Effect of Beta-blockers on Coronary Flow and Resistance in Patients With ANOCA: a Randomised, Placebo-controlled, Mechanistic Study

INTRODUCTION

Beta-blockers (BB) remain a mainstay in the management of cardiac diseases due to a wide range of cardiovascular effects. Through the antagonism of beta-adrenergic stimuli, BB reduce heart rate, cardiac contractility, and left ventricular wall stress, with the latter mediated in part by the antihypertensive action of the drug class. Whilst first-generation BB, such as propranolol, block both β1 and β2 adrenoceptors, second-generation BB (e.g. metoprolol and atenolol) are selective for β1 adrenoceptors and thus avoid the side effects seen with unwanted β2 adrenoceptor blockade, making them ideal antianginal and antiarrhythmic drugs. Third-generation BB - namely carvedilol and nebivolol - exert an additional vasodilatory effect through α-adrenoreceptor blockade and increased nitric oxide (NO) production, respectively, making them effective choices in the management of heart failure and hypertension.

Most recently, BB have been recommended for the treatment of coronary microvascular dysfunction (CMD). CMD is an increasingly recognised pathology affecting patients both with and without coronary artery disease. Its treatment with drugs such as BB has been shown to improve both symptoms and quality of life, leading to its inclusion in the latest European and American guidelines.

Yet, whilst numerous studies have assessed the cardiovascular effects of beta-blockers, many have yielded discordant results regarding their effect on coronary function. Billinger et al. found that IV metoprolol was associated with a significant increase in hyperaemic flow as measured by intracoronary Doppler, with a corresponding decrease in total coronary resistance, among patients with epicardial disease. However, a later study by Togni et al. employing intracoronary Doppler before and after the administration of intracoronary nebivolol, reported a significant increase in coronary flow reserve (CFR) driven by a reduction in resting flow in patients without CAD, and an increase in maximal coronary flow in patients with CAD.

Studies employing nuclear imaging have also yielded inconsistent results. Böttcher et al. found that healthy volunteers who underwent 13N-ammonia PET at baseline and 1 hour after the administration of 50 mg of oral metoprolol exhibited a decrease in resting myocardial blood flow (MBF) in line with a corresponding decrease in cardiac work, but a significant increase in hyperaemic MBF. This ultimately resulted in an increase in CFR. Conversely, Koepfli et al. reported a significant decrease in resting myocardial blood flow but no significant change in hyperaemic MBF in 36 CAD patients who underwent 13N-ammonia PET before and after 12 weeks of oral metoprolol or carvedilol. Studies employing transthoracic Doppler have also reported discordant results.