Objective: The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia). Approaches and Results: In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s, P <0.0001), Zc ( P <0.0005), and Pf ( P <0.0001) were higher and early systolic pulse pressure amplification lower ( P <0.0001) in those with precipitous events than in controls. In comparison to age- and sex-matched controls, independent of risk factors, pulse wave velocity, and Zc ( P <0.005 and <0.05) were more closely associated with premature events than events in older persons and Pf and early systolic pulse pressure amplification were at least as closely associated with premature events as events in older persons. Conclusions: Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.

BACKGROUND The contribution of steady-state pressures and the forward (Pf) and backward (reflected) (Pb) wave pressure components of pulse pressure to risk prediction have produced contrasting results. We hypothesized that the independent contribution of steady-state pressures (mean arterial pressure [MAP]), Pf and Pb, to cardiovascular damage is organ specific and age dependent. METHODS In 1,384 black South Africans from a community sample, we identified independent relations between MAP, Pf, or Pb (applanation tonometry and SphygmoCor software) and left ventricular mass index (LVMI) (n = 997) (echocardiography), carotid intima-media thickness (IMT) (n = 804) (B-mode ultrasound), or aortic pulse wave velocity (PWV) (n = 1,217). RESULTS Independent of risk factors, relations between Pf and IMT were noted in those over 50 years (P &lt; 0.02), whereas in those less than 50 years, MAP (P &lt; 0.005) was independently associated with IMT. Pb failed to show independent relations with IMT at any age (P &gt; 0.37) In contrast, independent relations between Pb and LVMI were noted in those less than (P &lt; 0.0001), and greater than (P &lt; 0.02) 50 years, whereas MAP was not independently associated with LVMI at any age (P &gt; 0.07) and Pf tended to show significant relations only in the elderly (P = 0.05). Moreover, although MAP (P &lt; 0.005) and Pb (P &lt; 0.01) showed independent relations with PWV at any age, Pf failed to show independent relations (P &gt; 0.10). CONCLUSION Independent of confounders, steady-state and aortic Pf and Pb show associations with end-organ measures that are organ specific and age dependent.

Aim: We aimed to determine whether the impact of aortic stiffness on atherosclerotic or small vessel end organ damage beyond brachial blood pressure depends in-part on stiffness-induced increases in central arterial pressures produced by an enhanced resistance to flow (characteristic impedance, Zc). Methods: We studied 1021 participants, 287 with stroke or critical limb ischaemia, and 734 from a community sample with atherosclerotic or small vessel end organ measures. Central arterial haemodynamics were determined from arterial pressure (SphygmoCor) and velocity and diameter assessments in the outflow tract (echocardiography). Results: Although Zc and carotid–femoral pulse wave velocity (PWV) were correlated (P < 0.0001), these relations were not independent of confounders (P = 0.90). Both Zc and hence central arterial pressures generated by the product of Zc and aortic flow (Q) (PQxZc), as well as PWV were independently associated with carotid intima–media thickness, estimated glomerular filtration rate (eGFR), endothelial activation markers [vascular cell adhesion molecule-1 (V-CAM-1)] and events. With further adjustments for brachial pulse pressure (PP) or SBP, PWV and PQxZc were both associated with eGFR and V-CAM-1. Relationships between PWV and eGFR or V-CAM-1 were independent of PQxZc (P < 0.05) and relationships between PQxZc and eGFR and V-CAM-1 were independent of PWV (P < 0.005). Similarly, with adjustments for confounders and brachial PP or SBP, across the full adult lifespan, both aortic PWV and PQxZc were increased in those with arterial events (P < 0.005). Relationships between PWV and events were again independent of PQxZc (P < 0.005) and between PQxZc and events were independent of PWV (P < 0.0001). Conclusion: Beyond brachial blood pressure, the impact of aortic stiffness on arterial damage involves effects that are both dependent (proximal aortic Zc and hence PQxZc) and independent (full aortic length indexed by PWV) of central arterial pulsatile load. Hence, PWV and brachial PP may be insufficient to account for all of the damage mediated by increases in aortic stiffness.

The ability of carotid intima–media thickness (IMT) to predict risk beyond plaque is controversial. In 952 participants (critical limb ischemia [CLI] or stroke, n = 473; community, n = 479), we assessed whether relationships with events for IMT complement the impact of plaque in young patients depending on the extent of thrombotic versus atherosclerotic disease. The extent of atherosclerotic versus thrombotic occlusion was determined in 54 patients with CLI requiring amputations. Thrombotic occlusion in CLI was associated with younger age ( P < .0001) and less plaque ( P = .02). Independent relations between plaque and CLI were noted in older (>50 years; P < .005 to <.0001) but not younger ( P > .38) participants, while independent relations between plaque and stroke ( P < .005 to <.0001) and between IMT and CLI ( P < .0001) were noted in younger participants. Although in performance (area under the receiver operating curve) for event detection, IMT thresholds failed to add to plaque alone in older patients (0.680 ± 0.020 vs 0.664 ± 0.017, P = .27), IMT improved performance for combined stroke and CLI detection when added to plaque in younger patients (0.719 ± 0.023 vs 0.631 ± 0.026, P < .0001). Because in younger participants the high prevalence of thrombotic occlusion in CLI is associated with less plaque, IMT adds information in associations with arterial vascular events.

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