The Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy

Abstract

Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that get activated in the syndrome in order to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to “push” the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart.

Introduction

Heart failure (HF) is a clinical syndrome that develops in response to a cardiac injury or insult that causes decline in the pumping capacity (contractile function) of the heart. It is marked by a perpetual interplay between the underlying myocardial dysfunction and the compensatory neurohumoral mechanisms that are activated in an effort to maintain cardiac output in the face of declining heart function. Among these neurohormonal mechanisms, elevated activities of the adrenergic (or sympathetic) nervous system (ANS), of the renin-angiotensin-aldosterone system (RAAS), and of several cytokines, play central roles.^1,2 These systems are initially able to compensate for the depressed myocardial function and preserve cardiovascular homeostasis. Upon long-term presence of the initial insult to the heart muscle however, cardiac function ultimately succumbs to their deleterious effects on cardiac structure and performance, leading to cardiac decompensation and progressively worsening function, unable to sustain daily life activities. The present review will discuss the role of the ANS in HF pathophysiology and therapeutics, starting with a discussion of its role in normal cardiac function.

ANS & Cardiac Function

The ANS exerts a wide variety of cardiovascular effects, including heart rate acceleration (positive chronotropy, predisposing to arrhythmias), increase in cardiac contractility (positive inotropy), accelerated cardiac relaxation (positive lusitropy), decrease in venous capacitance, and constriction of resistance and cutaneous vessels (Fig. 1). All of these effects aim to increase cardiac performance to prepare and enable the body for the so-called “fight or flight response”. Conversely, the mirror branch of the autonomic nervous system, the parasympathetic (cholinergic) nervous system, slows the heart rate (bradycardia) through vagal nerve impulses, with minimal or no effect on cardiac contractility. This is because the cardiac ventricles, whose contraction is responsible for pumping the blood into the systemic and pulmonary circulations, receive almost exclusively adrenergic fiber innervations, whereas the cholinergic system fibers run with the vagus nerve subendocardially, after it crosses the atrioventricular groove, and reach mainly the atrial myocardium with minimal connections to the ventricular myocardium.^3,4 Therefore, whereas heart rate can be controlled (in opposing fashion) by both autonomic branches, cardiac contraction/relaxation is controlled practically solely by the ANS (Fig. 1).

Figure 1. Overview of the ANS innervation of the cardiovascular system.

Note that, in contrast to the ANS which innervates both atria and ventricles of the heart, the cholinergic (parasympathetic) nervous system mainly innervates cardiac atria only. See text for more details. CSAR: Cardiac Sympathetic Afferent Reflex. (Illustration Credit: Ben Smith).

The ventricular ANS innervation is characterized by a gradient from base to apex.⁵ The cardiac neuronal system is composed of cell stations comprising afferent, efferent, and interconnecting neurons behaving as a control system.⁶ The ANS outflow to the heart and to the peripheral circulation is regulated by cardiovascular reflexes. Afferent fibers project to the central nervous system by the autonomic nerves, whereas efferent impulses travel from the central nervous system to peripheral organs. The main reflex responses originate from the aortic arch and the carotid baroreceptors (ANS inhibition), cardiopulmonary baroreceptors (diverse reflexes including the Bezold-Jarisch reflex, ANS inhibition), cardiovascular low-threshold polymodal receptors (ANS activation), and peripheral chemoreceptors (ANS activation).^4,7

ANS activation in the cardiovascular system translates into release of the two catecholamines that mediate its effects, i.e. norepinephrine (NE) (or noradrenaline) and epinephrine (Epi) (or adrenaline), and this can occur via the following mechanisms (Fig. 2): a) NE released by cardiac sympathetic nerve terminals located in the right stellate ganglion reaching the sinus and atrioventricular nodes (resulting in an increase in heart rate and shortening of atrioventricular conduction) and through the left stellate ganglion reaching the left ventricle (resulting in an increase in contractile strength), although NE release and reuptake can occur throughout the heart, b) Epi (and to a much lesser extent NE) released into the circulation by the adrenal medulla, affecting both the myocardium and peripheral vessels, and, finally, c) local release of NE and Epi by various peripheral adrenergic nervous systems that can synthesize and release these catecholamines in an autocrine/paracrine manner and are located in blood vessels and in cardiac myocytes themselves.^8,9

Figure 2. ANS input to the heart and its regulation.

See text for details. G_i/o: inhibitory or other G protein; G_s: stimulatory G protein; ACh: Acetylcholine; NET: NE transporter; Aldo: Aldosterone; MR: Mineralocorticoid Receptor. (Illustration Credit: Ben Smith).

Adrenergic Receptors (ARs) in the cardiovascular system

Cardiac AR signaling and regulation

The ANS neurotransmitters NE and Epi mediate their effects in cells and tissues by binding to specific cell surface ARs, which belong to the superfamily of G protein-coupled receptors (GPCRs) or seven transmembrane-spanning receptors or heptahelical receptors (7TMRs). Approximately 80% of NE released by ANS nerve terminals is recycled by the NE transporter (NET) type 1, whereas the remainder spills over into the circulation.¹⁰ The receptors for both ANS catecholamines are divided into three types and 9 total different subtypes, as follows: three α₁AR subtypes (α_1A, α_1B, α_1D), three α₂AR subtypes (α_2A, α_2B, α_2C), and three βAR subtypes (β₁, β₂, β₃).¹¹ All ARs primarily signal through heterotrimeric G proteins. The human heart contains all three βAR subtypes.¹² β₁AR is the predominant subtype in the (normal, healthy) myocardium, representing 75–80% of total βAR density, followed by β₂AR, which comprises about 15–18% of total cardiomyocyte βARs and the remaining 2–3% is β₃ARs (under normal conditions).¹³ The principal role of βARs in the heart is the regulation of cardiac rate and contractility in response to NE and Epi. Stimulation of β₁ARs (mainly) and of β₂ARs (to a lesser extent) increases cardiac contractility (positive inotropic effect), frequency (positive chronotropic effect), and rate of relaxation (lusitropic effect) as well as accelerates impulse conduction through the atrioventricular node (positive dromotropic effect) and pacemaker activity from the sinoatrial node.¹⁴ β₃ARs are predominantly inactive during normal physiologic conditions;¹⁵ however, their stimulation seems to produce a negative inotropic effect opposite to that induced by β₁ARs and β₂ARs, involving the nitric oxide synthase (NOS) pathway, ¹⁶ thus acting as a “fuse” against cardiac adrenergic overstimulation.¹⁷ Agonist-induced activation of βARs catalyzes the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G_α subunit of heterotrimeric G proteins, resulting in the dissociation of the heterotrimer into active G_α and free G_βγ subunits (always associated together, i.e. a heterodimer that functions essentially as a monomer) which can transduce intracellular signals independently of each other.¹⁸ The most powerful physiologic mechanism to increase cardiac performance is activation of cardiomyocyte β₁ARs and β₂ARs, which, in turn, activates G_s proteins (stimulatory G proteins). G_s protein signaling stimulates the effector adenylate cyclase (AC), which converts adenosine triphosphate (ATP) to the second messenger adenosine 3′,5′-monophosphate or cyclic AMP (cAMP), which in turn binds to and activates the cAMP-dependent protein kinase (protein kinase A, PKA). PKA is the major effector of cAMP (there is also Epac, exchange protein directly activated by cAMP, which can be activated by cAMP independently of PKA), and, by phosphorylating a variety of substrates, it ultimately results in significant raise in free intracellular Ca²⁺ concentration, which is the master regulator of cardiac muscle contraction (Fig. 3).¹⁹ Among the main targets of PKA phosphorylation in the cardiac myocyte are: the cell membrane-located L-type calcium channels (LTCC) and the sarcoplasmic reticulum (SR)-located ryanodine receptors (RyRs), both leading to an increase in Ca²⁺ entry into the cytoplasm;¹⁹ phospholamban (PLB), a negative modulator of SERCA (Sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase), whose phosphorylation by PKA deinhibits SERCA, thus accelerating Ca²⁺ reuptake by the SR after contraction and increasing SR Ca²⁺ stores available for the next contraction;¹⁹ hyperpolarization-activated cyclic nucleotide-gated channels, which generate the hyperpolarization-activated cation inward current (If) affecting the initiation and modulation of rhythmic activity in cardiac pacemaker cells;²⁰ troponin I and myosin binding protein-C, which reduce myofilament sensitivity to Ca²⁺, thereby accelerating the relaxation of myofilaments;²¹ and, finally, phospholemman (PLM), closely associated with Na^+/K⁺-ATPase and inhibiting its function, whose phosphorylation by PKA relieves this inhibition and stimulates the sodium pump, thereby accelerating cardiac muscle repolarization and relaxation (Fig. 3).²² Moreover, PKA can phosphorylate the βARs themselves (and other GPCRs) in the heart, causing G protein uncoupling and functional desensitization of the receptor (heterologous or agonist-independent desensitization).²³

Figure 3. Signal transduction of cardiac myocyte contraction and its regulation by cardiac ARs.

See text for details. LTCC: L-type Calcium Channel; NKA: Na⁺, K⁺-ATPase; PLM: Phospholemman; PLB: Phospholamban; SERCA: Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase; RyR: Ryanodine Receptor; IP₃R: IP₃ Receptor; PKC: Protein Kinase C; TRPV: Transient Receptor Potential Vanilloid. (Illustration Credit: Ben Smith).

Of note, β₂AR also mediates the effects of catecholamines in the heart, but in a qualitatively different manner from β₁AR, as it can also couple to the AC inhibitory G protein (G_i). In fact, this switching of β₂AR signaling from G_s to G_i proteins is postulated to be induced by the phosphorylation of the β₂AR by PKA.²³ Nonetheless, it is now generally accepted that in the heart, β₂AR signals and functions in a substantially different way compared to β₁AR.^24–26 Importantly, whereas β₁AR activation enhances cardiomyocyte apoptosis, β₂AR exerts antiapoptotic effects in the heart.^24–27 This essential difference between the two receptor subtypes is ascribed to the signal of β₂AR through G_i proteins.²⁵ Studies using transgenic mice, β₂AR-selective stimulation and adenoviral-mediated β₂AR overexpression, have demonstrated the protective effects of β₂AR signaling in the myocardium, including improved cardiac function and decreased apoptosis. Conversely, hyperstimulation or overexpression of β₁AR has detrimental effects in the heart.^27,28

Both α₂- and βARs, like the majority of GPCRs, are subject to agonist-promoted (homologous) desensitization and downregulation, a regulatory process that diminishes receptor response to continuous or repeated agonist stimulation.^29,30 At the molecular level, this process is initiated by receptor phosphorylation by a family of kinases, termed GPCR kinases (GRKs), followed by binding of βarrestins (βarrs) to the GRK-phosphorylated receptor (see below). The βarrs then uncouple the receptor from its cognate G proteins, sterically hinder its further binding to them (functional desensitization) and subsequently target the receptor for internalization.^29,30 Across all mammalian species, GRK2 and GRK5 are the most physiologically important members of the GRK family because they are expressed ubiquitously and regulate the vast majority of GPCRs. They are particularly abundant in neuronal tissues and in the heart.^31,32

Of note, the differences between the two predominant cardiac βARs, i.e. β₁AR & β₂AR, in terms of their signaling properties, might take a quite different shape and have a much bigger bearing on pathophysiologic implications in the setting of human HF: for instance, and as discussed in more detail in subsequent sections, β₁AR is selectively downregulated (i.e. functional receptor number reduced) in human HF, thus shifting the above mentioned stoichiometry of β₁AR: β₂AR towards 50:50 in the failing heart from ~75%:~20% in the normal, healthy heart.^33,34 However, β₂AR is also non-functional and does not signal properly in the failing heart.^32–34 In addition, emerging evidence suggests that β₂AR signaling in the failing heart is quite different from that in the normal heart, i.e. is more diffuse and non-compartmentalized and resembles more the pro-apoptotic “diffuse” cAMP signaling pattern of the β₁AR.³⁵ Therefore, this stoichiometric shift in favor of the supposedly “good” β₂AR in HF appears unable to help the heart improve its structure and function.

The human heart also expresses α_1A- and α_1BARs, albeit at much lower levels than βARs (~20% of total βARs).³⁶ How important a role cardiac α₁ARs play in cardiac physiology is still a matter of debate. In contrast, their role in regulation of blood flow by inducing constriction in the smooth muscle wall of major arteries (e.g. aorta, pulmonary arteries, mesenteric vessels, coronary arteries, etc.) is well known and indisputable.³⁷ The α₁ARs couple to the G_q/11 family of heterotrimeric G proteins, thereby activating phospholipase C (PLC)-β. PLCβ generates the second messengers inositol [1,4,5]-trisphosphate (IP₃) and 2-diacylglycerol (DAG) from the cell membrane component phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP₂). IP₃ binds specific receptors in the SR membrane which cause release of Ca²⁺ from intracellular stores, whereas DAG activates protein kinase C (PKC) and transient receptor potential (TRPV) channels (Fig. 3). The end result is again raised intracellular [Ca²⁺], which leads to contraction (vasoconstriction) (Fig. 3).

Finally, regarding α₂AR subtypes, α_2BARs are known to be present in vascular smooth muscle causing constriction of certain vascular beds, while centrally located α_2AARs can inhibit sympathetic outflow (presynaptic inhibitory autoreceptors) and thus lower systemic blood pressure.^38,39 The release of NE from cardiac sympathetic nerve terminals is controlled by both presynaptic α_2A- and α_2CARs,⁴⁰ and genetic deletion of both of these α₂AR subtypes leads to cardiac hypertrophy and heart failure due to chronically enhanced cardiac NE release, as well as enhanced NE and Epi secretion from the adrenal medulla.^8,41,42

AR polymorphisms & cardiac function

There are some very important genetic polymorphisms in human β- and αAR genes, which have been associated with heart failure phenotypes and interaction with β-blocker therapy, a mainstay of HF standard of care (see below), and can significantly influence cardiac function. Thus, it would be useful here to briefly discuss these polymorphisms and their functional consequences for the heart. The Arg389Gly human β₁AR gene polymorphism is probably the best studied AR gene polymorphism to date; it is associated with significantly elevated AC/PKA activities and hence β₁AR-stimulated cardiac contractility in the Arg389 variant carriers (compared to Gly389 carriers).⁴³ Another human β₁AR polymorphism is the Ser49Gly variation, associated with increased agonist-promoted receptor downregulation for the Gly49 over the Ser49 variant.⁴⁴ A lower prevalence of ventricular arrhythmias has been associated with the Gly389 allele.⁴⁵ Of note, African-American HF patients with an enhanced activity mutation (Leu41) of GRK5, the second (after GRK2) major cardiac GRK (see above), demonstrate improved survival (explained by this GRK5 mutant acting as a “genetic β-blocker”).⁴⁶ Additionally, the Gly49 allele of the human β₁AR gene has been shown to confer enhanced survival benefit in response to β-blocker treatment⁴⁷ and significant reduction in left ventricular end-diastolic diameter⁴⁸ compared to Ser49 homozygous carriers. Ameliorated cardiac adverse remodeling has been reported for Arg389 homozygous HF patients treated with the β-blocker carvedilol⁴⁹ and for Arg389Gly heterozygous carriers.⁵⁰ There are also negative studies however, reporting no associations of these polymorphisms with any cardiac outcome.^51–53 Further adding to the confusion, a dependency of whether the Ser49Gly polymorphism has any bearing on dilated cardiomyopathy outcomes on the dose of the β-blocker has been reported, according to which the Gly49 allele associates with worse outcomes than Ser49 allele homozygosity at low β-blocker doses, but at higher doses, genotype apparently has no effect.⁵⁴ On the other hand, HF patients carrying the Arg389 genotype had a greater agonist-promoted ventricular contractility and improved age-, sex-, and race-adjusted survival than Gly389 carriers in a BEST trial subcohort.⁵⁵

The human β₂AR gene is known to display two variations that are in linkage disequilibrium (and thus constitute a haplotype): Gly16Arg and Gln27Glu, which affect receptor downregulation, and a third polymorphism, Thr164Ile, which confers impaired receptor-G protein coupling and reduced AC-mediated signaling.⁵⁶ Finally, a four amino acid deletion in the human α_2CAR gene (Del322–325) leads to increased NE release from ANS cardiac nerve terminals⁵⁷ and this polymorphism, in combination with the β₁AR Arg389Gly polymorphism, were recently used to stratify patients according to the clinical response to the β-blocker bucindolol into “very favorable,” “favorable,” and “unfavorable” response genotypes.⁵⁸ The latter polymorphism (β₁AR Arg389Gly) belongs also to a set of three genetic polymorphisms that were recently shown to serve as predictors of appropriate implantable cardioverter-defibrillator (ICD) shock therapies in HF patients.⁵⁹ In conclusion, human AR genetic polymorphisms may prove to be very useful tools in guiding the individual “tailoring” (“personalization”) of HF therapy in the future.^60–62

Assessment of ANS activity

Plasma NE measurements represent the usual, crude method to assess ANS function/activity levels, since the latter depends on the rate of immediate NE reuptake as well as NE clearance from the circulation.⁶³ Two state-of-the-art techniques to quantify ANS activity in humans are radiotracer measurements of regional NE spillover and microneurography (microelectrode direct measurements of post-ganglionic nerve activity). These techniques can discern central from peripheral contributions of increased plasma NE levels and facilitate precise assessment of the regional (e.g. cardiac) sympathetic nerve function, both under physiological and pathological conditions. Cardiac neuronal distribution and function can be imaged with standard gamma-cameras and positron emission tomography (PET) scanners using radiolabeled NE analogs.⁶⁴ Cardiac ANS activity or its pharmacological inhibition can also be non-invasively assessed with [¹²³I]-labeled metaiodobenzylguanidine (MIBG), an analogue of NE.⁶⁵ β-blockade and RAAS inhibition are associated with an increase in [¹²³I]-labeled MIBG uptake and a reduced washout. [¹²³I]-labeled MIBG cardiac imaging has also been shown to carry independent prognostic information for risk stratification of HF patients in a complementary manner to more commonly used biomarkers such as left ventricular ejection fraction and B-type natriuretic peptide (BNP).⁶⁶

Regulation of ANS outflow & activity in health and in chronic HF

Cardiac sympathetic efferent nerves

There are several mechanisms by which the ANS controls cardiac function. The first one to be documented historically is through the aortic arch and carotid sinus (high pressure) and cardiopulmonary (low pressure) baroreceptor reflexes.⁶⁷ Aside from these baroreceptor inputs, additional factors that act within the central nervous system play a role in regulation of cardiac ANS activity. In particular, suprabulbar subcortical monoaminergic neurons and brainstem angiotensin II have attracted interest courtesy of their ability to regulate ANS outflow in HF (Fig. 2). NE turnover in subcortical regions in HF is significantly higher than that in the cortex and than in healthy subjects.⁶⁸ Moreover, the rate of subcortical NE release correlates well with global ANS activity, as measured by total body NE plasma spillover. Angiotensin II-dependent ANS activation plays an important role in adverse hemodynamic and left ventricular remodeling responses to myocardial infarction, possibly through superoxide formation.^69,70 Thus, part of the benefit of RAAS modulators in HF might derive from centrally-mediated suppression of ANS activity (see below).

As the heart becomes progressively unresponsive to the stimulatory effects of catecholamines, chronic stimulation of cardiac ANS nerve terminals leads to chronically elevated NE release from the heart (increased NE spillover). Presynaptic α₂ARs present on cardiac ANS nerve terminals and acting as NE release-inhibiting autoreceptors play a crucial role in regulation of cardiac NE release from sympathetic nerves.^38,39 Indeed, knockout (KO) mice lacking either the α_2A- or α_2CAR subtype show significantly enhanced cardiac ANS activity and circulating catecholamine levels, as well as significantly worse heart function and clinical indices, during the course of surgical pressure overload (by means of transverse aortic constriction, TAC)-induced HF compared with age-matched wild-type HF mice.^40,41 Moreover, double α_2A/α_2CAR KO mice exhibit even worse cardiac phenotypes than single α_2AAR KO mice and, by 4 months of age, they spontaneously develop cardiomyopathy (without stress or any specific insult).⁷¹ In HF patients, the expected inhibitory effects of α₂AR stimulation on NE spillover are markedly blunted, thereby contributing to the increase in cardiac NE spillover observed in chronic HF.⁷² In addition, the human α_2CAR Del322–325 variant that displays impaired signaling and sympatho-inhibitory function (see above) is alone associated with increased risk of HF in homozygous African-American carriers, especially when co-carried with the hyperfunctional cardiac β₁AR Arg389 variant, with the most probable mechanism being attenuated autoinhibitory feedback of, and thus enhanced NE release from the cardiac sympathetic nerves.⁵⁷ In fact, even in healthy humans, the α_2CAR Del322–325 variant is associated with increased sympathetic nervous and adrenomedullary hormonal activities, during both supine rest and pharmacologically evoked catecholamine release.⁷³ Thus, presynaptic inhibitory α₂-adrenergic autoreceptors crucially regulate ANS cardiac nerve activity and NE release into the heart and any dysfunction of these receptors either due to genetic polymorphisms or enhanced desensitization/downregulation (see below) translate into increased morbidity and mortality in chronic HF (Fig. 2). Perhaps the crucial role of presynaptic α₂ARs in regulating NE release from cardiac ANS nerves stems from the fact that they are the only presynaptic ARs that can inhibit NE release; presynaptic βARs (of the β₂AR subtype, mainly) are facilitatory autoreceptors enhancing NE release at sympathetic nerve terminals,⁷⁴ a phenomenon whose inhibition may contribute to the therapeutic benefit of β-blockers in HF (see below) (Fig. 2).

Adrenal glands

Circulating Epi and NE derive from two major sources in the body: the cardiac sympathetic nerve endings, which release NE directly onto the cardiac muscle, and the adrenal medulla, whose chromaffin cells synthesize, store and release Epi (mainly) and NE upon acetylcholine stimulation of the nicotinic cholinergic receptors (nAChRs) present on their cell membranes (Fig. 2).⁸ Epi represents approximately 80% of the total adrenal catecholamine secretion under normal conditions, with NE the rest ~20%.⁷⁵ However, these percentages vary widely depending on the physiological condition of the adrenal gland and of the whole body. Thus, all of the Epi in the body and a significant amount of circulating NE derive from the adrenal medulla, and the total amount of catecholamines presented to cardiac ARs at any given time is composed of these circulating NE & Epi plus NE released locally from sympathetic nerve terminals within the heart.⁸ The secretion of catecholamines from the adrenal glands is regulated in a complex manner by a variety of cell membrane receptors present in chromaffin cells. Many of these receptors are GPCRs, including, similarly to cardiac ANS nerve endings, α₂ARs that inhibit secretion (inhibitory presynaptic autoreceptors), and βARs that enhance it (facilitatory presynaptic autoreceptors) (Fig. 2).^8,38,41,42 Of note, although various presynaptic auto- and heteroreceptors, facilitate (increase) adrenal catecholamine secretion, e.g. βARs, muscarinic cholinergic receptors (mAChRs), angiotensin II-ergic, histaminergic, and adrenomedullin receptors, the α₂ARs are the only receptor type reported to date to inhibit adrenal catecholamine secretion.^8,42,76

An increase in GRK2 expression and activity (see above) has been documented in several cardiovascular diseases, including increased cardiac expression in HF^77–79 and increased expression in some vascular beds in hypertension.⁸⁰ A few years ago, we reported that GRK2 expression and activity are increased also in the adrenal medulla during HF.⁸¹ Specifically, our studies over the past few years have established that adrenal GRK2 upregulation is responsible for severe adrenal α₂AR dysfunction in chronic HF, which causes a loss of the sympathoinhibitory function of these receptors in the adrenal gland, and catecholamine secretion is thus chronically elevated (Fig. 2).^81–85 This emerging crucial role for adrenal GRK2 in HF is underlined by the fact that its specific inhibition, via adenoviral-mediated βARKct adrenal gene delivery (see below), leads to a significant reduction in circulating catecholamine levels, restoring not only adrenal, but also cardiac function in HF.⁸¹ Additional evidence for the crucial role of adrenal GRK2-regulated α₂ARs in regulating adrenal ANS tone in HF comes from the phenylethanolamine-N-methyl transferase (PNMT)-driven GRK2 KO mice.⁸² These mice, which do not express GRK2 in their adrenal medullae from birth, display decreased ANS outflow and circulating catecholamines in response to myocardial infarction, which translates into preserved cardiac function and morphology over the course of the ensuing HF.⁸² Of note, elevated GRK2-dependent α₂AR dysfunction during HF might also occur in other peripheral sympathetic nerve terminals of the heart (Fig. 2) and of other organs, thus contributing to the increased NE release and spillover, as well as to the presynaptic α₂AR dysfunction in ANS neurons observed in chronic HF (see above).^72,86

Effects of ANS overactivity in chronic HF

Myocardial systolic dysfunction is associated with neurohormonal hyperactivity as a compensatory mechanism to maintain cardiac output in the face of declining cardiac function. The neuronal part of this response is represented by ANS cardiac nerve terminals, whereas the hormonal (or humoral) part is represented by increased secretion, and elevated circulating levels of certain hormones, the most prominent being Epi & NE, along with the RAAS hormones (i.e. angiotensin II & aldosterone).⁸⁷ ANS hyperactivity is evidenced by increased plasma NE & Epi levels, elevated (central) sympathetic outflow, and heightened NE spillover from activated cardiac sympathetic nerve terminals into the circulation.⁸⁸ Cardiac NE spillover in untreated HF patients can reach up to 50-fold higher levels than those of healthy individuals under maximal exercise conditions.⁸⁹ The information on chronic ANS activation in HF with preserved left ventricular ejection fraction (i.e. diastolic HF) is very limited. In patients with hypertension, ANS hyperactivity may contribute to the development of left ventricular diastolic dysfunction and thus increase HF risk.⁹⁰ In systolic HF, patients may actually have decreased ANS neuronal density & function, resulting in decreased NE concentration within the heart, in addition to decreased postsynaptic βAR density, due to depletion of cardiac ANS neuronal NE stores and decreased NE presynaptic reuptake secondary to NE transporter downregulation.^91,92

Effects on cardiac ARs

The elevated ANS outflow and NE and Epi levels in chronic HF lead to chronically elevated stimulation of the cardiac βAR system which has detrimental repercussions for the failing heart. Extensive investigations over the past three decades have helped delineate the molecular alterations afflicting the cardiac βAR system that occur during HF, and it is now well known that in chronic human HF, cardiomyocyte βAR signaling and function are significantly deranged and the adrenergic reserve of the heart is diminished.^33,34,93 Cardiac βAR dysfunction in human HF is characterized at the molecular level by selective reduction of β₁AR density at the plasma membrane (downregulation) and by uncoupling of the remaining membrane β₁ARs and β₂ARs from G proteins (functional desensitization).³³ Importantly, myocardial levels and activities of the most important, versatile and ubiquitous GRKs, GRK2 and GRK5, are elevated, both in humans and in animal models of HF.^{32,77–79,94} The current consensus is that in chronic HF, the excessive amount of ANS-derived catecholamines “hitting” cardiac βARs extracellularly triggers the GRK2 upregulation inside the cardiomyocytes, thus leading to a reduction in cardiac βAR density and responsiveness and resulting in cardiac inotropic reserve depletion.^95,96 This GRK2 elevation possibly serves as a homeostatic protective mechanism aimed at defending the heart against excessive catecholaminergic toxicity. However, several studies soon refuted this assumption, demonstrating that GRK2 upregulation is detrimental for the heart and causes the functional uncoupling of βARs in vivo.⁹⁴ This finding prompted investigations of the role GRK2 plays in cardiac function, which revealed that cardiac GRK2 is an absolutely critical regulator of cardiac βAR-dependent contractility and function. Specifically, cardiomyocyte-restricted overexpression of GRK2 to the same level of upregulation found in human HF (i.e. 3–4 fold) markedly attenuated βAR signaling and contractile reserve, showing that GRK2 is the main culprit for the functional desensitization of cardiac βARs in HF (Fig. 3).⁹⁷ The proof for this was provided by studies of the in vivo inhibition of cardiomyocyte GRK2, which were enabled by the development of the βARKct mini-gene, which blocks cell membrane translocation and hence activation of GRK2, and its cardiomyocyte-specific expression in vivo in transgenic mice by virtue of the αMHC (myosin heavy chain) gene promoter.⁹⁷ Indeed, GRK2 inhibition in vivo in the heart with βARKct (or its partial genetic deletion) enhances cardiac contractility both at baseline and after adrenergic stimulation, reverses the contractile and βAR dysfunctions, and preserves or even augments cardiac function and survival in HF.^97–102 On the down side, loss of cardiac GRK2 can predispose the heart to catecholamine toxicity, exactly because it works, in essence, as a positive inotropic therapy.¹⁰³ In summary, elevated ANS activity in chronic HF causes enhanced GRK2-mediated cardiac β₁- and β₂AR desensitization and β₁AR downregulation, which leads to the progressive loss of the adrenergic and inotropic reserves of the heart, the hallmark molecular abnormality of this disease (Fig. 3).¹⁰⁴

With regards to the other major AR type expressed in the heart, α₁ARs in HF may function in a compensatory fashion to maintain cardiac inotropy, but their involvement in cardiac pathophysiology appears limited to situations of cardiac hypertrophy that ultimately lead to HF.¹⁰⁵ For instance, in the presence of pressure overload, cardiac α_1AARs get activated and promote cardiomyocyte survival (i.e. block apoptosis), protecting against adverse remodeling and decompensation to HF.^106,107

ANS cardiotoxicity

ANS cardiac toxicity is well documented. For instance, intravenous infusion of isoproterenol (a standard non-subtype selective βAR full agonist) or NE results in acute contraction band lesions attributed to relative hypoxia, increased sarcolemmal permeability, calcium overload, elevation of cAMP, activation of α- and βARs, and formation of oxidative catecholamine metabolites.^108,109 Chronic catecholamine administration in rats causes interstitial fibrosis, reduces βAR–mediated inotropic responses (adrenergic inotropic reserve), promotes cardiac apoptosis, and induces contractile dysfunction primarily through left ventricular dilatation.^110,111 Moreover, NE induces cardiac apoptosis via both β₁AR- and ROS–tumor necrosis factor (TNF)–caspase-mediated signaling pathways. ^112,113 A perfect example of catecholamine-induced cardiac toxicity leading to cardiac dysfunction is found in stress (Takotsubo) cardiomyopathy: high circulating levels of Epi trigger a form of “myocardial stunning”, which includes the signaling switch of the cardiac β₂AR from G_s to G_i proteins, especially in the region of the apical myocardium, where βAR density is highest,¹¹⁴ thus negatively affecting inotropy.¹¹⁵

ANS therapeutics in HF

AR blockers

β-blockers

β-blockers (Table 1) can be broadly classified into generations: first generation, which are non-subtype selective and competitively block both the β₁- and β₂ARs (propranolol, nadolol, timolol); second generation, with much higher affinity for the β₁- than for the β₂AR (atenolol, metoprolol, bisoprolol); and third generation, which may be subtype-selective (celiprolol, nebivolol) or non-selective (bucindolol, carvedilol, labetalol). The latter ones can also block α₁ARs, thereby causing peripheral vasodilation (bucindolol, carvedilol, labetalol). Celiprolol possesses also β₂AR agonist properties, while nebivolol can also induce nitric oxide (NO) synthesis.¹¹⁶ Cardioselectivity (i.e. selectivity for the β₁-over the β₂AR subtype) is dose-dependent and decreases with increasing dosage. Both subtype-selective and non-selective agents have negative chronotropic and inotropic effects. β₁AR-selective agents have a lesser inhibitory effect on the β₂AR and thus are less likely to cause peripheral vasoconstriction (and bronchoconstriction).¹¹⁶ Exercise performance may be impaired to a lesser extent by β₁AR-selective agents, since they spare the β₂AR which increases skeletal muscle blood flow (via vasodilation) in response to exercise. Finally, some β-blockers are mixed βAR agonists/antagonists (or partial agonists), i.e. at low concentrations antagonize the receptors but at high concentrations they actually activate βARs (act as agonists) causing cardiac stimulation. These β-blockers possess (the so-called) “intrinsic sympathomimetic activity” (ISA), e.g. pindolol, alprenolol, oxprenolol, and inhibit the effects of catecholamines through the high affinity binding state of the myocardial β₁AR, while mimicking catecholamines when binding to the low affinity state of the cardiomyocyte β₁AR.¹¹⁷ The β-blockers with ISA have a high propensity for arrhythmias and should not be used for chronic HF treatment. The majority of β-blockers are partially or completely metabolized by CYP2D6, a gene with considerable genetic variability.¹¹⁸ All β-blockers are approved for chronic HF treatment (Table 1).¹¹⁹ Conversely, they are all contraindicated in acute HF (due to the acute drop in cardiac output they cause).¹¹⁹ Chronic β-blocker therapy reverses left ventricular remodeling, reduces risk of hospitalization, improves survival, reduces risk of arrhythmias (sudden cardiac death), improves coronary blood flow to the heart (relieves angina), and protects the heart against cardiotoxic overstimulation by the catecholamines. All of these effects result in a decrease in the oxygen/energy and metabolic demands of the heart (cardiac workload is decreased) and in an increase in its oxygen/energy supply, thereby improving, in the long run, left ventricular function and performance. Various molecular mechanisms underlying these effects have been postulated: 1) direct antagonism of catecholaminergic cardiotoxic effects; 2) cardiac βAR upregulation and restoration of their signaling and function (i.e. increase in adrenergic and inotropic reserves of the heart), partly via cardiac GRK2 downregulation;¹²⁰ 3) suppression of the elevated cardiotoxic, adverse remodeling-promoting, and pro-apoptotic neurohormonal systems (RAAS, endothelin); 4) coronary blood flow enhancement (as a result of diastolic prolongation); and 5) restoration of the reflex controls on the heart and the circulation.¹²¹ In addition, restoration of adrenal GRK2-α₂AR-catecholamine secretion axis and suppression of NE release from cardiac ANS endings might contribute to the beneficial effects of β-blockers in chronic HF, as well.^74,85

Table 1.

Overview of ANS-related therapeutics in HF.

Therapeutic modality	Mechanism(s) of action in HF	Effect on ANS function	Effect(s) on HF phenotype	Clinical outcome(s)-indication(s) in HF	Other Notes
β-blockers	Cardiac βAR antagonism-ANS neuronal β2AR antagonism-↓ Cardiac & adrenal GRK2-↑ PNS outflow/activity	↓ Outflow/activity	Reversed adverse remodeling; ↓ arrhythmias; ↑ cardiac blood flow; protection against CA toxicity; ↓ cardiac oxygen, metabolic & energy demand/supply ratio	↓ all-cause & cardiac mortalities; ↑ adrenergic & inotropic reserves-Chronic HF, especially after MI	Contraindicated in acute HF; Certain polymorphisms in cardiac βAR & GRK5 genes affect response; individual agents not equal: carvedilol-metoprolol appear superior in HF
α-blockers	VSM α1AR (and α2AR) antagonism	↑ Outflow/activity(reflex response to α1AR blockade)	Worsening of HF; ↑ HF incidence; ↑ HF morbidity & mortality	↑ cardiac morbidity & mortality(prazosin-doxazosin)	Contraindicated in HF
Centrally acting sympatholytic agents	Central ANS & adrenalα2AR (and putative “imidazoline receptor”) agonism	↓ Outflow/activity	↓ Cardiac & renal ANS tones in HF; ↓ cardiac oxygen, metabolic & energy demand/supply ratio (?)	No clinical deterioration (clonidine) but ↑ mortality (due to excessive sympatholysis?) with moxonidine; benefit questionable	Contraindicated in acute HF; Central ANS & adrenalα2ARs desensitized/dow nregulated in chronic HF (due to ↑ GRK2), so efficacy might be limited
RAAS-modulating agents	↓ AngII production-AngII & Aldo antagonism, leading to ↓ NE release & ↑ NE reuptake from ANS neurons	↓ Outflow/activity	Well-established benefits in reversed adverse remodeling & ↓ cardiac oxygen, metabolic & energy demand/supply ratio	↓ all-cause & cardiac mortalities-Chronic HF, especially after MI	Part of benefit in chronic HF due to ANS outflow/activity lowering
Sympathomimetics	Cardiac βAR agonism or PDE3 inhibition, leading to ↑ cardiac & VSM cAMP levels	Indirect ↓ outflow/activity via improved cardiac hemodynamics but potential ↑ NE release from ANS neurons net effect unkown	Positive inotropy for acute HF; ↑ arrhythmias; ↑ cardiac oxygen, metabolic & energy demand/supply ratio	↑ all-cause & cardiac mortalities; ↓ adrenergic & inotropic reserves & cardiac βAR signaling/function over time (due to ↑ cardiac GRK2)-Acute HF ONLY (cardiogenic shock)	Contraindicated in chronic HF; PDE3 inhibitors (milrinone) provide additional (direct) vasodilatory benefit
Exercise training	Improved hemodynamics-↑ Cardiac βAR signaling/function-↓ Cardiac & adrenal GRK2-↑ ANS neuronal& adrenalα2AR function	↓Outflow/activity	Improved arterial & chemoreflex controls; ↑ cardiac blood flow; ↓ CA toxicity; ↓ cardiac inflammation	↓ all-cause & cardiac mortalities; ↑ adrenergic & inotropic reserves; ↓ Cardiac ANS tone	Under investigation for chronic HF treatment
Cholinergic system stimulation	↓ HR & cardiac NE release-↑ cardiac function-↓ adverse remodeling	↓Outflow/activity	Improved arterial & chemoreflex controls; ↓ arrhythmias; ↓ CA toxicity	↓Cardiac ANS tone-Under investigation for chronic HF treatment, especially along with β-blockers	Cholinergic system function (bradycardia & vasodilatation) ↓ in chronic HF; benefit in HF significantly enhanced by β-blockers

See text for details. PNS: Parasympathetic Nervous System; CA: Catecholamine; MI: Myocardial Infarction; VSM: Vascular Smooth Muscle; AngII: Angiotensin II; Aldo: Aldosterone; PDE3: Phosphodiesterase type III; cAMP: cyclic adenosine monophosphate; HR: Heart Rate.

α-blockers

HF patients receiving the α₁-blocker prazosin experienced worse outcomes than did those receiving the combined vasodilator therapy of hydralazine and isosorbide dinitrate (BiDil).¹²² Prazosin has been reported to increase catecholamine levels in a feedback manner, thus diminishing any potential benefit reaped from vascular smooth muscle α₁AR inhibition-induced vasodilation (Table 1).¹²³ Adding to the inappropriateness of α₁AR blockers for HF therapy, the doxazosin arm in the ALLHAT clinical trial was terminated early because of higher HF incidence (Table 1).¹²⁴

Centrally acting sympatholytic agents

Central α₂ARs inhibit ANS outflow via an autocrine negative feedback mechanism.³⁹ Clonidine is a centrally acting α₂AR agonist that significantly attenuates cardiac and renal sympathetic tones in HF patients (sympatholytic). It exerts marked sympathoinhibitory effects without clinical deterioration (Table 1).¹²⁵ Large clinical trials, however, are still needed to evaluate its true place in the chronic HF therapeutic armamentarium. Another centrally acting sympatholytic agent, moxonidine, also an imidazoline derivative like clonidine, has been used in clinical trials for HF. Moxonidine is also an α₂AR agonist as well as an agonist at the putative imidazoline receptors.^126,127 It causes marked reductions in plasma NE,¹²⁸ and it failed in clinical trials as it was found to increase HF-related mortality (Table 1).¹²⁹ As a possible explanation for this, excessive sympatholysis to a point that was incompatible with life was postulated. However, another explanation might have been the reported α₂AR desensitization and downregulation that accompanies HF,⁷² which renders α₂ARs dysfunctional, raising sympathetic outflow in HF and limiting efficacy of α₂AR sympatholytic agonists (see above) (Table 1).

RAAS modulating drugs

Hyperactivation of the RAAS is another neurohormonal hallmark of chronic HF and the degree of its activation correlates with prognosis. Angiotensin II enhances the release and inhibits the reuptake of NE at ANS nerve endings (Fig. 2).^130,131 Angiotensin-converting enzyme (ACE) inhibitors, by decreasing angiotensin II and aldosterone levels, increase plasma renin activity, while they also decrease circulating catecholamines and vasopressin thanks to the hemodynamic improvements they bring about.¹³² Plasma aldosterone levels may be elevated as high as 20-fold in HF patients, primarily due to increased production by the adrenal glands following stimulation by the high plasma angiotensin II concentrations.^133–135 Our lab has also recently identified another mechanism for the enhanced cardiotoxic aldosterone production by the adrenal cortex in HF: enhanced activity of adrenal βarrestin1, a co-factor of GRKs in receptor desensitization (see above), at the AT₁R angiotensin II receptor.^136,137 In addition to its electrolyte, hemodynamic and metabolic effects, aldosterone has several direct detrimental effects on the myocardium, promoting cardiac adverse remodeling and HF progression, and also mediates several of the cardiotoxic effects of angiotensin II in the cardiac muscle, e.g. myocardial fibrosis, increased oxidative stress, inflammation, etc.^133–135 With regards to the ANS in HF, aldosterone, like angiotensin II, can decrease NE reuptake from ANS presynaptic neurons, thereby contributing to the enhanced ANS outflow in chronic HF (Fig. 2).^131,133 Some of the beneficial effects of aldosterone antagonists, such as spironolactone and eplerenone, in human HF may thus derive from suppression of this effect of aldosterone on the ANS (i.e. partial sympatholysis) (Table 1).^138,139

Sympathomimetics (AR agonists)

Dopamine, dobutamine and milrinone (its congener amrinone has been withdrawn from the market) represent the most commonly used sympathomimetic drugs (adrenergic agonists) used as positive inotropes for acute HF (Table 1). All positive inotropes lead to cAMP accumulation inside cardiomyocytes, which increases contractility via elevation of intracellular free Ca²⁺ concentration (Fig. 3). Dopamine and dobutamine achieve that by binding to and activating cardiac β₁ARs, whereas milrinone blocks phosphodiesterase type 3 (PDE3, cAMP-specific phosphodiesterase), thereby preventing cAMP degradation.¹⁴⁰ Of course, the elevation of intracellular free Ca²⁺ inside cardioymocytes predisposes to arrhythmias (major adverse effect of positive inotropes). All three inotropes produce a vasodilatory effect and can cause a reduction in blood pressure; this is especially the case for milrinone, since there are no β₁ARs in vascular smooth muscle (β₂AR is the βAR subtype there) (Table 1).¹⁴¹ Finally, the effects of dobutamine and dopamine are blunted when the patient is already on β-blocker therapy.¹⁴² In that case, non-βAR-related inotropes are preferred, such as milrinone or glucagon (which can also increase cAMP in cardiomyocytes through its own G_s protein-coupled receptor). Despite the straightforward rationale for using positive inotropes in HF (drop in cardiac output, hence administration of an agent that will directly increase it), clinical trials have clearly demonstrated that sympathomimetics significantly increase mortality in chronic HF.¹⁴³ Therefore, they are reserved only for treatment of acute episodes of HF, characterized by clinically evident hypoperfusion or shock, or as a bridge to more definitive treatment, such as revascularization or cardiac transplantation (Table 1).

Another therapeutic strategy involving sympathomimetics in HF is combined β₁AR blockade with simultaneous β₂AR stimulation with clenbuterol (a β₂AR-selective agonist), which has been shown to help reverse severe HF in selected patients requiring left ventricular assist devices (LVADs).¹⁴⁴ The rationale for this approach is based on studies demonstrating that clenbuterol is able to improve left ventricular function at the whole heart and cellular levels by affecting cell morphology, excitation-contraction coupling, and myofilament sensitivity to calcium.¹⁴⁵ However, a recent small, randomized controlled trial showed that clenbuterol was associated with a significant increase in both lean mass and lean/fat ratio as well as in muscle strength, and an increase in exercise duration in chronic HF patients (presumably via enhanced vascular smooth muscle β₂AR-dependent vasodilation which increases skeletal blood flow), and it is, in fact, used in sports medicine as a performance enhancing drug (PED).¹⁴⁶ Therefore, determination of the ultimate role of clenbuterol in HF therapy requires further investigations in larger prospective trials.

Non-drug therapeutic modalities affecting ANS in HF

Exercise training

Exercise intolerance is a major symptom of chronic HF, and skeletal myopathies contribute to the reduced functional capacity in HF.¹⁴⁷ ANS activation serves as a coordinator of the heart and muscle vasculature to maintain adequate blood pressure during exercise.¹⁴⁸ However, ANS overactivity leads to skeletal myopathies in HF, because ANS-mediated vasoconstriction at rest and during exercise limits muscle blood flow and arteriolar elasticity, leading to hypoperfusion/ischemia, release of ROS, and chronic inflammation.¹⁴⁹ On the other hand, exercise training has been shown to improve central hemodynamics, peripheral muscle function and symptoms, and to actually reduce ANS activity in HF patients, alone or in conjunction with β-blocker therapy, resulting in reductions of all-cause and cardiovascular mortalities (Table 1).^150,151 The postulated mechanisms for these beneficial effects of exercise training in HF include improvements in arterial and chemoreflex controls, significant reduction in central ANS outflow, correction of central nervous system abnormalities, increases in peripheral blood flow and reduction in circulating pro-inflammatory cytokines.¹⁵² Additionally, studies from our laboratory and others in experimental HF animals have shown that exercise training improves cardiac βAR signaling and function, increases adrenergic and inotropic reserves of the heart ameliorating cardiac contractility and function and helping restore normal ANS activity/outflow and circulating catecholamine levels, partly via normalization of GRK2 activity and restoration of sympathoinhibitory α₂AR function in the adrenal gland (Table 1).^81,153,154

Cholinergic system modulation

There is a complex interplay between the parasympathetic (cholinergic) nervous system and the ANS. Indeed, vagus nerve afferent activation from the periphery can modulate efferent adrenergic and cholinergic function centrally and at the baroreceptors. Moreover, cholinergic neurons exert tonic inhibition of adrenergic neuron activation and of NE release from presynaptic ANS nerve terminals. The well known cardiovascular effects of the parasympathetic nervous system, i.e. heart rate reduction (bradycardia, indirectly via inhibition of the ANS and directly by hyperpolarization and pacemaker activity suppression of the sinoatrial node) and vasorelaxation (indirectly via NO synthesis)¹⁵⁵ are significantly attenuated in chronic HF, which leads, among other consequences, also to lifting of the “harness” of ANS activation which the cholinergic system normally imposes, and thus, (indirect) enhancement of ANS outflow (Table 1).¹⁵⁶ Clinical and experimental data suggest that β-blockade augments reflex vagal nerve control of heart rate in HF, via suppression of the cardiac sympathetic presynaptic β₂AR-facilitated NE release.¹⁵⁷ Additionally, muscarinic cholinergic M₂ receptors (M₂ mAChRs) are upregulated in the left ventricular free wall, resulting in reduced heart rate variability.^158,159 Finally, vagus nerve stimulation therapy, combined with chronic β-blocker therapy, has been shown to further improve left ventricular function and reverse remodeling beyond what is achieved with β-blockers alone (Table 1).^160,161

Conclusions/Future perspectives

A vast number of studies over the past few decades have established the crucial role of activated ANS in the compensatory response of the circulation to retain its hemodynamic stability in the face of a cardiac insult, and when this fails, its excessive activation that accelerates HF progression and poses severe toxicity on the chronically failing heart. Additionally, the benefits of β-blockers and other therapeutic modalities that mitigate or protect the heart against this ANS hyperactivity are also well documented nowadays. Several recent developments in the basic cardiovascular research field that are at various stages of preclinical testing to ultimately reach the bedside in HF therapeutics also aim at reducing the activity and/or the detrimental effects of the ANS on the failing heart. Among these are sympatholytic agents (α₂AR agonists), polymorphic variants of cardiac ARs that confer better prognosis in HF or better responses to current HF treatments, new sympathomimetics that seek to augment the function of the seemingly “cardioprotective” β₂AR while simultaneously blocking the “cardiotoxic” β₁AR (e.g. clenbuterol), activation of the cardiac parasympathetic nervous system, and, last but not least, augmentation of cardiac βAR-dependent function without the accompanying elevation of ANS activity/outflow. The latter is pursued with the very promising GRK2 inhibition therapeutic approach, which poses to improve cardiac adrenergic and inotropic reserves by restoring cardiac βAR signaling and function (i.e. to provide positive inotropy), while keeping the ANS outflow at bay by restoring or augmenting central, cardiac and adrenal sympathoinhibitory α₂AR function. Further understanding of the mechanisms of ANS activation and of the repercussions this has on regulation of cardiac function and structure in chronic HF is most certainly bound to provide the clinicians of the future with some, currently very desperately needed, newer and better weapons in the battle against this devastating disease.

Circulation Research Compendium on Heart Failure.

Research Advances in Heart Failure: A Compendium

Epidemiology of Heart Failure

Genetic Cardiomyopathies Causing Heart Failure

Non-coding RNAs in Cardiac Remodeling and Heart Failure

Calcium Cycling in Heart Failure

Heart Failure Gene Therapy: The Path to Clinical Practice

Cardiac Metabolism in Heart Failure

Integrating the Myocardial Matrix into Heart Failure Recognition and Management

The Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy

Emerging Paradigms in Cardiomyopathies Associated with Cancer Therapies

Dyssynchronous Heart Failure: Pathophysiology, Recognition, and Management

Molecular Changes Following Left Ventricular Assist Device Support for Heart Failure

Cell Therapy for Heart Failure

Eugene Braunwald, Editor

[Note: This is the master text box for this series. For each article this text box appears in, please make the title above of that article bold.]

Non-standard abbreviations and acronyms

HF

Heart failure

ANS

Adrenergic Nervous System

RAAS

Renin-angiotensin-aldosterone system

NE

Norepinephrine

Epi

Epinephrine

AR

Adrenergic receptor

GPCR

G protein-coupled receptor

NET

Norepinephrine transporter

NOS

NO synthase

AC

Adenylyl cyclise

ATP

Adenosine triphosphate

cAMP

Cyclic adenosine monophosphate

PKA

Protein kinase A (cAMP-dependent protein kinase)

LTCC

L-type calcium channel

RyR

Ryanodine receptor

PLB

Phospholamban

SERCA

Sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase

SR

Sarcoplasmic reticulum

PLM

Phospholemman

G_s

stimulatory G protein

G_i/o

inhibitory or other G protein

GRK

GPCR kinase

PLC

Phospholipase C

PIP₂

Phosphatidylinositol (4,5)-bisphosphate

PKC

Protein Kinase C

DAG

2-diacylglycerol

TRPV

Transient Receptor Potential Vanilloid

MIBG

Metaiodobenzylguanidine

KO

Knockout

TAC

Transverse aortic constriction

βARKct

βAR kinase carboxyl terminal

ROS

Reactive oxygen species

TNF

Tumor necrosis factor

CYP

Cytochrome P450 enzyme

ACE

Angiotensin converting enzyme

PDE

Phosphodiesterase

LVAD

Left ventricular assist device

PED

Performance enhancing drug

NO

Nitric oxide