Trombose

coronária

Enfarte do

miocárdio

Morte

súbita

Perda de

músculo

Remodelagem

Dilatação

ventricular

Insuficiência cardíaca

Morte

Isquemia

miocárdica

D.Coronária

Aterosclerose

HVE

Factores de risco:

• Hipertensão Arterial

• Hiperlipidemia

• Diabetes

• Obesidade

• Tabagismo

Adaptado de Dzau V e col., 1991

MORTALIDADE CARDIOVASCULARMORTALIDADE CARDIOVASCULARCadeia de eventosCadeia de eventos

MORTALIDADE CARDIOVASCULARMORTALIDADE CARDIOVASCULARCadeia de eventosCadeia de eventos

ActivaçãoActivação

neurohumoralneurohumoral

ActivaçãoActivação

neurohumoralneurohumoral

INSUFICIÊNCIA CARDÍACA

INSUFICIÊNCIA CARDÍACA

• SINDROME COMPLEXO, COM ETIOLOGIAS VÁRIAS

• ATINGE CERCA DE 20 MILHÕES DE PESSOAS EM TODO O MUNDO

• NÚMERO DE CASOS SOBE EXPONENCIAL- MENTE SOBRETUDO NO IDOSO

10% DOS IDOSOS COM IDADE > 75 ANOS

TÊM INSUFICIÊNCIA CARDÍACA

INSUFICIÊNCIA CARDÍACA

O PROGNÓSTICO É MAU

• A MORBILIDADE É MUITO SIGNIFICATIVA

• AS ADMISSÕES HOSPITALARES SÃO MUITO FREQUENTES ( CAUSA MAIS HABITUAL DE INTERNAMENTO EM IDADE > 65 ANOS)

INSUFICIÊNCIA CARDÍACA

PORQUE É QUE A INS. CARDÍACA AUMENTA?

• POPULAÇÃO MAIS ENVELHECIDA

• SUCESSO DA TERAPÊUTICA NA MELHORIA DA SOBREVIVÊNCIA PÓS-EAM (trombólise ou outras medidas)

• AUMENTO NA DURAÇÃO DA SOBREVIDA DOS DOENTES COM INSUFICIÊNCIA CARDÍACA

DEFINITIONDEFINITION

“The situation when the heart is

incapable of maintaining a cardiac

output adequate to accommodate

metabolic requirements and the

venous return."

“The situation when the heart is

incapable of maintaining a cardiac

output adequate to accommodate

metabolic requirements and the

venous return."E. BraunwaldE. Braunwald

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

MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in 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). congestive heart failure (MERIT-HF). LANCET. LANCET. 1999;353:2001-07.1999;353:2001-07.

Severity of Heart FailureModes of Death

12%12%

24%24%

64%64%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 103n = 103

NYHA IINYHA II

26%26%

15%15%

59%59%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 103n = 103

NYHA IIINYHA III

56%56%

11%11%

33%33%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 27n = 27

NYHA IVNYHA IV

Etiology of Heart FailureWhat 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

30%30%

70%70%

Diastolic DysfunctionDiastolic DysfunctionSystolic DysfunctionSystolic Dysfunction

(EF < 40%)(EF < 40%)(EF > 40 %)(EF > 40 %)

Left Ventricular Dysfunction• Systolic: Impaired contractility/ejection

– Approximately two-thirds of heart failure patients have systolic dysfunction1

• Diastolic: Impaired filling/relaxation

1 Lilly, L. 1 Lilly, L. Pathophysiology of Heart DiseasePathophysiology of Heart Disease. Second Edition p 200. Second Edition p 200

DETERMINANTS OF VENTRICULAR FUNCTION

DETERMINANTS OF VENTRICULAR FUNCTION

STROKE VOLUMESTROKE VOLUME

PRELOADPRELOAD

CONTRACTILITYCONTRACTILITY

CARDIAC OUTPUTCARDIAC OUTPUT

HEART RATE

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOADAFTERLOAD

Hemodynamic Basis for Heart Failure Symptoms

Hemodynamic Basis forHeart Failure Symptoms

LVEDP

Left Atrial Pressure

Pulmonary Capillary Pressure

Pulmonary Congestion

Left Ventricular DysfunctionSystolic 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

Disfunção miocárdica

Retenção H2O e sal Vasoconstrição

Redistribuição fluxoInotropia +Taquicardia

Dilatação e hipertrofia

Activação neurohumoral

ICC - Fase de respostas compensatórias

Melhoria transitória Melhoria transitória

Frank-Starling< stress da parede

Compensatory Mechanisms

• Frank-Starling Mechanism

• Neurohormonal Activation

• Ventricular Remodeling

Compensatory Mechanisms

Frank-Starling Mechanism

a. At rest, no HF

b. HF due to LV systolic dysfunction

c. Advanced HF

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)

VasodilatoresVasodilatoresNatriuréticosNatriuréticos

Anti-proliferativosAnti-proliferativosAnti-inflamatóriosAnti-inflamatórios

AntitrombogénicosAntitrombogénicos

Equilíbrio sistemas neuro-humorais reguladores perfusão

VasoconstritoresVasoconstritoresAnti-natriuréticosAnti-natriuréticosPró-proliferativosPró-proliferativosPró-inflamatóriosPró-inflamatóriosTrombogénicosTrombogénicos

DopaminaDopaminaANF, BNF, CNFANF, BNF, CNF

AdrenomedulinaAdrenomedulinaProstaciclinaProstaciclinaBradicininaBradicinina

NONO

Angiotensina 2Angiotensina 2AldosteronaAldosteronaAdrenalinaAdrenalina

NoradrenalinaNoradrenalinaEndotelinaEndotelina

VSPVSPTBX A2TBX A2UbaínaUbaína

Initially AdaptiveInitially Adaptive

ResponseShort-Term Effects

Salt and Water Retention Augments Preload

Vasoconstriction Maintains BP for perfusion of vital organs

Sympathetic Stimulation Increases HR and ejection

Neurohormonal Responses to ImpairedCardiac Performance

Jaski, B, MD: Jaski, B, MD: Basics of Heart Failure: A Problem Solving ApproachBasics of Heart Failure: A Problem Solving Approach

Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.

CNS sympathetic outflowCNS sympathetic outflow

Disease progressionDisease progression

Cardiac sympatheticCardiac sympatheticactivityactivity

11--

receptorsreceptors22--

receptorsreceptors11--

receptorsreceptors

VasoconstrictionVasoconstrictionSodium retentionSodium retention

Myocardial toxicityMyocardial toxicityIncreased arrhythmiasIncreased arrhythmias

SympatheticSympatheticactivity to kidneysactivity to kidneys

+ peripheral vasculature+ peripheral vasculature

ActivationActivationof RASof RAS

11-- 11--

Sympathetic Activation in Heart Failure

1 and 2 receptor densities in the failing and non-failing heart

Receptor density (ƒ mol/mg)Receptor density (ƒ mol/mg)

Non-failingNon-failing

FailingFailing

**pp<0.05<0.05

****pp=NS=NS

11 22

8080

6060

4040

2020

00

****

**

VasoconstrictionVasoconstriction

Oxidative StressOxidative Stress

Cell GrowthCell Growth ProteinuriaProteinuria

LV remodelingLV remodeling

Vascular remodelingVascular remodeling

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

AT I receptorAT I receptor

ReninRenin

AngiotensinAngiotensinConvertingConverting

EnzymeEnzyme

Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS)

Na+ retentionNa+ retention

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

• Diuretic and vasodilatory properties

– C-type Natriuretic Peptide (CNP)• Predominantly found in the central nervous system

• Limited natriuretic and vasodilatory properties

Hemodynamic Hemodynamic (balanced vasodilation)(balanced vasodilation)

•• veinsveins

•• arteriesarteries

•• coronary arteriescoronary arteries

NeurohormonalNeurohormonal

aldosteronealdosterone

norepinephrinenorepinephrine

RenalRenal

diuresis & natriuresisdiuresis & natriuresis

DR I

M

K

RG

S SS

SG

L

GF

CC

S S

GSGQVM

K V LR

RH

KPS

Pharmacological Actions of hBNP

Abraham WT and Schrier RW, 1994Abraham WT and Schrier RW, 1994

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

Mediators of Heart FailureCytokines

• 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

Initially Adaptive, Deleterious if SustainedInitially Adaptive, Deleterious if Sustained

ResponseShort-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

Neurohormonal Responses to ImpairedCardiac Performance

Jaski, B, MD: Jaski, B, MD: Basics of Heart Failure: A Problem Solving ApproachBasics of Heart Failure: A Problem Solving Approach

Disfunção miocárdica

Dilatação ventricularRemodelagem

Stress oxidativoCitocinasApoptose

Activação neurohumoral

ICC - Fase de descompensação

agravamento

Mitogénese Proliferação celular

Dilatação e hipertrofia

Perda de miócitos, necrose e fibrose

Alterações estruturais, miocárdio, tecido conjuntivo, vasos

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

sobrevidaMorbilidadeCapacidade de Exercicio Qualidade de vidaAlterações NeurohormonaisProgressão da CHFSintomas

sobrevidaMorbilidadeCapacidade de Exercicio Qualidade de vidaAlterações NeurohormonaisProgressão da CHFSintomas

Objectivos terapêuticosObjectivos terapêuticos

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

DRUGSHEMODYNAMIC EFFECTS

DRUGSHEMODYNAMIC EFFECTS

AAII

A + VA + V

VV

DD

Ventricular Filling PressureVentricular Filling Pressure

StrokeVolumeStrokeVolume

NormalNormal

CHFCHF

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

oCH3

OH

OHCH3

= O

- o- - o-HO -

HO -

o o o

HO -HO -

CH 3CH 3CH 3

- O -

Genina

Esteroide

Lactona

Tri-digitoxose (açucares)

Figura 1. Estrutura da digoxina, protótipo dos digitálicos

Na+Na+

K+K+

K+K+

Na+Na+

Na+Na+ Ca++Ca++

Ca++Ca++

Na-K ATPaseNa-K ATPase Na-Ca ExchangeNa-Ca Exchange

MyofilamentsMyofilaments

DIGOXINDIGOXIN

CONTRACTILITYCONTRACTILITY

Figura 2. Efeitos inotrópicos e neurais dos digitálicos

Efeito simpático-inibidor

Adaptado de Opie, 1990

aferências

Estimulação simpática

Estimulação vagal

Taquiarritmias

Aumento Ca2+ intracelular

TrocadorNa+/Ca2+

> Ca 2+

intracelular

> saídade sódio2K + 3Na +

Digitálicos

> sódiointracelular

EFEITO INOTRÓPICO POSITIVO

Doses

tóxicas

dosesterapêuticas

Normal Conduction Pathway in the Heart and the ECG

Sinoatrial (SA) Node Atrioventricular (AV) Node

Left Bundle Branches

Right Bundle Branch

Purkinje Fibers

P = Atrial DepolarizationQRS = Ventricular DepolarizationT = Ventricular Repolarization

P T

QRS

DIGOXIN PHARMACOKINETIC PROPERTIES

DIGOXIN PHARMACOKINETIC PROPERTIES

Oral absorption (%)Protein binding (%)Volume of distribution (l/Kg)Half lifeEliminationOnset (min)

i.v.oral

Maximal effect (h)i.v.oral

DurationTherapeutic level (ng/ml)

Oral absorption (%)Protein binding (%)Volume of distribution (l/Kg)Half lifeEliminationOnset (min)

i.v.oral

Maximal effect (h)i.v.oral

DurationTherapeutic level (ng/ml)

60 - 7525

6 (3-9)36 (26-46) h

Renal

5 - 3030 - 90

2 - 43 - 6

2 - 6 days0.5 - 2

60 - 7525

6 (3-9)36 (26-46) h

Renal

5 - 3030 - 90

2 - 43 - 6

2 - 6 days0.5 - 2

DIGOXIN

HEMODYNAMIC EFFECTSDIGOXIN

HEMODYNAMIC EFFECTS

Cardiac output

LVejection fraction

LVEDP

Exercisetolerance

Natriuresis

Neurohormonalactivation

Cardiac output

LVejection fraction

LVEDP

Exercisetolerance

Natriuresis

Neurohormonalactivation

DIGOXIN NEUROHORMONAL EFFECTS

DIGOXIN NEUROHORMONAL EFFECTS

Plasma Noradrenaline

Peripheral nervous system activity

RAAS activity

Vagal tone

Normalizes arterial baroreceptors

Plasma Noradrenaline

Peripheral nervous system activity

RAAS activity

Vagal tone

Normalizes arterial baroreceptors

DIGOXIN

LONG TERM EFFECTSDIGOXIN

LONG TERM EFFECTS

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions

DIGOXIN

CLINICAL USESDIGOXIN

CLINICAL USES

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs

DIGOXIN

CONTRAINDICATIONSDIGOXIN

CONTRAINDICATIONSABSOLUTE:

- 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

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

DIGOXIN TOXICITY

CARDIAC MANIFESTATIONSDIGOXIN TOXICITY

CARDIAC MANIFESTATIONS

ARRHYTHMIAS :- Ventricular (PVCs, TV, VF)- Supraventricular (PACs, SVT)

BLOCKS:- S-A and A-V blocks

CHF EXACERBATION

ARRHYTHMIAS :- Ventricular (PVCs, TV, VF)- Supraventricular (PACs, SVT)

BLOCKS:- S-A and A-V blocks

CHF EXACERBATION

DIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONSDIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONS

GASTROINTESTINAL:- Nausea, vomiting, diarrhea

NERVOUS:- Depression, disorientation, paresthesias

VISUAL:- Blurred vision, scotomas and yellow-green

vision HYPERESTROGENISM:

- Gynecomastia, galactorrhea

GASTROINTESTINAL:- Nausea, vomiting, diarrhea

NERVOUS:- Depression, disorientation, paresthesias

VISUAL:- Blurred vision, scotomas and yellow-green

vision HYPERESTROGENISM:

- Gynecomastia, galactorrhea

CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

MilrinonePiroximoneMilrinonePiroximone

POSITIVE INOTROPESPOSITIVE INOTROPES

ß-ADRENERGIC STIMULANTS

CLASSIFICATION

ß-ADRENERGIC STIMULANTS

CLASSIFICATION

B1 StimulantsIncrease contractility

Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol

B1 StimulantsIncrease contractility

Dobutamine Doxaminol XamoterolButopamine Prenalterol Tazolol

B2 StimulantsProduce arterial vasodilatation and reduce SVR

B2 StimulantsProduce arterial vasodilatation and reduce SVR

PirbuterolCarbuterolPirbuterolCarbuterol

RimiterolFenoterolRimiterolFenoterol

TretoquinolSalbutamolTretoquinolSalbutamol

TerbutalineSalmefamolTerbutalineSalmefamol

SoterenolQuinterenolSoterenolQuinterenol

MixedMixedDopamineDopamine

DOPAMINE AND DOBUTAMINEEFFECTS

DOPAMINE AND DOBUTAMINEEFFECTS

ReceptorsReceptors

ContractilityContractility

Heart RateHeart Rate

Arterial Press.Arterial Press.

Renal perfusionRenal perfusion

ArrhythmiaArrhythmia

DA (µg / Kg / min)DA (µg / Kg / min) DobutamineDobutamine

< 2< 2DA1 / DA2DA1 / DA2

±±

±±

±±

++++

--

2 - 52 - 5ß1ß1

++++

++

++

++

±±

> 5> 5ß1 + ß1 +

++++

++++

++++

±±

++++

ß1ß1

++++

±±

++++

++

±±

POSITIVE INOTROPES

CONCLUSIONSPOSITIVE INOTROPES

CONCLUSIONS

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy

CortexCortex

MedullaMedulla

ThiazidesInhibit active exchange of Cl-Na

in the cortical diluting segment of the ascending loop of Henle

ThiazidesInhibit active exchange of Cl-Na

in the cortical diluting segment of the ascending loop of Henle

K-sparingInhibit reabsorption of Na in the

distal convoluted and collecting tubule

K-sparingInhibit reabsorption of Na in the

distal convoluted and collecting tubule

Loop diuretics Inhibit exchange of Cl-Na-K in

the thick segment of the ascending loop of Henle

Loop diuretics Inhibit exchange of Cl-Na-K in

the thick segment of the ascending loop of Henle

Loop of HenleLoop of HenleCollecting tubuleCollecting tubule

DIURETICSDIURETICS

THIAZIDESMECHANISM OF ACTION

THIAZIDESMECHANISM OF ACTION

Excrete 5 - 10% of filtered Na+

Elimination of K

Inhibit carbonic anhydrase: increase elimination of HCO3

No dose - effect relationship

Excrete 5 - 10% of filtered Na+

Elimination of K

Inhibit carbonic anhydrase: increase elimination of HCO3

No dose - effect relationship

LOOP DIURETICSMECHANISM OF ACTION

LOOP DIURETICSMECHANISM OF ACTION

Excrete 15 - 20% of filtered Na+

Elimination of K+, Ca+ and Mg++

Resistance of afferent arterioles

-Cortical flow and GFR

- Release renal PGs

- NSAIDs may antagonize diuresis

Excrete 15 - 20% of filtered Na+

Elimination of K+, Ca+ and Mg++

Resistance of afferent arterioles

-Cortical flow and GFR

- Release renal PGs

- NSAIDs may antagonize diuresis

K-SPARING DIURETICS MECHANISM OF ACTION

K-SPARING DIURETICS MECHANISM OF ACTION

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

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

Volume and preloadImprove 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

Volume and preloadImprove 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

DIURETIC EFFECTSDIURETIC EFFECTS

DIURETICS ADVERSE REACTIONS

Thiazide and Loop Diuretics

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

Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis

Metabolic changes: glycemia, uremia, gout LDL-C and TG

Cutaneous allergic reactions

DIURETICSADVERSE REACTIONS

Thiazide and Loop Diuretics

DIURETICSADVERSE REACTIONS

Thiazide and Loop Diuretics

Idiosyncratic effects:Blood dyscrasia, cholestatic jaundice and acute pancreatitis

Gastrointestinal effectsGenitourinary effects:

Impotence and menstrual cramps

Deafness, nephrotoxicity (Loop diuretics)

Idiosyncratic effects:Blood dyscrasia, cholestatic jaundice and acute pancreatitis

Gastrointestinal effectsGenitourinary effects:

Impotence and menstrual cramps

Deafness, nephrotoxicity (Loop diuretics)

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

DIURETICSADVERSE REACTIONSK-SPARING DIURETICS

DIURETICSADVERSE REACTIONSK-SPARING DIURETICS

Changes in electrolytes:

Na+, K+, acidosis

Musculoskeletal:

Cramps, weakness

Cutaneous allergic reactions :

Rash, pruritis

Changes in electrolytes:

Na+, K+, acidosis

Musculoskeletal:

Cramps, weakness

Cutaneous allergic reactions :

Rash, pruritis

COCO

PRELOADPRELOAD AFTERLOADAFTERLOAD

Normal ContractilityNormal Contractility

Diminished Contractility Diminished Contractility

Normal ContractilityNormal Contractility

DiminishedContractility DiminishedContractility

VVVV AVAV

VASODILATOR DRUGSPRINCIPLES

VASODILATOR DRUGSPRINCIPLES

Venous Vasodilatation

Venous Vasodilatation

MIXEDCalcium antagonists -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

MIXEDCalcium antagonists -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

VENOUSNitrates

Molsidomine

VENOUSNitrates

Molsidomine

ARTERIALMinoxidil

Hydralazine

ARTERIALMinoxidil

Hydralazine

VASODILATORSCLASSIFICATIONVASODILATORSCLASSIFICATION

Arterial Vasodilatation

Arterial Vasodilatation

1- VENOUS VASODILATATION Preload

2- Coronary vasodilatation Myocardial perfusion

3- Arterial vasodilatation Afterload

4- Others

1- VENOUS VASODILATATION Preload

2- Coronary vasodilatation Myocardial perfusion

3- Arterial vasodilatation Afterload

4- Others

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

NITRATESHEMODYNAMIC EFFECTS

• Cardiac output

• Blood pressure

• Cardiac output

• Blood pressure

0.60.6

PROBABILITYOFDEATH

PROBABILITYOFDEATH

00

Placebo (273)Prazosin (183)Hz + ISDN (186)

Placebo (273)Prazosin (183)Hz + ISDN (186)

MONTHSMONTHS

0.70.7

0.50.5

0.30.3

0.40.4

0.20.2

0.10.1

VHefT-1N Engl J Med 1986;314:1547VHefT-1N Engl J Med 1986;314:1547

NITRATESSURVIVALNITRATESSURVIVAL

00 66 1212 1818 2424 3030 3636 4242

" Decrease in the effect of a drugwhen administered in a long-acting form"

" Decrease in the effect of a drugwhen administered in a long-acting form"

NITRATESTOLERANCE

NITRATESTOLERANCE

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

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

NITRATES

TOLERANCENITRATES

TOLERANCECan 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

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

s.l. NTG

ISDN

I 5-MN

Percutaneous NTG

s.l. NTG

ISDN

I 5-MN

Percutaneous NTG

TOLERANCE

TOLERANCE

HALF

LIFE

HALF

LIFE

NITRATESTOLERANCE

NITRATESTOLERANCE

NITRATES

CONTRAINDICATIONSNITRATES

CONTRAINDICATIONS

Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

WITH CAUTION:WITH CAUTION:� Constrictive pericarditis� Intracranial hypertension� Hypertrophic cardiomyopathy

� Constrictive pericarditis� Intracranial hypertension� Hypertrophic cardiomyopathy

NITRATES

CLINICAL USESNITRATES

CLINICAL USES

Pulmonary congestion

Orthopnea and paroxysmal nocturnal

dyspnea

CHF with myocardial ischemia

In acute CHF and pulmonary edema:

NTG s.l. or i.v.

Pulmonary congestion

Orthopnea and paroxysmal nocturnal

dyspnea

CHF with myocardial ischemia

In acute CHF and pulmonary edema:

NTG s.l. or i.v.

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

VASOCONSTRICTIONVASOCONSTRICTION VASODILATATION VASODILATATION

KininogenKininogen

KallikreinKallikrein

Inactive FragmentsInactive Fragments

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

RENINRENIN

Kininase IIKininase IIInhibitorInhibitor

ALDOSTERONEALDOSTERONE

SYMPATHETICSYMPATHETICVASOPRESSINVASOPRESSIN

PROSTAGLANDINSPROSTAGLANDINS

tPAtPA

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

ACEIMECHANISM OF ACTION

ACEIMECHANISM OF ACTION

A.C.E.A.C.E.

Retenção de Na+Retenção de Na+

Inflamação/procoagulabilidadeInflamação/procoagulabilidadeStress oxidativoStress oxidativo

Efeitos centraisEfeitos centrais

EstimulaçãoEstimulaçãosimpáticasimpática

Estimulação deEstimulação deprotooncogenesprotooncogenes

Libertação deLibertação deAldosteronaAldosteronae ET-1e ET-1

Hipertrofia cardíacaHipertrofia cardíacaFibrose intersticialFibrose intersticialPro-ateromatosePro-ateromatose

Hipertrofia/HiperplasiaHipertrofia/HiperplasiaRemodelagem vascularRemodelagem vascular

Angiotensina IIAngiotensina II

ACEI

HEMODYNAMIC EFFECTSACEI

HEMODYNAMIC EFFECTS

Arteriovenous Vasodilatation- PAD, PCWP and LVEDP- SVR and BP- CO and exercise tolerance

No change in HR / contractilityMVO2

Renal, coronary and cerebral flowDiuresis and natriuresis

Arteriovenous Vasodilatation- PAD, PCWP and LVEDP- SVR and BP- CO and exercise tolerance

No change in HR / contractilityMVO2

Renal, coronary and cerebral flowDiuresis and natriuresis

ACEI

ADVANTAGESACEI

ADVANTAGESInhibit 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 activationor reflex tachycardia

Tolerance to its effects does not develop

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 activationor reflex tachycardia

Tolerance to its effects does not develop

PlaceboPlacebo

EnalaprilEnalapril

1212111110109988776655

PROBABILITYOFDEATH

PROBABILITYOFDEATH

MONTHSMONTHS

0.10.1

0.80.8

00

0.20.2

0.30.3

0.70.7

0.40.4

0.50.5

0.60.6p< 0.001p< 0.001

p< 0.002p< 0.002

CONSENSUSN Engl J Med 1987;316:1429CONSENSUSN Engl J Med 1987;316:1429

ACEI SURVIVALACEI SURVIVAL

4433221100

ACEIINDICATIONS

ACEIINDICATIONS

Clinical cardiac insufficiency- All patients

Asymptomatic ventricular dysfunction

- LVEF < 35 %

Clinical cardiac insufficiency- All patients

Asymptomatic ventricular dysfunction

- LVEF < 35 %

ACEI

UNDESIRABLE EFFECTSACEI

UNDESIRABLE EFFECTS

Inherent in their mechanism of action- Hypotension- Hyperkalemia- Angioneurotic edema

Due to their chemical structure- Cutaneous eruptions- Neutropenia,

thrombocytopenia- Digestive upset

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.- Dry cough- Renal Insuff.

- Dysgeusia- Proteinuria- Dysgeusia- Proteinuria

ACEI

CONTRAINDICATIONSACEI

CONTRAINDICATIONS

Renal artery stenosis

Renal insufficiency

Hyperkalemia

Arterial hypotension

Intolerance (due to side effects)

Renal artery stenosis

Renal insufficiency

Hyperkalemia

Arterial hypotension

Intolerance (due to side effects)

IECAS VANTAGENS DESVANTAGENS

- reduzem mortalidade - efeitos acessórios

e morbilidade (tosse /angioedema)

- melhoram sintomas

- aumentam tolerância

ao esforço

- reduzem hospitalizações

- eficazes na I C assintomáticaNEJM 1987: 316;1429 JAMA 1988:259; 539 NEJM 1991:325;293

NEJM 1991: 325; 303 ANN INTERN MED 1992:117 ; 234

Mortality trials with ACE inhibitors in heart failure

Trial

CONSENSUS-1

V-HeFT-II

SOLVD

(treatment)

Treatments

Enalapril

Placebo

Enalapril

ISDN/Hydral

Enalapril

Placebo

n

253

804

2569

Treatment

duration

6 months

2 years

41 months

Mortality

(%)

26

44

18

25

35

40

p value

0.002

0.016

0.004

ISDN=isosorbide dinitrate; Hydral=hydralazine

ACE inhibitor trials in heart failure following AMI

Trial

AIRE

SAVE

TRACE

n

2006

2231

1749

Treatment

duration

15 months

42 months

4 years

Mortalit

y

(%)

17

23

20

25

35

42

p value

0.002

0.019

0.001

Treatments

Ramipril

Placebo

Captopril

Placebo

Trandolapril

Placebo

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. 0.67-0.88); p<0.001

• Redução significativa da mortalidade + hospitali-

zações por insuficiência cardíaca de 25%

– odds ratio 0.65 (95% C.I. 0.57-0.74); p<0.001

• Maiores benefícios em doentes com maior

deterioração da função cardíaca

AngiotensinogénioAngiotensinogénioAngiotensinogénioAngiotensinogénio

Angiotensina IAngiotensina IAngiotensina IAngiotensina I

Angiotensina IIAngiotensina IIAngiotensina IIAngiotensina II

BradicininaBradicininaBradicininaBradicinina

PeptídeosPeptídeosinactivosinactivosPeptídeosPeptídeosinactivosinactivos

Receptores ATReceptores AT11Receptores ATReceptores AT11 Receptores ATReceptores AT22Receptores ATReceptores AT22

Receptores BK 2Receptores BK 2Receptores BK 2Receptores BK 2

Óxido nítricoÓxido nítricoÓxido nítricoÓxido nítrico

ReninaRenina

ChymaseChymaseCAGE,CAGE,Calicreína, ...Calicreína, ...

Cathepsin G,Cathepsin G,Calicreína,Calicreína,Tonina,Tonina,TripsinaTripsina

ECAECA

--??

??

SISTEMA RENINA - ANGIOTENSINASISTEMA RENINA - ANGIOTENSINASISTEMA RENINA - ANGIOTENSINASISTEMA RENINA - ANGIOTENSINA

PGPGPGPG

VasoconstriçãoAntinatriureseProliferação celularInflamação, aterogeneseHipercoagulação

ALDO

VasodilataçãoEfeito antiproliferativoantiaterogenico

Antagonistas Antagonistas (AT(AT11))

ANGIOTENSIN II INHIBITORS

MECHANISM OF ACTIONANGIOTENSIN II INHIBITORS

MECHANISM OF ACTION

RENINRENIN

AngiotensinogenAngiotensinogen Angiotensin I

ANGIOTENSIN II

Angiotensin I

ANGIOTENSIN II

ACEACEOther pathsOther paths

VasoconstrictionVasoconstriction Proliferative Action

Proliferative Action

VasodilatationVasodilatation Antiproliferative Action

Antiproliferative Action

AT1 AT1 AT2AT2

AT1 RECEPTOR BLOCKERS

AT1 RECEPTOR BLOCKERS

RECEPTORSRECEPTORS

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

ATAT11 receptor receptor ATAT22 receptor receptor

• VasoconstrictionVasoconstriction

• Growth PromotionGrowth Promotion

• Anti-apoptoticAnti-apoptotic

• Pro-fibroticPro-fibrotic

• Pro-thromboticPro-thrombotic

• Pro-oxidantPro-oxidant

• VasodilationVasodilation

• Growth inhibitionGrowth inhibition

• Pro-apoptoticPro-apoptotic

• ? Fibrosis? Fibrosis

• ? Thrombosis? Thrombosis

• ? redox? redox

Angiotensin II Receptors

AT1 RECEPTOR BLOCKERSDRUGS

AT1 RECEPTOR BLOCKERSDRUGS

Losartan

Valsartan

Irbersartan

Candesartan

Losartan

Valsartan

Irbersartan

Candesartan

Competitive and selective

blocking of AT1 receptors

Competitive and selective

blocking of AT1 receptors

The ELITE-study

0

50

100

150

200

250

300

350

400

Number ofpatients

Adverseevents

Death andhospitalization

Death

Losartan

Captopril

Pitt et al. Lancet 1997: 349: 747-52

p = 0.035p = 0.075

Losartan Heart Failure Survival StudyELITE II

Study Design

60 years; NYHA II-IV; EF 40%ACEI/AIIA naive or <7 days in 3 months prior to entryStandard Rx (± Dig/Diuretics),-blocker stratification

Captopril50 mg 3 times daily

(n=1574)

Losartan50 mg daily(n=1578)

Event-driven(Target 510 Deaths)

~2 years

Primary Endpoint: All-Cause MortalitySecondary Endpoint: Sudden Cardiac Death and/or Resuscitated ArrestOther Endpoints: All-Cause Mortality/Hospitalizations

Safety and Tolerability

Losartan Heart Failure Survival Study – ELITE IIMortality by Cause (Adjudicated)

15

10

5

0Suddendeath

Heartfailure

MI Stroke OtherCV

Non-CV

Losartan (n=1578)

Captopril (n=1574)

% of Patients

INSUFICIÊNCIA CARDÍACAVALOR DOS ANTAGONISTAS DA AII

• MELHORAM OS SINTOMAS, AUMENTAM A QUALIDADE DE VIDA E AUMENTAM A TOLERÂNCIA AO EXERCÍCIO

• REDUZEM A MORBILIDADE E O NÚMERO DE HOSPITALIZAÇÕES.

• AUMENTAM A ADERÊNCIA AO TRATA- MENTO (poucos efeitos secundários).

ÓPTIMA ALTERNATIVA AOS IECAS

CONCEITO DOS INIBIDORES DAS VASOPEPTIDASES

- DUPLO BLOQUEIO DA NEP e da ECANEP e da ECA

Inibição dasvasopeptidases ECANEP

ANP e peptideos Análogos

Adrenomedulina

BK Angiotensina II

Vasodilatação Excreção sódio Efeitos antihipertróficos

Vasoconstrição Retenção sódio Efeitos hipertróficos

Pressão arterial Melhoria da performance cardíaca Protecção dos orgãos-alvo

Cardiomyopathic hamstersCardiomyopathic hamsters

OmapatrilatOmapatrilat

Su

rviv

al (

%)

Su

rviv

al (

%)

440440

146 d146 d 221 d221 d 290 d290 d

00

2020

4040

6060

8080

100100

36036032032028028024024020020016016012012080804040

Days of treatmentDays of treatment400400

Start treatmentStart treatment

CaptoprilCaptoprilPlaceboPlacebo

Omapatrilat: Survival BenefitOmapatrilat: Survival Benefit

Trippodo et al. J Cardiovasc Pharmacol 1999;34:782Trippodo et al. J Cardiovasc Pharmacol 1999;34:782

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)

ALDOSTERONEALDOSTERONE

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Collagen

deposition

Fibrosis - myocardium

- vessels

SpironolactoneSpironolactone

Edema Edema

Arrhythmias Arrhythmias

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

ALDOSTERONE INHIBITORSALDOSTERONE INHIBITORS

ALDOSTERONE INHIBITORSINDICATIONSALDOSTERONE INHIBITORSINDICATIONS

FOR DIURETIC EFFECT• Pulmonary congestion (dyspnea)• Systemic congestion (edema)

FOR ELECTROLYTE EFFECTS• Hypo K+, Hypo Mg+

• Arrhythmias• Better than K+ supplementsFOR NEUROHORMONAL EFFECTS• Please see RALES results, N Engl J Med 1999:341:709-717

FOR DIURETIC EFFECT• Pulmonary congestion (dyspnea)• Systemic congestion (edema)

FOR ELECTROLYTE EFFECTS• Hypo K+, Hypo Mg+

• Arrhythmias• Better than K+ supplementsFOR NEUROHORMONAL EFFECTS• Please see RALES results, N Engl J Med 1999:341:709-717

• Hyperkalemia

• Severe renal insufficiency

• Metabolic acidosis

• Hyperkalemia

• Severe renal insufficiency

• Metabolic acidosis

ALDOSTERONE INHIBITORSCONTRAINDICATIONSALDOSTERONE INHIBITORSCONTRAINDICATIONS

Pharmacologic ManagementBeta-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

1 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic 1 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 p. 20.Heart Failure in the Adult, 2001 p. 20.

ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines

Neurohormonalactivation

HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines

Neurohormonalactivation

HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative

5050

4040

3030

2020

1010

00

LV EJECTION FRACTIONLV EJECTION FRACTION< 30%< 30% 30-40%30-40% > 40%> 40%

%%

ß Blockerß Blocker Placebo Placebo

BHATJACC 1990;16:1327BHATJACC 1990;16:1327

ß BLOCKERSSURVIVAL

ß BLOCKERSSURVIVAL

ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?

ß-ADRENERGIC BLOCKERSIDEAL CANDIDATE?

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina

Carvedilol(n=696)

Placebo(n=398)

Survival

Days

0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction = 65%Risk reduction = 65%p<0.001

Packer et al (1996)

Lancet (1999)0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction = 34%Risk reduction = 34%

The MERIT-HF Study Group (1999)

Months of follow-up

Mortality %

0 3 6 9 12 15 18 21

20

15

10

5

0

Placebo

Metoprolol CR/XL

p=0.0062

Risk reduction = 34%Risk reduction = 34%

US Carvedilol StudyUS Carvedilol Study

blockers in blockers in heart failure -heart failure -

all-cause mortalityall-cause mortality

CIBIS-IICIBIS-II MERIT-HFMERIT-HF

• Antioxidant effects – reduction in myocyte apoptosis– decreased lipid peroxidation

• Antiproliferative effects– inhibition of vascular smooth muscle

cell proliferation

• Reduction in circulating endothelin-1

Additional benefits of carvedilol in CHF

Treatment Approach for the Patient with Heart FailureStage AStage A

At high risk, no At high risk, no structural diseasestructural disease

Stage BStage B

Structural heart Structural heart disease, disease,

asymptomaticasymptomatic

Stage DStage D

Refractory HF Refractory HF requiring specialized requiring specialized

interventionsinterventions

TherapyTherapy

• Treat HypertensionTreat Hypertension

• Treat lipid disordersTreat lipid disorders

• Encourage regular Encourage regular exerciseexercise

• Discourage alcohol Discourage alcohol intakeintake

• ACE inhibitionACE inhibition

TherapyTherapy

• All measures under All measures under stage Astage A

• ACE inhibitors in ACE inhibitors in appropriate patientsappropriate patients

• Beta-blockers in Beta-blockers in appropriate patientsappropriate patients

TherapyTherapy

• All measures under All measures under stage Astage A

Drugs:Drugs:

• DiureticsDiuretics

• ACE inhibitorsACE inhibitors

• Beta-blockersBeta-blockers

• DigitalisDigitalis

• Dietary salt restrictionDietary salt restriction

TherapyTherapy

• All measures under All measures under stages A,B, and Cstages A,B, and C

• Mechanical assist Mechanical assist devicesdevices

• Heart transplantationHeart transplantation

• Continuous (not Continuous (not intermittent) IV intermittent) IV inotropic infusions for inotropic infusions for palliationpalliation

• Hospice careHospice care

Stage CStage C

Structural heart Structural heart disease with disease with prior/current prior/current

symptoms of HFsymptoms of HF

Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001Heart Failure in the Adult, 2001

Tratamento da Ins. cardiaca Inibidores das fosfodiesterases redutores da

produçãode FNT e outras citocinas

Pimobendam, vesnarinona,

pentoxifilina

Ressincronização cardíaca