Stefan Anker, MD PhD

1
Defining New Targets Heart Failure as a Metabolic
Illness
Stefan Anker, MD PhD
Applied Cachexia Research, Cardiology, Charité
Campus Virchow-Klinikum, Berlin,
Germany. Clinical Cardiology, NHLI, London, UK.
2
Metabolic problems in HF withpotential
therapeutic impact

• Diabetis mellitus type II
• Metabolic illness high serum uric acid
• Obesity paradox
• Cachexia
• Anaemia

3
Metabolic problems in HF withpotential
therapeutic impact

• Diabetis mellitus type II
• Metabolic illness high serum uric acid
• Obesity paradox
• Cachexia

• PLUS
• ageing
• better care

4
Changing Population Demographics And The Effect
On The Number Of Persons With Heart Failure
772,000 new HF casesper year in 2040
100
348,000 new HF casesper year in 2000
77.2
80
Number of people ? 65 years (millions)
53.7
60
34.8
40
25.5
of people ? 65 years
16.6
20
20.5
16.5
12.7
11.3
9.2
0
Owan et al Prog Cardio Dis 2005
1960
1980
2000
2020
2040
5
Increasing Prevalence of Diabetes Mellitus
Between 1995-2025 in Developed and Developing
Countries
2025
8
7
2000
1995
6
2025
5
Prevalence ()
4
2000
1995
3
2
1
0
Developing
Developed
King et al. Diabetes Care 1998211414-1431
6
Incidence of CHF in Diabetic Subjects (n9591)
Compared to Control (n9591) Subjects
Incidence Rate per 1,000
80
73
71
Diabetic Subjects Control Subjects
70
60
60
65
50
53
37
40
35
26
30
20
15
10
4
10
2
5
1
0
lt45
45-54
55-64
65-74
75-84
85-94
95
Age at baseline
Nichols et al. Diabetes Care 2001241614-1619
7
Chronic HF trial diabetes
Prevalence
40
35
30
25
20
15
10
5
0
DIG
BEST
CIBIS-II
ATLAS
RALES
MACH-I
VHeFT-I
ELITE-II
COMET
VHeFT-II
Val-HeFT
PRAISE-I
SOLVD-T
MERIT-HF
OVERTURE
DIAMOND-HF
COPERNICUS
CONSENSUS-I
8
CHARM Outcomes in diabeticsand non-diabetics
All-cause mortality
CV death or hospitalisation due to HF
Cumulative incidence ()
60
Cumulative incidence ()
60
40
40
20
20
0
0
0
0.5
1
1.5
2
2.5
3
3.5
0
0.5
1
1.5
2
2.5
3
3.5
Follow-up (years)
Follow-up (years)
Low EF Diabetes
Low EF No diabetes
Preserved EF No diabetes
Preserved EF Diabetes
9
CHARM-OverallNew diagnosis of diabetes mellitus
Proportion of patients ()
12
Placebo
10
202 (7.4)
HR 0.78 (0.64-0.96) p0.020
8
163 (6.0)
6
Candesartan
4
2
0
years
0
1.0
2.0
3.0
3.5
Candesartan 2715 2565 2395 1662 Placebo
2721 2501 2304 1622
10
Insulin resistance and survival in CHF Divided by
median Si 1.82 min-1.µU.ml.104
RR 2.7 (95CI 1.5-4.7) P 0.001
Cumulative survival ()
100 80 60 40 20 0
83
76
Si gt median n 53
61
Si lt median n 52
44
Time (months)
0 12 24 36
48
Patients at risk Si gt median 53 44
43 26 21 Si lt
median 52 38 29
20 16
Doehner et al. JACC 2005
11
Metabolic Pathways and Uric Acid - CHF
Anker et al., Circulation 2003
Hyperglycemia
Hyperinsulinemia
Membrane damage
Free Radical Release
Glucose-6-P
Purine catabolism
PPRP
IR
Tissue Hypoxia
XO
3-P-Glycerol
Uric acid
Release of Cytokines
Cell death
vascular dysfunction
Hypertriglyceridemia
Hyperuricemia
Kidney Function Diuretic Treatment
12
High UA predicts impaired survival in CHF graded
relationship (n294)
Anker et al. Circulation 2003
Survival ()
UA 400 401-600 601-800 gt800
Risk Ratio vs UA 400
100
1.00 1.76 6.27 18.53
80
n100 27 deaths
60
n143 57 deaths
40
20
n39 32 deaths
n12 12 deaths
0
0
1
2
3
4
5
7
8
6
Time (years)
p0.016, plt0.0001
13
Hyperuricemia in CHF potential target for
tailored treatment
Change after allopurinol
120
100


80
Endothelium dependent vasodilation

60
40

ns
20
ns
0
normal UA
elevated UA
UA µmol/L 315 321
535 558 420
553 (baseline) Treatment acute (i.a.) 3
mon acute (i.a.) 1 week 1 mon 3
mon
Doehner Mercuro Doehner Doehner
Farquharson Mercuro
14
Fonarow et al. Am Heart J 2007
BMI distribution in 108,927 patientshospitalized
with heart failure
ADHERE 10/0112/04 263 hospitals all AHF pts
Over- weight
Healthy weight
Obese
Underweight
BMI (kg/m2) Q1 16.0-23.6 Q2 23.7-27.7
Q3 27.8-33.3 Q4 33.4-60.0
BMIlt20 8
BMI 20-23.6 17
15
Fonarow et al. Am Heart J 200715374-81.
BMI and in-hospital mortality ADHERE 108,927 HF
patients
ADHERE 10/0112/04 263 hospitals all AHF pts
BMI (kg/m2) Q1 16.0-23.6 Q2 23.7-27.7
Q3 27.8-33.3 Q4 33.4-60.0
Mortality Rate ()
Mortality Rate ()
Plt.0001
Plt.0001
N8,063
N8,691
N9,627
N11,520
N12,083
N11,951
N8,421
N10,800
LVEF gt40 N37,901
LVEF lt40 N43,255
For every 5-unit increase in BMI, the odds of
risk-adjusted mortality were 10 lower (95 CI
0.88-0.93), plt0.0001.
16
BMI in CHF in CHARM
Days lost due to death HF-hosp
BMI Categories
mortality
35
-12
-19
-29
27
-39
35
3034.9
2529.9
22
22.524.9
lt22.5

• N7599
• Median FU 38 months

CHARM weight change analysis, ESC 2007
17
Cardiac cachexia and survivalweight loss ? 7.5
survival ()
100
83

• Cardiac Cachexia
• prognostic value
• independently of
• Peak VO2
• LVEF
• NYHA class
• Na
• Age

n 171
80
RR 3.73 95 CI 1.93-7.23 p0.0003
60
50 cachectic n28 (16.4)
40

20
0
0 6
12
18
Anker et al., Lancet 1997
months
18
Cachexia prevention with an ACE-inhibitor
50 40 30 20 10 0
frequency of weight loss 6
Placebo Enalapril
n2090 risk reduction 21 p0.0015
4 8 12 24 36 48 months
Anker et al., Lancet 2003
19
Cholesterol and survival in ELITE II n3127
Risk ratio for death during follow-up
mean Cholesterol 5.34 1.19 mmol/L
RR 0.70 plt0.002
100
p0.0008 between decatiles
50
best group (RR 1.0)
1.99 - 3.91
3.92 - 4.33
4.34 - 4.68
4.68 - 4.96
4.97 - 5.25
5.26 - 5.56
5.57 - 5.90
5.90 - 6.27
6.28 - 6.85
6.87 - 12.52
Cholesterol (mmol/L)
20
Bacterial Toxins, Lipids Heart Failure

- circulating - in tissues (heart, periphery)
Hormones
Monocytes
LPS
TNF
Tissue Hypoxia
Lipoproteins HDL / LDL

LIVER

Thoracic
Duct
Bacteria / LPS
Portal
Vein
Gut Wall
Anker et al., AJC 1997 Rauchhaus,
Coats Anker, Lancet 2000 Niebauer et al.,
Lancet 1999 Rauchhaus et al, JACC 2003
21
Nutrition for Cardiac Cachexia
Patients n29, gt7.5 weight loss BMI 21.7 2
kg/m2 NYHA 2.7 0.5, LVEF 24 9 all on
ACEI, BB, spironol., diuretics Nutrition 6 w
intervention 12 w follow-up n19 600 kcal /
d (Nutricia) (protein 20g, carbohyd 72g, fat
26g) n6 Placebo 12 kcal /
d Investigations DEXA, lipids, cytokines, QoL
Rozentryt Anker (unpublished)
22
Nutrition for Cardiac Cachexia
Weight (kg)
MLWHF-QoL
TNF (pg/mL)
P0.057
P0.02
P0.001
P0.008
Pgt0.05
P0.0003
70
50
15
4724
12.717
4224
6611
65.410
65
40
10
3724
63.410
6.19
60
30
5
2.43
0
0
0
BL
6w 18w
BL
6w 18w
BL
6w 18w
Fat tissue 6w 1.4 kg, p0.002 18w 2.0 kg,
p0.02
Chol 6w 0.2 mmol/L 18w 0.6 mmol/L, p0.03
Rozentryt Anker (unpublished)
23
CACHEXIA prevalence, pts at risk mortality
prevalence pts at preval. Europe 1-year
in populat. risk in pts pts
with mortality at
risk cachexia COPD 3.5 15
50 1,200,000 15-25 CHF 2.0 8
0 10 720,000 20-40 (NYHA
II-IV) Cancer 0.5 90 30 540,000
20-60 (all types) RA 0.8 20
10 100,000 5 (severe
RA) (cachexia) 55 400,000
2 (muscle wasting) CKD 0.14
50 50 120,000 20
Population assumptions Europe 450 Mill, US
300 Mill, Japan 100 Mill
24
Metabolic problems in HF withpotential
therapeutic impact

• Diabetis mellitus type II
• Metabolic illness high serum uric acid
• Obesity paradox
• Cachexia
• Anaemia

• Interventions
• nutrition
• exercise
• XO inhibition