Parte I: Etiologa y Fisiopatologa de la Insuficiencia Cardiaca

Definicin de Insuficiencia Cardiaca (IC)Sndrome clnico complejo en donde el corazn no puede mantener un gasto cardiaco adecuado para las demandas del organismo y el retorno venoso.La I. C. es la va final de muchos procesos y se manifiesta como un sndrome clnico comn para todos ellos, requiere en muchos casos de un tratamiento especfico segn la cardiopata subyacente.

Definicin de Insuficiencia Cardiaca (IC)Los sntomas que acompaan al sndrome clnico de I. C., son muy pocos sensibles y nada especficos para alcanzar el diagnstico (descartar neumopatas, tiroideas, hepticas, nefropatas, etc.).Hay pocos estudios orientados a analizar el valor diagnstico de los sntomas de la I. C.

1 World Health Statistics, World Health Organization, 1995.2 American Heart Association, 2002 Heart and Stroke Statistical Update.Incidencia y prevalencia de la ICPrevalencia Mundial, 22 millones1 Estados Unidos, 5 millones2 Incidencia Mundial, 2 millones de nuevos casos por ao1Estados Unidos, 500,000 de nuevos casos por ao2IC presente en 10 de cada 1,000 personas mayores de 65 aos en E.E.U.U.2

Etiologa de la Insuficiencia CardiacaQu causa Insuficiencia Cardiaca?La prdida de una masa crtica de miocitos funcionales despus de un dao consecutivo a:Cardiopata Isqumica Hipertensin Miocardiopata IdiopticaInfecciones (p. ej. miocarditis viral, Enfermedad de Chagas)Toxinas (p.ej. alcohol o antimetabolitos) Valvulopatas Arritmias crnicasInfiltrativas (p. ej. Amiloidosis, leucemia, linfoma, etc.)Excesos de hormonas (hipertiroidismo, feocromocitoma, etc.)

Causas precipitantes

Arritmias rpidas o lentas

Anemia

Infecciones (cardiacas, pulmonares sistmicas)

Hipertiroidismo

Aumento importante de peso

Sobrecarga de presin o volumen

Enfermedad cardiaca concomitante

30%70%Disfuncin DiastlicaDisfuncin Sistlica(FE < 40%)(FE > 40 %)Disfuncin Ventricular IzquierdaSistlica: Contractilidad o eyeccin alteradaAproximadamente dos terceras partes de pacientes con IC tienen disfuncin sistlica1Diastlica: Llenado o relajacin alterados1 Lilly, L. Pathophysiology of Heart Disease. Segunda Edicin p 200

VolumenLatidoPrecargaPostcargaContractilidadGasto CardiacoFrecuencia CardiacaContraccin Sinrgica del VIIntegridad de la ParedSuficiencia ValvularDeterminantes de la Funcin VentricularGasto Cardiaco = FC X VL (cantidad de sangre que bombea el corazn en un minuto).

SobrecargaDe Volumen SobrecargaDe Presin Prdida de MiocardioContractilidadAlterada Disfuncin VIFE < 40%GastoCardiacoHipoperfusin Volumen Telesistlico Volumen TelediastlicoCongestin PulmonarDisfuncin Ventricular Izquierda

Bases Hemodinmicas delos sntomas de Insuficiencia CardiacaPDFVI Presin Atrial Izquierda Presin Capilar Pulmonar Congestin Pulmonar

Fisiopatologa.Mecanismos Compensadores Mecanismo de Frank-Starling Activacin Neurohormonal Remodelado Ventricular

Fisiopatologa.Mecanismos Compensadores

Mecanismo de Frank-Starling a.En reposo, sin ICb.IC debida a disfuncin del VIc.IC avanzada

Fisiopatologa.Mecanismos CompensadoresActivacin NeurohormonalMuchos mecanismos hormonales distintos estn comprometidos en mantener una homeostasis cardiovascular normal e incluyen:Sistema Nervioso Simptico (SNS)Sistema Renina-Angiotensina-Aldosterona(SRAA)Vasopresina (hormona antidiurtica, HAD)

Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52. Estmulo simptico del SNCProgresoDe la EnfermedadFisiopatologa.Activacin Simptica en Insuficiencia Cardiaca

VasoconstriccinEstrs OxidativoCrecimiento CelularProteinuriaRemodelado VIRemodelado VascularAngiotensingenoAngiotensina IAngiotensina IIReceptor AT IReninaEnzima Convertidora de Angiotensina(IECA)Fisiopatologa.Mecanismos Compensadores: Sistema Renina-Angiotensina-Aldosterona (SRAA)

PAM = (VS x FC) x RTPRenina-Angiotensina-Aldosterona( perfusin renal)Retencin Sodio-aguaSedAumentoSimpticoVasoconstriccinFisiopatologa.Mecanismos Compensadores: Sistema Renina-Angiotensina-Aldosterona (SRAA)Descenso de la PAM

Presin Arterial Media DisminuidaBaroreceptores CentralesEstimulacin del hipotlamo, que producevasopresina secretada por hipfisisSecrecin de vasopresina por la hipfisisVasoconstriccinAumento de la presin arterial mediaRetroalimentacin negativaFisiopatologa.Mecanismos Compensadores: Activacin Neurohormonal Vasopresina (HAD)Retencin de H20 (rin)

Fisiopatologa.Estimulacin Compensadora Neurohormonal: Resumen

Inicialmente Adaptativa, Nociva si persisteFisiopatologa.Respuestas Neurohormonales a la Falla CardiacaJaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

RespuestaEfectos a Corto-Plazo Efectos a Largo-PlazoRetencin de Sodio y AguaAumenta PrecargaCongestin Pulmonar, AnasarcaVasoconstriccinMantiene P.A. para perfusin a rganos vitalesExacerba la falla de bomba (postcarga excesiva), aumenta consumo miocrdico de oxgenoEstimulacin SimpticaAumenta FC y contractilidadAumento en el consumo miocrdico de oxgeno

Fisiopatologa.Otras Neurohormonas (Pptidos Natriurticos).1.- Pptido Natriurtico Atrial (ANP)Encontrado en las aurculas (sobrecarga y distension).2.- Pptido Natriurtico Cerebral (hBNP) Encontrado en los ventrculos (dilatacin). 3.- Pptido Natriurtico tipo C (CNP)Encontrado en el SNC. Propiedades limitadas.

Vasodilatadoras (actan sobre los vasos sanguneos).- Efectos natriurticos (excrecin de sal) y diurticos (excrecin de agua). - Inhinem la secrecin de renina, aldosterona y vasopresina (vasoconstrictivas).

Producidas por las clulas que recubren las arterias y venas denominado endotelio.

Factores relajantes derivados del endotelio Vasodilatadores:- xido Ntrico (NO)- Bradicinina- ProstaciclinaFactores constrictores derivados del endotelio Vasoconstrictores: - Endotelina I

Actan: en el mismo endotelio, clulas de msculo liso y paredes de vasos sanguneos.

Fisiopatologa.Substancias Vasoactivas Derivadas del Endotelio

Fisiopatologa.Mediadores de la Insuficiencia CardiacaCitocinasPequeas molculas proticas producidas por una variedad de tejidos y clulasInotrpicas negativasLos niveles elevados se asocian con mal pronsticoEjemplos:Factor de necrosis tumoral (TNF)-Interleucina 1-Interleucina-2Interleucina-6Interferon-

Disfuncin VIGasto cardiaco disminuidoy Presin arterial disminudaMecanismo de Frank-Starling RemodeladoActivacin NeurohormonalAumento del Gasto Cardiaco (via aumentode contractilidad y frecuencia cardiaca)Aumento de Presin Arterial (via vasoconstriccin y aumento de volumen sanguneo)Trabajo cardiaco aumentado(ya sea precarga o postcarga)Fisiopatologa.Crculo Vicioso de la Insuficiencia Cardiaca

Curry CW, et al. Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction delay as depicted by 3D tagged magnetic resonance imaging. Circulation 2000 Jan 4;101(1):E2. Fisiopatologa.Mecanismos CompensadoresRemodelado Ventricular Alteraciones en el tamao, forma, estructura y funcin del corazn en respuesta a los cambios hemodinmicos crnicos de la insuficiencia cardiaca.

Parte II:Diagnstico de la Insuficiencia Cardiaca

Diagnstico de Insuficiencia CardiacaHistoria ClnicaExamen FsicoExmenes de Laboratorio y Gabinete

Evaluacin diagnstica de Insuficiencia Cardiaca de nueva instalacinDeterminar el tipo de disfuncin ventricular (sistlica o diastlica)Determinar EtiologaDefinir el pronsticoOrientar el tratamiento

Disfuncin Ventricular IzquierdaSistlica y DiastlicaSntomasDisnea de EsfuerzoDisnea Paroxstica Nocturna TaquicardiaTosHemoptisis

SignosEstertores BasalesEdema Pulmonar Galope con 3er. RuidoDerrame PleuralRespiracin de Cheyne-Stokes

Insuficiencia Ventricular DerechaSistlica y DiastlicaSntomasDolor AbdominalAnorexiaNauseaAbotagamientoRetencin de lquidosSignosEdema PerifricoPltora YugularReflujo Hepato-yugularHepatomegalia

Criterios para el diagnsticode insuficiencia cardiacaModificado de FraminghamDos criterios mayores o Un mayor y dos menores

Criterios mayoresCriterios menoresCriterios mayores agregadosDPNEdema tibialPulso alternantePltora yugularTos nocturnaPulso deficienteEstertores pulmonaresDisnea de esfuerzoPulso decrecienteCardiomegalia radiogrficaHepatomegalia Pptido natriurticocerebralEdema agudo de pulmnDerrame pleuralGalope ventricularTaquicardia >120xGalope auricularPresin venosa >16 cm H2OReflujo hepatoyugularPeso 4.5 kg en 5 das

Evaluacin Diagnstica de la Insuficiencia Cardiaca de nueva instalacinEstudios iniciales:ECGSerie radiolgica de coraznLaboratorioEcocardiograma

Cuadro ClnicoElectrocardiograma:Ayuda a diagnosticar la causa que produce la I. C.

Importante buscar: Signos de infarto previo.Hipertrofia del V. I.Arritmias.Derrame pericrdico (alternancia elctrica, voltaje menor de 5 mm en derivaciones estndar y de 10 mm en las precordiales).Amiloidosis cardiaca (patrones de bajo voltaje y seudoinfarto en las derivaciones anteriores).

Cuadro Clnico (RAYOS X)Edema intersticialEdema agudo de pulmnDerramepleuralImagentpica de I. C.

Cuadro ClnicoEstudios de laboratorio:Aunque la I. C. es un diagnstico clnico,deber realizarse estudio de laboratorio completo en pacientes de reciente diagnstico.En la I. C. no descompensada prcticamente todo est dentro de lo normal.Electrolitos Sricos, suelen ser normales, pueden estar alterados por la propia enfermedad o por el tratamiento (diurticos).

Cuadro ClnicoEstudios de laboratorio:Hiponatremia puede indicar descompensacin de la I. C.En casos avanzados puede existir hiponatremia dilucional e hiperkalemia por reduccin de la filtracin glomerular.Hipokalemia (uso de diurticos).Pruebas de funcin heptica: puede haber elvacin de transaminasas, bilirrubinas y DHL por la hepatomegalia congestiva.Puede verse aumento del nitrgeno urico en proporcin mayor a la creatinina.EGO: proteinuria, cilindros, aumento en la densidad.Realizar PFT y los necesarios para cada caso.

Clasificacin Funcional Asociacin de Cardiologa de N.Y. (NYHA)Clase I:Sin sntomas con actividad normalClase II:Pequea limitacin de la actividad fsica. Sin problemas en reposo pero la ctividad fsica normal causa fatiga, taquicardia, disnea o anginaClase III:Limitacin importante a la actividad fsica. Sin problemas en reposo pero la actividad fsica ligera causa fatiga, taquicardia, disnea o angina.Clase IV:Incapaz de realizar cualquier actividad fsica sin molestias. Los sntomas de IC pueden estar presentes en el reposo.

Clasificacin de la IC: Evolucin y ProgresoCuatro clases de IC (Guas de ACC/AHA):Estado A: Pacientes con alto riesgo de desarrollar IC sin dao estructual cardiaco.Estado B: Pacientes con dao estructural cardiaco sin sntomas de ICEstado C: Pacientes con sntomas pasados o presentes de IC asociados a cardiopata estructural subyacente.Estado D: Pacientes con enfermedad terminal que requieren de tratamiento especializado.Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001

Parte III: Tratamiento Actual de la Insuficiencia Cardiaca Crnica

El Crculo Vicioso del Tratamiento de la Insuficiencia CardiacaIC CrnicaConsultaEmergenciaHospitalizacinDescomp. PesoDiurtico VODiurtico IV o IngresoDiuresis y Egreso

Tratamiento.Medidas GeneralesModificaciones alEstilo de Vida:Reduccin de pesoEliminar tabaquismoEvitar alcohol y otras substancias cardiotxicasEjercicioConsideraciones Medicas:Tratar HAS, hiperlipidemia, diabetes, arritmiasRevascularizacin CoronariaAnticoagulacinVacunacinRestriccin SodioPeso diarioVigilancia Estrecha

Tratamiento FarmacolgicoDigoxinaAumenta el Inotropismo del msculo cardiacoReduce activacin del SNC y SRAALos estudios controlaos han demostrado que el tratamiento crnico con digoxina produce:Reduccin de sntomasAumento en la tolerancia al ejercicioMejora en la hemodinmicaReduccin del progreso de la ICReduce la hospitalizacin de IC descompensadaNo mejora la sobrevida.

Tratamiento FarmacolgicoDiurticosSe usan para disminuir la retencin de lquidosMejoran la tolerancia al ejercicio, no la sobrevidaFacilitan el uso de otros frmacos indicados en I. C. A los pacientes se les puede ensear a regular la dosis de acuerdo a su peso corporalUna complicacin frecuente es el desequilibrio electrolticoNo deben usarse de manera aislada en la insuficiencia cardiacaLas dosis altas de diurticos se asocian con mortalidad alta

Tratamiento FarmacolgicoInhibidores de la ECABloquean la conversin de angiotensina I a angiotensina II; previenen el deterioro funcionalRecomendados para todos los pacientes con ICEliminan sntomas y mejoran la tolerancia al esfuerzoReducen el riesgo de muerte y enlentencen el progreso de la enfermedadLos efectos benficos se notan despus de 1-2 meses de tratamiento

Tratamiento FarmacolgicoBloqueadores BetaTienen efecto cardioprotector al evitar la estimulacin excesiva del SNC A corto plazo, los bloqueadores beta deprimen la contractilidad miocrdica (respuesta paradjica); sta aumenta despus de 1-3 meses de tratamientoEstudios a largo plazo, controlados con placebo, han demostrado mejora sintomtica en pacientes tratados con algunos bloqueadores beta1Su uso combinado con la terapia habitual para IC, reduce el riesgo de morbilidad, mortalidad y progreso de la enfermedad11 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 p. 20.

Tratamiento FarmacolgicoAntagonistas de la AldosteronaGeneralmente bien toleradosHan demostrado reducir la morbilidad y mortalidad por insuficiencia cardiaca Habitualmente reservados para pacientes en clases funcionales III-IV de la NYHALos efectos colaterales son hiperkalemia y ginecomastia. Los niveles de Potasio y creatinina deben vigilarse estrechamente

Tratamiento FarmacolgicoBloqueadores del Receptor de Angiotensina (ARA II)Bloquean los receptores AT1, que se unen a la angiotensina II circulanteEjemplos: valsartn, candesartn, losartn, telmisartnLos estudios realizados en insuficiencia cardiaca muestran resultados semejantes a los IECAEn la prctica clnica deben usarse en pacientes intolerantes a los IECA y en algunos casos pueden agregarse al tratamiento habitual

Receptor AT1Receptor AT2VasoconstriccinProliferacinAnti-apoptticoPro-fibrticoPro-trombticoPro-oxidanteVasodilatacinInhibe crec. Cel.Pro-apopttico? Fibrosis? Thrombosis? RedoxReceptores para Angiotensina II

Enfoque teraputico hacia el paciente con Insuficiencia CardiacaEstadio AAlto riesgo, sin dao estructural Estadio BDao estructural cardiaco, asintomtico Estadio DIC refractaria que requiere tratamiento especializadoTerapiaTratar HipertensinTratar dislipidemiaPromover ejercicio regularEvitar alcohol en excesoInhibicin ECA TerapiaTodas las medidas del Estadio AIECA en pacientes seleccionadosBeta-bloquedores en pacientes seleccionados

TerapiaTodas las medidas para el Estadio AMedicamentos:DiurticosIECABeta-bloqueadoresDigitalDieta y restriccin de sodioAntagonistas AldosteronaTerapiaTodas las medidas para los estadios A, B y CAsistencia mecnicaTransplante CardiacoUso continuo de medicacin endovenosa para mejora sintomticaCuidados domiciliariosEstadio CDao estructural cardiaco con sntomas previos o actuales de ICHunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001

ENFOQUE TERAPEUTICO HACIA ELPACIENTE CON INSUFICIENCIA CARDIACAEstadios de Insuficiencia Cardiaca y Opciones de Tratamiento para I. C. SistlicaNEJM, 2003;348: 2007-18

Under normal circumstances, the heart accepts blood at low filling pressures during diastole and then propels it forward at higher pressures during systole. A variety of disorders can impair the ability of the heart to meet the metabolic demands of the body. Heart failure (HF) can be defined as a complex clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.Today, substantial healthcare resources are used to treat heart failure patients, yet heart failure patients continue to have a poor quality of life and an unacceptably high mortality rate. According to the American Heart Association, the five-year mortality rate for heart failure patients is about 50%.

Heart failure is estimated to afflict more than 22 million people worldwide with an estimated 2 million new cases diagnosed annually.1In the United States it is estimated that 5 million people have HF, with 10 out of every 1,000 over the age of 65 being afflicted.2It is the only major cardiovascular disorder that is increasing in incidence and prevalence.Other Heart Failure Statistics:HF patients take an average of six medications378% of HF patients have had at least two hospital admissions per year3 Cost of HF in the U.S. is estimated to be between $10 billion and $38 billion annually4 5-year survival rate for all NYHA classes estimated at 50%2

1 World Health Statistics, World Health Organization, 1995. 2 American Heart Association, 2002 Heart and Stroke Statistical Update 3 English M and Mastream M. Crit Care Nurse Q 1995;18:1-6. 4 Havranek EP, Abraham WT, The Healthcare Economics of Heart Failure 1998; 14:10-18.

Listed above is the etiology of heart failure in order from most to least common causes.

As previously seen, there are many causes of heart failure. Some diseases, however, tend to more adversely affect the hearts 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.

Stroke volume is affected by preload, afterload, and contractility. Preload is the amount myocardial stretch at the end of diastole. Afterload is the resistance that needs to be overcome for the heart to eject the blood. There is an inverse relationship between afterload and ventricular function. As the resistance to contraction increases, the force of contraction decreases which results in a decreased stroke volume. Also, as an increase in resistance occurs, there is an increase in myocardial oxygen demand. Contractility is the inotropic state of the heart independent of the preload and the afterload. Synergistic LV contraction, wall integrity, and the competence of the valves also affect cardiac output.

LV dysfunction is defined as an ejection fraction of less than 40%. The number one cause of LV systolic dysfunction is loss of myocardium due to a myocardial infarction ( MI, or heart attack). Pressure overload due to uncontrolled hypertension is another major cause of systolic dysfunction. It is estimated that only 25% of all patients with hypertension are adequately treated. Impaired contractility also contributes to LV dysfunction and is usually the result of drugs such as alcohol or toxins such as chemotherapy. Volume overload from valvular diseases contribute to LV dysfunction. LV dysfunction causes decreased cardiac output, which in turn causes hypoperfusion of the bodys organs. In addition, LV dysfunction causes an increase in the amount of blood left in the ventricle when the heart squeezes, and therefore, both End Systolic and End Diastolic Volumes are subsequently increased. This increase in volume leads to pulmonary congestion and the patient being short of breath.

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.

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

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 patients 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.

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, lets 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 bodys 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.The sympathetic nervous systems 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 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).1McMurray, J and Cleland, J. Heart Failure in Clinical Practice. Second Edition. Martin Dunitz Ltd. p 101.2Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 pp 23-24

Angiotensin Receptor BlockersAngiotensin 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.

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

1McMurray, J and Cleland, J. Heart Failure in Clinical Practice. Second Edition. Martin Dunitz Ltd. p 199.

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.