heart failure and cancer: common pathophysiology...
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Thessaloniki, 16 Feb 2012
Heart failure and cancer:Heart failure and cancer:
common pathophysiology & therapycommon pathophysiology & therapy
Stefan D. Anker, MD PhD
Applied Cachexia Research, Center for Cardiovascular Research,Applied Cachexia Research, Center for Cardiovascular Research,
Charite Medical School, Berlin, Germany
Conflicts: I am not an oncologistConflicts: I am not an oncologist
I am President Elect of the European HF Association
I work with many cardiology companies
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USA
1970–2000
USA
1970–20001970–20001970–2000
Lenfant C.
NEJM 2003.
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Causes of death in cancer
• Neoplasm
• Cachexia• Cachexia
• Cardiovascular incl. sudden death• Cardiovascular incl. sudden death
• Thromboembolic
• Infection
• Unknown• Unknown
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Beta�blockers for cancer make headlines
• 466 patients with breast
cancer in UK & Germany
• 92 pats. received anti�
hypertensive therapy (47%
BBs)
• BBs related to: • BBs related to:
� better total survival
� 71% less cancer specific
mortality
� fewer metastais, both local
& distant
� 1,413 breast cancer patients (1995–2007), subgroup with triple�negative breast cancer (n = 377)
� patients who used BBs (n = 102), patients (n = 1,311) who did not use BBs
Melhem�Bertrand A et al., J Clin Oncol 2011
� overall: BB associated with better RFS (HR 0.52; 95%CI, 0.31–0.88) but not survival (P = .09)
� TNBC: BB assoc.w. better RFS (HR 0.30; 0.10–0.87; P=.027) , survial (HR 0.35 [ 0.12–1.00]; P=.05)
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Norepinephrine drives metastasis development of
PC�3 cells in BALB/c nude micePC�3 cells in BALB/c nude mice
Primary tumor Metastasis
Palm et al. Int J Cancer. 2006
Norepinephrine (N) stimulates the growth of metastasis.
Propranolol (P) blocks this effect.
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Propranolol increases survival in a
pancreatic cancer hamster model
NNK: nitrosamine 4�(methylnitrosamino)�1�(3�pyridyl)�1�butanone
Al-Wadei et al. Anticancer Drugs. 2009
NNK: nitrosamine 4�(methylnitrosamino)�1�(3�pyridyl)�1�butanone
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Carvedilol against
anthracycline�induced cardiomyopathyanthracycline�induced cardiomyopathy
• 25 patients per group in
Kayseri, TurkeyKayseri, Turkey
• Single�blind placebo
controlled, 6 months
• Mostly pats with breast�• Mostly pats with breast�
Ca & lymphoma (85%
were women)
• CARV dose: 12.5mg od• CARV dose: 12.5mg od
Kalay N et al.
JACC 2006;48:2258�62.
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Enalapril against high dose CT�induced
cardiomyopathycardiomyopathy
Control Enalapril
114 of 473 patients (24%) with raised were included when TnI raised >0.07 ng/mL
63% of patients were female
Randomised, open: Enalapril 20mg/d vs no treatment Randomised, open: Enalapril 20mg/d vs no treatment
Treatment start: 1 month after HD�chemo
1.EP: LVEF decrease >10% (43% vs 0%, p<0.001)Cardinale et al.
Circulation 2006;114:2474�81.
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Managing patient cardiac events with adjuvant HerceptinThe Cardiac Guidelines Consensus Committee
LVEF decline of >15% or LVEF decline of >10% and below LLN (LLN=50%)LVEF decline of >15% or LVEF decline of >10% and below LLN (LLN=50%)
LVEF 40�50% LVEF <40%
Continue Herceptina Hold Herceptin and seek cardiologist input b
Monitor LVEF every month Monitor LVEF in 3 months
LVEF >40% LVEF <40% LVEF >40% LVEF <40%
Reconsider Herceptin only
when / if appropriate and
consider cardiac support at
LVEF >40% LVEF <40% LVEF >40% LVEF <40%
Continue Herceptin, monitor LVEF every 3 months
and consider cardiac support at discretion of cardiologistconsider cardiac support at
discretion of cardiologist
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Amiodarone for Prevention of Atrial Fibrillation After
Lung Resection (NSCLC 78% & lung metastasis)
! 130 pats in Indianapolis / USA, randomised 1:1, open
! mean age 62 yrs, 50% female
! post!op therapy: BB 35%, statin 22%, ACEi 20%, CCB 2%
84 hrs
32%
84 hrs
14%
32%46 hrs
Tisdale et al. The Annals of Thoracis Surgery 2009
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Symptoms of Patients with Cancer
•• impaired exercise capacity
• fatigue• fatigue
• shortness of breath
• general malaise
•• depression
• pain• pain
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Symptoms of Patients with Cancer
•• impaired exercise capacity
• fatigue• fatigue
• shortness of breath
• general malaise
•• depression
• pain
very similar to
symptoms of • pain symptoms of
CHF patients
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Appetite in CHF & COPD cachexia
CHFCHF
”appetite” (1 10)
7.5±1 7.5±1 P<0.058
VAS ”appetite”
66±10
4
6
7.5±1 7.5±1
6.5±1
P<0.058
40
60 49±10
66±10
P=0.02
4
2
40
0
2021±11
0Control No Yes
Cachexia
0Control No Yes
Cachexia
Garcia et al., JCEM 2005Cachexia
Garcia et al., JCEM 2005
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“muscle hypothesis“ of SoB in cancer
Reduced peripheral
Blood flowTNF, insulin resistance,
muscle wasting
Vasoconstriction Catabolic
muscle wastingorgan / body
dysfunctionVasoconstriction
Endothelial dysfunctionCatabolic
metabolism
Increased sympathetic
activation Skeletal myopathie
IncreasedIncreased
Metabo&ergoreflex
Dyspnoe, FatigueIncreased Ventilationmodified from Coats et al.,
Br. Heart J 1994;72(Suppl 2):S36&9.
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Muscle wasting (“sarcopenia”) in cancer &
chemotherapy toxicitychemotherapy toxicity
55 women women with metastatic breast cancer resistant to anthracycline
and/or taxane treatment – 25% of pats. showed muscle wasting
Chemotherapy induced
toxicity (1 cycle)Time to tumor
progression
and/or taxane treatment – 25% of pats. showed muscle wasting
60
toxicity (1 cycle)
50%
P=0.03
150
progression
P=0.05173 days
(126–220)200
40
20
60 50%
20%
100
50
150101 days
(60–143)
0
20
No Yes
20%
0
50
No YesNo Yes
Muscle wasting
Prado CM, Baracos VM et al. Clin Cancer Res 2009
No Yes
Muscle wasting
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Muscle wasting (“sarcopenia”) in patients
with solid tumors vs survival
• Screened: 2115 respiratory & GI cancers
• Obese with BMI>30: 325 pats (15%)
• 250 pats with CT scan• 250 pats with CT scan
HR 4.2(95%CI 2.4–7.2)(95%CI 2.4–7.2)
P<0.0001
Prado CM et al & Baracos VE. Lancet Oncol 2008
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Changes in body composition
in cachectic patients with non�small cell lung cancer
compared to healthy controlscompared to healthy controls
70 Body weight (kg)The proportional changes seen
17.3
50
60Fat
The proportional changes seen
for muscle & fat tissue are similar
2.8
0.7
8.3
8.1
3.1
40
50
FatNon�Muscle
Protein
Muscle�Protein
Muscle�Protein
Non�Muscle
Protein
�82%
�75%
19.1 12.9
0.7
20
30 Intra�cellular
WaterIntra�cellular
Water
Muscle�Protein �75%
15.1 17.510
20
Extra�cellular
Water
Extra�cellular
Water
Minerals Minerals3 2.60
Cancer
Minerals Minerals
Fearon, Preston 2000
Controls
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Fat is a key to survival Fat is a key to survival
Energy storage
Isolation
Protection Protection
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MUSCLE = Fitness / QoL
BUTBUT
FAT + Muscle = SurvivalFAT + Muscle = Survival
Similar results are available for patients with
CHF, CKD, cancer and ageing.CHF, CKD, cancer and ageing.
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Definition of Cachexia
(resulting from consensus conference, Dec. 2006)(resulting from consensus conference, Dec. 2006)
Weight loss of at least 5% (edema�free) in 12 months or
less in the presence of underlying illness, PLUS THREEless in the presence of underlying illness, PLUS THREE
of the following criteria:
� decreased muscle strength (lowest tertile)� decreased muscle strength (lowest tertile)
� fatigue
� anorexia
� low fat�free mass index� low fat�free mass index
� abnormal biochemistrya) increased inflammatory markers (e.g. sialic acid, CRP, IL�6)
b) Anemia (< 12 g/dl)b) Anemia (< 12 g/dl)
c) Low serum albumin (< 3.2 g/dl)
The following needs to be excluded:The following needs to be excluded:
starvation, malabsorption, primary depression,
hyperthyroidism and age�related muscle loss
Evans WJ, Clin. Nutr. 2008
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Definition of Cachexia
(resulting from consensus conference, Dec. 2006)(resulting from consensus conference, Dec. 2006)
Weight loss of at least 5% (edema�free) in 12 months or
less in the presence of underlying illness, PLUS THREEless in the presence of underlying illness, PLUS THREE
of the following criteria:
When weight loss cannot be assessed a BMI<20 kg/m2When weight loss cannot be assessed a BMI<20 kg/m2
may be sufficient.
Some proposed other cut�offs, like 18.5 or 22.0 kg/m2.
Evans WJ, Clin. Nutr. 2008
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CACHEXIA: prevalence, pts at risk & mortality
prevalence pts at preval. Europe: 1�year
in populat. risk in pts pts with mortality
at risk cachexiaat risk cachexia
COPD 3.5 15 50 1,200,000 15�25(moderare severity)
CHF 2.0 80 10 720,000 20�40(NYHA II�IV)
Cancer 0.5 90 30 540,000 20�60Cancer 0.5 90 30 540,000 20�60(all types)
RA 0.8 20 10 100,000 5(severe RA) (cachexia)(severe RA) (cachexia)
55 400,000 2(muscle wasting)
CRF 0.14 50 50 120,000 20CRF 0.14 50 50 120,000 20
Population assumptions: Europe – 450 Mill, US – 300 Mill, Japan – 100 Mill
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Frequency of „malnutrition“
in patients with malignant cancer *in patients with malignant cancer *
Tumor Patients (%)
Pancreas up to 85
Head & Neck up to 67Head & Neck up to 67
Stomach up to 65
Esophagus up to 57Esophagus up to 57
Lung up to 46
Colorectal up to 33Colorectal up to 33
Ovary / Cervix up to 15
Urologic up to 9
Breast up to 5 * ambulatory &
hospitlized
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Pathophysiology of CHF & Cancer
Immune Activation / Inflammation
Neuroendocrine Activation
Hormone Resistance
Lack of Anabolism
Genetic Factors
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Cachexia and plasma angiotensin II
pg/mL
similar results for norepinephrine
and aldosterone200 pg/mL and aldosterone200
150
100
normal valuenormal
range
20 � 40 pg/mL
50
normal value< 40 pg/mL
20 � 40 pg/mL
Controls nc�CHF c�AIDS c�CHF c�Liverfailure
Starvation c�C���� ancer ideopathic
0
Starvation c�C���� ancer ideopathic
Anker & Coats, unpublished
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ACE inhibitors for cancer cachexia
A PHASE III TRIAL USING IMIDAPRIL (Vitor®)
IN CANCER CACHEXIA REPORTED
PROMISING RESULTS
1. weight: +1.2 kg1. weight: +1.2 kg
2. hand grip strength: higher
FDA APPROVAL FOR 2nd PHASE III TRIAL IN FDA APPROVAL FOR 2nd PHASE III TRIAL IN
NSCLC CACHEXIA ++ currently on hold
(ARK Therapeutics)
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Causes of death in cancer
• Neoplasm
• Cachexia• Cachexia
• Cardiovascular incl. sudden death• Cardiovascular incl. sudden death
• Thromboembolic
• Infection
• Unknown• Unknown
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Severe arrythmias in 24�hour ECG’s:
VT or >10,000 VESVT or >10,000 VES
p<0.05
6
86 of 44 (14.4%)
4
6
0
20 of 24 (0%)
0Controls Patients with
pancreatic cancer
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MR�proANP and severe arrythmias in
24�hour ECG’s of pats with pancreatic cancer24�hour ECG’s of pats with pancreatic cancer
300
Mean levels of MR�pro ANP (pmol/L)
ANOVA p�value: p=0.0125
200
300 ANOVA p�value: p=0.0125
100
0
none VES VT
median MR�proANP in 325 healthy volunteers:median MR�proANP in 325 healthy volunteers:
45.0 pmol/L (95% CI 43.0 – 49.1 pmol/L)
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New Cachexia Phenotyping Equipment
(Applied Cachexia Research ) CCR
ECGenie(non�invasive ECG)
EchoMRI�700(in�vivo body composition)
(Applied Cachexia Research )
for rats
TSE GS�meterrat front limb
Supermex(locomotor activity)
rat front limb
muscle strength
(locomotor activity)
= rat “QoL“
assessment oflean mass & fat mass:non�invasive, CV <2%
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Design �� Cachexia Prevention
Sacrifice:
plasmaTumor inoculation
male Wistar rats
approx. 200 g
108 AH 130 cellsorgan weight
tissue storage
ActivityBody composition (NMR)
Tumor inoculation10 AH 130 cells
Echocardiography
Activity
Food intake
Body composition (NMR)
day
�2/�1 �1 160 10/11 111�2/�1 �1 160 10/11 111
many compounds or placeboe.g. bisoprolol, nebivolol, carvedilol,
Activity
Food intakee.g. bisoprolol, nebivolol, carvedilol,
bucindolol, MT�102 etc etc
Food intake
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Advanced Cancer: echocardiography
ejection fraction
100
fractional shortening
60
40
60
80
100
%
40
60
%
0
20
40
0
20
p=0.0001
p=0.31 p=0.0025
p=0.0001
p=0.21 p=0.0025
p=0.0001 p=0.0001
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Advanced Cancer: haemodynamics
dP/dt max
12000
dP/dt min
0
6000
8000
10000
12000
mm
Hg
/s
�6000
�4000
�2000
0
mm
Hg
/s
0
2000
4000mm
Hg
/s
�10000
�8000
�6000
mm
Hg
/s
p=0.014
p=0.81 p=0.0454
p=0.0093
p=0.68 p=0.0121
p=0.014 p=0.0093
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Change in body weight
0
n= 49 13 14 23 20 11 12 6 16 16
�20
�10
0
�40
�30
�20
g ***
** **
*****
**
�60
�50
** ***
**
�70
0.5 2 5 50 2 5 50
bisoprolol oxypurinol spironolactoneplacebo
4 40
*
bisoprolol oxypurinol spironolactoneplacebo
sham: +59.8 ± 2.1g
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Change in lean mass during treatment
0
�20
�10
0
�30
�20
g***
*** *
*** ***
**
�50
�40
*�60
0.5 2 5 50 2 5 50
bisoprolol oxypurinol spironolactoneplacebo
4 40
*
bisoprolol oxypurinol spironolactoneplacebo
sham: +41.7 ± 2g
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Survival proportions
100
all doses in mg/kg/d
80
3mg MT�102 vs plac:
HR: 0.30 (95%CI: 0.15�0.62)
p=0.001ACT�ONE trial (phase II)ACT�ONE trial (phase II)
60
biso 5 mg
biso 50 mg
s�pindo 3 mg
Perc
en
t su
rviv
al
MT�102
ACT�ONE trial (phase II)
Coats et al. JCSM‘2011
ACT�ONE trial (phase II)
Coats et al. JCSM‘2011
40 biso 2 mgterta 0.5 mg
s�pindo 0.3 mg
Perc
en
t su
rviv
al
MT�102
20
40
biso 0.5 mg
nebi 1 mg
terta 0.5 mg
imida 0.4 mg
Perc
en
t su
rviv
al
0
20
terta 5 mg
imida 0.4 mg
imida 1 mgimida 10 mg
placebo
0 2 4 6 8 10 12 14 160
nebi 10 mgTime
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Aldosterone is elevated in tumor�bearing rats and lead to
cardiac fibrosis
aldosterone [pg/mL]
800
cardiac fibrosis
Day 7 Day 11
200
400
600
800sham
placebo
sham
0
200
Springer et al. unpublished
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LV mass & survival in cancer
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Human cancer (cachexia) causes cardiac fibrosis
Control (n=5) Cancer (n=6) cancer cachexia (n=6)
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Pathophysiology of CHF & Cancer
Immune Activation / Inflammation
Neuroendocrine Activation
Hormone Resistance
Lack of Anabolism
Genetic Factors
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Total gain in life expectancy: 10 yrsTotal gain in life expectancy: 10 yrs
- Cardiology has added 7.2 yrs
- Oncology 2.1 months
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Cancer as causes of death in heart failurefrom OPTIMAAL, age 67, mean follow�up 2.7 yrs, based on SAE reports
Event Rate
(per 100 at Cancer DeathsNew CancersPatients
Entering Each
Cleland et al. HFA 2005 (abstract)
84
(8.9%)
241
(4.4%)
All Events
(per 100 at risk/month*)
(and % of all deaths)
(and % of patients at risk)
Entering Each
Time Period
0.0
(8.9%)(4.4%)
None11
(0.2%)
54770"30 days
16 44 5040 180"365 days
7
(3.5%)
41
(0.8%)
524230"180 days 0.02
0.05
61 145 4892365"1200
16
(10.8%)
44
(0.9%)
5040 180"365 days 0.05
0.04
(16.9%)(4.7%)
4892days
* these data are censored for death – cancer deaths per 100 living�patient months
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cardiologist & oncologists need to talk !!