Response to Letter Regarding Article “Atherosclerosis 2005: Recent Discoveries and Novel Hypotheses”
We thank Drs Williams and Tabas for their interest in our work1 and agree that there is a substantial body of evidence supporting the role of hyperlipidemia in atherogenesis. In our review, we addressed this point and indicated that cholesterol may be sufficient to alter the homeostasis of the arterial wall in susceptible individuals even at levels previously considered “normal.” To explain the spectrum of atherosclerotic lesions at any given lipid level, we hypothesized that some individuals might have robust repair capability, rendering them resistant to aggressive lipidic offense, whereas others may be particularly vulnerable to hyperlipidemia. Furthermore, the lipidic injury may not only damage the arterial wall but also affect the repair mechanisms. Indeed, we have demonstrated that the supply of progenitor cells is prematurely exhausted in the marrow of apolipoprotein E−/− mice compared with wild-type animals.2
It is noteworthy that independent of hyperlipidemia, injuries can result in atherosclerotic/arteriosclerotic changes. For example, Buerger’s disease is an inflammatory disease of small-to-medium–sized limb arteries affecting young, tobacco-smoking men. Transplant vasculopathy is triggered by alloimmune injury of the endothelium. Furthermore, an array of vasculitis, such as Takayasu arteritis and polyarteritis nodosa, is associated with autoimmunity-mediated injury of the arterial wall and, perhaps also, the repair system. Although low-density lipoprotein particles could promote vascular injury, atherosclerosis/arteriosclerosis occurs in all the above disorders independent of elevated lipid levels.
Williams and Tabas make the point that there are no cases of atherosclerosis resulting from a lack of progenitor cells. This statement may not adequately reflect the current state of knowledge. First, a loss of endothelial progenitor cells (EPCs) has been observed in the circulation of patients with atherosclerosis.3,4 Higher levels of circulating EPCs were associated with a reduced risk of major cardiovascular events.5 Importantly, the development of vascular lesions and other manifestations can be affected by the administration of progenitor cells. Indeed, children with severe Hurler syndrome usually die before age 20, with autopsy showing valvular involvement and coronary artery narrowing. After umbilical cord blood transplantation, the lifespan of these patients is remarkably prolonged, with no clinical signs of cardiovascular lesions.6
Notably, our review1 was designed to address recent hypotheses related to the role of progenitor cells, or lack thereof, in arterial disorders. It was by no means a comprehensive review, nor was it intended to downplay the importance of existing work on the arterial injury triggered by abnormal lipids.
Goldschmidt-Clermont PJ, Creager MA, Losordo DW, Lam GKW, Wassef M, Dzau VJ. Atherosclerosis 2005: recent discoveries and novel hypotheses. Circulation. 2005; 112: 3348–3353.
Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003; 108: 457–463.
Kunz GA, Liang G, Cuculi F, Gregg D, Vata KC, Shaw LK, Goldschmidt-Clermont PJ, Dong C, Taylor DA, Peterson ED. Circulating endothelial progenitor cells predict coronary artery disease severity. Am Heart J. In press.