CKD Satellite Symposium

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1 CKD Satellite Symposium

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

3 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

4 25.9% 14.8% 6.9% 4.9% 2.1% - = 70,932/245,817 (28.7%)

5 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

6 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

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

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

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

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

11 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

12 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

13 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

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

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

16 β blocker Trials Conducted in Chronic Heart Failure

17 b blockers in CHF: All-cause Mortality Mortality % Survival US Carvedilol Study Carvedilol (n = 696) Placebo (n = 398) Risk reduction = 65% P < Days Packer et al (1996) MERIT-HF Metoprolol CR/XL Placebo Risk reduction = 34% P = Months of follow-up The MERIT-HF Study Group (1999) Survival % Survival CIBIS-II II P < Bisoprolol Placebo Risk reduction = 34% Time after inclusion (days) CIBIS-II II Investigators (1999) COPERNICUS (NYHA class IIIB, IV) Risk reduction=35% P = Months All-cause mortality. Carvedilol Placebo Packer et al. NEJM (2001)

18 Comparison Carvedilol Metoprolol IR in Congestive Heart Failure: COMET Trial Carvedilol Metoprolol % Mortality 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 p= Half time metoprolol IR = 3.5 hours Half time carvedilol = 7hours Time (years) % LVEF<35%, NYHA functional class II-IV Poole Wilson PA et al, Lancet 2003;362:7

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

20 β blockers Prolong Survival in Elderly with Heart Failure Parameter Elderly, n=4617 Nonelderly, n=8112 RR (95% CI) 0.76 ( ) 0.66 ( ) Trial n NHYA LVEF Duration Definition (β blocker used) Class (%) (months) of elderly BEST (bucindolol) < years Carvedilol US trials (carvedilol) < (median) 59 years CIBIS-2 (bisoprolol) < years COPERNICUS (carvedilol) < years MERIT-HF (metoprolol) <40 12 Upper tertile *

21 Starting and Target Doses for β Blockers

22 Progressive Adrenergic Activation Despite Use of ACE Inhibitors Change in Norepinephrine (pg/ml) *P<0.05 * Hydralazine-Isosorbide (HI) Enalapril (E) * 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.

23 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

24 Medical Therapies Proven to Reduce Death in Cardiovascular Disease

25 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

26 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

27

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

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