ЗАСТОЙНАЯ СЕРДЕЧНАЯ НЕДОСТАТОЧНОСТЬ Lolita Shaimanova KARDIOCENTER

Характеристика застойной сердечной недостаточности

Распространенность

миллиона американцев страдают ЗСН. Частота вновь выявляемых случаев ЗСН/год Заболеваемость Наиболее частая причина госпитализации у пожилых лиц Смертность 41,819 (1993); возрастает ежегодно на 220,000 смертных случаев. Смертность за 6 лет приблизительно составляет 80 % у мужчин и 65 % у женщин С 1979 до 1993,смертность по причине ЗСН возросла более чем на 100 %

Распространенность застойной сердечной недостаточности Зависимость застойной сердечной недостаточности от возраст и пола Соединенные Штаты: ряд 1 - мужчины; ряд 2 - женщины

Терапия ЗСН Мочегонные средства Ингибиторы АПФ Блокаторы ангиотензиновых рецеп-торов (не так предпочти-тельны как АПФ-1) Β-блокаторы Спиронолактон Препарата дигиталиса (симптомы но не выживаемость) Пересадка сердца Амиодарон Предсердные натрий уретические пептиды (ANP, BNP, CNP) Антиаритмические препараты Антикоагулянты Операция Балисты Бивентрикулярная стимуляция Антагонисты эндетелина α -Антагонисты ТНФ. Нитраты Ингибиторы вазопептидазы Антагонисты кальция Положительные инотропные средства Вазодилятаторы не АПФ Да?Нет

Digoxin and Heart Failure The DIG randomized trial §6800 patients with CHF and LVEF age 70, ~ ½ NYHA Class II, ~ 1/3 Class III, 2% Class IV. § Results: No difference total or CV deaths 12% deaths from CHF but corresponding in non- CHF deaths, mainly arrhythmic Hospitalization 8% § Digitalis Investigation Group, NEJM 1997; 336 : 525

ACE Inhibitors for CHF §SOLD: 2568 pts with CHF, 90% NYHA Class II-III, §Enalapril mg vs placebo, f/u 41 mos. Mortality § 16%. NEJM 1991; 325 : 293 §SOLD Prevention: 4228 asymptomatic pts with §LVEF 35%, enalapril mg vs placebo, f/u 37 §mos. CV mortality 12% (p=o.12) but enapril §signif incidence new CHF and hospitalizations § NEJM 1991; 327 : 685 §Many trials using ACE-1 post Ml, in pts with low EF §and/or CHF, found improved survival, recurrent Ml §and hospitalization rates

ACE Inhibitors for CHF:What dose? Assessment of Treatment with Lisinopril And Survival (ATLAS) mg (low dose, common practice) vs mg/day lisinopril patients in 287 centers with LVEF 30%, NYHA II-IV, most Class III. 46 months average follow-up low dose high dose odds ratio p N Total deaths 44.9% 42.5% Cardiovascular deaths Death or any hospitalization Total hospitalizations % CHF hospitalizations % Conclusion: low doses may provide half benefit of high doses Packer et al for the ATLAS Study Group. Circulation 1999, 100:2312

Блокаторы рецепторов ангиотензин- II §Блокирует соединения ангиотензин -II c рецепторами АТ-1 §Напрямую ингибирует РАС §Не нарушается синтез брадикинина §Реже вызывает кашель - но не другие побочные эффекты и - АПФ включая ангионевротический отек и опасность применения в первом триместре беременности §Может предотвращать выделение ангиотензина-2, который образуется не по пути ангиотензин - превращающего фермента

Angiotensin Receptor Blocker vs. ACE Inhibitor for CHF: ELITE II 3152 patients with NYHA Class II-IV CHF and LVEF 40% randomized to losartan 50 mg gd vs. captopril 50 mg tid. Follow-up 1.5 years. Results: No significant difference in all cause mortality-slightly Higher with losartan (17.7%) than captopril (15.9% OR 1.13) Thus in contrast to results of ELITE I study (which had too few Patients, and the ELITE I favorable results with losartin Were not significant) ACE inhibitors should be first choice In CHF, ARBs only if ACE-I not tolerated Pitt B et al for ELITE II Invest, Lancet 2000; 355:1582

Valsartan in CHF: Val-HeFT Trial §5010 CHF (NYHA II-IV) patients with LVEF < 40% (avg 26%) on §ACE-I (93%) (avg dose captopril 80 mg, enalapril 17 mg, lisinopril 19 mg/d) §Β-blockers (35%), diuretics (86%), digoxin (67%), few spironolactone (5%), §Randomized to maximum A II blockade valsartan up to 160 mg bid vs placebo §Results: §No difference in total mortality §13% reduction in mortality+morbidity (death +CHF hosp, cardiac arrest, or IV inotropes or vasodiators) with valsartan §27% decrease in CHF hospitalization with valsartan §Most benefit in 7% of patents not on ACE-I §Adverse effect of valsartan in those on ACE-I + beta blocker §1610 pts, 40% in mortality (p=.009), 16% mortality+morbidity (p=0.1) §Cohn et al. New Engi J Med 2001, 345:1667

Valsartan in CHF: Val-HeFT Trial §5010 CHF patients with LVEF < 40% on ACE-I (93%), β-blockers (35%), diuretics (86%), digoxin (67%), randomized to valsartan160 mg bid vs placebo §Valsartan caused: §No difference in total mortality §13% reduction in mortality+morbidity §27% decrease in CHF hosp. §Most benefit in 7% of pts not on ACE-I §Adverse effect of valsartan in pts on ACE-I + beta blocker §Cohn et al. New Engi J Med 2001, 345:1667

Randomized Aldactone Evaluation Study (RALES) 1663 patients with Class III or IV (1/3) CHF, LVEF 35% (avg 25,4%) on ACE-I, most on digoxin (73%), few on beta blocker (10%), randomized to spironolactone 25 mg/d vs placebo. Trial stopped prematurely after 24 mos due to benefit. placebo spirono RR p n Total deaths <.001 Cardiovascular deaths <.001 Death or any hospitalization <.001 Total hospitalizations <.02 CHF hospitalizations <.001 Pitt et al, NEJM 1999; 341:709

Randomized Aldactone Evaluation Study (Rales) §1663 pts with Class III - IV (1/3) CHF, LVEF 35% on ACE-I, most on digoxin (73%), few on beta blocker (10%), randomized to spironolactone 25 mg/d vs placebo. §Results: §Total deaths 30% §CHF deaths 36% §CHF hospitaliz 35% §Pitt et al, NEJM 1999; 341: months

Neurohormonal Activation in CHF

A Model of Heart Failure Модель сердечной недостаточности Повреждение миокарда Сократимость ЛЖ Активация нейрогуморальной системы Токсическое повреждение миокарда Вазоконстрикция периферических сосудов Терапевтическое воздействие Ухудшение синдрома СН

Neurohormonal Activation in CHF §Plasma norepinephrine §Angiotensin II, plasma rennin activity §Aldosterone §Endothelin §Arginine vasopressin §Atrial, brain, C-natriuretic peptides (ANP, BNP, CNP) §Inflammatory cytokines (? Role in cardiac cachexia, skeletal muscle catabolism and thus poor exercise performance, negative inotropism, myocardial cell apoptosis??) -Tumor necrosis factor (TNF) alpha -Interleukin (IL) 6 -Many others under study

Neurohormonal Factors in Heart Failure норма Сердечная недостаточность

β-Блокаторы при ХЗСН: §Предполагаемые механизмы действия §Восстановление чувствительности β рецепторов (активность которых была нарушена из-за высокого содержания катехоламинов). §Защита миоцитов от повреждения катехоламинами §Уменьшение активности других вазоконстрикторных нейрогуморальных систем, в частности РААС §Антиаритмические и анти ишемические свойства §Улучшение перфузии миокарда за счет урежения ЧСС и таким образом удлинение диастолы. §Переход от окисления жирных кислот к активации углеводного обмена

Copernicus: Carvedilol in Advanced CHF §CarvedilOl ProspEctive RaNdomIzed CUmulative Survival (COPERNICUS): 2200 patients with stable advanced CHF on ACE-1, diuretic, ±digoxin, ±amiodarone. Randomized to cardedilol or placebo, followed up to 29 months §Results: Study stopped early at 10.4 months §Total mortality: 11.4% carv 18.5% placebo 35% §Annuualized mort: 12.9% carv 19.7 placebo

Carvedilol for severe CHF: COPERNICUS 2289 patients with NYHA Class III or IV CHF, LVEF < 25% (mean 20%) 2/3 ischemic, randomized to carvedilol (3.125 titrated at 2 week intervals to target 25 bid) vs placebo. 99% on diuretic, 96% ACE-I, ~ 70% big, ~20% spironolacatone. Trial stopped early after 10.4 months. Carvedilol placebo risk reduction Results: Total deaths (yr) 11.4% 18.5% 35% death + hospitalize 24%

Bucindolol for CHF : BEST §2708 patients with NYHA III (92%) or IV (8%), LVEF < 35% (mean 23%) designed to recruit more blacks and females, randomized to bucindolol (non-selective β-blocker but strong β-2 with weak α vasodilating effect) vs. placebo. Study stopped early (avg f/u 2 yrs) as NO EFFECT! Results: §No diff (although trend) total deaths RR=0.90 §CV, favored bucindolol RR=0.86 §Signif CHF hospitaliz. R=0.78 §Signif total deaths in non-blacks

Beta Blockers for CHF Modern trials §No benefit with bucindolol (non-selective with intrinsic vasodilation), so may not be a class effect Beta-1 receptions are the most important receptors for contractility (metoprolol, bisoprolol are beta-1 selective) Beta-2 are less important for contractility (carvedilol, bucindolol are non- selective) Alpha-1 least important (carvedilol has additional alpha-1 effect) §So far no Head-to-head trials (but carvedilol vs metoprolol=COMET in progress) §Use carvedilol, metoprolol or bisoprolol, but start with very low dose, dont start when patient very symptomatic or fluid overloaded

Natriuretic Peptides as Therapy for CHF §ANP (A-type), BNP (brain) both produced in myocardium, CNP in endothelium – the hearts own endogenous endocrine system. All are vasodilating, growth inhibiting, natriuretic. ANP rises in atria in early CHF, BNP in ventricle later. §Sensitive markers for CHF, especially BNP, which is the most natriuretic and lusitropic (best in dropping wedge pressure), most resistant to degradation by neutral endopeptidases. §Although elevated in CHF, even with elevation there may be insufficient production, thus suggesting role not only as marker for the disease, but also possibly adding exogenous natriuretic peptides as therapy for CHF. §Nesiritide, recombinant BNP (Natrecor®) recently approved (IV, in hospital, for acute CHF only)

Far-outnew therapies for CHF Medical Therapies: dopamine, dobutamine holidays(may improve symptoms but may shorten survival) §milrinone, flosequinon, vesnarinone, other PDE inhibitors §amidarone (GESICA yes, CHF-stat no) §growth hormone §endothelin antagonists §vasopressin antagonists §vasopeptidase inhibitors Surgical Therapies: §Biventricular pacing §Ventricular reduction (Batista operation) ± mitral repair/replacement §Gene therapy or transplant of functioning myocardial cells §Left ventricular assist devices (LVAD) §Cardiac transplant (not far-out, but huge logistical issues)

Balista procedure Partrial Left Ventriculectomy for CHF

Balista procedure (Partial Left Ventriculectomy) for CHF: Cleveland Clinic Experience 59 patients with NYHA Class II or IV CHF and cardiomyopathy, 39 on inotropic support, 23 awaiting heart transplant, underwent PLV and mitral valve surgery , followed for mean 405 days. Mean 96 gm myocardium exised, 53 had mitral valve repair, most with one or both papillary muscle resection, 2 mitral replacement, 34 tricuspid repair Operative death: baseline 3 months 12 months Mean NYHA Class: 3,6 2,2 2,1 Echo LVEF: 13% 24% 2 Echo LVEDVI 167 ml/M yr freedom from death, LVAD, transplant, NYHA IV CHF: 26%

Resynchronization Therapy §Background/Rationale §Recent Clinical Trials (MUSTIC, MIRACLE) §Ongoing Trials

Prevalence of Ventricular Conduction Defects in Dilated Cardiomyopthies §VCD present in 30-50% of pts with heart failure (Wilensky et al Am J Card 1988) §More prognostic than NYHA class in some series (Francis et al Int J Card 1999)

Ventricular Conduction Defect: Marker of Fibrosis or Hemodynamic Consequence? §Advers effects of Ventricular Conduction Defects: - Loss of septal contribution to ejection -Mitral Regurgitation -Reduced Diastolic Filling Time

Rationale for Resynchronization §Improved chamber loading §Reduced mitral regurgitation §Improved contractile

Conclusion §Who benefits most? §Mortality benefit? §Cost effectiveness?

Cardiac Transplantation §About 2300 transplants per year un US §About 50% idiopathic dilated cardiomyopathy 40% untreatable coronary disease 10% all other §1 year post transplant % survival (transplants ) §4 year survival % §Cost - $ st year, then $21.000/year Selection for transplant: §End stage cardiac disease and life expectancy < 1 year §NYHA Class III or IV refractory to medical therapy §Inoperable CAD §Malignant arrhythmia unresponsive to medical or surg Rx §(many centers): are < 65 preferred PROBLEM IS SUPPLY OF DONOR HEARTS - which will never be able to meet demand given aging population and safer automobiles

Терапия ЗСН Мочегонные средства Ингибиторы АПФ Блокаторы ангиотензиновых рецеп-торов (не так предпочти-тельны как АПФ-1) Β-блокаторы Спиронолактон Препарата дигиталиса (симптомы но не выживаемость) Пересадка сердца Бивентрикулярная стимуляция Амиодарон Предсердные натрий уретические пептиды (ANP, BNP, CNP) Антиаритмические препараты Антикоагулянты Операция Балисты Антагонисты эндетелина α -Антагонисты ТНФ. Нитраты Ингибиторы вазопептидазы Антагонисты кальция Положительные инотропные средства Вазодилятаторы не АПФ Да?Нет