Arterial Stiffness and Extracoronary Calcification

In the studies which have evaluated the association between arterial stiffness and extracoronary calcification, it is not completely clear whether the calcification measures represent intimal or medial calcification or a combination of the two. In an early paper, Witteman et al. [15] evaluated the 9-year progression of aortic calcification (by x-ray) among women aged 45-64 at baseline. Progression of aortic calcification was associated with a decrease in diastolic BP of 10 mm Hg or more. On further analysis, this was shown to be true only for women above the median in increase in PP. Their longitudinal results support the hypothesis that progression of aortic calcification (which they used as an index of atheroma progression) precedes increases in arterial stiffness. Another study of 116 Japanese men and women (mean age 57.4 8 8.3, with controlled hyperlipidemia and any aortic calcification at baseline) evaluated the determinants of progression of abdominal aortic calcification (measured by standard CT) during a follow-up of approximately 6 years. After adjustment for age and sex, progression of aortic calcification was significantly associated with BMI, systolic BP, and PP, but PP was the strongest predictor of progression of aortic calcification.

In renal dialysis patients, a strong cross-sectional relationship has been demonstrated between higher number of extracoronary sites with calcifications (carotid, aorta, and femoral) and both lower diastolic BP (i.e. increased PP) [16] and stiffness of both the carotid and aorta [17]. In the second study, arterial stiffness was assessed by CCA incremental elastic modulus, distensi-bility and cfPWV, and the associations remained after adjustment for age, duration of dialysis, fibrinogen, and the prescribed dose of calcium-based phosphate binders. Extracoronary calcifications were assessed by B-mode ultrasound of the CCA, aorta, and femoral arteries, and x-ray of the abdomen, pelvis and femoral arteries, and analyzed semiquantitatively as a score (0-4) according to the number of arterial sites with calcifications. This definition includes intimal calcification (echogenic plaques), but may also include medial calcification, which is widespread among ESRD patients and would also be visible on x-rays.

In the Rotterdam study (>3,000 participants aged 60-101), higher cfPWV and decreased common carotid distensibility were associated with numerous non-coronary disease measures including higher carotid wall thickness and plaque, calcified aortic plaque, and peripheral vascular disease [18], independent of age, sex, mean arterial pressure, and heart rate. Carotid plaques were evaluated using B-mode ultrasound and summarized as a plaque index, and calcified aortic plaque was evaluated from lateral x-rays of the lumbar spine, and graded from 0 to 5 for severity based on size. Peripheral vascular disease was evaluated by ankle BPs. This large, population-based study of elderly men and women demonstrated a strong association of carotid and aortic stiffness with not only calcified aortic plaques, but also other measures of subclinical atherosclerosis.

Finally, an interesting study has reported differences in arterial stiffness according to carotid plaque morphology (by B-mode ultrasound), among 561 volunteers (mean age 58 8 10.8 years) without a history of coronary heart disease or stroke [19]. 71.5% had no plaques, 9.1% had echolucent and 19.4% had echogenic plaques. PWV was higher among those with echogenic (calcified) plaques (p < 0.01) compared to those with echolucent or no plaques, and mean PWV was not significantly different between those with echolucent plaques versus those with no plaques. Results remained significant after adjustment for gender, age, BMI, smoking habits, systolic BP, antihypertensive treatment, diabetes, total cholesterol, lipid-lowering medications, serum triglycerides, and CCA-intima-media thickness (IMT). These results are interesting, since they are counter-intuitive to current thinking that echolucent plaques should be more unstable and therefore more high risk than echogenic (calcified) plaques. However, the lack of association with echolucent plaques may be due to survivor bias, since prevalent CVD was an exclusion factor for the study. It is possible that those with both echolucent plaques and high arterial stiffness are at greatest risk of fatal or non-fatal CVD events, thereby excluding them from study and making it impossible to demonstrate an association between high levels of both.

In combination with the animal studies, these few reports suggest that extracoronary calcification, especially in the aorta, is associated with higher levels of large artery stiffness. However, it is unknown what proportion of the extracoronary calcification evaluated in the clinical and epidemiological studies represented medial calcification (arteriosclerosis) versus intimal calcification of focal plaque (atherosclerosis).

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