Roles of β-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

β-Adrenoceptors (β-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three β-ARs, β₁-AR, β₂-AR, β₃-AR are localized to the human heart. Activation of β₁-AR and β₂-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of β₁-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of β₁-AR is critical in the pathogenesis of cardiac arrhythmias while activation of β₂-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of β₂-AR in cardiovascular disease, particularly arrhythmia generation. All β-blockers used therapeutically to treat cardiovascular disease block β₁-AR with variable blockade of β₂-AR depending on relative affinity for β₁-AR vs β₂-AR. Since the introduction of β-blockers into clinical practice in 1965, β-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. β-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. β-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The β-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other β-blockers and is used successfully in the treatment of heart failure. The discovery of β₃-AR in human heart created interest in the role of β₃-AR in heart failure but has not resulted in therapeutics at this stage.