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Address correspondence to: Anastasios Lymperopoulos, PhD, FAHA, Assistant Professor, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr., HPD (Terry) Bldg/Room 1338, Fort Lauderdale, FL,, USA. Tel.: 954-262-1338, Fax: 954-262-2278, Or: Walter J. Koch, PhD, FAHA, Professor and Chair, Department of Pharmacology, Director, Center for Translational Medicine, Temple University School of Medicine, 3500 North Broad St, MERB Room 941, Philadelphia, PA 19140. Tel: 215-707-9820, Fax: 215-707-9890. 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. Du Battery Saver Pro Premium Apk Free Download on this page. 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., 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 (). 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., Therefore, whereas heart rate can be controlled (in opposing fashion) by both autonomic branches, cardiac contraction/relaxation is controlled practically solely by the ANS (). Overview of the ANS innervation of the cardiovascular system The ventricular ANS innervation is characterized by a gradient from base to apex. The cardiac neuronal system is composed of cell stations comprising afferent, efferent, and interconnecting neurons behaving as a control system. 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)., ANS activation in the cardiovascular system translates into release of the two catecholamines that mediate its effects, i.e. 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. The receptors for both ANS catecholamines are divided into three types and 9 total different subtypes, as follows: three α 1AR subtypes (α 1A, α 1B, α 1D), three α 2AR subtypes (α 2A, α 2B, α 2C), and three βAR subtypes (β 1, β 2, β 3). All ARs primarily signal through heterotrimeric G proteins.

The human heart contains all three βAR subtypes. Β 1AR is the predominant subtype in the (normal, healthy) myocardium, representing 75–80% of total βAR density, followed by β 2AR, which comprises about 15–18% of total cardiomyocyte βARs and the remaining 2–3% is β 3ARs (under normal conditions). The principal role of βARs in the heart is the regulation of cardiac rate and contractility in response to NE and Epi. Stimulation of β 1ARs (mainly) and of β 2ARs (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. Β 3ARs are predominantly inactive during normal physiologic conditions; however, their stimulation seems to produce a negative inotropic effect opposite to that induced by β 1ARs and β 2ARs, involving the nitric oxide synthase (NOS) pathway, thus acting as a “fuse” against cardiac adrenergic overstimulation. 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.

The most powerful physiologic mechanism to increase cardiac performance is activation of cardiomyocyte β 1ARs and β 2ARs, 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 Ca 2+ concentration, which is the master regulator of cardiac muscle contraction ().

Signal transduction of cardiac myocyte contraction and its regulation by cardiac ARs Of note, β 2AR also mediates the effects of catecholamines in the heart, but in a qualitatively different manner from β 1AR, as it can also couple to the AC inhibitory G protein (G i). In fact, this switching of β 2AR signaling from G s to G i proteins is postulated to be induced by the phosphorylation of the β 2AR by PKA.

Nonetheless, it is now generally accepted that in the heart, β 2AR signals and functions in a substantially different way compared to β 1AR. – Importantly, whereas β 1AR activation enhances cardiomyocyte apoptosis, β 2AR exerts antiapoptotic effects in the heart. – This essential difference between the two receptor subtypes is ascribed to the signal of β 2AR through G i proteins. Studies using transgenic mice, β 2AR-selective stimulation and adenoviral-mediated β 2AR overexpression, have demonstrated the protective effects of β 2AR signaling in the myocardium, including improved cardiac function and decreased apoptosis. Conversely, hyperstimulation or overexpression of β 1AR has detrimental effects in the heart., Both α 2- 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., 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., 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., Of note, the differences between the two predominant cardiac βARs, i.e. Β 1AR & β 2AR, 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, β 1AR is selectively downregulated (i.e. Functional receptor number reduced) in human HF, thus shifting the above mentioned stoichiometry of β 1AR: β 2AR towards 50:50 in the failing heart from ~75%:~20% in the normal, healthy heart., However, β 2AR is also non-functional and does not signal properly in the failing heart. – In addition, emerging evidence suggests that β 2AR 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 β 1AR. Therefore, this stoichiometric shift in favor of the supposedly “good” β 2AR 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).

How important a role cardiac α 1ARs 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. The α 1ARs 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 (IP 3) and 2-diacylglycerol (DAG) from the cell membrane component phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP 2).

IP 3 binds specific receptors in the SR membrane which cause release of Ca 2+ from intracellular stores, whereas DAG activates protein kinase C (PKC) and transient receptor potential (TRPV) channels (). The end result is again raised intracellular [Ca 2+], which leads to contraction (vasoconstriction) (). 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 β 1AR gene polymorphism is probably the best studied AR gene polymorphism to date; it is associated with significantly elevated AC/PKA activities and hence β 1AR-stimulated cardiac contractility in the Arg389 variant carriers (compared to Gly389 carriers).

Another human β 1AR polymorphism is the Ser49Gly variation, associated with increased agonist-promoted receptor downregulation for the Gly49 over the Ser49 variant. A lower prevalence of ventricular arrhythmias has been associated with the Gly389 allele. 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”). Additionally, the Gly49 allele of the human β 1AR gene has been shown to confer enhanced survival benefit in response to β-blocker treatment and significant reduction in left ventricular end-diastolic diameter compared to Ser49 homozygous carriers. Ameliorated cardiac adverse remodeling has been reported for Arg389 homozygous HF patients treated with the β-blocker carvedilol and for Arg389Gly heterozygous carriers. There are also negative studies however, reporting no associations of these polymorphisms with any cardiac outcome.

– 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. 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. The human β 2AR 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. Finally, a four amino acid deletion in the human α 2CAR gene (Del322–325) leads to increased NE release from ANS cardiac nerve terminals and this polymorphism, in combination with the β 1AR 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.

The latter polymorphism (β 1AR 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. 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. 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. 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. Cardiac ANS activity or its pharmacological inhibition can also be non-invasively assessed with [ 123I]-labeled metaiodobenzylguanidine (MIBG), an analogue of NE.

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). 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. 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 ().

NE turnover in subcortical regions in HF is significantly higher than that in the cortex and than in healthy subjects. 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., 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). 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 (). Epi represents approximately 80% of the total adrenal catecholamine secretion under normal conditions, with NE the rest ~20%. 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. 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, α 2ARs that inhibit secretion (inhibitory presynaptic autoreceptors), and βARs that enhance it (facilitatory presynaptic autoreceptors) ().,,, 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 α 2ARs are the only receptor type reported to date to inhibit adrenal catecholamine secretion.,, An increase in GRK2 expression and activity (see above) has been documented in several cardiovascular diseases, including increased cardiac expression in HF – and increased expression in some vascular beds in hypertension.

A few years ago, we reported that GRK2 expression and activity are increased also in the adrenal medulla during HF. Specifically, our studies over the past few years have established that adrenal GRK2 upregulation is responsible for severe adrenal α 2AR 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 (). – 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. Additional evidence for the crucial role of adrenal GRK2-regulated α 2ARs in regulating adrenal ANS tone in HF comes from the phenylethanolamine-N-methyl transferase (PNMT)-driven GRK2 KO mice. 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. Of note, elevated GRK2-dependent α 2AR dysfunction during HF might also occur in other peripheral sympathetic nerve terminals of the heart () and of other organs, thus contributing to the increased NE release and spillover, as well as to the presynaptic α 2AR dysfunction in ANS neurons observed in chronic HF (see above).

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). 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. Cardiac NE spillover in untreated HF patients can reach up to 50-fold higher levels than those of healthy individuals under maximal exercise conditions. 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. 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. 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.,, Cardiac βAR dysfunction in human HF is characterized at the molecular level by selective reduction of β 1AR density at the plasma membrane (downregulation) and by uncoupling of the remaining membrane β 1ARs and β 2ARs from G proteins (functional desensitization). ANS cardiotoxicity ANS cardiac toxicity is well documented. Β-blockers β-blockers () can be broadly classified into generations: first generation, which are non-subtype selective and competitively block both the β 1- and β 2ARs (propranolol, nadolol, timolol); second generation, with much higher affinity for the β 1- than for the β 2AR (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 α 1ARs, thereby causing peripheral vasodilation (bucindolol, carvedilol, labetalol). Celiprolol possesses also β 2AR agonist properties, while nebivolol can also induce nitric oxide (NO) synthesis. Cardioselectivity (i.e.

Selectivity for the β 1-over the β 2AR subtype) is dose-dependent and decreases with increasing dosage. Both subtype-selective and non-selective agents have negative chronotropic and inotropic effects.

Β 1AR-selective agents have a lesser inhibitory effect on the β 2AR and thus are less likely to cause peripheral vasoconstriction (and bronchoconstriction). Exercise performance may be impaired to a lesser extent by β 1AR-selective agents, since they spare the β 2AR 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 β 1AR, while mimicking catecholamines when binding to the low affinity state of the cardiomyocyte β 1AR. 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. All β-blockers are approved for chronic HF treatment ().

Conversely, they are all contraindicated in acute HF (due to the acute drop in cardiac output they cause). 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; 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.

In addition, restoration of adrenal GRK2-α 2AR-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. Α-blockers HF patients receiving the α 1-blocker prazosin experienced worse outcomes than did those receiving the combined vasodilator therapy of hydralazine and isosorbide dinitrate (BiDil). Prazosin has been reported to increase catecholamine levels in a feedback manner, thus diminishing any potential benefit reaped from vascular smooth muscle α 1AR inhibition-induced vasodilation ().

Adding to the inappropriateness of α 1AR blockers for HF therapy, the doxazosin arm in the ALLHAT clinical trial was terminated early because of higher HF incidence (). Centrally acting sympatholytic agents Central α 2ARs inhibit ANS outflow via an autocrine negative feedback mechanism.

Clonidine is a centrally acting α 2AR agonist that significantly attenuates cardiac and renal sympathetic tones in HF patients (sympatholytic). It exerts marked sympathoinhibitory effects without clinical deterioration (). 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 α 2AR agonist as well as an agonist at the putative imidazoline receptors., It causes marked reductions in plasma NE, and it failed in clinical trials as it was found to increase HF-related mortality (). 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 α 2AR desensitization and downregulation that accompanies HF, which renders α 2ARs dysfunctional, raising sympathetic outflow in HF and limiting efficacy of α 2AR sympatholytic agonists (see above) (). 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 ()., 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. 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. – 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 AT 1R angiotensin II receptor., 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. – 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 ()., 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) (). 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 (). All positive inotropes lead to cAMP accumulation inside cardiomyocytes, which increases contractility via elevation of intracellular free Ca 2+ concentration (). Dopamine and dobutamine achieve that by binding to and activating cardiac β 1ARs, whereas milrinone blocks phosphodiesterase type 3 (PDE3, cAMP-specific phosphodiesterase), thereby preventing cAMP degradation.

Of course, the elevation of intracellular free Ca 2+ 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 β 1ARs in vascular smooth muscle (β 2AR is the βAR subtype there) (). Finally, the effects of dobutamine and dopamine are blunted when the patient is already on β-blocker therapy. 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. 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 ().

Another therapeutic strategy involving sympathomimetics in HF is combined β 1AR blockade with simultaneous β 2AR stimulation with clenbuterol (a β 2AR-selective agonist), which has been shown to help reverse severe HF in selected patients requiring left ventricular assist devices (LVADs). 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. 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 β 2AR-dependent vasodilation which increases skeletal blood flow), and it is, in fact, used in sports medicine as a performance enhancing drug (PED). Therefore, determination of the ultimate role of clenbuterol in HF therapy requires further investigations in larger prospective trials. Exercise training Exercise intolerance is a major symptom of chronic HF, and skeletal myopathies contribute to the reduced functional capacity in HF. ANS activation serves as a coordinator of the heart and muscle vasculature to maintain adequate blood pressure during exercise.

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. 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) 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 ().

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 β 2AR-facilitated NE release. Additionally, muscarinic cholinergic M 2 receptors (M 2 mAChRs) are upregulated in the left ventricular free wall, resulting in reduced heart rate variability., 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 ().

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 (α 2AR 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” β 2AR while simultaneously blocking the “cardiotoxic” β 1AR (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 α 2AR 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.