Conduit arteries become stiffer with age due to alterations in their morphology and the composition of the their major structural
proteins,
elastin and
collagen. The elastic lamellae undergo fragmentation and thinning, leading to
ectasia and a gradual transfer of mechanical load to
collagen, which is 100-1000 times stiffer than
elastin. Possible causes of this fragmentation are mechanical (
fatigue failure) or enzymatic (driven by matrix metallo
proteinases (
MMP) activity), both of which may have genetic or environmental origins (fetal programming). Furthermore, the remaining
elastin itself becomes stiffer, owing to calcification and the formation of cross-links due to
advanced glycation end-products (AGEs), a process that affects
collagen even more strongly. These changes are accelerated in the presence of disease such as
hypertension, diabetes and uraemia and may be exacerbated locally by
atherosclerosis. Raised
MMP activity, calcification and impaired endothelial function are also associated with a high level of plasma
homocysteine, which itself increases with age. Impaired endothelial function leads to increased resting vascular smooth muscle tone and further increases in vascular stiffness and mean and/or pulse pressure. The effect of increased stiffness, whatever its underlying causes, is to reduce the reservoir/buffering function of the conduit arteries near the heart and to increase pulse wave velocity, both of which increase systolic and pulse pressure. These determine the peak load on the heart and the vascular system as a whole, the breakdown of which, like that of any machine, depends more on the maximum loads they must bear than on their average. Reversing or stabilising the increased arterial stiffness associated with age and disease by targeting any or all of its causes provides a number of promising new approaches to the treatment of
systolic hypertension and its sequelae, the main causes of mortality and morbidity in the developed world.