Mechanisms of the beneficial effects of beta-adrenoceptor antagonists in congestive heart failure

Abstract

Many clinical studies have documented favourable effects (reduced morbidity and mortality) of beta-adrenoceptor (β-AR) antagonists, such as carvedilol, metoprolol, propranolol, atenolol and bisoprolol, in congestive heart failure. These agents attenuate the effects of sympathetic activation during the development of heart failure, prevent ventricular remodelling and improve cardiac function. Because β-AR blockers are known to exert negative inotropic action, the mechanisms responsible for their beneficial effects in heart failure have been a subject of debate. While attenuation of changes in β-AR cyclic AMP-mediated signal transduction in heart failure is considered to be responsible for the beneficial effects of β-AR antagonists, other mechanisms such as the effects of these agents on subcellular remodelling, oxidative stress, apoptosis and defect in calcium handling, are equally important in preventing cardiac alterations in the failing heart. Moreover, β-AR antagonists are not a homogeneous group of drugs because they differ in their pharmacokinetics and pharmacodynamics, in addition to the selective and nonselective nature of their actions on β-AR. Various β-AR blocking agents have been shown to possess different ancillary properties and produce effects that are independent of β-AR. In fact, different β-AR antagonists have been observed to lower the elevated levels of plasma catecholamines in heart failure. Thus, the beneficial effects of β-AR antagonists are not only elicited through their interaction with mediated β-AR signal transduction sites in the myocardium, but other mechanisms may also contribute to their favourable actions in heart failure.

The sympathetic nervous system (SNS) regulates cardiac function through the release of noradrenaline and subsequent activation of beta-adrenergic receptors (β-AR) and, to some extent, alpha-adrenergic receptors (α-AR) (1). It is now well known that the SNS is activated during the development of congestive heart failure (CHF), and its prolonged activation results in the change in the size and shape of the heart (ventricular remodelling) and progression of cardiac dysfunction (2). Accordingly, some agents with β-AR-blocking activity were developed for the treatment of heart failure; however, their use was discontinued because these agents were found to exert negative inotropic action on the heart (3). In spite of some reservations and a great deal of caution, recent years have witnessed a renewed interest in the use of β-AR antagonists for the treatment of CHF, and there is a surge in the development of these drugs. It is, therefore, considered worthwhile to discuss the results of some clinical studies showing beneficial effects of β-AR-blocking agents in CHF. We also plan to highlight the β-AR signal transduction mechanisms, which become defective during the course of development of CHF.

β-AR signal transduction pathways and β-AR antagonists

Under physiological conditions, the SNS remains in a resting state and exerts no influence on heart function (4). However, in the event of heart failure, the SNS is activated and initially helps to maintain cardiac function by increasing inotropic support (5), but prolonged activation of the SNS causes ventricular remodelling and progression of heart failure (6). Three types of β-AR (β₁, β₂ and β₃) and one type of α-AR (α₁) are expressed in the human heart and play a role in the regulation of cardiac function. β₁-AR and β₂-AR are coupled via stimulatory G protein to the effector enzyme, adenylyl cyclase, which converts ATP to cyclic AMP (cAMP). cAMP acts as a second messenger and produces inotropic, chronotropic and growth-promoting effects through protein kinase A (PKA) via phosphorylation of different proteins (7). PKA phosphorylates voltage-dependent L-type calcium channels, resulting in an increase in Ca²⁺ influx into cardiomyocytes during action potential and, thus, is responsible for the inotropic effect (8,9). However, phosphorylation of phospholamban and troponin I induces Ca²⁺ uptake into the sarcoplasmic reticulum (SR) and reduces the affinity of Ca²⁺ to troponin C, resulting in a lusitropic effect (10). β₁-AR and β₂-AR are also responsible for positive chronotropic, dromotropic and bathmotropic effects (10). However, there is evidence that the effects mediated by β₁-AR are also regulated by mechanisms independent of PKA (11). It was observed that apoptosis of cardiomyocytes can be caused by stimulation of β₁-AR, leading to an increase in intracellular Ca²⁺ concentration and activation of Ca²⁺ calmodulin-dependent protein kinase II (11). This theory was further supported by a study (12) that demonstrated that inhibition of Ca²⁺ calmodulin-dependent protein kinase II results in more effective inhibition of apoptosis compared with inhibition of calpain, calcineurin/PP2B or death-associated protein kinase.

β₂-AR are involved in proliferation of cardiomyocytes. One study (13) documented that activation of β₂-AR and subsequent increase in cAMP caused proliferation of cardiac fibroblasts in adult rats. However, another study (14) conducted on human cardiac fibroblast reported that an increase in cAMP and mitogen-activated protein kinase activation did not induce proliferation of cardiac fibroblast. Furthermore, the increased proliferation of cardiac fibroblast by β₂-AR was shown to be caused by the secretion of heat-sensitive growth factors (14). On the other hand, β₂-AR stimulation has been reported to prevent cardiac apoptosis because of their coupling with inhibitory G (G_i) proteins and inhibition of the adenylyl cyclase-cAMP-PKA pathway (15). The other pathway through which β₂-AR contribute to the antiapoptosis effect is the activation of phosphatidylinositol 3-kinase by β₂-AR G_i coupling. Phosphatidylinositol 3-kinase stimulates protein kinase B and results in attenuating concurrent β₂-AR stimulatory G protein-mediated activation of PKA and decreasing apoptosis (16). It is evident from the above discussion that β₂-AR stimulation may cause cardiac hypertrophy and may protect the myocardium from the apoptotic effects of prolonged activation of the SNS. Such observations need to be taken into consideration when prescribing β-AR antagonists in heart failure.

It is suggested that β₃-AR are coupled to adenylyl cyclase via G_i proteins and, thus, their negative inotropic action is considered to be elicited by changing the adenylyl cyclase activity (6). These receptors have been suggested to neutralize the inotropic, chronotropic and dromotropic effects of β₁-AR and β₂-AR (6). This action is particularly significant in pathological states associated with adrenergic hyperactivity because β₃-AR receptors are stimulated at higher concentrations of catecholamines than β₁-AR and β₂-AR (17,18). The effects of β₃-AR are also mediated through the activation of endothelial nitric oxide (NO), which results in increased production of cyclic GMP (cGMP) and activity of cGMP-dependent protein kinase (17,18). The activation of cGMP-dependent protein kinase stimulates phosphodiesterase and results in myocardial relaxation (19,20). Apart from their action on the myocardium, β₃-AR stimulation produces coronary and peripheral vasodilation (17). However, β₃-AR stimulation can have detrimental effects in end-stage heart failure due to their negative inotropic action (21). Because β₃-AR are stimulated only in the hyperadrenergic state and cause negative inotropism, β-AR antagonists can be useful in these settings.

AR antagonists are classified into three categories, namely, α-AR antagonists, β-AR antagonists and mixed antagonists (22,23). The major AR antagonists and their receptor selectivity are listed in Table 1. The α₁-AR are coupled via the G_q protein to the effector enzyme phospholipase C, which may produce diacylglycerol and result in the activation of protein kinase C (23). It is suggested that β-AR antagonists are further divided into three types depending on their antiadrenergic profile and presence of ancillary properties. The first-generation compounds are nonselective and block both β₁-AR and β₂-AR with equal affinity; the main prototypes of this group are propranolol and timolol. The second-generation compounds are cardioselective agents that block β₁-AR with greater affinity than β₂-AR; two agents in this group are metoprolol, which is 75 times more selective for β₁-AR compared with β₂-AR, and bisoprolol, which is 120 times more selective. The third-generation compounds include carvedilol and bucindolol, which block both β₁-AR and β₂-AR with almost equal affinity and have some additional properties that differentiate them from the first-generation compounds. Carvedilol blocks α₁-AR and, in addition, has antioxidant action. Bucindolol has vasodilatory action and shows intrinsic sympathomimetic activity (24). Thus, it is evident that AR antagonists may affect cardiac function by acting on cardiac and noncardiac sites through specific and nonspecific AR-mediated signal transduction mechanisms or on modification of other cellular events (Figure 1).

TABLE 1.

Adrenergic antagonists and their receptor selectivity

	Adrenergic antagonist	Receptor selectivity
Alpha (α)-antagonist	Prazosin, doxazosin, tamsulosin	α1
	Phenoxybenzamine	α1 > α2
	Phentolamine	α1 and α2
	Yohimbine	α2
Beta (β)-antagonist	Metoprolol	β1
	Atenolol	β1
	Acebutalol	β1
	Betaxolol	β1
	Esmolol	β1
	Propranolol	β1 and β2
	Carteolol	β1 and β2
	Timolol	β1 and β2
	Butoxamine	β1
Mixed antagonist	Labetalol	β1, β2 and α1
	Carvedilol	β1, β2 and α1

Figure 1).

Pathways through which beta-adrenergic receptor (β-AR) antagonists exert beneficial effects in chronic heart failure. Apart from their action on β-AR, they result in the reduction of sympathetic activity by acting directly on prereceptor nerve endings. In addition, they preserve energy and have antioxidant and antiarrhythmic actions; the latter is responsible for beneficial effects in heart failure

It is important to know the effects of sustained adrenergic drive on the failing heart to understand the mechanism by which long-term β-AR antagonist therapy produces beneficial results in heart failure. In healthy hearts, approximately 60% to 80% of the β-AR expressed are β₁, 20% to 40% are β₂ and approximately 2% are β₃ (6). It has been documented that in failing hearts, β₁-AR undergoes selective downregulation and the ratio of β₁:β₂ changes from 77:23 to 60:38 (25). Because α₁-AR are upregulated in heart failure, this changes the AR profile from predominantly β₁ to a mixed profile with a β₁:β₂:α₁ ratio of 2:1:1 (26,27). It should be noted that β-AR-mediated signal transduction depends on the stage of heart failure and is differently regulated in the left and right ventricles. While the signal transduction parameters are depressed after eight to 24 weeks of myocardial infarction (MI) in the left ventricle, the right ventricle shows increased signal transduction at eight weeks and depressed signal transduction at 24 weeks (28). These differential changes may be due to differences in the type and stage of hypertrophy because β₁-AR expression was increased in the hypertrophied heart due to volume overload, but was unaltered at the early stage of heart failure due to pressure overload (29). However, in the late stages of both types of hypertrophy, there is a downregulation of β-AR. Accordingly, it appears that in earlier compensated stages of heart failure, β-AR are upregulated or unchanged but, at later decompensated stages, they are downregulated. Apart from changes in the expression of β-AR, G protein levels play a critical role in the pathogenesis of heart failure. It has been documented that there are increased levels of G_i proteins in the myocardium of patients with heart failure (30). Another theory for the alterations in the β-AR signal transduction is the change in the affinity of the receptors. A decrease in the affinity of β-AR was reported in CHF (31). However, a subsequent study (27) showed no change in the affinity. Nonetheless, it is becoming clear that alterations in the β-AR and G proteins depend on the stage of heart failure and various stressful stimuli.

In an interesting experiment, transgenic mice with heart-specific overexpression of β₁-AR were studied; these mice showed increased contractility of the heart at a young age, but developed cardiac hypertrophy, which was followed by progressive heart failure. The results suggested that overexpression of β₁-AR leads to initial improvement of heart function and ultimately results in heart failure (32). In a similar study (33), it was reported that overexpression of alpha-stimulatory G protein over the life of a transgenic mouse resulted in cardiomyocyte degeneration and replacement fibrosis as well as hypertrophy of the remaining cells; these changes were responsible for heart failure. It has also been shown that stimulation of β₁-AR increases apoptosis through the cAMP-dependent pathway, while β₂-AR stimulation inhibits apoptosis via G_i coupling (34). However, a high level of overexpression of β₂-AR ultimately results in systolic dysfunction and cardiomyopathy (35). These data indicate that chronic AR activation, which is a compensatory mechanism at initial stages, may exert harmful effects in chronic stages. It is known that in heart failure, β-AR signal transduction is reduced because of desensitization of β-AR and changes in G_i protein as well as expression of adenylyl cyclase enzyme (22). Because a substantial signalling capacity remains despite significant loss of signal transduction at the end stage of heart failure (22), it was suggested that decreased signal transduction is an adaptive mechanism to prevent progression of heart failure, and any therapy that supplements this intrinsic mechanism would be beneficial. It has been documented that a state of protracted sympathetic hyperactivity in chronic heart failure occurs, and this hyperactivity is inversely proportional to the left ventricular ejection fraction (36). Furthermore, it has been indicated that this hyperactivity is not in response to a decrease in arterial pressure, but due to an impairment of reflexes from heart receptors that inhibit efferent sympathetic activity (36).

Mechanisms of beneficial effects of β₁-AR antagonists in heart failure

Although attenuation of changes in β-AR-mediated signal transduction in failing heart contribute to the beneficial effects of β-AR antagonists in heart failure, it appears that some other mechanisms are equally responsible. It was suggested that several benefits of β-AR antagonists were due to reduction in the heart rate. A study (37) was conducted to investigate whether metoprolol and a pure heart rate-reducing agent, ivabradine, had similar effects on cardiac hemodynamics, ventricular remodelling and Ca²⁺ handling in MI-induced heart failure in rats. It was found that although ivabradine had beneficial effects on cardiac hemodynamics, metoprolol had additional benefits in preventing left ventricular dilation and hypertrophy. Metoprolol was associated with increased contractility of isolated cardiomyocytes and better Ca²⁺ handling in the post-MI rat heart (37). Such observations indicated that some other mechanism apart from the action on AR must be responsible for the effects of metoprololol.

While comparing the effects of different β-AR antagonists on rat heart sarcolemmal (SL) Ca²⁺ transport activities (38), it was found that propranolol and oxyprenolol had biphasic actions; the lower concentrations were stimulatory while higher concentrations were inhibitory. In addition, pindolol was stimulatory, while acebutolol had no effect on SL Ca²⁺ transport (38). Those observations suggest that the SL membrane is the site of action of β-AR antagonists; however, the exact role of SL Ca²⁺ pump activity in heart failure is not clear. On the other hand, SR dysfunction due to abnormalities in SR proteins was indicated to play a major role in heart failure, and the genes expressing SR Ca²⁺ pump, Ca²⁺-release channels and other regulatory proteins could be potential targets for the treatment of heart failure (39). Moreover, improvement of human heart muscle function due to β-AR antagonists (carvedilol, metoprolol and atenolol) was associated with restoration of normal SR ryanodine receptor (RyR2) channel activity (40). Similar effects on SR Ca²⁺ leak from RyR2 were seen with propranolol (41). Furthermore, metoprolol was reported to improve cardiac function by preventing alterations in Ca²⁺ cycling proteins, such as RyR2, and the ratio of SERCA2a and Na⁺-Ca²⁺ exchanger in addition to increasing Ca²⁺ transients in the failing heart (42). However, carvedilol treatment was found to result in a more significant improvement of SERCA expression than metoprolol (43). Carvedilol has been proven to directly inhibit L-type Ca²⁺ current similar to Ca²⁺ antagonists and, thus, decrease the influx of Ca²⁺ in cardiomyocytes (44). Because one of the mechanisms associated with the progression of left ventricular hypertrophy and heart failure is catecholamine-induced Ca²⁺ overload and PKA activation, carvedilol was shown to decrease Ca²⁺ load by depressing the L-type Ca²⁺ currents (45). It was also demonstrated in a study (46) using SR vesicles isolated from the left ventricle that carvedilol improved intracellular Ca²⁺ handling in heart failure by correcting defective interdomain interaction within the RyR2, thereby improving cardiac function. The expression of SERCA messenger RNA (mRNA) and protein, which is downregulated after MI, is restored with low-dose carvedilol treatment (47). The antioxidant property of carvedilol plays a crucial role in restoring the expression of SERCA mRNA and protein (48). These findings support the view that restoration of Ca²⁺ pump and Ca²⁺-release channel functions is one of the possible explanations for beneficial effects of β-AR antagonists in failing hearts (40).

It is now well known that activation of the SNS results in the release of noradrenaline from the sympathetic nerve endings and adrenaline from the adrenal medulla and, thus, the elevated levels of plasma catecholamines are associated with ventricular remodelling and heart failure (6,49). Noradrenaline exerts its effects by acting on AR in the heart where the type of receptor plays an important role; β₁-AR is involved in noradrenaline-induced cardiac apoptosis (50) whereas β₂-AR is known to prevent this (51). It was also found that noradrenaline caused apoptosis in rat cardiomyocytes through downregulation of Bcl-2 and activation of caspase-2 pathways (51); caspase inhibitors were observed to prevent noradrenaline-induced cardiac apoptosis. In rats with MI-induced heart failure, both low and high doses of atenolol and propranolol attenuated cardiac dysfunction and depressed the MI-induced increase in adrenaline; the increased noradrenaline levels due to MI were lowered by high doses of these agents but were unaffected by low doses (52). It was observed in patients with chronic heart failure that atenolol improved ventricular function and clinical status without affecting the plasma levels of noradrenaline (53). On the other hand, a nonselective β-AR antagonist, propranolol, was reported to cause a reduction in noradrenaline spillover in heart failure patients (54). Likewise, carvedilol caused a significant decrease in cardiac and systemic noradrenaline spillover in patients with heart failure, whereas metoprolol failed to produce such changes (55). Carvedilol, unlike atenolol, significantly blunted the increase in plasma noradrenaline during exercise and this effect was attributed to the blockade of presynaptic β₂-AR (56). While the different β-AR antagonists depressed the release of noradrenaline due to their effects on preterminal nerve endings (57), vagal stimulation was found to improve long-term survival of rats with chronic heart failure (58). Moreover, in rats with adriamycin-induced heart failure, it was seen that carvedilol treatment resulted in the upregulation of muscarinic cholinergic receptors in the endocardial tissues of the left ventricle (59). Thus, it appears that the antiadrenergic effects independent of β-AR may be another pathway through which β-AR antagonists prevent the progression of heart failure (Figure 1).

Apart from their action at the cellular and molecular level, β-AR antagonists were shown to produce favourable changes in heart failure by acting on myofibrils (60). It was observed in a study (60) conducted on heart failure in rats that atenolol and propranolol treatment attenuated MI-induced depression in myofibrillar Ca²⁺-stimulated ATPase activity and phosphorylated the cardiac troponin I protein. The MI-induced decrease in the α-myosin heavy chain (MHC) and the increase in β-MHC proteins were also attenuated by both propranolol and atenolol at low and high doses (60); the changes in gene expression for α-MHC and β-MHC were not attenuated with low-dose propranolol (60). Similar effects on myofibrillar function were also observed with metoprolol and carvedilol (61). These studies support the view that both selective and nonselective β-AR antagonists exert beneficial effects by their effects on contractile and regulatory proteins in heart failure.

It was first reported that propranolol exerted antioxidant properties independent of β-AR blockade and this mechanism was considered to be responsible for the protection against SL lipid peroxidation (62,63). In one such study (64) on cultured human coronary artery endothelial cells, it was found that adrenaline-induced apoptosis was associated with the activation of Fas-Fas ligand and caspase-3 signal transduction pathway, and carvedilol was more effective than atenolol in attenuating these effects of adrenaline because of its antioxidant property. Effects of treatment with carvedilol, metoprolol and metoprolol plus bunazocin (selective α₁-AR antagonist) were investigated on experimental MI in rat hearts (65). In this study, carvedilol showed a greater antioxidant activity, attenuation of inflammatory mediators and activation of nuclear factor-kappaB. Furthermore, addition of bunazocin to metoprolol did not add to the effects of metoprolol alone (65). Another study (66) demonstrated that oxidative stress-induced apoptosis was independent of α-AR and β-AR, and carvedilol treatment delayed the process; this effect was not seen with other β-AR antagonists such as metoprolol, propranolol and atenolol. However, N-acetyl-L-cysteine and the combination of N-acetyl-L-cysteine and propranolol showed antioxidant activity similar to carvedilol (66). The effects of carvedilol and its hydroxylated analogue on apoptosis were tested in an experimental MI model of the rat heart. It was observed that although carvedilol treatment prevented apoptosis, its hydroxylated analogue did not; these data support the view that carvedilol has antiapoptotic effects independent of β-AR antagonism (67). In another study (68), the effects of carvedilol on abnormality of L-type Ca²⁺ current induced by oxygen-free radical in a single guinea pig cardiomyocyte were examined; this drug treatment resulted in the reduction of this defect. Carvedilol, unlike metoprolol, was found to inhibit reactive oxygen species because its molecular structure favours redox recycling (69,70). While metoprolol was observed to produce beneficial effects on ventricular remodelling by improving Ca²⁺ handling only, carvedilol improved cardiac redox state and Ca²⁺ handling, thus highlighting the contribution of its antioxidant action (71). Carvedilol inhibited mitochondrial oxygen consumption and superoxide production during Ca²⁺ overload in isolated heart mitochondria (69). From these observations, it appears that carvedilol has a more potent antioxidant effect than any other β-AR antagonist, and this property is not only involved in preventing catecholamine-induced apoptosis but also abnormalities in Ca²⁺ handling. However, it has been reported that metoprolol also exerted antioxidant properties similar to carvedilol and, thus, attenuated ventricular remodelling (72). Such conflicting results appear to be due to differences in doses of different β-AR antagonists used in various studies.

Carvedilol has been shown to possess several ancillary properties that are responsible for the improvement of heart failure independent from the upregulation of β-AR (73). In addition to the antioxidant effect, carvedilol was found to improve endothelial dysfunction because it increased NO levels and upregulated NO synthase 3 mRNA (74) in rats with streptozotocin-induced diabetes. Other β-AR antagonists, such as propranolol and metoprolol, inhibited the synthesis and release of endothelin (75). In a rat heart model of isoproterenol-induced hypertrophy, it was observed that carvedilol produced better effects on cAMP production and cardiac hypertrophy, as well as reduced left ventricular weight without affecting the heart rate and blood pressure compared with metoprolol (76). It should also be noted that ventricular arrhythmias are the major cause of morbidity in heart failure and the increase of transmural heterogeneity of ventricular repolarization plays an important role in causing these arrhythmias (77). Carvedilol decreases the transmural heterogeneity of ventricular repolarizations due to its direct electrophysiological property rather than its effects on ventricular remodelling (78). Another mechanism through which carvedilol prevents apoptosis was demonstrated in a study (79) in which the expression of autophagic-, antiapoptotic- and apoptotic-related proteins were studied in rat hearts with MI induced by coronary artery ligation. It was observed that antiapoptosis-related proteins increased in response to upregulation of autophagy by carvedilol treatment. Carvedilol, unlike metoprolol, was also found to reduce the effect of β-AR antagonists on the increased expression of β₃-AR in chronic heart failure (80). Another mechanism responsible for beneficial effects of metoprolol in attenuating ventricular remodelling is related to decreasing cardiomyocyte loss through apoptosis. It was found that the number of nuclear DNA defragmentation events in cardiomyocytes, which is a marker of apoptosis, was lower in dogs who experienced heart failure and were treated with metoprolol (81). Because β₁-AR stimulation due to adrenergic activation in heart failure increases the expression of proapoptotic protein Bxl-X(S), metoprolol has been shown to attenuate the expression of this proapoptotic protein indicating this pathway is one of the mechanisms responsible for its beneficial effect in heart failure (82). In a study (83) conducted on MI-induced heart failure in rats, it was observed that apoptosis was attenuated by β₂-AR antagonists to a greater extent than by the β₁-AR antagonists.

Although it is not fully understood how the blockade of β-AR pathway increases contractility of the heart and improves cardiac function in heart failure, some investigators have attributed these effects to the prevention of the β-AR signal transduction abnormalities and subsequent retardation of ventricular remodelling. β-AR antagonists, such as metoprolol, improve the efficiency of the AR signalling pathway by restoring the down-regulated receptors and, thus, increasing their numbers. On the other hand, carvedilol showed no effect on the number of AR receptors but inhibited receptor kinase and, thus, improved the efficiency of β-AR signalling pathway (7,22).

Propranolol was found to be ineffective in post-MI rats who experienced heart failure in terms of improvement in left ventricular remodelling, systolic function or intracellular Ca²⁺ handling (84). However, it was observed that long-term treatment with propranolol failed to attenuate cardiac hypertrophy, but abolished the oxidative stress in a rat model of heart failure in addition to a reduction in the sensitivity to catecholamine-induced arrhythmias (85).

In another study (86), the effects of β-AR antagonists in the brain were investigated to examine whether their actions contributed to beneficial effects in heart failure. It was found that chronic intracerebroventricular administration of metoprolol resulted in slowing of the progression of ventricular remodelling in MI-induced heart failure in rats.

Metoprolol was also seen to attenuate the myocardial expression of tumour necrosis factor-alpha and interleukin-1β in rats with MI-induced heart failure, thus revealing another mechanism through which β-AR antagonists may be helpful in chronic heart failure (87). On the other hand, nebivolol has been shown to prevent hydroxyl radical-induced contractile dysfunction through a direct effect on myofilaments and by preserving the function of SR (88). Thus, there appears to be several mechanisms that could be responsible for the benefits of β-AR antagonists in heart failure (Figure 1).

In some experiments, the effects of carvedilol treatment on cardiac function, ventricular remodelling and the adrenergic system were compared with that of metoprolol (89). It was observed that carvedilol and metoprolol produced the same degree of β-AR blockade as evidenced by changes in heart rate; however, carvedilol produced greater improvement in ventricular function in the failing heart. It was also found that carvedilol, unlike metoprolol, lowered the coronary sinus noradrenaline levels. In addition, metoprolol increased cardiac β-AR density, whereas carvedilol showed no effect on cardiac β-AR expression (89). The superiority of carvedilol over metoprolol in the treatment of heart failure was also reported by other investigators (90). In another study on the post-MI rat heart, carvedilol prevented left ventricular remodelling with respect to volume expansion and segmental hypertrophy in a dose-dependent manner, whereas metoprolol prevented left ventricular dilation without any effect on cardiac hypertrophy (91). Furthermore, carvedilol significantly reduced myocardial collagen in the noninfarcted myocardium in MI-induced heart failure in rats, whereas metoprolol had no effect (92). Although metoprolol attenuated postinfarct ventricular remodelling by blocking β₁-AR, it did not improve myocardial energy metabolism and function (93). When the effects of atenolol were compared with metoprolol in dogs with microembolization-induced heart failure, it was found that atenolol prevented the decrease in ejection fraction, whereas metoprolol increased the ejection fraction, indicating the superiority of metoprolol over atenolol (94). The effects of long-term therapy with metoprolol on ventricular remodelling and progression of heart failure were also examined in dogs with heart failure. It was observed that treatment with metoprolol resulted in a 46% reduction in replacement fibrosis, 54% reduction in interstitial fibrosis and 20% reduction in cardiac hypertrophy (95). The data from these studies suggest that various β-AR antagonists may prevent ventricular remodelling, but the mechanisms of their beneficial effect in heart failure seem to be different from each other.

Clinical trials of β-AR antagonists in heart failure

Analysis of some studies (96) conducted in the mid-1970s showed favourable effects of β-AR antagonists on left ventricular function and clinical symptoms in heart failure (96). These trials revealed that β-AR antagonist therapy in heart failure improved the ejection fraction, and reduced the mortality and hospitalization time (97,98). A meta-analysis (99) that included 22 trials and 10,135 patients with heart failure (New York Heart Association [NYHA] class II and III) demonstrated the impact of β-antagonist therapy. The data revealed that there were 624 deaths among 4862 patients who received placebo, while only 444 deaths were reported among 5273 patients who received β-AR antagonists. The best estimate of the benefits is 3.8 lives saved and four fewer hospitalizations per 100 patients treated for one year. The majority of the studies in this metaanalysis were conducted on metoprolol and carvedilol; however, some studies used bisoprolol, bucindolol and nebivolol. The major clinical studies conducted on various β-AR antagonists (Table 2) are discussed in the following section (100–109).

TABLE 2.

Results of the major clinical studies of beta (β)-adrenoceptor antagonists in chronic heart failure

Agent	Receptor selectivity	Effects	Reference
Metoprolol	β1	Improved systolic function between one and three months, regression of left ventricular mass and change in shape from spherical to normal elliptical	(100)
Metoprolol	β1	Decreased mortality (RR reduction of 34%)	MERIT-HF (101)
Carvedilol	Nonselective	5.7% more reduction in mortality compared with metoprolol tartrate	COMET (102)
Carvedilol	Nonselective	Reduced hospitalizations and mortality	(103)
Carvedilol	Nonselective	Reduced all-cause mortality, cardiovascular mortality and nonfatal myocardial infarction	CAPRICORN (104)
Carvedilol	Nonselective	Improved clinical status and reduced mortality, well tolerated even in patients with very low systolic blood pressures (85 mmHg to 100 mmHg)	COPERNICUS (105)
Atenolol	β1	Improved survival rates but lower than metoprolol	(106)
Bisoprolol	β1	Reduced mortality independent of severity of heart failure	CIBIS-II (107)
Nebivolol	β1	Reduced mortality	SENIORS (108)
Propranolol	Nonselective	Reduced mortality in patients with ejection fraction of 40% or greater	(109)

CAPRICORN The Carvedilol Post Infarct Survival Control in Left Ventricular Dysfunction; CIBIS-II The Cardiac Insufficiency Bisoprolol Study II; COMET Carvedilol Or Metoprolol European Trial; COPERNICUS Carvedilol Prospective Randomized Cumulative Survival; MERIT-HF Metoprolol CR/XL Randomized Intervention Trial in Heart Failure; SENIORS Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure

Metoprolol

A study (100) was performed to examine the time course of improvement of cardiac function in patients with dilated cardiomyopathy when administered metoprolol. It was observed that after an initial decline in ventricular function, there was an improvement between one and three months of therapy. It was also observed that there was regression of a left ventricular mass and change in the shape from spherical to normal elliptical by 18 months of therapy (100). A large randomized trial (Metoprolol CR/XL Randomized Intervention Trial in Heart Failure [MERIT-HF; 101]) was designed to assess whether the improvement in the cardiac hemodynamics and function produced by metoprolol were associated with a reduction in mortality and morbidity in heart failure. This study was conducted at 313 sites in the United States and Europe; 3991 patients with chronic heart failure (NYHA class II to IV) and ejection fraction of 40% or less, and well maintained on standard therapy were included. On randomization, 1990 patients received metoprolol and 2001 patients received placebo. Metoprolol succinate starting from either 12.5 mg/day in NYHA class III and IV, or 25 mg/day in NYHA class II and titrated six to eight weeks up to a target dose of 200 mg/day was given to patients in this study group. It was observed that all-cause mortality was 7.2% in the treatment group and 11% in the placebo group; there was a RR reduction of 34%. Moreover, RR reductions were 38% for cardiovascular deaths, 41% for sudden deaths and 49% for deaths due to worsening heart failure. Although the study was planned for three years, it had to be stopped at the halfway point because of the mortality benefits in the treatment group (101). In another study (Carvedilol Or Metoprolol European Trial [COMET; 102]), the effects of carvedilol on mortality in heart failure were compared with those of metoprolol. Patients with chronic heart failure with NYHA class II to IV and an ejection fraction of 35% receiving treatment with angiotensin-converting enzyme (ACE) inhibitors and diuretics were included in the study. In this trial, 3029 patients were randomly assigned to receive either metoprolol (metoprolol tartrate, target dose 50 mg twice daily) or carvedilol (target dose 25 mg twice daily). It was observed that all-cause mortality was 34% for carvedilol and 40% for metoprolol. The absolute reduction in the mortality rate over five years was 5.7% (102).

Carvedilol

As it became clear that β-AR antagonists produced hemodynamic and symptomatic improvement in heart failure, a study (103) was planned to investigate the effects of carvedilol on mortality and morbidity in patients with chronic heart failure. In this study, 1094 patients with mild, moderate or severe heart failure with an ejection fraction of 35% or less were enrolled; 696 patients received carvedilol and 398 patients received placebo. The standard therapy comprising digoxin, diuretics and ACE inhibitors was continued, and the patients were observed for six months for hospitalizations and deaths related to cardiovascular causes. It was found that there was a reduction in the risk of death and hospitalizations with carvedilol treatment (103). Another study (The Carvedilol Post Infarct Survival Control in Left Ventricular Dysfunction [COPERNICUS; 104]) was designed to investigate the effects of carvedilol on morbidity and mortality in patients with post-MI heart failure. In this multicentre randomized trial (104), 1959 patients treated for MI and left ventricular ejection fraction of 40% or less were randomly assigned to receive either carvedilol (6.25 mg at start and gradually increased to 25 mg twice a day) or placebo. It was observed that cardiovascular mortality, nonfatal MI and all-cause mortality were lower in the carvedilol group (104). Clinicians were apprehensive of using carvedilol in high-risk heart failure patients with low blood pressure, fearing that it would interfere with the homeostatic action of the sympathetic nervous system and would result in dizziness, hypotension and worsening of heart failure. Thus, a multicentre study (COPERNICUS; 105]) was designed to investigate the influence of pretreatment systolic blood pressure on the efficacy and safety of carvedilol in patients with chronic heart failure (105). Patients with severe heart failure having dyspnea or fatigue at rest or on minimal exertion for two or more months and an ejection fraction of less than 25% despite treatment were enrolled. Unlike other studies, this study even included patients with a very low systolic blood pressure (85 mmHg to 100 mmHg). Patients were randomly assigned in a double-blinded fashion to receive either carvedilol (3.125 mg initially to be titrated to a target dose of 25 mg twice daily) or placebo. Results showed that carvedilol not only improved the clinical status of patients, but also resulted in reduction of mortality and hospitalizations. It was also found that carvedilol was well tolerated in patients with low blood pressure; these patients had the greatest need for treatment with carvedilol (105).

Atenolol

Atenolol has also been shown to be beneficial in heart failure. In a study by Celic et al (106), 150 patients on standard treatment with NYHA class II and III and an ejection fraction of 40% or less were randomly assigned to three groups, namely metoprolol, atenolol and a control group. The cumulative survival rate for patients treated with metoprolol was 88% and for those treated with atenolol, the survival rate was 78%; while for the control group, the survival rate was just 48%. Although atenolol showed a favourable effect on patient survival in heart failure, metoprolol was more effective (106). However, in a cohort study (110) of high-risk patients with heart failure, it was found that the adjusted risk of hospitalization for heart failure was not significantly different in patients receiving atenolol, carvedilol or short-acting metoprolol tartrate (110).

Bisoprolol

A multicentre, double-blinded, randomized controlled clinical trial (The Cardiac Insufficiency Bisoprolol Study II [CIBIS-II; 107]), including 2647 symptomatic patients with NYHA class III or IV and an ejection fraction of 35% or less receiving standard therapy with diuretics and ACE inhibitors, was conducted to investigate the efficacy of bisoprolol in decreasing all-cause mortality in patients with chronic heart failure. Patients were randomly assigned to receive bisoprolol 1.25 mg or placebo – the drug dose being gradually increased to 10 mg per day. The study had to be stopped after the second interim analysis because the bisoprolol-treated group showed a significant reduction in the mortality rate; these effects were independent of the severity or cause of heart failure. It was also found that bisoprolol reduced mortality in patients with heart failure at all tolerated dose levels and its withdrawal increased mortality (111). The benefits seen with bisoprolol treatment in terms of all-cause mortality were the same as with enalapril, but bisoprolol treatment showed fewer sudden deaths; however, more episodes of worsening of heart failure were seen with bisoprolol treatment (112).

Nebivolol and propranolol

Nebivolol is the most selective β₁-AR antagonist having vasodilator properties without any action on α-AR (113). It stimulates β₃-AR resulting in NO production, not only in the vascular system but also in the myocardium; thus having a favourable effect on heart failure (114). The clinical effects of this drug in terms of mortality were investigated in a randomized trial (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure [SENIORS; 108]) including 2128 patients 70 years of age or older with heart failure regardless of the ejection fraction. It was found that the all-cause mortality rate was lower in the nebivolol-treated group (108). In older patients with post-MI heart failure and an ejection fraction of 40% or greater on diuretics and ACE inhibitors, propranolol treatment resulted in a reduction in mortality and improvement in left ventricular ejection fraction (109).

CONCLUSION

The paradox of β-AR antagonist use in heart failure has aroused such an interest in contemporary investigators that many hypotheses have been proposed to explain the intricate mechanisms of these agents. From the foregoing discussion of the hypotheses, it is clear that β-AR antagonists not only benefit heart failure through AR but also through other pathways. In the chronic stages of heart failure β₁-AR are downregulated and the affinities of the receptors are also decreased. These changes attenuate the systolic function, but at the same time prevent β₁-AR-mediated apoptosis. Moreover, the decreased affinity of these receptors and downregulation is an intrinsic adaptive mechanism to decrease the workload and energy consumption of the heart. This leads us to the question, ‘How do β-AR antagonists help in this scenario?’ These agents not only result in supplementing to this adaptive mechanism, but also protect the heart in the event of sudden deteriorations, which are associated with increased sympathetic stimulation. Moreover, in the hyperadrenergic state, β₃-AR are stimulated and result in a decrease of systolic function, which can be detrimental in end-stage heart failure. This can be effectively attenuated by nonselective β-AR antagonists. Because β₂-AR stimulation is considered to be beneficial in heart failure, blockade of these receptors by some β-blockers can be seen to exert detrimental effects in the failing heart. Apart from the action on AR, these agents improve Ca²⁺ handling by their effects on SL L-type Ca²⁺channels and SR RyR2. In addition to exerting antiapoptotic effects mediated by their antioxidant action, β-AR antagonists have direct action on myofibrils and various regulatory proteins in cardiomyocytes. Antiadrenergic action independent of receptors is another pathway through which these agents attenuate the effects of noradrenaline on the heart.

Various β-AR antagonists differ in their selectivity for receptors and ancillary properties. There is evidence to suggest that the nonselective β-antagonist, carvedilol, has the most potent antioxidant action, improves Ca²⁺ handling and exerts prereceptor antiadrenergic effects. Clinical studies have also documented the superiority of carvedilol in comparison with other β-AR antagonists. There were some reservations about the COMET study that metoprolol tartrate was used instead of metoprolol succinate to compare with carvedilol. However, it is clear from the overall experimental data and clinical studies that carvedilol produces the maximum benefits in chronic heart failure and is well tolerated even in patients with low blood pressure. Other agents, such as metoprolol and bisoprolol, are also very effective in preventing ventricular remodelling. However, more work needs to be performed on setting guidelines for these agents in different stages of heart failure and with different etiologies of heart failure. Particularly, the ancillary properties of β-AR antagonists should be kept in mind while prescribing these agents. Furthermore, the noncardiac effects of β-AR antagonists including those on sympathetic nerves and endothelium may play a critical role in inducing beneficial actions of these agents in heart failure.