3Treatment Objectives* SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changesProgression of CHFSymptomsTreatment of Heart Failure.ObjectivesThe 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.
4Treatment All Prevention. Control of risk factors Life style Treat etiologic cause / aggravating factorsDrug therapyPersonal care. Team workRevascularization if ischemia causes HFICD (Implantable Cardiac Defibrillator)Ventricular resyncronizationVentricular assist devicesHeart transplantArtificial heartNeoangiogenesis, Gene therapyAllSelected patients
5*ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapypacemaker; H-ISDN = hydralazine and isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LVAD = left ventricularassist device; LVEF = left ventricular ejection fraction; MR antagonist = mineralocorticoid receptor antagonist; NYHA = New York Heart Association.a Diuretics may be used as needed to relieve the signs and symptoms of congestion (see Section 7.5) but they have not been shown to reduce hospitalization or death.b Should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose.c Asymptomatic patients with an LVEF ≤35% and a history of myocardial infarction should be considered for an ICD.d If mineralocorticoid receptor antagonist not tolerated, an ARB may be added to an ACE inhibitor as an alternative.e European Medicines Agency has approved ivabradine for use in patients with a heart rate ≥75 b.p.m. May also be considered in patients with a contraindication to a beta-blockeror beta-blocker intolerance.f See Section 9.2 for details—indication differs according to heart rhythm, NYHA class, QRS duration, QRS morphology and LVEF.g Not indicated in NYHA class IV.h Digoxin may be used earlier to control the ventricular rate in patients with atrial fibrillation—usually in conjunction with a beta-blocker.i The combination of hydralazine and isosorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor or an ARB.
8ESSENTIALS of HF TREATMENT *An ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF ≤40% to reduce the risk of HF hospitalization and the risk of premature death.A beta-blocker is recommended, in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated), for all patients with an EF ≤40% to reduce the risk of HFhospitalization and the risk of premature death.An MRA is recommended for all patients with persisting symptoms (NYHA class II–IV) and an EF ≤35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a beta-blocker, to reduce the risk of HF hospitalization and the risk of premature death.
10Essential to control symptoms secondary to fluid retention Diuretics*Essential to control symptoms secondary to fluid retentionThe effects of diuretics on mortality and morbidity have not been studied in patients with HF, unlike ACE inhibitors, betablockers, and MRAs (and other treatments).However, diuretics relieve dyspnoea and oedema and are recommended for this reason in patients with signs and symptoms of congestion, irrespective of EF.Loop diuretics produce a more intense and shorter diuresis than thiazides, which cause a more gentle and prolonged diuresis.Thiazides may be less effective in patients with reduced kidney function. Loop diuretics are usually preferred to thiazides in HF-REF although they act synergistically and the combination may be used (usually on a temporary basis) to treat resistant oedema.The aim of using diuretics is to achieve and maintain euvolaemia (the patient’s ‘dry weight’) with the lowest achievable dose.This means that the dose must be adjusted, particularly after restoration of dry body weight, to avoid the risk of dehydration leading to hypotension and renal dysfunction.
11Diuretics Thiazides Cortex K-sparing Loop diuretics Medulla Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of HenleCortexK-sparingInhibit reabsorption of Na in thedistal convoluted and collecting tubuleLoop diureticsTreatment of heart failure.Diuretics: Classification and mechanisms of actionDiuretics 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.Inhibit exchange of Cl-Na-K inthe thick segment of the ascendingloop of HenleMedullaLoop of HenleCollecting tubule
13Loop Diuretics / Thiazides. Practical Use Start with variable dose. Titrate to achieve dry weightMonitor serum K+ at “frequent intervals”Reduce dose when fluid retention is controlledTeach the patient when, how to change doseCombine to overcome “resistance”Do not use alone
14Loop diuretics. Dose (mg) Initial MaximumBumetanide 0.5 to 1.0mg/12-24h 10mg /dayFurosemide 20 to 40mg/12-24h 400mg /dayTorsemide 10 to 20mg/12-24h 200mg /day
16ACE-i. Mechanism of Action VASOCONSTRICTIONVASODILATATIONALDOSTERONEPROSTAGLANDINSVASOPRESSINKininogentPASYMPATHETICKallikreinAngiotensinogenRENINBRADYKININTreatment of Heart FailureAngiotensin Converting-Enzyme Inhibitors (ACEI) :Mechanisms of actionACE-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.Angiotensin IA.C.E.InhibitorKininase IIANGIOTENSIN IIInactive Fragments
17ACE-I. Clinical Effects* Improve symptomsReduce remodelling / progressionReduce hospitalizationImprove survivalTreatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of actionACE-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.
18Mortality Reduction with ACE-i Study ACE-i Clinical SetingCONSENSUS Enalapril CHFSOLVD treatment Enalapril CHFAIRE Ramipril CHFVheft-II Enalapril CHFTRACE Trandolapril CHF / LVDSAVE Captopril LVDSMILE Zofenopril High riskHOPE Ramipril High risk
19ACE-i. Indications Symptomatic heart failure Asymptomatic ventricular dysfunction- LVEF < %Selected high risk subgroups (CAD+HT, DM+HT with LVH)Treatment of Heart FailureAngiotensin 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%.
20ACE-i Practical Use* Start with very low dose Increase dose if well toleratedRenal function & serum K+ after 1-2 wAvoid fluid retention / hypovolemia (diuretic use)Dose NOT determined by symptomsCombine to overcome “resistance”Treatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of actionACE-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.
21ACE-i Dose (mg) Initial Maximum Captopril 6.25 / 8h 50 / 8h Enalapril 2.5 / 12 h 10 to 20 / 12hFosinopril 5 to 10 / day 40 / dayLisinopril 2.5 to 5.0 / day 20 to 40 / dayQuinapril 10 / 12 h 40 / 12 hRamipril to 2.5 / day 10 / day
22ACE-I. Adverse Effects* Hypotension (1st dose effect)Worsening renal functionHyperkalemiaCoughAngioedemaRash, ageusia, neutropenia, …Treatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI) : Undesirable EffectsThese 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).
23ACE-I. Contraindications* Intolerance (angioedema, anuric renal fail.)Bilateral renal artery stenosisPregnancyRenal insufficiency (creatinine > 3 mg/dl)Hyperkalemia (> 5,5 mmol/l)Severe hypotensionTreatment of Heart FailureAngiotensin 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.
24ß-Adrenergic Blockers Mechanism of action* Density of ß1 receptorsInhibit cardiotoxicity of catecholaminesNeurohormonal activationHRAntiischemicAntihypertensiveAntiarrhythmicAntioxidant, AntiproliferativeTreatment of congestive heart failure.Possible benefits of beta adrenergic blockersThe 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.
26ß-Adrenergic Blockers Indications* Symptomatic heart failureAsymptomatic ventricular dysfunctionLVEF < %After AMITreatment of Heart FailureAngiotensin 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%.
27ß-Adrenergic Blockers When to start* Patient stableNo physical evidence of fluid retentionNo need for i.v. inotropic drugsStart ACE-I / diuretic firstNo contraindicationsIn hospital or not
29ß-Adrenergic Blockers Adverse Effects* HypotensionFluid retention / worsening heart failureFatigueBradycardia / heart blockReview treatment (+/-diuretics, other drugs)Reduce doseConsider cardiac pacingDiscontinue beta blocker only in severe cases
30ß-Adrenergic Blockers Contraindications* Asthma (reactive airway disease)AV block (unless pacemaker)Symptomatic hypotension / BradycardiaDiabetes is NOT a contraindicationProgressive severe PAD (relative)
31- Digitalis Na-K ATPase Na-Ca Exchange Na+ K+ Na+ Ca++ Ca++ K+ Na+ Treatment of heart failure.Digoxin: Mechanism of actionDigoxin 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.MyofilamentsCa++K+Na+CONTRACTILITY
33Digitalis Clinical Effects* Improve symptomsModest reduction in hospitalizationDoes not improve survivalIn patients with symptomatic HF and AF, digoxin may be used toslow a rapid ventricular rate, although other treatments are preferredDigoxin may also be used in patients in sinus rhythm with symptomaticHF and an LVEF ≤40%Digoxin can cause atrial and ventricular arrhythmias, particularlyin the context of hypokalaemia, and serial monitoring of serumelectrolytes and renal function is mandatory
34Digitalis. Indications* When no adequate response to ACE-i + diuretics + beta-blockers, in combination with ACE-i + diuretics if persisting symptomsAF, to slow AV conductionDose to mg / day
35Digoxin. Contraindications* Digoxin toxicityAdvanced A-V block without pacemakerBradycardia or sick sinus without PMPVC’s and VTMarked hypokalemiaW-P-W with atrial fibrillationTreatment of heart failureDigoxin: ContraindicationsThe 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.
36- Spironolactone Aldosterone Inhibitors ALDOSTERONE Edema Fibrosis Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)Retention Na+Retention H2OExcretion K+Excretion Mg2+CollagendepositionFibrosis- myocardium- vesselsEdemaTreatment of congestive heart failure.Aldosterone inhibitors: Mechanism of actionAldosterone 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.Arrhythmias
37Mineralocorticoid/aldosterone receptor antagonists * Spironolactone and eplerenone block receptors that bind aldosteroneand other corticosteroids, and are best characterized as MRAs.
38Spironolactone. Practical use * Do not use if hyperkalemia, renal insuf.Monitor serum K+ at “frequent intervals”Start ACE-i firstStart with 25 mg / 24hIf K+ >5.5 mmol/L, reduce to 25 mg / 48hIf K+ is low or stable consider 50 mg / dayNew studies in progress
39Other Drugs. (only in selected patients)* Inotropics: refractory HFNitrates: ischemia, angina, pulmonary congestionARB: Contraindications to ACE-iAntiarrhythmics: (only amiodarone) H risk arrhyth.Anticoagulants: High risk of embolysmCa channel blockers: (only amlodipine) ischemia28
40Angiotensin I ANGIOTENSIN II Angiotensin II Receptor Blockers (ARB)RENINAngiotensinogenAngiotensin I ANGIOTENSIN IIACEOther pathwaysAT1ReceptorBlockersTreatment of congestive heart failure.Angiotensin II inhibitorsAngiotensin 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.RECEPTORSAT1AT2VasoconstrictionProliferativeActionVasodilatationAntiproliferativeAction
41Angiotensin II Receptor Blockers (ARB) Candesartan, Eprosartan, IrbesartanLosartan, Telmisartan, ValsartanEfficacy not equal / superior to ACE-INot indicated with beta blockersIndicated in patients intolerant to ACE-ITreatment of congestive heart failure.Angiotensin II inhibitorsDrugs which create a selective and competitive block of the AT1 receptors include: losartan, valsartan, irbersartan and candersartan.AHA / ACC HF guidelines 2001ESC HF guidelines 2001
43NITRATES HEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload 2- Coronary vasodilatationMyocardial perfusion3- Arterial vasodilatation Afterload4- OthersPulmonary congestion Ventricular size Vent. Wall stress MVO2Treatment of Heart Failure.Nitrates: Hemodynamic effectsAt 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
44Nitrates. Clinical Use CHF with myocardial ischemia Orthopnea and paroxysmal nocturnal dyspneaIn acute CHF and pulmonary edema:NTG sl / ivNitrates + Hydralazine in intoleranceto ACE-I (hypotension, renal insufficiency)Treatment of Heart Failure.Nitrates: Use in Heart FailureThrough 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.
45IVABRADIN*Ivabradine is a drug that inhibits the If channel in the sinus node. Its only known pharmacological effect is to slow the heart rate in patients in sinus rhythm (it does not slow the ventricular rate in AF).Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB)
46Positive Inotropes Digitalis Sympathomimetics Catecholamines B-adrenergic agonistsPhosphodiesterase inhibitorsAmrinone, Milrinone, EnoximoneCalcium sensitizersLevosimendan, PimobendanTreatment of heart failure.Positive inotropic agentsThe 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.
47Positive Inotropic Therapy* May increase mortalityException: Digoxin, LevosimendanUse only in refractory CHFNOT for use as chronic therapyTreatment of heart failure.Inotropes: General problemsPositive 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.
48Drugs to Avoid (may increase symptoms, mortality) Inotropes, long term / intermittentAntiarrhythmics (except amiodarone)Calcium antagonists (except amlodipine)Non-steroidal antiinflammatory drugs (NSAIDS)Tricyclic antidepressantsCorticosteroidsLithiumESC HF guidelines 2001
52Heart Transplantation Indications Refractory cardiogenic shockDocumented dependence on IV inotropic support to maintain adequate organ perfusionPeak VO2 < 10 ml / kg / minSevere symptoms of ischemia not amenable to revascularizationRecurrent symptomatic ventricular arrhythmias refractory to all therapeutic modalitiesContraindications: age, severe comorbidity
53Heart Failure and Myocardial Ischemia Coronary HD is the cause of 2/3 of HFSegmental wall motion abnormalities are not specific if ischemiaAngina : coronary angio and revascularizationTreatment of Heart Failure.Correction of aggravating factorsOften a lack of response to conventional therapy for heart failure is due to the presence of uncorrected aggravating or precipitating factors. It is important to always consider the possibility of such factors, particularly in cases of refractory failure. AF: atrial fibrillation.
54Supraventricular Arrhythmias Risk of embolization (AF)Anticoagulation in AFSystolic & diastolic dysfunctionDigoxin, beta blockersAmiodarone if b-blocker ineffective/ contraind.Treatment of Heart Failure.Correction of aggravating factorsOften a lack of response to conventional therapy for heart failure is due to the presence of uncorrected aggravating or precipitating factors. It is important to always consider the possibility of such factors, particularly in cases of refractory failure. AF: atrial fibrillation.
55Ventricular Arrhythmias / Sudden Death Antiarrhythmics ineffective (may increase mortality)Amiodarone do not improve survivalß-blockers reduce all cause mortality and SDControl ischemiaControl electrolyte disturbancesICD (Implantable Cardiac Defibrillator)Treatment of Heart Failure.Correction of aggravating factorsOften a lack of response to conventional therapy for heart failure is due to the presence of uncorrected aggravating or precipitating factors. It is important to always consider the possibility of such factors, particularly in cases of refractory failure. AF: atrial fibrillation.
56Diastolic Heart Failure/HF-PEF Treat as HF with low LVEFControl:HypertensionTachycardiaFluid retentionMyocardial ischemiaOngoing research
57HEART FAILURE MODELS* CONGESTIVE - Digoxin, Diurétics HEMODYNAMIC - VasodilatorsNEUROHUMORAL - ACE inhibitors,- Blockers, SpironolactoneDespite advances in treatment of systolic heart failure, our pending task is diastolic heart failure that appears isolated in 40% of patients. Symptomatic treatment includes administration of nitrates and adequate doses of diuretics. Studies suggest that beta blockers (BB) and calcium channel blockers (CCB) could be beneficial in some patient subgroups. We don’t know about the effects of ACE inhibitors in these patients, although because of their antihypertensive, antiproliferative and antianginal properties could be expected to have beneficial effects.IMMUNOLOGICAL - Cytokine inhibitors
59TEDAVİ Genel yaklaşımlar Engelleyici tedavi Hipertansiyonu DM ve metabolik abnormaliteleri tespit etmek ve tedaviMiyokard iskemisini uygun bir şekilde tedaviBozulmuş ventrikül fonksiyonlarını semptomlar gelişmeden düzeltmekOptimal tedavi ile ventrikülü artmış yükten kurtarmak, duvar gerilimini azaltmak, miyokard oksijen ihtiyacını azaltmak, nörohormonal aktiviteyi düzenlemek
60TEDAVİ Kolaylaştırıcı faktörleri tedavi etmek Aktivite ve diyet Yaşam tarzı modifikasyonu KY septomlarını ve tedavi ihtiyacını azaltır.Orta ileri KY de geçici fiziksel aktivite kısıtlanması ve yatak istirahatiSu ve tuz kısıtlaması (1.5-2 g/gün)Emosyonel stres ve psikolojik destek
61FARMAKOLOJİK TEDAVİ 3 ana amaç 1—preload azaltımı Pulmoner kapiller hidrostatik basınç intertisyel mesafe ve alveol içi sıvı transudasyonu azalır2—afterload azaltımı (sistemik vasküler direnç)KO renal perfuzyon -diurez3—RAAS ve nörohormonal sistem inhibisyonuVasodilatasyonKO oksijen ihtiyacı İlk 2 amaç semptomatik gerileme sağlar iken RAAS ve nörohormonal vasokonstriktör inhibisyonu mortalite ve morbidite üzerine anlamlı etkileri vardır.
62FARMAKOLOJİK TEDAVİ Preload azaltımı Nitrogliserin Loop diuretikler NTG en etkin , hızlı preload azaltımıSublingual NTG 5 dakika içinde preload ve az afterload Topikal NTG SL kadar etkin fakat ciddi KY de cutanöz kan akımı azalmıştırIV NTG titre edilebilir hızlıLoop diuretiklerTedavinin temelini oluştururlarFrosemid en sık kullanılan, bumetanide biyoyararlanın daha yüksek ciddi KY de kullanılabilirPreloadı 2 yolla azaltırlar 1-diurez 2-pulmoner arter vasodilatasyon ve venodilatasyon
63FARMAKOLOJİK TEDAVİ Potasyum tutucu diuretikler Bir çok hastada diurez dk gecikebilirDiyastolik KY olgularında sıvı tutulumu daha azdır, klinik tablo düzeldikten sonra diuretikler kliniği kötüleştirebilirlerde.Potasyum tutucu diuretiklerSpiranolakton, triamterene,amiloride distal renal tubule etki ederler. Distal Na tutulumu K ve H ion exchange mekanizması ile yürütülür.Hepsi aktif Na tutulumu ve K atılımını engeller—hiperkalemi riski
65FARMAKOLOJİK TEDAVİ ACE inhibitörleri Afterload azaltımıatım hacmi artar KO Preload Hemodinamisi kötü hastalarda dikkatRemodelling üzerine etkili
66FARMAKOLOJİK TEDAVİ Ang II reseptör blokerleri Hidralazine ACE inhibitörlerini tolere edemeyen olgulardaÖksürükDaha sık kullanılmaktaKKY de ACE ve Ang II bloker kombinasyonu faydası klinik çalışmalarla desteklenmektedir.HidralazineACE öncesi en populer pre/afterload azaltıcı ajanDirekt vasodilatörUzun etkili nitratlara kullanıldığında KKY olgularında Yaşam süresini uzattığı gösterilmişACE ye en üstün özelliği gebelerde kullanılabilmesidir, ACE yi tolere edemeyen olgularda kullanılır
67Beta-blokerlerSemptomları azaltır, egzersiz toleransını arttırır, kardiyak hemodinami üzerine olumlu etkileri vardırKKY de mortaliteyi azaltırUzun dönemde kardiyak fonksiyonlarda düzelme sağlar, miyokard iskemisini azaltır,miyokard oksijen ihtiyacını azaltırVentriküler aritmilere bağlı ani ölüm sıklığını azaltırEtkilerin görülmeye başlanması için 1-3 aylık süreç yapısal değişimler için ise 1-1,5 yıl süreç gereklidir.Tedaviye başlangıç elektif şartlarda kontraindikasyon olmayan olgularda düşük dozda uygulanır.Dekompanse olgularda klinik düzelme sağlanmadan uygulanmamalı, intoleran olgularda tedavi kesilir
68FARMAKOLOJİK TEDAVİ İnotropik destek Digoksin Yıllarca KKY tedaviisinin temellerini oluşturduMevcut tek oral inotropik ajandırNa+/K+-ATPase transport pompasını ve Na ,K hücre duvarında transferini engeller buda kalp kasının kasılma hızı ve kısalmasını artttırır (Hem sağlıklı hemde yetmezlikli kalpte, atriyal ve ventriküler kasta)Pozitif inotropik etki sitozoldeki Ca artışı nedeni iledirSistemik vasküler direnç yada KB değiştirmezTüm veriler kısa dönemde orta düzeyde etkin inotropik etkinlik sağlar.Tedavide entoksikasyondan kaçınmak gereklidir. Bazı ilaçlar kan seviyesini yükseltirBöbrek yetm doz ayarlaması gerekirYaşam süresini uzatmazlar fakat hastane kalım süresini kısaltırlar. Yaşam kalitesini arttırırlarAtriyal taşiaritm tedavisinde etkindir
69FARMAKOLOJİK TEDAVİ nitroprusside Düz kas relaksasyonu ile pre/afterload azaltımı fakat en etkin mekanizma afterload azaltımıdırPotent ve hızlı etkilidir kritik hastalarda kullanılırAfterload azaltımı sonucunda KO artarCiddi KB düşmelerinden kaçınmak için yakın hemodinamik monitorisayyon yapmak gereklidirUzun süreli kullanımlarda thiocyanidte toksisitesiGebelerde fetal thiocyanidte toksisitesi
70FARMAKOLOJİK TEDAVİ Dobutamine (sempatomimetik) B1 reseptör agonisti (B2 ve alfa reseptör aktivitesi vardır)IV uygulamada yeterli inotropik etkinlil sağlar ve hafif kronotropik etkiside vardırHafif periferik vasodilatasyon (afterload azaltımı)Bu etkilerinde ciddi KO artımı aluşurDekompanse hastalarda IV formu ile IV NTG ideal tedavidirKlinik uygulamada <80 mmHg altındaki hastalarda çok dikkatli kullanılmalıdır.
71FARMAKOLOJİK TEDAVİ Dopamine Vasküler ve miyokardiyal reseptör etkileri doza bağımlıdırEtki dopaminerjik reseptör uyarılması ile gerçekleşir0.5-3 mcg/kg/dk böbrek kan akımında artma ve diurez etkisi vardır3-10 mcg/kg/dk miyokardta B reseptorlerini uyarır kontraktilite ve kalp hızı artarYüksek dozlarda alfa reseptörlerde uyarılırperiferik vasokonstriksiyonkan basıncı yükselirAritmojeniketkiye sahiptirlerMiyokard oksşjen ihtiyacını artttırırlarKY de dobutamin tolere edemeyen olgularda kullanılır (ciddi hipotansiyonu olan olgular)
72Fosfodiesteraz inhibitörleri NorepinefrinPrimer olarak alfa reseptörlerini uyarırCiddi afterload artışı olur PVR artar ve KO azalırCiddi hipotansiyonu olan olgulardaKan basıncı düzelen olgularad kesilerek diğer tedavi yöntemlerine geçilirFosfodiesteraz inhibitörleriHücre içi cAMP artışına—periferik vaodilatasyon, inotropik etki, pulmoner vasküler direnç azalıradrenereseptör aktiviteye ihtiyaç duymazlarTolerans gelişmez, taşiaritmiye neden olurOral ajanların Önemi yok hatta klas IV KKY olgularında mortaliteyi % 53 arttırmıştırKardiyak aritmi sıklığı artmıştır
73Diyastolik kalp yetmezliği tedavisi 2 tedavi yaklaşımı1---diyastolik yetmezliğe neden olan durum tedavisi2---doluş basıncını ve venöz kongesyonu zaltmak
74Diyastolik disfonksiyon tedavisi Perikardiyectomi—konstrktif perikarditSistolik yüklenmenin giderilmesiACE ve Ang II reseptörleri miyokard fibrozunu azaltır hatta geriletebilir.Anti iskemik ajanlarB-bloker, Ca kanal blokerleri, NTGTrombolitik tedavi yada primer anjiyoplastyVerapamil ventrikül gevşeme özelliğini arttırır ve hipertrofik kardiyomiyopati ve hipertansif kalp hastalıklarında etkilidirVentriküler hipertrofinin düzeltilmesiHipertansiyonun etkin tedavisiAort kapak darlıklarında kapak cerrahisi
75FARMAKOLOJİK TEDAVİ Ventrikül doluş basıncının düşürülmesi Tuz kısıtlanmasıDiuretikler ve venodilatörlerNTG yada uzun etkili nitratlarNormal ritmin ve hızın korunmasıDiyastolik yetmezliğin öncelikli olduğu olgularda digoksin kullanımının anlamı yoktur. İyi korunmuş ejeksiyon fraksiyonu olan olgularda kliniği kötüleştirebilirler.
76FARMAKOLOJİK TEDAVİ İntraaortik balon pompası Perkütan olarak femoral arterden retrograd ilerletilerek aort içine yerleştirilirAort kapandıktan sonra şişip açılmadan kapanmalıdırSistolik ve diyastolik KB üzerine etkileri vardırAfterload azaltılır—KO artarVentrıkül stresi azaltılır, Sol Vent. Hacmi küçülürKoroner kan akımı miyokard perfuzyonu artarDoluş basıncını % azaltır KO %20 artarKesin tedavi uygulanabilinecek olgularda geçiş tedavisi olarak Kardiyojenik şok tablosundaki hastalarda kullanılırAkut kalp yetmezliklerinde hayat kurtarıcıdır
77FARMAKOLOJİK TEDAVİ Ventriküler asist device Biventriküler Pacemaker Transplant adayı hastalarda geçiş tedavisiBiventriküler PacemakerGeniş QRS ve uzun PR mesafesi olan KMP li hastalardaKardiyomyoplastiVentrikülektomiKalp nakli