4.1. β-Adrenergic Physiology
The sympathetic nervous system (SNS) has a key role in the neurohormonal control of cardiovascular functions. The SNS mediates the neural and hormonal responses of fear and stress, and exercises with the cardiovascular functions to meet the increasing demands of the body with a rapid increase in the cardiac output (fight or flight response) [
39]. Sympathetic activation triggers an increase in heart rate (chronotropic), the force of contraction (inotropy), relaxation rate (lusitropy), and conduction (dromotopy) [
40]. Positive chronotropy is generated by phosphorylation changes in intracellular Ca coupling similar to increasing a cyclic adenosine 3′,5′-cyclic monophosphate (cAMP) mediated response that, together, accelerate diastolic depolarization in the sinoatrial (SA) node through the membrane and Ca-coupled clocks, leading to faster impulse generation [
41]. Faster rates of heart and K
+ channel phosphorylation typically abbreviate cardiac repolarization, and it is necessary to facilitate a shorter cycle length to counterbalance the increase in I
Cal required to increase the contractility [
42,
43].
If the spontaneous diastolic depolarization reaches the threshold voltage, the action potential upstroke is activated. The “Funny” current (I
f) is a well-known ionic pacemaker current, responsible for phase 4 spontaneous depolarization. Channels that accommodate I
f currents are triggered by hyperpolarization (increasingly negative voltage) and primarily canalize sodium ions. After the membrane voltage becomes more negative than −50 mV, I
f is activated. Decreasing the I
f activity causes a delay in the time to reach the threshold potential (TP), which leads to a prolongation in phase 4 [
44]. Phase 4 depolarization in a pacemaker cell is depicted in
Figure 1.
Parasympathetic (cholinergic) stimulation leads to antagonistic sympathetic stimulation, thereby decelerating the depolarization process [
46]. Thus, the excitation rate is suppressed. In addition, the stimulation enhances acetylcholine-sensitive K
+ channels that are accessible during the resting period. Positively charged K
+ ions come out through this “inward rectifier” channel, which varies from the K
+ channel that is favorable in phase 3 repolarization, generating an outward current that accommodates the diastolic potential to be more negative. The whole effect of I
f suppression, including the more negative maximum diastolic potential (MDP) and the less negative threshold level, decelerates the excitation level and leads to a reduced intrinsic heart rate [
44].
Beta-blocker usage results in an alteration in the autonomic nervous system, which has an impact on the SA node′s firing rate. Beta-blockers stimulate an inhibition of the beta-adrenergic sympathetic effect. Therefore, they decelerate the SA node′s phase 4 depolarization, resulting in a decrease in heart rate [
47]. Beta-blockers are well known as a first-line therapy for hypertension, although the mechanisms involved in reducing blood pressure are still not clear [
48]. Reducing blood pressure is reached by decreasing the cardiac output related to lowering the heart rate and decreasing the contractility [
49]. The cholinergic and sympathetic effects are depicted in
Figure 2, and the beta-blockers are listed in
Table 1.
One of the most important arrhythmia triggers is an increase in the sympathetic tone, which can be prevented by beta-blockers [
50]. In addition to exerting positive tropic effects in response to physiological and pathological stressors, β-adrenergic stimulation influences cardiac electrophysiology and leads to disturbances of the heart rhythm and potentially lethal arrhythmias, particularly in pathological settings. Due to this, beta-blockers are utilized clinically as antiarrhythmics [
51,
52]. Cardiac-selected beta-blockers minimize the symptoms that may occur from the organization of vague beta-blockers where there is a blockage of the different adrenoreceptors (i.e., β
2, β
3, α
1, and α
2). Different receptors evoke an assortment of reactions in the body, and their blockage could cause a wide scope of responses; however, β
1 adrenoreceptors are cardio-specific, which makes bisoprolol ideal for the treatment of cardiac events. Bisoprolol has a higher degree of β
1 selectivity compared to other β
1-selective beta-blockers, such as atenolol, metoprolol, and betaxolol [
53].
4.2. Cardio-Selective Beta-Blockers Associated with Lung Function
One study involved 51 chronic obstructive pulmonary disease (COPD) patients and heart failure and directly compared the therapy of bisoprolol, metoprolol, and carvedilol for six weeks. From the study, the authors found that the carvedilol group had the lowest forced expiratory volume in one second (FEV1) and that the bisoprolol group had the highest FEV1 with metoprolol in between. In a randomized controlled trial (RCT) study comparing bisoprolol (mean dose of 6.4 mg) and carvedilol (mean dose of 47 mg) in patients with heart failure and COPD, there was a significantly improved FEV1 for approximately 137 mL in the bisoprolol group, but not in the carvedilol group [
54].
In a subgroup involving 2712 patients who had conducted a series of spirometry tests in a cohort study for more than four years, there were no aggravating effects in either the FEV1 or forced vital capacity (FVC) with long-term beta-blocker consumption (88% were administered cardio-selective agents) [
55]. Bisoprolol had the highest ratio of β
1/β
2 receptor selectivity among atenolol and metoprolol, with ratios of 14:1, 5:1, and 2:1, respectively [
56]. Nebivolol possessed greater in vitro β
1/β
2 receptor selectivity than bisoprolol in the human myocardium and also extinguished nitric oxide in endothelial tests [
53]. Terbutaline-induced hypokalemia was significantly greater with the bisoprolol and atenolol therapy groups compared to the nebivolol therapy group. Nebivolol generated significant blunting terbutaline-induced glucose and insulin responses compared to the placebo. In conclusion, cardio-selective beta-blockers can be cautiously prescribed for patients with COPD and cardiovascular disease (CVD) [
57].
4.3. Clinical Use of Beta-Blockers
Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties. Beta-blockers are effective in preventing cardiovascular disease but are no longer suitable for the routine initial treatment of hypertension. Research has proven that β-blocker therapy may antagonize certain direct and indirect arrhythmogenic effects due to an increase in sympathetic activity. Depending on the type of arrhythmia, β-blockers reduce the risk of proarrhythmia by suppressing sympathetic-mediated triggers and functional reentrant substrates, and by suppressing the rate of the SA and AV nodes [
58]. β-blockers are the selected drugs to manage arrhythmic conditions; they are commonly safe agents as they suppress ventricular ectopic beats and arrhythmias and prevent sudden cardiac death in a variety of heart diseases [
59]. According to the guidelines, β-blockers are indicated in all patients except for those with AV blocks, bradycardia, or asthma and are recommended for all patients with heart failure no matter what baseline rhythm the patients have. β-blockers are also used to control ventricular rates in order to evade irregular ventricular activation during atrial fibrillation [
60].
Beta-blockers, such as bisoprolol, are the drug of choice for LQTS. Beta-blockers are recommended in LQTS patients and should be administered in patients who carry LQTS mutations. The most common trigger of arrhythmias in long-QT syndrome type 1 (LQT1) (mostly caused by mutations in the KCNQ1 gene that leads to the production of drug-induced or slow-activating delayed rectifier potassium currents (IKs)) is an increased sympathetic tone (e.g., during exercise) and this can be prevented by using beta-blockers [
61]. Clearly, the QT prolongation induced by hydroxychloroquine and azithromycin, such as in LQT1, can be prevented by using beta-blockers. Unlike in LQT1, beta-blockers are considered to be less effective in long-QT syndrome type 2 (LQT2) (caused by loss of function IKr). Recent studies have shown that propranolol is similarly effective compared to nadolol, whereas metoprolol has less efficacy as an antiarrhythmic therapy [
62]. Nadolol has the greatest efficacy among other beta-blockers, such as in LQT1 and LQT2 treatment [
63]. Beta-blockers can reduce the risk in patients with long-QT syndrome type 3 (LQT3) (caused by a lack of sodium flow), although previous studies have shown that beta-blockers are not effective in LQT3 treatment compared to LQT1 or LQT2 treatment [
64].
Nebivolol, a selective β
1-blocker, has vasodilating effects to reduce peripheral vascular resistance [
65]. Nebivolol has been reported, in hypertension patients, to improve the indicators of myocardial repolarization heterogeneity and electrical instability, such as the QT dispersion, QTc, and corrected dispersion QT (QTcd) [
66].
Bisoprolol therapy has been shown to lead to QTc shortening in LQT1 gene-positive and LQT2 patients and is quite well tolerated for long-term consumption [
67]. A retrospective cohort study involved 114 consecutive gene-positive LQT1 and LQT2 patients who were administered bisoprolol, nadolol, or atenolol. The basic heart rate and QTc were equal between each therapy group. QTc shortening was found in the bisoprolol (ΔQTc −5 ± 31 ms;
p = 0.049) and nadolol (ΔQTc −13 ± 16 ms;
p = 0.02) groups, but not in the atenolol group (ΔQTc 9 ± 24 ms;
p = 0.16) [
68]. We conclude that bisoprolol is the only option for COVID-19 treatment due to its cardio-selective properties.
Similar to cluster of differentiation 147 (CD147), beta-adrenergic blockers block the entry of SARS-CoV-2 through the ACE2 receptor. Beta-blockers with negative regulation on juxtaglomerular cells in the kidney reduce the activity of both arms of the renin–angiotensin–aldosterone system (RAAS) pathway, and so the ACE2 levels decrease. ACE2 is known as the gate where SARS-CoV-2 enters a cell, and by the mechanism above, beta-adrenergic blockers can reduce SARS-CoV-2 entry. Propranolol triggers CD147 downregulation [
69]. Therefore, beta-adrenergic blocker treatment in COVID-19 will decrease SARS-CoV-2 cell entry by the downregulation of both ACE2 and CD147 [
70]. Activation of the beta-adrenergic receptors plays a role in interleukin (IL)-6 secretion, and beta-blockers in IL-4 reduce cardiac disorders in SARS-CoV-2 patients. Beta-adrenergic blockers have been shown to decrease a variety of pro-inflammatory cytokine expressions, including IL-1, IL-1β, IL-6, tumor necrosis factor-α (TNFα), and interferon-γ (IFNγ). Additionally, beta-adrenergic blockers reduce cytokine storms by decreasing pro-inflammatory cytokines (
Figure 3) [
70].
Recent trends suggest that beta-adrenergic blockers are beneficial in septic shock and also reduce mortality in acute respiratory distress syndrome (ARDS). Norepinephrine for treating septic shock should be avoided because it increases the catecholamine level [
70]. Critically ill COVID-19 patients may also experience a sympathetic storm, i.e., an increasing catecholamine level in the body. An increasing catecholamine level leads to an increase in renin release, which increases the activity of both of its arms, including an increase in ACE2 expression, thereby facilitating SARS-CoV-2 cellular entry and worsening the condition. Some severe COVID-19 patients may end up in septic shock [
70].