© 2003 European Society of Cardiology
Myocardial beta-1 adrenoceptor down-regulation in aging and heart failure: implications for beta-blocker use in older adults with heart failure
Divisions of Gerontology and Geriatric Medicine, University of Alabama at Birmingham 1530 3rd Avenue South, CH19-219, Birmingham, AL 35294-2041, USA
* Corresponding author. Tel.: +1-205-934-9632; fax: +1-205-975-7099. Email address: aahmed{at}uab.edu
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Abstract |
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 TopNotes Abstract 1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Heart failure is associated with increased sympathetic nervous stimulation that results in down-regulation of myocardial beta-1 receptors. The failing heart might depend more on beta-2 receptors for positive inotropic support than the normal heart. Suppression of both beta-1 and beta-2 adrenoceptors by a non-selective beta-blocker, such as carvedilol, is likely to eliminate the failing heart's much needed inotropic support, resulting in an exacerbation of symptoms. Use of a beta-1 selective blocker, such as metoprolol, on the other hand, is likely to be well tolerated. Unlike carvedilol, the use of metoprolol is associated with up-regulation of beta-1 receptors. The clinical significance of the pharmacodynamic differences between these two beta-blockers in terms of their short-term hemodynamic and long-term beneficial effects is not clearly understood. However, in clinical trials, both carvedilol and metoprolol improved left ventricular function, heart failure symptoms and survival. Both drugs are well tolerated as well. Aging itself is associated with elevated myocardial and serum norepinephrine levels, which is associated with down-regulation of beta-1 receptors. In this article, we reviewed the literature to examine the clinical implications of this dual (age- and heart failure-related) sympathetic stimulation and beta-1 receptor down-regulation on selection of beta-blockers in older adults with heart failure.
Key Words: Aging • Heart failure • Beta-blocker • Beta adrenoceptors • Down-regulation
Received December 31, 2002; Revised February 24, 2003; Accepted April 23, 2003
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1. Introduction |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Heart failure had long been known as a simple mechanical pump failure. However, over the past two decades, it has been understood as a neurohormonal syndrome. In addition to renin–angiotensin–aldosterone system activation that occurs with heart failure, there is an activation of the sympathetic nervous system, associated with an increase in myocardial and serum norepinephrine levels [1]. In the early stages of heart failure, this activation of the sympathetic nervous system provides inotropic support to the failing heart. A prolonged activation of the sympathetic nervous system that occurs in patients with heart failure, however, results in numerous deleterious effects including down-regulation of beta-1 receptors and decreased myocardial contractile ability to respond to sympathetic stimulation [1].
Beta-blockers improve left ventricular systolic dysfunction, heart failure symptoms, and survival in patients with heart failure. Because in heart failure most of the down-regulation of beta adrenoceptors involves beta-1 subpopulation, it is not known if a beta-1 selective blocker such as metoprolol or bisoprolol is more beneficial than a non-selective beta-blocker such as carvedilol. Aging, itself, is also associated with a similar activation of the sympathetic nervous system [2,3]. The clinical implications of age- and heart failure-related sympathetic activation and beta-1 receptor down-regulation in the selection of beta-blockers in the treatment of heart failure in older adults are unknown. Would suppression of both beta-1 and beta-2 adrenoceptors by a non-selective beta-blocker further diminish the inotropic reserve of the failing heart in older adults in the short run? Would a more comprehensive suppression of the dual (age- and heart failure-related) sympathetic stimulation by a non-selective beta-blocker be more beneficial for older adults with heart failure in the long run?
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2. Cellular physiology of beta-adrenergic receptor system |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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The beta-adrenergic receptors are members of the G-protein-coupled receptor family, which act by coupling with guanine nucleotide binding proteins, also known as G proteins. The beta adrenoceptors are composed of amino acid sequences, most of which are located inside the cell membrane. The N-terminal of the amino acid sequence is located extracellularly and the C-terminal is intracellular. Between the two terminals, the amino acid sequence traverses the membrane seven times forming three extracellular and four intracellular loops [4]. The third intracellular loop is the largest and is believed to be the site for G protein coupling. There are primarily two different kinds of beta adrenoceptors in the human myocardium, namely beta-1 and beta-2. The amino acid sequences of these two receptor subtypes are almost identical.
The primary neurotransmitter or first messenger for the beta-adrenoceptor mediated signal transduction system in the human myocardium is norepinephrine. Norepinephrine is synthesized and stored in the sympathetic nerve terminals. The affinity of norepinephrine is primarily for beta-1 receptors [5], which are located mostly in and around the synaptic cleft areas of the sympathetic nerve terminals. Over 75% of all beta-receptors in the normal human myocardium are of beta-1 subtype [6]. Beta-2 receptors, on the other hand, are located away from the sympathetic nerve terminals. The primary first messenger for beta-2 receptors is epinephrine, which is formed mostly in the adrenal medulla and is released into circulation in response to systemic sympathetic stimulation. Epinephrine has equal affinity for beta-1 receptors.
The second messenger for both beta-receptors is cyclic adenyl monophosphate (cAMP), which is formed from adenosine triphosphate (ATP) by the adenylyl cyclase enzyme. In addition to the beta-adrenoceptor itself, this beta-adrenergic receptor mediated signal transduction system is composed of the Gs proteins, adenylyl cyclase enzyme and the cAMP-dependent protein kinase A (PKA). The G proteins are composed of three subunits, alpha, beta and gamma (Fig. 1). There are two major G proteins, Gs and Gi proteins, respectively known as stimulatory and inhibitory G proteins. The alpha subunits of the Gs and Gi proteins are distinct, while the beta and gamma subunits are identical. When norepinephrine or epinephrine binds with beta-receptors, the latter activates the G protein, the alpha subunit of which then binds to guanine triphosphate (GTP). The Gs-alpha and GTP complex then stimulates the catalytic unit, adenylyl cyclase, which then catalyzes the formation of cAMP [1]. Stimulation of beta-1 receptors results in coupling with Gs protein alone. Stimulation of beta-2 receptors results in coupling with both Gs and Gi proteins. Coupling with Gi proteins is believed to inhibit Gs mediated responses [7]. The cAMP activates PKA, which in turn phosphorylates several myocardial proteins resulting in positive inotropic and chronotropic responses [4].
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The PKA also phosphorylates phospholamban, which is a calcium-stimulated Mg-ATPase located on the sarcoplasmic reticulum membrane (Fig. 1). Phospholamban inhibits the ATP-dependent calcium pump at the sarcoplasmic reticulum, thereby reducing the influx of calcium from cytosol to the reticulum. Phosphorylation of phospholamban removes this inhibition and causes a fast influx of calcium ions into the reticulum, resulting in increased myocardial contraction and relaxation [8]. Chronic stimulation of the beta-adrenergic receptors results in the phosphorylation of the receptors themselves by PKA, which results in the desensitization of the receptors. Receptor desensitization is also mediated by phosphorylation of the beta-adrenergic receptor kinases (BARK), which are members of the G-protein-coupled receptor kinase family.
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3. Changes in the beta-adrenergic receptor system in heart failure |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Heart failure is associated with several abnormalities of the beta-adrenergic system. The primary of these abnormalities is the sustained beta-adrenergic stimulation. This sustained beta-adrenergic stimulation is mediated mainly by increased norepinephrine activities in the myocardium and in the serum [1]. Norepinephrine has a greater affinity for beta-1 than beta-2 receptors [5]. The norepinephrine mediated activities initially provide inotropic support to the failing heart. However, as the overworked failing heart finds it difficult to handle this sustained adrenergic stimulation, it looks for ways to evade this stimulation. The failing heart accomplishes this through a selective down-regulation of beta-1 receptors [6]. In one of the pioneering experiments to determine the status of the subpopulation of beta adrenoceptors in normal and failing heart, Bristow et al. demonstrated that the proportions of beta-1 and beta-2 receptors in normal hearts were, respectively, 77 and 23% [6]. However, in the failing heart, the respective proportions were 60 and 38%. This decrease in the proportion of beta-1 receptors and the relative increase in the proportion of beta-2 receptors were postulated to be a result of selective down-regulation of the beta-1 receptors, with little or no change in beta-2 receptors.
Enhanced norepinephrine activity is also associated with uncoupling of the beta-2 receptors from the adenylyl cyclase, with resultant decrease in response to beta agonist stimulation and reduction in myocardial reserve. In addition, in patients with ischemic dilated cardiomyopathy, beta-1 receptors are also known to undergo uncoupling. Heart failure is also associated with an increase in the BARK level. By phosphorylating beta-adrenergic receptors that are occupied by beta-agonists such as norepinephrine, BARK play a role in desensitizing beta-adrenergic receptors [9]. PKA is also associated with phosphorylation of beta-adrenergic receptors. Currently, there is no evidence that this enzyme is altered in the failing heart. Heart failure is also associated with up-regulation of inhibitory G proteins, which might also contribute to the uncoupling of the beta-adrenergic receptors. However, there is no evidence that this enhanced inhibitory G protein activity results in decreased levels of cAMP in heart failure.
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4. Down-regulation of beta-1 adrenoceptors |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Down-regulation of beta-1 adrenoceptors is the only change in the myocardial beta-adrenergic system that is consistently observed in heart failure [1]. The location and occurrence of beta-1 receptor down-regulation also depends on the location and nature of systolic dysfunction [1]. In right ventricular systolic dysfunction resulting from primary pulmonary hypertension, the number of beta-1 adrenoceptors has been shown to be selectively diminished in the affected right ventricle [10] and the loss of beta-1 receptors is more remarkable in idiopathic than in ischemic dilated cardiomyopathy [11]. It is possible that because most of the myocardial adrenergic response is mediated via beta-1 receptors, the failing heart responds to an overactive adrenergic system by down regulating these receptors. This is supported by the observation that, in transgenic mice, over-expression of beta-1 receptors by 5–15 times than the normal numbers results in a short-term inotropic response followed by the development of dilated cardiomyopathy [12]. Over-expression of beta-2 receptors by 60 times the normal level, on the other hand, results in an enhanced basal cardiac function without subsequent development of cardiomyopathy [13]. However, in the latter study, over-expression of beta-2 receptors at even higher levels (100 times and higher) resulted in the development of cardiomyopathy and early death.
The selective down-regulation of the beta-1 receptors due to a sustained increase in serum norepinephrine is an extension of the physiological feedback regulation of the beta-receptor function [14]. As stated earlier, the cAMP activated PKA phosphorylates several myocardial proteins. Under conditions of over-stimulation, the activated PKA and protein kinase C phosphorylate both beta-1 and beta-2 receptors, which results in conformational changes in the receptors that interfere with Gs protein coupling, while activating the Gi protein [4]. Receptor down-regulation is also mediated via phosphorylation by BARK. Beta-receptors phosphorylated by BARK bind with beta-arrestin, which interferes with receptor coupling with Gs proteins and enhances internalization and degradation of the receptors. It has been suggested that down-regulation of beta-1 receptors is due to the decrease in receptor mRNA level; and the level of decrease in the beta 1-adrenergic receptor mRNA levels has been correlated with the New York Heart Association (NYHA) functional classification (7% decrease in NYHA class II compared with >50% decrease in NYHA class IV) [15].
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5. Sustained adrenergic stimulation: toxic myocardial damage |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Chronically increased levels of myocardial and serum norepinephrine lead to progressive myocardial damage including ventricular hypertrophy, chamber remodeling, apoptosis, necrosis and cell death [1]. Remodeling is a process by which cardiac chambers assume dilated and rather spherical shapes. The exact mechanism of remodeling is not completely understood. However, because remodeling can be partly reversed by beta-blockers in patients with idiopathic or ischemic dilated cardiomyopathy [16], it is believed that beta-adrenergic stimulation might play a role in the process of remodeling. One possible mechanism for cell death by necrosis is the direct toxic effect of norepinephrine. Norepinephrine is known to be cytotoxic to myocardial cells in vitro [17]. Clinical conditions associated with elevated catecholamine level such as pheochromocytoma, therapeutic use of catecholamine, and brain injuries are known to be associated with myocardial damage. Apoptosis (programmed cell death without inflammation and with an apparently intact cell membrane) is believed to be due to chronic beta-adrenergic stimulation of the terminally differentiated cardiac cells and is also reversed by beta-blockers [18]. These biological adverse effects are presumed to be mediated via the beta-adrenergic receptor system. Even though beta-1 receptors are down-regulated and the inotropic response to adrenergic stimulation is muted, there is evidence that the failing heart continues to retain some capacity to respond to the chronically elevated norepinephrine levels [1]. The exact mechanism of action of norepinephrine mediated progressive myocardial damage is not clearly known.
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6. Effects of heart failure related changes in the beta-receptor system |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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As mentioned earlier, one of the most important effects of prolonged increased sympathetic stimulation is the down-regulation of the beta-1 receptors. The clinical significance of this beta-1 adrenoceptor down-regulation is the resultant loss of myocardial reserve and functional capacity [1]. Bristow et al. demonstrated that, even though in the normal heart, myocardial contractility in response to an adrenergic stimulation is mediated via both beta-1 and beta-2 receptors, most of the inotropic response in the normal heart is mediated via beta-1 receptors [6]. However, in the failing heart, because of the significant down-regulation of beta-1 receptors, most of the inotropic response is mediated via beta-2 receptors [5]. In patients with heart failure, chronic therapy with metoprolol, a beta-1 selective blocker, has been shown to up-regulate myocardial beta-1 receptors and increase inotropic response to beta agonist stimulation [19]. However, carvedilol, a non-selective beta-blocker does not reverse down-regulation of beta-1 receptors in heart failure [20]. Metoprolol is also known to reverse uncoupling of myocardial beta-2 receptors that occurs in heart failure [5].
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7. Age-related changes in the beta-adrenergic receptor system |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Aging is associated with a sustained increase in the level of serum norepinephrine and a diminished beta-adrenergic response to catecholamine [2,3]. This age-related decline in beta-adrenergic response in the non-failing human heart is primarily due to a selective down-regulation of beta-1 receptors as seen in patients with heart failure [21]. Other supposed mechanisms are decreased agonist binding of beta-1 receptors, uncoupling of beta-2 receptors, and abnormal G protein-mediated signal transduction. However, unlike heart failure, there is no evidence of increased BARK activity or up-regulation of Gi proteins [22]. Aging is also not associated with any change in myocardial excitation contraction coupling.
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8. Pathophysiologic basis of effects of beta-blockers in heart failure |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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It would appear that because the failing heart has already responded to an increased adrenergic stimulation by down-regulation of beta-adrenergic receptors to agonist stimulations, blockade of the beta-adrenergic receptors would further reduce the failing heart's ability to respond to an adrenergic drive and, thereby, further reduce the myocardial reserve. This is supported by the acute negative inotropic effects of beta-blockers in patients with heart failure. This is believed to be due to suppression of an already enhanced adrenergic system, which provides inotropic support to the failing heart [23]. Use of beta-blockers is not associated with such early negative inotropic effects in those with a normal heart [24]. However, the long-term use of beta-blockers in chronic heart failure is associated with the reversal of many adverse effects that resulted from a chronically activated adrenergic system [16]. These changes involve up-regulation of the down-regulated myocardial beta-1 receptors, re-coupling of the uncoupled beta-2 receptors, prevention of further remodeling and reversal of existing remodeling and improvement in left ventricular systolic function [1].
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9. Beta-1 receptor down-regulation and beta-blocker selectivity |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Metoprolol and carvedilol are the two most common beta-blockers used in the United States for the treatment of heart failure due to systolic dysfunction. Metoprolol selectively antagonizes beta-1 receptors at lower doses. Carvedilol, on the other hand, is a non-selective beta-blocker, which also blocks alpha-1 adrenoceptors. Because the failing heart depends on beta-2 receptors to respond to adrenergic stimulation, it is reasonable to assume that selective beta-1 blockers might be well tolerated by patients with chronic heart failure, especially in the short run, when the primary action of beta-blockers is to suppress the already increased norepinephrine levels in the myocardium and blood [23]. However, acute hemodynamic effects of metoprolol and carvedilol have been reported to be similar in patients with chronic heart failure [25,26], suggesting that the beta-2 receptor mediated inotropic support to the failing heart may not be physiologically significant.
Therapy with a beta-1-selective blocker is also associated with a beta-2 receptor mediated increase in myocardial contractile force in chronic heart failure patients, which is believed to be due to re-coupling of the uncoupled beta-2 receptors to adenylyl cyclase [5]. Therapy with metoprolol, but not with carvedilol, is associated with up-regulation of beta-1 receptors in chronic heart failure [27]. However, the clinical significance of this up-regulation is not clearly understood. Beta-1 receptor up-regulation has been attributed to better maximal exercise response, which is heart rate dependent [28]. However, a comprehensive suppression of myocardial beta-1 and beta-2 adrenoceptors might be more desirable in chronic heart failure, as evidenced by a better survival profile of carvedilol (65% reduction in mortality) [23] compared with metoprolol (44% reduction in mortality) [29]. This viewpoint is also supported better by left ventricular function, and reduced mortality and hospitalization in patients treated with higher doses of carvedilol [30]. However, such comparison is limited by differences in methodology between trials involving metoprolol and carvedilol, including use of a pre-randomization run-in phase in carvedilol trials. In addition, use of bucindolol, another non-selective beta-blocker did not result in any significant survival benefit for heart failure patients with systolic dysfunction [31].
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10. Age-related beta-1 receptor down-regulation: implications for beta-blocker selectivity in older adults with heart failure |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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Older adults with heart failure are likely to have enhanced adrenergic stimulation and down-regulation of beta-1 adrenoceptors compared with younger adults with heart failure. The average age of heart failure patients participating in randomized beta-blocker trials is approximately a decade younger than the typical patient seen in clinical practice. Most data on older adults are derived from subgroup analysis of data from these trials. Theoretically, in the short run, older adults with heart failure are likely to tolerate a beta-1 selective blocker such as metoprolol better than a non-selective beta-blocker such as carvedilol. However, data from subgroup analyses of clinical trails indicate that both carvedilol and metoprolol are well tolerated and improve survival in older adults with heart failure [29,32,33]. Clinicians caring for frail older adults with heart failure and left ventricular systolic dysfunction might consider a beta-1 selective blocker such as metoprolol or bisoprolol when initiating therapy with beta-blockers, and later switch to a non-selective beta-blocker such as carvedilol, if necessary. Data from younger patients indicate that patients do tolerate such switching well [26]. However, currently there is no evidence to recommend such an approach for general practice.
A subgroup analysis of the beta-blocker evaluation survival trial demonstrated that older adults (mean age 72 years) were able to tolerate the initiation of bucindolol, a non-selective beta-blocker, as well as their younger counterparts (mean age 52 years) [34]. However, they were less likely to tolerate a dose increase. In one small 12-week randomized trial involving older adults (mean age 77 years), carvedilol improved left ventricular function without improving heart failure symptoms [35]. In that study, carvedilol was well tolerated and did not adversely affect functional or cognitive ability.
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11. Conclusion |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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The clinical implications of down-regulation of beta-1 receptors in aging and heart failure for use of beta-blockers in older adults with heart failure are not clearly understood. Beta-1 receptor down-regulation is correlated with severity of heart failure (NYHA Class). In younger adults with heart failure, both carvedilol and metoprolol appear to improve left ventricular function, heart failure symptoms and survival of patients with various degrees of severity. Available evidence based on post-hoc analysis of data from randomized trials indicates that both these drugs are likely to be similarly effective in older adults. Based on our current understanding of beta-1 down-regulation in aging and heart failure, one cannot recommend that a beta-1 selective blocker is superior to a non-selective beta-blocker or vice-versa. The carvedilol or metoprolol European trial (COMET) has been designed to directly compare the effects of these two drugs in moderate to severe heart failure patients [36]. The results of the COMET trial, expected to be published soon, will allow a more objective comparison of the two drugs. Until then, either carvedilol or metoprolol may be appropriately used for older adults with heart failure and left ventricular systolic dysfunction.
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Acknowledgements |
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The author wishes to thank Julie Locher, Ph.D., Assistant Professor of Medicine, Division of Gerontology and Geriatric Medicine, University of Alabama at Birmingham, USA, for reviewing the manuscript.
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Notes |
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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1 Divisions of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, Department of Epidemiology and International Health, School of Public Health, Center for Aging, Center for Outcomes and Effectiveness Research and Education, Geriatric Heart Failure Clinic, University of Alabama at Birmingham; Sections of Geriatrics and Geriatric Heart Failure Clinic, Veterans Affairs Medical Center; and Heart Failure Project, Alabama Quality Assurance Foundation, Birmingham, Alabama.
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TopNotesAbstract1. Introduction2. Cellular physiology of...3. Changes in the...4. Down-regulation of beta-1...5. Sustained adrenergic...6. Effects of heart...7. Age-related changes in...8. Pathophysiologic basis of...9. Beta-1 receptor down...10. Age-related beta-1 receptor...11. ConclusionReferences |
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