Biomarkers of Cardiovascular Disease- Ettinger

Question 1

troponintext försvunnen på s 98-99 i kopian. Kolla ettinger

Answer 1

troponintext försvunnen på s 98-99 i kopian. Kolla ettinger

Question 2

Troponin: the release pattern may be biphasic with ………………… being released first. If the insult continues or becomes more severe, persistent release from structurally bound stores may occur, representing irreversible damage to the cardiac ………………

Answer 2

the release pattern may be biphasic with cytosolic pool being released first. If the insult continues or becomes more severe, persistent release from structurally bound stores may occur, representing irreversible damage to the cardiac sarcomere.

Question 3

The concentration of circulating cardiac troponins is a balance among?

Answer 3

Its release from the myocardium,
leakage into the circulation,
degradation by serum proteases, and,
as most marker proteins with molecular weights above 20 kDa, clearance in organs with a high metabolic rate such as the liver, kidney, and the reticuloendothelial system.

Question 4

A potential explanation for the cTnI release without lethal sarcolemmal disruption is?

Answer 4

The cellular release of proteolytic cTnI degradation products.

Question 5

In a metaanalysis study using 500 simultaneously measured serum samples in a variety of clinical conditions in dogs and cats, cTnI is elevated earlier and more frequently than cTnT.[ Why?

Answer 5

The reason for this elevation is unknown, but it may result from a structurally closer binding of cTnT to the tropomyosin chain.

Question 6

….NP is mostly expressed in the brain and endothelium, and …NP is currently only found in the venom of the Green Mamba snake

Answer 6

CNP is mostly expressed in the brain and endothelium, and DNP is currently only found in the venom of the Green Mamba snake

Question 7

Natriuretic peptides modulate blood …………. and ………………., antagonize the ……………………., induce bronch………………., and inhibit …………………………. proliferation.

Answer 7

1. Modulate blood volume and pressure,
2. Antagonize the renin-angiotensin-aldosterone system (RAAS),
3. Induce bronchodilation, and
   4.Inhibit smooth muscle cell proliferation.

Question 8

Natriuretic peptides are synthesized as pre-prohormones and share a central loop containing 17 amino acids closed by a disulfide bond between 2 cysteine residues, with variable carboxy-terminal (exception is CNP isotypes that lack a carboxy-terminal portion) and amino-terminal fragments

Answer 8

Natriuretic peptides are synthesized as pre-prohormones and share a central loop containing 17 amino acids closed by a disulfide bond between 2 cysteine residues, with variable carboxy-terminal (exception is CNP isotypes that lack a carboxy-terminal portion) and amino-terminal fragments

Question 9

ANP is primarily produced in the atria in response to increased atrial-wall tension following an increase of intravascular volume or pressure. It may also be expressed in ……………….. tissue of fetuses and in …………………myocardium in disease.

Answer 9

ANP is primarily produced in the atria in response to increased atrial-wall tension following an increase of intravascular volume or pressure. It may also be expressed in ventricular tissue of fetuses and in ventricular myocardium in disease.

Question 10

The renal alter ego of ANP is ………………, which is produced in the renal distal tubules and only has local functions in the sodium and volume regulation in the kidneys.

Answer 10

urodilatin

Question 11

BNP is a 32-amino-acid peptide that shares structural and biologic similarities to ANP. The biologically active peptide sequence of BNP lies in the carboxy terminal of the proBNP peptide as with ANP. Unlike ANP, BNP is stored to a much lesser extent and increased release requires increased synthesis. The translation of the BNP gene is mainly evoked by cardiac myocyte …………. and ……………, however, other stimuli such as ……………, ………………, and …………………..agonists also result in the production of the pre-prohormone, mainly preproBNP1-134.

Answer 11

BNP is a 32-amino-acid peptide that shares structural and biologic similarities to ANP. The biologically active peptide sequence of BNP lies in the carboxy terminal of the proBNP peptide as with ANP. Unlike ANP, BNP is stored to a much lesser extent and increased release requires increased synthesis. The translation of the BNP gene is mainly evoked by cardiac myocyte stretch and ischemia, however, other stimuli such as angiotensin II, endothelin-1, and adrenergic agonists also result in the production of the pre-prohormone, mainly preproBNP1-134.

Question 12

Under normal conditions, BNP is primarily produced in the cardiac ………….with very little synthesis in the ……………. This changes with cardiac pathologies due to chronic pressure or volume overload, as ……………… myocytes become the major source of BNP synthesis.

Answer 12

Under normal conditions, BNP is primarily produced in the cardiac atria with very little synthesis in the ventricles. This changes with cardiac pathologies due to chronic pressure or volume overload, as ventricular myocytes become the major source of BNP synthesis.

Question 13

The principal physiologic actions of ANP and BNP are to?

Answer 13

Tp oppose those exerted by the RAAS and the sympathetic nervous system, giving protection to the cardiovascular system from volume overload.

Question 14

ANP and BNP act via the natriuretic peptide receptor type-A (NPR-A) via 3′,5′-cyclic guanosine monophosphate (cGMP) to induce ………….. and ……………. by inhibiting tubular ………….. transport in the ………………… duct of the kidney. The NPR-A receptor also mediates ………………… of systemic and pulmonary a………………, leading to decreased systemic and pulmonary vascular ………………, and inhibition of …………. and ……………..release (Figure 236-1).

Answer 14

ANP and BNP act via the natriuretic peptide receptor type-A (NPR-A) via 3′,5′-cyclic guanosine monophosphate (cGMP) to induce diuresis and natriuresis by inhibiting tubular sodium transport in the collecting duct of the kidney. The NPR-A receptor also mediates vasodilatation of systemic and pulmonary arterioles, leading to decreased systemic and pulmonary vascular resistance, and inhibition of renin and aldosterone release (Figure 236-1).

Question 15

The sensitivity of the NPR-A for NPs is currently reported as DNP > ANP ≥ BNP = VNP ≫> CNP. The NPR-A receptors are widely distributed and can be found in the lungs, heart, kidneys, adrenals, and vasculature and central nervous systems. A second receptor, natriuretic peptide receptor type B (NPR-B), also responds to ANP and BNP but preferentially binds CNP (CNP > VNP ≫ ANP = DNP ≥ BNP.[55],[57] The NPR-B appears more abundant in veins as compared with arteries, in contrast to NPR-A receptors that are expressed comparably in arteries and veins. The NPR-B is also expressed in the brain, lungs, skin, kidneys, adrenal glands, uterus, and ovaries.

Answer 15

The sensitivity of the NPR-A for NPs is currently reported as DNP > ANP ≥ BNP = VNP ≫> CNP. The NPR-A receptors are widely distributed and can be found in the lungs, heart, kidneys, adrenals, and vasculature and central nervous systems. A second receptor, natriuretic peptide receptor type B (NPR-B), also responds to ANP and BNP but preferentially binds CNP (CNP > VNP ≫ ANP = DNP ≥ BNP.[55],[57] The NPR-B appears more abundant in veins as compared with arteries, in contrast to NPR-A receptors that are expressed comparably in arteries and veins. The NPR-B is also expressed in the brain, lungs, skin, kidneys, adrenal glands, uterus, and ovaries.

Question 16

Mature ANP and BNP are mainly removed from circulation via two main mechanisms: Which ones?

Answer 16

(1) natriuretic peptide receptor type-C (NPR-C), which serves as a clearance receptor by internalization of natriuretic peptides (ANP > BNP) leading to lysosomal degradation and
(2) membrane-bound enzyme neutral endopeptidase 24.11 (NEP), which cleaves the natriuretic peptides (CNP > ANP > BNP > DNP) into inactive fragments.

Question 17

The plasma half-life of active BNP is 12.1 minutes in humans but considerably shorter, 90 seconds, in dogs. The half-lives of NT-proBNP have not been studied in dogs but are suspected to be longer as the N-terminal fragments of proANP and proBNP are removed more slowly from circulation compared with their C-terminal counterparts because their clearance is more dependent on organs with a high degree of blood flow (e.g., kidneys), instead of enzymatic degradation via NEP. Furthermore, among the more important fragments of BNP that circulate is BNP3-32, which results from the cleavage of BNP1-32 by dipeptidyl peptidase-IV, which appears not to change the molecules’ resistance to further final degradation by neural endopeptidase.

Answer 17

The plasma half-life of active BNP is 12.1 minutes in humans but considerably shorter, 90 seconds, in dogs. The half-lives of NT-proBNP have not been studied in dogs but are suspected to be longer as the N-terminal fragments of proANP and proBNP are removed more slowly from circulation compared with their C-terminal counterparts because their clearance is more dependent on organs with a high degree of blood flow (e.g., kidneys), instead of enzymatic degradation via NEP. Furthermore, among the more important fragments of BNP that circulate is BNP3-32, which results from the cleavage of BNP1-32 by dipeptidyl peptidase-IV, which appears not to change the molecules’ resistance to further final degradation by neural endopeptidase.

Question 18

In general, plasma concentrations of natriuretic peptides are increased in disease states characterized by an …………… volume, stimulation of ………………. production (e.g., disease states caused by ventricular hypertrophy, tachycardia, hypoxia, arrhythmias, ectopic production from tumor, or excessive circulating glucocorticoid and thyroid hormones) and significant …………………. dysfunction.

Answer 18

In general, plasma concentrations of natriuretic peptides are increased in disease states characterized by an expanded fluid volume, stimulation of peptide production (e.g., disease states caused by ventricular hypertrophy, tachycardia, hypoxia, arrhythmias, ectopic production from tumor, or excessive circulating glucocorticoid and thyroid hormones) and significant renal dysfunction.

Question 19

Adrenomedullin

Adrenomedullin is another peptide (52 amino acids) produced in larger quantities by cardiac myocytes under conditions of stress and is a component of a precursor, preproadrenomedullin, which is synthesized in the heart, lungs, kidneys, and adrenal medulla. It is a potent ………………………with natriuretic properties and production appears to be stimulated by cardiac volume and pressure overloads. In humans, concentrations of the midregional proadrenomedullin peptide have been shown to independently predict outcome in patients following myocardial infarction, adding information to that derived from NT-proBNP. Circulating and ventricular adrenomedullin concentrations have been shown to increase in dogs with experimentally induced heart failure. No clinical trials have been identified with adrenomedullin in either dogs or cats.

Answer 19

Adrenomedullin is another peptide (52 amino acids) produced in larger quantities by cardiac myocytes under conditions of stress and is a component of a precursor, preproadrenomedullin, which is synthesized in the heart, lungs, kidneys, and adrenal medulla. It is a potent vasodilator with natriuretic properties and production appears to be stimulated by cardiac volume and pressure overloads. In humans, concentrations of the midregional proadrenomedullin peptide have been shown to independently predict outcome in patients following myocardial infarction, adding information to that derived from NT-proBNP. Circulating and ventricular adrenomedullin concentrations have been shown to increase in dogs with experimentally induced heart failure.[86] No clinical trials have been identified with adrenomedullin in either dogs or cats.

Question 20

ST2, a member of the ……………………….receptor family, is a circulating soluble protein for which the ligand appears to be interleukin-33 that is induced and released by ……………… myocytes, much like BNP and ………………… In humans, concentrations appear to increase with heart failure class and in a separate study in human patients with heart failure, an increase in ST2 during a 14-day period was an independent predictor of death or the need for cardiac transplantation. Currently, the overall excitement in human medicine over the two myocyte stress markers ST2 and adrenomedullin is that they appear to yield information supplementary to that provided by natriuretic peptides. It is premature to identify their benefit in clinical veterinary medicine.

Answer 20

ST2, a member of the interleukin-1 receptor family, is a circulating soluble protein for which the ligand appears to be interleukin-33 that is induced and released by stretched myocytes, much like BNP and adrenomedullin. In humans, concentrations appear to increase with heart failure class and in a separate study in human patients with heart failure, an increase in ST2 during a 14-day period was an independent predictor of death or the need for cardiac transplantation. Currently, the overall excitement in human medicine over the two myocyte stress markers ST2 and adrenomedullin is that they appear to yield information supplementary to that provided by natriuretic peptides. It is premature to identify their benefit in clinical veterinary medicine.

Question 21

NEUROHUMORAL MARKERS

Endothelin

Endothelin, the most potent ………………….. and ……………….. substance discovered to date, was first identified in the supernatant of cultured porcine aortic endothelial cells. The family of endothelins is composed of endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), each containing 21 amino acids and two disulfide bridges. The sequence of ET-1 and ET-2 is identical between humans and dogs; however, ET-3 has not been sequenced in the dog but has been assumed to be identical to human ET-3.

ET-1 has been sequenced in cats revealing a switch at position seven, where leucine replaced methionine, resulting in an unexpected difference between cat ET-1 and ET-1 of dogs and humans (Figure 236-4). Currently, ET-2 and ET-3 have not been isolated in cats and their existence remains uncertain.
The predominant isoform expressed in the vasculature and the most potent vasoconstrictor currently known is still ET-1.

Answer 21

NEUROHUMORAL MARKERS

Endothelin

Endothelin, the most potent pressor and vasoconstrictor substance discovered to date, was first identified in the supernatant of cultured porcine aortic endothelial cells. The family of endothelins is composed of endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), each containing 21 amino acids and two disulfide bridges, The sequence of ET-1 and ET-2 is identical between humans and dogs; however, ET-3 has not been sequenced in the dog but has been assumed to be identical to human ET-3. ET-1 has been sequenced in cats revealing a switch at position seven, where leucine replaced methionine, resulting in an unexpected difference between cat ET-1 and ET-1 of dogs and humans (Figure 236-4). Currently, ET-2 and ET-3 have not been isolated in cats and their existence remains uncertain.

The predominant isoform expressed in the vasculature and the most potent vasoconstrictor currently known is still ET-1.

Question 22

A variety of vasoactive substances stimulate the expression of preproendothelin-1 messenger RNA including…?

Answer 22

Including angiotensin II, vasopressin, bradykinin, and norepinephrine along with cardiotrophin-1, tumor necrosis factor-alpha (TNF-α), interleukin-1, transforming growth factor-beta, lipoproteins, insulin, endotoxin, hypoxia, and low shear stress.

The major site of generation of ET-1 is in endothelial cells, but it is also produced in the heart, kidney, central nervous system and posterior pituitary.
After it is released from endothelial cells, ET-1 acts on adjacent vascular smooth muscle cells (VSMCs) via both paracrine and autocrine mechanisms to induce potent vasoconstriction and proliferation of VSMCs.
ET-1 has been shown to be a potent growth factor for several cell types including cardiomyocytes, VSMCs, and endothelial cells.

Question 23

The major site of generation of ET-1 is in ……………………. cells, but it is also produced in the heart, kidney, central nervous system and posterior pituitary.
After it is released from endothelial cells, ET-1 acts on adjacent ……………………… via both paracrine and autocrine mechanisms to induce potent …………….. and ………………. of VSMCs.

Answer 23

The major site of generation of ET-1 is in endothelial cells, but it is also produced in the heart, kidney, central nervous system and posterior pituitary.
After it is released from endothelial cells, ET-1 acts on adjacent vascular smooth muscle cells (VSMCs) via both paracrine and autocrine mechanisms to induce potent vasoconstriction and proliferation of VSMCs.

Question 24

ET-1 has been shown to be a potent growth factor for several cell types including ………………………..(3)

Answer 24

ET-1 has been shown to be a potent growth factor for several cell types including cardiomyocytes, VSMCs, and endothelial cells.

Question 25

Endothelins function via their receptors, endothelin-receptor subtype A (ETA) and endothelin-receptor subtype B (ETB), which are members of a superfamily of guanidine-nucleotide-binding proteins (G proteins). Cardiac myocytes and VSMCs mainly express ETA receptors mediating cardiac ...................., ......................, and VSMC .................... Endothelin-receptor subtype B is expressed predominantly on endothelial cells mediating vasodilatation and proliferation with a lesser expression of the receptor on VSMCs.

Answer 25

Endothelins function via their receptors, endothelin-receptor subtype A (ETA) and endothelin-receptor subtype B (ETB), which are members of a superfamily of guanidine-nucleotide-binding proteins (G proteins). Cardiac myocytes and VSMCs mainly express ETA receptors mediating cardiac hypertrophy, vasoconstriction, and VSMC proliferation. Endothelin-receptor subtype B is expressed predominantly on endothelial cells mediating vasodilatation and proliferation with a lesser expression of the receptor on VSMCs. Given its potency, it could be expected that circulating endothelin concentration is maintained at a low physiologic concentration through removal within 2 to 7 minutes by the pulmonary and vascular beds through receptor binding and internalization[94] and by degradation by neutral endopeptidase

Question 26

Endothelins in Disease .............., a major factor in the pathogenesis of thrombosis, is a relatively potent inducer of ET-1 expression.[104] Both in vitro and vivo, ET-1 causes ................... in microcirculation of rats and endothelial expression of von Willebrand factor in animals models. Von Willebrand factor is a ........... recognized as leading to attachment of ..............., which contributes to thrombus formation. An increased ET-1 expression has been found in lung tissues from patients with primary pulmonary .............., a condition in which pulmonary vascular thrombosis is a common feature. Furthermore, abnormalities of ET metabolism mainly related to its defective pulmonary clearance and/or increased pulmonary production are detected in human patients with acute pulmonary thromboembolism. Endothelin levels in cats with systemic thromboembolism have not been evaluated.

Answer 26

Endothelins in Disease Thrombin, a major factor in the pathogenesis of thrombosis, is a relatively potent inducer of ET-1 expression.[104] Both in vitro and vivo, ET-1 causes coagulation in microcirculation of rats[105] and endothelial expression of von Willebrand factor in animals models.[105] Von Willebrand factor is a protein recognized as leading to attachment of platelets, which contributes to thrombus formation.[105] An increased ET-1 expression has been found in lung tissues from patients with primary pulmonary hypertension,[106] a condition in which pulmonary vascular thrombosis is a common feature.[107] Furthermore, abnormalities of ET metabolism mainly related to its defective pulmonary clearance and/or increased pulmonary production are detected in human patients with acute pulmonary thromboembolism.[108] Endothelin levels in cats with systemic thromboembolism have not been evaluated.

Question 27

In CHF, as myocardial performance deteriorates, systemic neurohumoral reflexes function to maintain cardiac output, organ perfusion, and circulatory homeostasis with the activation of the renin-angiotensin-aldosterone axis, vasopressin, and the sympathetic nervous system. However, these adaptive responses have the unfortunate effect of augmenting peripheral vascular tone and increasing afterload in the failing heart. These neurohumoral factors also enhance the production of the potent ............. ET-1, which can be both beneficial and harmful, adding to the quagmire of CHF. ET-1 enhances .............in the failing heart, and up-regulation of endothelin pathways may be beneficial in providing short-term ................ support for the failing myocardium in which beta-adrenergic responsiveness is frequently attenuated.

Answer 27

In CHF, as myocardial performance deteriorates, systemic neurohumoral reflexes function to maintain cardiac output, organ perfusion, and circulatory homeostasis with the activation of the renin-angiotensin-aldosterone axis, vasopressin, and the sympathetic nervous system. However, these adaptive responses have the unfortunate effect of augmenting peripheral vascular tone and increasing afterload in the failing heart. These neurohumoral factors also enhance the production of the potent vasoconstrictor ET-1, which can be both beneficial and harmful, adding to the quagmire of CHF. ET-1 enhances contractility in the failing heart, and up-regulation of endothelin pathways may be beneficial in providing short-term inotropic support for the failing myocardium in which beta-adrenergic responsiveness is frequently attenuated.

Question 28

However, in the long term, it is unclear whether up-regulation of the myocardial endothelin system in CHF is beneficial or harmful. Prolonged stimulation by an up-regulated endothelin system may have maladaptive effects on myocardial function and can contribute to the induction of fatal ventricular ............. In fact, the up-regulated myocardial endothelin system may aggravate the progression of CHF because long-term treatment with an endothelin receptor antagonist improves the survival rate with CHF. Plasma ET-1 levels are elevated in humans with CHF and appear to predict mortality.[114] Elevations of plasma ET-1 concentrations in experimental canine models of CHF[115],[116] are reported, as are elevations in naturally occurring CHF in dogs[117] and cats.[118] In dogs with experimentally induced heart failure, treatment with ET-receptor antagonists appears to improve long-term survival[111] and hemodynamic performance. The cellular effects of ET, including cell ..............., ................. of cardiac myocytes,................of vascular smooth muscle, and the activation of cardiac ..................., are associated with pathologic remodeling and clinical manifestation of heart failure. Other endothelin effects that may contribute to the pathogenesis of heart failure include effects on sodium excretion of the kidney, the autonomic nervous system, and baroreflex responses.

Answer 28

However, in the long term, it is unclear whether up-regulation of the myocardial endothelin system in CHF is beneficial or harmful. Prolonged stimulation by an up-regulated endothelin system may have maladaptive effects on myocardial function and can contribute to the induction of fatal ventricular arrhythmias.[110] In fact, the up-regulated myocardial endothelin system may aggravate the progression of CHF because long-term treatment with an endothelin receptor antagonist improves the survival rate with CHF.[111] Plasma ET-1 levels are elevated in humans with CHF[112],[113] and appear to predict mortality.[114] Elevations of plasma ET-1 concentrations in experimental canine models of CHF[115],[116] are reported, as are elevations in naturally occurring CHF in dogs[117] and cats.[118] In dogs with experimentally induced heart failure, treatment with ET-receptor antagonists appears to improve long-term survival[111] and hemodynamic performance. The cellular effects of ET, including cell proliferation, hypertrophy of cardiac myocytes, constriction of vascular smooth muscle, and the activation of cardiac fibroblasts, are associated with pathologic remodeling and clinical manifestation of heart failure. Other endothelin effects that may contribute to the pathogenesis of heart failure include effects on sodium excretion of the kidney, the autonomic nervous system, and baroreflex responses.

Question 29

Arginine Vasopressin Arginine vasopressin (AVP), also referred to as antidiuretic hormone, is a ............. that is synthesized in the ............... and stored in the .................... pituitary gland and has .................. and ............... properties. The amino acid sequence is highly conserved in most mammals and is identical in dogs, cats, and humans.

Answer 29

Arginine Vasopressin Arginine vasopressin (AVP), also referred to as antidiuretic hormone, is a nonapeptide that is synthesized in the hypothalamus and stored in the posterior pituitary gland and has vasoconstrictor and antidiuretic properties. The amino acid sequence is highly conserved in most mammals and is identical in dogs, cats, and humans.

Question 30

Release of AVP from the .................. is stimulated by ............. plasma .............. or ................ and can also be induced to release by ...................... or ...................... stimulation. AVP reacts with V....receptors in the heart and vasculature and with V..... receptors in the kidney, stimulating water reabsorption via .................... channels in the ......................... Excessive release of AVP intensifies heart failure associated with dilution ....................., fluid ................, and systemic .................. Plasma levels of AVP are elevated in humans with heart failure and appear associated with a poor clinical outcome. A combined V1/V2 blocker has shown efficacy in dogs with experimentally induced heart failure and in humans with severe CHF.

Answer 30

Release of AVP from the neurohypophysis is stimulated by increased plasma osmolality or hypovolemia and can also be induced to release by angiotensin II or sympathetic stimulation. AVP reacts with V1 receptors in the heart and vasculature and with V2 receptors in the kidney, stimulating water reabsorption via aquaporin-2 water channels in the collecting ducts. Excessive release of AVP intensifies heart failure associated with dilutional hyponatremia, fluid accumulation, and systemic vasoconstriction. Plasma levels of AVP are elevated in humans with heart failure and appear associated with a poor clinical outcome. A combined V1/V2 blocker has shown efficacy in dogs with experimentally induced heart failure and in humans with severe CHF.

Question 31

MARKERS OF INFLAMMATION Markers of inflammation were one of the first biomarkers studied in coexistence with heart failure more than 50 years ago with C-reactive protein (CRP) leading the pack of inflammatory markers measured. CRP is described as an acute-phase reactant synthesized by ................. in response to the proinflammatory cytokine interleukin-....... Other proinflammatory cytokines that appear to be produced by ............ cells in the heart include ..........., interleukin-...., and interleukin-...... In the cytokine hypothesis of heart failure, proinflammatory cytokines are produced by a damaged myocardium and the production can be enhanced by stimulation of the sympathetic nervous system. The proinflammatory cytokines can cause myocyte .............. and ............ along with activation of ............. leading to more production of the same cytokines, which then act to further impair myocardial function. Once in heart failure, some of the detrimental effects of cytokines include further deterioration of myocardial function, endothelial dysfunction, remodeling, and cachexia. In human patients, increased concentrations of cytokines have been shown to coincide with a worse outcome when in heart failure. Several studies in veterinary patients with naturally occurring heart disease and heart failure have assessed markers of inflammation, in some circumstances revealing significant changes in these patients. Fas, a member of the TNF-...... receptor family, is expressed on a variety of cells, including myocytes. The activation of Fas by the Fas ligand mediates .............. and appears to play an important role in the progression of heart failure. Inhibition of soluble Fas in mice reduces postinfarction ventricular remodeling and improves survival. A novel and exciting treatment option of using a nonspecific immunomodulating agent (intravenous immunoglobulins or pentoxifylline) reduces plasma levels of Fas, as well as CRP, and is reported to improve left ventricular function in patients with dilated or ischemic cardiomyopathy. There is growing evidence of inflammatory stimulation in our veterinary patients with heart disease. It may, as in human patients, represent a possible prognostic marker and a therapeutic target, which could prove to be a viable option in our treatment protocols.

Answer 31

Markers of inflammation were one of the first biomarkers studied in coexistence with heart failure more than 50 years ago with C-reactive protein (CRP) leading the pack of inflammatory markers measured. CRP is described as an acute-phase reactant synthesized by hepatocytes in response to the proinflammatory cytokine interleukin-6. Other proinflammatory cytokines that appear to be produced by nucleated cells in the heart include TNF-α, interleukin-1, and interleukin-18. In the cytokine hypothesis of heart failure, proinflammatory cytokines are produced by a damaged myocardium and the production can be enhanced by stimulation of the sympathetic nervous system. The proinflammatory cytokines can cause myocyte apoptosis and necrosis along with activation of monocytes leading to more production of the same cytokines, which then act to further impair myocardial function. Once in heart failure, some of the detrimental effects of cytokines include further deterioration of myocardial function, endothelial dysfunction, remodeling, and cachexia. In human patients, increased concentrations of cytokines have been shown to coincide with a worse outcome when in heart failure. Several studies in veterinary patients with naturally occurring heart disease and heart failure have assessed markers of inflammation, in some circumstances revealing significant changes in these patients. Fas, a member of the TNF-α receptor family, is expressed on a variety of cells, including myocytes. The activation of Fas by the Fas ligand mediates apoptosis and appears to play an important role in the progression of heart failure. Inhibition of soluble Fas in mice reduces postinfarction ventricular remodeling and improves survival. A novel and exciting treatment option of using a nonspecific immunomodulating agent (intravenous immunoglobulins or pentoxifylline) reduces plasma levels of Fas, as well as CRP, and is reported to improve left ventricular function in patients with dilated or ischemic cardiomyopathy. There is growing evidence of inflammatory stimulation in our veterinary patients with heart disease. It may, as in human patients, represent a possible prognostic marker and a therapeutic target, which could prove to be a viable option in our treatment protocols.

Question 32

Troponin C

Answer 32

The Ca binding element. Complete homology exist with the skeletal isoform

Question 33

Troponin I

Answer 33

Tropomyosin inhibitory element Prevents interaction between actin and myosin until intracellular calcium is bound by cardiac troponin C. CTnI is normally bound tp the actin filament via cardiac troponin T, but in response to sarcomeric injury, it detaches and is released into the cytosol and extracellular space

Question 34

Troponin T

Answer 34

The troponin binding element Binds the troponin-tropmyosin complex to the actin filament

Question 35

Other myocardial proteins?

Answer 35

Creatine kinase MB fraction Myosin light chain-1