Prof' Livio Dei Cas

1
Heart Failure Prevention and Management From
drugs to devices. Genova, 1-2 Aprile 2005
Fattori di rischio e rischio di insufficienza
cardiaca quale ruolo ha la iperdislipidemia?Ris
k Factors and Heart Failure RiskDoes
Hyperlipidemia Play a Role?

• Prof. Livio Dei Cas
• Cattedra e U.O. di Cardiologia
• Università e Spedali Civili di Brescia

2
Hyperlipidaemia and Heart Failure

• Epidemiology
• As a risk factor of coronary artery disease (CAD)
  and LV hypertrophy
• As an independent risk factor
• Treatment effects of statins
• Mechanisms of action
• Cholesterol dependent
• Cholesterol independent (pleiotropic) effects
• Clinical results

3
Hyperlipidaemia and Heart Failure

• Epidemiology
• As a risk factor of coronary artery disease (CAD)
  and LV Hypertrophy
• As an independent risk factor
• Treatment effects of statins
• Mechanisms of action
• Cholesterol dependent
• Cholesterol independent (pleiotropic) effects
• Clinical results

4
Serum Cholesterol and Incidence of Coronary
Artery Disease (Framingham Study)
2
Male subjects (30-49 years) 8 years of
observation
1,6
1,2
Incidence of coronary artery disease
0,8

• 1 serum cholesterol
• ? 2-3 coronary events

0,4
0
180
200
220
240
260
Serum Cholesterol (mg/dl)
5
Coronary Artery Disease, Especially when Combined
with Hypertension, is the Main Cause of Heart
Failure (Framingham Study)
Diseases Concomitant with CAD
Main causes
7
18
24
57
53
23
16
2
Valvular diseases
Coronary artery disease
Valvular diseases
Isolated
Hypert.
Valv. Hypert.
Others
Hypertension
Ho et al., Circulation 199388107
6
New Ischemic Events Increase the Risk of Death in
the Patients with LV Dysfunction (SOLVD Trials)
Myocardial infarction
Unstable Angina
70
30
60
MI
50
20
40
Angina
Event
Event
30
No Angina
10
20
No MI
10
Plt0.001
Plt0.001
0
0
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
Months
Months
Yusuf et al., Lancet 19923401173
7
Hyperlipidaemia, Coronary Artery Disease and
Heart Failure Effects of Statin Therapy

• Heart failure was an exclusion criteria in statin
  trials
• Incidence of heart failure reduced to a similar
  extent as that of major coronary events in all
  the statin trials
• ?HF incidence likely caused by ?coronary events
  incidence
• Patients with low LVEF (25-40) without
  symptomatic heart failure, included only in CARE
• Similar beneficial effects on survival as in the
  patients with LVEF gt 40

8
Simvastatin Reduces the Incidence of Heart
Failure and the Mortality Once Heart Failure has
Developed in Coronary Artery Disease Patients (4S
Study)
Incidence of heart failure
Mortality
1
35
?19
Placebo
30
0,98
Simvastatin
25
Simvastatin
0,96
20
Proportion without heart failure
0,94
Patients ()
Placebo
15
0,92
?28
10
Plt.015
0,9
5
0
0
12
24
36
48
60
72
Heart failure
No heart failure
Months since randomization
Kjekshus et al., J Cardiac Fail 19973249
9
Statin Therapy and Reduction in the Incidence of
CHF
Number needed to
treat
4S
CARE
LIPID
500
100
80
50
60
31
40
20
0
? CHF incidence ? incidence of MI
10
Effects of Pravastatin in Patients with Low
LVEFCARE Prespecified Subanalysis
LVEF lt 40 Risk reduction ?28 (95CI, 4 to
45) P 0.02
LVEF gt 40 Risk reduction ?23 (95CI, 11 to
33) P lt 0.001
35
30
30
25
112/353
25
436/1725
20
84/353
345/1728
20
15
of patients with
of patients with
major coronary events
major coronary events
15
10
10
5
5
0
0
Placebo
Pravastatin
Placebo
Pravastatin
Sacks et al., New Engl J Med 19963351001
11
Hyperlipidaemia and LV Hypertrophy

• In hypertensive patients
• ?LV mass ?LV diastolic function associated with
• ? total cholesterol (inconstant)
• ? HDL-cholesterol
• ?triglycerides
• In the general population
• 475 subjects studied when 50 years old, followed
  for 20 years and who then underwent Echo-Doppler
  in Uppsala County, Sweden
• LV hypertrophy independently associated with
• ? LDL/HDL cholesterol
• ? Triglycerides

Sundstrom et al., Circulation 2001 103836
12
Increased Body Weight and Dyslipidemia are
Independent Predictors of LV HYpertrophy
P lt 0.05 n.s. n.s. n.s. P lt 0.05 P lt
0.05 n.s.
Body mass index Systolic blood
pressure Diastolic blood pressure Total
cholesterol LDL/HDL Cholesterol
ratio Triglycerides Glucose
0.7
0.9
1.1
1.3
1.5
1.7
Adjusted Odds Ratio (95 CI)
Adjusted for ischemic heart disease, valvular
disease, use of antihypertensives at age 70
Sundstrom et al., Circulation 2001 103836
13
Hyperlipidaemia and Heart Failure

• Epidemiology
• As a risk factor of coronary artery disease (CAD)
  and LV hypertrophy
• As a risk factor independent of CAD and LVH?
• Treatment effects of statins
• Mechanisms of action
• Cholesterol dependent
• Pleiotropic effects
• Clinical results

14
Hyperlipidaemia as a Risk Factor for Heart Failure

• It is controversial whether hyperlipidaemia is a
  risk factor for heart failure independently from
  its effects on the incidence of coronary artery
  disease and LV hypertrophy
• High serum cholesterol is associated with a
  favorable prognosis in the patients with chronic
  heart failure
• Reverse epidemiology of the patients with chronic
  heart failure

15
Risk Factors for Heart Failure1. Factors
strongly and consistently associated with
HF(Framingham studies)

• Age, sex, ethnicity
• Hypertension
• ECG LV hypertrophy
• Myocardial infarction
• Diabetes mellitus
• Valve disease
• Overweight / Obesity

Kenchaiah, Narula, Ramachandran, Vasan. Med Clin
N Am 2004 881145
16
Risk Factors for Heart Failure2. Factors less
consistently associated with HF(Framingham
studies)

• Dyslipidemia
• Alcohol consumption
• Cigarette smoking
• Renal insufficiency
• Sleep-disordered breathing
• Low physical activity
• Low socioeconomic status
• Increased heart rate

• Mental stress and depression
• Coffee consumption
• Dietary sodium intake
• Iatrogenic/pharmacologic (chemotherapy, NSAIDs,
  cocaine)
• Biochemical
• Albuminuria
• Homocysteine
• Low Insulin-like growth factor
• C-reactive protein
• Inflammatory cytokines

Kenchaiah, Narula, Ramachandran, Vasan. Med Clin
N Am 2004 881145
17
Reverse Epidemiology of Cardiovascular Risk
Factors in Chronic Heart Failure
Kalantar-Zadeh, Block, Horwich, Fonarow. J Am
Coll Cardiol 2004 431439
18
Better Risk-adjusted Survival in the Overweight
and Obese CHF Patients
Horwich, Fonarow, Hamilton et al., J Am Coll
Cardiol 2001 38789
19
The relationship between cholesterol and survival
in patients with chronic heart failure
Quartile 1 cholesterol 100-173 mg/dl Quartile 2
cholesterol 174-205 mg/dl Quartile 3
cholesterol 206-231 mg/dl Quartile 4
cholesterol 232-350 mg/dl
Log rank p0.0016 for the differences between
quartiles
Racchaus et al., J Am Coll Cardiol.
2003421933-40.
20
Low Total Cholesterol (TC), Low LDL-cholesterol
and Low Tryglicerides (TG) and High
HDL-cholesterol are associated with worse
prognosis in CHF
Survival free from death or urgent transplant
Horwich et al., J Cardiac Fail 2002 8216
21
Continuous Relationship Between Total Cholesterol
and 5-years Rates of Death or Urgent
Transplantation
Horwich, Hamilton, Maclellan, Fonarow. J Cardiac
Fail 2002 8216
22
Relationship Between Total Cholesterol and
5-years Rates of Death or Urgent Transplantation
in Ischemic and Nonischemic Patients
Horwich, Hamilton, Maclellan, Fonarow. J Cardiac
Fail 2002 8216
23
Low serum cholesterol and progression of HF
Advanced heart failure
Low serum lipoproteins
?
? endotoxin binding removal
Bowel wall edema
Bacterial and endotoxin absorption
? endotoxin clearance
? endotoxin
Inflammation ? cytokine production
Rauchhaus, Coats, Anker. Lancet 2000 356930
24
Hyperlipidaemia as a Risk Factor for Heart Failure

• It is controversial whether hyperlipidaemia is a
  risk factor for heart failure independently from
  its effects on the incidence of coronary artery
  disease and LV hypertrophy
• High serum cholesterol is associated with a
  favorable prognosis in the patients with chronic
  heart failure
• Reverse epidemiology of the patients with chronic
  heart failure
• Statin therapy seems to be beneficial in the
  patients with heart failure independently from
  serum cholesterol levels

25
Beneficial Effects of Statins on Mortality are
Independent from Serum CholesterolResults from
the PRAISE Trial
P0.04
P0.96
P0.09
P0.04
Mozzafarian, Nye, Levy. Am J Cardiol 2004 931124
26
Statins Are Associated with Improved Survival in
Advanced Heart Failure Irrespective of Total
Cholesterol Levels
TC Total cholesterol
Horwich,MacLellan,Fonarow. J Cardiac Fail 2004
10S98
27
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

28
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

29
Fluvastatin Attenuates LV Remodeling after
Experimental Myocardial Infarction
LV End-Diastolic
LV Fractional
Diameter
Shortening

6
40



30
4

mm

20



2
10
0
0
Baseline
Day 1
Day 28
Baseline
Day 1
Day 28
Sham
Myocardial Infarction
Myocardial Infarction Fluvastatin
Hayashidani et al., Circulation 2002 105868
30
Fluvastatin Attenuates LV Hypertrophy and
Fibrosis after Experimental Myocardial Infarction
Myocyte cross-
Collagen volume
sectional area
fraction
10

400

8
300
6


microm2

200
4
100
2
0
0
Sham MI MI Fluva
Sham MI MI Fluva
Sham
Myocardial Infarction
Myocardial Infarction Fluvastatin
Hayashidani et al., Circulation 2002 105868
31
Simvastatin Prevents Cardiac Hypertrophy Induced
by Pressure Overload and Inhibits Ras Activation
LV Weight/ Body weight (mg/gr)
Short-term Long-term
Sham Aortic Simva banding
Indolfi et al. Circulation 2002 1062118
32
Small Guanine Nucleotide-Binding Proteins (Ras,
Rho, Rac1) Regulate Gene Expression and
Hypertrophy
GPCR G protein-coupled receptors
Clerk Sugden. Circ Res 2000 861019
33
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

34
Oxygen Free Radical Release in Human
FailingMyocardium, Rac1-GTPase Activity and
Effects of Statins

• Reactive oxidative species (ROS) contribute to HF
  development
• NADPH oxidase
• Potential source of ROS
• Activated by the GTP-binding protein rac1
• Human LV myocardium from patients with ischemic
  cardiomyopathy (ICM) or dilated cardiomyopathy
  (IDC)
• ? 1.5 fold of NADPH oxidase
• ? 3 fold of rac1-GTPase activity
• Pretreatment with atorvastatatin or pravastatin
• ? 6812 and 6614 rac1-GTPase activity
• ? angiotensin II stimulated but not basal
  NADPHoxidase activity

Maack C et al., Circulation. 20031081567-1574
35
Increased NADPH oxidase-related Reactive
Oxidative Species (ROS) Production is associated
with increased Rac1 in the Failing Heart
Maack C et al., Circulation. 20031081567-1574
36
Increased Oxidative Stress in the Failing
Myocardium
Maack C et al., Circulation. 20031081567-1574
37
Increased NADPHoxidase Activity in the Failing
Myocardium
Maack C et al., Circulation. 20031081567-1574
38
Statin Treatment Decreases Angiotensin II
Stimulated NADPH-oxidase Activity in the Failing
Myocardium
Maack C et al., Circulation. 20031081567-1574
39
Statin Treatment Decreases Rac1 mRNA in the
Failing Myocardium
Maack C et al., Circulation. 20031081567-1574
40
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

41
Statin-Induced Improvement of Endothelium-Dependen
t NO-mediated Vasodilation After Experimental
Myocardial Infarction
Landmesser Drexler, Circulation 2004 1101933
42
Statin therapy Improves Endothelial Function in
Patients with Dilated Cardiomyopathy
Node et Al. Circulation 2003 108839
43
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

44
Statin-Induced Improvement of Endothelial
Progenitor Cell (EPCs) Mobilization After
Experimental Myocardial Infarction with a NO
Synthase Dependent Mechanism
Landmesser Drexler, Circulation 2004 1101933
45
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Increased bioavailability of nitric oxide
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

46
Statin-Induced Improvement of Left Ventricular
Function and Survival After Experimental
Myocardial Infarction Requires Endothelial Nitric
Oxide Synthase

• Aim
• Assess the effects of statins after myocardial
  infarction (MI) and the role of eNO availability
• Results
• 4 weeks of atorvastatin therapy started after MI
• ?LV remodeling and fibrosis
• ?endothelium dependent vasodilation
• ? endothelial progenitor cells mobilization
• ? myocardial border zone neovascularization
• ? survival
• No effect in eNO synthase knockout mice
• ? All the effects dependent on NO availability

Landmesser Drexler, Circulation 2004 1101933
47
Statin-Induced Improvement in Survival After
Myocardial Infarction Requires eNO Synthase
Wild type eNOS
-/- knocout
Landmesser Drexler, Circulation 2004 1101933
48
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Increased bioavailability of nitric oxide
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

49
Inflammation and Prognosis of Heart Failure
Independent prognostic value of hsCRP
Yin WH et al, Am Heart J 2004147931
50
Inflammation and Prognosis of Heart Failure
Independent prognostic value of Cytokines VEST
Database, 384 placebo treated patients
TNF
IL-6
gt 75 percentile
50-75 percentile
1
1
25-50 percentile
0,9
lt 25 percentile
0,9
0,8
0,8
0,7
0,7
Plt0.007
Plt0.007
0,6
0,6
Cumulative survival
0,5
sTNFR1
sTNFR2
1
1
0,9
0,9
0,8
0,8
0,7
0,7
0,6
P0.0001
P0.0001
0,6
0,5
0
20
40
60
80
0
20
40
60
80
Weeks
Weeks
Deswal et al., Circulation 20011032055
51
Association of lipoproteins with cytokines and
cytokine receptors in heart failure patients
Total Cholesterol / Cholesterol HDL Vs.
solubleTNF Receptor 2
Triglycerides vs. soluble TNF Receptor2
Conraads et al, Eur Heart J 2003 242221
52
Statin Therapy Decreases TNF and IL-6 Plasma
Levels in Patients with Dilated Cardiomyopathy
TNF-alpha
IL-6
Node et al. Circulation 2003 108839
53
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Increased bioavailability of nitric oxide
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

54
Statins Inhbit Beta-1 Adrenergic
Receptor-Stimulated Apoptosis in Cardiomyocytes
via a Rac1-Dependent Mechanism
Frequency of Apoptosis
Rac1 Activity
30
7


6
25
5
20
4

15
TUNEL-Positive Myocytes ( total)
Fold Increase

3
10
2
5
1
0
0
Control Stat Beta-1 Beta-1 Stat
Control Stat Beta-1 Beta-1 Stat
Stat Statin (cerivastatin) Beta-1 Beta-1
stimulation (norepinephrine prazosin)
ItoColucci. Circulation 2004110412
55
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Increased bioavailability of nitric oxide
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor

56
High-dose Simvastatin Normalizes Autonomic Neural
Control in Experimental Heart Failure
(Continuous ventricular pacing in rabbits)
Renal Sympathetic
Norepinephrine
activity
1500

60


1000
40
pg/ml
of maximum
nitroprusside induced
500
20
0
0
Norm CHF 0.3 1.5 3
simvastatin (mg/kg/day)
Piquett, Zucker. Circulation 20031072493
57
Additional Beneficial Effects of Statins
(Independent of Anti-ischemic Effects)

• Inhibition of myocardial hypertrophy and
  remodeling
• Antioxidant effects
• Increased bioavailability of nitric oxide
• Improvement of endothelial dysfunction
• Stimulation of bone marrow endothelial progenitor
  cell mobilization ? neoangiogenesis
• Antiinflammatory effects ? immunomodulation
• Inhibition of myocardial apoptosis
• Inhibition of sympathetic hyperactivity
• Downregulation of AT1 receptor (cholesterol
  dependent)

58
Statin-Sensitive Increased AT1 Receptor Function
in Hypercholesterolemic Men Blood Pressure
Response to Angiotensin II Infusion
Increased BP Response in Hypercholesterolemic vs.
Normocholesterolemic Subjects
Normalized BP Response after Simvatatin or
Atorvastatin Administration
Nickenig Bohm. Circulation. 19991002131
59
Statin-Sensitive Increased Platelet AT1 Receptor
Density in Hypercholesterolemic Men
Increased AT1 receptor Density in
Hypercholesterolemic vs. Normocholesterolemic
Subjects
Normalization of AT1 Receptor Density after
Simvatatin or Atorvastatin Administration
Nickenig Bohm. Circulation. 19991002131
60
Correlation Between Plasma LDL-Cholesterol and
Platelet AT1 Receptor Density
Nickenig Bohm. Circulation. 19991002131
61
Statins in Chronic Heart Failure

• Potential beneficial effects
• Reduction in ischemic events
• Non-cholesterol dependent (pleiotropic) effects
• Potential unfavorable effects
• Ubiquinone hypothesis
• Endotoxin hypothesis

62
Potential Limitations of Statin Therapy in Heart
Failure

• The ubiquinone (Co Q10) hypothesis
• Ubiquinone is an antioxidant shown to be
  beneficial in some HF trials
• Synthesized by HMG-CoA reductase
• ? ubiquinone during statin treatment
• The endotoxin hypothesis
• Plasma lipoproteins bind and inactivate
  endotoxins
• ?endotoxin binding during statin treatment
• ?cytokine activation and inflammation

Krum McMurray, JACC 2002 391567
63
Effects of Statins in Chronic Heart Failure

• Experimental studies
• Beneficial effects on LV function and mortality
  in models of coronary artery ligation

64
Effects of Statins in Chronic Heart Failure

• Experimental studies
• Beneficial effects on LV function and mortality
  in models of coronary artery ligation
• Clinical studies
• Single centre
• Beneficial effects on LV function and symptoms

65
Fluvastatin Improves Survival after Experimental
Myocardial Infarction
Hayashidani et al., Circulation 2002 105868
66
Statin therapy Improves LV Function and Symptoms
in Patients with Dilated Cardiomyopathy
Node et al. Circulation 2003 108839
67
Effects of Statins in Chronic Heart Failure

• Experimental studies
• Beneficial effects on LV function and mortality
• Clinical studies
• Single centre
• Beneficial effects on LV function and symptoms
• Multicentre
• No prospective trial
• Heart failure was an exclusion criteria in
  statins trials
• Retrospective analyses
• Prevention trials (4S, CARE) ? beneficial effects
• Chronic heart failure trials ? beneficial effects
• ELITE II, Eur J Heart Fail 2000
• PRAISE, Am J Cardiol 2004
• UCLA Cardiomyopathy Center, JACC 2004
• Ontario elderly population study, Arch Intern Med
  2005

68
Statin Therapy Improves Survival in Ischemic and
Non-Ischemic Patients an Analysis of 551 Patients
Non-Ischemic
Ischemic
Cardiomyopathy
Cardiomyopathy
Statin
100
100
Statin
80
80
No statin
60
60
No statin


40
40
20
20
P lt 0.001
P lt 0.001
0
0
0
4
8
12
0
4
8
12
Months
Months
Horwich, McLellan, Fonarow. J Am Coll Cardiol
200443642
69
Statin Use and Survival in Elderly patients with
Heart Failure A Population based Retrospective
study in Ontario (62250 patients 66 to 85 years)
Ray, J. G. et al. Arch Intern Med 200516562-67.
70
Mortality Beneficial Effects of Statins are
Independent from Serum Cholesterol UCLA Study
HR0.44 P0.002
HR0.38 P0.05
Horwich, McLellan, Fonarow. J Am Coll Cardiol
200443642
71
Mortality Beneficial Effects of Statins are
Independent from S-Cholesterol Results from
PRAISE Trial
P0.04
P0.96
P0.09
P0.04
Mozzafarian, Nye, Levy. Am J Cardiol 2004 931124
72
Statins Are Associated with Improved Survival in
Advanced Heart Failure Irrespective of Total
Cholesterol Levels
Horwich,MacLellan,Fonarow. J Cardiac Fail 2004
10S98
73
Conclusions

• Serum cholesterol as risk factor for heart
  failure
• Powerful independent risk factor of coronary
  heart disease (and consequently of heart failure)
• Weak independent relation with heart failure
• Inverse relation between cholesterol and
  prognosis in chronic heart failure
• Lipid lowering therapy (statins)
• Beneficial both in the prevention of heart
  failure and (likely) in established heart failure
• Cholesterol independent (pleiotropic) effects of
  statins
• Need of prospective trials
• GISSI-HF, CORONA

74
(No Transcript)
75
Lifetime Risk for Developing Congestive Heart
Failure The Framingham Heart Study

• Lifetime risk
• Absolute cumulative risk of an individual
  developing a disease during his/her remaining
  lifetime
• Framingham Heart Study
• Unique opportunity to estimate the lifetime risk
  of CHF
• Study group
• 3757 men 4472 women followed-up from 1971
  through 1996
• Lifetime risk of CHF
• 1 in 5 for both men and women, regardless of the
  index age

Lloyd-Jones DM et al., Circulation 20021063068
76
Cumulative risk for CHF at selected index ages
for men and women. The Framingham Heart Study
Lloyd-Jones DM et al., Circulation 20021063068
77
Cumulative lifetime risk for different diseases
for men and women. The Framingham Heart Study
Lloyd-Jones et al., Circulation
20021063068 Lloyd-Jones et al., Circulation
20041101042
78
Lifetime Risk of Heart Failure is 30.2 at Age 55
Years. The Rotterdam Study (7983 Participants
aged gt 55 years)
Bleumink et Al., Eur Heart J 2004 251614
79
Survival After Incident Heart Failure is 35 at 5
ys. The Rotterdam Study (7983 Participants aged gt
55 years)
Bleumink et Al., Eur Heart J 2004 251614
80
Progression of Heart Failure
Stage D Refractory HF requiring specialized
Interventions
Stage C Structural heart disease with prior or
current HF symptoms
Stage B Structural heart disease but without HF
symptoms
Stage A At high risk but without structural
disease or symptoms

• Patients with
• hypertension
• CAD
• diabetes

Refractory symptoms of HF at rest
Patients with marked symptoms at rest despite
maximal medical therapy

• Patients with
• - known structural heart disease
• shortness of breath, fatigue, reduced ex.
  tolerance

• Patients with
• previous MI
• LV systolic dysfunction,
• asymptomatic valve disease

Structural heart disease
Development of symptoms of HF
(ACC/AHA Guidelines, JACC 2001 382092)
81
Risk reduction ?28 (95CI, 4 to 45)
112/353
436/1725
84/353
345/1728
82
Statins Inhbit Beta-1 Adrenergic
Receptor-Stimulated Apoptosis in Cardiomyocytes
via a Rac1-Dependent Mechanism
83
(No Transcript)
84
Survival in ambulatory CHF Subdivided on the
basis of Cachexia and Peak VO2
Cachectic vs. Non-cachectic
Peak VO2
Anker, S. D. et al. Chest 1999115836-847