Hemodynamic Adaptive Mechanisms in Heart Failure

Chapter 5

Hemodynamic Adaptive Mechanisms in Heart Failure Alexander Hussey1, Lucas Eastaugh1,2, Robert G. Weintraub1,2,3 1The

Royal Children’s Hospital, Melbourne, VIC, Australia; 2Murdoch Children’s Research Institute, Melbourne, VIC, Australia; 3University of Melbourne, Melbourne, VIC, Australia

INTRODUCTION To understand the pathophysiological processes that occur in heart failure we need to first understand the normal cardiovascular physiology. To facilitate the autoregulation of blood pressure, there is a complex interplay of circulatory, neurohormonal, and molecular changes to not only help maintain distal organ perfusion but also trigger cardiac muscle changes to compensate for any abnormality. In a healthy well-functioning heart these compensatory mechanisms are usually efficient and only transiently stimulated. However, in a failing heart these mechanisms are chronically overstimulated and change from being physiological and adaptive to pathophysiological and maladaptive.

CARDIAC FUNCTION Stroke Volume In a structurally and functionally normal heart, the right ventricle ejects a volume of blood into the pulmonary artery, and almost simultaneously the left ventricle (LV) ejects a volume into the aorta with each cardiac contraction. If these “stroke volumes” (SV) are averaged over time then the SV from each ventricle can be considered to be equal. In general terms, SV is defined as the volume of blood ejected by the LV into the aorta with each contraction. If the heart has an intracardiac shunt (e.g., atrioventricular (AV) septal defect, ventricular septal defect) or left AV valve regurgitation, then this definition becomes flawed, as some of the SV will not be ejected into the aorta. A more precise definition for SV is the difference between ventricular end-diastolic volume (EDV) and end-systolic volume (ESV). SV = EDV − ESV



The three primary factors that regulate EDV and ESV, and therefore SV, are as follows: Preload Afterload l Contractility (inotropy) l l

Preload This is the force that stretches the cardiac myocytes prior to contraction and is dependent on sarcomere length. Preload is increased by the following: Increased central venous pressure (CVP), e.g., from decreased venous compliance due to sympathetic activation; increased blood volume; respiratory augmentation; increased skeletal pump activity. l Increased ventricular compliance. l Increased atrial contraction. l Reduced heart rate (increased ventricular filling time). l Increased afterload (increased ESV, reduces SV, and leads to a secondary increase in preload). l

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Preload is decreased by the following: Decreased CVP (e.g., hypovolemia). Impaired atrial contraction (e.g., due to atrial arrhythmias). l Increased heart rate (decreased ventricular filling time). l Decreased afterload (reduced ESV, increases SV, and leads to secondary decrease in preload). l AV valve stenosis l l

The effect of preload on SV is described by the Frank–Starling mechanism (Fig. 5.1) eponymously attributed to the German-born doctor and physiologist, Otto Frank (1865–1944), and later work by the English physiologist, Ernest Starling (1866–1927). This is described as the “principal mechanism by which the heart adapts to changing inflow of blood. When the cardiac muscle becomes stretched an extra amount, as it does when extra amounts of blood enter the heart chambers, the stretched muscle contracts with a greatly increased force, thereby automatically pumping the extra blood into the arteries” [1]. In laboratory studies, when isolated cardiac muscle is stimulated to contract at a low resting length (low preload) with all other factors kept constant, the amount of active tension that develops is relatively small. If the cardiac muscle is stimulated to contract at a larger preload length, the active tension is greatly increased in a directly proportional way. There is an increased sensitivity of troponin C to calcium (Ca2+) in the cardiac myocytes [2,3] and less spacing between the myofilaments, which allows a greater number of actin–myosin cross bridges to form. This results in a greater force of contraction and so increased SV [2,4,5]. When a normal cardiac muscle fiber is allowed to shorten against a fixed afterload (isotonic contraction), an increase in muscle length prior to contraction (increased preload) causes an increase in the amount of shortening but to the same minimal length, as well as an increase in the velocity of shortening. This response is intrinsic to the individual heart and can be modified by extrinsic neurohormonal mechanisms and by the afterload and inotropic state. Increasing afterload or decreasing inotropy shifts the curve downward and rightward, resulting in a lower SV at a given left ventricular end-diastolic pressure (LVEDP). Conversely, decreasing the afterload and increasing inotropy shifts the curve upward and leftward, resulting in a greater SV at a given LVEDP. The active tension that develops due to preload can increase but only to a maximal limit, which corresponds to the length of a sarcomere (1.6–2.2 μm) [6]. The greater stiffness of cardiac muscle normally prevents its sarcomeres from being stretched beyond their length, unlike sarcomeres in skeletal muscle, which can stretch beyond their length. In the early stages of heart failure, the Frank–Starling mechanism has an important compensatory role to maintain SV. However, in established heart failure, the relevance of the Frank–Starling mechanism is controversial. Some studies have shown that the failing heart is unable to develop an appropriate increase in SV when subjected to increased preload (Fig. 5.2). This is shown by the Frank–Starling curve being so significantly flattened that the failing heart operates at the top or near the top of the curve already [7,8]. This is thought to be due to a failure in troponin C developing an increase in Ca2+ sensitivity [9].

Afterload This is the “load” the heart must eject against following ventricular contraction and is affected by aortic pressure and systemic vascular resistance (SVR). SVR is the combined resistance to blood flow from all of the systemic vasculature (not the pulmonary vasculature). An isolated increase in afterload due to increased SVR should theoretically result in a decrease in SV due to 100 75

SV (ml)

50 25 0

0

5

10

15

20

LVEDP (mmHg) FIGURE 5.1  Frank–Starling mechanism—increasing preload increases LVEDP and SV. In an adult the mean operating point (dot on curve) occurs at LVEDP ∼8 mmHg and SV ∼70 ml. LVEDP, left ventricular end-diastolic pressure; SV, stroke volume.

Hemodynamic Adaptive Mechanisms in Heart Failure Chapter | 5  61

FIGURE 5.2  Effect of heart failure on the Frank–Starling curve. Increase in LVEDP (from A to B) can result either in a significant or in a negligible increase in SV depending on the steepness of the Frank–Starling curve. Thus preload responsiveness occurs in normal functioning hearts, and relative preload unresponsiveness occurs in impaired ventricular contractility. LVEDP, left ventricular enddiastolic pressure; SV, stroke volume. (Adapted from Science Direct database: Guerin, Monnet, Teboul, Monitoring volume and fluid responsiveness: From static to dynamic indicators, Best Practice Res. Clin. Anaesthesiol. 27 (2) (2013) 177–185).

Normal contractility

SV (ml)

Impaired contractility

B

A

LVEDP (mmHg)

Afterload

C

100

A

75

SV (ml)

Afterload

B

50

FIGURE 5.3  Effect of afterload on Frank–Starling curve. Increasing afterload shifts the curve down and to the right (from point A to B), which decreases SV and increases LVEDP. In contrast, a decrease in afterload shifts the Frank–Starling curve up and to the left (A to C), which increases SV and at the same time reduces LVEDP. LVEDP, left ventricular end-diastolic pressure; SV, stroke volume. Adapted and used with permission by Dr Richard E. Klabunde, Cardiovascular Physiology Concepts (cvphysiology.com).

25 0

0

5

10

15

20

LVEDP (mmHg)

diminished ventricular muscle fiber shortening (increased left ventricular end-systolic volume, LVESV). However, the process is a lot more complicated in a healthy heart due to the Anrep effect where homeostatic mechanisms try to maintain a relatively constant SV as the arterial blood pressure varies [10]. If there is a sudden increase in afterload, there is a compensatory rapid decrease in cardiac ejection and so increase in LVESV and LVEDV. The LV responds by initially increasing contractility (as per the Frank–Starling mechanism (Fig. 5.3)), which is largely due to increased troponin C sensitivity to Ca2+. However, if this increased afterload is sustained for 10–15 min, contractility increases further and LVESV and LVEDV begin to decrease. This delayed compensatory response likely involves several mechanisms that promote increased calcium release by the sarcoplasmic reticulum mediated by various mediators (e.g., endothelin-1, angiotensin II) and increased calcium sensitivity with consequent rise in cross-bridge formation and myocardial force generation. In heart failure, SV is very sensitive to changes in afterload due to the already impaired contractility and that the Anrep effect does not adequately compensate for the physiological changes. The ventricular wall is usually thin around a dilated cavity, and so at a given pressure, wall stress is increased and this leads to further maladaptive structural and molecular changes. SVR is determined by vessel diameter, vessel length, and blood viscosity, which is represented by Poiseuille’s equation:



F=

π Δ P · r4 8η · L

F, flow; ΔP, pressure difference; r, radius of vessel; η, viscosity of fluid; L, length of vessel.

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Jean Léonard Marie Poiseuille was a 19th century French physician who described that a decrease in vessel radius would increase the resistance to the power of four of the change in radius. This was assuming that the flow was laminar and constant velocity, and that the fluid was incompressible and Newtonian. So a reduction in the radius by 50% will increase resistance by a factor of 16 and thus decrease blood flow by a factor of 16 assuming the pressure gradient is constant, laminar flow conditions, and that the resistance of the segment studied is representative of the total resistance to flow. Systemic vascular function curves (Fig. 5.4) compare the effects on right atrial pressure (RAP) by changes in cardiac output (CO). If CO is stopped, then the aortic blood pressure falls and RAP increases and peaks at the mean circulatory filling pressure (Pmc) if the baroreceptor response to the hypotension is blocked. In a healthy adult heart the Pmc is approximately 8 mmHg, which is due to the 10–20 times greater compliance of veins in comparison to arteries. So when the heart stops, the volume and pressure of blood in the arteries decreases and increases in the veins. If the CO is restarted, then RAP decreases as CO increases (curve moves upward and leftward). When RAP falls below 0 mmHg, the increase in CO plateaus because the venae cavae collapse, thus limiting venous return to the heart. The systemic vascular function curve is affected by blood volume, venous compliance, and SVR (graph A). If blood volume is increased, or venous compliance is decreased due to activation of the sympathetic division of the autonomic nervous system, there is a shift of the curve to the right. Then if the heart is stopped, the resultant Pmc value is increased. Conversely, if SVR is increased (graph B), the slope of the curve decreases with little or no change in the Pmc value due to the relatively less arterial compliance. SVR is affected by local regulatory systems and by extrinsic mechanisms. Locally, organs are able to regulate their own blood flow through the vascular endothelium and by various vasoactive metabolites released by the tissue surrounding blood vessels. Important extrinsic mechanisms are the autonomic nervous system and circulating vasoactive hormones (e.g., angiotensin II, epinephrine, norepinephrine, vasopressin, atrial natriuretic peptide, and endothelin), which are all stimulated in heart failure. SVR is also affected by blood viscosity. Viscosity is an intrinsic property of a fluid related to the internal friction (resistance) with adjacent fluid levels sliding past one another. Water is a homogenous fluid that is described as Newtonian, and therefore under nonturbulent conditions, its viscosity is independent of flow velocity. However, blood is a non-Newtonian fluid as it consists of plasma and cells, which means that its viscosity changes with flow velocity. Under normal conditions, red cells have the greatest effect on viscosity with an increase in hematocrit leading to a nonlinear increase in relative viscosity and an increase in blood flow resistance. This effect is enhanced in heart failure where the microcirculatory blood flow in the tissues is reduced because of reduced arterial pressures. Low flow states can lead to a large increase in viscosity and allow increased molecular interactions to occur between cells and plasma proteins. This may lead to rouleaux formation where red cells stick together to form chains within the microcirculation, which further increases blood viscosity and may lead to thrombus formation if the coagulation system is also stimulated [11].

Contractility This is the intrinsic ability of a ventricle to contract at a defined preload and afterload. Skeletal muscle is able to modulate the contractile force generation through changes in motor nerve activity and motor unit recruitment. However, when cardiac muscle contracts then all the muscle fibers are activated and only changes in fiber length (preload) and changes in inotropy alter the amount of force generated. However in heart failure, contractility is often impaired, which will decrease SV. This will be exacerbated by the structural and molecular changes that occur to the myocytes due to the chronic overstimulation of the neurohormonal compensatory mechanisms as discussed later.

(A)

CO (L/min)

(B)

10 Vol or Cv

5

CO (L/min)

10

SVR

5 SVR

Vol or Cv

0

0

0 RA P (mmHg)

Pmc

10

0 RA P (mmHg)

Pmc

10

FIGURE 5.4  Systemic vascular function curves. CO, cardiac output; CV, venous compliance; Pmc, mean circulating filling pressure; RAP, right atrial pressure; SVR, systemic vascular resistance; Vol, blood volume. (Adapted and used with permission by Dr Richard E. Klabunde, Cardiovascular Physiology Concepts (cvphysiology.com).)

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Cardiac Output/Cardiac Index The CO is the cumulative SV over a minute and is measured in milliliters per minute (ml/min). CO = SV × HR = (EDV − ESV) × HR.



CO, cardiac output; SV, stroke volume; HR, heart rate; EDV, end-diastolic volume; ESV, end-systolic volume. Basal CO differs among individuals of different sizes and so cardiac index is a more useful measurement. This is the CO per body surface area and has unit, ml/min/m2. The factors that affect heart rate and SV will affect CO. The maintenance and regulation of CO is normally proportional to the demand for oxygen and other nutrients by other tissues and organs. During exercise, the normal physiological response is to increase CO by increasing chronotropy and inotropy. If we consider heart failure where there is low CO due to poor contractility, various neurohormonal mechanisms are stimulated to compensate. The most rapid compensatory change is positive chronotropy, which is mainly achieved via various neurohormonal mechanisms but primarily stimulation of the sympathetic division of the autonomic nervous system. This is initially a helpful adaptive process to try to improve CO. However, as the heart rate increases it leads to reduced time for diastolic relaxation, reduced diastolic-dependent coronary perfusion and increased myocardial oxygen demand. If sustained this can lead to myocardial ischemia. The American physiologist, Arthur Guyton, carried out animal studies in the 1950s and 1960s [11a,11b] assessing the relationship between cardiac function and SVR. These interactions were described in cardiac function curves Fig. 5.5, which are similar to Frank–Starling curves except have RAP replacing LVEDP on the x-axis and CO replacing SV on the y-axis. The curves show that very small changes in RAP, a matter of a few mmHg, can lead to large changes in CO. If cardiac function is enhanced (e.g., during exercise) by increased inotropy, increased chronotropy, or reduced afterload, then CO increases more with smaller changes in RAP. When cardiac performance is depressed (e.g., in heart failure), then the changes are less marked. When cardiac and vascular function curves are combined (Fig. 5.6), the intersect of the two curves (point A) represents the steady-state operating point for those particular physiological conditions. If cardiac function is depressed as in heart failure then the cardiac function curve shifts downward and rightward, and the intercept moves to point B. This describes the increase in RAP and venous pressures along with a decrease in CO. If the depressed cardiac function is accompanied by an increase in blood volume, reduced venous compliance or increased SVR, which occurs in heart failure, the systemic function curve will shift rightward with a reduced slope gradient. The new operating point moves to point C where there is an improvement in CO in comparison to point B. This demonstrates how systemic vascular function changes help to partially restore CO despite depressed cardiac function. However, this comes at the expense of increased RAP and venous pressures, which leads to worsening features of congestive cardiac failure.

Enhanced Contractility

Normal Contractility

10

CO (L/min)

Impaired Contractility

5

0

0

5

10

RA P (mmHg) FIGURE 5.5  Cardiac function curves. CO, cardiac output; RAP, right atrial pressure. Adapted and used with permission by Dr Richard E. Klabunde, Cardiovascular Physiology Concepts (cvphysiology.com).

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Normal contractility

10

Impaired contractility

CO (L/min) 5

0

A B

0

Vol Cv SVR

C

5

10

15

20

RA P (mmHg) FIGURE 5.6  Combined cardiac and vascular function curves. CO, cardiac output; CV, venous compliance; RAP, right atrial pressure; SVR, systemic vascular resistance; Vol, volume. (Adapted and used with permission by Dr Richard E. Klabunde, Cardiovascular Physiology Concepts (cvphysiology.com).)

NEUROHORMONAL COMPENSATORY MECHANISMS Neurohormonal mechanisms describe a complex interaction between the autonomic nervous system, catecholamines (epinephrine, norepinephrine), circulating hormones (renin-angiotensin-aldosterone system), and a variety of peptides, growth factors and cytokines. In response to the effects of reduced cardiac function from heart failure, these neurohormonal mechanisms are stimulated to help compensate. Neurohormonal is actually a historical misnomer originating from the early recognition that some of the early compensatory mechanisms were neuroendocrine and acted in an endocrine fashion. It is now recognized that some of these “neurohormones” are also produced by the myocardium and act in a paracrine and autocrine fashion and some are actually peptides, growth factors, or cytokines produced by a number of cell types.

Autonomic Nervous System and Circulating Catecholamines The autonomic nervous system has many biological roles including an important rapid-acting autoregulatory effect on the cardiovascular system. It originates in the medulla oblongata in the brainstem and consists of two main divisions—sympathetic and parasympathetic nervous systems. These two divisions generally have antagonistic effects, but usually complement each other to modulate vital functions to achieve homeostasis. In simple terms, the sympathetic nervous system is a “quick response mobilizing system,” while the parasympathetic nervous system is a “more slowly activated dampening system.”

Sympathetic Nervous System The preganglionic neurons of the sympathetic nervous system originate in the lateral gray column from the thoracic and lumbar spinal cord (T1 to L2-3) where they emerge and synapse with postganglionic neurons at ganglia before innervating various organs. The preganglionic neurons also synapse directly with the chromaffin cells of the adrenal medulla. The chromaffin cells are modified postganglionic sympathetic neurons that have lost their axon and dendrites and when stimulated secrete catecholamines into the bloodstream by exocytosis [12]. Sympathetic efferent nerves are present throughout the atria (especially the sinoatrial (SA) node) and ventricles, including the conduction system of the heart. They also innervate the vascular system by traveling along arteries and veins and are found in the adventitia (outer wall of a blood vessel). Small enlargements along the nerve fibers called varicosities, are the site of neurotransmitter (primarily norepinephrine) release stimulating vascular changes.

Circulating Catecholamines When the sympathetic nervous system stimulates the chromaffin cells of the adrenal medulla, there is a release of catecholamines into the bloodstream. The two circulating catecholamines are epinephrine and norepinephrine, which are released in times of stress (e.g., exercise, heart failure, hemorrhage, and pain). About 80% of the total catecholamine released from the chromaffin cells is epinephrine and 20% is norepinephrine [13]. The primary source for norepinephrine is the sympathetic nerves innervating blood vessels, as described above [14]. The sympathetic nervous system is not just the only stimulant of the chromaffin cells, there are in fact a number of different receptors attached on the cell membrane, which when activated lead to catecholamine release. These include muscarinic cholinergic receptors [15], angiotensin II receptors [16], and histaminergic receptors [17].

Hemodynamic Adaptive Mechanisms in Heart Failure Chapter | 5  65

When epinephrine binds to β1-adrenoceptors (β1-ARs) on myocytes, it rapidly causes an increase in the cytosolic Ca2+ concentration through Ca2+ influx, Ca2+ release from the sarcoplasmic reticulum, and also increases the rate up Ca2+ uptake by the sarcoplasmic reticulum through disinhibition of a protein called phospholamban. This results in increased heart rate (positive chronotropy), increased force of contraction (positive inotropy), increased speed of electrical conduction of AV node (positive dromotropy), and increased relaxation in diastole (positive lusitropy). In addition, at low-to-moderate concentrations of epinephrine, it preferentially binds to β2-ARs causing peripheral vasodilation (decreased SVR) and increased blood flow to the muscle and liver. However, at higher concentrations, there is an increased proportion of binding to α-ARs, which shifts the result to net vasoconstriction (increased SVR) and affecting blood flow to other organs and tissues. When norepinephrine binds to β1-ARs on myocytes it transiently causes positive chronotropy, positive inotropy, positive dromotropy, and positive lusitropy but these actions are rapidly counteracted by the activation of baroreceptors and the parasympathetic branch of the autonomic nervous system. The predominant effect of norepinephrine is vasoconstriction of systemic blood vessels through stimulation of postjunctional α1-AR and α2-AR (increased SVR). In the short term, activation of the sympathetic nervous system acts rapidly in providing beneficial homeostasis of many body systems [18]. However, when the sympathetic nervous system is chronically overstimulated, as is the case in heart failure, then it leads to negative pathophysiological consequences [19]. When overstimulated, there tends to be regional stimulation preferentially directed to the heart and kidneys rather than affecting all the normal target organs [20]. In normal conditions, most of the norepinephrine released by sympathetic nerves is reabsorbed and metabolized by the nerves and extra-neuronal tissues, and only a small amount spills over into the circulation. However, at times of high sympathetic nerve stimulation, this amount of spill-over dramatically increases [21], and there is good evidence that plasma concentration of norepinephrine is negatively associated with survival in heart failure patients [22]. The effects of the overstimulated sympathetic nervous system have been understood from patients suffering with pheochromocytoma. This is a rare neuroendocrine tumor usually of the chromaffin cells of the adrenal medulla. The effects include the following: Positive chronotropy and inotropy, which increases metabolic demand and reduced coronary perfusion [23]. Increased risk of tachyarrhythmia l  Reduced diastolic function. This is related to the combined effects of less time for passive ventricular filling due to tachycardia and reduced myocardial compliance due to myocardial hypertrophy and fibrosis [24]. l Myocyte hypertrophy by direct action by binding to α–ARs and selective β-ARs on cardiac myocytes [25,26]. l Myocyte toxicity and associated cardiac structural changes through promotion of myocyte apoptosis and necrosis, free radical production monocytic inflammation, and calcium deposition [27,28]. l Fibroblast hyperplasia with increased collagen deposition and myocardial fibrosis [29]. l Stimulates release of proinflammatory cytokines [30]. l l

The body responds to these deleterious effects by deactivating the β-ARs by a process called desensitization. This is achieved by reducing the number (downregulation) [31,32] and loss of function (receptor uncoupling) [32,33] of the βARs. In fact the β1-subtype undergoes more downregulation, while the β2-subtype undergoes more uncoupling [34,35]. Reduction in the receptor numbers occurs early on in heart failure [36] and correlates with disease severity [25]. Several mechanisms occur to cause receptor uncoupling. The most prominent mechanism involves firstly phosphorylation of the receptor by a specific G protein-coupled receptor kinase called β-AR kinase [37], which is then bound by the β-arrestin protein [38]. This final process inhibits the β-AR function by up to 70% [39,40]. This is also the first step in the internalization and downregulation of the receptor. This process of desensitization is considered to be cardioprotective to counteract the deleterious effects of chronic sympathetic nervous system overstimulation but at the detriment of reduced inotropy [41].

Parasympathetic Nervous System The parasympathetic division of the autonomic nervous system has a craniosacral outflow with efferent nerves originating in the brainstem (cranial nerves III, VII, IX, X) and at the sacral spinal cord (S2-S4). The left and right vagus nerves (cranial nerve X) leave the medulla oblongata, pass through the jugular foramen, and enter into the carotid sheath between the internal carotid artery and the internal jugular vein down to the neck, thorax, and abdomen, where they innervate many organs including the heart, lungs, liver, and stomach. The right vagus nerve primarily innervates the SA node, whereas the left vagus nerve innervates the AV node; however, there can be significant overlap in the anatomical distribution. Atrial muscle is also innervated by vagal efferents, while the ventricular myocardium is only sparsely innervated. In heart failure, activation of the parasympathetic nervous system is decreased by reduced vagal ganglionic transmission, reduced muscarinic receptor activity, altered receptor composition, and decreased acetylcholinesterase activity [42,43]. Therefore the sympathetic nervous system remains overstimulated without the dampening effect of the parasympathetic nervous system.

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Renin–Angiotensin–Aldosterone System The Renin–Angiotensin–Aldosterone System (RAAS) (Fig. 5.7) is an important hormonal compensatory mechanism, which helps regulate blood volume and SVR during periods of low arterial blood pressure. It has less immediate effects on the cardiovascular system in comparison to the other major compensatory mechanism, the sympathetic nervous system. The main trigger for activation of RAAS is stimulation of baroreceptors within the wall of the glomerular afferent arterioles in the kidney. These respond to reduced perfusion pressure by stimulating the release of the proteolytic enzyme, renin, into the circulation by the juxtaglomerular cells of the kidneys [44]. Renin acts by cleaving amino acids from the circulating substrate, angiotensinogen, to form angiotensin I (AT I). AT I is then converted to angiotensin II (AT II) by angiotensin-converting enzyme (ACE). ACE is present in the vascular endothelium, particularly in the lungs. AT II is also synthesized locally by numerous body tissues, including the heart. This may lead to the chronic homeostasis of the cardiovascular system, which may be important in heart failure. AT II receptor-binding sites have been found on the myocardium and cardiac adrenergic nerves [45]. Studies on the denervated heart [46] and on hearts subject to β-adrenergic receptor blockade [47] have shown that AT II retains the positive inotropic effect, which suggests that the positive inotropic effect of AT II on the heart is likely to be direct. This effect is significant in heart failure as there is no decrease in ventricular AT II receptor levels with the condition [45]. AT II has a number of effects on the body: Potent vasoconstrictor causing an increase in SVR. Positive inotropy and chronotropy [48]. l Stimulates sodium reabsorption at several renal tubular sites, thereby increasing sodium and water retention [49]. l Stimulates the release of aldosterone from the adrenal cortex. l Stimulates the release of vasopressin from the posterior pituitary. l Stimulates thirst centers in the brain so increasing fluid intake. l  Stimulates norepinephrine release from the sympathetic nerve endings and inhibits norepinephrine reuptake by nerve endings, thereby enhancing sympathetic adrenergic function [45]. l Direct stimulation of prohypertrophic, proapoptotic, and profibrotic signaling pathways in cardiac myocytes [50,51]. l Stimulates the release of proinflammatory cytokines [52]. l l

Angiotensinogen Renin

Angiotensin I ACE

Angiotensin II

AT1 receptor

Hemodynamic

AT2 receptor

Non-hemodynamic

Hemodynamic

Non-hemodynamic

- Vasoconstriction - RBF

- Na + /water reabsorption - Aldosterone

- Vasodilation

- Kidney development

- BP

-

- Pgc

- TGF- β

Cell proliferation

- Antifibrotic effects - Pressure natriuresis -

Nitric oxide

- PGE 2

PGF 2α

FIGURE 5.7  Renin–angiotensin–aldosterone system (RAAS). ACE, angiotensin-converting enzyme; BP, blood pressure; PG, prostaglandin; Pgc, glomerular capillary hydrostatic pressure; RBF, renal blood flow; TGF-β, transforming growth factor-β. (Adapted from Science Direct database: M.W. Taal, B.M. Brenner, Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists, Kidney Int. 57 (5) (2000) 1803–1817.)

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Aldosterone is a steroid hormone produced by the zona glomerulosa of the adrenal cortex of the adrenal gland. As we have mentioned, aldosterone synthesis is stimulated by plasma AT II; however, it is also stimulated by adrenocorticotropic hormone (ACTH) released from the anterior pituitary gland, acidemia, hyperkalemia, the sympathetic nervous system, and by stimulation of arterial and atrial baroreceptors. These baroreceptors are found in the vessel walls of all the large arteries of the thorax and neck, especially in the sinuses of the carotid arteries and the aortic arch. A low arterial blood pressure or low circulating volume is sensed by baroreceptors and atrial stretch receptors, stimulating the release of aldosterone to counteract the original abnormality. Aldosterone acts by: Increasing sodium and water reabsorption (and potassium excretion) by upregulation and activation of the basolateral sodium/potassium ion pumps in the distal tubules and collecting ducts of the nephron. l Increasing sodium and water reabsorption by upregulation of apical membrane epithelial sodium channels in the renal collecting ducts and the colon. l Increasing sodium and water reabsorption by stimulating the sodium/potassium ion pump in the gut, salivary glands and sweat glands. l Regulates acid–base balance by stimulating the secretion of hydrogen ions in exchange for potassium ions in the intercalated cells of the cortical collecting renal tubules. l Important growth effects and is a key regulator of cardiac fibrosis by promoting collagen synthesis [53]. l

In heart failure, RAAS is chronically activated by reduced arterial blood pressure and renal blood flow. The effects of AT II and aldosterone are to promote sodium and water retention with vasoconstriction. The resultant increased preload and afterload is a compensatory process to improve the new steady-state operating point (see Fig. 5.6) and thus partially restore CO despite depressed cardiac function. However, this comes at the expense of increased RAP and venous pressures, which leads to worsening features of congestive cardiac failure [54]. Unfortunately there are other effects of RAAS stimulation, which also become maladaptive in heart failure. These include direct and indirect stimulation of cardiac myocyte chronotropy and inotropy. This increases metabolic demand on the failing heart and can compromise coronary perfusion. Myocardial AT II is also involved in ventricular remodeling by augmenting apoptosis via increasing cytosolic calcium and by reactive oxygen species formation, and also stimulating cytokine synthesis (especially the proinflammatory cytokines, e.g., Transforming Growth Factor-β (TGF-β)). These play a key role in hypertrophic and fibrotic remodeling of the heart leading to cardiac myocyte growth, fibroblast activation, and extracellular matrix deposition [55–57].

Natriuretic Peptides These are peptide hormones that are primarily produced by the brain and the heart. In simple terms they act as a counterregulatory system to RAAS and so help regulate blood volume and arterial blood pressure by promoting vasodilation, diuresis, and natriuresis [58]. There are three known natriuretic peptides: Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP), and C-type Natriuretic Peptide (CNP). ANP is a 28-amino acid peptide that is produced and stored by atrial myocytes as pre-pro-ANP. In response to atrial distension, AT II, ET-1, and sympathetic stimulation, pre-pro-ANP is cleaved to pro-ANP and finally the biologically active peptide, ANP. BNP is a 32-amino acid peptide, which was first isolated in brain tissue but is predominantly made by the cardiac ventricles. Initially it is in the form pre-pro-BNP, which is then cleaved to pro-BNP in a similar response to physiological triggers as ANP. Pro-BNP is 108 amino acids long and is proteolysed by the enzyme corin to N-terminal piece of pro-BNP (NT-pro-BNP) and BNP. Both BNP and NT-pro-BNP are sensitive diagnostic markers for heart failure severity. CNP is a 22-amino acid peptide that is widely expressed especially in the brain [59], chondrocytes, and endothelial cells. Initially it is in the form pre-pro-CNP, which is then cleaved to form pro-CNP, which in turn is cleaved by the enzyme furin to form CNP-53. This peptide has some biological activity but is normally further processed to CNP. CNP release is stimulated by proinflammatory cytokines (e.g., TNF, IL-1, TGF-β), bacterial lipopolysaccharide, and sheer stress. Unlike the other natriuretic peptides, CNP has predominantly local effects by acting as a paracrine and an autocrine regulator where it acts as a potent vasodilator but unlike ANP and BNP it does not have direct natriuretic activity [60]. The natriuretic peptides act on specific receptors of which three types have been identified, NPR-A, NPR-B, and NPR-C. ANP and BNP bind and activate NPR-A, while CNP binds and activates NPR-B. NPR-C functions as a clearance receptor by binding and sequestering the natriuretic peptides from the circulation. The natriuretic peptides are removed from the circulation by receptor-mediated endocytosis and lysosomal degradation via CNP, but also by enzymatic degradation by neural endopeptidase.

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The effects of the natriuretic peptides are as follows: Venous vasodilation (increased venous compliance), which decreases preload and thus reduces SV [61]. Arterial vasodilation, which decreases afterload and further reduces arterial blood pressure [62]. l Positive lusitropy. BNP only [63]. l Increasing glomerular filtration rate (GFR) and filtration fraction. This promotes natriuresis (increased sodium excretion) and diuresis (increased fluid excretion) [64]. ANP and BNP only. l Inhibits renin release and so antagonizes RAAS, so decreasing circulating levels of AT II and aldosterone. This leads to further natriuresis and diuresis. ANP and BNP only. l Inhibits vasopressin release. l Blocks sympathetic nervous system activity [65,66]. l Inhibit myocardial fibrosis formation by inhibiting fibroblast proliferation and collagen synthesis [67–69]. l Inhibits cardiac myocyte hypertrophy [70,71]. l l

In heart failure, the venous pressures are elevated due to increased preload from the effects of RAAS and other neurohormones Fig. 5.8. This causes chronically increased atrial and ventricular distension, which stimulates the increased myocardial secretion of the natriuretic peptides into the circulation [69,72]. The action of ANP and BNP acts not only as a counterregulatory mechanism to RAAS but also counteracts the other deleterious maladaptive changes that occur in heart failure albeit unsuccessfully. This includes attenuation of the hypertrophic signaling pathways in cardiac myocytes so can be considered as an endogenous “antiremodeling” hormone.

Vasopressin Vasopressin, also known as antidiuretic hormone, is a peptide hormone that was first isolated in the 1950s [73]. The main actions of vasopressin are as follows: Increased water permeability and thus reabsorption by increased expression of aquaporin-2 water channels in the collecting ducts and distal convoluted tubules in the kidneys by stimulation of the cAMP-dependent V2 receptors. l Increase SVR by stimulation of V1a receptors on the vascular smooth muscle [74]. l Increase ACTH release by binding to V1b receptors on the anterior pituitary gland, which in turn stimulates aldosterone release [75]. l

Hypertrophy

+

Sympathetic Nervous System

Fibrosis Hypertrophy

Natriuretic Peptides (ANP, BNP)

Fibrosis

Angiotensinogen

+

+

Renin

Angiotensin I

Natriuresis

Na + intake

Blood volume

Blood volume

Aldosterone secretion

Aldosterone secretion

BP

BP

Endothelial permeability

Endothelial permeability

ACE

Vasoconstriction

Angiotensin II

FIGURE 5.8  Interaction between the natriuretic peptides, renin-angiotensin-aldosterone system, and the sympathetic nervous system to maintain cardio–renal homeostasis. ACE, angiotensin-converting enzyme; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; BP, blood pressure. (Adapted from Science Direct database: M. Volpe, Natriuretic peptides and cardio-renal disease, Int. J. Cardiol. 176 (3) (2014) 630–639.)

Hemodynamic Adaptive Mechanisms in Heart Failure Chapter | 5  69

It is synthesized by the hypothalamus in the brain, transported by axons, and stored in vesicles in the posterior pituitary gland. Vasopressin release is stimulated by baroreceptors responding to low blood pressure and volume, osmoreceptors in the hypothalamus responding to hyperosmolality, sympathetic nervous system, and increased AT II levels. Vasopressin release is inhibited by ANP. Paradoxically vasopressin secretion is stimulated in heart failure despite the normally inhibiting effect of increased blood volume and atrial pressures. It is thought that this occurs due to the more dominant effect of the sympathetic nervous system and RAAS activation on stimulating vasopressin release. In normal circumstances vasopressin has a compensatory homeostatic function, but in heart failure it has a negative pathophysiological effect by further increasing preload and afterload [76] (Fig. 5.9). At higher physiological circulating vasopressin concentrations, activation of the V1a receptors mediate coronary vasoconstriction and thus reduced coronary blood flow [75]. Vasopressin induces myocyte hypertrophy indirectly by increasing afterload, but also directly by binding to V1a receptors on the myocytes [77–80].

Endothelin The endothelin family consists of three structurally and functionally similar 21 amino acid peptides. Endothelin-1 (ET-1) is the predominant isoform and was first identified in 1985 [81] from the culture media of bovine aortic endothelial cells and was found to be a potent vasoconstrictor. Four years later [82], two further isoforms were identified, endothelin-2 (ET-2) and endothelin-3 (ET-3). The latter of which we shall not cover in this chapter as it is considered to be the “brain” endothelin peptide.

Hyperosmolarity Reduced Atrial Stretch

Angiotensin II

Hypothalamus

Sympathetic Nervous System

Posterior Pituitary

Vasopressin V1a

Vasoconstriction

Afterload

V1a

LV Hypertrophy/Remodeling

Preload

V2

H 2 O Reabsorption

Hyponatremia

FIGURE 5.9  Schematic diagram of the triggers, synthesis, and function of vasopressin with the implications for chronic stimulation with heart failure. LV, left ventricular.

70  SECTION | I  Basic Science of Heart Failure

VASCULAR EPITHELIAL CELL

Prostacyclin, NO, ANP, BNP, heparin

mRNA Prepro-ET-1

Adrenaline, anglotensin II, vasopressin, steroids

Prepro-ET-1

IL-1, TGF- , endotoxin, endothelin, VEGF, tacrolimus, cyclosporin A

Furin-like endopeptidase

Big ET-1 ECE

ET B

Hypoxia, osmolarity

ET-1

Thrombin, glucose ET-1 PGI 2

NO

SMOOTH MUSCLE CELL ET B

Vasodilation Inhibition of apoptosis

ET A

Vasoconstriction Cell Proliferation

FIGURE 5.10  Schematic diagram of ET-1 synthesis and actions on smooth muscle cells. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; ECE, endothelin converting enzyme; ET, endothelin; IL-1, interleukin-1; NO, nitric oxide; PGI2, prostaglandin I2 (prostacyclin); TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor. (Adapted from Science Direct database: Trow, Taichman, Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism, Respir. Med. 103 (7) 2009 951–962.)

ET-1 is an extremely potent and long-acting vasoconstrictor that is likely to be involved in blood flow autoregulation throughout the body. It is primarily produced by the vascular endothelial cells but is also produced by various types of epithelial cells (e.g., in lungs, kidneys, and colon), inflammatory cells, and certain neurons and reactive glial cells in the central nervous system. ET-1 is synthesized and released continuously from endothelial cells. The endothelin pathway (Fig. 5.10) consists of an initial gene transcription to form preproendothelin, which is followed by proteolytic cleavage due to the enzyme furin. This forms the 39 amino acid peptide “Big endothelin.” Big endothelin has three isoforms, 1–3, which are cleaved by endothelin converting enzyme to form the respective endothelin peptides. Levels of preproendothelin are predominantly affected not only at the level of transcription by various factors but also by certain physiological and pathophysiological conditions, e.g., AT II, vasopressin, thrombin, cytokines, hypoxia, and also by shearing forces acting on the vascular endothelium [83]. ET-2 is similar to ET-1 in the way it is synthesized, its location, and function. However, there is increasing evidence that ET-2 should be considered as having distinct physiologic and potentially pathophysiological role. In particular it has a distinct chemokine action, where at low concentrations it acts as a chemoattractant for neutrophils but an inhibitor at high concentrations [84]. The endothelin family binds to two types of G protein-coupled receptors, ETA [85] and ETB [86]. In studies on adult mouse tissues, endothelin receptor mRNA is detected in all tissues receiving a blood supply, reflecting the expression of ETA on vascular smooth muscle (especially in heart and lungs) and ETB on endothelial cells (especially in the brain and lung peripheries) [87]. In the human heart, ETA comprises 90% of the endothelin receptor subtype in cardiac myocytes, while ETB receptors are more abundant in the AV conducting system [88].

Hemodynamic Adaptive Mechanisms in Heart Failure Chapter | 5  71

These two receptor subtypes have contrasting phenotypic actions on the cardiovascular system under normal physiologic conditions: Vasoconstriction via ETA receptors in smooth muscle cells. Vasodilation via ETB receptors in the endothelium by the release of nitric oxide [89].

l l

When ET-1 binds to smooth muscle cell ETA and ETB receptors it triggers myosin light chain phosphorylation, which results in smooth muscle contraction. When ET-1 binds to ETB on the endothelium then the formation of nitric oxide (NO) is stimulated. NO has a number of vascular effects including direct vasodilation, indirect vasodilation by vasoconstrictor inhibition (e.g., inhibits AT II), antithrombotic, antiinflammatory, and antiproliferative. In normal conditions, the predominant effect of ET receptor activation is vasoconstriction. However, in the absence of smooth muscle ET receptor stimulation, then NO formation predominates causing vasodilation. ET-1 causes [90]: Smooth muscle contraction through stimulation of ETA and ETB receptors. Positive inotropy and chronotropy through stimulation of cardiac ETA and ETB receptors. l  Vasodilation through stimulation of vascular endothelial ETB receptors in the absence of smooth muscle ET receptor stimulation. l Stimulates aldosterone secretion. l Decreases renal blood flow and GFR. l Stimulates ANP release. l l

In heart failure, circulating ET-1 levels are increased [91] along with increased myocardial expression of ET-1, and both ETA and ETB receptors [92]. The elevated cardiac ET-1 levels have chronic deleterious effect on the already failing heart by inducing sustained vasoconstriction, severe cardiac inflammation, ventricular dysfunction, fibrosis, and cardiac hypertrophy [93–96].

CONCLUSION The cardiovascular system undergoes a number of complex and interrelated changes in response to heart failure. The changes involve hemodynamic changes to improve the reduced SV (related to poor contractility) by increasing preload and afterload. The heart is also encouraged to work harder with increased chronotropy and inotropy. These hemodynamic changes are stimulated by a number of different, yet interrelated neurohormonal mechanisms. Unfortunately when these mechanisms are chronically stimulated their effects become pathophysiological and cause maladaptive changes. These changes often lead to cardiac structural alterations involving myocyte hypertrophy, cell death, and extracellular fibrosis. As a result, the patient usually becomes more symptomatic due to disease progression. Understanding the physiological mechanisms of cardiovascular homeostasis is the key to the pathophysiological mechanisms of heart failure and is the basis for drug development and pharmacotherapy to manage the condition.

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