CKD Satellite Symposium

CKD Satellite Symposium

Recommended Therapy by Heart Failure Stage AHA/ACC Task Force on Practice Guideline 2001

Natural History of Heart Failure Patients surviving % Mechanism of death Sudden death 40% Worsening CHF 40% Others 20% Progression Further damage Excessive wall stress Neurohormonal activation Myocardial ischemia Annual mortality Asymptomatic Mild Moderate Severe Left ventricular dysfunction and symptoms

25.9% 14.8% 6.9% 4.9% 2.1% - = 70,932/245,817 (28.7%)

Neurohormonal Activation in LV Dysfunction Renin-Angiotensin-Aldosterone System Angiotensin II Sympathetic Nervous System Norepinephrine Hypertrophy, Apoptosis, Ischemia, Arrhythmias, Remodeling, Fibrosis Progressive LV Dysfunction Morbidity and Mortality

Effect of Sympathetic Activation in Heart Failure CNS Sympathetic Outflow Cardiac sympathetic activity Sympathetic activity to kidneys & blood vessels β1 Receptors β2 Receptors α1 Receptors Activation of RAS Myocyte death Increased arrhythmias Vasoconstriction Sodium retention Disease Progression

Selected Components of the Cardiac Myocyte β1- and β2-adrenergic Receptor Pathways L-type calcium channel Phospholamban/SERCA TnI, MyBP-C

Mechanisms of β-adrenergic Receptor Desensitization and Internalization Gβγ endosome GRK family: GRK2 (βark1), GRK5 in heart

Proposed Changes in β-adrenergic Receptor Signal System and Sarcoplasmic Reticulum in Severe CHF

Downregulation of β-adrenergic Receptors in Myocardium from Patients with Heart Failure

Beta receptor levels in heart failure Normal Heart β 1 80 : β 2 20 Severe Heart Failure β 1 60 : β 2 40 β 1 receptors to selectively down-regulate secondary to high levels of catecholamine β 2 agonists retain full inotropic activity mediated through a β 2 population that is not significantly decreased

Biological Responses Mediated by Adrenergic Receptors in the Human Heart Biological Response Positive inotropic response Positive chronotropic response Myocyte toxicity Myocyte apoptosis Cardiac myocyte growth Fetal gene induction Proarrhythmic Adrenergic Receptor Mediation β1, β2, α1(minimal) β1, β2 β1>>β2 β1 β1>> β2, α1 β1 >> β2, α1 β1, β2, α1

Potential Beneficial Cellular Effects of β-adrenergic Blocker Therapy in Heart Failure Upregulation of β 1 -receptor Correction of Gs and Gi abnormalities Protection against cytosolic Ca 2+ overload Shift in metabolic substrate utilization from Fatty acid to Glucose Decrease in Renin release Prevention of Myocyte hypertrophy Antioxidant effect Decrease in Apoptosis Antiarrhythmic effects

Adrenergic Receptor Blocking Affinities of β-blocking Agents in Human Receptors

Effects of Different β Blocking Agents NE NE Bisoprolol Metoprolol NE Carvedilol β 1 β 2 α 1 Cofactors Cardiac cell toxicity

β blocker Trials Conducted in Chronic Heart Failure

b blockers in CHF: All-cause Mortality Mortality % Survival US Carvedilol Study 1.0 0.9 0.8 0.7 0.6 Carvedilol (n = 696) Placebo (n = 398) Risk reduction = 65% P < 0.001 0 50 100 150 200 250 300 350 400 Days Packer et al (1996) MERIT-HF 1.0 0.9 0.8 0.7 0.6 Metoprolol CR/XL Placebo Risk reduction = 34% P = 0.0062 0 3 6 9 12 15 18 21 Months of follow-up The MERIT-HF Study Group (1999) Survival % Survival CIBIS-II II 1.0 0.8 0.6 0 P < 0.0001 Bisoprolol Placebo Risk reduction = 34% 0 200 400 600 800 Time after inclusion (days) CIBIS-II II Investigators (1999) COPERNICUS (NYHA class IIIB, IV) 100 90 80 70 60 50 Risk reduction=35% P = 0.00013 0 4 8 12 16 20 24 28 Months All-cause mortality. Carvedilol Placebo Packer et al. NEJM (2001)

Comparison Carvedilol Metoprolol IR in Congestive Heart Failure: COMET Trial Carvedilol Metoprolol % Mortality 40 30 20 10 0 Metoprolol IR b.i.d (mean dose 85 mg/day) Carvedilol b.i.d. (mean dose 41.8 mg/day) metoprolol carvedilol HR 0.83 CI 0.74-0.93 p=0.0017 Half time metoprolol IR = 3.5 hours Half time carvedilol = 7hours 0 1 2 3 4 5 Time (years) 1511 1366 1259 1155 1002 383 1518 1359 1234 1105 933 352 17% LVEF<35%, NYHA functional class II-IV Poole Wilson PA et al, Lancet 2003;362:7

Class Clinical Effects of β-adrenergic Blocking Agents in Chronic Heart Failure

β blockers Prolong Survival in Elderly with Heart Failure Parameter Elderly, n=4617 Nonelderly, n=8112 RR (95% CI) 0.76 (0.64-0.90) 0.66 (0.52-0.85) Trial n NHYA LVEF Duration Definition (β blocker used) Class (%) (months) of elderly BEST (bucindolol) 2708 3-4 <35 24 65 years Carvedilol US trials (carvedilol) 1094 2-4 <35 6.5 (median) 59 years CIBIS-2 (bisoprolol) 2647 3-4 <35 15.6 71 years COPERNICUS (carvedilol) 2289 3-4 <25 10.4 65 years MERIT-HF (metoprolol) 3991 2-4 <40 12 Upper tertile *

Starting and Target Doses for β Blockers

Progressive Adrenergic Activation Despite Use of ACE Inhibitors Change in Norepinephrine (pg/ml) 300 250 200 150 100 50 0-50 -100 *P<0.05 * Hydralazine-Isosorbide (HI) Enalapril (E) * 0 6 12 18 24 30 36 42 48 HI n=300 E n=312 n=240 n=265 Months n=186 n=200 n=119 n=124 n=67 n=62 Francis et al. Circulation. 1993;87:V140-V148.

Mortality Benefit of β Blockers and ACEIs in CHF Trials % death at 1 year SOLVD (1991) CIBIS II MERIT-HF (1999) diuretic diuretic diuretic diuretic digoxin digoxin digoxin digoxin ACEi ACEi ACEi β blocker

Medical Therapies Proven to Reduce Death in Cardiovascular Disease

Beta blockers in HF Stable patients with mild to moderate symptoms without significant congestion Additional benefit even in severe but stable HF and post-mi LV dysfunction Carvedilol seems better than metoprolol Not always beneficial with all kinds of β blockers and study populations

Limitations of β-blocker Therapy in Chronic Heart Failure Contraindications to β-blockade such as reactive airway disease, sinus node or conduction system disease with bradycardia and advanced HF with hemodynamic decompensation Initiation of therapy and uptitration of β blocking agent can be difficult Some patient do not respond to β blockade; not yet clear mechanism

Alterations in β-adrenergic Pathway in the Failing Heart chronic adrenergic sti Desensitization + degradation Decreased β-adrenergic response