SELF-ASSESSMENT
Netherlands Institute for Continuing
Cardiovascular Education
(CVOI)
self-assessment
In collaboration with Mediselect and supported by the company Novartis, the textbook Heart Failure, edited by Dirk Jan van Veldhuisen and Adriaan Voors, was published in Autumn 2003.
This textbook was primarily intended for the cardiology training course (OCC) in 2003. In like manner, the CVOI intends to publish textbooks on Atherosclerosis and Thrombosis in 2004 and Electrocardiography and Electrophysiology in 2005.
Following publication of the book, brieffocused reviews of its chapters will be published in consecutive issues ofthe Netherlands Heart Journal. After each of these articles, there will be two multiple-choice questions, which can be answered in the section Questions & Answers ofthe website of the CVOI, www.cvoi.org. Correct answers will be honoured with 1 credit, while wrong answers to one or both questions will connect the participant to a section that presents and discusses the correct answers, after which the procedure can be repeated. Correct answers to both questions will automatically lead to registration of the CME credits in the Cardiologist Registration Accreditation System (CRAS) on the CVOI website. All textbooks contain eight chapters; participants can therefore obtain 16 credit points. This experiment that connects CME articles to web-based self-assessment programmes and accreditation may pave the way for similar future developments and a reliable verifiable accreditation of CME articles.
Heart failure: chapter 3 Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart' R.L. Braam, C.A.J.M. Gaillard
Heart failure is not a disease confined to the heart. When cardiac function is inadequate the main purpose of the circulation, i.e. providing adequate tissue oxygenation, delivery of enough nutrients and removal of waste products, fails. This will lead to the activation of a great number of (neuro)humoral regulatory mechanisms, some of which will act beneficially, but others will have more detrimental effects. Many ofthese regulatory mechanisms serve as a target in the treatment of heart failure. The purpose of this paper is to provide the reader with an overview of the different regulatory mechanisms of importance in the progression and treatment of heart failure. The role of hypertension will also be addressed, along with diabetes mellitus and anaemia. Under normal circumstances the kidneys receive a large part of the cardiac output. When cardiac output Correspondence to: C.A.J.M. Gaillard E-mail: [email protected]
Netherlands Heart Joumal, Volume 12, Number 6, June 2004
falls a number ofrenal compensatory mechanisms are activated As a consequence the kidneys are very susceptible to decreases in cardiac output and renal insufficiency is frequently observed during treatment of patients with heart failure. Hence renal aspects in heart failure will also be addressed. Failure of the heart versus failure of the cirulation In heart failure common symptoms are shortness of breath, decreased ability to perform exercise and fatigue. The severity of these symptoms does not correlate well with the severity of left ventricular dysfunction ofpatients in rest. It appears that changes in the peripheral circulation in heart failure patients are also of importance. During exercise the blood flow to the peripheral circulation seems unable to increase adequately at a certain point when maximal cardiac reserve has not yet been reached. This is probably caused by a decrease in the number and quality of available peripheral blood vessels (due to rarefaction 303
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
and remodelling), disturbances in the NO vasodilatory system and/or increased activity of vasoconstrictive factors in these patients. Also structural changes in skeletal muscles (metabolism and function) occur. Hypertension and diabetes mellitus In heart failure Hypertension plays a pivotal role in the development of heart failure, not only because of the associated increase in afterload and accelerated coronary atherosclerosis, but also because of the development of left ventricular hypertrophy, with accompanying diastolic dysfunction. Indeed, adequate treatment of hypertension has been shown to decrease the incidence of heart failure. Also, diabetes mellitus increases the risk of heart failure independently ofthe associated coronary atherosclerosis. Achieving an optimal glycaemic control along with aggressive blood pressure lowering are the two most important aspects in treating diabetic patients. Anaemia and heart failure Anaemia causes an increase in cardiac output.2 When anaemia is extreme, heart failure may ensue due to high-output failure, even in the absence of underlying heart disease.2 Anaemia will reduce oxygen transport capacity; however, peripheral vasodilatation and improved rheological flow properties (decreased blood viscosity) cause cardiac output to increase and act as compensatory mechanisms to increase oxygen delivery.2 One third to half of all congestive heart failure patients appear to be anaemic.3 The severity of congestive heart failure appears to be correlated to the severity of anaemia.3 Anaemia is an independent risk factor for mortality in heart failure patients.3 Anaemia itself can have many different causes. One of the possible mechanisms in heart failure patients is reduced production of erythropoietin in the kidneys. This is particularly interesting because some degree of renal insufficiency is frequently seen in heart failure patients. Erythropoietin is a hormone mainly synthesised by peritubular cells in the cortex-medullary border ofthe kidney and in the liver, mainly during foetal life.4 The production of erythropoietin appears to be regulated by the tissue oxygen tension at the site ofthe erythropoietin oxygen sensor in the kidney.5 Erythropoietin influences the growth of erythroid progenitor cells in the bone marrow. However, many other properties have been ascribed to erythropoietin. Erythropoietin could enhance platelet activation, induce angiogenesis and stimulate the production ofendothelin. It has also been shown to have vasoconstrictor effects on isolated renal and mesenteric resistance vessels.4 In heart failure patients the administration of subcutaneous erythropoietin together with intravenous iron has been shown to improve cardiac function and reduce the need for hospitalisation.6'7 Exercise capacity in patients with moderate to severe chronic heart failure has also been shown to increase after treatment with erythropoietin.8
304
Table 1. Activated (neuro)humoral mechanisms in heart failure.
Sympathetic nervous system Renin-angiotensin system Endothelin system Natriuretic-peptide system Arginine-vasopressin Cytokines
However, hypertension develops in 20 to 30% of patients on chronic intermittent haemodialysis who are treated with erythropoietin.4 Correction of the haematocrit values to normal levels in patients with end-stage renal failure and heart failure has been shown to be associated with more cardiovascular events.9 Further research to predict which patients benefit most of treatment with erythropoietin has to be awaited. Vasoactive mechanisms in the systemic circulation The primary goal of the circulation is to maintain adequate tissue perfusion. In order to do so the heart has to generate a minimal perfusion pressure. Many organs, such as the kidneys and brain, are capable of autoregulation: in a certain range ofpressures perfusion is independent ofblood pressure. However the failing heart may not be able to maintain the minimal pressure needed. The consequence is that a number of regulatory mechanisms are activated that try to help maintain the minimum perfusion pressure (table 1). These different systems will now be addressed. Role of the sympathetic nervous system in heart failure In heart failure the sympathetic nervous system is activated, while the parasympathetic is suppressed. This
leads to secretion of norepinephrine, which stimulates myocardial contractility, and enhances sodium retention and vasoconstriction. The normal suppression ofthe sympathetic system under the influence ofarterial and cardiopulmonary receptors is decreased in heart failure. The plasma level of norepinephrine correlates well with the severity of left ventricular dysfunction and mortality. In the ventricles of patients with heart failure the density of beta-adrenergic receptors is decreased. This is probably due to the increased concentration of norepinephrine, leading to downregulation of the betal receptor. The detrimental effects of sympathetic activation can be reversed using beta-blockers. Treatment of patients with beta-blockers was initially perceived as contraintuitive. Activation of the sympathetic system was seen as a compensating mechanism helping the heart to maintain adequate cardiac output. However chronic beta-blockade has been shown to improve
Netherlands Heart Journal, Volume 12, Number 6, June 2004
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
cardiac function and decrease mortality in heart failure patients. Role of the renin-anglotensin system The renin-angiotensin system (RAS) is one ofthe most potent regulatory mechanisms. After the discovery of renin by Tigerstedt and Bergmann, its components were gradually unravelled. An overview of the system can be found in figure 1. Renin activity and the plasma level of angiotensin II are frequently elevated in heart failure. Angiotensin II is a potent vasoconstrictor of the renal and systemic circulation. In the kidney the efferent rather than the afferent arteriole is constricted. It stimulates norepinephrine secretion at the sympathetic nerve endings and the secretion of aldosterone. Inhibition ofthe RAS with an ACE inhibitor lowers the systemic vessel resistance, the afterload and increases the cardiac output. However, all components ofthe RAS can be found in many different tissues: the vessel wall, heart and kidneys. Inhibition of the local RAS is probably as important as inhibition ofthe RAS active in the circulation. The target receptor for angiotensin II in the vessel wall is the AT1 receptor. An abundant number ofAT1 receptors have also been found in the kidneys, heart, on smooth muscle cells, in the brain, adrenal glands, on platelets, fat tissue cells and the placenta. AT2 receptors appear to be important in foetal development. Most undesirable effects of angiotensin II are mediated by the AT, receptor. This receptor is blocked by angiotensin-receptor antagonists. Aldosterone is mainly produced by the adrenal cortex. However, smooth muscle cells of the vessel wall and heart can produce aldosterone. Its physiological role is to prevent loss ofwater and salt in times ofsalt deficiency. Angiotensin II stimulates aldosterone production. Aldosterone acts on receptors on the cellular membrane and on nuclear receptors. In heart failure aldosterone seems to play a role in the development of myocardial and vascular fibrosis.
Endothelin Endothelin (ET), discovered in 1988, is a potent vasoconstrictor secreted by endothelial cells. Four endothelin peptides have been identified. Many factors influence the secretion of endothelin-1: 'shear-stress', 'pulsatile stretch', epinephrine, angiotensin II, thrombin, cytokines and hypoxia. A neutral endopeptidase metabolises endothelin-1. At least two subtypes of endothelin receptors exist (type A and B). Endothelin causes vasoconstriction through activation of ET-A and ET-B receptors. However, endothelial ET-B receptors cause NO-mediated vasodilation. In heart failure endothelin-1 levels are elevated, contributing to vasoconstriction and fluid retention. Antagonists of endothelin receptors have caused blood pressure lowering and increased survival in animal experiments. Nctherlands Heart Journal, Volume 12, Number 6, June 2004
Afflrnt artridee
ulomendus
vasodilatation
i
Prostaglandins,
Dita tubule thaieduetics triamterene spironolactone
Proximal tubub A
I
-- --niotensin II-- J
CofctDng duct ADH
Figure 1.
The renin-angiotensin system.
However, recent trials (REACH-I and HEAT) showed worsening of some aspects ofheart failure in some the patients.
Endothellal dysfunction Endothelial function can be measured in a number of ways. It can be done invasively by infusion of vasoactive substances either into the heart (intracoronary) or into the brachial artery and using forearm plethysmography. Echography ofthe brachial artery can be used as a noninvasive method to measure flow-mediated dilatation following a period of ischaemia. Moreover, several markers, such as plasma Von Wlllebrand factor, plasmat-PA and PAI-1, can be used as a measure of endothelial function. In heart failure, endothelial function is disturbed. It has been shown that sympathetic activation can induce endothelial dysfunction. Unclear is to what extent endothelial function in heart failure is disturbed through sympathetic activation and to what extent the underlying cause (atherosclerosis etc.) is responsible. Natriuretic peptides Three natriuretic peptides can be discerned: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP) and C-natriuretic peptide (CNP). ANP is stored in the atria and is released following atrial stretch. ANP causes vasodilation and natriuresis. BNP is mainly found in the ventricles. BNP has properties comparable with those of ANP. CNP is found in the vessel wall. There are at least three receptors (A, B and C) for the natriuretic peptides. The A and B receptors mediate the vasodilatory and natriuretic properties of the natriuretic peptides. The C receptor appears to be concerned with the clearance ofthe natriuretic peptides together with neutral endopeptidase. 305
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
ANP and BNP are both elevated in heart failure. Infusion of nesiritide (a natriuretic peptide) has been shown to cause haemodynamic improvement in patients with heart failure. The same has been shown for omapatrilat, a inhibitor of neutral endopeptidase. Inflammatory cytokines Levine et al. were the first to show that the level of tumour necrosis factor-alpha (TNFax) was elevated in patients with end-stage heart failure. TNFa is a proinflammatory cytokine produced by a great number of cells, such as macrophages, lymphocytes, neutrophils, fibroblasts and smooth muscle cells. Chronic infusion of TNFa in rats leads to the development of a dilated cardiomyopathy. After stopping the infusion left ventricular function gradually improved. In a mice model administration of an adenoviral vector coding for a TNF-binding protein protected against the development of extracellular matrix remodelling. However anticytokine therapy in humans has so far been disappointing. Two trials (RENAISSANCE and RECOVER) were prematurely stopped because oflack of effect. Renal dysfunction and heart failure The kidneys play a pivotal role in the regulation of intravascular volume and total body water. To do so, they are capable of producing either diluted or concentrated urine. Moreover, because of autoregulation, the kidneys can operate largely independently ofblood pressure. However, in heart failure the kidneys retain water and salt (through activation of different mechanisms such as the RAS), despite an increased blood volume. In the early phase of heart failure the sodium balance is in equilibrium due to, among other things, activity of natriuretic peptides. In later stages of heart failure, however, progressive sodium and water retention occur, leading to increase in preload. Diuretics
All diuretics except spironolactone function as blockers of transporter proteins in tubular cells. The water excretion is increased secondary to the inhibition of sodium reabsorption. Each diuretic has its own site of action (figure 2). Loop diuretics as furosemide and bumetanide block the Na-K-2Cl cotransporter in the thick ascending loop ofHenle. Loop diuretics are quite effective diuretics. The reason for this is that the thick ascending loop is responsible for a large part ofsodium reabsorption and inhibition of sodium reabsorption at this site will prevent the formation of a high oncotic pressure in the renal medulla, leading to less water reabsorption in the collecting ducts under the influence of antidiuretic hormone (ADH). Loop diuretics are therefore called 'high-ceiling' diuretics. Thiazides block the Na-Cl cotransporter in the distal tubule. Because of their more distal blockade, 306
Angiotensinogen
I
ii Renin
Bradykinin Substance P Encephalin
Angiotensin I
J|
Non ACE Ch}mase CAGE
ACE
_
Angiotensin 11
campson u7
fragments
Angiotg 7nnr Aldosterone secretion
GM-I fIactive
ptor
SS vympathetic
Vasoconstriction
activation
Blood pressure
regulation
and other effects
Figure 2. Sites ofaction ofthe diffrrent diuretics on the nephron and regulation ofglomerular haemodynamics by angiotensin II.
these diuretics are less effective. They are called 'lowceiling' diuretics. Spironolactone is a steroid blocking the effects of aldosterone. Triamterene and amiloride block a sodium channel located in the collecting duct. Combining diuretics with different sites of action causes an increase in the diuretic effect: the sequential nephron blockade. In patients with heart failure addition of a thiazide diuretic can be helpful when a loop diuretic, given in an adequate dose, has insufficient effect. However, in this case tubular regulation is largely blocked, which can cause severe electrolyte disturbances and renal failure. While diuretics increase sodium excretion, ADH is involved in water handling. Under normal circumstances ADH secretion is directly dependent on plasma osmolality. However, in case of decreased (effective) circulating volume, ADH secretion is also stimulated. This causes decreased renal water excretion in heart failure patients, leading to hyponatraemia. New compounds, the so-called 'aquaretics', that stimulate water excretion are being developed. Arginine vasopressin Arginine vasopressin, ADH, is a nonpeptide secreted by the posterior lobe of the pituitary gland. Secretion of arginine vasopressin is increased when plasma osmolality increases and in case of hypovolaemia or hypotension. There are three known receptors of vasopressin: Vla receptors are located on vascular smooth muscle cells and cause vasoconstriction; Vlb receptors are found in the anterior lobe ofthe pituitary gland and stimulate ACTH secretion and V2 receptors are located in the distal tubules and collecting ducts of the kidney. Activation of this receptor causes translocation of so-called aquaporines from their intracellular location to the apical membrane. Hence water permeability of the collecting duct increases. Ncthcriands Heart Journa, Volume 12, Number 6, June 2004
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
In heart failure vasopressin is elevated. V2-receptor antagonists are currently being developed, such as tolvaptan, causing a watery diureses. Side effects of frequently used therapies In heart failure hyponatraemia is frequently encountered. This condition can occur when the excretion ofwater is impaired. Even when the secretion of sodium is disturbed, dilutional hyponatraemia can occur when water excretion is affected to a larger extent than sodium excretion. Because diuretics (saliuretics) cause sodium loss and may reverse the disturbed sodium excretion and not the disturbed water excretion, diuretics may increase hyponatraemia unless water restriction is instituted. Hyperkalaemia is frequently found, caused by drugs such as ACE inhibitors and spironolactone and/or accompanying renal insufficiency. Treatment consists of stopping potassium suppletion and lowering the dose of potassium-sparing diuretics and/or ACE inhibitors. In the kidney prostaglandins play an important role in the regulation ofsodium excretion. Prostaglandins cause vasodilation ofthe afferent arteriole. Nonsteroidal anti-inflammatory drugs (NSAIDs) (by decreasing prostaglandin synthesis), can also cause a decrease in glomerular filtration rate and disturbed sodium and water excretion. This can lead to worsening ofrenal insufficiency. NSAIDs should, therefore, be avoided in patients already being treated with diuretics and ACE inhibitors.
Conclusions In heart failure a great number of regulatory mechanisms are activated. In the early phase these mechanisms have a beneficial effect; however in the long run activation ofthe sympathetic system, the RAS and the endothelin system are unfavourable. In large randomised, placebo-controlled trials a number of drugs have been shown to decrease mortality and morbidity in patients with heart failure (such as ACE inhibitors, j-blockers and spironolactone). These drugs block the action of different systems. However, a great number of drugs acting on other systems are currently under investigation (such as endothelin-receptor antagonists, natriuretic peptides, and vasopressin antagonists). i References 1
2
3 4
Braam RL, Rabelink AJ, Gaillard CAJM. Onderliggende pathologie bij hartfalen, 'failure of the circulation versus failure of the heart'. In: Leerboek Hartfalen. Leusden: Mediselect bv, 2003. Leschke M, Schoebel F, Strauer BE. Anemia and the Heart. In: Bauer C, Kock KM, Scigalla P, Wieczorek L, editors. Erythropoietin, molecular physiology and clinical applications. New York: Marcel Dekker Inc., 1993. Silverberg DS, Wexler D, Blum M, Schwartz D, WoUlman Y, Iaina A. Erythropoietin should be part of congestive heart failure management. Kidney International2003;64:(Suppl. 87):S40-7. Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003;59:538-48.
Netherlands Heart Joumal, Volume 12, Number 6, June 2004
5
6
7
8
9
Goldberg MA. Biology of erythropoietin. In: Garnick MB, editor. Erythropoietin in clinical applications, an international perspective. New York: Marcel Dekker Inc., 1990. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for treatment of the anemia of severe resistant congestive heart failure improves cardiac and renal function, functional cardiac class, and markedly reduces hospitalizations. JAm Coll Cardiol 2000;35:1737-44. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. JAm Coll Cardiol 2001;37:1775-80. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 2003;107:294-9. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. NEnglJMed 1998;339:584-90.
Question 1 What is the expected absolute increase in ejection fraction when a heart failure patient is treated for eight months with a P,-selective receptor blocker such as metoprolol XR or with carvedilol. a. 4% with metoprolol XL, 8% with carvedilol. b. 14% with metoprolol XL, 18% with carvedilol. c. 24% with metoprolol XL, 28% with carvedilol.
Question 2 A 55-year-old-man is complaining of dyspnoea on exertion. He suffered a major anterior myocardial infarction three months earlier. Echocardiography currently reveals an ejection fraction of 35%. His medication consists of acetylsalicylic acid, clopidogrel, fosinopril 10 mg once daily, spirinolactone 25 mg once daily and furosemide 40 mg once daily. Patient is in sinus rhythm. The blood pressure is 150/90 mmHg, heart rate 60 beats/min. Laboratory investigation reveals a haemoglobulin level of 7.5 mmol/l. What would your first next step be in treating this patient? a. Increasing the dose of furosemide to 80 mg two times a day. b. Increasing the dose of fosinopril to 20 mg once
daily. c. Increasing the dose of spironolactone to 50 mg once daily. d. Adding a n-receptor blocking agent to the treatment. e. Adding digoxin to the treatment. f Consulting an internist to start treatment with
erythropoietin. The articles of this series can also be found on the websites cardiologie.nl (www.cardiologie.nl, section 'Elektronische nascholing') and www.cvoi.org. You will find the questions and answers on the Q&A section of the CVOI website.
307
Netherlands Institute for Continuing
Cardiovascular Education
(CVOI)
self-assessment
In collaboration with Mediselect and supported by the company Novartis, the textbook Heart Failure, edited by Dirk Jan van Veldhuisen and Adriaan Voors, was published in Autumn 2003.
This textbook was primarily intended for the cardiology training course (OCC) in 2003. In like manner, the CVOI intends to publish textbooks on Atherosclerosis and Thrombosis in 2004 and Electrocardiography and Electrophysiology in 2005.
Following publication of the book, brieffocused reviews of its chapters will be published in consecutive issues ofthe Netherlands Heart Journal. After each of these articles, there will be two multiple-choice questions, which can be answered in the section Questions & Answers ofthe website of the CVOI, www.cvoi.org. Correct answers will be honoured with 1 credit, while wrong answers to one or both questions will connect the participant to a section that presents and discusses the correct answers, after which the procedure can be repeated. Correct answers to both questions will automatically lead to registration of the CME credits in the Cardiologist Registration Accreditation System (CRAS) on the CVOI website. All textbooks contain eight chapters; participants can therefore obtain 16 credit points. This experiment that connects CME articles to web-based self-assessment programmes and accreditation may pave the way for similar future developments and a reliable verifiable accreditation of CME articles.
Heart failure: chapter 3 Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart' R.L. Braam, C.A.J.M. Gaillard
Heart failure is not a disease confined to the heart. When cardiac function is inadequate the main purpose of the circulation, i.e. providing adequate tissue oxygenation, delivery of enough nutrients and removal of waste products, fails. This will lead to the activation of a great number of (neuro)humoral regulatory mechanisms, some of which will act beneficially, but others will have more detrimental effects. Many ofthese regulatory mechanisms serve as a target in the treatment of heart failure. The purpose of this paper is to provide the reader with an overview of the different regulatory mechanisms of importance in the progression and treatment of heart failure. The role of hypertension will also be addressed, along with diabetes mellitus and anaemia. Under normal circumstances the kidneys receive a large part of the cardiac output. When cardiac output Correspondence to: C.A.J.M. Gaillard E-mail: [email protected]
Netherlands Heart Joumal, Volume 12, Number 6, June 2004
falls a number ofrenal compensatory mechanisms are activated As a consequence the kidneys are very susceptible to decreases in cardiac output and renal insufficiency is frequently observed during treatment of patients with heart failure. Hence renal aspects in heart failure will also be addressed. Failure of the heart versus failure of the cirulation In heart failure common symptoms are shortness of breath, decreased ability to perform exercise and fatigue. The severity of these symptoms does not correlate well with the severity of left ventricular dysfunction ofpatients in rest. It appears that changes in the peripheral circulation in heart failure patients are also of importance. During exercise the blood flow to the peripheral circulation seems unable to increase adequately at a certain point when maximal cardiac reserve has not yet been reached. This is probably caused by a decrease in the number and quality of available peripheral blood vessels (due to rarefaction 303
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
and remodelling), disturbances in the NO vasodilatory system and/or increased activity of vasoconstrictive factors in these patients. Also structural changes in skeletal muscles (metabolism and function) occur. Hypertension and diabetes mellitus In heart failure Hypertension plays a pivotal role in the development of heart failure, not only because of the associated increase in afterload and accelerated coronary atherosclerosis, but also because of the development of left ventricular hypertrophy, with accompanying diastolic dysfunction. Indeed, adequate treatment of hypertension has been shown to decrease the incidence of heart failure. Also, diabetes mellitus increases the risk of heart failure independently ofthe associated coronary atherosclerosis. Achieving an optimal glycaemic control along with aggressive blood pressure lowering are the two most important aspects in treating diabetic patients. Anaemia and heart failure Anaemia causes an increase in cardiac output.2 When anaemia is extreme, heart failure may ensue due to high-output failure, even in the absence of underlying heart disease.2 Anaemia will reduce oxygen transport capacity; however, peripheral vasodilatation and improved rheological flow properties (decreased blood viscosity) cause cardiac output to increase and act as compensatory mechanisms to increase oxygen delivery.2 One third to half of all congestive heart failure patients appear to be anaemic.3 The severity of congestive heart failure appears to be correlated to the severity of anaemia.3 Anaemia is an independent risk factor for mortality in heart failure patients.3 Anaemia itself can have many different causes. One of the possible mechanisms in heart failure patients is reduced production of erythropoietin in the kidneys. This is particularly interesting because some degree of renal insufficiency is frequently seen in heart failure patients. Erythropoietin is a hormone mainly synthesised by peritubular cells in the cortex-medullary border ofthe kidney and in the liver, mainly during foetal life.4 The production of erythropoietin appears to be regulated by the tissue oxygen tension at the site ofthe erythropoietin oxygen sensor in the kidney.5 Erythropoietin influences the growth of erythroid progenitor cells in the bone marrow. However, many other properties have been ascribed to erythropoietin. Erythropoietin could enhance platelet activation, induce angiogenesis and stimulate the production ofendothelin. It has also been shown to have vasoconstrictor effects on isolated renal and mesenteric resistance vessels.4 In heart failure patients the administration of subcutaneous erythropoietin together with intravenous iron has been shown to improve cardiac function and reduce the need for hospitalisation.6'7 Exercise capacity in patients with moderate to severe chronic heart failure has also been shown to increase after treatment with erythropoietin.8
304
Table 1. Activated (neuro)humoral mechanisms in heart failure.
Sympathetic nervous system Renin-angiotensin system Endothelin system Natriuretic-peptide system Arginine-vasopressin Cytokines
However, hypertension develops in 20 to 30% of patients on chronic intermittent haemodialysis who are treated with erythropoietin.4 Correction of the haematocrit values to normal levels in patients with end-stage renal failure and heart failure has been shown to be associated with more cardiovascular events.9 Further research to predict which patients benefit most of treatment with erythropoietin has to be awaited. Vasoactive mechanisms in the systemic circulation The primary goal of the circulation is to maintain adequate tissue perfusion. In order to do so the heart has to generate a minimal perfusion pressure. Many organs, such as the kidneys and brain, are capable of autoregulation: in a certain range ofpressures perfusion is independent ofblood pressure. However the failing heart may not be able to maintain the minimal pressure needed. The consequence is that a number of regulatory mechanisms are activated that try to help maintain the minimum perfusion pressure (table 1). These different systems will now be addressed. Role of the sympathetic nervous system in heart failure In heart failure the sympathetic nervous system is activated, while the parasympathetic is suppressed. This
leads to secretion of norepinephrine, which stimulates myocardial contractility, and enhances sodium retention and vasoconstriction. The normal suppression ofthe sympathetic system under the influence ofarterial and cardiopulmonary receptors is decreased in heart failure. The plasma level of norepinephrine correlates well with the severity of left ventricular dysfunction and mortality. In the ventricles of patients with heart failure the density of beta-adrenergic receptors is decreased. This is probably due to the increased concentration of norepinephrine, leading to downregulation of the betal receptor. The detrimental effects of sympathetic activation can be reversed using beta-blockers. Treatment of patients with beta-blockers was initially perceived as contraintuitive. Activation of the sympathetic system was seen as a compensating mechanism helping the heart to maintain adequate cardiac output. However chronic beta-blockade has been shown to improve
Netherlands Heart Journal, Volume 12, Number 6, June 2004
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
cardiac function and decrease mortality in heart failure patients. Role of the renin-anglotensin system The renin-angiotensin system (RAS) is one ofthe most potent regulatory mechanisms. After the discovery of renin by Tigerstedt and Bergmann, its components were gradually unravelled. An overview of the system can be found in figure 1. Renin activity and the plasma level of angiotensin II are frequently elevated in heart failure. Angiotensin II is a potent vasoconstrictor of the renal and systemic circulation. In the kidney the efferent rather than the afferent arteriole is constricted. It stimulates norepinephrine secretion at the sympathetic nerve endings and the secretion of aldosterone. Inhibition ofthe RAS with an ACE inhibitor lowers the systemic vessel resistance, the afterload and increases the cardiac output. However, all components ofthe RAS can be found in many different tissues: the vessel wall, heart and kidneys. Inhibition of the local RAS is probably as important as inhibition ofthe RAS active in the circulation. The target receptor for angiotensin II in the vessel wall is the AT1 receptor. An abundant number ofAT1 receptors have also been found in the kidneys, heart, on smooth muscle cells, in the brain, adrenal glands, on platelets, fat tissue cells and the placenta. AT2 receptors appear to be important in foetal development. Most undesirable effects of angiotensin II are mediated by the AT, receptor. This receptor is blocked by angiotensin-receptor antagonists. Aldosterone is mainly produced by the adrenal cortex. However, smooth muscle cells of the vessel wall and heart can produce aldosterone. Its physiological role is to prevent loss ofwater and salt in times ofsalt deficiency. Angiotensin II stimulates aldosterone production. Aldosterone acts on receptors on the cellular membrane and on nuclear receptors. In heart failure aldosterone seems to play a role in the development of myocardial and vascular fibrosis.
Endothelin Endothelin (ET), discovered in 1988, is a potent vasoconstrictor secreted by endothelial cells. Four endothelin peptides have been identified. Many factors influence the secretion of endothelin-1: 'shear-stress', 'pulsatile stretch', epinephrine, angiotensin II, thrombin, cytokines and hypoxia. A neutral endopeptidase metabolises endothelin-1. At least two subtypes of endothelin receptors exist (type A and B). Endothelin causes vasoconstriction through activation of ET-A and ET-B receptors. However, endothelial ET-B receptors cause NO-mediated vasodilation. In heart failure endothelin-1 levels are elevated, contributing to vasoconstriction and fluid retention. Antagonists of endothelin receptors have caused blood pressure lowering and increased survival in animal experiments. Nctherlands Heart Journal, Volume 12, Number 6, June 2004
Afflrnt artridee
ulomendus
vasodilatation
i
Prostaglandins,
Dita tubule thaieduetics triamterene spironolactone
Proximal tubub A
I
-- --niotensin II-- J
CofctDng duct ADH
Figure 1.
The renin-angiotensin system.
However, recent trials (REACH-I and HEAT) showed worsening of some aspects ofheart failure in some the patients.
Endothellal dysfunction Endothelial function can be measured in a number of ways. It can be done invasively by infusion of vasoactive substances either into the heart (intracoronary) or into the brachial artery and using forearm plethysmography. Echography ofthe brachial artery can be used as a noninvasive method to measure flow-mediated dilatation following a period of ischaemia. Moreover, several markers, such as plasma Von Wlllebrand factor, plasmat-PA and PAI-1, can be used as a measure of endothelial function. In heart failure, endothelial function is disturbed. It has been shown that sympathetic activation can induce endothelial dysfunction. Unclear is to what extent endothelial function in heart failure is disturbed through sympathetic activation and to what extent the underlying cause (atherosclerosis etc.) is responsible. Natriuretic peptides Three natriuretic peptides can be discerned: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP) and C-natriuretic peptide (CNP). ANP is stored in the atria and is released following atrial stretch. ANP causes vasodilation and natriuresis. BNP is mainly found in the ventricles. BNP has properties comparable with those of ANP. CNP is found in the vessel wall. There are at least three receptors (A, B and C) for the natriuretic peptides. The A and B receptors mediate the vasodilatory and natriuretic properties of the natriuretic peptides. The C receptor appears to be concerned with the clearance ofthe natriuretic peptides together with neutral endopeptidase. 305
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
ANP and BNP are both elevated in heart failure. Infusion of nesiritide (a natriuretic peptide) has been shown to cause haemodynamic improvement in patients with heart failure. The same has been shown for omapatrilat, a inhibitor of neutral endopeptidase. Inflammatory cytokines Levine et al. were the first to show that the level of tumour necrosis factor-alpha (TNFax) was elevated in patients with end-stage heart failure. TNFa is a proinflammatory cytokine produced by a great number of cells, such as macrophages, lymphocytes, neutrophils, fibroblasts and smooth muscle cells. Chronic infusion of TNFa in rats leads to the development of a dilated cardiomyopathy. After stopping the infusion left ventricular function gradually improved. In a mice model administration of an adenoviral vector coding for a TNF-binding protein protected against the development of extracellular matrix remodelling. However anticytokine therapy in humans has so far been disappointing. Two trials (RENAISSANCE and RECOVER) were prematurely stopped because oflack of effect. Renal dysfunction and heart failure The kidneys play a pivotal role in the regulation of intravascular volume and total body water. To do so, they are capable of producing either diluted or concentrated urine. Moreover, because of autoregulation, the kidneys can operate largely independently ofblood pressure. However, in heart failure the kidneys retain water and salt (through activation of different mechanisms such as the RAS), despite an increased blood volume. In the early phase of heart failure the sodium balance is in equilibrium due to, among other things, activity of natriuretic peptides. In later stages of heart failure, however, progressive sodium and water retention occur, leading to increase in preload. Diuretics
All diuretics except spironolactone function as blockers of transporter proteins in tubular cells. The water excretion is increased secondary to the inhibition of sodium reabsorption. Each diuretic has its own site of action (figure 2). Loop diuretics as furosemide and bumetanide block the Na-K-2Cl cotransporter in the thick ascending loop ofHenle. Loop diuretics are quite effective diuretics. The reason for this is that the thick ascending loop is responsible for a large part ofsodium reabsorption and inhibition of sodium reabsorption at this site will prevent the formation of a high oncotic pressure in the renal medulla, leading to less water reabsorption in the collecting ducts under the influence of antidiuretic hormone (ADH). Loop diuretics are therefore called 'high-ceiling' diuretics. Thiazides block the Na-Cl cotransporter in the distal tubule. Because of their more distal blockade, 306
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Figure 2. Sites ofaction ofthe diffrrent diuretics on the nephron and regulation ofglomerular haemodynamics by angiotensin II.
these diuretics are less effective. They are called 'lowceiling' diuretics. Spironolactone is a steroid blocking the effects of aldosterone. Triamterene and amiloride block a sodium channel located in the collecting duct. Combining diuretics with different sites of action causes an increase in the diuretic effect: the sequential nephron blockade. In patients with heart failure addition of a thiazide diuretic can be helpful when a loop diuretic, given in an adequate dose, has insufficient effect. However, in this case tubular regulation is largely blocked, which can cause severe electrolyte disturbances and renal failure. While diuretics increase sodium excretion, ADH is involved in water handling. Under normal circumstances ADH secretion is directly dependent on plasma osmolality. However, in case of decreased (effective) circulating volume, ADH secretion is also stimulated. This causes decreased renal water excretion in heart failure patients, leading to hyponatraemia. New compounds, the so-called 'aquaretics', that stimulate water excretion are being developed. Arginine vasopressin Arginine vasopressin, ADH, is a nonpeptide secreted by the posterior lobe of the pituitary gland. Secretion of arginine vasopressin is increased when plasma osmolality increases and in case of hypovolaemia or hypotension. There are three known receptors of vasopressin: Vla receptors are located on vascular smooth muscle cells and cause vasoconstriction; Vlb receptors are found in the anterior lobe ofthe pituitary gland and stimulate ACTH secretion and V2 receptors are located in the distal tubules and collecting ducts of the kidney. Activation of this receptor causes translocation of so-called aquaporines from their intracellular location to the apical membrane. Hence water permeability of the collecting duct increases. Ncthcriands Heart Journa, Volume 12, Number 6, June 2004
Chapter 3: Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'
In heart failure vasopressin is elevated. V2-receptor antagonists are currently being developed, such as tolvaptan, causing a watery diureses. Side effects of frequently used therapies In heart failure hyponatraemia is frequently encountered. This condition can occur when the excretion ofwater is impaired. Even when the secretion of sodium is disturbed, dilutional hyponatraemia can occur when water excretion is affected to a larger extent than sodium excretion. Because diuretics (saliuretics) cause sodium loss and may reverse the disturbed sodium excretion and not the disturbed water excretion, diuretics may increase hyponatraemia unless water restriction is instituted. Hyperkalaemia is frequently found, caused by drugs such as ACE inhibitors and spironolactone and/or accompanying renal insufficiency. Treatment consists of stopping potassium suppletion and lowering the dose of potassium-sparing diuretics and/or ACE inhibitors. In the kidney prostaglandins play an important role in the regulation ofsodium excretion. Prostaglandins cause vasodilation ofthe afferent arteriole. Nonsteroidal anti-inflammatory drugs (NSAIDs) (by decreasing prostaglandin synthesis), can also cause a decrease in glomerular filtration rate and disturbed sodium and water excretion. This can lead to worsening ofrenal insufficiency. NSAIDs should, therefore, be avoided in patients already being treated with diuretics and ACE inhibitors.
Conclusions In heart failure a great number of regulatory mechanisms are activated. In the early phase these mechanisms have a beneficial effect; however in the long run activation ofthe sympathetic system, the RAS and the endothelin system are unfavourable. In large randomised, placebo-controlled trials a number of drugs have been shown to decrease mortality and morbidity in patients with heart failure (such as ACE inhibitors, j-blockers and spironolactone). These drugs block the action of different systems. However, a great number of drugs acting on other systems are currently under investigation (such as endothelin-receptor antagonists, natriuretic peptides, and vasopressin antagonists). i References 1
2
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Braam RL, Rabelink AJ, Gaillard CAJM. Onderliggende pathologie bij hartfalen, 'failure of the circulation versus failure of the heart'. In: Leerboek Hartfalen. Leusden: Mediselect bv, 2003. Leschke M, Schoebel F, Strauer BE. Anemia and the Heart. In: Bauer C, Kock KM, Scigalla P, Wieczorek L, editors. Erythropoietin, molecular physiology and clinical applications. New York: Marcel Dekker Inc., 1993. Silverberg DS, Wexler D, Blum M, Schwartz D, WoUlman Y, Iaina A. Erythropoietin should be part of congestive heart failure management. Kidney International2003;64:(Suppl. 87):S40-7. Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin. Cardiovasc Res 2003;59:538-48.
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Goldberg MA. Biology of erythropoietin. In: Garnick MB, editor. Erythropoietin in clinical applications, an international perspective. New York: Marcel Dekker Inc., 1990. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for treatment of the anemia of severe resistant congestive heart failure improves cardiac and renal function, functional cardiac class, and markedly reduces hospitalizations. JAm Coll Cardiol 2000;35:1737-44. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. JAm Coll Cardiol 2001;37:1775-80. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 2003;107:294-9. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. NEnglJMed 1998;339:584-90.
Question 1 What is the expected absolute increase in ejection fraction when a heart failure patient is treated for eight months with a P,-selective receptor blocker such as metoprolol XR or with carvedilol. a. 4% with metoprolol XL, 8% with carvedilol. b. 14% with metoprolol XL, 18% with carvedilol. c. 24% with metoprolol XL, 28% with carvedilol.
Question 2 A 55-year-old-man is complaining of dyspnoea on exertion. He suffered a major anterior myocardial infarction three months earlier. Echocardiography currently reveals an ejection fraction of 35%. His medication consists of acetylsalicylic acid, clopidogrel, fosinopril 10 mg once daily, spirinolactone 25 mg once daily and furosemide 40 mg once daily. Patient is in sinus rhythm. The blood pressure is 150/90 mmHg, heart rate 60 beats/min. Laboratory investigation reveals a haemoglobulin level of 7.5 mmol/l. What would your first next step be in treating this patient? a. Increasing the dose of furosemide to 80 mg two times a day. b. Increasing the dose of fosinopril to 20 mg once
daily. c. Increasing the dose of spironolactone to 50 mg once daily. d. Adding a n-receptor blocking agent to the treatment. e. Adding digoxin to the treatment. f Consulting an internist to start treatment with
erythropoietin. The articles of this series can also be found on the websites cardiologie.nl (www.cardiologie.nl, section 'Elektronische nascholing') and www.cvoi.org. You will find the questions and answers on the Q&A section of the CVOI website.
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