Biological Stress-related

Mechanisms Specific to the Onset of

the Acute Coronary Syndromes and
Sudden Cardiac Death

APS Preconference Workshop

Daichi Shimbo, MD
Cardiovascular Disease (CVD)
•Leading cause of mortality in industrialized
nations
•Associated with significant patient
morbidity and poor quality of life
•Despite many evidence-based
preventive/treatment strategies for reducing
CVD, event rates remain high.
•Traditional risk factors do not explain all
CVD events
•Psychosocial factors – independent
predictors of CVD events.
http://en.wikipedia.org/wiki/File:Circulatory_System_en.svg
 Delivery of Oxygen to Tissue

Normal Blood Flow

Blockage +/- Increased Tissue Damage

Ischemia, Damage, Death
Coronary Arteries (Focus of this Talk)

Terms: CVD, CHD, CAD, ACS, SCD

 Coronary Arteries

•Atherosclerosis progression is
linear.
•Eventual occlusion of lumen causes
clinical events.
•Risk of future events are a
consequence of stenosis severity
(stenosis > 70%).
 In Reality

•68% of MIs are due to lesions < 50%

•18% of MIs are due to lesions 50-70%
•14% of MIs are due to lesions > 70%

On Cardiac Catheterization
Schoenhagen et al. JACC 2001;38:297-306 Nissen S. JACC 2003;41:103S-112S
 Thrombus Formation
•In sudden coronary death,
80% have intracoronary
thrombus overlying a coronary
plaque. 20% have no thrombus
present (spasm, emboli,
abnormal myocardium).
•Similar percentages of
thrombus formation are found
in AMI.

Fuster V et al. N Engl J Med 1992;326:242-250

Davies MJ. Circulation 1992;85:119-124
Fuster V et al. JACC. 2005;46:937-954
 Newer Paradigm
•Non-stenotic, ruptured “vulnerable”
plaques with overlying thrombus
formation commonly lead to clinical
events.
•Lesions are probably underestimated due
to positive remodeling.
•What leads to a plaque and its growth?
•What leads to thrombus formation over
the plaque?
Endothelial
Dysfunction Inflammation

Ross R. N Engl J Med. 1999;340:115-26

 Plaque Rupture
Inflammation and Thrombosis

Ross R. N Engl J Med. 1999;340:115-26

 Plaque Erosion

•50 consecutive cases of sudden

death caused by coronary thrombosis.
•28 (56%) of cases had
plaque rupture.
•22 (44%) of cases had
superficial erosion of plaque

Farb A, Virmani R et al. Circulation. 1996;93:1354-1363

In Summary, Three Biological Pathways
Are Involved in ACS/SCD

•Thrombus Formation
•Endothelial Dysfunction
•Inflammation
Platelet Aggregation
Thrombosis

Coagulation Cascade
 Platelet Aggregation

-Aspirin
-Ticlopidine
-Clopidogrel
-GPIIb/IIIa
Inhibitors

Primary and Secondary Waves

Vorchheimer et al. JAMA. 2001;286:2154-6
Coagulation Cascade

-Heparin
-Hirudin
-Bivalirudin
 Measures of Thrombosis
•Platelets
 Aggregation – manual/beside assays
 Surface marker expression - flow cytometry
 Soluble markers (e.g. P-selectin, PF4) –
ELISA
 Bleeding time
 Shape change - imaging (EM)
 Ex-vivo vascular injury models
 Measures of Thrombosis

•Coagulation
 Fibrinogen, D-dimer, factor V Leiden
 Coagulation factors
 Anticoagulation factors (protein C and S,
thrombomodulin, antithrombin III, TFPI)
 Fibrinolysis activity (t-PA, PAI-1)
 Endothelial Dysfunction
 Endothelium is normally responsible for Nitric
Oxide (NO) synthesis and release.
 Triggered by shear stress and other factors
(agonist binding)
 NO diffuses into vascular smooth muscle and
leads to dilation of the blood vessel (via
cGMP-dependent and –independent pathways).
 Paradigm: Endothelial “dysfunction” is due to
an impairment in NO-dependent vasodilation
(i.e. decreased NO bioavailability)
Vasodilation as a Measure of
Endothelial Function
Non-invasive Peripheral

Invasive Peripheral; Coronary

 Endothelial Dysfunction

"Blind monks examining an elephant”

(a print by Hanabusa Itchō)
 Not Just about Vasodilation
•Increased permeability to lipoproteins
•Up-regulation of leukocyte adhesion molecules
•Up-regulation of endothelial adhesion
molecules
•Migration of leukocytes into the arterial
wall
•Increased circulating endothelial cells or
microparticles
•Down-regulation of bone marrow-derived
endothelial progenitor cells
 Inflammation

•Both Innate and Adaptive Immunity

play major roles in the inflammatory
processes that underlie
atherosclerosis development.
 Inflammatory Biomarkers
•hs-CRP
•IL-6, IL-1, TNF-α
•CD40 ligand (CD154)
•myeloperoxidase
•Lp-PLA2
•pentraxin-3
•metalloproteinase-9
•leukocyte count
•serum amyloid A
 Drugs that May Improve Endothelial
Dysfunction and Inflammation

•Statins and other lipid lowering agents

•Angiotensin-converting enzyme
inhibitors
• Oral hypoglycemic agents (e.g.
glitazones)
• Anti-oxidant vitamins
• Direct effects?
• Improvement in endothelial function =
reduction in cardiovascular events?
Crosstalk Among Pathways
Endothelial
Dysfunction

Inflammation
Thrombus
Formation

Atherosclerosis
 Stress Paradigms

Cardiovascular
Stress
Disease
 Stress Paradigms

•Endothelial
Dysfunction
Stress •Thrombosis
•Inflammation
 Stress Paradigms: Trait

•Endothelial
Dysfunction
Trait •Thrombosis
•Anger/hostility •Inflammation
•Anxiety
•Stress
•Depression
 Stressor Paradigms:
Chronic Stressors

•Endothelial
Dysfunction
Stress •Thrombosis
•Low social support •Inflammation
•Discrimination
•Low SES
 Stress Paradigms: Emotional
Trigger

•Endothelial
Dysfunction
State •Thrombosis
•Laboratory-induced •Inflammation
•Natural
environment
 Emotional Triggers

•Laboratory-induction
 Mental stress tasks
 Anger recall
 Mood induction

•Endothelial
Dysfunction
•Thrombosis
•Inflammation
 Emotional Triggers

•Natural environment
 Earthquakes, War, Sporting events,
Terrorism (stressors)
 Post-cardiac event after an reported
episode of stress, anger, depression,
etc.
•Endothelial
Dysfunction
•Thrombosis
•Inflammation
 Stress Paradigms:
Behavioral Pathways

•Endothelial
Dysfunction
Stress Behavior •Thrombosis
•Diet, exercise, •Inflammation
smoking
•Medical non-
adherence
 Research Questions
•Trait x state interaction?
•Acute  chronic stress?
 When does the biological effects of acute
stress become chronically dysregulated?
•Are acute increases in biological
measures prognostic/relevant?
• Stress occurring in the natural
environment vs. laboratory-induced?
 Research Questions
•Relevance of stress affecting
different pathways of endothelial
dysfunction, inflammation, and
thrombosis?
• Can we separate out the biological
effects of different phenotypes of
stress?
• Bidirectional pathways between stress
and biological pathways?
 Interrelationships with More
Proximal Stress Pathways?

Stress and CVD

•Endothelial
•HPA Axis
Dysfunction
•Autonomic System
•Neuroimmune
Function
? •Thrombosis
•Vascular
Inflammation
 Heart Rate Variability and
Cardiovascular Reactivity
•Focus on the literature on the
relations of stress with either reduced
heart rate variability or dysregulatied
cardiovascular reactivity.
• Future research should be conducted to
clarify where along the causal chain
these pathways are located in relation
to endothelial dysfunction,
inflammation, thrombosis.
Q & A