Acute Coronary Syndrome: From Pathophysiology to Management
Nasser Lakkis, MD
Baylor College of Medicine
Houston TX, USA
STEMI
Clinical finding
EKG
Serum markers
Risk assessment
Non-cardiac chest pain
Stable angina
UA
NSTEMI
Negative
Positive
ST-T wave changes
ST elevation
Low probability
Medium-high
risk
Thrombolysis Primary PCI
Aspirin + GP IIb/IIIa inhibitor
clopidogrel + heparin/
LMWH + anti-ischemic Rx Early invasive Rx
Discharge
Negative
Diagnostic rule out MI/ACS
pathway
STEMI
Negative
Atypical
pain
Low
risk
Aspirin, heparin/low-molecular-weight heparin (LMWH) + clopidogrel Anti-ischemic Rx Early conservative therapy
Ongoing pain
DM=diabetes mellitus.
Cannon, Braunwald. Heart Disease. 2001.
Rest pain, Post-MI, DM, Prior Aspirin
Exertional pain
The Spectrum of ACS
Inconsistent Approach to ACS
Multiplicity of interpretation of Clinical trials
Protocol variation
Propensity of PCI in clinical studies
Personal preference of physicians
Unclear guidelines
Inflammation
Atherosclerosis
Thrombosis
Thrombus
Quiescent
plaque
Platelets
and thrombin
Plaque rupture
Acute Coronary Syndromes Evolving Understanding of Pathophysiology
Relative Risk of Cardiovascular Events According to Several Biochemical Markers
Relative Risk of Future CV Events
0
1.0
2.0
4.0
6.0
Lipoprotein(a)
LDL-cholesterol
Homocysteine
Total cholesterol
Apolipoprotein B
TC:HDL-C ratio
hs-CRP
hs-CRP + TC:HDL-C Ratio
Adapted from Ridker PM, et al. N Engl J Med. 2000;342:836-843.
Thrombosis of a Disrupted Atheroma
Weakening of the fibrous cap
Thrombogenicity of the lipid core
The signals that regulate these features of the plaque remain uncertain
Collagenase expression and circumferential stress in human coronary atheroma
MMP-1
Lee RT et al. Art Thromb Vasc Biol 1996;16:1070
Percentage Distribution of
Coronary Atherosclerotic Plaque Ruptures
Other Than the Culprit Lesion
%
# of Ruptured Plaque Distinct From the Culprit Lesion
Rioufol G. et al., Circulation 2002; 106:804-8.
0 1 2 3 4 5
Markers of Increased Risk in ACS
ST segment changes
Serum markers
Necrosis
Inflammation
LV dysfunction
Hemodynamic instability
0 30 60 90 120 150 180
10
8
6
4
2
0
Days
ST ↓ ACS
T- wave
inversion
GUSTO-IIb Study: Correlation of 6-Month Mortality With Baseline ECG Findings in Patients With ACS
Cumulative Mortality At 6 Months, %
Savonitto S, et al. JAMA. 1999;281:707-713.
Copyrighted 1999, American Medical Association.
Association of Troponin Elevation with Risk of Mortality in ACS
Antman EM. N Engl J Med 1996; 335: 12342-1349.
* x upper limit of normal
Relationship Between Elevated CK-MB and Mortality at 6 months
Alexander JH et al. Circulation. 1999; Suppl 1:1-629.
4.9%
5.7%
9.2%
12.6%
14.5%
19.9%
(n=5,681) (n=1,098) (n=294) (n=302) (n=249) (n=211)
CK-MB levels during hospitalization
TACTICS: Outcome by Troponin Status and CAD on Cath at 6 months
Lindahl B, et al. N Engl J Med. 2000;343:1139-1147.
Predictive Value of Troponin T and hs-CRP for Mortality From ACS in FRISC II
Troponin I (TnI), C-Reactive Protein (CRP), and B-type Natriuretic Peptide (BNP) as Determinants of 30-Day Mortality in ACS
Sabatine MS, et al. Circulation. 2002;105:1760-1763.
n=67
n=150
n=155
n=78
n=504
n=717
n=324
n=90
Inflammation in ACS: Myeloperoxidase
Circulation 2003
Inflammatory Marker Predicts Invasive Success in FRISC II
Lindmark et al. JAMA 2001;286:2107-13
Goals in ACS Management
Relieve symptoms
Minimize loss of muscle
Reduce mortality
Treat specific complications
Therefore….
Reduce thrombus burden
Limit thrombus progression
Prevent micro-embolization
Promote healing and homeostasis of the injured vessel wall
Event incidence (%)
Day
Cohen, et al. Am Heart J 2002;143:63.
*Leading to urgent revascularization
Peak- Day 2
Peak- Day 8
0
0.5
1
1.5
2.5
1
6
11
16
21
2
Day
In-Hospital Events in ACS ESSENCE/TIMI 11b (N=7,081)
ACS Treatment Strategies
Medical Theapy
Risk Modification
CABG
PCI
Antithrombotic therapy
Other medical therapy
ADP antagonists
Nitrates
BBs
STATINS
ACE-I
OTHERS
Reperfusion/Revascularization therapy
Heparin
ASA
GPIIb/IIIas
FRISC II Investigators. Lancet. 1999;354:708-715.
Cannon C, et al. N Engl J Med. 2001;344:1879-1887.
FRISC II TACTICS-TIMI 18
Dalteparin Tirofiban
Day 7:
OR=0.59
P=0.033
Day 30:
OR=0.51
P=0.002
0
30
60
90
Time (days)
120
150
180
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Probability of Death/MI
Invasive
Conservative
Conservative
Invasive
UA/NSTEMI: Benefit of Early Invasive Strategy
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0
0 30 60 90 120 150 180
Time since start of open phase (days)
Conservative + tirofiban
Early intervention + tirofiban
6-month Death/MI/ Re-hospitalization
(%)
11.8
20.3
12.8
16.1
19.5
30.6
0
5
10
15
20
25
30
35
Low 0–2
Intermediate 3–4
High 5–7
TACTICS-TIMI 18: Early Intervention versus Conservative
Cannon C, et al. N Engl J Med. 2001;344:1879-1887.
TMPG Post-stent and Composite Events by 48 Hrs & 1 Yr
Composite Event (%)
1 Year Death, MI, Urgent TVR
p = 0.01
32.4%
4.2%
1/24
11/34
All Patients Have TIMI 3 Flow at Completion of Stenting
Stain
Slow
Pale
Normal
Gibson CM et al, Am Heart J. 2002 Jan;143(1):106-110.
Troponin Elevations on Admission are Associated with Tissue Level Perfusion Following PCI: TACTICS TIMI 18
p=0.004
p=0.013
% TMPG 0/1
% TMPG 0/1
Circulation 2002
Sites of Anti-thrombotic Drug Action
Intrinsic Pathway
Extrinsic Pathway
Plasma clotting
cascade
Prothrombin
Thrombin
Fibrinogen
Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Platelet Agonists
Thromboxane A2
ADP
AT III