This prospective analysis of the MESA cohort, whose participants were initially free of symptomatic CVD, showed that SAE provided incremental predictive information for any CVD event and for each of its different components: myocardial infarction and CHD death, angina, heart failure, stroke, and peripheral vascular disease. This predictive value was significant not only after adjustment for demographic and anthropometric characteristics but also with further adjustment for CVD risk factors. In contrast to SAE, LAE was also predictive of CVD events in models adjusted for demographic factors, but in the fully adjusted model (model 2) it retained statistical significance only for heart failure. The NRI, conditional on base risk, was 0.11. SAE and the part of SAE that is derived solely from the waveform, SAE × SVR, were similarly predictive of total CVD events.
Several noninvasive methods exist for assessing arterial stiffness/elasticity. The largest amount of evidence regarding arterial stiffness as an additive predictor beyond traditional risk factors for CVD events has been derived from carotid-femoral pulse wave velocity. Initial studies were mainly focused on subjects at high risk (end-stage renal disease, diabetes, hypertension) (22
). Among the few studies of asymptomatic people, in the Rotterdam Study, a Dutch study of apparently healthy persons aged ≥55 years, aortic pulse wave velocity was associated with CHD and stroke (10
). In a small group of 141 elderly persons (age range, 70–100 years), aortic pulse wave velocity was associated with cardiovascular death (11
). In the Health ABC Study, which included people aged 70–79 years, aortic pulse wave velocity was associated with higher CVD mortality, CHD, and stroke, although the association was not as strong as might have been expected in the highest quartile of pulse wave velocity, and no association was found in predicting heart failure (8
). In an asymptomatic Danish population aged 40–70 years, aortic pulse wave velocity showed a trend toward prediction of CHD after controlling for traditional risk factors (9
). A smaller study of Japanese Americans living in Hawaii showed that aortic pulse wave velocity was associated with CVD death (12
). In the Framingham Offspring Study (151 incident CVD events in 2,232 persons; average age = 63 years), the relative hazard was 1.48 per standard-deviation increase in aortic pulse wave velocity but was not significant for augmentation index (23
). The above findings, plus findings in diseased persons, were summarized in a meta-analysis (24
). A second meta-analysis (25
) from the same group of investigators considered measures of central hemodynamics. The augmentation index was positively associated with CVD outcome and all-cause mortality in studies of diseased persons.
Interpretation of the 2 measures, LAE and SAE, as pertaining to elasticity of the large and small arteries is based on a literal interpretation of the windkessel (“air chamber”) model (18
). An accessible heuristic description of the windkessel model is rapid drainage of the blood into a large sink (the larger arteries), with subsequent evacuation from the sink into a smaller container (the smaller arteries). There has been some skepticism in the literature regarding LAE and SAE (26
). LAE and SAE are derived from an algebraic decomposition of the diastolic waveform into one part that is primarily declining between aortic closure and aortic opening (decaying exponential function) and a second part that is largely flat but may be oscillating (sinusoidal function dampened by a decaying exponential function) (18
). An alternative to the windkessel model is to interpret SAE by considering the possible sources of the oscillations during diastole (second part of the algebraic decomposition), when the left ventricle is considered to be “still.” The oscillations could be the result of a variety of activities of the arterial system during diastole, including left ventricular filling and untwisting, accommodation of reflection waves, spontaneous contraction of the vascular smooth muscle cells, and slow dissipation of the blood over the precapillary sphincters.
The pulse wave velocity (derived from behavior of the large arteries), augmentation index (derived from the systolic waveform), LAE, and SAE (derived from the oscillatory component of the diastolic waveform) appear to impart some common information, given that they were correlated in several studies (27
). Observed correlations between SAE and augmentation index included −0.36 (27
), −0.59 (28
), and −0.71 (29
), while correlations of LAE with augmentation index were −0.36 (28
) and −0.41 (30
). The correlation between aortic pulse wave velocity and augmentation index was 0.56 (30
); that between SAE and femoral-popliteal pulse wave velocity was −0.52 in healthy subjects and −0.34 in older subjects with diabetes, while corresponding correlations with LAE were −0.32 and −0.46 (31
). Concordance among pulse wave velocity, augmentation index, and SAE was further elucidated in the experimental study by Gilani et al. (32
). They blocked nitric oxide release by NG
-arginine methyl ester in 10 healthy persons; this blockade resulted in an increase in aortic pulse wave velocity (8.25–8.98 m/second; P
= 0.04), an increase in augmentation index (48.3%–64.6%; P
< 0.05), and a decrease in SAE (9.9–6.9 mL/mm Hg × 100; P
< 0.001). LAE, in contrast, did not change significantly (32
). However, there are also differences among these measures. This was illustrated in the Anglo-Cardiff Collaborative Trial, where a different age course was seen for augmentation index (increased rapidly during middle age and slowly in the elderly) than for pulse wave velocity (changed slowly during middle age and rapidly in the elderly) (30
). Morbidity and mortality studies comparing and contrasting these 3 measures and other measures would be useful.
In a theory of a temporal sequence of events, vascular disease originates in endothelial dysfunction, which has a profound influence on the microvasculature. In this view, evaluation of the smaller arteries and other microvasculature would be helpful in predicting early clinical events, consistent with our study. Stiffening of the small arteries, whether as a consequence of endothelial dysfunction, vasoconstriction, or structural changes due to remodeling, alters the magnitude and timing of reflected waves. Loss of arterial elasticity strengthens the early reflected pressure wave; the consequent increased afterload may eventually result in heart failure, as we observed in this study. In line with this temporal sequence hypothesis, the relatively weak predictive ability of LAE may reflect several features of the MESA sample, including the absence of people with clinical heart disease, their relatively low blood pressure, and the lack of extended follow-up. We speculate that abnormalities in large arteries, such as those reflected in low LAE, will gain predictive power as some MESA participants develop clinical CVD.
The current study was strengthened by the large sample size, the community-based setting, the multiethnic sample, and standardized subclinical atherosclerosis assessments and risk factor measurements. Other strengths were the prospective design and the reliance on adjudicated symptomatic endpoints, which avoids detection bias related to less thoroughly investigated CVD events or to cross-sectional evaluation of subjects with known subclinical atherosclerosis. This report fills a need, called for in a consensus document on arterial stiffness, to obtain “evidence, in a longitudinal study, that systemic arterial stiffness or systemic arterial compliance has independent predictive value for CV events” (33, p. 2594). Limitations include the relatively small number of peripheral vascular disease events to date. Results could be different for long-term CVD prediction, especially as this population ages and specific clinical manifestations of CVD emerge. Caution should be exercised in interpreting P values in light of the multiple comparisons made; the statistical tests were correlated because a participant may have had more than 1 of the outcome diagnoses. In addition, the exact value of NRI is sensitive to categorization and cutpoints selected to represent the base and augmented risk functions.
In conclusion, the present observation in a population sample without clinically overt CVD or a history of CVD demonstrated that standardized and quality-controlled noninvasive measurement of the radial artery pulse contour over a few heart cycles was significantly associated with future CVD events above and beyond classic risk factors.