Nebivolol for Improving Endothelial Dysfunction, Pulmonary Vascular Remodeling, and Right Heart Function in Pulmonary Hypertension

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 studied8, 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 (; 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.


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