Pleiotropy is a lovely word. It is from the Greek, πλεinline imageων, meaning “more,” and τροπinline image, meaning “turn, convert.” Applied to pharmacology, it refers to a drug’s beneficial actions, usually unanticipated, other than those for which the agent was specifically developed. The best-known example is the many actions of statins independent of lipid-lowering. The proposal that β-blockers may have favorable pleiotropic actions, benefits beyond blood pressure (BP) reduction and their other well-documented effects on cardiovascular function, is the topic of a very interesting contribution by Cockroft and Pedersen1 to this issue of the journal.

This is a review of a number of conditions that have some epidemiologic association with hypertension, namely chronic obstructive pulmonary disease (COPD), osteoporosis, and peripheral arterial disease (PAD). The emphasis is on possible common pathophysiologic factors, particularly inflammation and endothelial dysfunction, the usual bad actors in so many diseases. There is also much about the utility of β-blockers in treating all of these conditions, and the point is forcefully made that the β-blocker of choice is nebivolol. Thus is the narrative somewhat pressed into the commercial mould.

In the COPD section, it is suggested that the arterial stiffness, inflammation, and endothelial dysfunction described in patients with COPD are all independent of either past or current cigarette-smoking, but I believe that the evidence for this is flimsy. The most straightforward model is that in which cigarette-smoking causes all of the vascular dysfunction associated with COPD, and would thus account for much of the cardiovascular morbidity and mortality in COPD patients. Also, there are also other features of COPD that might contribute to bad cardiovascular outcomes, including arterial hypoxemia, secondary polycythemia and the increased risk of blood clotting, and pulmonary hypertension with right ventricular hypertrophy and failure.

The authors quote a 2005 Cochrane Collaboration meta-analysis2 to state that the use of cardioselective β-blockers in the treatment of hypertension in patients with COPD is all right. However, a careful examination of that meta-analysis tells us that the mean forced expiratory volume in 1 second decline with treatment was always greater with the β-blocker than with placebo, although none of these differences achieved statistical significance, due primarily to the very large confidence intervals. COPD is a complex disease in which increased airways resistance is caused by an inflammatory infiltrate, mucosal edema, mucus in the lumen, and in a not insignificant number of patients, bronchospasm. Most hypertension experts would regard COPD with bronchospasm as a relative contraindication to the use of β-blockers, even of the β1-selective variety. It may be predicted that nebivolol is safer than bisoprolol for example, because it is almost 3 times more β1-selective, as measured by radioligand-specific binding assay on human myocardial tissue.3 There are some small studies of nebivolol in patients with mild to moderate COPD to show that it was well tolerated,4 but there are no studies in significant numbers of patients to support safety over the range of COPD severity. We also need to remember that carvedilol, a β-blocker shown in clinical trials to benefit patients with heart failure, and commonly used for that purpose, is not β1-selective, and therefore should not be prescribed for patients with significant bronchospasm.

There are epidemiologic correlations between hypertension and osteoporosis; however, both are diseases primarily of the elderly, and in both there are elements of chronic inflammation, as there is likely to be in older persons. Of course, there are correlations between osteoporosis and cardiovascular mortality, because both are more common in the elderly. This reverts back to the old question of whether a statistical correlation between events tells us anything about causality. However, this review brings the two together, consistent with basic concepts of integrative physiology.

Do β-blockers promote bone formation? The answer is, almost certainly yes. β-Adrenergic receptors on osteoblasts inhibit their proliferation, although there is some controversy about the subclass, β1 or β2. Of great interest is the recent discovery that leptin influences bone density via an adrenergic mechanism. However, before we rush to prescribe β-blockers for our patients with osteoporosis, let us pause to consider a case-control study from Denmark5 that reported that there was a reduced fracture risk in patients treated not only with β-blockers, but also in those given angiotensin-converting enzyme inhibitors or calcium channel blockers. This leaves us wondering whether this is due to a specific effect on bone caused by each of the 3 classes of drugs or it is an indirect effect on fall and fracture risk due to the treatment of the underlying cardiovascular disease.

It would be surprising if there were not a close association between hypertension and peripheral arterial disease. It is easy to conceive of one both causing and resulting from the other. Here, nebivolol, a vasodilator β-blocker, could be useful in the treatment of hypertension in patients in whom β-blockade is needed, as in patients with established and symptomatic coronary artery disease, post–myocardial infarction, or heart failure.

Nebivolol is an excellent drug that doesn’t need this degree of promotion to convince clinicians that it represents a major advance in β-blocker therapy. This excellent review would have been even better if there had been fewer suggestions for its use beyond the clinical trials evidence.


  1. Top of page
  2. References
  • 1
    Cockroft JR, Pedersen ME. Beta-blockade: benefits beyond blood pressure reduction? J Clin Hypertens (Greenwich). DOI: 10.1111/j.1751-7176.2011.00552.x.
  • 2
    Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;4:CD003566.
  • 3
    Brixius K, Bundkirchen A, Bölck B, et al. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in the human myocardium. Br J Pharmacol. 2001;133:13301338.
  • 4
    Dal Negro R. Pulmonary effects of nebivolol. Ther Adv Cardiovasc Dis. 2009;3:329334.
  • 5
    Rejnmark L, Vestergaard P, Mosekilde L. Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study. J Hypertens. 2006;24:581589.