Basic Sciences and Clinical Implications for Heart Failure Treatment'

1
Basic Sciences and Clinical Implications for
Heart Failure Treatment.

• Mariell Jessup MD
• Professor of Medicine
• University of Pennsylvania
• Philadelphia, Pennsylvania

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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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The only therapies that demonstrate mortality and
anti-remodeling benefit are those that block the
RAAS and/or the sympathetic nervous system

• Chronic Heart Failure Studies
• CONSENSUS I
• V-HeFT II
• SOLVD
• RALES
• Val HeFT
• US Carvedilol Trials
• CIBIS II
• MERIT-HF
• COPERNICUS

• Post-infarction studies
• SAVE
• AIRE
• TRACE
• CAPRICORN/CARMEN
• EPHESUS
• VALIANT

Remember ?-adrenergic blockers are also potent
inhibitors of the RAAS!
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ARB vs ACE inhibitors in Heart Failure
ELITE-II (Chronic HF)
OPTIMAAL (Post-MI)
Pitt et al. Lancet 2001. Dickstein et al.
Lancet 2002
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Mortality Trials in Systolic Heart Failure
1986-2004
Inotropic agents PROMISE VEST DIG OPTIME-II
?-Blockers MDC U.S. Carvedilol ANZ
Carvedilol MERIT-HF CIBIS-II BEST COPERNICUS CAPRI
CORN
ACE inhibitors CONSENSUS-II V-HeFT-II SOLVD-T SOLV
D-P SAVE AIRE TRACE ATLAS
Cytokine antagonists RENAISSANCE RECOVER
Endothelin antagonists ENABLE-2
Vasodilators V-HeFT FIRST PRAISE-I/-II
ARBs ELITE-II Val-HeFT OPTIMAAL CHARM VALIANT
Sympatholytic agents MOXCON
Aldosterone antagonists RALES EPHESUS
Positive Borderline/Neutral Negative
ACE/NEP Inhibitors OVERTURE
Slide courtesy of G. Francis
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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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OVERTURE ACE/NEP Inhibitors in Heart Failure
Does inhibition of BNP degradation (when coupled
to ACE inhibition) with omapatrilat improve
survival?
Packer et al, Circulation 2002
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Soluble TNF Receptor (p75) FcFusion Protein
(ENBREL, Etanercept)
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Etanercept Survival Study (RENEWAL)
(n1500)
(n1500)
Mann et al, HFSA 2002
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ENABLE I II bosentan (ETA ETB Antagonist) In
Heart Failure (n1,613)
of Patients (Event-Free from death/HF hosp)
100
90
80
70
60
50
40
30
Bosentan Placebo
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Log rank p-value 0.8986
10
0
Weeks from Randomization
0
13
26
39
52
65
78
91
104
117
130
No. at Risk
804 680 615 573 542 502 393 238 123 16 0 807 723 6
55 613 577 512 388 229 113 19 0
Packer et al, ACC Late-Breaking Trials 2002
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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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Natriuretic PeptidesThe Heart as a Secretory
Organ

• Atrial/ventricular stretch receptors link blood
  volume to renal function
• Distension of a balloon catheter in atria of
  dogs resulted in diuresis
• Henry, et al. (1956)
• Secretory granules discovered in the atria
• Kisch (1956)
• Jamieson and Palade (1964)
• de Bold, et al (1981) report natriuresis in rats
  after injection of atrial extracts
• BNP was characterized by amino acid sequence and
  DNA clones
• (Sudoh, et al. 1988 and Seilhamer, et al. 1989).

Jamieson and Palade J Cell Biol 196423151
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Family of Natriuretic Peptides
BNP
CNP
ANP
Diureticnatriuretic

• Diuretic
• Natriuretic
• Vascular relaxation
• Inhibition of RAAS, SNS
• Atria

• Same actions as ANP
• In atria and ventricles
• Longer 1/2 life
• Excellent marker
• Used as therapy

• No natriuresisor diuresis
• Potent vasodilator

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B-Type Natriuretic Peptide (nesiritide) as Therapy
BNP
CNP
ANP
NeN
NeN
Diureticnatriuretic

• Diuretic
• Natriuretic
• Vascular relaxation
• Inhibition of RAAS, SNS
• Atria

• Same actions as ANP
• In atria and ventricles
• Longer 1/2 life
• Excellent marker
• Used as therapy

• No natriuresisor diuresis
• Potent vasodilator

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B-Type Natriuretic Peptide
NT-proBNP Roche / Dade-Behring
BNP Biosite, Bayer, Abbott, Beckman-Coulter
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Nesiritide in Heart Failure VMAC
PULM
Pulmonary Capillary Wedge Pressure (absolute and
change)
Primary End Point PCWP through 3 Hours
Young et al, JAMA 2002
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New Diuretics- Adenosine Receptor Modulators

• Adenosine1 receptor antagonists - ? afferent
  arteriole flow
• BG9719 (CVT-124)

Gottlieb et al, Circulation 2002
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Conivaptan andTolvaptanNew Aquaretic Agents

• Conivaptan - an AVP-1 and AVP-2 receptor blocker
  promotes an aquaresis, corrects hyponatremia, and
  has vasodilator activity (reduces pulmonary
  capillary wedge pressure and raises cardiac
  output).
• Tolvaptan an AVP-1 receptor blocker that
  corrects hyponatremia in edematous patients with
  hyponatremia via an aquaresissurvival study
  underway (EVEREST)

Francis and Tang, JAMA 2004
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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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Partial Fatty Acid Oxidation (pFOX) Inhibition
Ranolazine, Trimetazidine, and Etomoxir
FattyAcids
Glucose

• Inhibit fatty acid oxidation only at high fatty
  acid concentrations
• Permit normal fatty acid oxidation rates at
  physiologic fatty acid concentrations
• Preserve high-energy phosphates and
  contractile function
• Reduce accumulation of lactic acid and maintains
  tissue pH
• Delay or prevent onset of biochemical
  myocardial ischemia
• Allow more energy to be produced from each O2
  molecule consumed

Lactic acid (?) H (?)
Pyruvate
pFOXInhibition
KrebsCycle
Oxidative Phosphorylation
Energy ATP
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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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Anemia in Ambulatory Heart Failure
Tang et al. ACC Presentation 2003
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Erythropoietin in Heart Failure

• Double blind, randomized, placebo-controlled
  study evaluating the safety and efficacy of
  erythropoietin in the treatment of patients with
  heart failure and anemia
• Darbepoetin (Amgen) STAMINA-HeFT- exercise
  study HIPOCRATES -survival study
• Concerns about ? thrombosis

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Sleep Apnea in Heart Failure

• 50 of patients with heart failure have sleep
  apnea
• 37 - central sleep apnea
• 13 - obstructive sleep apnea
• CPAP consistently improves obstructive sleep
  apnea, and may improve central sleep apnea
• 60 of patients tolerate CPAP

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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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Modified Dor Procedure
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LV Reconstruction (Dor)
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Effects of CSD on Cell Structure and Function
Saavedra WF et al JACC 2002392069-76 Sabbah
HN et al Circ Res 2003931095-1101
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Novel Mechanical Anti-remodeling Therapies in
Heart Failure
Myosplint
ACORN
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Surgical Procedures for Advanced Heart Failure at
Cleveland Clinic
Slide courtesy of G. Francis
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Directions in Heart Failure Therapy

• Blocking the RAAS and Sympathetic Nervous system
• Blocking several neurohormonal / cytokine systems
• Enhancing compensatory mechanisms in acute heart
  failure BNP
• Blocking metabolic pathways
• Treating concomitant problems
• Devices and mechanical support
• Surgical reconstruction
• Pharmacogenomics

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Addition of angiotensin receptor blockers
(ARBs), endothelin receptor blockers, and tumor
necrosis factor-a (TNFa) receptor blockers have
not resulted in improvement of survival or even
life expectancy. Patients vary in their response
to medications not only in terms of their
response to treatment and in their ability to
tolerate the medication. These limitations mean
that the time now has come to target therapy in a
systematic manner so that patients obtain maximum
benefit. One approach is to tailor therapy
depending on their pharmacogenomic profile. Such
an approach should not only improve survival but
will also result in the patient taking fewer
medications thus, better compliance should
ensue.
Baliga, Narula. Med Clin N Amer 200387569
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Baliga, Narula. Med Clin N Amer 200387569
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adrenergic receptor gene
Feldman A. Ann Thorac Surg 200376S2246
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Feldman A. Ann Thorac Surg 200376S2246
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ACE II
ACE ID
ACE DD
Feldman A. Ann Thorac Surg 200376S2246
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ACE II
ACE ID
ACE DD
no BB at entry
Rx with BB
no BB
all ACE DD
Feldman A. Ann Thorac Surg 200376S2246
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Several studies in the literature have already
suggested that some of the commonly used
medications work better in certain ethnic groups
of patients. For example, the hydralazine-isosorbi
de mononitrate combination is more effective in
blacks than whites, whereas ACE-I inhibitors are
more effective in whites than black patients.
Some b-blockers (eg, bucindolol) are less
effective in black patients, whereas others (eg,
carvedilol) are equally effective.
Baliga, Narula. Med Clin N Amer 200387569
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• To test the hypothesis that nitric oxide
  enhancing therapy with a fixed-dose combination
  of isosorbide dinitrate and hydralazine
  (ISDN/HYD) may provide additional benefit to
  African-American patients with advanced heart
  failure

A-
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Study Design

• Double-blind, placebo-controlled trial
• 1,050 African American patients with New York
  Heart Association Class III or IV heart failure
  and dilated ventricles
• Randomized to receive the fixed-dose ISDN/HYD (20
  mg/37.5 mg) or placebo in addition to current
  standard heart failure treatments
• Designed for 18 months, but discontinued early
  due to a significant survival benefit at median
  follow-up of 10 months

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Commentary

• Blood pressure effects (absolute difference up to
  3.1-3.2 mmHg) in a largely preserved BP group.
• Discrepancy between NYHA III-IV classification
  and annualized mortality of 8.5 in placebo
  group.
• Mechanism of isosorbide dinitrate and nitric as
  oxide donor in vivo needs validation
• Ethnicity differences

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Baliga, Narula. Med Clin N Amer 200387569
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Pipeline Drug Development in Heart Failuresome
winners and losers

• Phosphodiesterase-3 Inhibitor
• Enoximone (EMPOWER, ESSENTIAL, EMOTE)
• Immune Modulators
• Etanercept (RENAISSANCE, RECOVER)
• Infliximab (ATTACH)
• Immune modulator, VAS-991 (ACCLAIM)
• Miscellaneous
• AGE cross-link breaker, ALT-711 (DIAMOND,
  SAPPHIRE, SILVER)
• Nebivolol (SENIORS)
• BiDil (A-HeFT)
• darbepoetin (STAMINA-HeFT, HIPOCRATES)

• Selective Aldosterone Antagonists
• Eplerenone (4E, EPHESUS)
• Endothelin Receptor Antaginst (ERA)
• Bosentan (REACH-1, ENABLE-1 -2)
• Tesozantan (RITZ-1 to -5)
• Darusentan (EARTH)
• Enrasentan (ENCOR)
• Vasopeptidase Inhibitors (VPI)
• Omapatrilat (OVERTURE, OCTAVE, OPERA)
• Natriuretic Peptides
• Nesiritide (PRECEDENT, VMAC, FUSION1,2)
• Imidazoline-1 Rececptor Antagonist
• Moxonidine (MOXCON, MOXSE)
• Calcium Sensitizers
• Levosimendan (LIDO, RUSSLAN, REVIVE)

Slide courtesy of G. Francis