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Insuficiência cardíaca

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1 Insuficiência cardíaca
MORTALIDADE CARDIOVASCULAR Cadeia de eventos Trombose coronária Enfarte do miocárdio Isquemia miocárdica Perda de músculo Morte súbita Activação neurohumoral D.Coronária Aterosclerose HVE Slide 42. Chain of Events Leading to Cardiovascular Mortality Hypertension, as well as hyperlipidemia, diabetes and smoking, account for the initial risk factors at the very beginning of the chain of events leading to cardiovascular death [Dzau et al, 1991]. Typically, the development of left ventricular (LV) hypertrophy is an early and important finding that may have direct pathophysiological implications on the progression from early hypertension to cardiovascular death [Dzau et al, 1991; Levy et al, 1996]. Through this elegant appraisal by Dzau et al of the factors leading to cardiovascular death, the critical role of LV hypertrophy can be appreciated. More than a risk factor, LV hypertrophy, together with atherosclerosis, marks the very beginning of the process culminating with heart failure and, in some cases, death. Indeed, LV hypertrophy is a stronger prognostic indicator of cardiovascular disease than BP, smoking or cholesterol, imparting a two- to four-fold increase in the risk of cardiovascular events [Kanel et al, 1972; Levy et al, 1996; Ghali et al, 1992; Koren et al, 1991]. Following the development of LV hypertrophy or atherosclerosis, patients typically progress to coronary artery disease, marked by thrombosis and ischemia and generally culminating in MI. It is at this step that the role of sympathetic activation takes on importance, leading to the myocardial remodeling that appears to be key to the subsequent development of heart failure. Consequently, the importance to cardiovascular mortality of LV hypertrophy, atherosclerosis, MI, and heart failure cannot be overemphasized. Therapeutic strategies that prevent, or reverse, the presence of these factors can break major links in the chain of events leading to cardiovascular morbidity and mortality. Remodelagem Dilatação ventricular Factores de risco: • Hipertensão Arterial • Hiperlipidemia • Diabetes • Obesidade • Tabagismo Insuficiência cardíaca Morte Adaptado de Dzau V e col., 1991





6 DEFINITION “The situation when the heart is
incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." Definition of Heart Failure. There is no single definition of heart failure. Classically, heart failure is understood as the situation when the heart is incapable of maintaining a cardiac output adequate to accommodate the body’s metabolic requirements and the venous return. This concept is ambiguous and incomplete, however, because heart failure is a composite of clinical symptoms, physical signs, and abnormalities on the hemodynamic, neurohormonal, biochemical, anatomic and cellular levels. In addition, the actual cardiac output, venous return or absolute metabolic requirements are not usually measured in clinical practice. Heart failure is a syndrome characterized by symptoms and physical signs which are secondary to a change in function of the ventricles, valves or load conditions. Braunwald E.: Heart Diseases. W.B. Saunders Co E. Braunwald

7 New York Heart Association Functional Classification
Class I: No symptoms with ordinary activity Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest After completing a thorough history and physical exam, physicians will commonly use the New York Heart Association (NYHA) functional classification to help describe the degree of physical disability a patient has. The NYHA class is also commonly used to determine entry criteria for patients participating in clinical research trials.

8 Severity of Heart Failure Modes of Death
NYHA II NYHA III CHF CHF 12% Other 26% Other 24% Sudden 59% Death Sudden 64% 15% Death n = 103 Interestingly, most patients who suffer from sudden cardiac death (64%) are the patients who are minimally symptomatic with Class II heart failure. The sickest, most symptomatic patient (Class IV) experience heart failure deaths (56%) from pump failure, rather than sudden cardiac death (33%). It is important to remember that although it can be said that a heart failure patient in NYHA Class II may have a higher risk of SCD, their relative annual risk of dying is less than the other NYHA classes. The SCD-HeFT Trial (Sudden Cardiac Death in Heart Failure Trial) which enrolled NYHA Class II and III patients, hopes to answer whether patients in these classes are truly at a higher risk for SCD and need protection. n = 103 NYHA IV CHF 33% Other 56% Sudden Death 11% n = 27 MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET ;353:

9 Etiology of Heart Failure
What causes heart failure? The loss of a critical quantity of functioning myocardial cells after injury to the heart due to: Ischemic Heart Disease Hypertension Idiopathic Cardiomyopathy Infections (e.g., viral myocarditis, Chagas’ disease) Toxins (e.g., alcohol or cytotoxic drugs) Valvular Disease Prolonged Arrhythmias Listed above is the etiology of heart failure in order from most to least common causes.

10 Left Ventricular Dysfunction
Systolic: Impaired contractility/ejection Approximately two-thirds of heart failure patients have systolic dysfunction1 Diastolic: Impaired filling/relaxation As previously seen, there are many causes of heart failure. Some diseases, however, tend to more adversely affect the heart’s systolic function (ventricular contraction/ejection), while others tend to more adversely affect diastolic function (ventricular filling/relaxation). This provides a useful way of classifying heart failure from a hemodynamic standpoint. Most patients who have systolic dysfunction also have a component of diastolic dysfunction. 30% (EF > 40 %) (EF < 40%) 70% Diastolic Dysfunction Systolic Dysfunction 1 Lilly, L. Pathophysiology of Heart Disease. Second Edition p 200

CONTRACTILITY PRELOAD AFTERLOAD Pathophysiology of Congestive Heart Failure. Determinants of ventricular function. Ventricular function, and cardiac function in general, depends upon the interaction of four factors that regulate the volume of blood expelled by the heart (the cardiac output): contractility, preload, afterload, and heart rate. The first three determine the volume of blood expelled with each beat (the stroke or ejection volume), while the heart rate affects the cardiac output by varying the number of contractions per unit time. These four factors, which are intrinsic regulators of heart function, are all influenced by the nervous system. In the failing heart, especially in ischemic heart disease, it is also important to consider some purely mechanical factors, such as the synergy of ventricular contraction, the integrity of the septum, and the competence of the atrioventricular valves. STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence HEART RATE CARDIAC OUTPUT

12 Hemodynamic Basis for Heart Failure Symptoms
Animated slide (works in slide show): In this schematic, notice when the LVEDP rises due to an increase in LV end diastolic volume (mouse click to add arrow), and it causes the left atrial pressure to rise (mouse click), which causes elevated pressures in the lungs (mouse click). This elevated pulmonary pressure causes fluid to seep out of the pulmonary capillaries, and causes pulmonary congestion. This pulmonary congestion causes the patient to be short of breath. Slide courtesy of Dr. Philip B. Adamson, Director, Congestive Heart Failure Treatment Program University of Oklahoma, Oklahoma City, OK

13 Hemodynamic Basis for Heart Failure Symptoms
LVEDP  Left Atrial Pressure  Pulmonary Capillary Pressure  Pulmonary Congestion This slide represents what we have seen on the previous 2 slides: a rise in LVEDP causes a rise in Left Atrial Pressure which causes a rise in pulmonary capillary pressure, and subsequently pulmonary congestion and shortness of breath.

14 Left Ventricular Dysfunction Systolic and Diastolic
Symptoms Dyspnea on Exertion Paroxysmal Nocturnal Dyspnea Tachycardia Cough Hemoptysis Physical Signs Basilar Rales Pulmonary Edema S3 Gallop Pleural Effusion Cheyne-Stokes Respiration It is important to understand that the symptoms of systolic and diastolic heart failure are the same. Whether a patient has systolic or diastolic heart failure depends on the ejection fraction. If the EF is less than 40%, it is labeled systolic heart failure. If it is greater than 40%, it is labeled diastolic heart failure. Remember that almost all systolic heart failure has a component of diastolic failure. Patient symptoms must correlate to the physical signs in order for them to be diagnostic of heart failure. The symptoms of left ventricular dysfunction and the physical signs are all resultant of increased left arterial pressure, capillary pressure, and pulmonary congestion.

15 ICC - Fase de respostas compensatórias
Melhoria transitória Disfunção miocárdica Melhoria transitória Activação neurohumoral Dilatação e hipertrofia Frank-Starling < stress da parede Retenção H2O e sal Vasoconstrição Redistribuição fluxo Inotropia + Taquicardia

16 Compensatory Mechanisms
Frank-Starling Mechanism Neurohormonal Activation Ventricular Remodeling Several natural compensatory mechanisms are called into action to help buffer the fall in cardiac output and help maintain sufficient blood pressure in order to perfuse vital organs. These compensatory mechanisms include: Frank-Starling mechanism Neurohormonal activation Ventricular remodeling

17 Compensatory Mechanisms
Frank-Starling Mechanism a. At rest, no HF b. HF due to LV systolic dysfunction c. Advanced HF The Frank-Starling mechanism plays an important compensatory role in the early stages of HF, which is demonstrated in this slide. On the graph, there are three points, A, B, and C. Point A is a healthy patient where cardiac performance increases as preload increases (the amount of stretch on the ventricle before contraction due to an increase in volume). Point B represents the same individual after developing LV systolic dysfunction. Since the heart is no longer able to contract as effectively as it did, stroke volume falls. As a result, there is a decrease in LV emptying which leads to an elevation of the end-diastolic volume (preload). Since point B is on the ascending portion of the curve, the increased end-diastolic volume initially serves a compensatory role because it leads to a subsequent increase in stroke volume (i.e., more diastolic stretch, the greater the contractility, and the greater the stroke volume...the Frank-Starling mechanism). This is less than the increase a normal patient would experience. As the patient’s heart failure progresses (represented by point C), which is on the relatively flat portion of the curve, stroke volume only increases slightly relative to further increases in end-diastolic volume (preload). Here the ability of the Frank-Starling mechanism to compensate for worsening LV function is nearly exhausted. In such circumstances, marked elevation of the end-diastolic volume and end-diastolic pressure results in pulmonary congestion, while decreasing cardiac output leads to increasing fatigue and exercise intolerance. Eventually, the curve starts downward due to decompensation of the heart muscle. It is of note that when cardiac resynchronization (discussed later) is implemented, the hope is to put the HF patient back on top of the curve rather than on the downward slope.

18 Compensatory Mechanisms
Neurohormonal Activation Many different hormone systems are involved in maintaining normal cardiovascular homeostasis, including: Sympathetic nervous system (SNS) Renin-angiotensin-aldosterone system (RAAS) Vasopressin (a.k.a. antidiuretic hormone, ADH) Neurohormonal activation is an important compensatory mechanism involved in maintaining the mean arterial pressure. Hormones and neurohormonal systems play a important role in maintaining normal cardiovascular hemostasis; they also play an important compensatory role in the early stages of heart failure. First, let’s start by defining what a neurohormone is. A hormone is simply a biologically active substance that originates in one tissue and is transported through the bloodstream to another part of the body where it acts to either increase the activity of that tissue or stimulate the release of another hormone. Hormones that are formed by neurosecretory cells and are liberated by nerve stimulation are called neurohormones. In general, activation of the body’s various neurohormonal systems serve to increase systemic vascular resistance, thereby attenuating any fall in blood pressure (recall: Blood Pressure = Cardiac Output x Total Peripheral Vascular Resistance). In addition, many neurohormones encourage salt and water retention, which increases intravascular volume and LV preload so as to maximize stroke volume via the Frank-Starling mechanism. But as was the case with remodeling, too much of a good thing over the long-term eventually becomes detrimental to the failing heart. Because of the importance of neurohormonal activation in the cascade of events that lead to chronic heart failure, and ultimately death, the following slides will review the various neurohormones and neurohormonal systems in detail, starting with their role in maintaining normal cardiovascular hemostasis, and then later their contribution to the progression of heart failure. The acute effects of neurohormonal stimulation are beneficial but the long term or chronic activation of these mechanisms is detrimental.

19 Equilíbrio sistemas neuro-humorais reguladores perfusão
Vasodilatores Natriuréticos Anti-proliferativos Anti-inflamatórios Antitrombogénicos Vasoconstritores Anti-natriuréticos Pró-proliferativos Pró-inflamatórios Trombogénicos Key Message: VPIs enhance levels of vasodilatory peptides and inhibit production of the vasoconstrictor Ang II, thereby restoring CV balance. Traditionally, the therapeutic approach to hypertension management has been to inhibit vasoconstriction or produce vasodilation. Increasingly, studies on hypertension show that BP regulation is a balance of endogenous vasodilators and vasoconstrictors. VPIs simultaneously augment the action of endogenous vasodilatory peptides and inhibit the production of the vasoconstrictor Ang II. This new approach favorably corrects the imbalance of CV vasoactive peptides in hypertension, resulting in greater BP reduction than other therapeutic approaches. Angiotensina 2 Aldosterona Adrenalina Noradrenalina Endotelina VSP TBX A2 Ubaína Dopamina ANF, BNF, CNF Adrenomedulina Prostaciclina Bradicinina NO

20 Neurohormonal Responses to Impaired Cardiac Performance
Initially Adaptive Response Short-Term Effects Salt and Water Retention Augments Preload Vasoconstriction Maintains BP for perfusion of vital organs Sympathetic Stimulation Increases HR and ejection End-stage Heart Failure Continued progression of heart failure eventually leads to a critical reduction in blood flow to vital organs. In this final phase, the body maximizes all its vasoconstrictor systems (norepinephrine, vasopressin, endothelin) in an attempt to redirect blood flow to these critical organ systems. But the activation of these systems only add to the hemodynamic burden of the failing heart; thus, ventricular function progressively deteriorates, and terminal heart failure ensues. Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

21 Sympathetic Activation in Heart Failure
 CNS sympathetic outflow  Cardiac sympathetic activity  Sympathetic activity to kidneys + peripheral vasculature The sympathetic nervous system’s goal is to increase cardiac sympathetic activity. This response is mediated through three receptors: Beta 1, Beta 2, and Alpha 1. In normal situations the Beta 1 receptor increases cardiac sympathetic activity. In heart failure patients, the Beta 1 and Beta 2 receptors are activated. Alpha receptors and their role is yet to be fully delineated. Beta 1, Beta 2, and Alpha 1 receptors lead to myocardial toxicity in the ventricles. Myocardial toxicity leads to decreased ejection fraction, arrhythmias, and tachyarrhythmias caused by sympathetic activation. Increase in sympathetic activity also affects the kidneys and peripheral vasculature through the Beta 1 and Alpha 1 receptors. This mediates activation of the renin-angiotensin system ( discussed on the next slide ), which causes vasoconstriction, sodium retention, and thirst. All of these responses causes the disease to progress. Prolonged neurohormone release also has direct adverse effects on the heart tissue itself. Norepinephrine, for example, is known to be directly cardiotoxic. In fact, studies have established that in patients with heart failure, the probability of survival is markedly worse for those whose plasma norepinephrine levels are >400 pg/ml than for those whose levels are <400 pg/ml. 1- receptors 2- 1- Activation of RAS 1- b1- Myocardial toxicity Increased arrhythmias Vasoconstriction Sodium retention Disease progression Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.

22 1 and 2 receptor densities in the failing and non-failing heart
Receptor density (ƒ mol/mg) 80 60 40 20 Non-failing Failing *p<0.05 **p=NS * **   2

23 Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS)
Angiotensinogen Renin Angiotensin I Angiotensin Converting Enzyme Angiotensin II The other mechanism in the neurohumoral response to heart failure is the renin-angiotensin-aldosterone system (RAAS). In the RAAS, Renin ( secreted by the kidney ) acts on Angiotensinogen (secreted by the liver) to make Angiotensin I. The Angiotensin converting enzyme (secreted by the lungs) acts on Angiotensin I to make Angiotensin II. Angiotensin II in turn causes vasoconstriction, an increase in aldosterone, facilitates the release of norepinephrine from the SNS, causes sodium reabsorption, stimulates vasopressin secretion from the brain (discussed later), and increases contractility. Subsequently, remodeling of the heart occurs. In a heart failure patient, the effects of Angiotensin II are not beneficial. Why not think about using a medication to block the conversion of Angiotensin I to II? Or, an agent that blocks the Angiotensin I receptor? These blocking agents will be discussed later when we talk about the treatment of heart failure. Na+ retention AT I receptor Vasoconstriction Vascular remodeling Oxidative Stress LV remodeling Cell Growth Proteinuria

24 Other Neurohormones Natriuretic Peptides: Three known types
Atrial Natriuretic Peptide (ANP) Predominantly found in the atria Diuretic and vasodilatory properties Brain Natriuretic Peptide (hBNP) Predominantly found in the cardiac ventricles C-type Natriuretic Peptide (CNP) Predominantly found in the central nervous system Limited natriuretic and vasodilatory properties Natriuretic Peptides The third neurohormone system on our list includes the natriuretic peptides. The natriuretic peptides—ANP, BNP, and CNP-- are vasodilating neurohormones. As such, they play an important role in counter-regulating the vasoconstricting effects of other neurohormones.  These peptides are made and stored in specialized cells in the atria and ventricles, and are released when the atria are stretched (e.g., in volume overload, which distends the atria) or when the ventricles are dilated. The natriuretic peptides act directly on blood vessels to cause vasodilatation. They also have natriuretic (salt excreting) and diuretic (water excreting) effects because of their ability to inhibit the secretion of renin, aldosterone, and vasopressin.

25 Pharmacological Actions of hBNP
Hemodynamic (balanced vasodilation) • veins • arteries • coronary arteries Neurohormonal aldosterone norepinephrine Renal diuresis & natriuresis Human brain natriuretic peptide (hBNP) is found mainly in the cardiac ventricles which suggests that this particular natriuretic peptide may be more sensitive to ventricular disorders. Its level seems to correlate with the amount of shortness of breath and left ventricular volume and pressure. For this reason, the level of BNP may be the first “white count” for heart failure. For example, a low BNP level may mean that heart failure is unlikely in a patient. It also may be a way of following the progression of disease. Natriuretic peptide levels, like norepinephrine, are also directly related to mortality. Abraham WT and Schrier RW, 1994

26 Endothelium-Derived Vasoactive Substances
Produced by a thin lining of cells within the arteries and veins called the endothelium Endothelium-derived relaxing factors (EDRF) – Vasodilators: Nitric Oxide (NO) Bradykinin Prostacyclin Endothelium-derived constricting factors (EDCF) – Vasoconstrictors: Endothelin I Endothelium-Derived Vasoactive Substances These hormones are produced by a thin lining of cells within the arteries and veins called the endothelium. Most of the effects of these substances are local, meaning that they exert their effects mostly on their local environment (unlike the circulating neurohormones discussed previously that tend to have a more diffuse effect).Their actions are primarily directed at one of three targets: the endothelium itself, the underlying smooth muscle cells of blood vessel walls (which cause the vessel to constrict or dilate), or on other substances circulating nearby in the blood. Endothelium-derived vasoactive substances that signal the blood vessels to relax (vasodilate) are called endothelium-derived relaxing factors (EDRF). Nitric oxide (NO), bradykinin, and prostacyclin are three such substances. In contrast, vasoactive substances that lead to constriction (vasoconstriction) are called endothelium-derived constricting factors (EDCF). One of the most important EDCFs is Endothelin I, which is one of the most potent vasoconstricting substances known (it also directly decreases cardiac contractility, as does nitric oxide).

27 Mediators of Heart Failure
Cytokines Small protein molecules produced by a variety of tissues and cells Negative inotropes Elevated levels associated with worse clinical outcomes Examples: Tumor necrosis factor (TNF)-alpha Interleukin 1-alpha Interleukin-2 Interleukin-6 Interferon-alpha Cytokines The cytokines are small protein molecules that decrease the strength of contraction, and thus are known as negative inotropes. Included in this class are tumor necrosis factor (TNF)-alpha, interleukin 1-alpha, interleukin-2, interleukin-6, and interferon-alpha. Tumor necrosis factor (TNF)-alpha, a cytokine, is known to have deleterious effects in heart failure. TNF-alpha used to be called cachectin. It is elaborated by cancers and causes the marked cachexia seen in patients with certain forms of cancer, and likely also causes the weight loss in certain patients with heart failure. Like norepinephrine and the natriuretic peptides, increased plasma levels of TNF-alpha are associated with a poor prognosis.

28 Neurohormonal Responses to Impaired Cardiac Performance
Initially Adaptive, Deleterious if Sustained Response Short-Term Effects Long-Term Effects Salt and Water Retention Augments Preload Pulmonary Congestion, Anasarca Vasoconstriction Maintains BP for perfusion of vital organs Exacerbates pump dysfunction (excessive afterload), increases cardiac energy expenditure Sympathetic Stimulation Increases HR and ejection Increases energy expenditure End-stage Heart Failure Continued progression of heart failure eventually leads to a critical reduction in blood flow to vital organs. In this final phase, the body maximizes all its vasoconstrictor systems (norepinephrine, vasopressin, endothelin) in an attempt to redirect blood flow to these critical organ systems. But the activation of these systems only add to the hemodynamic burden of the failing heart; thus, ventricular function progressively deteriorates, and terminal heart failure ensues. Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

29 ICC - Fase de descompensação
agravamento Disfunção miocárdica Dilatação ventricular Remodelagem Stress oxidativo Citocinas Apoptose Dilatação e hipertrofia Activação neurohumoral Mitogénese Proliferação celular Alterações estruturais, miocárdio, tecido conjuntivo, vasos Perda de miócitos, necrose e fibrose

30 General Measures Lifestyle Modifications: Weight reduction
Discontinue smoking Avoid alcohol and other cardiotoxic substances Exercise Medical Considerations: Treat HTN, hyperlipidemia, diabetes, arrhythmias Coronary revascularization Anticoagulation Immunization Sodium restriction Daily weights Close outpatient monitoring The treatment of heart failure has changed considerably over the past decade, primarily because we now understand the importance of neurohormonal activation in the progression of this disease. In this section we will learn about the treatment of heart failure; however, the focus will be on the ever-expanding armamentarium the pharmacologic agents used to treat this disease. [Note: The material discussed in this section is based on the ACC/AHA Practice Guidelines 2001, Circulation December 2001.] General Measures: An important part of heart failure management is identifying and treating factors that are known to encourage heart failure and its progression. This often requires encouraging patients to adopt lifestyle changes to address these factors. Lifestyle Modifications: Weight Reduction—Obese patients should lose weight Smoking—Smokers should stop smoking Alcohol—Excessive alcohol use, and the use of other cardiotoxic substances, should be avoided Exercise—Improve physical conditioning where appropriate

31 Objectivos terapêuticos
sobrevida Morbilidade Capacidade de Exercicio Qualidade de vida Alterações Neurohormonais Progressão da CHF Sintomas Treatment of Heart Failure. Objectives The objectives of treatment of the patient with heart failure are many, but they may be summarized in two principles: decrease symptoms and prolong life. In daily practice, the first priority is symptom control and the best plan is to adjust to the individual patient’s particular circumstances over the course of therapy. Nevertheless, the rest of the listed objectives should not be forgotten, as medical therapy now has the potential for decreasing morbidity (hospital admissions, embolism, etc.), increasing exercise capacity (all of the usually prescribed drugs), improve the quality of life, control neurohormonal changes (ACE-I, beta blockers), retard progression (ACEI) and prolong life.

32 Tratamento da Ins. cardiaca
Diureticos e digitalicos Vasodilatadores Directos e nitratos Inibidores da ECA Antagonistas dos receptores AT1 Bloqueadores beta Antiarrítmicos, anticoagulantes Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas) Ressincronização cardíaca

33 Ventricular Filling Pressure
DRUGS HEMODYNAMIC EFFECTS Normal A I Stroke Volume Treatment of Heart Failure. Theoretical hemodynamic effects of different drugs for heart failure Effects of different treatments on the relationship between ventricular filling pressure (LVEDP) and stroke volume. Diuretics (D) and venous vasodilators (V) decrease the ventricular filling pressure in patients with heart failure and normal or elevated LVEDP, but except in patients with marked elevation of LVEDP, the stroke volume does not change. The pure arterial vasodilators (A) produce an increase in the stroke volume in patients with failure and an elevated LVEDP. Inotropic drugs (I) increase the stroke volume with a lesser effect of the ventricular filling pressure. A + V V CHF D Ventricular Filling Pressure

34 Pharmacologic Management
Digoxin Enhances inotropy of cardiac muscle Reduces activation of SNS and RAAS Controlled trials have shown long-term digoxin therapy: Reduces symptoms Increases exercise tolerance Improves hemodynamics Decreases risk of HF progression Reduces hospitalization rates for decompensated HF Does not improve survival Digoxin Digoxin has been used in the management of heart failure for more than 200 years, yet it wasn’t formally approved by the FDA for this indication until 1997. Digoxin enhances inotropy (contractility) of cardiac muscle and, at the same time, reduces activation of the SNS and RAAS. These neurohormonal effects are sustained during prolonged treatment with digoxin. Randomized, double-blind, placebo-controlled trials such as PROVED (Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin) and RADIANCE (Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme) have shown that long-term therapy with digoxin reduces symptoms and increases exercise tolerance1. These two trials demonstrated that “patients with mild to moderate chronic heart failure due to left ventricular systolic dysfunction, who are clinically stable on either maintenance therapy of Digoxin and diuretics (PROVED), or with additional background therapy with ACE Inhibitors (RADIANCE), are at considerable risk for clinical deterioration if Digoxin is withdrawn.”2 Unfortunately, the Digoxin Investigation Group (DIG) Trial demonstrated that digoxin had no effect on mortality; however, digoxin did reduce the hospitalization rate for decompensated heart failure3 . The ACC/AHA Guidelines support the use of digoxin in conjunction with diuretics, an ACE inhibitor, and a beta-blocker in patients with LV systolic dysfunction who remain symptomatic despite treatment with an ACE inhibitor and a beta-blocker, and in those in whom heart failure is accompanied by rapid atrial fibrillation.The usual digoxin dose is mg per day, and should be adjusted for age, renal function, and body mass. The Guidelines note that although the adverse effects of digoxin, such as cardiac arrhythmias and gastrointestinal and neurologic complaints, occur primarily at high doses, these higher doses are usually not necessary to achieve clinical benefits in patients with heart failure. 1 Young, J. Clinical Management of Heart Failure. Professional Communications, Inc p 97. 2 McMurray, J and Cleland, J. Heart Failure in Clinical Practice. Second Edition. Martin Dunitz Ltd. p 232. 3 Young, J., p. 111

35 Figura 1. Estrutura da digoxina, protótipo dos digitálicos
Genina o CH3 OH = O - o- HO - CH 3 - O - Tri-digitoxose (açucares) Lactona Esteroide Figura 1. Estrutura da digoxina, protótipo dos digitálicos

36 DIGOXIN Na-K ATPase Na-Ca Exchange
Treatment of heart failure. Digoxin: Mechanism of action Digoxin attaches to specific receptors which form a part of the enzyme, Na+/K+-dependent ATP-ase (sodium pump), inhibiting it. This blockade produces a progressive increase in the intracellular concentration of Na, which in turn activates the exchange of Na+-Ca++ and increases the influx of Ca++ and its intracellular concentration, [Ca++]i. This increase in the [Ca++]i at the level of the contractile proteins explains the resultant increase in cardiac contractility. Myofilaments Ca++ K+ Na+ CONTRACTILITY

37 Figura 2. Efeitos inotrópicos e neurais dos digitálicos
Efeito simpático-inibidor aferências doses terapêuticas Digitálicos Estimulação vagal > saída de sódio 3Na + 2K + Trocador Na+/Ca2+ Estimulação simpática Doses tóxicas > Ca 2+ intracelular > sódio intracelular Taquiarritmias EFEITO INOTRÓPICO POSITIVO Aumento Ca2+ intracelular Adaptado de Opie, 1990

38 Normal Conduction Pathway in the Heart and the ECG
Sinoatrial (SA) Node Atrioventricular (AV) Node The heart's primary impulse generator is the sinoatrial (SA) node located in the right atrium. The impulse is carried through the cardiac muscle tissue of the atria. This causes the atria to contract. The impulse then travels through the network to the ventricles causing them to contract. The resulting action causes blood to be pumped through the body via connecting blood vessels. Left Bundle Branches Right Bundle Branch Purkinje Fibers P T QRS P = Atrial Depolarization QRS = Ventricular Depolarization T = Ventricular Repolarization

Oral absorption (%) Protein binding (%) Volume of distribution (l/Kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) Duration Therapeutic level (ng/ml) 25 6 (3-9) 36 (26-46) h Renal 5 - 30 2 - 4 3 - 6 2 - 6 days Treatment of heart failure. Digoxin: Pharmacokinetics Oral absorption is 60-75% of the administered dose; when given by this route, maximal levels are reached after minutes and its action is maximal after 3-6 h. When given i.v., onset of action is at 5-30 min and this reaches its maximum at 2-4 h. It is approximately 25% bound to plasma proteins and is widely distributed through the body, crossing the blood brain barrier and the placenta. It accumulates in skeletal muscle, liver and heart, where it may reach concentrations that are 10 to 50 times higher than serum levels. This explains why hemodialysis eliminates little of the digoxin load in digoxin toxicity. Cardiac uptake of digoxin increases in patients with hypokalemia and decreases in the presence of hyperkalemia, hypercalcemia or hypomagnesemia. Digoxin undergoes very little biotransformation, and is mainly eliminated through glomerular filtration and somewhat by tubular secretion. In patients with renal insufficiency, the half life of digoxin increases 2-4 times, so that the maintenance dose must be determined according to the creatinine clearance, generally requiring half of the usual dose and, in severe cases, intermittent dosing.

Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation Treatment of heart failure. Digoxin: Hemodynamic effects Digoxin increases contractile force, maximal shortening velocity (dp/dt max) and the cardiac output, decreases the LV filling pressure and volume, the pulmonary capillary wedge pressure, wall stress and the cardiothoracic ratio. Digoxin displaced the ventricular function curve up and to the left, meaning that it increases the cardiac output at any filling pressure. All of these effects explain when digoxin decreases the signs of congestion and peripheral hypoperfusion in the patient with heart failure. The increase in cardiac output reduces the heart rate, the peripheral vascular resistance, and offsets the increased myocardial demand for oxygen that the increase in contractility might create.

Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors Treatment of heart failure. Digoxin: Neurohormonal effects Digoxin, at the doses which augment cardiac contractility, restores the inhibitory effect of the arterial baroreceptors and markedly inhibits the activity of the sympathetic nervous system, which can be seen in the reduction of plasma levels of noradrenaline, the activity of peripheral sympathetic system, and the activity of the renin-angiotensin- aldosterone system (RAAS). This neurohormonal inhibition reduces the heart rate, the peripheral vascular resistance and the signs of congestion and peripheral hypoperfusion in the patient with heart failure. This creates the question to what point do the beneficial effects of digoxin reflect its positive inotropic quality. Digoxin also decreases the reabsorption of Na and water; this natriuretic action, secondary to the increase in cardiac output, increases renal perfusion and the glomerular filtration rate, decreasing renal vasoconstriction and the activation of the RAAS.

Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions Treatment of heart failure. Digoxin: Effect on long term course The results obtained in 3 controlled studies that included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality were similar in both treatment groups. In the DIG study (Digitalis Investigator Group), the survival of 7788 patients with heart failure classes II-III and LVEF < 45% and sinus rhythm treated over 37 months ( ) with digoxin, to determine if it increased or decreased the mortality of patients with symptoms of heart failure. There was no observed effect on survival, but it decreased slightly the number of admissions for cardiovascular causes and also increased the incidence of serious arrhythmias and episodes of acute myocardial infarction. The results of this study probably demand redefinition of the indication for the use of digoxin in patients with heart failure.

43 DIGOXIN CLINICAL USES AF with rapid ventricular response
CHF refractory to other drugs Other indications? Can be combined with other drugs Treatment of heart failure. Digoxin: Clinical uses Digoxin is the drug of choice for patients with heart failure associated with atrial fibrillation/flutter with rapid ventricular response. Accompanied by diuretics and ACEI it is also useful in patients in sinus rhythm with systolic heart failure. The best results are obtained when cardiomegaly (cardiothoracic index > 60%) and important systolic dysfunction (LVEF < 40%, symptoms at rest, third heart sound) are present. It is also useful in patients who do not respond to diuretics and vasodilators and in severe heart failure associated with hypotension when vasodilators are contraindicated. Digoxin is more effective in heart failure with low cardiac output associated with cardiomyopathies, ischemic cardiomyopathy, arterial hypertension or rheumatic valvular disease with left ventricular failure. It is relatively inefficacious in heart failure with high cardiac output (associated with hyperthyroidism, anemia, arteriovenous fistulas, glomerulonephritis or Paget’s disease) and in heart failure secondary to hypertrophic cardiomyopathy. The results of the study of survival with digoxin require a reassessment of the indications for digoxin use in patients with heart failure. Probably digoxin will become a second-line drug, and its use may be restricted to patients with refractory symptoms, except in patient with rapid atrial fibrillation.

ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVC’s and TV - Marked hypokalemia - W-P-W with atrial fibrillation Treatment of heart failure Digoxin: Contraindications The only absolute contraindication for digoxin use is the presence of digoxin toxicity. Relative contraindications include: a) presence of advanced A-V blocks without pacemaker, as incremental blockade of conduction through the A-V node increases the risk of complete A-V block; b) ventricular extrasystoles and tachycardias, as these may be aggravated; nevertheless, digoxin may be given if the patient’s extrasystoles are secondary to heart failure; c) marked bradycardia or sinus node disease without pacemaker; d) marked, uncontrolled hypokalemia, and e) patients with Wolff-Parkinson-White syndrome and atrial fibrillation.

ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION Treatment of heart failure. Digoxin toxicity Digoxin has a narrow therapeutic margin, and digoxin intoxication remains relatively frequent although it has diminished somewhat as it has become better recognized and lower doses are being prescribed. Cardiac manifestations. Digoxin may cause any type of cardiac arrhythmia, although at times the ECG may be nonspecific. At the ventricular level, isolated or multifocal PVC’s, bigeminy, tachycardia and ventricular fibrillation may occur; at the supraventricular level, digoxin may induce extrasystoles and paroxysmal tachycardias which may result in atrial flutter or fibrillation. In addition, depression of sinoatrial node function may produce bradycardia and even complete sinoatrial block. It prolongs the refractory period and depresses conduction velocity across the A-V node (lengthens the PR interval on the ECG), thereby creating different grade of conduction block, which may precede the appearance of reentrant nodal tachycardias and nodal rhythms. Exacerbation of heart failure in patients treated with digoxin should raise the question of digoxin toxicity.

GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM: - Gynecomastia, galactorrhea Treatment of heart failure. Digoxin intoxication Extracardiac adverse reactions: a) Gastrointestinal: anorexia, nausea, vomiting, diarrhea, weight loss. b) Nervous: depression, disorientation, confusion, delirium, neuritis and paresthesias. c) Visual changes: blurry vision, scotomas, yellow-green vision. d) Digoxin inhibits the metabolism of ß-estradiol and can produce signs of hyperestrogenism: gynecomastia and galactorrhea or vaginal plaques which may be confused with carcinoma in postmenopausal women.

Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Treatment of heart failure. Positive inotropic agents The use of inotropic agents in heart failure is intended to increase contractility and cardiac output to meet the metabolic needs of the body. Theoretically, their use should be greatest in heart failure associated with a decrease in systolic function and marked cardiomegaly, depression of ejection fraction and elevated left ventricular filling pressure. In addition to the cardiac glycosides, other positive inotropic agents include: a) the sympathomimetics, represented by the ß1 agonists (which stimulate cardiac contractility) and ß2-adrenergics (vasodilators). Both groups increase the intracellular concentration of cAMP by stimulating the activity of adenylate cyclase which converts ATP to cAMP; b) Phosphodiesterase inhibitors, which inhibit the enzyme that breaks down cAMP, increase cardiac contractility and have arteriovenous vasodilatory effect; c) other ionotropic drugs including glucagon and Na+ channels agonists. Milrinone Piroximone

48 B1 Stimulants B2 Stimulants Mixed
ß-ADRENERGIC STIMULANTS CLASSIFICATION B1 Stimulants Increase contractility Dobutamine Doxaminol Xamoterol Butopamine Prenalterol Tazolol Treatment of heart failure. ß-adrenergic agonists: Classification In an attempt to find options to digoxin, in the 1980’s different positive inotropic drugs became available, among them ß-adrenergic agonists and phosphodiesterase III inhibitors. Both groups of drugs increase the intracellular concentration of cAMP; ß-adrenergic agonists by stimulating the activity of adenylate cyclase which converts ATP into cAMP, and the phosphodiesterase III inhibitors by inhibiting the breakdown of cAMP. The ß-adrenergic agonists can be classified according to the capacity for stimulating the cardiac ß1 receptors (increasing contractility and heart rate), ß2-vasodilatory receptors or both (mixed). SVR = Systemic vascular resistance B2 Stimulants Produce arterial vasodilatation and reduce SVR Pirbuterol Carbuterol Rimiterol Fenoterol Tretoquinol Salbutamol Terbutaline Salmefamol Soterenol Quinterenol Mixed Dopamine

DA (µg / Kg / min) Dobutamine < 2 2 - 5 > 5 Treatment of heart failure Dopamine (DA) and dobutamine: Hemodynamic effects The hemodynamic effects vary, depending on the dose used: At low doses (0.2-2 µg/kg/min), DA stimulates DA1 and DA2 receptors, producing renal, mesenteric, cerebral and coronary vasodilatation. Renal vasodilatation increases glomerular filtration rate, urine production and renal excretion of Na; the majority of Na excretion seems to be due to a direct tubular action of DA and stimulation of DA2 receptors that inhibit the liberation of aldosterone. Inhibition of sympathetic tone produced by the stimulation of DA2 receptors explains why at these doses the arterial pressure decreases slightly and the heart rate remains the same or even falls. These doses are used for induction of diuresis, particularly in patients who do not respond to furosemide. At intermediate doses (2-5 µg/kg/min) DA also stimulates cardiac ß1 and ß2 receptors, increasing contractility, heart rate and cardiac output at the same time as it decreases peripheral resistance (stimulation of DA1 and ß2 receptors). These doses are used in the treatment of heart failure without hypotension. At high doses (> 5 µg/kg/min) DA also stimulates a-adrenergic receptors, increasing peripheral resistance and blood pressure. In addition, the marked stimulation of the cardiac ß1 receptors increases the heart rate and contractility, the myocardial O2 demand, and may produce arrhythmias. These doses are only used in patients with severe hypotension and/or cardiogenic shock. Receptors DA1 / DA2 ß1 ß1 + a ß1 Contractility ++ ++ ++ Heart Rate + ++ Arterial Press. + ++ ++ Renal perfusion ++ + + Arrhythmia - ++

May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy Treatment of heart failure. Inotropes: General problems Positive inotropic drugs which increase cellular levels of cAMP have important proarrhythmic effects and seem to accelerate the progression of heart failure. Their hemodynamic effects decreased with prolonged treatment which suggests that they should not be used for chronic treatment. Safety and efficacy increases when they are used in low doses, with which the increase in contractility is slight. This points out that their beneficial effects probably do not depend on their positive inotropic action. The reduction in neurohumoral activation produced by digoxin and ibopamine, the antiarrhythmic action of Vesnarinone or the vasodilatory effects of dopamine, dobutamine or PDE III inhibitors may be more important than the increase in contractility that until recently was though to be their utility in the treatment of heart failure. With the exception of digoxin, chronic administration of these drugs increases mortality, so their use, in low doses, should be restricted to patients with refractory heart failure, with persistent symptoms despite treatment with combinations of other drugs. As it is precisely the sickest patients who manifest the increase in mortality, treatment with inotropic drugs is not likely to prolong the survival of these patients.

51 DIURETICS Cortex Medulla Thiazides K-sparing Loop diuretics
Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Treatment of heart failure. Diuretics: Classification and mechanisms of action Diuretics are drugs which eliminate Na and water by acting directly on the kidney. This category does not include other drugs with principle actions different from the diuretics, but which increase diuresis by improving heart failure or by mechanisms on the kidney which are incompletely understood. The diuretics are the primary line of therapy for the majority of patients with heart failure and pulmonary congestion. Diuretics (loop, thiazides and potassium-sparing) produce a net loss of Na and water acting directly on the kidney, decrease acute symptoms which result from fluid retention (dyspnea, edema). Diuretic drugs are classically divided into three groups: 1) thiazides, 2) loop diuretics and 3) potassium-sparing. Thiazide diuretics inhibit the active transport of Cl-Na in the cortical diluting segment of the ascending limb of the Loop of Henle. Loop diuretics inhibit the transport of Cl-Na-K in the thick portion of the ascending limb of the Loop of Henle. Potassium-sparing diuretics inhibit the reabsorption of Na in the distal convoluted and collecting tubules. Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Medulla Loop of Henle Collecting tubule

Excrete % of filtered Na+ Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO3 No dose - effect relationship Treatment of heart failure. Diuretics: Mechanism of action of the thiazides The thiazides are diuretics of intermediate potency, excreting 5-10% of the filtered fraction of Na. The act from the luminal surface inhibiting the active transport of Cl and the subsequent diffusion of Na and water in the cortical diluting segment of the ascending portion of the loop of Henle. The also increase elimination of K by increasing the exchange of Na/K in the distal convoluted tubule and increase the urinary elimination of HCO3 by inhibiting carbonic anhydrase. In addition they increase tubular reabsorption of uric acid, Ca and Mg. There are important differences in the strength and duration of diuretic action depending on which thiazide is used.

Excrete % of filtered Na+ Elimination of K+, Ca+ and Mg++ Resistance of afferent arterioles Cortical flow and GFR Release renal PGs NSAIDs may antagonize diuresis Treatment of heart failure. Diuretics Mechanism of action of loop diuretics Loop diuretics are the strongest, prompting the excretion of 15-20% of the filtered Na+. They act in the thick segment of the ascending loop of Henle, inhibiting the cotransport of Cl--Na+-K+ at the luminal surface. They also increase the elimination of K+, as the increase in Na that reaches the distal convoluted tubule stimulates its exchange for K+ and H+; in addition, they also stimulate the secretion of renin and the production of aldosterone which augments the elimination of K+. By inhibiting carbonic anhydrase, they increase the urinary elimination of HCO-3. They also increase elimination of Ca++ and Mg++. GFR: glomerular filtration rate; PGS: prostaglandins; NSAIDs: nonsteroidal anti-inflammatory drugs.

Eliminate < 5% of filtered Na+ Inhibit exchange of Na+ for K+ or H+ Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na+ channels controlled by aldosterone Treatment of heart failure. Diuretics: Mechanism of action of potassium-sparing diuretics Potassium-sparing diuretics inhibit reabsorption of Na+ at the level of the distal convoluted tubule and the collecting duct and its exchange for K+ or H+. Their diuretic strength is slight, as the fraction of Na eliminated is no more than 5%. Spironolactone is a competitive antagonist of aldosterone, interfering with its induction of synthesis of proteins which specifically facilitate Na reabsorption. As a result, its diuretic action depends on the role that aldosterone plays in the retention of water and Na. Triamterene and amiloride block the exchange of Na+-K+/H+, but their effect is independent of the levels of aldosterone. All of these drugs moderately increase the renal excretion of Na+, Cl- and HCO-3, at the same time that they diminish the excretion of K+, H +and ammonium, and may therefore cause hyperkalemia and hypochloremic acidosis.

55 DIURETIC EFFECTS Volume and preload No direct effect on CO, but
Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activation Levels of NA, Ang II and ARP Exception: with spironolactone Treatment of heart failure. Diuretics: Mechanisms of action Diuretics decrease volume and preload, and as a result are very effective at improving the signs of pulmonary and systemic venous congestion. They do not change the cardiac output (CO), but CO may fall if an excessive decrease in preload occurs. They slightly improve arterial distensibility, but this effect is of no clinical relevance. The main drawback to diuretics use is their effect on the neurohormonal milieu, increasing the plasma levels of noradrenaline (NA), angiotensin II (Ang II) and aldosterone, and the plasma renin activity (PRA).

56 DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics
Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Thiazide and loop diuretics create electrolyte imbalances: hypovolemia, hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia and metabolic alkalosis. They also create metabolic changes (hyperglycemia, hyperuricemia, gout, increase in LDL-cholesterol and triglycerides), impotence and menstrual cramps. Hypokalemia can be treated with K+ supplements or with the simultaneous use of potassium-sparing diuretics. Cutaneous allergic reactions (rash, pruritis) are frequent. In addition, these are cross-reactions between the various thiazides (except chlorthalidone) and because of their chemical resemblance, with furosemide and bumetanide. Thiazides can aggravate myopia in pregnant women.

57 DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics
Idiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitis Gastrointestinal effects Genitourinary effects: Impotence and menstrual cramps Deafness, nephrotoxicity (Loop diuretics) Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Known adverse reactions include parenchymal (pancreatitis, cholestatic jaundice, hemolytic anemia, thrombocytopenia), gastrointestinal effects (ethacrynic acid), myalgias (bumetanide, piretanide) and muscle cramps related to electrolyte disorders. Loop diuretics are associated with ototoxicity with loss of hearing and balance and these are more frequent in patients with renal insufficiency or with concomitant use of aminoglycoside antibiotics. They may also cause interstitial nephritis.

58 Pharmacologic Management
Diuretics Used to relieve fluid retention Improve exercise tolerance Facilitate the use of other drugs indicated for heart failure Patients can be taught to adjust their diuretic dose based on changes in body weight Electrolyte depletion a frequent complication Should never be used alone to treat heart failure Higher doses of diuretics are associated with increased mortality Most patients with heart failure require a diuretic to relieve fluid retention. In addition to rapidly decreasing symptoms such as pulmonary congestion and peripheral edema, diuretics improve exercise tolerance and facilitate the use of other drugs indicated for heart failure. Treatment with a diuretic is generally started at a low dose and then gradually tapered upward until a threshold dose is established. Some patients with heart failure can be taught to adjust their diuretic dose themselves based on changes in body weight, which should be monitored daily. After fluid retention has resolved, diuretic therapy is continued to prevent its recurrence. Electrolyte depletion is a frequent complication of long-term diuretic therapy; therefore, electrolyte levels need to be monitored frequently during initial stages of therapy and after increases in diuretic dose. Diuretics are usually used along with ACE inhibitors and beta-blockers in heart failure, and should never be used alone. Increased doses of diuretics have been associated with increased mortality.

K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis Treatment of heart failure. Diuretics: Adverse reactions to potassium-sparing agents The main adverse reaction to these agents is hyperkalemia, which occurs mostly in patients with renal failure, particularly if they are also receiving ACE inhibitors. They may also create metabolic acidosis, muscle cramps and weakness, and cutaneous allergic reactions.

Normal Contractility Normal Contractility CO VV AV Diminished Contractility Diminished Contractility PRELOAD AFTERLOAD

Venous Vasodilatation VENOUS Nitrates Molsidomine MIXED Calcium antagonists a-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside Arterial Vasodilatation ARTERIAL Minoxidil Hydralazine

1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestion Ventricular size Vent. Wall stress MVO2 Treatment of Heart Failure. Nitrates: Hemodynamic effects At therapeutic doses, nitrates produce venodilatation that reduces systemic and pulmonary venous resistances. As a consequence, right atrial pressure, pulmonary capillary pressure, and LVEDP decrease. The preload reduction improves the signs of pulmonary congestion and decreases myocardial wall tension and ventricular size, which in turn reduce oxygen consumption. With higher doses, nitrates produce arterial vasodilatation that decreases peripheral vascular resistance and mean arterial pressure, leading to a decrease in afterload, and thereby reduce oxygen consumption. This arterial vasodilatation increases cardiac output, counteracting the possible reduction caused by the reduction in preload caused by venodilatation. The overall effect on cardiac output depends on the LVEDP; when LVEDP is high, nitrates increase cardiac output, while when it is normal nitrates can decrease cardiac output. Nitrates can also produce coronary vasodilatation, as much through reducing preload as through a direct effect on the vascular endothelium. This vasodilatation can decrease the mechanical compression of subendocardial vessels and increases blood flow at this level. Additionally, nitrates reduce coronary vascular tone, overcoming vasospasm. • Cardiac output • Blood pressure

Placebo (273) Prazosin (183) Hz + ISDN (186) 0.6 0.5 PROBABILITY OF DEATH Treatment of Heart Failure. Nitrates: Survival Mortality curves of heart failure patients. In men with class II-III heart failure, the VHeFT-I study showed that for patients already treated with digoxin and diuretics, the combination of hydralazine (300mg/day) and isosorbide dinitrate (160mg/day) improved symptoms and functional status. More importantly, combination therapy was associated with a 23% reduction in mortality at 3 years; this effect was not seen in patients treated with prazosin (30mg/day). Selection of the treatment arms in this study was based on certain suppositions. The placebo group received digitalis and diuretics, and subsequent to this study the combination has been administered obligatorily in control groups. The combined administration of hydralazine (arterial vasodilator) and a nitrate (venodilator) was designed to provide equilibrated vasodilatation. Prazosin combined both arterial and venous vasodilatory capacities in one medication, and was initially assumed to be better than combination therapy. The lack of effect of prazosin was probably due to development of tolerance. Perhaps the most relevant finding of the study was that, in practice, the effects of a medicine on symptoms or hemodynamic effects do not correlate well with effects on overall survival. Veterans Administration Cooperative Study (VHefT-1). N Engl J Med 1986;314:1547 0.4 0.3 0.2 0.1 VHefT-1 N Engl J Med 1986;314:1547 6 12 18 24 30 36 42 MONTHS

64 NITRATES TOLERANCE " Decrease in the effect of a drug
when administered in a long-acting form" Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels Treatment of Heart Failure. Nitrates: Tolerance Repetitive administration of nitrates over days is accompanied by a reduction in intensity and duration of its effects (tolerance), that obligates sequential increases in dose to obtain the desired effect. Nitrate tolerance appears with all nitrates, crosses over from one nitrate preparation to another (explaining the poor effect that IV NTG can have in patients on oral nitrate therapy), and is not dose dependent. Additionally, tolerance appears within 8-24 hours of administration of preparations that allow for maintenance of stable plasma nitrate levels (i.v., patch), but disappears rapidly (<48hrs) after stopping treatment. Increasing dosage does not overcome the tolerance effect. Tolerance can be avoided, however, by using the lowest effective dose, and by avoiding continuous plasma levels (drug-free periods).

65 NITRATES TOLERANCE Can be avoided or minimized
- Intermittent administration - Use the lowest possible dose - Intersperse a nitrate-free interval Allow peaks and valleys in plasma levels - Vascular smooth muscle recovers its nitrate sensitivity during the nadirs - Patches: remove after 8-10 h Treatment of Heart Failure. Nitrates: Tolerance Tolerance can be minimized through intermittent dosing, using the lowest possible dose, and allowing for “drug-free periods”. Peaks and valleys of drug levels occur; during valleys the plasma concentration is less than the minimal effective concentration, which allows the vascular smooth muscle to recover its nitrate-sensitivity. For this reason it is recommended to use oral nitrates 2-3 times during the day and to remove the nitrate patches for a 12 hour period.

H A L F I E s.l. NTG ISDN I 5-MN Percutaneous NTG Treatment of Heart Failure. Nitrates: Tolerance Tolerance is related to the duration of the nitrate effects, such that the longer the half-life, the higher the risk that tolerance will occur.

Previous hypersensitivity Hypotension ( < 80 mmHg) AMI with low ventricular filling pressure 1st trimester of pregnancy Treatment of Heart Failure. Nitrates: Contraindications Nitrates are contraindicated in patients with histories of nitrate hypersensitivity, marked hypertension or shock, acute infarction with low filling pressures, and first-trimester pregnancy. They should also not be given to patients with anemia, increased intracranial pressure, severe aortic or mitral stenosis, cardiac tamponade, constrictive pericarditis or coronary thrombosis. Nitrates can aggravate angina in the setting of hypertrophic cardiomyopathy. WITH CAUTION: Constrictive pericarditis Intracranial hypertension Hypertrophic cardiomyopathy

Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v. Treatment of Heart Failure. Nitrates: Use in Heart Failure Through venodilation, nitrates reduce LVEDP, PAD, and PCWP, thereby improving pulmonary congestion and exercise tolerance. The reduction in end-diastolic pressure and volume decrease wall tension and oxygen consumption. Cardiac output and arterial pressure are not significantly changed, although a decrease in the LVEDP of 12 mmHg can decrease cardiac output. Nitrates are particularly useful in patients with signs of pulmonary congestion (PCWP > 18 mm Hg) and normal cardiac outputs, or in patients with orthopnea and PND. Recommended doses are well tolerated and rarely cause reflex tachycardia or hypotension. In patients with acute heart failure accompanied by pulmonary edema nitroglycerine can be given sublingually or i.v. I.V. administration allows for immediate onset of action, and rapid disappearance of effect within minutes of stopping the infusion. Patients receiving I.V. nitroglycerin should be monitored. In patients with low cardiac output, nitrates can be used in conjunction with arterial vasodilators, dopamine, or dobutamine. In the treatment of chronic heart failure preparations with long half-lives are used. Topical nitroglycerine and other nitrates administered qHS are effective in patients with orthopnea and PND.

69 Pharmacologic Management
ACE Inhibitors Blocks the conversion of angiotensin I to angiotensin II; prevents functional deterioration Recommended for all heart failure patients Relieves symptoms and improves exercise tolerance Reduces risk of death and decreases disease progression Benefits may not be apparent for 1-2 months after initiation Angiotensin Converting Enzyme (ACE) inhibitors are recommended for all heart failure patients, whether they are symptomatic or not. Use of ACE inhibitors relieves symptoms and improves exercise tolerance in patients with chronic heart failure. Data from placebo-controlled trials show that ACE inhibitors can also reduce the risk of death and disease progression in heart failure patients. The benefits of ACE inhibitor therapy may not become apparent for 1-2 months after initiation of treatment. But even in the absence of symptomatic improvement, continued long-term ACE inhibitor therapy is recommended to reduce the risk of death or hospitalization. Most patients with heart failure tolerate long-term ACE inhibitor therapy. Potential side effects include a decrease in blood pressure, transient worsening of kidney function, hyperkalemia, and chronic cough. Angioedema, a disorder characterized by the development of large, edematous areas of the skin, mucous membranes, and organs, is an infrequent, but life-threatening complication of ACE inhibition, and obviously, ACE inhibitors should not be used in patients with a history of this condition. Enalapril (Vasotec) and Captopril (Capoten), have been shown to decrease mortality in large heart failure clinical trials. For this reason, these two are typically the drugs of choice.

VASOCONSTRICTION VASODILATATION ALDOSTERONE PROSTAGLANDINS VASOPRESSIN Kininogen tPA SYMPATHETIC Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) :Mechanisms of action ACE-inhibitors competitively block the converting enzyme that transforms angiotensin I into angiotensin II. The reduction in angiotensin II levels explains its arteriovenous vasodilatory actions, as angiotensin II is a potent vasoconstrictor that augments sympathetic tone in the arteriovenous system. Additionally, angiotensin causes vasopressin release and produces sodium and water retention, both through a direct renal effect and through the liberation of aldosterone. Since converting enzyme has a similar structure to kinase II that degrades bradykinin, ACE-inhibitors increase kinin levels that are potent vasodilators (E2 and F2) and increase release of fibrinolytic substances such as tPA. Kallikrein Angiotensinogen RENIN BRADYKININ Angiotensin I A.C.E. Inhibitor Kininase II ANGIOTENSIN II Inactive Fragments

71 Inflamação/procoagulabilidade
Retenção de Na+ Libertação de Aldosterona e ET-1 Efeitos centrais Hipertrofia cardíaca Fibrose intersticial Pro-ateromatose Estimulação simpática Angiotensina II Estimulação de protooncogenes Hipertrofia/Hiperplasia Remodelagem vascular Inflamação/procoagulabilidade Stress oxidativo

Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO2 Renal, coronary and cerebral flow Diuresis and natriuresis Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

73 ACEI ADVANTAGES Inhibit LV remodeling post-MI
Modify the progression of chronic CHF Survival Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Advantages In class II-IV heart failure patients treated with diuretics and digitalis, ACE-inhibitors decrease symptoms, improve hemodynamics and functional class, and increase exercise tolerance. Additionally, they reduce left ventricular dimensions, improve the cardiothoracic index, improve renal function, and improve hyponatremia. More importantly, ACE-inhibitors are the best drugs to date for preventing expansion and dilatation of the left ventricle post infarction, thereby decreasing the number and duration of hospitalizations, and improving symptoms and survival. They also retard progression to heart failure in patients with asymptomatic ventricular dysfunction. ACE-inhibitors differ from other vasodilators in that they do not produce neurohormonal activation or reflex tachycardia, and tolerance to these agents does not seem to develop over time. ACE-inhibitors increase plasma renin, bradykinin, and angiotensin I activities, and reduce plasma and tissue levels of angiotensin II, and plasma levels of aldosterone and cortisol. ACE-inhibitors can also decrease plasma norepinephrine levels, especially after long-term therapy, which has been attributed to the suppression of the stimulating effect angiotensin II has on the synthesis and release of norepinephrine. ACE-inhibitors also reduce arginine-vasopressin levels.

0.8 0.7 Placebo 0.6 PROBABILITY OF DEATH p< 0.001 0.5 Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival CONSENSUS. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure. The first study to demonstrate this effect was CONSENSUS I. This graph shows the cumulative mortality curves of the treatment and placebo group in this randomized, double-blind trial. The study analyzed the effect of enalapril on prognosis of 253 patients with class IV heart failure, who also received digitalis, diuretics, and conventional vasodilators. At the end of 6 months of treatment, there was a clear-cut improvement in functional class, a reduction in the need for medications, and a 40% reduction in mortality (p<0.002). After 12 months the mortality reduction was 31% (p<0.001). Nonetheless, there were no differences in the incidence of sudden death between the two groups, or in the sub-group that received other conventional vasodilators. Another characteristic of this study was variability of the dose that was used for each patient (adjusted for tolerance and symptoms): mg/day. This aspect shows the importance of individualized treatment for heart failure patients. The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429. 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 CONSENSUS N Engl J Med 1987;316:1429 1 2 3 4 5 6 7 8 9 10 11 12 MONTHS

75 Clinical cardiac insufficiency
ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 % Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibits (ACEI) Indications. ACE-inhibitors probably constitute the cornerstone of drug therapy for heart failure, in that administration over time leads to amelioration of symptoms, beneficial hemodynamic changes, increased functional capacity, regression of structural changes, and, unequivocally, prolongation of survival. Thus, ACE-inhibitors are first-line therapy, not only in symptomatic heart failure patients, but also in patients with asymptomatic left ventricular dysfunction. The exact degree of ventricular dysfunction below which it is advisable to begin therapy with an ACE-inhibitor has not been defined; however, in general terms they can be helpful in patients with ejection fractions less than 35%.

Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset - Dry cough - Renal Insuff. Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Undesirable Effects These can be classified into two groups. One group includes those effects that are inherent to its mechanism of action, and therefore are common to all ACE-inhibitors. The other includes those effects that are related to the specific chemical structure of the drug. In this case, substitution of one ACE-inhibitor for another could possibly reduce the intensity of the adverse reaction (e.g. choosing an ACE-inhibitor without a sulfhydryl moiety). - Dysgeusia - Proteinuria

Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) Contraindications. There are few absolute contraindications for the use of ACE-inhibitors. The most important one is the presence of renal artery stenosis. The most frequent contraindication is intolerance of the drug. Hypotension, the presence of renal insufficiency, or hyperkalemia limits their use, or the ability to administer adequate doses, in up to 20% of patients.

- reduzem mortalidade efeitos acessórios e morbilidade (tosse /angioedema) - melhoram sintomas - aumentam tolerância ao esforço - reduzem hospitalizações - eficazes na I C assintomática NEJM 1987: 316; JAMA 1988:259; NEJM 1991:325;293 NEJM 1991: 325; ANN INTERN MED 1992:117 ; 234

79 Mortality trials with ACE inhibitors in heart failure
CONSENSUS-1 V-HeFT-II SOLVD (treatment) Treatment duration 6 months 2 years 41 months Treatments Enalapril Placebo Enalapril ISDN/Hydral n 253 804 2569 Mortality (%) 26 44 18 25 35 40 p value 0.002 0.016 0.004 ISDN=isosorbide dinitrate; Hydral=hydralazine

80 ACE inhibitor trials in heart failure following AMI
AIRE SAVE TRACE Treatment duration 15 months 42 months 4 years Treatments Ramipril Placebo Captopril Placebo Trandolapril Placebo n 2006 2231 1749 Mortality (%) 17 23 20 25 35 42 p value 0.002 0.019 0.001

81 Estudos de mortalidade com In ECA na insuficiência cardíaca e E
Estudos de mortalidade com In ECA na insuficiência cardíaca e E. miocárdio 32 estudos randomizados em 7105 doentes Redução significativa da mortalidade global odds ratio 0.77 (95% C.I ); p<0.001 Redução significativa da mortalidade + hospitali-zações por insuficiência cardíaca de 25% odds ratio 0.65 (95% C.I ); p<0.001 Maiores benefícios em doentes com maior deterioração da função cardíaca

Angiotensinogénio Cathepsin G, Calicreína, Tonina, Tripsina Renina Bradicinina Angiotensina I ECA Chymase CAGE, Calicreína, ... Slide 4. The renin-angiotensin system The renin-angiotensin system (RAS) is critical in the regulation of blood pressure and body fluid and sodium homeostasis. The cascade begins when the protein, renin, secreted by the juxtaglomerular cells of the kidney, converts angiotensinogen to the inactive decapeptide angiotensin I. Angiotensin I is subsequently converted by angiotensin converting enzyme (ACE) to angiotensin II (A II), the principal effector hormone [ref: Oliverio & Coffman, 1997]. Angiotensina II Peptídeos inactivos ? - Antagonistas (AT1) Receptores BK 2 ALDO Vasoconstrição Antinatriurese Proliferação celular Inflamação, aterogenese Hipercoagulação Receptores AT1 Receptores AT2 Óxido nítrico ? Vasodilatação Efeito antiproliferativo antiaterogenico PG

MECHANISM OF ACTION RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II ACE Treatment of congestive heart failure. Angiotensin II inhibitors Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan. Other paths AT1 RECEPTOR BLOCKERS RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

84 Pharmacologic Management
Angiotensin Receptor Blockers (ARBs) Block AT1 receptors, which bind circulating angiotensin II Examples: irbesartan, valsartan, candesartan, losartan Should not be considered equivalent or superior to ACE inhibitors In clinical practice, ARBs should be used to treat patients who are ACE intolerant due to intractable cough or who develop angioedema Angiotensin Receptor Blockers Angiotensin receptor blockers, or “ARBs,” are the newest class of drugs to be promoted as a potential treatment for patients with heart failure. ARBs are most often given when a patient cannot tolerate an ACEI. To understand how these unique drugs work, we must first take a closer look at angiotensin II and and the receptors that bind it. Angiotensin II, as we learned previously in this program, is produced from angiotensin I by the action of angiotensin converting enzyme (ACE). As we now know, angiotensin II has a number of potentially adverse effects that contribute to the development and progression of HF, including vasoconstriction, salt and water retention, and activation of the SNS. In addition, angiotensin II is associated with collagen deposition, fibrosis, and myocardial and vascular hypertrophy, which contribute to cardiac remodeling. The effects of angiotensin II throughout the body are mediated via two receptor subtypes, designated AT1 and AT2, which bind angiotensin II. The AT1 receptor has been extensively studied, and has been shown to be widely distributed in the vasculature, heart, kidneys, adrenal glands, and brain. The AT1 receptor subtype is responsible for most of the physiologic effects of angiotensin II on blood pressure, salt and water balance, and cell growth, and therefore plays a central role in the pathogenesis of heart failure.

85 Angiotensin II Receptors
AT1 receptor AT2 receptor Vasoconstriction Growth Promotion Anti-apoptotic Pro-fibrotic Pro-thrombotic Pro-oxidant Vasodilation Growth inhibition Pro-apoptotic ? Fibrosis ? Thrombosis ? redox These drugs for HF are still under clinical investigation and have not been proven better than or equal to ACE inhibitors Angiotensin receptor blockers bind to AT1. These receptors are widely distributed in the heart and appear responsible for the mediation of all the classical effects of Angiotensin II.1 1 McMurray, J and Cleland, J. Heart Failure in Clinical Practice. Second Edition. Martin Dunitz Ltd. p 199.

86 Competitive and selective blocking of AT1 receptors
AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Treatment of congestive heart failure. Angiotensin II inhibitors Drugs which create a selective and competitive block of the AT1 receptors include: losartan, valsartan, irbersartan and candersartan. Competitive and selective blocking of AT1 receptors

87 The ELITE-study 400 350 Losartan 300 Captopril 250 200 150 100 50
Number of Adverse Death and Death patients events hospitalization Pitt et al. Lancet 1997: 349:

88 Losartan Heart Failure Survival Study ELITE II
Study Design ³60 years; NYHA II-IV; EF £40% ACEI/AIIA naive or <7 days in 3 months prior to entry Standard Rx (± Dig/Diuretics), b-blocker stratification Captopril 50 mg 3 times daily (n=1574) Losartan 50 mg daily (n=1578) Event-driven (Target 510 Deaths) ~2 years Primary Endpoint: All-Cause Mortality Secondary Endpoint: Sudden Cardiac Death and/or Resuscitated Arrest Other Endpoints: All-Cause Mortality/Hospitalizations Safety and Tolerability

89 Losartan Heart Failure Survival Study – ELITE II Mortality by Cause (Adjudicated)
% of Patients 15 Losartan (n=1578) Captopril (n=1574) 10 5 Sudden death Heart failure MI Stroke Other CV Non-CV



92 Inibição das vasopeptidases
NEP ECA ANP e peptideos Análogos Adrenomedulina BK Angiotensina II Vasoconstrição Retenção sódio Efeitos hipertróficos Vasodilatação Excreção sódio Efeitos antihipertróficos Pressão arterial Melhoria da performance cardíaca Protecção dos orgãos-alvo


94 Cardiomyopathic hamsters
Omapatrilat: Survival Benefit Cardiomyopathic hamsters 100 80 60 Survival (%) Key Message: Omapatrilat is superior to full dose captopril in enhancing survival in preclinical models of HF. A series of major clinical trials1–9 has demonstrated the enhanced benefits (eg, improved organ function and reduced mortality) of ACE inhibitors to reduce the actions of the RAAS. These trials have shown that ACE inhibition exerted beneficial effects on LV function and survival. In a preclinical HF study with 6-month-old cardiomyopathic hamsters comparing the effects of omapatrilat and captopril, survival in captopril-treated animals increased by 51% compared with placebo.10 In omapatrilat-treated animals, survival increased by 99% vs placebo and 31% vs captopril. The increased survival time for both treatment groups was significant (P<0.001 captopril vs placebo, for all comparisons; P<0.001 omapatrilat vs captopril, for all comparisons). The results with omapatrilat treatment suggest greater benefit than with ACE inhibition for long-term survival in HF. References 1. Enalapril Congestive Heart Failure Investigators. Long-term effect of enalapril in patients with congestive heart failure: a multicenter, placebo-controlled trial. Heart Failure 1987;3: 146 d 221 d 290 d 40 20 Placebo Captopril Omapatrilat 40 80 120 160 200 240 280 320 360 400 440 Days of treatment Start treatment Trippodo et al. J Cardiovasc Pharmacol 1999;34:782

95 Pharmacologic Management
Aldosterone Antagonists Generally well-tolerated Shown to reduce heart failure-related morbidity and mortality Generally reserved for patients with NYHA Class III-IV HF Side effects include hyperkalemia and gynecomastia. Potassium and creatinine levels should be closely monitored REDUÇÂO MORTALIDADE ASSOCIADOS AOS InECA (estudo RALES) Aldosterone Antagonists Spironolactone, long known for its potassium-sparing diuretic effects, is an aldosterone antagonist, and the only aldosterone antagonist available for clinical use in the US. The RALES study (Randomized Aldactone Evaluation Study), a multi-center mortality trial examined the effect of adding low-dose spironolactone to standard diuretic/ACE inhibitor therapy in HF (NYHA Class III and IV patients) has shown to reduce mortality in heart failure patients1. ACC/AHA Guidelines recommends the use of spironolactone in patients with severe HF. The role of spironolactone in patients with mild to moderate HF has not been defined, and use of the drug cannot be recommended in such individuals 2. Hyperkalemia is a concern. Serum potassium and creatinine should be closely monitored, and patients with a potassium level >5 or creatinine >2.5 should not be treated with spironolactone. While therapy with spironolactone is generally well-tolerated, about 9% of patients in the Randomized Aldactone Evaluation Study experienced gynecomastia (swelling of the mammary glands in the male). 1 McMurray, J and Cleland, J. Heart Failure in Clinical Practice. Second Edition. Martin Dunitz Ltd. p 101. 2 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 pp 23-24

Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Treatment of congestive heart failure. Aldosterone inhibitors: Mechanism of action Aldosterone acts directly on specific receptors. At the renal level it produces retention of sodium and water, resulting in an increase in preload and afterload, edema formation and the appearance of symptoms of pulmonary and systemic venous congestion. In addition, it increases the elimination of potassium and magnesium, creating an electrolyte imbalance which may be responsible in part for cardiac arrhythmias. At the tissue level, aldosterone stimulates the production of collagen, being in large part responsible for the fibrosis that is found in hypertrophied myocardium and in the arterial walls of patients with heart failure. The beneficial effects of spironolactone derive from the direct and competitive blockade of specific aldosterone receptors. Aldosterone inhibitors therefore have three types of effects: - Diuretic effect, which is most noticeable when fluid retention and increased levels of aldosterone are present. - Antiarrhythmic effect, mediated by the correction of hypokalemia and hypomagnesemia. - Antifibrotic effect. This effect, demonstrated in animal models, can contribute to a decrease in the progression of structural changes in patients with heart failure. Retention Na+ Retention H2O Excretion K+ Excretion Mg2+ Collagen deposition Fibrosis - myocardium - vessels Edema Arrhythmias

FOR DIURETIC EFFECT • Pulmonary congestion (dyspnea) • Systemic congestion (edema) FOR ELECTROLYTE EFFECTS • Hypo K+, Hypo Mg+ • Arrhythmias • Better than K+ supplements FOR NEUROHORMONAL EFFECTS • Please see RALES results, N Engl J Med 1999:341: Treatment of congestive heart failure. Aldosterone inhibitors: Indications Spironolactone has been used for several decades for its diuretic effect in heart failure. It is currently considered a second line diuretic, to be considered when more potent diuretics, such as the loop diuretics, are inadequate. Retention of K+ and Mg+ prompted by spironolactone has an antiarrhythmic effect which may be helpful in patients with low serum levels of those electrolytes. One indication is when potassium supplementation is required; in these cases, spironolactone administration is preferable. Finally, spironolactone, by virtue of its neurohormonal effects, probably influences the progression and prognosis of patients with heart failure. Its effect on survival is being assessed in a prospective study, compared to placebo (Randomized ALdactone Evaluation Study) in 1400 patients with chronic severe heart failure. The results of this will allow better definition of the indications for spironolactone in patients with chronic congestive heart failure.

98 • Severe renal insufficiency • Metabolic acidosis
ALDOSTERONE INHIBITORS CONTRAINDICATIONS • Hyperkalemia • Severe renal insufficiency • Metabolic acidosis Treatment of congestive heart failure. Aldosterone inhibitors: Contraindications The contraindications for spironolactone use include hyperkalemia and chronic renal insufficiency.

99 Pharmacologic Management
Beta-Blockers Cardioprotective effects due to blockade of excessive SNS stimulation In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months of use Long-term, placebo-controlled trials have shown symptomatic improvement in patients treated with certain beta-blockers1 When combined with conventional HF therapy, beta-blockers reduce the combined risk of morbidity and mortality, or disease progression1 Beta-Blockers Beta-blockers exert their cardioprotective effects through blockade of excessive sympathetic stimulation of the myocardium, peripheral vasculature, and kidneys. While a short-term fall in myocardial contractility is to be expected, it is usually followed by a rise in ejection fraction over the next 1-3 months of use. In the past, beta-blockers were believed to be contraindicated in patients with heart failure because of the LV depression that occurs with short-term use. More recently, the favorable long-term effects of beta-blockade on the heart have been recognized, and the ACC/AHA guidelines support the use of beta-blockers for patients with stable NYHA Class I, II or III heart failure related to LV systolic dysfunction. Beta-blockers are generally well-tolerated. Hypotension associated with dizziness, light-headedness, or blurred vision may occur within the first few days of treatment, but tends to subside with continued drug administration. Decreases in heart rate and alterations in cardiac conduction produced by beta-blockers may also lead to to bradycardia or heart block. These changes can be severe, causing symptomatic hypotension, especially when high doses are used. In these cases, the dose must be reduced or discontinued if the condition persists. Carvedilol (COPERNICUS Trial), bisoprolol (CIBIS-II Trial), and metoprolol CR/XL (MERIT-HF Trial) have all shown to decrease mortality in patients with mild to severe HF1. Currently, carvedilol and metoprolol-CR/XL are the only FDA approved beta-blockers for HF patients. 1 Young, J. Clinical Management of Heart Failure. Professional Communications, Inc pp 96, 100, 178. 1 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 p. 20.

100 Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR
ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of ß1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative Treatment of congestive heart failure. Possible benefits of beta adrenergic blockers The use of ß-blockers in patients with heart failure is controversial. Nevertheless, this slide lists some of the potentially beneficial effects of these drugs for patients in heart failure.

50 ß Blocker 40 Placebo 30 Treatment of Heart Failure. Possible Benefits of Beta-Blockers In the Beta-Blocker Heart Attack Trial the decrease in mortality associated with propranolol use was found to be inversely related to the pre-treatment ejection fraction. Beta Blocker Heart Attack Trial (BHAT). JACC 1990;16:1327 % 20 10 < 30% 30-40% > 40% BHAT JACC 1990;16:1327 LV EJECTION FRACTION

IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina Treatment of Heart Failure. Possible Benefits of Beta-Blockers The ideal candidate for beta-blocker therapy has not yet been established. Nonetheless, having other indications for beta-blocker therapy could be an initial criterion for selection. Examples of these indications include sinus tachycardia, ventricular arrhythmia, hypertension, or angina in a heart failure patient.

103  blockers in heart failure -
US Carvedilol Study Survival 1.0 0.9 0.8 0.7 0.6 0.5 Carvedilol (n=696)  blockers in heart failure - all-cause mortality Placebo (n=398) Risk reduction = 65% p<0.001 50 100 150 200 250 300 350 400 Evidence supporting the mandate for  blockade in the treatment of chronic heart failure. Mortality results from the US Carvedilol Programme, the Second Cardiac Insufficiency Bisoprolol Study (CIBIS-II) and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) have all shown the benefits of  blockade in class II-III heart failure. Risk reductions for mortality were highly significant in all three trials: 65% in the US Carvedilol Programme and 34% in both CIBIS-II and MERIT-HF. Days Packer et al (1996) Survival Mortality % CIBIS-II 20 MERIT-HF Placebo Bisoprolol 15 Metoprolol CR/XL 10 Placebo Risk reduction = 34% Risk reduction = 34% 5 p=0.0062 p<0.0001 3 6 9 12 15 18 21 Time after inclusion (days) Lancet (1999) Months of follow-up The MERIT-HF Study Group (1999)

104 Additional benefits of carvedilol in CHF
Antioxidant effects reduction in myocyte apoptosis decreased lipid peroxidation Antiproliferative effects inhibition of vascular smooth muscle cell proliferation Reduction in circulating endothelin-1

105 Treatment Approach for the Patient with Heart Failure
Stage A At high risk, no structural disease Stage B Structural heart disease, asymptomatic Stage C Structural heart disease with prior/current symptoms of HF Stage D Refractory HF requiring specialized interventions Therapy Treat Hypertension Treat lipid disorders Encourage regular exercise Discourage alcohol intake ACE inhibition Therapy All measures under stage A ACE inhibitors in appropriate patients Beta-blockers in appropriate patients Therapy All measures under stage A Drugs: Diuretics ACE inhibitors Beta-blockers Digitalis Dietary salt restriction Therapy All measures under stages A,B, and C Mechanical assist devices Heart transplantation Continuous (not intermittent) IV inotropic infusions for palliation Hospice care Stages (as classified in ACC/AHA guidelines) in the evolution of heart failure and recommended therapy Hunt, SA, Baker, DW, Chin, MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2001. Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001

106 Tratamento da Ins. cardiaca
Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas Pimobendam, vesnarinona, pentoxifilina Ressincronização cardíaca

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