The effect of adrenergic nervous system in heart failure along with cardiac remodeling

Abstract 

Heart failure constitutes syndrome which develops in response to some form of cardiac injury. Alternatively, it can be caused by the heart’s decline in pumping activity which is related to the contraction function of the heart. This syndrome is characterized by declining heart function, resulting in the interplay between compensating neuro-hormonal functions and myocardial dysfunctions. Some of the neuro-hormonal mechanisms activated during reduced heart function include the increased activity in the adrenergic nervous system (ANS), also known as the sympathetic nervous system. There is also hyper—activity in the renin-angiotensin-aldosterone system (RAAS), as well as those of several other systems including cytokines. The hyper-activity of these systems play major roles in achieving compensation for the reduced contraction rates of the heart during initial stages of the dysfunction. They are therefore able to maintain cardiovascular homeostasis. Nevertheless, long-term function of these compensation mechanisms eventually results in the cardiac function succumbing to the effects of the heart structure and performance. Cardiac remodeling has been accepted as a general determinant for the course of heart failure (HF). Cardiac remodeling considers different effects of cardiac stress and injury, including the changes in shape, size and function of the heart during cardiac injury and modifies the heart at the molecular, cellular and interstitial level to achieve optimum cardiac function for patients. This remodeling is considered alongside other factors such as neuro-hormonal activation and hemodynamic loads among others to determine the kind of treatment to receive. In any case, cardiac deterioration could occur with or without cardiac remodeling, in the presence of other vitiating factors. In a different part of this paper, the role of cardiac remodeling in increased chances of cardiac failure are considered alongside the roles of ANS. 

Introduction

Heart failure constitutes syndrome which develops in response to some form of cardiac injury. Alternatively, it can be caused by the heart’s decline in pumping activity which is related to the contraction function of the heart. This syndrome is characterized by declining heart function, resulting in the interplay between compensating neuro-hormonal functions and myocardial dysfunctions. Some of the neuro-hormonal mechanisms activated during reduced heart function include the increased activity in the adrenergic nervous system (ANS), also known as the sympathetic nervous system. There is also hyper—activity in the renin-angiotensin-aldosterone system (RAAS), as well as those of several other systems including cytokines. The hyper-activity of these systems play major roles in achieving compensation for the reduced contraction rates of the heart during initial stages of the dysfunction. They are therefore able to maintain cardiovascular homeostasis. Nevertheless, long-term function of these compensation mechanisms eventually results in the cardiac function succumbing to the effects of the heart structure and performance. This status quickly deteriorates leading to cardiac de-compensation and worsening functions until a point where daily life activities can no longer be sustained. Among other things, the paper discusses the role of ANS in heart failure pathophysiology. A discussion on the role of ANS in normal cardiac function will also be briefly pursued. 

On a different spectrum, cardiac remodeling has been accepted as a general determinant for the course of heart failure (HF). Cardiac remodeling considers different effects of cardiac stress and injury, including the changes in shape, size and function of the heart during cardiac injury and modifies the heart at the molecular, cellular and interstitial level to achieve optimum cardiac function for patients. This remodeling is considered alongside other factors such as neuro-hormonal activation and hemodynamic loads among others to determine the kind of treatment to receive. Slowing and reversing remodeling has recently become a goal for heart failure therapy, despite the fact that major remodeling has consistently resulted in worsening cardiac function. In any case, cardiac deterioration could occur with or without cardiac remodeling, in the presence of other vitiating factors. In a different part of this paper, the role of cardiac remodeling in increased chances of cardiac failure are considered alongside the roles of ANS. 

ANS and the Cardiac Function 

The Adrenergic Nervous System is responsible for a wide range of cardiovascular effects. These include the acceleration of one’s heart rate, which occurs due to positive chronotropy and a predisposing to arrhythmias; increased cardiac contractility, which occurs due to positive isotropy; cardiac relaxation on an accelerated scale, which occurs as a result of positive lusitropy, differences in constriction of resistance, decreased venous capacitance and the control of cutaneous vessels. All these functions empower the heart to perform optimally in the face of a fight or flight response. 

On the other hand, the parasympathetic nervous system slows the heart rate through nerve impulses, which do not have an effect on the heart’s ability to contract. This is because the ventricles in the heart, responsible for the pumping function of the blood, receive almost exclusive adrenergic innervations. This is different from the parasympathetic system whose fibers are on the vagus nerve on a sub-endocardia level after crossing the atrio-ventricular groove. As a result, when it reaches the atrial myocardium, there is minimal connectivity to the ventricular myocardium. As a result, it is possible to conclusively say that heart rate is controlled by both ANS and its converse system. However, cardiac contraction and relaxation is solely within the bounds of the ANS system. 

Figure 1 : Overview of the ANS system interaction with the cardiovascular system 

The ANS innervation within the ventricular myocardium contains a gradient from its base to the apex. The neuronal system in the heart comprises cells stations with efferent, afferent and interconnecting neurons, which are its controlling system. Cardiovascular reflexes regulate the manner of ANS outflow as well as circulation to the peripheries. Efferent impulses travel to the peripheral organs from the central nervous system, whereas afferent fibers, through the autonomic nerves, project to the central nervous system. Different reflex responses are present, the chief one being from the aortic arch. Various other reflex responses are equally obtained, and important to the flow including those from carotid baroreceptors, resulting in ANS inhibition; cardiovascular low-threshold polymodal receptors resulting in ANS activation; cardiopulmonary baroreceptors, which result in ANS inhibition alongside other functions, including the Bezold-Jariscch reflex; and the peripheral chemoreceptors, also responsible for ANS activation.

Activation of ANS in the system means the release of two major catecholamines, namely norepinephrine (NE), which is noradrenaline and epinephrine (Epi), also known as adrenaline. These two determine and mediate the functions of the cardiovascular system at this point, where the subject is met with a fight or flight response. Figure two expounds on the mechanisms through which this can happen:

Figure 2 : ANS input and regulation in the heart 

NE is released in the sympathetic nerve terminals. These are located at the right stellate ganglion, which is in contact with the sinus and atrio-ventricular nodes. The result is increased heart rate and a shortened atrio-ventricular conduction. It proceeds to the left stellate ganglion into the left ventricle, increasing the heart’s contractility. Uptake and release could occur throughout the entire heart.

Adrenaline (Epi) is released by the adrenal medulla into circulation, alongside traces of NE. it affects the myocardium and peripheral vessels.

A local release of both NE and Epi by the peripheral ANS systems, which synthesize these catecholamines and are located in blood vessels and cardiac mycocytes.

Adrenergic Receptors in the Cardiovascular System

Adrenergic Receptors Signaling and Regulation

ANS neurotransmitters normally mediate their effects in cells through binding activity with cell surface adrenergic receptors (ARs). These cell surface ARs belong to G protein-coupled receptors (GPCRs). Alternatively, they could also belong to the superfamily of heptahelical receptors (7TMRs). Up to 80% of NE produced and released by the ANS terminals is recycled by the NE transporter type 1 (NET type 1) while the remainder is left in circulation. ANS catecholamines receptors are primarily divided into three types, each with three additional sub-types, which can be outlined as follows: three α 1 AR subtypes (α 1A , α 1B , α 1D ); three βAR subtypes (β 1 , β 2 , β 3 ); and three α 2 AR subtypes (α 2A , α 2B , α 2C ). Primarily, all AR signals come through heterotrimeric G proteins. All three βAR subtypes (β 1 , β 2 , β 3 ) are found within the human heart. In a healthy and normal myocardium, β 1 AR is the predominant type presently available, accounting for between 75-80% of their total AR density. β 2 AR are also normally present with between 15-18% density, while the remaining 2-3% density accounts for β 3 ARs. Notably, this is the conditions for a normal and healthy human heart. Their role in the heart structure is to ensure that cardiac rate is adequately regulated and contractility is properly done when responding to NE and Epi.

Going into detail, therefore, stimulating β 1 ARs (mainly) and of β 2 ARs (to a lesser extent) results in increased cardiac contractility, frequency and relaxation rates alongside accelerated impulse conduction in the atrio-ventricular node. This is the lusotropic effect, positive chronotopy and a positive dromotropic effect. Where subjects have a pacemaker, there is increased activity in the sino-atrial node. During this activity, β 3 ARs are generally inactive. When they are activated, there is a negative inotropic effect, which negates that produced by the other two types. This negative effect involves the nitric oxide synthase pathway. As a result, it brings about the effect of a fuse, “breaking the circuit” in cases of adrenergic overstimulation of the heart. βARs, when activated in an agonist-induced manner, catalyzes guanosine triphosphate (GTP) exchange to guanosine diphosphate (GDP). This occurs on G α  subunit of heterotrimeric G proteins and results in heterotrimer dissociation. The two products of this dissociation are active G α  and free G βγ subunits, which although always associated together will now transduce intracellular signals independently.

Increasing cardiac performance can be achieved most powerfully by activating cardio-myocyte β 1 ARs and β 2 ARs. In turn, they will activate G s  proteins whose signals stimulate adenylate cyclase (AC). Immediate conversion of adenosine triphosphate (ATP) occurs, becoming cyclic AMP (cAMP) and binds to activate cAMP-dependent protein kinase (PKA). This is a major effector of cAMP and phosphorylates a number of substrates, resulting in a rise in free intracellular Ca 2+  concentration – the master regulator in cardiac muscle contraction. Figure 3 contains the pictorial details of this process:

Figure 3 : Cardiac Myocyte Contraction and AR regulation 

Different targets exist for the PKA phosphorylation occurring within the cardiac myocyte including the L-type calcium channels located on cell membranes and ryanodine receptors (RyRs), located within the sarcoplasmic reticulum, since both lead to an increase in calcium ion entry to the cytoplasm. The action of phospholamban empowers calcium ion reuptake in the SR due to its phosphorylation activity by PKA, which de-inhibits SERCA and results in the increased SR calcium ion stores which are present for the next contraction. Hyper-polarization activates cyclic nucleotide-gated channels, also activating a cation in-ward current. This affects the modulation of rhythmic activity within pacemaker cells. Hyper-polarization also prompts troponin I and myosin binding protein-C, which causes myofilament relaxation as sensitivity to Ca 2+ is reduced. Finally, phospholemman (PLM) is phosphorylated by PKA and relieves the inhibition and simultaneously activates the sodium pump. Cardiac muscle is repolarized and myofilaments relax. PKA can also phosphorylate the βARs in the heart structure; G proteins uncouple and functional desensitization in the receptor occurs. This desensitization could be heterologous or agonist-independent in nature.

Notably, β 2 AR is also involved in mediating the effect of catecholamines presence in the heart. However, its operation is significantly different from that of β 1 AR. β 2 AR could couple with AC inhibitory G protein (G i ). Moreover, this switching from G s  to G i  proteins is thought to be induced after the PKA phosphorylation of the β 2 AR. In any case, general consensus is present that β 2 AR functions differently from β 1 AR in a substantial manner. The most important distinction is that β 2 AR has anti-apoptotic effects while the activation of β 1 AR results in cardio-myocyte apoptosis. This is because of the signal β 2 AR sends through G i  proteins. Studies using mice have shown a protective effect when β 2 AR is signaling within the myocardium, with improved cardiac function alongside decreased apoptosis. On the other hand, where β 1 AR is overly stimulated, there are detrimental effects to the heart.

For both α 2 - and βARs, they are also subjected to desensitization and down-regulation – a homologous regulation process which diminishes the receptor’s response to sustained agonist stimulation. This process is began at the molecular level by the receptor phosphorylation by GPCR kinases. This is followed by βarrestins (βarrs) binding to the GRK-phosphorylated receptor. Thereafter, the βarrs uncouple the receptors from the respective cognate G proteins, resulting in a hindrance of further binding (also known as functional desensitization). The receptor is subsequently targeted for internalization. For mammals, GRK2 and GRK5 are physiologically critical GRK members since they regulate the largest number of GPCRs. These are abundant in the heart and neuronal tissue.

Notably, differences between the dominant cardiac βARs take shape when considered in light of their signaling properties. In fact, they have bigger bearing for pathophysiological implications for human heart failure. For instance, β 1 AR is normally down-regulated in human heart failure cases, thus shifting the stoichiometry of the ratios of type1 to type 2 from ~75%:~20% (when normal) towards 50:50 in the failing heart. Even so, β 2 AR is non-functional as it cannot signal properly in a failing heart. Furthermore, emerging evidence suggests β 2 AR signaling in a failing heart to be significantly different from its function in a normal heart. Among some of the differences include non-compartmentalization and semblance to pro-apoptotic and “more diffuse” cAMP signaling pattern, characteristic of the β 1 AR. As a result, the shift in favor of the perceived “good” effect of type 2 ARs does not help the situation where heart failure is occurring.

The human heart equally presents α 1A - and α 1B ARs at approximately 20% less percentage points compared to βARs. While the role of α 1 ARs in cardiac physiology is still a subject of debate, their role in blood flow regulation is clear. They induce constriction in the muscle walls of major arteries; this role is without dispute. They couple with G q/11  family of heterotrimeric G proteins resulting in the activation of phospholipase C (PLC)-β. This, in turn, produces molecules from the cell membrane which specifically bind receptors, thereby release Calcium ions from the intracellular stores. One of the products, DAG, activates the protein kinase C as well as the transient receptor potential channels. This causes a double increase in the number of Calcium ions within the system, resulting in vasoconstriction. An illustration of this process is provided in figure 3.

Finally consideration is given to α 2 AR subtypes. α 2B AR are present in the vascular smooth muscles. They induce constriction in certain vascular beds, whereas α 2A ARs inhibit outflow and lower blood pressure. Releasing NE from the sympathetic nerve terminals is controlled by both α 2A - and α 2C ARs. Deleting these subtypes can result in hypertrophy of the heart and HF, especially where there is enhanced NE and Epi secretion.

The Role of AR polymorphisms in Cardiac Function

There are some vital genetic polymorphisms found in human β- and αAR genes. Their presence is associated with heart failure phenotypes. They also interact with β-blocker therapy; this is a mainstay of heart failure standard of care which influences cardiac function. This section thus briefly discusses them and their effect on heart function. With this function in mind, studies have equally reported that polymorphisms have no effect on cardiac outcome. Confusion has been created where questions on the effect of Ser49Gly polymorphism on dilated cardiomyopathy outcomes have been questioned. In any case, this is not the subject matter of the paper. Notwithstanding, heart failure patients with Arg389 genotype were found to have greater odds of survival with factors such as age and sex catered for compared to those with Gly389 carriers. This being said, polymorphisms could indeed have bearing on cardiac function, considering that this paper conceives every possible alternative.

The human β 2 AR gene contains the two polymorphisms – Gly16Arg and Gln27Glu. Noting the effect of this gene in receptor down-regulation as discussed above, it is noted that these two aid in that function. A third one - Thr164Ile – confers impaired coupling of the receptor-G protein as well as reduced AC-mediated signaling. Deleting four amino acids from the α 2C AR gene triggers increased release of NE from the ANS nerve terminals. This polymorphism combined with β 1 AR Arg389Gly polymorphism were used together to categorize patients’ responses to β-blocker bucindolol. These polymorphism was one of three recently used to predict the appropriateness of implantable cardioverter-defibrillator shock therapy for heart failure patients. While the role of polymorphs is not agreed upon by many parties, it could be a future response to HF therapy.

Effects of ANS Over-activity in HF

Myocardial systolic dysfunction operates due to hyperactivity of neurohormones, which occur as a compensatory mechanism. The goal of this mechanism is to maintain the cardiac output despite declining function. The neuronal response is at the ANS cardiac nerve terminals while the hormonal response is in increased secretion of specific hormones, prominent among them being Epi and NE. this hyperactivity sees plasma contain increasing NE and Epi levels, heightened NE spill overs from sympathetic nerve terminals and elevated sympathetic outflows within circulation. It is found that the cardiac NE spillover could be as high as 50 times in untreated HF patients compared to healthy people in maximal exercise condition. For patients with hypertension, the risk for developing HF is higher as ANS hyperactivity could lead to left ventricle dysfunction. For systolic heart failure, the opposite is true. Patients have decreased ANS hyperactivity, thereby occasioning decreasing concentrations of NE in the heart. They also have decreased postsynaptic βAR density because cardiac ANS NE stores have been depleted, and there is also reduced presynaptic reuptake when the NE transporter is down-regulated.

Effects on cardiac ARs

Higher ANS outflows, NE and Epi levels for heart failure patients all lead to runaway elevation levels for the cardiac βAR system stimulation – the effects of which are detrimental to an already failing heart. It is now a well-known fact that cardiomyocyte βAR signaling and its other function are irreparably damaged alongside the adrenergic reserved for the heart. Different βAR dysfunction changes occur; myocardial levels for important components such as GRKs, GRK2 and GRK5 are all elevated strongly.

As a result, there is general consensus that excess ANS-derived catecholamines upsets the balance of ARs, reducing cardiac responsiveness and inotropic reserves depletion. Summarily, according to the evidence provided by several studies, increased ANS activity for HF patients’ results in an enhanced process of GRK2-mediated cardiac β 1 - and β 2 AR desensitization and β 1 AR down regulation. As a result, continuous loss of adrenergic reserves is experienced, as shown in figure 3 above. ARs remain active in a compensatory manner, but their activities are limited to hypertrophic scenarios which lead to HF anyway.

Cardiac Remodeling

This is a term coined in 1982 describing a myocardial infarction model. Scar tissue would be used to replace cardiac infarcted tissue. The term was equally used to describe a number of other procedures including the progressive increment of the cavity of the left ventricle in MI for rats. In the turn of the millennium, consensus was reached on the use of this term, allowing it to refer to groups of changes affecting the size, shape and function of the heart at the molecular, cellular and interstitial level as a response to heart injury. Two main forms of remodeling have been recognized: adaptive and pathological remodeling. For the purpose of this paper, pathological remodeling is considered.

Clinical Characterization

When morphological changes are detected, the diagnosis for remodeling is made. Such changes include those in the diameter of cavity, mass, areas of scarring after MI, inflammatory infiltrates and the geometry of the heart. An example of clinical detection is done when one is done during the acute phase of a myocardial infarction. The infarcted area is dilated once an expansion process in the acute stage is discovered. Alternatively, where eccentric hypertrophy of an infarcted area occurring due to different stimuli is discovered in its chronic phase, remodeling may be called for. The size of the ventricle is the chief characteristic of a post-infarction remodeling exercise.

Clincal Implications of Remodeling

Dysfunction

Dysfunction of the heart is the chief consequence of remodeling. Remodeling is in fact a pathophysiological substrate for the beginning and progression of dysfunction within the ventricles. Genetic changes respond to cardiac injury, where fetal genes begin to re-express themselves. As a result, there are changes at the cellular and molecular level. Ventricles begin to loss their ability to function, becoming asymptomatic at first and progressively moving to heart failure. Consider the figure below, which presents the progression:

Figure 4 : Progression of HF after Cardiac Remodeling 

Quite importantly, it is important to consider that dysfunction of the ventricles can affect prognosis. This is so much the case that half of cardiac dysfunction patients die within five years. More so, 40% of the patients die within the first year of hospitalization with cardiac failure. Specifically, a significant number of these deaths are associated with cardiac remodeling, where the patients were asymptomatic. This means that even asymptomatic dysfunction is not a guarantee for a good prognosis. As a result, this makes the morbidity levels of the concern at unacceptably high levels.

Arrhythmias

Research has established that cardiac remodeling has relation to malignant ventricular arrhythmias, which includes consistent ventricular tachycardia and fibrillation. Various changes occurring as a result of the remodeling brings about these changes. One such change is that of ion channels. Sodium channels are deactivated, whereas sodium and potassium channels change. Additional changes are experienced in the sodium/calcium exchange.

Moreover, gap junctional intercellular communication experiences changes. As a result, challenges for contact between adjacent cells and consequently electric coupling are experienced. Gap junction proteins are also known as connexins. During this change process, there is a decrease in the labeling intensity of the connexin, which is not experienced in a normal heart. Moreover, the protein is redistributed along the long sides of the cells, thereby leading to a prolonging effect of the QT interval, and thus arrhythmias.

In final check, remodeling also results in increased collagen content. The myocardial fibrillar collagen has three compartments, namely: perimysium, endomysium and epimysium. The entire muscles is sheathed by the epimysium and further consists the endocardium and epicardium. From this part, muscles are wrapped inter-connectively through the perimysium. Increase in collagen content results in fibrosis, occasioning a blockage of electrical conduction and arrhythmia. Therefore, arrhythmias and sudden death normally find their root in fibrosis. Strategies to reduce collagen-induced fibrosis are implemented to reduce chances of developing and succumbing to arrhythmias.

Mechanisms of Dysfunction

Remodeling the ventricles leads to significant deterioration of their function. Meanwhile, the phenomenon is not fully understood. Nevertheless, potential factors are available for review, as summarized in the table below and discussed thereafter:

Table 1 : Pathophysiology of cardiac ventricular dysfunction in remodeling 

Mechanism	Main changes	Consequence
Cell death	↑ apoptosis, ↑necrosis ↓ autophagy	Progressive myocyte loss
Energy metabolism	β oxidation Triglyceride accumulation ↑ glycolysis Mitochondrial dysfunction Mitochondrial atrophy	Lipo-toxicity ↓ energy ↑ oxidative stress
Oxidative stress	↑ NADPH oxidase ↑ catecholamine degradation ↑ xanthine oxidase Mitochondrial dysfunction ↓ antioxidant systems	Lipid peroxidation Protein oxidation DNA damage Cell dysfunction Fibroblast proliferation Metalloproteinase activation ↑ apoptosis ↑ signaling pathways to hypertrophy
Inflammation	innate response Adaptive response dysfunction	↑ inflammatory cytokines Macrophage, T cell and B cell dysfunction
Collagen	Fibroblast proliferation ↑ metalloproteinases	Degradation of normal collagen Fibrosis
Contractile proteins	β-myosin ↓ α-myosin ↑ troponin T type 2 ↓ troponin I phosphorylation	↓ contractility
Calcium transport	↓ L-type calcium channels ↓ ryanodine ↓ calsequestrin ↓ calmodulin ↓Phospholamban phosphorylation ↓ SERCA 2a	↓ Calcium in systole ↑ Calcium in diastole
Geometry	LV cavity ↓ wall thickness Elliptical shape → spherical shape	↑ parietal stress of the LV
Neuro-hormonal activation	↑ renin-angiotensin-aldosterone system ↑ Sympathetic	↑ cell death, ↑ oxidative stress, ↑ inflammation, ↑metalloproteinases and fibroblasts, hypertrophy, vasoconstriction

Cell Death

Three mechanisms can be identified as responsible for the death of mycocytes: apoptosis, necrosis and autophagy. Cell death was a widely accepted as a factor in the progression of dysfunction in HF patients. However, the roles of these processes was not clear. Evidence from studies has now linked apoptosis and necrosis as two faces of one process, which is necroptosis. Autophagy, on the other hand, is a process which occurs when unnecessary citoplasmatic components are destroyed by lysosomes. Protein homeostasis depends on delicate balances between protein functions such as synthesis, transport, modification and degrading. Where these processes are not aligned, accumulation of waste proteins occurs in a process known as proteo-toxicity. Autophagy is a last resort option aimed at preventing this intoxication by excess proteins. Evidence has thus shown that this process can be affected by progressed ventricular dysfunction, causing it to be adaptive or deleterious altogether. As a result, the loss of myocytes seems to influence the remodeling process.

The Metabolism of Energy

This is another factor that has potential to be involved in cardiac functions post-remodeling. It occurs when an imbalance between oxygen supply and consumption is present in the heart. Normally, free fatty acids consist the major energy substrate for the heart. Normal occurrence is at 60-90% of the energy supply. These fatty acids alongside glucose metabolites go into the citric acid cycle β-oxidation and glycolysis, respectively, thereby generating FADH2 and NADH. These, in turn, participate within the electron transport chain. The energy generated during this process is stored and transported as phosphocreatine.

With changes in metabolism in the remodeled heart, free fatty acids oxidation decreases and glucose oxidation increases. Decreased β-oxidation could result in triglycerides and lipotoxicity accumulating. Moreover, mitochondrial atrophy occurs. Altered mitochondrial function have been found present in cardiac remodeling. In the end, there is low energy availability for ATPase activity. Reactive oxygen species are generated, oxidative stress occurs and the consequences follow.

Oxidative Stress

Reactive oxygen species are produced in several places in the heart, such as the mitochondrial electron transport chain, cyclooxygenase enzyme activity, and xanthine oxidase and catecholamine degradation among others. Normally, there is a balance between these species production and antioxidant defense systems. Where oxidative stress is present, there is excessive reactive oxygen species overwhelming the antioxidant systems. Evidence puts the occurrence of oxidative stress in strong relation with cardiac remodeling. This occurs as a result of increased reactive species production and decreasing antioxidant forces. As a result, different conditions occur including DNA damage, cellular dysfunction, activation of metalloproteinases and changes in calcium-transport proteins among others. By reason of this, oxidative stress plays a significant pathophysiological role in remodeling.

Inflammation

Scientists believe that innate and adaptive immune responses occur responding to cardiac injury. The innate system brings about a nonspecific inflammatory response. The adaptive system, on the other hand, induces more specific response, which is mediated by B and T cells. Evidence from experiments points to the re-expression of fetal genes, which is further manifested in cellular growth and progressive loss of myocytes in the process of apoptosis. Moreover, innate responses from toll-like receptors was seen after remodeling. The fact that inflammatory response is present shows that remodeling can induce problematic heart changes.

Collagen

Collagen networks in the heart occur in complex manners. For instance, the interstitium is 95% type I and III collagen fiber. This network largely regulates apoptosis, maintains the alignment of structures, regulates transmission strength during fiber shortening, holds growth factors and restores pathological deformations among other functions. Due to their functions, they are interlinked with chemical bonds resistant to most protease degradation processes. Should a collagen network collapse, several adverse consequences could occur within the ventricles, affecting their function and architecture. For MIs, increased metalloproteinase activity resulted in cardiac dysfunction arising from ventricular dilation. Where metalloproteinase are inhibited, cardiac dysfunction has been ameliorated.

During cardiac injuries, abnormal accumulation of type III and type I collagen (which is harder, more stable and longer) was found. They were induced by several chemical pathways. As a result, fibrosis at this point is characterized by myocardial stiffness, weak contractions, impaired coronary flow and malignant arrhythmias among others. In the end, this fibrosis could predict mortality for affected patients. Collagen changes are thus witnessed during the aftermath of MIs in which remodeling is pursued.

Contractile Proteins

Remodeling the ventricles occurs when the main contractile protein – myosin – is changed. The composition of iso-enzymes within these proteins determines the overall contractile capacity for myocytes. Where remodeling is involved, V1 isoform is seen to decrease while the V3 form increases. Where this occurs, there is chance of reduced contractile capacity for the human heart as these forms require an equilibrium for proper cardiac function. During remodeling, the V1 form drastically reduces, affecting heart function.

Calcium transport

Calcium transportation is a complex process, containing many components. Intra-cellular systems regulation the supply of calcium to the contractile proteins involved in contraction of the heart. Additionally, when calmodulin kinase and phosphorylation is set in motion, enzymes responsible for calcium uptake regulation are activated, enhancing cardiac relaxation. Evidence supports changes in the calcium transport system during remodeling and ventricular dysfunction. These include decreased calsequestrin and calmodulin kinase activity, fewer L-type calcium channels as well as ryanodine receptors. This being the case, remodeling results in a reduction in calcium release during systole while calcium release increases during diastole. Calcium changes in the heart after injury could contribute to the dysfunction in remodeled hearts.

Cardiac Geometry Changes

Considering previous descriptions on the matter, remodeling is associated with changes in mechanisms which finally lead to cardiac dysfunction. In other models, there are changes in the cardiac geometry to include wall thickness, normal configuration in the left ventricle and cavity diameter – all of which have consequence on heart function. For rat models which were infarcted, there was overall increased ventricular cavity, leading to depressed systolic functions but a preserved contractile function of the myocyte. In the model where the aorta was constricted, almost half of the animals experienced a dilation of the left ventricle alongside pulmonary congestion. In both groups, however, there was no difference in contractile function. Therefore, these tests proved that geometry changes by themselves could affect global ventricular function through the ability to affect cardiac load.

Heart geometry also impacts on the ventricular rotation and torsion. The heart rotates slightly on a horizontal axis during the pumping process, both in a clockwise and anticlockwise direction. Torsion, on the other hand, describes the degree of myocardial deformation corrected during diastole. Systolic torsion normally increases intra-cavity pressure, reducing the energy demand. In cardiac remodeling, changes to the geometry and architecture of the heart could lead to changed torsion levels, leading to cardiac dysfunction.

Neuro-hormonal activation

The two main systems operating after cardiac remodeling are the sympathetic and renin-angiotensin-aldosterone systems. When both systems are activated, intracellular signaling pathways are activated, aiding in synthesis of protein in myocytes. These eventually cause hypertrophy and fibrosis. A variety of other effects have also been witnessed during this process, including the metalloproteinases, hemodynamic overload through vasoconstriction and water retention, increased oxidative stress and a cytotoxic effect. Blocking these systems catalyzes prevention of cardiac remodeling stimuli.

Beta Blockers

Beta blockers are drugs which are used to bind beta-adrenoreceptors. As a result, there is a blockage that does not allow NE and Epi to bind to these receptors. This therefore interferes with the normal sympathetic effects actualized by these receptors. Beta-blockers are drugs which are sympatholytic in nature. As a result, when they bind to the beta-adrenoreceptors, the result is an activated receptor which cannot bind with Epi anymore. These partial agonists provide background sympathetic activity and are said to have intrinsic sympathomimetic activity (ISA) characteristic. Other beta-blockers also have the membrane stabilizing activity (MSA) characteristic. This activity is similar to what the sodium-channel blockers provide during class 1 anti-arrhythmics.

In their first generation, beta-blockers were normally non-selective, where they blocked both beta-1 (β1) and beta-1 (β2) adrenoceptors. Later on, they were made more selective in that they were more selective for beta-1 receptors. Where higher doses of the drug were administered, the relative selective nature was lost. In their third generation, beta-blocker drugs possessed vasodilator actions that could aid in blocking vascular alpha-adrenoreceptors.

Operation in the Heart

Beta-blockers are designed to bind with beta-adrenoreceptors found in the cardiac nodal tissues, its conducting system and the myocytes. Noting that the heart has both beta-1 and 2 receptors, it is critical to note the role of beta-blockers – chief being the beta-1 adrenoreceptors, which are the predominant ones performing the various functions. These receptors mainly bind NE and Epi circulating in the blood from the sympathetic adrenergic nerves. Additionally, they equally bind NE and Epi flowing in the blood, while preventing the normal ligand from binding with beta-adrenoreceptors through competition for binding sites.

It is also possible for beta-adrenoreceptors to be bound to Gs-proteins. These are the same which activate adenylyl cyclase to cAMP, from the ATP compound. Where cAMP is largely activated, the largely cAMP-dependent PKA is formed. The result is an increased phosphorylation of L-type calcium channels, resulting in increased diffusion of calcium into the cell. Where calcium increases within the cell, there is enhanced release of calcium by the sarcoplasmic reticulum, resulting in increased inotropy. The activation of Gs protein also increases chronotropy. The phosphorylation of sarcoplasmic reticulum sites by PKA leads to enhanced calcium release through ryanodine receptors, which are associated to the sarcoplasmic reticulum. The result is more calcium being provided for the binding of troponin-C to calcium, enhancing inotropy. In conclusion, the PKA can phosphorylate myosin chains, thereby contributing to positive inotropic effects on the beta-adrenoreceptors stimulation. Due to the existence of a general sympathetic tone on the heart, beta-blockers adequately reduce sympathetic influences, which will stimulate heart rate, contractility, relaxation and electrical conduction. The effect of beta-blockers is thus the decrease in contractility, relaxation rates, conduction velocity and contractility. Moreover, they have a greater effect in cases of elevated sympathetic activity. 

Operations in Blood Vessels

Beta-2 adrenoreceptors are located within the vascular smooth muscles and are activated by NE released in the sympathetic adrenergic nerves or as a response to Epi in circulation. Like those receptors in the heart, these receptors couple with Gs proteins, resulting in the formation of cAMP. Despite the effect of cAMP in increasing mardiac myocyte contraction, their action in the vascular smooth muscle result in smooth muscle relaxation. This is because cAMP inhibits the action of myosin light chain kinase, which normally phosphorylates the smooth muscle myosin. Due to this, increased intracellular cAMP occurring as a result of beta-2 agonists causes the inhibition of myosin light chain kinase. This results in the production of a lower contractile force (that is, the promotion of relaxation). 

A comparison of their effects in the human heart, beta-blockers are found to have lower vascular effect due to the modulatory role of the beta-2 adrenoreceptors on the basal vascular tone. In any case, blockades staged against beta-2 adrenoreceptors are associated with small degrees of vasoconstriction within vascular beds. Beta-blockers can only remove small β 2 -adrenoceptor influence on the vasodilator. Normally, this is the function opposing dominant vasoconstrictor mediated by alpha-adrenoreceptors. 

Therapeutic Uses of Beta-blockers

Among other things, beta-blockers treat hypertension, myocardial infarctions, arrhythmias, heart failure and angina. 

Hypertension

Beta-blockers can decrease pressure in the arteries through the reduction of cardiac output. Several forms of hypertension will be characterized by increased blood volume and cardiac outputs. As a result, it is necessary to treat this by the reduction of cardiac output. Using beta-blockades to reduce this output has proved effective in dealing with such challenges, especially when this drug is administered alongside a diuretic. Nevertheless, using a beta-bliocker to treat the acute condition will not work in the long run, as reducing arterial pressure will result in a compensation for vascular resistance in the body. This may occur as baroreceptor reflexes work with reduced β 2  vasodilatory influences, thereby setting off alpha-adrenergic mediated vascular tone. Chronic treatment using these drugs will lower arterial pressure more than in acute cases. It is possible this is the case because there is already reduced renin levels. As areuslt, the beta blockade acts effectively on the central and nervous peripheral nervous system. These drugs also have the benefit of treating hypertension due to their ability to inhibit renin release from the kidneys. This release is partly regulated by the action of β 1 -adrenoceptors within the kidneys. Decreased renin circulation leads to reduced angiotensin II and aldosterone levels, which leads to higher losses of sodium and water in the kidneys, thereby furthering the decrease of arterial pressure. 

Where hypertension in a patient is the result of emotional stress, and subsequent increased sympathetic activity, beta-blockers are extremely effective for them. Thuus, beta-blockers can be used in the management of hypertension which is a result of pheochromocytoma, a condition which is characterized by elevated circulation of catecholamines. Where the drugs are used for this condition, the blood pressure is initially controlled by an alpha-blocker and then a beta-blocker will be administered carefully to reduce the increased cardiac stimulation thorugh the action of catecholamines. Of critical importance is the administration of the beta-blocker after vascular adrenoreceptors are effectively blockers, lest a hypertensive crisis occurs due to unopposed stimulation of alpha-adrenoceptor. 

Angina and Myocardial Infarction 

Beta-blockers contain an anti-anginal effect attributed to the cardio-depressant and hypotensive characterisitcs. Beta-blockers are effective in reducing heart rate, contractility and arterial pressure. These reduce the workload for the heart and the subsequent oxygen demand. Where oxygen demand is reduced, the oxygen supply/demand ratio significantly improves, thereby relieving a patient from angina pain which is the result of the lower levels of the oxygen supply-demand ratio present due to coronary artery disease. Beta-blockers are also critical to the treatment of myocardial infarctions, where they have shown reduced morbidity. The benefit is derived partly from the improved oxygen supply/demand ratio and their effect in effectively reducing subsequent cardiac remodeling options. 

Arrhythmias

Beta blockers contain anti-arrhythmic properties due to their ability to inhibit sympathetic influences for cardiac electrical activity. Sympathetic nerves increase the automaticity in the sino-atrial node through the increase in pacemaker current, thereby increasing sinus rates. Activation of the sympathetic system equally increases conduction velocity in the atrio-ventricular node and stimulates pacemaker activity. The mediation of these sympathetic influences is largely done at the mercy of β 1 -adrenoceptors. Where beta-blockers are administered, these sympathetic effects are inhibited, resulting in decreased sinus rate, conduction velocity and aberrant pacemaker activity. In addition, decreased conduction velocity could result in blocked reentry mechanisms. The administration of beta-blockers could also affect action which is not related to pacemaker thereby increasing action potential duration and the refractory period. Where such incidence occurs, arrhythmias can effectively be blocked via reentry mechanisms. 

Heart Failure

Majority of HF patients have systolic dysfunction, meaning that there is a depression of the heart’s contractile function, meaning lost inotropy. Despite the fact that it could seem counterintuitive to use cardio-inhibitory drugs to treat systolic dysfunction, clinical studies have concluded in favor of specific beta-blocker use to improve cardiac function and reduce morbidity and mortality. In fact, these studies have shown reduced deleterious cardiac remodeling occurring for chronic HF patients. Despite this, the impact of beta-blockers resulting in this effect is poorly understood. Nevertheless, it is considered to be the result of reduced sympathetic influences on the heart which have detrimental effects to a failing heart. 

Beta-Blocker Classes and Drugs 

Beta-blockers used clinically can be divided into two main classes: non-selective and relatively selective beta-1 blockers. Non-selective blockers act on both beta-1 and beta-2 receptors, whereas relatively selective blockers work for beta-1 receptors. Other blockers contain additional benefits aside from beta-1 blockage, leading to their unique pharmacological applications and profiling. The table below lists the two classes of beta-blockers along with their specific compounds. Resources for each drug could be found on different websites, not considered for this paper. In any case, the table indicates on- and off-label uses for the beta-blockers. For instance, where a blocker is approved for the treatment of hypertension, yet physicians use it for the treatment of angina, such use is listed within the table. 

	Clinical Uses
Class/Drug	Hypertension	Angina	Arrhythmias	MI	Chronic HF	Comments
Non-selective β 1 /β 2
carteolol	X					ISA; long acting; also used for glaucoma
carvedilol	X				X	α-blocking activity
labetalol	X	X				ISA; α-blocking activity
nadolol	X	X	X	X		long acting
penbutolol	X	X				ISA
pindolol	X	X				ISA; MSA
propranolol	X	X	X	X		MSA; prototypical beta-blocker
sotalol			X			several other significant mechanisms
timolol	X	X	X	X		primarily used for glaucoma
β 1 -selective
acebutolol	X	X	X			ISA
atenolol	X	X	X	X
betaxolol	X	X	X			MSA
bisoprolol	X	X	X		X
esmolol	X		X			ultra short acting; intra or postoperative HTN
metoprolol	X	X	X	X	X	MSA
nebivolol	X					relatively selective in most patients; vasodilating (NO release)

Side effects and Possible Contraindications

Effects on the Heart Function

Beta-blockers, while effective, may contain several side effects related to heart function, including a reduced capacity to exercise, heart failure, atrio-ventricular nodal conduction blockage, bradycardia and hypotension. Beta-blockers are thus contraindicated for pateints with sinus bradycardia and partial blockage of the atrio-ventricular node. These side effects occue where there is excessive inhibition of normal sympathetic activity in the heart. Where the beta-blocker is being administered with a selective calcium channel blocker, it is necessary to take extra care as these two acting together can result in extreme reductions in electrical and mechanical activity in the heart. 

Other Side Effects

Other side effects have also been noted when using non-selective beta blockers including bronchoconstriction. Non-selective beta-blockers are thus normally contraindicated for patients with asthma or chronic pulmonary disease. This side effect occurs as sympathetic nerves innervate the bronchioles, they will activate beta-2 adrenoreceptors, where broncho-dilation is promoted. The beta-blockers could also mask the tachycardia, which is the warning signal for hypoglycemia in diabetic patients. It therefore goes without saying that beta blockers should be used extremely carefully with diabetic patients. 

Conclusion: Is Cardiac Remodeling Good or Bad?

Heart failure is the single most common cause of death in the developed world. Often preceded by remodeling processes, this process sees patients have alterations made to their heart to reduce stress by both internal and external stimuli. The goals of remodeling are in fact to successfully cause adaptation to reduced wall tension and the preservation of the heart pumping function in HF patients. As a result, remodeling processes have been classified under both beneficial and maladaptive processes, expected to change heart function appropriately depending on the cardiac injury in question.

Hypertrophic remodeling initially compensates for the reduction of ventricular stress with temporary preservation of the heart pumping function. However, as shown above, this quickly deteriorates into maladaptive changes resulting in heart failure and morbidity. As discussed in a detailed fashion above, pathological remodeling contains several processes of maladaptive mechanisms, including calcium uptake handling, gene expression and metabolic pattern changes and fibrosis, ultimately leading to the failure of processes around and within the heart. For instance, cardiac stress increases with neuro-hormonal activations and abnormal mechanical stretch (geometry changes in the heart), which result in additional stress for the heart. Several heart messengers such as calcium, kinases and other critical components are no longer quantities, leading to a critical and/or fatal scenario for the patient. With many reviews on the impact of these components on the remodeling process, it is therefore much easier to conclude on the benefit or detriment of the maladaptive remodeling process as a conclusion to this paper.

Cardiac Remodeling is the Tuning of a Machine? 

In many instances, cardiac remodeling has been otherwise termed as the maintenance of a machine which is subjected to a heavy workload. This machine could be optimized by technicians to ensure performance after being provided with different fuels and spare parts. This machine is the heart, its optimization is remodeling, the technicians are the key components mentioned above and fuel is the metabolism. The endeavors of modeling can be long-term – as is the case for hypertrophy; or short-term, where immediate responses are seen – as is the case mostly when cardiac injury occurs. 

When this allegory is transposed into pathophysiology of the heart, a solid opinion cannot be easily arrived at on the goodness or badness of this procedure. Many factors are indeed in play and a simplistic answer cannot be offered to this question. As the ambigram below will reveal, when looking for something positive, the word ‘good’ will become apparent to the viewer, whereas a person looking to find something negative will see the word ‘evil’.

Figure 5 : An Illustration of Good and Evil as an Optical Illusion 

When focusing on this goodness or badness search, therefore, this section will look at two main components examined throughout this paper and determine their final role in the successful labeling of this procedure: protein kinase and calcium regulating processes.

Protein Kinase a – responsible for signaling after remodeling

This particular component, earlier referred to as PKA, is the downstream effector for the β-adrenergic in cardiac signaling. When this component comes into play, critical signaling chains and downstream effectors are activated, thereby effectively controlling the infamous ‘fight or flight’ response. Effects on inotropy, chronotropy and lusitropy are evident. As a result, the PKA is the ‘heart’ of all myocyte signaling pathways, enabling the integration of stimuli and stressors into cascades which enhance remodeling for the short-term or long-term. As a result, its activity after remodeling will affect cellular integrity and homeostasis. Recent research can be elucidated to see the effect of remodeling on the function of the PKA in the midst of complex interplay between components for smooth cardiac functions.

Research in this regard began with a fairly erratic view that PKA was a detrimental player in remodeling concepts. However, research further afield helped to interpret the function of this component in light of others such as calcium-related factors, leading to a complex understanding of its function. For this, PKA was found to have protective effects on immediate β-adrenergic stimulation. On the other hand, transgression to HF was found to be in play when there was decreased PKA dependent target phosphorylation. Such findings supported that PKA had pronounced roles in early remodeling compared to chronic stress. 

Additionally, the activation of PKA became an area of interest due to its role in downstream effects. Although it was well-known previously that the β-adrenergic cascade was known for PKA activation, alternative viewpoints including Reactive Oxygen Species (ROS) have been suggested as alternative PKA activator mechanisms. ROSs are integral parts of subcellular signaling in cells and contribute to the myocyte stress response and remodeling efforts. If this be the case, ROS could have far—reaching abilities, including altering calcium signaling and contractility, regulate homeostasis, and alter contractility among others. As studies went on to confirm, PKA effects can be dependent on multiple factors such as β-adrenergic stimulation, and ROS among others. All these studies confirm that PKA is quite the essential component for all these scenarios. This example explains how differentiated PKA activation through ROS and its subsequent effects complicates the signaling and remodeling mechanisms of the cardiomyocyte. 

CaMKII-Signaling in Remodeling 

Again, the critical role of calcium elaborated in the course of this paper, impacting the heart’s response to external and internal stimuli, is apparent. Its impact after remodeling has been studied in depth. Similarly, calcium has been found to have multiple forms of activation such as glycosylation, nitrosylation and oxidation apart from its interaction with intra-cellular proteins. Where calcium is possibly activated through ROS mechanisms, it presents another area of interest similar to that in PKA. The reality of such an activation is almost within grasp, considering that PKA and CaMKII share a large number of binding partners and downstream effectors. These include sarcomeric proteins, calcium handling proteins, and calcium and sodium channels. In fact, this is so much the case that researchers have explored the possibility of competition between the two components as PKA has been found to shut out CaMKII signaling tracks. 

In second consideration of contrary evidence, the importance of key signaling of CaMKII after cardiac remodeling can be seen. While this is the case, evidence points to the fact that there are intricate and multi-layered mechanisms of regulation. For instance, the proposition of the isoform CaN and PKA instead of CaMKII to describe variances in downstream signaling could complicate the situation for the school of thought placing full responsibility on CaMKII. Moreover, the multi-adaptor z-disc protein known as myopodin has been found to be phosphorylated by PKA, CaMKII and calcineurin, representing another series of multiplicity and redundancy. Despite the fact that the implications of this revelation are not substantiated, they cast significant doubt on the fact that the effect of CaMKII can single-handedly result in HF after remodeling. 

Therefore, there is consensus to the fact that duration, intensity and the environment of both intrinsic and extrinsic factors could lead to changes in the downstream mediation of remodeling. With this, single effectors cannot be pinned for specific downstream effects leading to HF for remodeled hearts. 

A Final Commentary

In final consideration, cardiac remodeling presents a concept intertwined with complexity and its effects without proper understanding, redundant. The first part of this review examined the heart function of HF patients examining ANS activity and ARs effects. Thereafter, cardiac remodeling was investigated, with focus on the specific pathophysiological outcomes expected as a result of its occurrence. Finally, a look at divergent views on the specific causes of HF post-remodeling have been evaluated, thereby presenting a balanced critique of the entire scenario. The field of medicine and human biology have definitely strived to provide knowledge on the effects of pivotal mediators, PKA and CaMKII, on remodeling. Nonetheless, evidence of specific and actionable effects of this relationship for each of the specific effectors on heart failure is scarce, if present at all.

Be it as it may, this paper has gone to full lengths to describe the complexities of processes involved in PKA and CaMKII in previous sections, which have not been dispelled by the studies examined in this last part. If anything, these studies have confirmed the assertion made in previous sections regarding the complexity of processes involved in the ultimate failure of the heart after cardiac remodeling. While multiplicity and redundancy have been noted in the course of determining the effects of PKA and CaMKII on heart failure post-remodeling, current evidence has not been dispelled as to effects of this and other effectors in resulting to challenged heart function. It still underlines the concept that remodeling, as a procedure most patients with cardiac injury has gone through, often precedes heart failure in those patients. The understanding of the specifics is yet to gain widespread consensus, but the result remains evidence of the fact that a common denominator – cardiac remodeling – is behind it.

Be it as it may, cardiac remodeling is a procedure that gives the patient additional time and compensated heart function, if not for any other purpose, to get their affairs in order after the first instance of cardiac injury. Remodeling may not provide a long-term fix, but its short-term benefits accrue to the beneficiaries nonetheless. Conclusively then, the question of its goodness and badness lies, and proverbially so, ‘in the eyes of the beholder’.

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