Pathophysiology of Heart Failure Ettinger Flashcards

Question

Afterload represents the sum................................ and is often expressed as the ................... or ................... experienced by the ventricles during the period of ejection.

Answer 1

Afterload represents the sum of all those forces that oppose the ejection of blood from the ventricle into the circulation and is often expressed as the systolic tension or wall stress experienced by the ventricles during the period of ejection.

Answer 2

1. The peripheral (systemic) vascular resistance (SVR), 2. The physical properties (compliance) of the arterial tree, 3. The volume of blood in the ventricle at the onset of systole.

Answer 3

Afterload and all of its determinants tend to be increased in patients with heart failure; but the predominant change is increased SVR. Increased afterload leads to a reduction in the rate of ejection or even the amount of blood ejected at any given preload.

Answer 4

Aortic pressure (P1) -right atrial pressure (P2) Cardiac output (flow) = Systemic vascular resistance (R)

Answer 5

Operation of the systemic circulation requires relatively high pressures, and maintenance of systemic blood pressure is a mandated physiologic priority in all patients with heart failure. When cardiac output falls, systemic blood flow is preferentially directed to certain vital centers by a variety of adaptive responses increasing the tone of the resistance vessels supplying less vital regions.

Answer 6

Other influential changes altering the functional and structural properties of the vascular wall include 2. Down regulation of parasympathetic tone, 3. Upregulation of the renin-angiotensin system, 4. Increased expression and release of endothelin and arginine vasopressin, 5. Alterations in the processes that autoregulate blood flow to specific vascular beds.

Answer 7

Norepinephrine, angiotensin II, endothelin, and arginine vasopressin effect vasoconstriction via specific smooth muscle membrane receptors linked to the G protein, Gq, which serves the activation of phospholipase C and the inositol triphosphate (IP3) signaling system.

Answer 8

The IP3 system regulates calcium ion release via the IP3 receptor (a calcium release channel) in the sarcoplasmic reticulum of smooth muscle cells, thereby stimulating calcium-mediated vasoconstriction.

Answer 9

With chronic IP3 signaling, diacylglycerol activates protein kinase C (PKC), initiating a cascade of intracellular signals that initiate smooth muscle hypertrophy and replication, as well as a plethora of associated changes in the extracellular matrix (vascular remodeling).[16] Reduced activity of the parasympathetic limb of the autonomic nervous system contributes to generalized vasoconstriction by withdrawal of its vasodilatory influence. Muscarinic receptors, stimulated by acetylcholine, activate guanylyl cyclase, causing the formation of cyclic GMP, which inhibits calcium entry into the cell and decreases intracellular calcium concentrations.

Answer 10

Nitric oxide (NO), produced in endothelial cells from L-arginine via the action of endothelial nitric oxide synthase (eNOS), diffuses into smooth muscle cells and contributes to vasodilation by several different mechanisms. Nitric oxide increases intracellular cGMP levels in vascular smooth muscle cells and directly activates potassium channels leading to hyperpolarization of the cell and vasodilation. In patients with heart failure, impaired endothelial cell function causes decreased NO synthesis, contributing further to excessive vasoconstriction.

Answer 11

Wall stress = pressure x radius/2 x wall thickness

Answer 12

Wall stress, heart rate, and contractility are the main determinants of the work performed by the heart, which is directly related to oxygen demand. The law of Laplace emphasizes that any increase in chamber size should be accompanied by a proportional increase in wall thickness if normal wall stress is to be maintained. This relationship provides a rationale for observed changes in cardiac architecture when an abnormal hemodynamic burden is chronically imposed on the heart. Hence, pressure overloads are compensated for (wall stress is normalized) by increases in wall thickness with little or no changes in chamber size. Despite this compensation, the total work of the pressure-overloaded heart is increased relative to normal, imposing a persistent requirement for increased energy production and oxygen delivery.

Answer 13

Volume overload, in turn, is characterized by an enlarged chamber and only a modest increase in wall thickness, sufficient to normalize wall stress. In this fashion, the workload is redistributed appropriately to the cardiomyocytes, forward stroke volume is normalized, and the patient's functional capacity is, at least theoretically, normalized. The total work of the volume-overloaded heart is increased relative to the normal heart but substantially less than is observed in a pressure-overloaded heart.[

Answer 14

Figure 234-3 The heart responds to hemodynamic challenges in a predictable fashion as described by Laplace's equation. In response to chronic pressure overload, ventricular wall thickness increases to normalize wall stress. Chamber diameter and wall thickness increase proportionally during athletic training and pregnancy to maintain normal wall stress. Wall stress is increased in patients with heart failure due to dilated cardiomyopathy as the chamber dimensions increase disproportionately to wall thickness.

Answer 15

The total work of the heart includes the mechanical work performed during ejection and the internal work performed developing tension (potential energy) that is not directly used to propel blood into the circulation.

Answer 16

The external mechanical work of the heart is conveniently estimated as the product of: mean systolic blood pressure × stroke volume, often referred to as stroke work.

Answer 17

Minute work, in turn, is defined as stroke work × heart rate.

Answer 18

The external work performed by the heart is most accurately estimated in patients with heart disease as the area inscribed within the pressure volume loop. Internal work can be estimated as the area of the triangle inscribed when the end-systolic pressure/volume point is extrapolated to baseline.

Answer 19

The ratio of external work/total work, often estimated as external work/oxygen uptake, is a measure of the working efficiency of the heart. The efficiency of the normal heart at rest is only 15% to 25% but can increase to 40% with exercise due to the combined effects of peripheral vasodilation and increased myocardial contractility.

Answer 20

In patients with overt heart failure, as in dilated cardiomyopathy, stroke work is reduced and the resting heart rate must increase to maintain a normal level of minute work. The level of internal work is increased because of the elevated heart rate and because the failing heart experiences greater wall stress as the diameter of the chambers increases (Laplace's law). Thus, the efficiency of the failing heart is reduced and the consequences of this deficiency become strikingly apparent when exercise is attempted

Answer 21

Prior to the development of compensatory cardiac hypertrophy, increased heart rate and contractility are the dominant compensatory mechanisms employed to combat declining cardiac performance. Resting cardiac output is often restored to nearly normal levels in patients with heart failure by a moderate increase in heart rate. The precise effect of heart rate on cardiac output has immense clinical relevance. Cardiac output increases linearly with heart rate up to a certain threshold value; thereafter, the shortened diastolic interval causes a reduction in stroke volume blunting the slope of this curve. (Figure 234-4).[24]

Answer 22

At very fast heart rates, stroke volume is diminished to the extent that cardiac output begins to decline. It is noteworthy that stroke volume begins to decline at a lower heart rate and to a greater extent in heart failure patients than in normal individuals. This imposes a very real limitation on this adaptive response and contributes to the dismal performance of heart failure patients attempting to exercise. Drugs used to treat heart failure patients can alter the heart rate either by design to reach a therapeutic objective or unintentionally as an undesirable side effect. Agents used to control an excessively elevated heart rate include digoxin, beta-receptor blockers, calcium channel blockers, and the recently introduced funny channel blockers.

Answer 23

Figure 234-4 In dogs with heart disease, maximal cardiac output is achieved at a lower heart rate than in healthy dogs. When ventricular function is compromised, excessive heart rates lead to a substantial decline in stroke volume (SV) and a reduction in cardiac output. It should be noted that it is very difficult to determine optimal heart rate in an individual patient.

Answer 24

Heart rate is determined by the automaticity of the SA node, which in turn is subject to autonomic regulation and other environmental (e.g., temperature) and metabolic factors (e.g., thyroid levels).

Answer 25

Deactivation of the potassium channel, Ik, and activation of slow inward calcium current, ICaL, are essential processes in determining the firing rate of the SA node.

Answer 26

Adrenergic stimulation increases heart rate, in part, by increasing ICaL. Increased vagal tone slows the heart rate primarily by hyperpolarizing SA nodal cells via activation of the inward rectifying potassium current, IK.Ach, although it also reduces ICaL when it has been activated by adrenergic stimulation.

Answer 27

Recent studies suggest that the rate of depolarization of SA nodal cells is also mediated by an inward pacemaker current, If, that is activated by hyperpolarization of the cell membrane and by intracellular cyclic AMP. Stimulation of beta-adrenergic receptors increases the firing rate of SA nodal cells by shifting the If activation curve to more positive voltages via Gs dependent stimulation of adenylyl cyclase. Stimulation of muscarinic receptors by ............decreases heart rate by shifting the If activation to more negative voltages via Gi dependent inhibition of ............. synthesis. The importance of the If channel as the controlling pacemaker current varies depending on the resting membrane potential of SA nodal cells. The If current inhibitor ivabradine has recently been approved to reduce heart rate in human patients with angina. A cited advantage of ivabradine is its If selectivity and lack of effect on other cardiac or vascular ion channels or receptors, a feature lacking in other agents that are used to control heart rate.

Answer 28

Myocardial contractility is that innate property of the myocardium, independent of loading or heart rate, which defines the force of contraction. If preload and afterload are held constant, augmented contractility increases the extent of fiber shortening, resulting in a larger stroke volume. Most dogs with signs of heart failure have reduced myocardial contractility. Reduced myocardial contractility is consistently present in dogs with CHF due to dilated cardiomyopathy wherein the primary defect is as yet unidentified. Myocardial contractility also declines progressively in dogs with mitral regurgitation and other types of volume overload wherein the expression cardiomyopathy of volume overload is used to emphasize the consequence of this hemodynamic burden. Moreover, patients with heart failure suffer a further progressive reduction in myocardial contractility over time as a result of a number of molecular mechanisms that alter the functional integrity of the contractile proteins, induce deficits in the excitation-contraction coupling process, disrupt the structural and functional integrity of the cytoskeleton, or produce deficiencies in energy production, storage, or availability

Answer 29

myosin, actin, tropomyosin, and three troponin molecules: I, C, and T.

Answer 30

Contractility is a function of the rate of cross-bridge cycling, a term used to describe the interaction of myosin heads with actin filaments in the presence of ATP and calcium. As a result of this interaction, the actin filaments are moved inward toward the M disc at the center of the sarcomere and the adjacent Z discs are drawn closer together, shortening the sarcomere. The sarcomere shortens from a resting diastolic length of 2.2 µm to about 1.9 µm at end-systole as each muscle cell shortens in length by about 15%.

Answer 31

During the process of shortening, the width of the myocyte increases, contributing to the reduction in ventricular volume at end-systole.

Answer 32

Actin and myosin filaments are kept in register by a group of sarcomeric skeletal proteins that include α-actinin, myomesin, M-protein, myosin binding protein C (MBP-C), and titin, a gigantic scaffolding protein that extends from the Z disc to the M disc at the center of the sarcomere.

Answer 33

The usual response of the heart to altered (malfunctioning) sarcomeric proteins is to produce more contractile elements. Hence, most cases of human hypertrophic cardiomyopathy are due to alterations in the genes encoding myosin (β-myosin heavy chain), MBP-C, tropomyosin, troponin I, and troponin T. In Maine Coon and Ragdoll cats, hypertrophic cardiomyopathy has been linked to alterations in MBP-C.

Answer 34

Calcium plays an essential role in the contractile process in several respects. 1. In order for myosin and actin to interact, Ca++ must first bind to troponin C and remove the inhibiting influence of troponin I and T. 2. This essential process causes repositioning of tropomyosin relative to the actin filaments and permits the myosin head to attach to actin. 3. Calcium also increases the activity of myosin ATPase located on the heads of the heavy chains, facilitating the requisite reaction and conformational change required to produce movement of the myosin molecule relative to actin.

Answer 35

During each cardiac cycle, small amounts of Ca++ diffuse through the L-type calcium channels situated in the T tubules and activate a cluster of calcium release channels (ryanodine receptors) in the adjacently located sarcoplasmic reticulum (SR). In this fashion, a large numbers of calcium ions are discharged from the sarcoplasmic reticulum into the cytosol to interact with troponin C and effect excitation-contraction coupling.

Answer 36

Each calcium release channel is composed of four ryanodine receptor molecules that are bound to a variety of phosphatases and protein kinases, which act to modify the contractile response by regulating the amount of calcium entering through the L-type calcium channels.

Answer 37

Diastole commences with closure of the L-type calcium channels and the active removal of Ca++ from the vicinity of the contractile proteins via the action of the SR calcium pump, SERCA (Sarco/Endoplasmic Reticulum Ca++ ATPase). Calcium transport by SERCA is a direct function of the Ca++ concentration in the SR. After calcium is ejected from the SR by the ryanodine receptor, regional calsequestrin calcium stores become depleted and calcium transport through SERCA is facilitated. In like fashion the activity of SERCA declines when calcium levels are high within the SR.

Answer 38

The activity of SERCA is inhibited by the important regulatory protein, phospholamban, when it is in a resting, or dephosphorylated state. Deinhibition of SERCA is accomplished by phosphorylation of the inhibitory protein phospholamban at two different sites, one by the action of calcium-dependent calmodulin kinase and the other by cAMP-activated protein kinase A (PKA).

Answer 39

Calcium cycling is abnormal in most patients with heart failure and these alterations contribute substantially to systolic and diastolic dysfunction. Importantly, the total amount of calcium stored in the sarcoplasmic reticulum is reduced in heart failure patients. This reduction has been linked to (1) lowered SERCA levels or reduced SERCA ATPase activity, (2) increased removal of intracellular calcium by the sodium-calcium exchanger, and (3) alterations in calcium release via the ryanodine receptor. As a direct consequence, the onset of the peak calcium transient in working cardiomyocytes is delayed and the time to return to baseline is prolonged. Enhanced activity of the sodium-calcium exchanger compensates for diminished reuptake via SERCA to some extent, but eventually the rate of Ca++ removal during diastole is reduced

Answer 40

These perturbations in calcium handling predispose the cardiomyocyte to early and delayed after-depolarizations, increasing the likelihood of serious ventricular arrhythmias and increasing the risk of sudden death. Myocardial contractility is further impaired by reduced myofibrillar ATPase activity observed in association with altered patterns of troponin I phosphorylation resulting from increased PKC and reduced PKA mediated processes.[37] Different isoforms of the contractile proteins and associated regulatory proteins also may contribute to declining contractility depending on the species and underlying cause of heart failure. Such changes relate to reduced expression of adult isoforms and increased expression of isoforms that were expressed during cardiac development, the so-called fetal gene program.

Answer 41

For the heart to function effectively as a pump, the forces generated by the contracting myofilaments must be efficiently transmitted to the cell membrane, the extracellular matrix, and to surrounding myocytes. The molecules participating in this essential structural network also must function as mechanical stress sensors, participating in the signaling pathways that modulate energy production, as well as the remodeling processes of cardiomyocytes and the extracellular matrix.[39-41] Costameres are complex, riblike thickenings of the cell membrane that are oriented opposite to the Z discs and which serve to connect the sarcomere to the cell membrane and the extracellular matrix. Costameres consist of aggregates of integrin molecules linked to the contractile apparatus via complexes composed of α-actinin/vinculin/talin and integrin-linked kinase/paxillin/parvin. Abnormal or reduced expression of vinculin, talin, and paxillin in knock-out models results in a dilated cardiomyopathy-like phenotype.[39] Located in close proximity to the costameres, dystrophin-sarcoglycan complexes (composed of dystrophin, sarcoglycans, dystroglycan, dystrobrevins, syntrophins, sarcospan, and caveolin-3) tether the internal cytoskeleton of the cardiomyocyte to the basement membrane of the cell.[40] Dystrophin connects intracellular actin to extracellular laminin, the major noncollagenous component of basement membrane. Alterations in the normal gene sequences for dystrophin, sarcoglycans, and laminin induce a dilated cardiomyopathy phenotype.[42]

Answer 42

Adjacent myocardial cells are joined together by intercalated discs that, in turn, are composed of three types of membrane junctions: gap junctions, fascia adherens, and desmosomes. Gap junctions facilitate the spread of action potentials from one cardiomyocyte to the next by facilitating ion transport. Fascia adherens and desmosomes function to physically join the Z discs and cytoskeletons of adjacent cardiomyocytes. Defects in any of the five major proteins of desmosomes (desmoglein, desmocollin, desmoplakin, plakoglobin, and plakophillin) results in a form of cardiomyopathy known as arrhythmogenic right ventricular dysplasia, a disorder characterized by cardiomyocyte cell death, systolic pump failure, and malignant arrhythmia.

Answer 43

Protein complexes comprising the fascia adherens are similar to those seen in costameres and are presumed to perform similar functions. Other cytoskeletal proteins, such as actin, desmin, and tubulin, have equally important structural and signaling roles in cardiomyocytes. Inasmuch as actin serves as a contractile protein and is also a component of costameres and intercalated discs, it is not surprising that inherited alterations of this protein may cause dilated or hypertrophic cardiomyopathy. Aggregates of desmin form a band around the Z discs and below the costameres, connecting adjacent sarcomeres and keeping them in register and participating in the large intracellular construct of intermediate filaments. Tubulin forms microtubules that function to transmit chemical and mechanical signals within and between cells; whereas nesprins provide an important structural link between a variety of intracellular organelles including mitochondria, sarcoplasmic reticulum, Golgi apparatus, and the nucleus (where nesprins are bound to emerin and lamin). These protein complexes provide one of several means by which the genetic machinery is able to sense and respond to physical stress.

Answer 44

Contractility is difficult to measure precisely either in the laboratory working with isolated cardiac muscle or in a clinical setting working with patients. In the laboratory, contractility is often estimated as Vmax, which is an extrapolated value of the theoretical maximal shortening velocity of heart muscle under zero load and is obtained by measuring the velocity of isolated muscle under a variety of loading conditions (Figure 234-5).[45] In patients, one useful index of systolic performance is the maximal rate of ventricular pressure development, +dp/dtmax, which can be measured at the time of left heart catheterization. This index does not always provide a true measure of contractility because it is sensitive to loading conditions and heart rate. The most accurate technique for estimating myocardial contractility in clinical patients involves the generation of a family of pressure-volume loops under a variety of loading conditions and measuring the slope, Es, of the end-systolic pressure volume relationship (ESPVR) (Figure 234-6).[46] This method removes the confounding effects of afterload and preload, but it is rarely employed in clinical practice because it is very cumbersome to perform. In the clinical setting, various less rigorous estimates of contractility, such as ejection fraction or end-systolic volume index, are used even though they are sensitive to loading conditions and suffer a number of other limitations.

Answer 45

Figure 234-5 The upper tracing is a left ventricular (LV) pressure tracing obtained from a healthy dog using a high-fidelity microtransducer-tipped catheter. The first derivative of the LV pressure tracing (dp/dt) is shown in the lower tracing. Peak +dp/dt is often used to estimate LV contractility while −dp/dt is used as an estimate of ventricular relaxation.

Answer 46

Figure 234-6 Ventricular systolic function is most accurately described using a family of pressure-volume loops obtained by altering preload or afterload. At the left, ventricular function in a healthy dog (blue) is defined by Emax, representing the slope of the line joining the group of pressure-volume curves at end-systole. To the right, a single pressure-volume loop is shown from a dog with dilated cardiomyopathy. End-systolic volume is markedly increased in this dog and Emax is shown to be reduced.

Answer 47

Contractility measurements are positively influenced by the level of sympathetic nervous system activity, by the concentration of circulating catecholamines, and to some extent, by heart rate. In the early stages of myocardial failure, declining contractility is concealed by adrenergic activation. Beta-adrenergic stimulation leads, via a series of complex G-protein mediated processes, to activation of adenylyl cyclase (via the action of the stimulatory Gs protein) and the formation of cyclic AMP (cAMP), which, in turn, activates protein kinase A (PKA).[20],[47] Activated PKA exerts a plethora of effects in the myocyte that increase energy metabolism. Activated PKA also phosphorylates a number of key proteins (such as the L-type calcium channels, ryanodine, phospholamban, and SERCA2) that facilitate calcium transport across the sarcolemma, that augment calcium-induced calcium release by the sarcoplasmic reticulum (SR), and that increase calcium reuptake by the SR.[2],[47] Protein kinase A also increases the activity of a variety of other proteins that augment the rate and force of contraction of the myofilaments (troponin I and myosin-binding protein C).

Answer 48

In contrast, the parasympathetic nervous system acts to reduce heart rate and depress cardiac contractile performance. Interaction of acetylcholine with muscarinic receptors reduces myocardial contractility indirectly by inhibiting the formation of cyclic AMP (via the action of the inhibitory Gi protein) and directly by inducing the formation of inhibitory cyclic GMP.[48] Other factors reducing myocardial contractility include anoxia, ischemia, and acidemia.

Answer 49

Substantial effort has been devoted to the development of drugs that are able to improve myocardial contractility or modify the rate at which it declines. The complex mechanism of excitation-contraction coupling has been exploited by a number of therapeutic strategies designed to improve myocardial contractility in heart failure patients. Adrenergic agonists, such as dobutamine and dopamine, exert potent inotropic effects via the beta-receptor/cyclic AMP/PKA pathway.[49] The limitations and liability of these agents include desensitization of the beta-receptor pathway, their positive chronotropic effects, and arrhythmogenic actions that are likely related to their unavoidable effects on intracellular calcium currents. Moreover, improved contractile performance comes at the expense of substantial increases in energy production and oxygen demand. mechanism.

Answer 50

Amrinone and milrinone increase myocardial contractility via selective type III phosphodiesterase inhibition (PDEI). Phosphodiesterase III breaks down cAMP to AMP in the vicinity of the sarcoplasmic reticulum. Thus, PDEIs act to increase the activity of the cAMP/PKA pathway without the involvement of the beta-adrenergic receptor or Gs. The intracellular actions of PDEI are otherwise very similar to those of beta-receptor agonists, without the liabilities of receptor down-regulation or uncoupling. Some have suggested that unwanted effects on calcium channel currents can be minimized by using highly selective type III phosphodiesterase inhibitors, administered in low doses.[50]

Answer 51

Phosphodiesterase inhibitors are potent vasodilators and much of their clinical efficacy is attributed to their action on vascular smooth muscle. As a result, these agents are often referred to as inodilators. Increased cAMP in vascular smooth muscle activates protein kinase G, which effects potent vasodilation in the systemic and pulmonary vascular beds.[51] An indirect benefit of this mechanism is the modest energy and oxygen burden that is incurred compared with adrenergic agents.

Answer 52

Recent efforts to identify safe and effective positive inotropic drugs are focused on agents that increase the sensitivity of the myofilaments to Ca++, thereby avoiding the inherent liabilities of increasing the amount of Ca++ cycled with each heartbeat.[52] These positive inotropic agents act to increase the calcium binding affinity of troponin C (central mechanism) or act on other elements of the myofilaments (downstream mechanism) to increase contractility without altering intracellular calcium levels. It should be appreciated that many of the calcium-sensitizing agents identified so far have some upstream effect on cAMP levels as an integral, albeit modest, part of their mechanism of action.

Answer 53

Other drugs, such as pimobendan, exert their positive inotropic actions through a combination of mechanisms, relying both on PDEI and calcium sensitization exerted primarily through the central

Answer 54

Optimal cardiac performance requires the coordinated contraction of the ventricular walls in a fashion that optimizes the efficiency of ejection. When the normal sequence of electrical activation produces an abnormal temporal pattern of mechanical contraction, ventricular ejection is substantially impaired and stroke volume declines. This phenomenon, referred to as ventricular dyssynchrony, is observed most noticeably, but not exclusively, in heart failure patients with marked QRS prolongation on the surface electrocardiogram. The importance of dyssynchrony is dramatically illustrated by the marked functional and clinical improvement that is observed in many patients with refractory heart failure treated by cardiac pacemaker resynchronization therapy.

Answer 55

Ventricular dyssynchrony, as defined earlier, should not be confused with the term ventricular dyssynergy, which is used to describe alterations in regional or segmental wall motion amplitudes as commonly observed in patients with ischemic heart disease. Ventricular performance is diminished in this circumstance as well.

Answer 56

Excessive pericardial restraint, Obstructions to venous inflow, Impaired myocardial relaxation, Reduced ventricular compliance. Excessively fast heart rates, Weak or poorly timed atrial contractions Reduced systolic performance can also impair diastolic function.

Answer 57

Diastolic dysfunction plays a predominant role in the development of heart failure in patients with certain myocardial diseases such as systemic hypertension, fixed subvalvular aortic stenosis, and hypertrophic cardiomyopathy wherein global measures of systolic function are typically normal. Such patients are appropriately described as suffering from diastolic heart failure. Diastolic dysfunction is also displayed, sometimes prominently, in patients with systolic dysfunction. The relative contribution of diastolic dysfunction to the development of heart failure is difficult to determine in this circumstance, but patients with combined systolic and diastolic failure do not fare as well as patients with isolated systolic pump failure

Answer 58

1. The first phase is the initial phase of isovolumic relaxation. 2. The second phase is the period of rapid ventricular filling. 3. The third phase, termed diastasis, is a period of much reduced flow that serves as a reserve to be encroached upon when heart rate increases. 4. The fourth and final phase is the late filling period, which is associated with atrial systole.

Answer 59

Isovolumic relaxation begins when the semilunar valves close and lasts until the AV valves open. The time interval between these events is the isovolumetric relaxation time (IVRT), which is one of the most useful and sensitive measures of diastolic function.

Answer 60

Prolongation of IVRT suggests impaired relaxation, but some consideration must be given to heart rate and loading conditions. During the period of isovolumic relaxation, ventricular pressure falls as the concentration of calcium ions in the vicinity of the contractile elements declines. The rate and extent of myocardial relaxation is dependent on the rate at which cytosolic calcium ions are resequestered in the sarcoplasmic reticulum (SR) by the ATP-dependent calcium pump, SERCA.

Answer 61

Phospholamban, in the dephosphorylated state, inhibits the activity of SERCA; and this inhibitory influence is removed, in part, by the action of cAMP-activated PKA. Thus, increased adrenergic activity is seen to have a stimulatory effect on the rate of myocardial relaxation. Systolic loading conditions and the inherent viscoelastic properties of the heart are also important factors in determining the rate and extent of myocardial relaxation. Modest increases in afterload improve relaxation, but excessive afterload has an adverse effect.[56]

Answer 62

The rate of myocardial relaxation, The force of elastic recoil, The atrioventricular pressure gradient, The passive compliance properties of the atrium and ventricle.

Answer 63

The maximal rate of pressure decline in the ventricle, −dp/dtmax, observed during the isovolumic relaxation phase provides a useful measure of diastolic function that correlates well with measures of rapid ventricular filling.

Answer 64

Tau, the time constant of relaxation, can be derived from the same ventricular pressure tracing and is defined as the negative inverse of the semilogarithmic slope of the LV pressure decline from maximum negative dP/dt to the level of LV end-diastolic pressure (LVEDP).

Answer 65

Unlike −dp/dtmax, tau describes the rate of pressure decline in LV pressure in a way that is independent of loading conditions. Tau is often used as the gold standard to which other measures of relaxation are compared.

Answer 66

Hypertrophied hearts relax more slowly and less uniformly than normal hearts. When the ventricle is diseased, the onset of relaxation is often delayed and the rate and extent of relaxation are reduced, either globally or to varying degrees in different regions of the heart (diastolic asynergy). Diastolic filling may also be impaired when relaxation is delayed in one region as a consequence of delayed activation (diastolic asynchrony).

Answer 67

Doppler echocardiography with careful analysis of IVRT, transmitral flow velocities, pulmonary vein velocities, and annular tissue velocities (Figure 234-7).

Answer 68

With impaired relaxation, IVRT is prolonged; the peak velocity of early transmitral flow (E wave) is reduced in amplitude; E wave deceleration time is prolonged; and atrial systole produces a relatively high transmitral velocity profile (A wave), resulting in reversal of the normal E/A velocity ratio. Tissue velocity profiles of the mitral annulus reveal a similar velocity pattern that is opposite in direction but less subject to alterations caused by high filling pressures that act to conceal abnormalities of relaxation

Answer 69

Figure 234-7 Diastolic function is often defined by Doppler echocardiography in a clinical setting. At the top, transmitral flow velocity is shown. In the middle, the tissue velocity of the mitral annulus is displayed. At the bottom, the velocity of pulmonary venous flow is indicated. a’, Velocity of the mitral valve annulus (mva) during the atrial kick; A, velocity of filling wave from atrial systole; e’, velocity of the mva during rapid filling; E, velocity of the rapid ventricular filling wave; IVRT, isovolumetric relaxation time (tome from closure of the aortic valve to opening of the mitral valve); PVa, reversal of flow in the pulmonary veins with atrial systole; PVs, PVd, velocity of proximal pulmonary venous flow during systole and diastole; s’, velocity of mva during systole.

Answer 70

Late diastolic filling is a similarly complicated period wherein the booster function of the atria interacts with the passive filling characteristics of the ventricular chamber. Increased atrial systolic function often compensates for diminished early diastolic filling as evidenced by accentuation of the A wave in the transmitral velocity profile when relaxation is impaired. Reduced filling at end diastole, with diminution of the A wave, can be a consequence of diminished force of atrial systole, increased resistance resulting from reduced ventricular compliance, or a combination of the two.

Answer 71

Ventricular compliance is the reciprocal of stiffness and is determined by the volume and geometry of the chamber, as well as the thickness and tissue characteristics of its walls. The concept of ventricular compliance is best explained by a graphic display of the ventricle's end-diastolic pressure-volume relationship, the slope of which defines compliance at any given level of preload (Figure 234-8).[60]

Answer 72

Distensibility is closely related to compliance and refers to the pressure that is required to fill the ventricle to a specified volume.

Answer 73

Given the same end-diastolic volume, end-diastolic pressure will be higher if the ventricle is stiffer (less distensible and less compliant) than normal. Markedly reduced compliance is observed when the myocardium or endocardium is infiltrated with scar tissue or when the ventricular walls are excessively hypertrophied. Estimates of myocardial stiffness, which specifically assess the properties of the myocardium that impede lengthening, require a rigorous evaluation of instantaneous wall stress-strain relationships in the latter part of diastole.[61] Treatment of ventricular compliance failure is difficult unless the primary abnormality can be resolved. As a result, optimization of preload, control of heart rate, and maintenance of sinus rhythm are crucial to the successful treatment of most patients with compliance failure.

Answer 74

Figure 234-8 Ventricular compliance is the reciprocal of stiffness and is determined by the volume and geometry of the chamber, as well as the thickness and tissue characteristics of its walls. This graphic displays the relationship of ventricular end-diastolic pressure to the volume of the ventricle for a healthy subject (A) and a patient with reduced ventricular compliance (B), defined as the slope of the diastolic pressure-volume relationship. At any given volume, patients with reduced ventricular compliance will have a higher end-diastolic pressure compared with a healthy subject. LV, Left ventricle.

Answer 75

Neuroendocrine responses to developing heart failure have been well documented in human patients wherein there is a demonstrable increase in the activity of the adrenergic nervous system, overexpression of atrial and brain natriuretic peptides, activation of the renin-angiotensin-aldosterone system, augmented synthesis and release of adrenomedullin, endothelin and arginine vasopressin, and amplified expression of a number of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1, and interleukin-6.

Answer 76

More recently conducted studies in dogs and cats with heart disease indicate the operation of qualitatively similar neuroendocrine responses. Understanding these complex systems is vital to understanding the pathogenesis of heart failure and the rationale of modern treatment strategies. The neuroendocrine hypothesis of heart failure proposes that the progression of heart failure is a consequence of the excessive operation of certain maladaptive neuroendocrine responses, such as the adrenergic and renin-angiotensin-aldosterone systems. The obvious corollary is that treatment strategies that blunt or otherwise modify these responses will be of benefit to patients with heart failure. Familiarity with the mediators of these adaptive responses aids the astute observer in that plasma concentrations of certain neurohormones, such as proBNP, are able to serve as valuable biomarkers that can be used to more accurately establish a diagnosis of heart failure.

Answer 77

The short-term alterations in autonomic function that develop in patients with heart failure are similar to those evoked by blood loss or dehydration wherein the maintenance of systemic arterial pressure and fluid retention are prioritized at the expense of other physiologic obligations. The systemic effects of generalized sympathetic activation include arteriolar constriction, which, together with an increase in contractility and heart rate, helps maintain systemic arterial pressure.

Answer 78

Myocardial performance in patients with diminished contractile reserves may be negatively impacted by the resulting mismatch of afterload to contractility. This consequence is also exaggerated in patients with chronic heart failure wherein down-regulation and uncoupling of cardiac β1-receptors further diminishes the contractile response. Depletion of myocardial norepinephrine stores also augments mismatching as it renders the heart overly reliant on circulating levels of catecholamines. The process of down-regulation is accomplished by reduced transcription of mRNA and this mechanism is well established for the β1 receptor.[64] By a distinctly different process, increased myocardial expression of beta-receptor kinase (βARK) facilitates uncoupling of cardiac β1- and β2-receptors from G proteins, via the action of β arrestin, thereby reducing the subsequent production of cyclic AMP.[65] The result of all these perturbations is a diminished increase in heart rate and myocardial contractility in response to adrenergic stimulation.

Answer 79

Chronic exposure to high norepinephrine levels stimulates myocardial hypertrophy and contributes to the process of pathologic vascular and cardiac remodeling, promoting arrhythmogenesis and inducing premature death of myocytes either from necrosis or apoptosis. These effects are mediated, in part, through alpha-adrenergic receptors that, in turn, are linked through the G protein, Gq, to the activation of phospholipase C, subsequent translocation and activation of protein kinase C (PKC) and eventually to the extracellular signal-related kinase, ERK1/2.

Answer 80

Extracellular signal-related kinase 1/2 is one of four known mitogen-activated protein kinase (MAPK) pathways operating in the heart to regulate protein transcription and gene expression.[64] The MAPK ERK1/2 pathway is of particular importance when the heart hypertrophies in response to pressure overload. Other MAPK pathways described in the heart include a group of stress-activated protein kinases best known as c-Jun N-terminal protein kinases (JNKs) and the p38 pathway, which is involved in cell differentiation and apoptosis. These pathways appear to be activated in both pressure and volume overload. Extracellular signal-related kinase 5, known as ERK5, is another important pathway involved in remodeling and appears to be activated by very specific growth stimuli.[69] The operation of these MAP kinase pathways is complex and there is considerable cross-talk between these pathways and other cellular processes modifying gene expression such as the calcineurin–Nuclear Factor of Activated T cells (NFAT) pathway and the Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase-3 (PI3/Akt/GSK-3β) signaling system.[70] The pattern of gene expression evoked by the operation of these pathways is reminiscent of the pattern seen during embryonic development and is sometimes referred to as the fetal gene program. This is an understandable if unpardonable oversimplification of processes that orchestrate different responses to differing stimuli.

Answer 81

Adrenergic venous constriction in patients with heart failure results in an immediate increase in venous return (preload), which augments cardiac output but concomitantly increases venous and capillary pressures and the propensity to develop symptomatic congestion.

Answer 82

Increased adrenergic activity also alters the pattern of renal blood flow in a manner that leads to reduced sodium and water excretion and augments the actions of other compensatory responses contributing to the severity of congestion and edema. Moreover, norepinephrine (NE) augments the activity of the renin-angiotensin-aldosterone system (RAAS) and stimulates the synthesis and release of arginine vasopressin (ADH). Reduced sensitivity of atrial stretch receptors diminishes the reflex inhibition of ADH release, further amplifying the effects of NE. The eventual results of these alterations include 1. Diminished and redistributed renal blood flow, 2. A concomitant reduction in sodium excretion 3. Elevated plasma levels of arginine vasopressin with retention of solute-free water.

Answer 83

Reduced responsiveness of the arterial baroreceptor reflex, possibly due to aldosterone excess, has also been demonstrated in dogs with chronic heart failure, offering an explanation for the elevated heart rate and reduced heart rate variability noted to be present in patients with chronic heart failure. The adrenal medulla synthesizes and stores both norepinephrine and epinephrine and releases them into the circulation in response to acute stress. Unlike the adrenal gland, peripheral nerves lack the enzyme, phenylethanolamine N-methyltransferase, and do not synthesize or release epinephrine. Thus, norepinephrine, not epinephrine, plays a central role as a neurotransmitter and is constantly released from terminal sympathetic nerve endings. Despite reuptake and inactivation of most of the NE released in this fashion, a small portion leaks into the circulating blood so that plasma levels of norepinephrine, measured at rest, can serve as a useful index of sympathetic nervous system activity. Plasma NE concentrations in human CHF patients correlate with the severity of heart failure and are inversely related to survival.[74] Furthermore, rising concentrations of NE in human patients treated for CHF correlate with a decline in clinical status.[75] In some human patients, increased epinephrine and dopamine concentrations are detected as well but this response is variable. Importantly, catecholamine plasma concentrations are known to rise in many circumstances other than heart failure, including emotional stress and physical exertion, emphasizing the rather poor specificity of such measures. For these reasons, interpretation of plasma catecholamine levels in individual patients will always be problematic.

Answer 84

Plasma concentrations of norepinephrine (NE) correlated directly with the severity of heart failure and they tended to be higher in dogs with DCM compared with dogs with DVD. Plasma epinephrine (EPI) levels in dogs with heart failure were also slightly higher than those measured in control dogs, but the difference was not statistically significant. In some human patients, increased epinephrine and dopamine concentrations are detected as well but this response is variable. In cats with hypertrophic or restrictive cardiomyopathy that were not in heart failure, we found plasma epinephrine and norepinephrine concentrations above 1500 pg/mL and 1700 pg/mL, respectively. These results convincingly establish that sympathetic nervous system activity is increased in dogs and cats with naturally occurring heart disease, not unlike that observed in human patients

Answer 85

Renin-Angiotensin-Aldosterone System The major circulating form of renin is prorenin, which is formed in juxtaglomerular cells in the kidney from preprorenin by removal of a signal peptide and by glycosylation as it is transported through the rough endoplasmic reticulum.[79] Prorenin is an inactive prohormone that is converted to the active renin enzyme by removal of a 43-amino acid segment either within intracellular storage granules or following release into the circulation. The half-life of activated plasma renin is on the order of 10 to 20 minutes.

Answer 86

1. Decreased effective renal perfusion, 2. Reduced sodium reabsorption by the renal tubules 3. β1 adrenergic stimulation. Not surprisingly, low-sodium diets, dehydration, blood loss, and vigorous exercise all stimulate renin release from the juxtaglomerular apparatus.

Answer 87

Angiotensin II inhibits renin formation exemplifying the phenomenon of classic feedback inhibition.

Answer 88

The main action of renin is to accelerate the conversion of the large prohormone, angiotensinogen, to the decapeptide, angiotensin I, which is subsequently converted to the octapeptide, angiotensin II, via angiotensin-converting enzyme (ACE; see Chapter 243). Angiotensinogen is a globular glycoprotein produced in the liver and released into the circulating plasma, which serves as the primary storage reservoir. In humans, the production of angiotensinogen is up-regulated and plasma levels are increased by infection, thyroid administration, and hyperadrenocorticism. Conversely, production is down-regulated in hypothyroidism and Addison's disease.

Answer 89

When first discovered, the renin-angiotensin-aldosterone system (RAAS) was thought to act almost exclusively within the confines of the vascular bed. Now, the vast majority of ACE in the body is known to reside in the tissues with less than 10% in the circulation. Moreover, all of the various components of RAAS can be found in a variety of tissues including the brain, myocardium, vasculature, adrenal gland, and kidney, and many investigators believe that tissue RAAS is activated at an earlier stage of heart failure than the circulating components.[83] It is likely that the role of the tissue RAAS varies in different circumstances and in accordance with the nature of the underlying disease.

Answer 90

Angiotensin II, derived from cardiomyocytes and fibroblasts, plays a particularly substantive role in the development of the certain types of pathologic remodeling, acting via Gq and the operation of multiple mitogen activated protein kinases (MAPKs). ACE is a dipeptidyl carboxypeptidase and acts by cleaving terminal dipeptides from the C-terminus of substrate peptides. The selectivity of ACE is such that it cleaves any substrate peptide, R1-R2-R3-OH, where R1 is a protected L–amino acid, R2 is any L–amino acid except proline, and R3 is any L–amino acid with a free carboxy-terminal. Thus, ACE converts angiotensin I to active angiotensin II (ATII) and also inactivates the potent vasodilator, bradykinin.

Answer 91

The conversion of angiotensin I to angiotensin II can be accomplished by enzymes other than ACE including cathepsin G, elastase, tissue plasminogen activator, chymase, and chymostatin-sensitive AII-generating enzyme (CAGE). The importance of these alternate pathways is species dependent, and several reports suggest that tissue chymase is more active than ACE in the myocardium and extracellular matrix of dog and cats. Sequential actions of aminopeptidase and ACE acting on angiotensin I produces angiotensin III, a 7–amino acid peptide (heptapeptide) that has actions similar to but less potent than angiotensin II.

Answer 92

The physiologic actions of angiotensin II (AT II) have been thoroughly explored and all of its important physiologic effects appear to be mediated by AT1 receptors, which are abundantly located in blood vessels, the kidney, liver, heart, pituitary, and adrenal glands.[79],[87] The half-life of circulating AT II is on the order of 1 or 2 minutes as it is rapidly hydrolyzed to inactive peptide fragments by circulating and tissue angiotensinases.

Answer 93

1. Role as a potent vasoconstrictor, 2. Promotes sodium and water retention via direct effects on the renal tubules and indirectly by stimulating aldosterone production and release from the adrenal glands.

Answer 94

Angiotensin II and aldosterone play essential roles regulating sodium and water balance and maintaining vascular pressure when the circulating blood volume is reduced by hemorrhage or salt and water deprivation.

Answer 95

Reactive oxygen species (ROS), generated as a consequence of increased angiotensin II and aldosterone expression, are central to the development of myocardial hypertrophy and the detrimental vascular and ventricular remodeling processes observed in patients with chronic heart failure.[84,88,89] Specifically, RAAS activation increases the activity of NAD(P)H oxidases in cardiomyocytes, fibroblasts, and vascular smooth muscle. NAD(P)H oxidases catalyze the 1-electron reduction of oxygen using NADH or NADPH as the electron donor, resulting in the production of and other reactive oxygen species. Reactive oxygen species, such as , are key stimulants of the p38 MAPK and ERK1/ERK2 intracellular signaling pathways that mediate pathologic cardiac and vascular remodeling.[90] Major stimuli for aldosterone

Answer 96

1. Angiotensin II, 2. Elevated potassium levels, 3. Corticotropin (ACTH). Other messengers, including plasma catecholamines, endothelin-1, and arginine vasopressin, are also known to promote the production and release of aldosterone into the tissues and blood.

Answer 97

The main physiologic effects of aldosterone have traditionally been attributed to its effects on the kidney, where it exerts sodium-conserving effects. In this regard, aldosterone acts on epithelial cells of the distal collecting ducts, where it diffuses into the cytoplasm and binds to cytoplasmic mineralocorticoid receptors (MRs).[79,84,88] Following their entry into the nucleus, activated MRs induce a cascade of events that ultimately increase absorption of sodium ions and excretion of potassium. Aldosterone mediates similar sodium-conserving processes in the sweat and salivary glands and in the colon. However, aldosterone is now known to exert important physiologic effects in addition to those related to sodium, water, and potassium homeostasis. Aldosterone production is not confined to the adrenal gland and mineralocorticoid receptors are more widely distributed than previously realized.

Answer 98

In patients with heart failure, aldosterone contributes to baroreceptor dysfunction, enhancing the activity of the sympathetic and diminishing the actions of the parasympathetic nervous systems. Aldosterone also contributes to generalized vasoconstriction via mineralocorticoid receptor-mediated stimulation of sympathetic nervous system activity, via inhibition of norepinephrine uptake and degradation in the periphery, and via other complex actions contributing to endothelial cell dysfunction. Of particular interest is the emerging role of aldosterone as a mediator of inflammation, fibrosis, and other biologic processes, such as oxidative stress, involved in pathologic remodeling in the vasculature, kidney, and heart.

Answer 99

Aldosterone-induced cytokine synthesis is an important component of these pathologic remodeling processes. Many of the advances in the treatment of heart failure and systemic hypertension realized in the past decade have resulted from the use of compounds that prevent the formation of angiotensin II via inhibition of ACE, that block the interaction of angiotensin II with AT1 receptors (ARBs), or that antagonize the actions of aldosterone.

Answer 100

Substantial elevations of plasma renin activity and serum aldosterone levels have been identified in dogs with overt congestive heart failure due to mitral regurgitation (MR) and dilated cardiomyopathy (DCM), as well as in cats with hypertrophic or restrictive cardiomyopathy (HCM, RCM). Activation of RAAS is particularly marked in dogs and cats with acquired heart disease when furosemide is used to alleviate congestive signs. There is some disagreement about the role of RAAS in patients with less severe heart disease. Several investigators have noted that plasma renin activity and aldosterone concentrations are within the normal range or only slightly elevated in dogs and cats with heart disease prior to the onset of overt heart failure. It is also noteworthy that plasma renin activity and aldosterone concentrations are not always elevated in patients with overt congestive heart failure. Inasmuch as the physiologic effects of RAAS activation include volume expansion and vasoconstriction, both of which serve to diminish renin production, the activity of this system tends to be phasic and to conceal its activation. Thus, while there is unanimity of opinion regarding the activation of RAAS in dogs and cats with overt congestive heart failure, there is uncertainty regarding the precise point of its up-regulation in patients with less severe heart disease.

Answer 101

Atrial and brain (B-type) natriuretic peptides, ANP and BNP, released from the heart and C-type natriuretic peptide, located mainly in the vasculature, play important regulatory roles in the circulation. In healthy humans, cats, and dogs circulating forms of BNP and ANP are probably derived mainly from the atria, where they are stored as precursor molecules, proANP and proBNP, in membrane-bound granules for later release.[94-97] The third natriuretic peptide, C-type or CNP, is located primarily in the vascular endothelium. Circulating levels of CNP are much lower than those of ANP and BNP in healthy animals and humans, suggesting that it acts in a paracrine fashion inducing local relaxation of vascular smooth muscle and inhibiting vascular remodeling. Sudden rises in plasma ANP and BNP levels are accomplished by their release from atrial storage granules mainly by the stimulus of atrial stretch. Sustained increases in circulating ANP and BNP, as seen in patients with heart disease, are accomplished by increased m-RNA expression in different regions of the heart

Answer 102

In patients with myocardial disease, plasma BNP concentrations rise dramatically and often surpass ANP levels as the major site of BNP production switches from the atria to the ventricles.[99-102] In cats with hypertrophic cardiomyopathy there are marked increases in the expression of BNP in both the atria and ventricles.[103] Others, studying dogs with experimental, pacing-induced heart failure, reported that ventricular BNP expression remains rather modest and that the atria remain the predominant source of most circulating BNP.[104] The physiologic actions of ANP and BNP generally oppose those exerted by the renin-angiotensin-aldosterone system.[105],[106]

Answer 103

Atrial and B-type natriuretic peptides act via the A-type natriuretic peptide receptor, NPR-A, to induce natriuresis and diuresis by inhibiting tubular sodium transport in the inner medullary collecting duct of the kidney. This same receptor type mediates vasorelaxation of systemic and pulmonary arterioles, thereby decreasing systemic and pulmonary vascular resistance. Additional actions of ANP and BNP mediated by NPR-A include direct inhibition of the release of renin by the kidney and the release of aldosterone from the adrenal cortex. A second receptor, NPR-B, responds to ANP and BNP but preferentially mediates vasodilation from locally produced CNP. The NPR-C receptor acts to clear mature ANP and BNP from the circulation. ANP and BNP are also cleared by the action of membrane-bound neutral endopeptidase, which cleaves them into inactive peptide fragments. Neutral endopeptidase and NPR-C show greater affinity for ANP than BNP, offering an explanation for the longer plasma half-life of BNP.[105-107] N-terminal fragments of proANP and proBNP are thought to be removed more slowly from the circulation than their C-terminal counterparts because clearance of these peptides is more dependent on renal excretion. As a result, NT-proANP and NT-proBNP plasma levels are higher than and not as labile as their C-terminal counterparts. Both N-terminal peptides are sensitive markers of heart disease in humans and their levels tend to correlate closely with the severity of any underlying heart disease.

Answer 104

Measurements of plasma natriuretic peptide concentrations, especially BNP, are helpful for discriminating human patients with dyspnea due to heart failure from those with pulmonary disease or other disorders.[109-114] In the Breathing Not Properly Multinational Study, a BNP level lower than 50 pg/mL had a negative predictive value of 96% while a BNP level greater than 100 pg/mL was 90% sensitive for detecting heart failure in human patients.[115] The mean BNP concentrations of human patients with NYHA class III and IV heart failure was eightfold to tenfold fold higher than the cutoff value for subjects without heart failure.[116] In a recently reported study of cats with myocardial disease, measures of plasma BNP levels appear to have similar diagnostic potential.[78] Plasma BNP levels, elevated more than tenfold, distinguished cats with heart failure from control cats better than plasma ANP levels, which were increased fourfold to fivefold. The diagnostic potential of plasma BNP levels does not appear quite as promising in dogs where the magnitude of the change is less dramatic than that observed in cats and humans.[117],[118] In contrast to cats and humans, plasma NT-proANP levels may prove more useful than BNP levels as a marker of heart disease and heart failure in dogs wherein the prevalence of valvular heart disease is much migher.[110,117-119] In a recently completed study of dogs presented for dyspnea, plasma NT-proANP was better than plasma BNP or endothelin-1 for identifying dogs with congestive heart failure.[120]

Answer 105

Endothelin Vascular tone is modulated by the endothelium-derived vasodilators, nitric oxide and prostacyclin, and by the complex actions of the potent endothelium-derived vasoconstricting peptide, endothelin.[121],[122] Three related peptides, endothelin-1, endothelin-2, and endothelin-3, comprise the endothelin family.[123] Circulating endothelins are derived from larger peptides produced by vascular endothelial cells (myocytes and a variety of other cells) in a sequence of steps analogous to that described for natriuretic peptides.[123-125] Thus, preproendothelin gives rise to biologically inactive proendothelin, also termed big endothelin, which is subsequently cleaved at the N-terminus by endothelial-converting enzyme (ECE) to yield the active mature peptide, endothelin-1 (ET-1). Endothelin-1 mRNA expression and ET-1 production are stimulated by hypoxia and mechanical factors, including stretch and low shear stress; by vasoactive substances such as angiotensin II, arginine vasopressin, norepinephrine, and bradykinin; and by growth factors and cytokines including transforming growth factor beta, tumor necrosis factor alpha, and interleukin-1.[124-126] Other vasoactive endothelin derivatives are produced by the action of tissue chymases, but the biologic importance of this and other alternate pathways is not yet clear.[127]

Answer 106

Endothelin-1 acts via two receptors, ETA and ETB, to exert complex biologic effects serving to maintain normal vascular tone.[124-128] Vasoconstriction of smooth muscle, increases in myocardial contractility, and aldosterone secretion are among the more prominent effects mediated by ETA receptor stimulation. Chronic stimulation of ETA receptors and persistently elevated ET-1 levels cause proliferation and hypertrophy of vascular smooth muscle and myocardial hypertrophy. In addition to its direct vasoconstricting effects in heart failure, ET-1 inhibits the endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA); and this effect can be blocked by ETA receptor antagonists.[129] Vasodilation, mediated by increased nitric oxide (NO) production, and aldosterone secretion results from stimulation of endothelial cell ETB receptors, providing an elegant and complex means of balancing vascular tone. Increased NO levels, in turn, inhibit ET-1 synthesis, exemplifying a negative feedback mechanism. Following intravenous injection of endothelin-1, blood pressure first declines transiently and then increases, reflecting the action of these two receptor subtypes. The interactions of endothelin and RAAS are complex, but the net effect is suppression of renin production and stimulation of aldosterone secretion.[127] Therapeutic strategies based on blocking ET receptors and inhibition of endothelin-converting enzyme have not produced convincing clinical benefits. In healthy people and animals, most circulating endothelin-1 is derived from the vasculature and ET-1 levels are very low, reflecting its paracrine role in the maintenance of normal vascular tone. Myocardial production of ET-1 is thought to contribute to the increased plasma concentrations of ET-1 observed in human, dogs, and cats with heart failure. It is noteworthy that the magnitude of elevation of ET-1 in heart failure is not as dramatic as that seen with the natriuretic peptides. Plasma ET-1 levels more than double in dogs with CHF due to DVD or DCM and increase more than threefold in cats with cardiomyopathy and CHF or systemic thromboembolism.[128],[129] Significant but more modest elevations are observed in dogs and cats with less severe disease. In a study of dogs presented for dyspnea, plasma ET-1 levels were less accurate than plasma NT-proANP for distinguishing dogs with CHF from those with dyspnea from other causes.[120] Endothelin-1 concentrations are also consistently elevated in patients with pulmonary hypertension and some forms of renal disease, but, interestingly, not in patients with systemic hypertension.[124],[130]

Answer 107

Arginine Vasopressin Arginine vasopressin (AVP), often referred to as antidiuretic hormone (ADH) in the veterinary literature, is a nonapeptide with the amino acid, arginine, at the 8 position.[131],[132] The amino acid sequence of the mature peptide is highly conserved in most mammals and is identical in humans, dogs, and cats.[87],[133] Provasopressin, derived from preprovasopressin, is produced by neurons whose cell bodies are located in the hypothalamus. Subsequently, provasopressin is processed into the mature peptide, vasopressin, in vesicles that are transported along the length of axon to the posterior pituitary, where they become secretory granules containing the active peptide within the nerve endings.

Answer 108

1. Increased plasma osmolality 2. hypovolemia.

Answer 109

When plasma volume is reduced, stretch receptors in the atria and large veins decrease their firing rate, stimulating release of AVP. Sympathetic stimulation and angiotensin II also stimulate AVP release. Following its release, vasopressin reacts with V1A receptors in the vasculature and heart, mediating weak vasoconstrictive and inotropic actions, and with V2 receptors in the kidney, stimulating water reabsorption. This latter effect is accomplished via regulation of the number of aquaporin-2 water channels inserted into the luminal membrane of cells in the renal collecting ducts. Baroreceptor V2 receptors respond to elevated plasma AVP levels by augmenting baroreceptor reflexes, which lower the heart rate in order to maintain arterial blood pressure in the normal range.

Answer 110

In dogs with heart failure induced by rapid pacing, plasma levels of arginine vasopressin rise prior to the development of congestive signs in association with activation of the RAA system. Marked increases are observed with the onset of congestive signs. Elevated plasma arginine vasopressin levels are detectable in some human patients with CHF, particularly those with severe heart failure and dilutional hyponatremia.[131],[136] The paradox of increased AVP release in the face of reduced plasma osmolality and high filling pressures may be due to baroreceptor signaling caused by low arterial blood pressure.

Answer 111

Whatever the mechanism, selective V2 or combined V1A/V2 receptor antagonists have been shown to normalize plasma sodium concentrations and to alleviate congestive signs in affected patients.[137-139] These agents are sometimes referred to as aquaretics because they cause the elimination of free-water without changing urinary excretion of sodium or potassium. Conivaptan, a combined V1A/V2 blocker, has shown efficacy in dogs with experimentally induced heart failure and in human patients with severe symptomatic CHF.[139],[140] Tolvaptan is a more selective orally active vasopressin V2 receptor antagonist also being evaluated in clinical trials.[141] Increased levels of circulating AVP have been documented in dogs with dilated cardiomyopathy, but no observations have yet been reported in dogs with other forms of heart disease or in cats.[142]

Answer 112

Adrenomedullin Adrenomedullin (ADM) is a potent natriuretic and vasodilating 52–amino acid peptide with positive inotropic properties. Adrenomedullin has been detected in a variety of tissues including the adrenal medulla, heart, lung, and kidney. Plasma levels of ADM are increased in human heart failure patients and in dogs with pacing-induced experimental heart failure. Recent studies indicate that angiotensin II stimulates ADM production and secretion from cardiac myocytes and fibroblasts and that ACE inhibition can block this response. Thus ADM appears to have endocrine, autocrine, and paracrine effects. Interestingly, ADM serves as a marker of ventricular hypertrophy but acts to attenuate myocardial hypertrophy and collagen production. Adrenomedullin has received little attention in dogs or cats with naturally occurring heart disease. This is likely to change because there is increasing interest in ADM as a possible therapeutic agent

Answer 113

Cytokines, more appropriately referred to as protein regulatory factors, are small water-soluble signaling proteins or glycoproteins produced by a wide variety of cell types that are used extensively in cellular communication. Cytokines exhibit a combination of endocrine, paracrine, and autocrine actions via membrane bound receptors that up- and down-regulate the expression of groups of genes and their transcription factors, thereby acting as potent modifiers of protein synthesis. The biologic effects of cytokine-receptor interactions are mediated via complex intracellular signaling cascades composed of a mitogen-activated protein kinase (MAPKs), MAP kinase kinase (MAP2K), and MAP kinase kinase kinase (MAP3K). Often categorized into families based on the type of membrane receptor they interact with, cytokines play an important and well-known role in inflammatory conditions, such as myocarditis.

Answer 114

Increased production and elevated plasma concentrations of proinflammatory cytokines, including interleukin-1, interleukin-6, and tumor necrosis factor alpha (TNF-α), have been identified in human patients with chronic heart failure and are regarded as important negative prognostic indicators. Increased TNF-α levels act to depress myocardial function, and chronic elevations of TNF-α promote apoptosis. Unfortunately, clinical trials of agents blocking the actions of TNF-α in human subjects were disappointing.

Answer 115

Other cytokines, working in concert with growth factors and membrane-bound integrins, have important roles in coordinating tissue remodeling during embryogenesis, postnatal growth, exercise, pregnancy, and in response to a wide variety of pathologic insults.[150] Osteopontin and cardiotrophin-1 are two such regulatory proteins intimately involved in the coordination of the remodeling processes of myocardial cells, fibroblasts, and other constituents of the interstitium to produce the phenomena we recognize as physiologic and pathologic hypertrophy. Osteopontin (OPN), also referred to as cytokine Eta-1, plays an important role in functional and pathologic cardiac remodeling.[151-153] Recent studies indicate that OPN is required for the differentiation and activity of myofibroblasts formed in response to the profibrotic cytokine TGF-β1.[151] Osteopontin is a nonstructural secreted matrix protein containing the arginine-glycine-aspartic acid-serine cell binding sequence found in many extracellular matrix proteins. In healthy animals, osteopontin is found mainly in bone and epithelial tissues, but, in pathologic circumstances, it is produced in abundant quantities by endothelial cells, smooth muscle cells, fibroblasts, and cardiomyocytes.[153] Cardiomyocyte OPN expression increases, together with β1 integrin expression, in response to pressure overload and activation of RAAS. Myocardial sources of angiotensin II and transforming growth factor-beta 1 (TGF-β1) induce the expression of osteopontin in concert with the development and progression of myocardial hypertrophy as demonstrated in a variety of heart failure and hypertension models. Marked up-regulation of AT1 receptors by aldosterone makes it difficult to determine if OPN production is induced directly by aldosterone as well. Studies conducted by the author indicate that OPN expression is modestly increased in the hearts of dogs with dilated cardiomyopathy and that it is markedly increased in the hearts of cats with hypertrophic or restrictive cardiomyopathy. Interestingly, based on immunohistochemical staining, osteopontin expression does not appear to be increased in the hearts of dogs with end-stage mitral regurgitation. This observation is concordant with studies of dogs with experimentally induced mitral regurgitation, wherein TGF-β1 was down-regulated together with cell-matrix scaffolding genes controlled by TGF-beta pathway. Plasma levels of OPN are elevated in human patients with heart failure due to ischemic or dilated cardiomyopathy, and OPN levels correlate with NYHA class, predicting mortality independent of NT-pro-BNP levels.[155]

Answer 116

Cardiotrophin-1 (CT-1) and the structurally related leukemia inhibitory factor (LIF) are members of the interleukin-6 (IL-6) family of cytokines that exert their effects via the glycoprotein 130 (gp130) signaling pathway.[156] Two distinct pathways mediate the actions of gp130 activation in cardiac myocytes: (1) the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and (2) a mitogen-activated protein kinase (MAPK) pathway.[157] Plasma levels of CT-1 are elevated in human patients with systemic hypertension or valvular heart disease, indicating that this cytokine plays a role in the development of both concentric and eccentric myocardial hypertrophy.[158] Of particular interest is the unique observation that overexpression of CT-1 can stimulate the assembly of sarcomeric units in series (end-to-end) resulting in the eccentric hypertrophy phenotype.[159] This phenotype is thought to result from the stimulation of multiple hypertrophy-inducing signaling pathways while simultaneously inhibiting the assembly of sarcomeres in parallel via expression of the MEK5-ERK5 (big MAPK 1 or BMK1) pathway.[160] Thus, CT-1 is believed to play an important modulating role in those remodeling responses observed in mitral regurgitation and other forms of volume overload. Cardiotrophin-1 is also thought to play an important role in the progression of pathologic remodeling and development of myocardial failure in patients with ischemic and other forms of heart disease wherein the end result is a dilated, poorly contracting ventricle. Cardiotrophin-1 may also prove to be a useful biomarker of cardiovascular disease because plasma levels appear to rise even before those of BNP.[161] Plasma CT-1 levels are elevated in human patients with valvular heart disease with preserved ventricular function and in patients with heart failure due to ischemic heart disease and dilated cardiomyopathy.[162] Plasma CT-1 levels offer prognostic information because they have also been shown to be predictive for heart failure and death in human subjects with a prior myocardial infarction.[163]

Answer 117

Integrins comprise a large family of transmembrane cell adhesion receptors that, together with a network of cytoskeletal proteins (described later), sense mechanical stress and trigger intracellular signaling pathways regulating hypertrophy and remodeling.[164-166] Functioning integrin complexes consist of two transmembrane glycoprotein subunits, an alpha and beta chain that are noncovalently bound. Each integrin subunit consists of a large extracellular domain, a single transmembrane segment, and a short intracytoplasmic domain. In the heart, integrins in the sarcolemma aggregate on the cell surface in register with the underlying Z disc, to form riblike structures (costameres) around the cardiomyocytes. In this location, the intracytoplasmic extensions of the integrin molecules are linked to the contractile apparatus at the Z disc via complexes composed of α-actinin/vinculin/talin and integrin-linked kinase/paxillin/parvin. Signaling molecules associated with the complex include focal adhesion kinase (FAK) and phosphatidyl inositol phosphate kinase, both of which participate in the activation of hypertrophic and remodeling responses. The external domains of integrin are bound to fibronectin, collagen, and other adhesive proteins of the extracellular matrix. When myocytes change their shape during the process of hypertrophy, integrin molecules on the cell surface are rearranged, resulting in an inside-out signaling process that serves coordinated remodeling of the extracellular matrix.

Answer 118

Many other processes also serve the function of mechanical force transduction and hypertrophic signaling in the heart.[167-169] Titin molecules woven into the Z disc are thought to transmit the stress of diastolic filling to the muscle LIM protein, MLP, which then acts as the stretch sensor signaling the development of the eccentric hypertrophy phenotype.[167] Pressure overload hypertrophy is associated with stretch-induced, agonist-independent activation of angiotensin type 1 receptor signaling.[168] Other proposed mechanical stress sensors include stretch-sensitive ion channels and cytoskeletal filaments.[169]

Answer 119

CARDIAC REMODELING Chronic perturbations in the circulation and pathologic insults to the heart elicit anatomic and morphologic changes in the heart that are broadly referred to as cardiac remodeling. Cardiac hypertrophy is the foundation of the remodeling response given the extremely limited ability of the heart to add new cardiomyocytes. When the heart is healthy, cardiomyocytes occupy about three fourths of the volume of the heart and comprise about one third of the total number of cells.[170] These muscle cells are embedded in a collagen-rich extracellular matrix produced by large numbers of fibroblasts, and both components are nourished by an extensive network of coronary vessels lined by endothelial cells and richly endowed with smooth muscle cells.

Answer 120

Noncellular constituents of the extracellular matrix include mainly type I and type III collagens, a rich soup of proteoglycans and a large variety of signaling peptides and extracellular proteases.[171] Interstitial collagen is organized in a complex fashion that serves to connect and bundle the myofibers in a sophisticated weave that facilitates the primary function of collagen, which is the transmission of force.

Answer 121

Approximately 2% to 4% of the heart is composed of collagen, and the majority of this is type.....collagen. Endomysial collagen surrounds individual myocytes, giving rise to collagen struts that connect to neighboring myocytes and to capillaries. Perimysial collagen fibers form a complex weave of collagen surrounding groups of myocytes and joining adjacent groups of myocytes to one another. Epimysial collagen forms a sheath that encompasses muscle bundles and is connected to the perimysium by strong, tendonlike cables. From this perspective, the heart can be viewed as a collagen fiber–reinforced composite material that is designed to support the working cardiomyocytes during diastolic filling and systolic ejection.

Answer 122

Inasmuch as the interstitium and myocardium are inextricably linked, changes in either one alter the biologic responses and remodeling processes of the other. In humans, heart weight can decline by as much as 25% to 30% during prolonged bed rest or weightlessness and can increase to an extreme of 50% to 60% with extreme exercise.[174] Mechanical stress, growth factors, and neurohormonal stimuli act in concert to elicit paracrine and autocrine signaling mechanisms integral to these physiologic remodeling processes. Reorganization of the interstitium is appropriately coordinated with the symmetric growth of myocardial cells, and these changes are reversible once the physiologic challenge is resolved, as in exercise- or pregnancy-induced cardiac hypertrophy. Reverse remodeling is accomplished by deactivation of pro–growth signaling pathways and activation of other signaling pathways that disassemble the adaptive constructs of the hypertrophied heart. The number of myocytes in the mature heart declines with age and the remaining myocytes must, by necessity, remodel as they assume a greater percentage of the hemodynamic burden. Pathologic cardiac remodeling shares many of the adaptive processes and signaling pathways of physiologic remodeling, but the end result is often irreversible remodeling, reduced systolic or diastolic performance, and eventual cardiac decompensation. Forty years ago, Meerson and colleagues[175] identified three phases of the hypertrophic response: (1) an initial stage wherein hypertrophy develops in response to increased wall stress, (2) a compensated stage wherein wall stress has been normalized by the hypertrophic response, and (3) an exhaustion phase characterized by the death of cardiomyocytes, development of myocardial fibrosis, ventricular dilation, and reduced cardiac output. Compensatory and adaptive remodeling processes are transformed when the hemodynamic stresses are prolonged in duration or excessive in magnitude; when physiologic patterns of neurohormonal activation are excessively modified (RAAS, NE, ET-1); and when vascular remodeling exerts its toll on myocardial perfusion.

Answer 123

Abrupt increases in systolic wall tension (stress), such as that caused by experimentally created aortic stenosis, induce an abrupt increase in LV end-systolic volume and a concomitant decrease in stroke volume. During this phase the size and number of mitochondria increase to meet the increased demands for energy.[176] Over time, the myocardium responds to pressure overload through the process of concentric hypertrophy, wherein the sarcomeres replicate in parallel (side to side), causing the muscle fibers to thicken, increasing left ventricular and septal wall thickness. The radius of the ventricle is unchanged or may even decrease slightly due to encroachment by the thickened ventricular walls. In this fashion, systolic wall stress is normalized and the patient experiences little or no functional compromise.

Answer 124

Fibroblasts in the interstitium also experience the increased pressure load and elevated levels of locally generated transforming growth factor beta-1 (TGF-β1), angiotensin II (AT II), aldosterone, CT-1, and osteopontin. They respond to these stimuli by proliferating and by increasing the synthesis and deposition of collagen, mediated at least in part by reduced expression of adaptor molecule DOC-2 in activated fibroblasts. In the interstitium, the breakdown of collagen is reduced due to increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and the corresponding reduced activity of the matrix metalloproteinases, MMP1 and MMP 9.[177] Few studies have examined the available spectrum of MMPs and TIMPs, and a variety of changes will no doubt be reported over the next few years.

Answer 125

When the initiating insult is mild, long-term cardiac compensation is achieved with minimal functional compromise, as evidenced by the long survival time of dogs with mild to moderate outflow tract obstructions. However, when pressure overload is sufficiently severe, myocardial function is compromised. Capillary density and myocardial perfusion do not keep pace in proportion to large increases in wall thickness, and chronic myocardial hypoxia results in premature death of myocardial cells and more extensive myocardial fibrosis. Not surprisingly, the most common consequence of severe subvalvular aortic stenosis in dogs is sudden death from ventricular arrhythmia, presumably as a result of myocardial ischemia and its sequelae. In some patients, severe concentric hypertrophy and ischemia-induced myocardial fibrosis act to compromise left ventricular compliance, precipitating diastolic heart failure. On occasion, global systolic pump failure develops as a consequence of terminal remodeling processes culminating in myocardial fiber elongation, myofibrillar lysis, and death of cardiomyocytes. During the exhaustion phase the rate of collagen breakdown exceeds the rate of synthesis and the hypertrophied ventricle begins to dilate and fail.

Answer 126

The response of the heart to volume overload differs substantially from that observed in pressure overload. Common causes of volume overload include valvular insufficiency and congenital shunting lesions, such as patent ductus arteriosus and ventricular septal defect. Pure volume overload is characterized by increased diastolic wall stress to which cardiomyocytes respond by replicating new sarcomeres in series (end to end). The ventricle becomes more spherical and the diameter of the chamber becomes larger in a process referred to as eccentric hypertrophy. Wall thickness increases only modestly so as to maintain a normal ratio of wall thickness to radius, thereby normalizing wall stress. The closest clinically relevant model of volume overload is mitral regurgitation wherein the additional volume load is ejected into a low-pressure reservoir, the left atrium.

Answer 127

Other forms of volume overload, such as aortic valve insufficiency and patent ductus arteriosus, represent examples of combined volume and pressure overload wherein an additional volume of blood is ejected into a high-pressure reservoir, the aorta. When examining the mechanisms of volume overload, it is useful to focus attention on mitral regurgitation rather than on disorders where cardiac adaptation represents a combination of volume and pressure overload.

Answer 128

Compared with pressure overload, volume overload induces a relatively modest increase in heart weight and protein synthesis. Interestingly, the increase in heart weight occurring secondary to mitral regurgitation results mainly from a reduced rate of protein degradation. This observation reinforces the concept that signals mediating volume overload differ from those elicited by pressure overload and that there must be a corresponding difference in the pattern of gene activation. Myocytes from volume-overloaded hearts are elongated relative to normal or pressure-overloaded hearts.[179] Inasmuch as CT-1 levels are increased, overexpression of the MEK5-ERK5 (big MAPK 1 or BMK1) pathway is anticipated to be important in establishing the eccentric hypertrophy phenotype. It is presumed that differences in mechanoreceptor signaling are largely responsible for the remodeling differences between pressure and volume overload inasmuch as increased levels of norepinephrine, CT-1, and AT II are common to the pathogenesis of both forms of hypertrophy. Nonetheless, the integrated operation of these signaling pathways is still poorly understood and other factors, not apparent at this time, may be responsible for some of the observed differences. The extracellular matrix is drastically altered in the hearts of dogs with experimentally induced mitral regurgitation. This change is characterized by a loss of collagen and disappearance of the elaborate collagen scaffold tethering the cardiomyocytes. Several mechanisms for this alteration have been identified. Collagen synthesis in cardiac fibroblasts is substantially reduced in dogs with mitral regurgitation, paralleling the observed reduction in sarcomeric protein synthesis. The rate of collagen degradation is augmented by the increased activities of MMP-1 and MMP-9, in absolute terms and relative to MMP tissue inhibitor levels. The population of mast cells in the interstitium increases in dogs with mitral regurgitation.[180] In addition, tissue expression of TGF-β1 is reduced together with down-regulation of cell-matrix scaffolding genes controlled by the TGF-β1 pathway. These alterations are most obvious early in the course of volume overload; they tend to normalize during the compensated phase only to reactivate again in the late stages of the disorder.

Answer 129

The remodeling processes of ischemic myocardial disease and dilated cardiomyopathy differ qualitatively and quantitatively from those described for pressure or volume overload. In the compensated phase of ischemic cardiomyopathy, the adaptive responses are more similar to those observed in pressure overload due to the chronic operation of potent neuroendocrine adaptive responses. However, in the decompensated phase, cardiomyocytes begin to elongate, the collagen matrix begins to disintegrate, and the chamber dilates, indicating a shift in intracellular signaling. The hearts of dogs with dilated cardiomyopathy (DCM) show a mixed remodeling pattern as well, but the eccentric hypertrophy phenotype predominates. Given the varying pathologic manifestations of DCM in different breeds, it is likely that cardiac remodeling processes are modified according to the etiology of their disorder and the resulting alterations in signaling that result.

Answer 130

CHANGES IN ENERGY METABOLISM IN HEART FAILURE Prior to the onset of heart failure, cardiomyocytes performing additional external work generate more energy and recycle more calcium than cells that are not similarly burdened. As more energy is produced, more heat is produced and the cell experiences greater oxidative stress. As a result, more energy must also be dedicated to cell maintenance and repair. Thus, it is not surprising that one of the first responses of overworked cells is to increase the number of mitochondria to address the need for energy. Additional energy must be devoted to the construction and maintenance of the pathways used to store and distribute energy as well. These adaptive processes eventually fall short, resulting in abnormalities of calcium cycling, systolic and diastolic dysfunction, and cell death. In patients with heart failure, there is a switch in substrate utilization from fatty acids to carbohydrates and a decrease in aerobic ATP production.

Answer 131

The amount of ATP in failing cardiomyocytes is not altered, but the rate of use and rate of replenishment of ATP are reduced as the capacity of the mitochondria to produce ATP becomes limited. Heart failure is characterized by declining levels of creatine phosphokinase in the cytosol and mitochondria and a correspondingly reduced creatine phosphate/ATP ratio. This alteration has been described in explanted hearts from human patients with end-stage heart failure, in dogs with experimentally created mitral regurgitation, and in dogs with spontaneously occurring DCM. O’Brien and colleagues[188] found reduced mRNA content and enzyme activity for markers of calcium cycling, glycolysis, and oxidative phosphorylation in dogs with DCM. More recently, Oyama and Chittur[189] reported reduced expression of genes involved in glycolysis and oxidative phosphorylation. Lopes and colleagues[190] reported similar patterns of altered energy production reflected in the protein expression profiles of mitochondria from dogs with pacing-induced and naturally occurring cardiomyopathy.

Answer 132

These functional changes are reflected in structural alterations of the mitochondria, which become smaller and more numerous. These changes are accompanied by alterations and disruption of the internal cristae. In context, there is also a breakdown in the architecture of other cellular constituents with dissolution of the myofilaments and disorganization of cytoskeletal elements. Ischemia is a rather obvious cause of diminished energy production and is of paramount importance in human patients with atherosclerosis. Regional ischemia, associated with vascular remodeling, is a likely cause of altered energy production and cell death in some of our animal patients, most notably in cats with hypertrophic cardiomyopathy and dogs with subaortic stenosis wherein the remodeling of intramyocardial coronary arterioles is often quite marked. These vascular lesions are commonly associated with focal myocardial scars completely devoid of functioning myocytes.

Pathophysiology of Heart Failure Ettinger Flashcards

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