β-blockers: acting in the brain but healing the heart

New experimental evidence supports the idea that future therapeutic strategies for treating cardiovascular disease could target sites within the brain. Our recent study demonstrates the existence of previously unrecognized central nervous β-adrenoceptor (β-AR) mechanisms, blockade of which has a beneficial effect on the failing heart. It has been assumed that β-AR antagonists (β-blockers) have a direct favorable influence on the heart, but our results challenge this view, suggesting that β-blockers may also act directly in the brain and that this action could contribute to their clinical effectiveness in heart failure. These data add to an increasing body of evidence supporting the idea that novel approaches might be found to treat cardiovascular disease by aiming at sites within the CNS.

Heart failure (HF) is one of the most important public health problems. Morbidity and mortality associated with HF remain high, despite considerable achievements in its treatment. Analysis of recent clinical trials indicates similar, or possibly superior, beneficial effects of β-AR blockade in comparison to angiotensin-converting enzyme (ACE) inhibition. In fact, the choice of ACE inhibitors as first-line therapy in patients with HF has recently been questioned [1], indicating that treatment with β-blockers is becoming the most important component of HF therapy.

It is surprising and obviously counter-intuitive that, in the face of a progressively failing left ventricular (LV) function, the long-term application of negative inotropic compounds like β-blockers improves cardiac performance, increases exercise capacity, slows remodeling processes and decreases mortality. However, β-blockers used in HF patients constitute a group of compounds with significant individual differences in pharmacology. Efficacy of three β-blockers bisoprolol, metoprolol (acting mainly at β₁-ARs) and carvedilol (acting at α₁-, β₁- and β₂-ARs) in HF treatment have been demonstrated in large clinical trials [2–5]. Patients treated with carvedilol and metoprolol displayed an improvement in LV function and a delayed progression of LV remodeling and, as a consequence, a reduction in the number of deaths from worsening HF. On the other hand, bisoprolol decreased mortality, mainly by reducing incidences of sudden cardiac death [2]. Nebivolol, a third-generation lipophilic β-blocker has been developed recently and its efficacy in HF has been tested in a large clinical trial [6,7]. As yet, it remains to be determined whether nebivolol is superior to other β-blockers such as carvedilol and bisoprolol in HF treatment. In addition, some β-blockers (e.g., bisindolol) have been found to be ineffective when used in patients with HF [8], indicating that the beneficial effects of β-blockers on LV remodeling, sudden cardiac death and mortality in HF cannot be referred to as a class effect, nor can they be satisfactorily explained by blockade of a specific subtype of β-ARs.

A number of mechanisms explaining the variable effects of different β-blockers in HF patients have been proposed (e.g., variability in heart rate responses, modulation of systemic neurohormonal activity, antagonism of the toxic actions of norepinephrine on the myocardium and favorable effects on myocardial energetics [9]). Recently, differences in therapeutic responses to β-blockade in cardiac patients have been linked to β-adrenoceptor gene polymorphisms [10,11]. The evidence, however, could not fully account for variable effects of β-blockers in HF. Indeed, there are data showing beneficial effects [12,13] of β-blockers in β-AR polymorphisms, or no effect at all [14,15].

It appears, however, that the β-blockers that produce a significant beneficial effect in HF all have in common a relatively high degree of lipophilicity and, as a result, have the ability to cross the blood–brain barrier [16]. Over the years, the CNS effects of β-blockers (e.g., fatigue, headache and sleep disturbances) have been considered as side effects to their therapeutic action [17]. However, back in 1990, the first experimental evidence was published demonstrating that the beneficial actions of lipophilic β-blockers in preventing ventricular fibrillation, could be attributed to their possible action within the CNS [18].

Our recent experimental study provides the first direct evidence that an action of β-blockers within the CNS could underlie their beneficial effect on the failing heart [19]. In this study, chronic administration of the β₁-blocker metoprolol directly into the brain attenuated the progression of LV remodeling in a rat model of myocardial infarction-induced HF. This action of metoprolol appears to be mediated via reductions in sympathetic outflow to the heart. These data indicate the existence of a CNS β-AR mechanism, blockade of which is beneficial in HF. However, the precise CNS location of this mechanism remains obscure. Although our data suggest that β-blockers may exert their beneficial action at sites located in the medulla oblongata [19], the evidence obtained is rather indirect. Immunohistochemical and in situ hybridization studies in experimental animals revealed widespread β-AR expression throughout the mammalian brain [20,21]. However, β-AR imaging in the human brain is not yet well developed [22].

Improvement of the latter technique and its implementation in this field may help to identify potential targets of HF treatment within the CNS. Further experimental studies should include novel approaches that produce selective inhibition or silencing (using siRNAs, for example) of β-adrenoceptors in carefully selected areas of the brain. Preventing siRNA effects from spreading to unspecified areas of the brain will require the use of viral expression of shRNA- or miRNA-based constructs. It is crucial to identify the location of β-ARs in the CNS, that when blocked, evoke the most profound beneficial effects on the failing heart. It is also important to determine whether the benefit of central β-AR blockade can be demonstrated when this treatment is initiated early, following the onset of myocardial ischemic injury, as well as at a later stage of HF progression, in particular when cardiac dysfunction has already developed.

The notion that cardiovascular disease can be viewed as a disease of the brain involving autonomic nervous system dysfunction is by no means new. It is supported by a vast body of evidence, which is impossible to list here, demonstrating increased activity of the sympathetic nervous system, decreased vagal tone and decreased heart rate variability in HF patients, hypertensives, diabetics and obese patients. There is also evidence that congenital cardiovascular disease is associated with autonomic dysfunction [23]. Progression of many cardiovascular diseases to congestive HF is associated by characteristic increases in the sympathetic activity [24,25], which are believed to be maladaptive and detrimental, contributing to the progression of LV dysfunction [26–29].

If alterations in the CNS mechanisms controlling autonomic activity contribute to the development of cardiovascular disease, then targeting these mechanisms could be of high therapeutic value. For example, there is evidence that the brain renin–angiotensin–aldosterone system and an upregulation of brain cytokines contributes to HF progression following myocardial infarction. This is supported by experimental evidence showing that chronic brain infusion of either the AT₁-receptor antagonist losartan, the aldosterone receptor antagonist spironolactone, or central gene transfer of IL-10 to attenuate hypothalamic inflammation all reduce LV remodeling in rats following myocardial infarction (reviewed recently in [28]). Wang et al. described attenuation of LV remodeling, improved LV function and reduced sympathetic tone after myocardial infarction in transgenic rats deficient in brain angiotensinogen [30]. In line with these findings, our recent data demonstrate that the blockade of β-ARs in the CNS produces a similar beneficial effect [19].

These different strands of evidence provide a clear indication of the potential for developing new effective therapeutic approaches to treat cardiovascular disease, by aiming at sites within the brain. Development of these novel clinical treatments, which selectively target particular cellular and/or molecular mechanisms in specified central nervous structures controlling the activities of the cardiovascular system through the autonomic outflow, is not an easy task. Far more basic and clinical research must be carried out. However, there is very little doubt that, sooner or later, such treatments will be developed and used in a clinical setting for the benefit of patients suffering from cardiovascular disease.

Acknowledgments

We thank Professor Julian Paton and Dr Oleg Osadchii for helpful discussions.

Financial & competing interests

The authors’ experimental work described in this paper was supported by The Peter Samuel Royal Free Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.