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Cardiovascular Research 2003 58(3):723-724; doi:10.1016/S0008-6363(03)00284-0
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

A different view on human albumin—authors’ reply

Wei-jian Zhang and Balz Frei*

Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331, USA

balz.frei{at}oregonstate.edu

* Corresponding author. Tel.: +1-541-737-5078; fax: +1-541-737-5077.

Received 7 February 2003; accepted 11 February 2003

We thank Drs Nohe and Dieterich for their comments on our recent article in this journal, in which we reported that physiological concentrations of bovine serum albumin (BSA) and recombinant human serum albumin (HSA) selectively inhibit TNF{alpha}-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells [1]. In contrast, neither E-selectin nor intercellular adhesion molecule-1 (ICAM-1) expression were inhibited by BSA [1]. We also observed that BSA inhibits TNF{alpha}-induced VCAM-1 expression in human umbilical vein endothelial cells (HUVEC) [2]. This result is consistent with the inhibitory effect of HSA on TNF{alpha}-mediated VCAM-1 expression in HUVEC reported by Nohe et al. [3]. However, these authors also found that contaminants in two different preparations of HSA can upregulate expression of ICAM-1 and E-selectin in resting and TNF{alpha}-stimulated HUVEC, respectively [3].

Nohe and Dieterich assert that in our article [1] we exclusively discussed the beneficial effects of albumin and did not take into account possible risks of albumin supplementation. The goal of our study was not to assess the efficacy of clinical albumin supplementation, but to understand the biologic and cellular mechanisms by which albumin inhibits endothelial activation, and thus potentially atherosclerosis. Based on the striking anti-inflammatory effects of albumin, but not other proteins such as {gamma}-globulin, on NF{kappa}B activation and VCAM-1 expression, we suggested "that increasing albumin levels may be an effective strategy to lower cardiovascular risk" [1]. However, we did not suggest, nor do we recommend, the use of albumin supplementation. It is obvious that albumin therapy is not practical to prevent coronary heart disease (CHD) or other chronic inflammatory conditions, nor is it desirable, as it can upset serum osmolarity and have adverse side-effects due to pro-inflammatory contaminants, as pointed out by Nohe and Dieterich. Rather, the implication of our study is that lifestyle changes that increase steady-state serum albumin concentrations may be beneficial in lowering cardiovascular risk. Since serum osmolarity is maintained within a narrow range, albumin levels are down-regulated when levels of other prominent serum proteins increase, such as {gamma}-globulin or acute phase reactants. Thus, the most effective way to achieve high albumin levels is to avoid infection or inflammation [4]. Interestingly, our results suggest that increasing albumin levels may further enhance, in a feed-forward loop, resistance to infection and inflammation. Other ways to maintain high serum albumin levels are abstinence from tobacco use, regular exercise and a protein-rich diet [5–9].

Epidemiologic studies have found an inverse association between serum albumin and CHD [10,11] and stroke [12]. For example, low serum albumin was associated with a 50% increased risk of CHD [10] and a two-fold increased risk of total cardiovascular mortality [10,13–16]. In contrast, one study did not find an association between serum albumin and CHD [17]. More recently, the large prospective Framingham Offspring Study, after more than 20 years of follow-up, found that lower serum albumin concentrations are associated with an increased risk of CHD in both sexes, and with all-cause mortality in women [18]. These associations persisted after adjusting for traditional risk factors [18]. While these observational studies cannot demonstrate a causal relationship between increased albumin levels and decreased cardiovascular risk, our data showing that albumin inhibits cytokine-induced endothelial activation and monocyte adhesion [1], which are initiating steps in atherosclerosis [19], provide a plausible mechanism for a cardioprotective role of albumin.

We agree with Nohe and Dieterich that contamination of clinical albumin preparations with kinins and other pro-inflammatory mediators may induce severe hypotension and flushing and other harmful effects [20]. Nevertheless, HSA has been used successfully for more than six decades in the treatment of patients with shock, burns and surgery [21]. Administration of HSA is justified for acute circulatory problems caused by hypovolemia, but is rarely warranted to raise albumin concentrations in hypoalbuminemia. Instead, we suggest that a healthy lifestyle with regular exercise, abstinence from tobacco use, adequate protein intake and, in particular, avoidance of infection and inflammation, may be an effective long-term strategy to increase and maintain serum albumin concentrations in hypo- and normo-albuminemic subjects, respectively, and thus lower cardiovascular risk.


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