Pathophysiology and Treatment of Heart Failure
The Issues to Discuss Incidence of HF Pathophysiology of HF Treatment of HF
Basil S. Lewis, MD, FRCP
– evidence-based medicine and results of clinical trials
Lady Davis Carmel Medical Center Bruce Rappaport School of Medicine, Technion-IIT, Haifa Lady Davis Carmel Cardiovascular Center
Epidemiology of Heart Failure
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Prevalence of HF in Pts Hospitalized in Internal Med and Cardiology Depts in Haifa SUSPECTED HF TOTALCHF 33.6%
68 (6.2%)
NO HF
HF 300 (27.4%) 20,000
727 (66.4%)
43,000
500,000 new cases of HF per year in USA Data from LDCMC registry and Euro Heart Survey (Lewis et al, J Isr Heart Soc 2003;13:40)
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Pathophysiology of HF Clinical aspects Hemodynamics Skeletal muscle Renal function Anemia
Molecular biology Neurohormonal aspects
Immunology
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Lady Davis Carmel Cardiovascular Center
Myocardial Function: Molecular Biology
Hemodynamics: Ventricular function
Assessment of LV Contractility Assessment of myocardial contractility is based on relations between
Abnormalities of ventricular function:
• Force
Systolic function
• Velocity
Diastolic function
• Fiber length Medical Center Center LadyLady DavisDavis CarmelCarmel Cardiovascular
Systolic Function: Starling Curves
The Pressure-Volume Loop Decreased contractility
Onset of systole
LV Wall Stress and LV Hypertrophy Stress = P X R 2W Wall stress: - circumferential - meridional - radial - tends to remain=k
Wall Stress and LVH Pressure load
LV Wall Stress and LV Hypertrophy
Wall Stress and LVH Volume load
Stress = P X R 2W Wall stress: - circumferential - meridional - radial - tends to remain=k
Diastolic Dysfunction
Regional Wall Motion Global LV function and dysfunction
Decreased ventricular compliance
Increased LV end-diastolic pressure
Regional LV dysfunction - hypokinesis - akinesis - dyskinesis
Increased LA pressure and pulmonary venous pressure
Interstitial edema, intra-alveolar edema
Shortness of breath, pulmonary edema
- regional asynchrony
Diastolic Dysfunction: Etiology
LV hypertrophy
Hypertension Aortic valve disease Hypertrophic heart disease
Fibrosis
The Pressure-Volume Loop
Post-myocardial infarction, other
Ischemia
Coronary artery disease
Onset of systole
Diastolic dysfunction
Diastolic function: The P-V relation
Preserved LV Function in HF Patients (Diastolic dysfunction) % patients 70 60
Reduced LV Preserved LV 54
50
46
50
52
50
48
40 30 20 10 0 ESC survey
ADHERE registry (US)
Israel survey 2003
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HF with Preserved LV Function: The Israel National HF Survey 2003 Pt characteristics
Mortality
Digoxin
P<0.0001
100 90
p=0.003
80
71 72
70
P<0.0001
79 P<0.0001
60
69
92 75
52
50 40
29
30 20 10 0 Age (yr)
Females (%)
HTN (%)
Coronary disease (%)
20 18 16 14 12 10 8 6 4 2 0
Clinical Trials for HF: Where Do We Stand?
Reduced LV Preserved LV
19 14
ACE inhibitors Angiotensin II receptor antagonists Beta blockers
p=0.005
p=0.01
5 3
Hospital mortality
Aldosterone antagonists New drugs - Endothelin antagonists, other
6 month mortality
Non-pharmacologic therapies
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Effect of Digoxin on All-cause Mortality
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Effect of Digoxin on Death/Hospitalization for Worsening Heart Failure
Placebo
Digoxin
RRR 25%, p<0.001
DIG investigators, NEJM 1997; 336:525-33
DIG investigators, NEJM 1997; 336:525-33
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Lady Davis Carmel Cardiovascular Center
Adjusted Outcomes (Hazard Ratios) by Serum Digoxin Levels Adjusted outcomes*
HR (≥ ≥1.2 Placebo HR (0.5HR (0.90.8 ng/mL) 1.1 g/mL) ng/mL)
All-cause mortality
Referent
0.80
0.89
1.16
Cardiovascular mortality
Referent
0.86
0.93
1.21
Worsening heart failure
Referent
0.66
0.86
0.95
All-cause hospitalization
Referent
0.83
1.02
0.90
Hospitalization for worsening heart failure
Referent
0.56
0.74
0.65
Rathore SS et al. JAMA 2003;289:871-878
Digoxin improves symptoms and decreases hospitalizations Dig withdrawal may cause worsening of symptoms No survival benefit in the DIG trial, but this may have been due to proarrhythmia in pts with high serum dig levels Lady Davis Carmel Cardiovascular Center
Neurohormonal Effects in HF
Angiotensin II
Digoxin: What Have We Learnt?
Renin – Angiotensin – Aldosterone System (RAAS)
Norepinephrine Non-ACE pathways (chymases)
- Hypertrophy, apoptosis, ischemia, arrhythmia, remodelling, fibrosis - Vasoconstriction, afterload
Effects of Angiotensin II – The Bad Guy
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The Neurohormonal Response
Effect of ACE-Inhibitor on Mortality Risk ratio
12 mth placebo mortality rate 15.6%
SOLVD Rx, 1991 (NYHA IIII-III)
52.4% 52.4%
CONSENSUS I, 1987 1987 (NYHA IV)
38.5%
Real World patients (hospitalized)
0
0.25
ACE-inhibitors: What Have We Learnt?
0.5
0.75
1.0
Favours treatment
ACE-inhibitors carry survival benefit
– with reduced LV function – post-MI (SAVE, others) – high risk pts, even without CHF or reduced LVEF (HOPE study)
Mechanisms – Hemodynamic effect – Myocardial effect (anti-proliferative, anti-fibrosis, antiapoptosis)
1.25
– Vascular effect (anti-atherosclerosis) – Renal protection
Favours placebo
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VAL-HeFT Trial: Benefit of Valsartan Added to HF Treatment
The Losartan Heart Failure Survival Study–ELITE II Primary Endpoint: All-Cause Mortality
5010 pts with HF (NYHA II-IV)
Probability of survival
Kaplan-Meier Estimates for Survival 1.0 0.8 Losartan (n=1578) Captopril (n=1574)
0.6 0.4
Hazard ratio (95.7% CI): 1.13 (0.95, 1.35); p=0.16)
0.2 0
0
100
200
300
400
500
600
700
• No significant difference between losartan and captopril in reducing all-cause mortality in heart failure RR 0.87 (0.77-0.97)
Days of follow-up
CI = confidence interval
Survival
Adapted from Pitt B et al Lancet 2000;355:1582-1587.
Survival/hospitalization for HF
Cohn et al, NEJM 2001;345:1667-75
Study design
CHARM-Added: Primary outcome
Dose-titration and visit schedule
16 mg 8 mg 32 mg 4 mg 16 mg 8 mg
Time 0 w Visit
1
32 mg
2w
4w
6w
2
3
4
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CV death or CHF hospitalisation 50
Candesartan/ matching placebo once daily
%
Placebo
40 30
538 (42.3%) 483 (37.9%)
Candesartan
20 10
Every 4 months 6 m until study end 31 March 2003 5
0
HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010
0
Number at risk Candesartan 1276 Placebo 1272 35
1
2
3
1176 1136
1063 1013
948 906
3.5 years 457 422 36
EFFECT OF ALDOSTERONE
ARB’s: What Have We Learnt?
Normal heart
Aldosterone (plus salt)
ARB’s carry survival benefit
– In pts who do not tolerate ACE-inhibitors – May improve morbidity in those already receiving ACEinhibitors
– Should be used instead of ACE-inhibitors in pts postMI or HF where necessary
In hypertension – Are superior to beta-blocker based Rx with regard to CNS effect
– Decreased stroke, mental deterioration (LIFE, SCOPE) Weber, NEJM 2001;345:1689-1697
Perivascular fibrosis
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Effect of Spironolactone in CHF: The RALES Study
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EPHESUS Trial: Primary Endpoints 6632 pts post-AMI, with LV dysfunction and HF
All-cause All-cause Mortality Mortality
CV CV Death Death or or Hospitalization Hospitalization
RR RR 0.85 0.85 p=0.008 p=0.008
20% 20%
RR RR 0.83 0.83 p=0.005 p=0.005
40% 40% 16.7% 16.7%
15% 15%
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EPHESUS Trial: Secondary Endpoint CV CV Death Death
20% 20%
5% 5%
10% 10%
Eplerenone Eplerenone
Placebo Placebo
N N Engl Engl JJ Med Med 2003;348:1309-21 2003;348:1309-21
0% 0%
30.0% 30.0% 26.7% 26.7%
Eplerenone Eplerenone
Placebo Placebo
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NEUROHORMONAL EFFECTS IN HF Angiotensin II
RR RR 0.87 0.87 p=0.002 p=0.002
20%
30% 30%
10% 10%
0% 0%
Pitt et al, N Engl J Med, 1999;341:709-717
14.4% 14.4%
Norepinephrine
14.6% 14.6%
15% 12.3% 12.3%
10% 5% 0%
N N Engl Engl JJ Med Med 2003;348:1309-21 2003;348:1309-21
Hypertrophy, apoptosis, ischemia, arrhythmia, remodelling, fibrosis Eplerenone Eplerenone
Placebo Placebo
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Lady Davis Carmel Cardiovascular Center
β Blockers In Heart Failure AllAll-cause Mortality
Survival
US Carvedilol Study Carvedilol (n=696)
1.0
Effect of Carvedilol on Survival in Severe Chronic Heart Failure: COPERNICUS (Class 3b3b-4)
0.9 Placebo (n=398)
0.8
AllAll-cause mortality
Risk reduction = 65%
0.7
100
p<0.001 0.6
0 50 100 150 200 250 300 350 400 Days
Survival
Mortality % 20
CIBISCIBIS-II
1.0
MERITMERIT-HF Placebo
Bisoprolol
15
0.8
0
p=0.0062
0 200
400
Time after inclusion (days)
600 800 Lancet (1999)
Placebo
p=0.00013 35% risk reduction
Risk reduction = 34%
5
p<0.0001 0
70 60
Placebo
Risk reduction = 34%
Carvedilol
80
Metoprolol CR/XL
10
0.6
90
% Survival
0.5
Packer et al (1996)
0
3 6 9 12 15 Months of follow-up
18
0
0
3
6
9
The MERIT-HF Study Group (1999)
Effect of Carvedilol on AllAll-cause Mortality PostPost-MI: CAPRICORN Study (Class 1)
12
Months
21
15
18
21
Packer et al, NEJM 2001;344:1651-1658
Packer, AHA 2000
Beta Blockers for HF and LV Dysfunction: What Have we Learnt?
1958 pts post-AMI
Beta blockers indicated for pts with class 22-3 HF (US and NZ carvedilol; CIBIS; MERIT) Carvedilol indicated in pts with Class 33-4 HF (Copernicus)
RR 0·77 (0·60-0·98)
Carvedilol indicated for post AMI pts with LVEF<40% (Capricorn) Pts should be stable, no fluid overload, dose increased gradually
Dargie, Lancet 2001;357: 1385-90
Established Pharmacotherapy For Heart Failure: Summary
Other Approaches and Studies Endothelin antagonists – Bosentan, tezosentan
Digoxin
ANP system – Nesiritide (BNP type substance)
Diuretics ACE inhibitors Angiotensin II receptor antagonists Beta blockers Aldosterone antagonists Other Rx – Drugs, Devices, Surgical
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Immune system – antagonize TNF-α (Enbrel), modulate immune response – RESTORE study, VASOGEN-ACCLAIM study Treat anemia – Erythropoietin, Fe Mechanical devices, surgical approaches – Pacing and synchronous (biventricular) pacing – LVAD’s, newer surgical approaches Lady Davis Carmel Cardiovascular Center
The Endothelin System
The Endothelin System
Big ET-1
Big ET-2
Enzyme Leu
Ser
Ser
Met
Cys Ser Cys
Trp
N
Leu
Asp Lys
Big ET-3 ECE
ECE Ser
Ser
Cys Ser Cys
Tyr
N
ET-1
Ile Trp
C
Lys
Thr
Phe
Lys
Cys Thr Cys
N
Asp
Asp Glu Cys Val Tyr Phe Cys His Leu Asp Ile
Glu Cys Val Tyr Phe Cys His Leu Asp Ile
Ile Trp
Lys
C
Glu Cys Val Tyr Tyr Cys His Leu Asp Ile
ET-2
Ile Trp
C
ET-3
EC ET B
Receptor
RITZRITZ-2: Cardiac Index
Change From Baseline Over Time
ET
50
B
P = 0.048
40
0.4 Placebo Tezosentan 50 mg/hr Tezosentan 100 mg/hr
0.2
% Patients
L/min/m2
A
RITZRITZ-2: Dyspnea Score at 24 Hours (Seven(Seven-point Scale)
0.6
0
SMC ET
Placebo Tezosentan 50 and 100 mg/hr
30 20 10
0
6
12
18
Time (h) Torre-Amione et al, ACC 2001
24
30
Treatment stop
Endothelin Antagonists in HF: The ENABLE Study
0 Torre-Amione et al, ACC 2001
Improved
Worsened
ANP System: Nesiritide (Noratak)
1400 pts with Class 3-4 CHF Bosentan (62.5-125mg b.i.d.) for >18 mths Primary end-point: all-cause mortality or hospitalization for CHF Secondary: clinical status at 9 mths
No additional benefit Lady Davis Carmel Cardiovascular Center
Lady Davis Carmel Cardiovascular Center
Immune Modulation in HF
Anemia in Heart Failure: Etiology Blood loss
TNF-α is upregulated in myocardium of pts with HF Circulating TNF-α levels are elevated in HF TNF-α is associated with depressed myocardial function, cachexia TNF- α antagonists (enbrel, etanercept) so far have failed (RESTORE study)
Dietary, lack of absorption Renal failure – common disease process (atheroma, HTN, DM) – pre-renal
Resistance to erythropoietin (TNF-α)
ACCLAIM study of immunomodulation currently in progress
Unrelated causes Lady Davis Carmel Cardiovascular Center
Hemoglobin values recorded in 5249 (92% of total enrolled) men in EuroHeart Failure survey
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Anemia: Hemodynamics Decreased O2 transport capacity Vasodilatation, increased cardiac output Volume overload Implications for LV function – Systolic function – Diastolic function
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Device Therapy for HF: Cardiac Resynchronization (CRT) for Pts with LBBB
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Lady Davis Carmel Cardiovascular Center
Effect of Pacing Site on LV Function: Pressure-Volume Loops
Kass et al, Circulation 1999;99:1567-1573
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Surgical treatments for CHF Revascularization for ischemic/hibernating myocardium LV aneurysmectomy/remodeling (Dor) LV resection (Batista procedure)
Improved Clinical Outcome in HF 1 year mortality (Class 4 pts) • 1987 (CONSENSUS 1) –52% (placebo arm)
Cardiomyoplasty
• 2000 (MERIT-HF)
LV assist devices
–17% (treatment arm)
Transplantation Lady Davis Carmel Cardiovascular Center
Drug Treatment of Heart Failure 1974-2004 Old treatment (1974)
New treatment (2004)
Failed treatments
Digoxin
Digoxin
Milrinone
Diuretic
Diuretic
Xamoterol
ACE inhibitor/ARB
Flosequinan
Beta blocker
Vesnarinone
Aldosterone antagonist
Pimobendan
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Thank you Pfizer Israel - for their never-ending support All of you for listening
Flolan Sotalol Bosentan Omapatrilat Enbrel (anti TNF)
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Fall 2004 Lady Davis Carmel Cardiovascular Center
