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Department of Internal Medicine – VCU
Grand Rounds November 20, 2008
Cardiac remodeling following
acute myocardial infarction
Antonio Abbate, MD
Assistant Professor of Medicine
Virginia Commonwealth University
Division of Cardiology
Department of Internal Medicine
Richmond, VA, USA
Definitions
Cardiac (or ventricular) remodeling
following acute myocardial infarction
refers to changes in size, shape,
and thickness of the left and right
ventricle involving both the infarcted
and noninfarcted segments
Key concepts
1) Epidemiology of AMI and heart
failure complicating AMI
2) Pathophysiology of post-AMI
cardiac remodeling
3) Treatment for AMI survivors
Key concepts
1) Epidemiology of AMI and heart
failure complicating AMI
2) Pathophysiology of post-AMI
cardiac remodeling
3) Treatment for AMI survivors
Epidemiology
1.73 million
hospital discharges for ACS
UA/NSTEMI
STEMI
1.4 million
discharges/yr
0.33 million
discharges/yr
CAD = coronary artery disease; ACS = acute coronary syndrome; UA = unstable angina;
MI = myocardial infarction; NSTEMI = non–ST-segment elevation MI;
STEMI = ST-segment elevation MI.
American Heart Association. Heart Disease and Stroke Statistics—2005 Update; 2005.
Estimates for STEMI and NSTEMI proportions of MI extrapolated from statistics in
Wiviott S, et al. J Am Coll Cardiol. 2003;41(suppl 2):365A-366A.
Spectrum of Acute Coronary Syndromes (ACS)
Presentation
Ischemic discomfort at rest
ECG
NSTE-ACS
STEMI
ED
–
In-hospital
6–24 hr
Unstable Angina
+
+
Non–Q-wave MI
(NSTEMI)
Adapted from Braunwald E, et al. Available at:
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
Accessed December 5, 2005.
+ Cardiac
markers
Q-wave MI
(STEMI)
Braunwald’s lecture in 1997 *
“Triumphs, concerns and opportunities”
ECG monitoring
Defibrillators
Hemodynamics
30
20
Reperfusion
Aspirin
Beta-blockers
10
%
Pre-CCU
(before 1962)
FRAMINGHAM STUDY *
30-day Mortality
30-day Mortality
“Triumphs…”
Reperfusion
CCU
(after 1984)
* Braunwald E – Shattuck Lecture – N Engl J Med 1997
15
10
5
%
1970-79
1980-89
1990-99
* Velagaleti RS, Circulation 2008
“Triumphs, concerns and opportunities”
“… concerns …”
FRAMINGHAM STUDY **
Death
CHF
Incidence at 30 days
20
15
10
5
%
1970-79
1980-89
* Braunwald E – Shattuck Lecture – N Engl J Med 1997
1990-99
** Velagaleti RS, Circulation 2008
“Triumphs, concerns and opportunities”
“… concerns …”
Adjusted OR
WORCESTER
HEART ATTACK STUDY **
Death
CHF
1.5
1.0
0.5
%
1975-78
1981-91
* Braunwald E – Shattuck Lecture – N Engl J Med 1997
1993-2001
* * Goldberg RJ, Am J Cardiol 2004
“Triumphs, concerns and opportunities”
“… opportunities”
New goals:
To reduce AMI-related mortality and
To prevent post-AMI heart failure
* Braunwald E – Shattuck Lecture – N Engl J Med 1997
Key concepts
1) Epidemiology of AMI and heart
failure complicating AMI
2) Pathophysiology of post-AMI
cardiac remodeling
3) Treatment for AMI survivors
ACUTE MYOCARDIAL INFARCTION
Acute thrombosis
of an epicardial
coronary
artery
Ischemic damage to
the myocardium
Post-infarction cardiac remodeling
left ventricle
right ventricle
INFARCT
AREA
Clinical scenario (2):
Mr. XY presents several months
after acute non-reperfused lateral
STEMI, with symptoms of CHF.
LV (and RV) enlargement and
dysfunction is present
UNCOMPLICATED
AMI
Clinical scenario:
Mr. XY presents few
months after reperfused
acute lateral STEMI,
LV is normal in size
and function.
LEFT VENTRICULAR
DILATATION
BIVENTRICULAR
ENLARGEMENT
No reperfusion
LV end-systolic volume index (ml/m2)
Influence of IRA patency
Modified from Pizzetti et al. J Am Coll Cardiol 1996
TCO – total
coronary occlusion
NTCO – non TCO
TCO
NTCO
Hosp Admission
7 days
3 MONTHS
6 MONTHS
Early reperfusion and the ‘golden hour’
1-year mortality (%)
Paradigm: Time is muscle
RR is  by 8%
for each 5 min
delay (P=0.04)
12
9
Modified from
DeLuca et al.
Circulation 2004
6
3
60
120
180
240
300
360
Symptoms-Balloon Inflation (min)
Early reperfusion and the ‘golden hour’
Paradigm: Time is muscle
Short-term Mortality
Aspirin (vs placebo)
19% RRR / 2.5% ARR
10.7% vs 13.7%
Fibrinolysis (vs placebo)
18% RRR / 1.9% ARR
PCI (vs fibronolysis)
35% RRR / 2.9% ARR
9.6% vs 11.5%
5.5% vs 8.4%
PCI (vs placebo) hypothetical
52% RRR / 6.0% ARR
5.5% vs 11.5%
0.1
0.5
Repefusion
better
1.0
1.5
2.0
Alternative
better
Therapeutic goals
1) Prompt reperfusion of the infarctrelated artery (within 60-90 min),
PCI preferred
Late presentation / No reperfusion
LV end-systolic volume index (ml/m2)
Influence of IRA patency
Modified from Pizzetti et al. J Am Coll Cardiol 1996
failed PTCA
* P<0.05
?
TCO
successful PTCA
NTCO
Hosp Admission
7 days
3 MONTHS
6 MONTHS
TCO – total
coronary occlusion
NTCO – non TCO
Late presentation / No reperfusion
GUSTO – I angiographic substudy
Modified from Puma et al. Am J Cardiol 1999
Occluded IRA
mortality (%)
10
P<0.001
8
Open IRA
P<0.001
6
P<0.001 *
4
2
overall
days
1-30
days
31-365
* Independent of
infarct size and
ejection fraction
Late presentation / No reperfusion
Better late than never ?
Modified from Abbate et al. J Am Coll Cardiol 2008
 10 studies  3,560 patients
 late PCI of the infarct-related artery >12h of AMI
 median 12 days (range 1-26 days) after AMI
 10 studies  over more than 15 years
 variable inclusion and exclusion criteria
 variable interventional and non-interventional tx
 the Occluded Artery Trial (OAT) is the largest, most
recent, and better known of the 10 studies
Late presentation / No reperfusion
Better late than never ? Maybe not
Modified from Hochman et al. N Engl J Med 2006
2,166 patients with total IRA occlusion 3-21 days after AMI
Late presentation / No reperfusion
Better late than never ? Or is it better?
Modified from Abbate et al. J Am Coll Cardiol 2008
Meta-analysis of 3,560 patients from 10 different RCTs
Study
or sub-category
ALKK
BRAVE-2
DECOPI
Horie et al
OAT
Silva et al
SWISSI II
TOAT
TOMIIS
TOPS
PCI
n/N
6/149
4/18
8/109
1/44
87/1082
0/1
3/
2/32
1/2
0/42
Medical Rx
n/N
17/151
8/183
9/103
5/39
84/1084
2/18
22/105
1/34
1/19
0/45
1779
1781
Total (95% CI)
Total events: 112 (PCI), 149 (Medical Rx)
Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%
Test for overall effect: Z = 2.15 (P = 0.03)
0.01
OR (random)
95% CI
OR (random)
95% CI
0.33 [0.13, 0.86]
0.49 [0.15, 1.66]
0.83 [0.31, 2.23]
0.16 [0.02, 1.42]
1.04 [0.76, 1.42]
0.18 [0.01, 3.99]
0.12 [0.04, 0.42]
2.20 [0.19, 25.52]
0.75 [0.04, 12.82]
Not estimable
0.49 [0.26, 0.94]
Outcome: Death
0.1
1
10
100
Favours PCI Favours medical Rx
Late presentation / No reperfusion
Better late than never ? Or is it better?
OR (random)
95% CI
Modified by Abbate et al. J Am Coll Cardiol 2008
Meta-analysis of 3,560 patients from
OAT10 different RCTs
Study
or sub-category
ALKK
BRAVE-2
DECOPI
Horie et al
OAT
Silva et al
SWISSI II
TOAT
TOMIIS
TOPS
PCI
n/N
6/149
4/18
8/109
1/44
87/1082
0/1
3/
2/32
1/2
0/42
Medical Rx
n/N
17/151
8/183
9/103
5/39
84/1084
2/18
22/105
1/34
1/19
0/45
OR (random)
95% CI
O
0.49
[0.26, 0.94]
OR (random)
95% CI
0.33 [0.13, 0.86]
0.49 [0.15, 1.66]
0.83 [0.31, 2.23]
0.16 [0.02, 1.42]
1.04 [0.76, 1.42]
0.18 [0.01, 3.99]
0.12 [0.04, 0.42]
2.20 [0.19, 25.52]
0.75 [0.04, 12.82]
Not estimable
1779
1781
0.49 [0.26, 0.94]
Total (95% CI)
Total events: 112 (PCI), 149 (Medical
Rx)
Outcome:
Death
(NNT 48)
Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%
Outcome: Death
Test for overall effect: Z = 2.15 (P = 0.03)
0.01 0.1
1
10
100
0.01
0.1
1
10 Favours100
PCI Favours medical Rx
Favours PCI
Favours medical Rx
Late presentation / No reperfusion
OR (random)
difference
95% in
CI outcome?
Why such a
Longer follow up  greater benefit
Review:
Late percutaneous coronary intervention for infarct-related artery occlusionOAT
Comparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion
Outcome:
Death
Medical
Rx
Study
PCI
MedicalPCI
Rx
OR
(random)
OR (random)
n/N
n/N
or sub-category
n/N
n/N
95% CI
95% CI
17/151
6/149
17/151 6/149
0.33 [0.13, 0.86]
ALKK
4/18
8/183
4/18
8/183
0.49 [0.15, 1.66]
BRAVE-2
9/103
8/109
9/103 8/109
0.83 [0.31, 2.23]
DECOPI
1/44
5/39
1/44
5/39 87/1082
0.16 [0.02, 1.42]
Horie et al
84/1084
87/1
84/1084
1.04 [0.76, 1.42]
OAT
2/18
0/1
2/18 0/1
0.18 [0.01, 3.99]
Silva et al
3/
22/105
3/
22/105
0.12 [0.04, 0.42]
SWISSI II
2/32
1/34
2/32
1/34 1/2
2.20 [0.19, 25.52]
TOAT
1/19
0.49
1/2
1/19 0/42
0.75 [0.04, 12.82]
TOMIIS
0/45
0/42
0/45
Not estimable
TOPS
O
1779
1781
[0.26, 0.94]
1781 0.49 [0.26, 0.94]
1779
Total (95% CI)
Outcome: Death
(NNT 48)
Total events: 112 (PCI), 149 (Medical Rx)
Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%
Test for overall effect: Z = 2.15 (P = 0.03)
0.01
10 10 100 100
0.01
0.1 0.1 1 1
Favours PCI Favours medical Rx
Favours PCI
Favours medical Rx
Late presentation / No reperfusion
OR (random)
95% CIin
difference
Why such a
outcome?
Presence of ischemia  greater benefit
Review:
Late percutaneous coronary intervention for infarct-related artery occlusion
OAT
Comparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion
Outcome:
Death
PCI
Medical Rx
Study
PCI
Medical
OR
OR (random)
n/NRx
n/N(random)
or sub-category
n/N
n/N
95% CI
95% CI
6/149
17/151
6/149
17/151
0.33 [0.13, 0.86]
ALKK
4/18
8/183
4/18
8/183
0.49 [0.15, 1.66]
BRAVE-2
8/109
9/103
8/109
9/103
0.83 [0.31, 2.23]
DECOPI
1/44
5/39
1/44
5/39
0.16 [0.02, 1.42]
Horie et al
87/1082
84/1084
87/1
84/1084
1.04 [0.76, 1.42]
OAT
0/1
2/18
0/1
2/183/
0.18 [0.01, 3.99]
Silva et al
22/105
3/
22/105
0.12 [0.04, 0.42]
SWISSI II
2/32
1/34
2/32
1/341/2
[0.19, 25.52]
TOAT
1/19
0.49 2.20
1/2
1/190/42
0.75 [0.04, 12.82]
TOMIIS
0/45
0/42
0/45
TOPS
[0.26, 0.94] Not estimable
1779
1781
1779
1781
0.49 [0.26, 0.94]
Total (95% CI)
Outcome:
Death
(NNT
48)
Total events: 112 (PCI), 149 (Medical Rx)
Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%
Test for overall effect: Z = 2.15 (P = 0.03)
0.01
0.10.01 0.11 1
10
10
100 100
Favours PCI Favours medical Rx
O
Favours PCI
Favours medical Rx
Therapeutic goals
1) Prompt reperfusion of the infarctrelated artery (within 60-90 min),
PCI preferred
2) Late revascularization in selected
patients (younger, [+]ischemia, low EF%)
Epicardial revascularization =
myocardial tissue reperfusion ?
No-reflow phenomenon
The No-reflow is a dissociation between epicardial
artery patency and myocardial perfusion.
Epicardial revascularization =
myocardial tissue reperfusion ?
Estimates of myocardial tissue reperfusion
1) Patency of the epicardial
coronary tree
2) TIMI coronary flow grade
2)
3) Myocardial blush grade
4) Myocardial perfusion at
contrast echo/
cardiac MR
3,4)
1)
No Reflow
A patient with anterior STEMI s/p primary
PCI with angiographic no-reflow
MAY 2003
JULY 2004
EDV and  EF%
No Reflow
A patient with anterior STEMI s/p primary
PCI with angiographic no-reflow
MAY 2003
No Reflow
JULY 2004
Full-thickness scar
MAY 2003
No Reflow
JULY 2004
No-Reflow phenomenon
Patients with no-reflow are denied the
benefit of reperfusion
Modified from van t’Hof et al. Circulation 1998
* All patients with
successful PCI
** Independent of TIMI
coronary flow
No-Reflow
No-Reflow phenomenon
Original paradigm
Expanded paradigm
Potential targets
for intervention
CORONARY OCCLUSION
1) Reduced
ischemic time
PROLONGED ISCHEMIA
MICROVASCULAR
DAMAGE
PLATELET/ENDOTHELIAL
ACTIVATION
VASOCONSTRICTION
(PARADOXICAL)
INFLAMMATORY RESPONSE
MYOCARDIAL EDEMA
OXYGEN-DERIVED FREE
RADICALS
CALCIUM OVERLOAD
2) Platelet inhibitors
DISTAL EMBOLIZATION
DURING PCI
5)Anti-thrombotic agents
(ASA, clopidogrel, Abciximab)
3) Vasodilators
(adenosine, nitroprusside,
verapamil)
4) Anti-inflammatory
agents (statins)
[+2)]
(heparins,bivalirudin)
6) Thrombectomy/
Thrombus aspiration
NO-REFLOW
Therapeutic goals
1) Prompt reperfusion of the infarctrelated artery (within 60-90 min),
PCI preferred
2) Late revascularization in selected
patients (younger, [+]ischemia, low EF%)
3) Prevent (or treat) No-Reflow
Baseline
Acute MI
Compensatory hypertrophy
Angiotensin II
Beta-adrenergic
stimulation
Aldosterone
Stretch stress
Cytokines (IL-1)
Angiotensin II
Beta-adrenergic
stimulation
Aldosterone
Stretch stress
Cytokines
(i.e.
IL-1)
Infarct expansion
Progressive dilatation
APOPTOSIS
NECROSIS
APOPTOSIS
APOPTOSIS
ischemia
APOPTOSIS
coronary
occlusion
hours
 End-stage HF
days
* Abbate et al. Int J Biochem Cell Biol 2006
weeks
months
years
“Dilatation begets further dilatation”
Modified from LeJemtel/Frishman/Sonnenblick – Hurst – The Heart manual
Left Ventricular Dysfunction  Dilatation
Neuro-hormonal
activation
Stretch-induced
hypertrophy
Inflammatory
response
Angiotensin II
Norepinephrine
Aldosterone
BNP/ANP
Wall stress
Dyssinchrony
Hypertension
Interleukin-1
Toll-like receptor
response
Tumor Necrosis
Factor
Neuro-hormonal activation
In the past decades we
have witnessed a shift in
paradigm:
• from the effects of
AT2 and Aldo on the
kidney and vessels
• to the direct effects of
AT2 and Aldo on the
heart
Neuro-hormonal activation
From bench to bedside
Angiotensin II,
Aldosterone, and
Norepinephrine
ACE-inhibitors (see ISIS-4 and GISSI-3 studies)*
Aldosterone-blockers (see EPHESUS study)
Beta-blockers (see ISIS-1, MIAMI, COMMIT studies)#
Cardiac Apoptosis, Prevent Adverse
Inflammation, and Remodeling and
Heart Failure
Fibrosis
Heart Failure
Intravenous ACE-inhibitor
and Beta-blockers should be
used cautiously in patients
with STEMI – oral
administration is preferred
[CONSENSUS and COMMIT trials]
Reduce Early and Late Mortality
(approx 0.5% ARR at 30 days within 30 days with ACE-inh
and Beta-block; 1.2% ARR [high risk pts] for eplerenone)
Therapeutic goals
1) Prompt reperfusion of the infarctrelated artery (within 60-90 min),
PCI preferred
2) Late revascularization in selected
patients (younger, [+]ischemia, low EF%)
3) Prevent (or treat) No-Reflow
4) Neuro-hormonal blockade with ACEinhibitors, Beta-blockers and
Aldosterone blockers
Stretch-induced hypertrophy
From bench to bedside
Stretch-induced
hypertrophy
Limited clinical data in AMI, however
Amelioration of volume/pressure overload
due to valvular heart disease
Cardiac Resynchronization therapy
Aggressive treatment of hypertension
Cardiac Apoptosis, May Prevent Adverse
Inflammation, and Remodeling and
Heart Failure
Fibrosis
Heart Failure
Likely Reduce Mortality
Therapeutic goals
1) Prompt reperfusion of the infarctrelated artery (within 60-90 min),
PCI preferred
2) Late revascularization in selected
patients (younger, [+]ischemia, low EF%)
3) Prevent (or treat) No-Reflow
4) Neuro-hormonal blockade with ACEinhibitors, Beta-blockers and
Aldosterone blockers
5) Correction of severe valvular disease
and cardiac resynchronization tx
Therapeutic goals
6) Prevention of cardiac sudden death in
AMI survivors with AICDs
Therapeutic goals
6) Prevention of cardiac sudden death in
AMI survivors with AICDs
7) Hemodynamic support for patients
with cardiogenic shock as a bridge to
recovery or a bridge to transplant
Therapeutic goals
6) Prevention of cardiac sudden death in
AMI survivors with AICDs
7) Hemodynamic support for patients
with cardiogenic shock as a bridge to
recovery or a bridge to transplant
8) Experimental therapy for patients at
high risk for heart failure after AMI
 cell therapy
 cytokine therapy
CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION
“the dogma has been abated”
REGENERATING CARDIOMYOCYTES
DERIVING FROM MOBILIZED BONE MARROW STEM CELLS
Regenerating myocardium provides
significant survival benefits
Orlic et al. PNAS 2001
CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION
Modified from Lipinski et al. J Am Coll Cardiol 2007
Meta-analysis of 10 RCTs
Study
ASTAMI
Bartunek et al
BOOST
Jannsens et al
MAGIC-3
Meluzin et al
REPAIR-AMI
Strauer et al
TCT-STAMI
Zhan-Quan et al
EF change % (SE)
-1.4000
-3.1000
-2.8000
-1.1000
-5.2000
-2.0000
-2.5000
-1.0000
-6.7000
-5.5000
EF change % (random)
EF change % (random)
(0.7200)
(3.0800)
(1.1200)
(0.7900)
(1.0100)
(0.4900)
(0.5400)
(1.5600)
(1.6300)
(0.8500)
-1.40
-3.10
-2.80
-1.10
-5.20
-2.00
-2.50
-1.00
-6.70
-5.50
[-2.81,
[-9.14,
[-5.00,
[-2.65,
[-7.18,
[-2.96,
[-3.56,
[-4.06,
[-9.89,
[-7.17,
0.01]
2.94]
-0.60]
0.45]
-3.22]
-1.04]
-1.44]
2.06]
-3.51]
-3.83]
Year
2005
2005
2004
2006
2006
2006
2006
2002
2006
2006
-2.97 [-4.06, -1.88]
Test for heterogeneity: Chi² = 33.62, df = 9 (P = 0.0001), I² = 73.2%
Test for overall effect: Z = 5.35 (P < 0.00001)
-10
-5
0
5
10
Favours cell therapy Favours control
A small yet consistently greater improvement in LVEF (+3%) is
found with bone-marrow derived stem cell therapy
CELL DEATH in
ACUTE MYOCARDIAL INFARCTION
Time 3h
NECROSIS
Accidental Death  Chest Pain
Time 7d
APOPTOSIS
Programmed Death  Silent
NOVEL ANTIAPOPTOTIC TREATMENTS
INTERLEUKIN-1 RECEPTOR ANTAGONIST
Anakinra
1 mg/Kg for 7 days after AMI
REDUCES APOPTOSIS BY 75% IN A MODEL OF
PERMANENT ARTERY OCCLUSION IN MICE
INFARCT SIZE
100
APOPTOSIS at 7 days
5
P=NS
80
4
60
3
40
2
20
1
%
%
treated
untreated
P<0.001
treated
Modified from Abbate et al. Circulation 2008
untreated
NOVEL ANTIAPOPTOTIC TREATMENTS
INTERLEUKIN-1 RECEPTOR ANTAGONIST
Anakinra
1 mg/Kg for 7 days after AMI
REDUCES APOPTOSIS BY 75% IN A MODEL OF
PERMANENT ARTERY OCCLUSION IN MICE
LVESD and FS at 7 days
P=0.001
SURVIVAL at 7 days
50
100
40
80
3
30
60
2
20
40
1
10
20
mm
%
%
5
P=0.040
4
LVESD
FS
* P=0.020
2
4
Modified from Abbate et al. Circulation 2008
6
days
Virginia Commonwealth University
Anakinra Remodeling Trial (VCU-ART)
Double blind placebo-controlled randomized controlled trial
Cardiac MRI, Doppler Echocardiography, BNP and EPC determination
1:1 randomization
# cECG
monitoring
STEMI
reperfusion
#
Complete history
and physical
24-96 h
IL-1RN
genotyping
* *
*
10-14 weeks
blood sampling
* (CBC with diff.)
Anakinra 100 mg or
equivalent matching placebo
given SQ every 24 hours
for 14 days
Figure 3. Study design.
Abbreviations: BNP: brain natriuretic peptide; cardiac MRI: cardiac magnetic resonance imaging study; CBC: complete
blood cell count; cECG: continuous electrocardiographic monitoring; EPC: endothelial progenitor cells;
STEMI: ST segment elevation acute myocardial infarction; SQ: subcutaneously
Conclusions
1) AMI remains a common cause of death
2) AMI survivors are at high risk for
delayed death due to heart failure
3) The aging of the population and the
greater survival rates in AMI will lead
to an increase in post-AMI heart
failure cases
Conclusions
4) The ‘healing’ after an AMI is a highly
dynamic process, and adverse cardiac
remodeling and heart failure can be,
at least in part, prevented
5) A strategy including established
treatment options and novel
therapeutic approach is necessary to
limit the ‘heart failure epidemics’
For further slides on these topics
please feel free to visit the
metcardio.org website:
http://www.metcardio.org/slides.html