Pulmonary arterial hypertension (PAH) is caused by progressive obstruction of the pulmonary distal precapillary bed. This raises the afterload of the right ventricle (RV), which responds with hypertrophy and sooner or later, with failure¹. Acute β-adrenergic receptor (β-AR) stimulation facilitates cardiac adaptation and maintenance of cardiac output through positive inotropism and chronotropism. Chronic β-AR overstimulation, however, has a negative impact on cardiac structure and function. Countering this phenomenon with β-AR blockers is one of the cornerstones of left heart failure therapy and has been demonstrated to significantly improve survival². Chronic β-AR overstimulation has also been demonstrated in PAH and may contribute to maladaptive RV remodeling and the development of arrhythmias in the long run³. However, the use of β-AR blocking agents is generally considered contraindicated in PAH. In 2010, Peacock and Ross stated that "their negative inotropic and chronotropic effects are poorly tolerated in this condition, where cardiac reserve is compromised by a reduced and fixed stroke volume, and their administration can result in significant cardiorespiratory compromise"⁴. Patients with PAH have a decreased stroke volume at rest, and because of an inability to increase stroke volume, they depend on their heart rate response to increase cardiac output during exercise. Nonetheless, more than a decade ago antiadrenergic therapy with β-AR blocking agents was also highly debated in chronic left heart failure and has since then evolved from a contraindication to an established treatment for mild-to-moderate heart failure caused by primary or secondary dilated cardiomyopathies².

It is important to take into consideration that β-AR blockers are a wide and heterogeneous group of molecules. β-AR blockers differ in terms of adrenergic β-receptors selectivity, adjunctive effects on α-receptors, and effects on oxidative stress and inflammation⁵. The "first-generation" compounds, such as propranolol and nadolol, are nonselective agents with equal affinities for blocking β1 and β2 receptors and no important pharmacological properties other than β-blockade. The "second-generation" of β-AR blockers, such as metoprolol or bisoprolol, are β1-selective (cardioselective), and the lack of β2-receptor blockade reduces some of the peripheral and pulmonary side effects. The "third generation" β-AR blockers, such as carvidolol and nebivolol, have vasodilating activity; they were designed to treat hypertension. Nebivolol is markedly β1-selective and its vasodilatory action appears to be due to potentiation of nitric oxide (NO). Carvedilol is a slightly β1-selective agent that becomes nonselective at high target doses. The α1-blockade is responsible for the moderate vasodilator properties of carvedilol². Hence, 3rd generation β-AR blockers have the advantage of afterload reduction to counteract the negative inotropic properties of adrenergic withdrawal.

The belief that β-AR blockers may be harmful in PAH was strengthened by a small study in 10 patients with portopulmonary hypertension, in whom withdrawal of propranolol (8/10) or atenolol (2/10) treatment was associated with an increased exercise capacity⁶. However, this is not surprising since administration of first-generation compounds, such as propranolol, causes a decrease in contractile state. This, plus a concomitant increase in systemic vascular resistance, leads to a profound decrease in cardiac output, which results in a drug intolerance rate of 20% in dilated cardiomyopathy². The β2-subtype is the predominant β-AR present in the pulmonary vasculature. Blockade of the β2-receptors may lead to smooth muscle contraction, which could result in a further increase in pulmonary vascular resistance and RV pressures⁷. In several recent observational studies, clinical, functional and hemodynamic outcomes were analyzed for PAH patients coincidentally taking β-AR blockers, e.g. for treatment of arrhythmias. In these studies, second generation β-AR blockers (mainly metoprolol) did not appear to exert detrimental effects in PAH patients even if beneficial effects of β-AR blockers were not specifically studied^{8, 9}. In another observational study dealing with second generation β-AR blockers (mainly bisoprolol), their use was associated with a reduction in RV dilatation and an improvement of Tricuspid Annular Plane Systolic Excursion (TAPSE), which was attributed to a reduction of RV fibrosis¹⁰. In a single-arm open-label pilot study (clinicaltrials.gov; NCT00964678) designed to evaluate the feasibility and safety of add-on treatment with carvedilol in six patients with stable PAH and RV dysfunction (functional classes II and III), the initial data suggested that treatment with carvedilol (3rd generation β-AR blocker) in patients with PAH receiving standard vasodilator drug therapy is feasible and safe, and leads to significant improvement in RVEF and stroke volume, without changes in LV ejection fraction¹¹. Therapy with nebivolol (3rd generation β-AR blocker activating the endothelial-dependent NO pathway, β1/β2 selectivity = 321) led to a significant functional improvement in 12 patients with idiopathic PAH and reductions in RV dimensions and blood ET-1 levels¹².

Recently we demonstrated that PAH pulmonary endothelial cells (P-EC)s overexpressed the pro-inflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more pulmonary artery (PA) smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide-dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension¹³. Hence nebivolol could not only improve RV function but can also alleviate the endothelial dysfunction responsible for the pulmonary vascular remodeling precipitating PAH.

Conclusion and Perspective

Clinical data so far suggest that cardioselective and vasodilatory β-AR blockers can be safely used in PAH patients. Before a sufficiently powered randomized clinical trial is conducted, the efficacy of β-AR blocker treatment in PAH remains undetermined. Clinical trials of nebivolol are warranted on the basis of its distinguishing mechanism of action. Nebivolol is a 1:1 racemic mixture of a D- and an L-isomer. Although nebivolol's D-isomer appears to possess relevant selective β1 -blocking and mild vasodilatory properties, the L-isomer determines the stimulation of eNOS and subsequent endothelium-dependent vasodilation, and only at suprapharmacologic dosages does it exert β –blocking effects¹⁴. These differences between isomers might well have clinical implications, and separate administration of one of the two could be hypothesized for PAH patients.

References

1. Vonk-Noordegraaf A, Haddad F, Chin KM, et al. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Col. Cardiol 2013;62:D22–33.
2. Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–569.
3. Velez-Roa S, Ciarka A, Najem B, Vachiery J-L, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004;110:1308–1312.
4. Peacock A, Ross K. Pulmonary hypertension: a contraindication to the use of {beta}-adrenoceptor blocking agents. Thorax 2010;65:454–455.
5. Barrese V, Taglialatela M. New advances in beta-blocker therapy in heart failure. Front Physiol 2013;4:323.
6. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 2006;130:120–126.
7. Leblais V, Delannoy E, Fresquet F, et al. beta-adrenergic relaxation in pulmonary arteries: preservation of the endothelial nitric oxide-dependent beta2 component in pulmonary hypertension. Cardiovasc Res 2008;77:202–210.
8. So PP-S, Davies RA, Chandy G, et al. Usefulness of beta-blocker therapy and outcomes in patients with pulmonary arterial hypertension. Am J Cardiol 2012;109:1504–1509.
9. Thenappan T, Roy SS, Duval S, Glassner-Kolmin C, Gomberg-Maitland M. β-blocker therapy is not associated with adverse outcomes in patients with pulmonary arterial hypertension: a propensity score analysis. Circ Heart Fail 2014;7:903–910.
10. Moretti C, Grosso Marra W, D'Ascenzo F, et al. Beta blocker for patients with pulmonary arterial hypertension: A single center experience. Int J Cardiol 2015;184:528–532.
11. Grinnan D, Bogaard H-J, Grizzard J, et al. Treatment of group I pulmonary arterial hypertension with carvedilol is safe. Am. J. Respir. Crit Care Med 2014;189:1562–1564.
12. Martyniuk TV, Konosova ID, Chazova IE. [Use of nebivolol in patients with idiopathic pulmonary hypertension: results of the pilot study]. Te. Arkh 2012;84:49–53.
13. Perros F, Ranchoux B, Izikki M, et al. Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension. J Am Col. Cardiol 2015;65:668–680.
14. Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol 2009;54:1491–1499.

Keywords: Adrenergic beta-Antagonists, Animals, Arm, Arrhythmias, Cardiac, Atenolol, Benzopyrans, Bisoprolol, Carbazoles, Cardiomyopathy, Dilated, Chemokine CCL2, Dilatation, Endothelial Cells, Endothelin-1, Endothelium, Ethanolamines, Fibroblast Growth Factor 2, Heart Failure, Heart Rate, Heart Ventricles, Humans, Hypertension, Hypertension, Pulmonary, Hypertrophy, Inflammation, Interleukin-6, Metoprolol, Mitosis, Monocrotaline, Muscle Contraction, Myocytes, Smooth Muscle, Nadolol, Nitric Oxide, Oxidative Stress, Phenotype, Pilot Projects, Propanolamines, Propranolol, Pulmonary Artery, Rats, Receptors, Adrenergic, beta, Stroke Volume, Vascular Resistance, Vasodilation, Vasodilator Agents

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