational data of 17,635 patients. The analysis indicates that consideration of PWV, in addition to other recognized cardiovascular risk markers, improves the overall 10-year risk classification for intermediate-risk patients by 13%. Hope and colleagues first reported in 2007 that aorto-radial PWV, measured invasively with 2F Millar pressure transducer-tipped catheters at the time of coronary angiography, was associated with both the extent and severity of coronary artery disease. Both extent and severity scores were associated with increasing age and male sex but not blood pressure or central aortic augmentation index. In this issue of the Journal, Hofmann and colleagues sought to determine whether carotid to femoral PWV (cfPWV), as measured noninvasively using an oscillometric technique, would reflect the extent of coronary artery disease in 155 patients who underwent coronary arteriography. These authors found that in a multiple regression model, severity of coronary artery disease emerged as an independent predictive marker for cfPWV. Thus, cfPWV was of value in both the detection of atherosclerosis and the extent of coronary artery disease. The precise mechanism underlying the association of PWV with extent of coronary artery disease is not apparent. Atherosclerosis is a patchy disease, and PWV reflects more extensive alterations in the proximal arterial circulation. There is regional diversity in aortic stiffness reflecting the relative amounts of collagen and elastin, and these properties are modified by the presence of atherosclerosis. In 2013, the European Society of Hypertension/ European Society of Cardiology published guidelines for the management of arterial hypertension. These included a recommendation that PWV be measured to evaluate the presence of subclinical target organ damage and suggested a cutoff of 10 m/s to discriminate between normal aortic elasticity and aortic stiffening. In the present study, the patients in the oldest age group with the greatest coronary artery disease burden had a velocity of 9.7 1.4 m/s and thus would fall in the normal range by the European Society of Hypertension/ European Society of Cardiology guidelines. Therefore, it is clear that more work is needed before widely applicable guidelines can be established. As has been reviewed elsewhere, important differences in absolute PWV values exist between methodologies and/or between populations. Furthermore, there is evidence that noninvasively measured central systolic blood pressures as compared with brachial blood pressures are different between men and women, as are calculations of augmentation index, and differ by instrument used. Hofmann and associates state that they did detect a cfPWV sex dependency but did not include the data because of the small size of the female patient group. Other issues to be determined include the relationship of blood pressure with both PWV and extent/severity of coronary disease, as the results from Hope and colleagues and the present study appear to conflict. Ikonomidis and colleagues have described that yet another biomarker, Lp-PLA2 concentration, is related to endothelial dysfunction, carotid atherosclerosis, impaired coronary flow reserve, and increased arterial stiffness as measured by PWV, and adverse outcome in coronary disease patients. The interrelationships of endothelial dysfunction to arterial stiffness, PWV, and coronary flow reserve require further definition. This study supports that of Hope and colleagues that PWV correlates with both the extent and severity of coronary atherosclerosis, but importantly introduces and validates the use of a noninvasive oscillometric technique for cfPWV measurement. There is now enough evidence to recommend the addition of measurement of vascular stiffening by recording PWV to current US screening guidelines. This may be of most importance in younger individuals in whom early intervention may be of great benefit. It has been suggested that cardiovascular risk determinations begin at age 20 and that total (global) risk reported. What remains is to show that vascular stiffness can be a therapeutic target and that treatmentrelated changes result in improved outcomes. We are optimistic that this will be the case.