Reduction of blood pressure variability: an additional protective cardiovascular effect of vasodilating beta-blockers?

Abstract

According to updated guidelines on the management of hypertension [1], the major drug classes recommended for its treatment [renin–angiotensin–aldosterone system inhibitors, beta-blockers, calcium-channel blockers (CCBs), and diuretics] are similarly effective in reducing major cardiovascular events and mortality, provided that blood pressure (BP) control is achieved. Nevertheless, some differences in their ability to prevent specific outcomes have emerged, together with compelling or possible contraindications and preferential use in specific conditions for each drug class [1,2]. In this scenario, beta-blockers have been shown to be particularly useful for the treatment of hypertension in patients with symptomatic angina, postmyocardial infarction (MI) with left ventricular (LV) dysfunction, heart failure with reduced ejection fraction, arrhythmias in particular when heart rate (HR) control is required, and in hypertensive pregnant women or in women of child-bearing potential with high BP [1]. In parallel, beta-blockers have been associated with a less favorable metabolic profile, with reduced ability in preventing or regressing cardiovascular damage, including LV hypertrophy, carotid intima–media thickness, aortic stiffness, and small artery remodeling [3], and with consistently limited efficacy in the prevention of stroke, possibly due to their lower ability to reduce central BP and BP variability (BPV). In this issue of Journal of Hypertension, Del Mauro et al.[4] compare the effects on hemodynamic parameters and on hypertension-mediated organ damage of the so-called third-generation beta-blockers carvedilol and nebivolol with those of amlodipine and of a ‘second-generation’ beta-blocker, atenolol, in spontaneously hypertensive rats (SHR) [4]. As widely known, in fact, beta-blockers are not a homogeneous class, and different selectivity at the receptor level combined with additional vasodilating properties characterize molecules such as carvedilol, nebivolol, labetalol, compared with other nonselective (propranolol, sotalol) or beta1-selective (atenolol, bisoprolol, metoprolol) ones (Table 1). The study by Del Mauro et al.[4] shows better hemodynamic properties for vasodilating beta-blockers compared with atenolol, as highlighted by a greater attenuation of central BP and short-term BPV. This effect was similar to what observed for amlodipine, which has an established efficacy on BPV modulation. In addition, chronic treatment with carvedilol, nebivolol, or amlodipine compared with treatment with atenolol was more effective in the prevention of organ damage, expressed in terms of cardiac hypertrophy, cardiac and aortic collagen deposit, and local expression of fibrotic and inflammatory biomarkers.TABLE 1: Selected properties of different beta-blockersThe more favorable properties of these ‘third-generation’ beta-blockers compared with atenolol in reducing central BP are not novel. A retrospective study on hypertensive patients aged 35–65 years on chronic therapy with either angiotensin receptor blockers (ARBs), carvedilol/nebivolol, or atenolol showed that, for similar brachial BP and aortic stiffness, treatment with vasodilating beta-blockers was associated with lower central SBP than treatment with atenolol [5]. The more favorable central hemodynamic effects observed for carvedilol and nebivolol were similar to those of ARBs. Similarly, a study on sinoaortic-denervated rats treated with either carvedilol/nebivolol, atenolol, and verapamil, showed that the ‘third-generation’ beta-blockers induced a greater reduction in short-term BPV compared with atenolol, which was similar to that induced by the CCB, supporting the added benefit of these drugs to cardiovascular protection besides their effect on BP lowering [6]. The CENTRAL study, a prospective, open-label, randomized small controlled trial compared the effects of atenolol (n = 19) and carvedilol (n = 22) on brachial and central hemodynamic parameters in patients with uncomplicated essential hypertension [7]. After 4 weeks of treatment, central and brachial SBP and DBP were reduced by both drugs to a similar extent, but carvedilol resulted in more favorable pulse pressure (PP) amplification and augmentation index (P = 0.02) by increasing arterial compliance and reducing the magnitude of wave reflection, respectively. Nebivolol and atenolol have also been compared in another small, double-blind, randomized, cross-over study in 16 naïve individuals with isolated systolic hypertension [8]. Brachial BP and arterial stiffness were significantly reduced after both drugs, but nebivolol reduced aortic PP more than atenolol (50 ± 2 versus 54 ± 2 mmHg; P = 0.02), potentially due to a mixed beta-blocker/nitro-vasodilator effect of the former, translating in less bradycardia and less increase in augmentation index than treatment with the latter. Endothelial function is, in fact, improved after nebivolol, an effect suggested to be due to greater nitric oxide bioav