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Pathophysiology of Brain & Body
USSJJQ-20-3
Cardiovascular Disease (CVD)
Coronary Heart Disease (CHD)
&
Stroke
CardiovascularDisease (CVD)
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Diseases of the heart and circulatory system
Main cause of death in the UK
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Main forms of CVD are Coronary Heart (or Artery)
Disease (CHD or CAD) and Stroke
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~ half of deaths from CVD are from CHD (80,500 deaths in UK in 2010)
~ quarter are from stroke
CHD most common single cause of death in the UK
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179,000 deaths from CVD in 2010 (32% of total)
1 in 6 men and 1 in 8 women
17% of premature deaths in men and 8% in women (20,000 premature
deaths, <75 years)
Other forms of circulatory disease caused around
50,000 deaths in the UK in 2010
CHD/CAD aka Ischaemic Heart Disease (IHD)

Blood flow obstruction
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Atheroma, Thrombosis,
Embolism
Diminished coronary
perfusion
Compromised myocardial
function
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Ischaemia  Angina
Infarction  Necrosis
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Inflammation
Granulation tissue
Fibrous scarring
Myocardial Ischaemia
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Extent/timescale of compromised blood flow 
spectrum of presentation (increasingly ‘acute’)
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silent ischaemia ( cumulative damage/stress?)
exertion-induced angina (‘stable’)
unstable angina (seemingly random occurrence)
acute myocardial infarction (AMI/MI/‘heart attack’)
Last two termed Acute Coronary Syndrome
(ACS)
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Characterised by the common involvement of an
atherosclerotic plaque
Tends to affect systolic (ie pumping) function
~ 110,000 admissions/year in UK
Coronary Atherosclerosis – common sites
•Left Coronary Artery
•Anterior Descending
(LAD)
•Left Circumflex (LCx)
LCx
•Right Coronary Artery
•Risk factors –
Hypertension, Diabetes
& Smoking,
Life style, Diet,
Hypercholesterolemia
Male, Age, Genetic
LAD
Deaths / 100 pts / month
Cumulative 6-month mortality
from Ischaemic Heart Disease
N = 21,761; 1985-1992
Diagnosis on adm to hosp
Duke Cardiovascular Database
25
20
15
Acute MI
Unstable angina
Stable angina
10
5
0
0
1
2
3
4
5
6
Months after hospital admission
• Patients with ischaemic
discomfort may present with
or without ST segment
elevation on the ECG (STEMI)
• ST-segment elevation usually
 a Q-wave MI (QwMI)
• Non-ST-segment elevation is
either unstable angina or a
non–St segment elevation MI
(NSTEMI)
Atheroma - Coronary Artery
Atheroma - Coronary Artery
Calcification
Atheroma with Thrombosis
Coronary Atherosclerosis with Thrombosis
Normal Myocardium
MI 18-24 h
loss of nucleus, striations, coagulation necrosis
Old ‘healed’ MI - Collagen Scar
MI – Collagen Scar
Complications
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Arrhythmias/conduction defects
Extension of infarction, or re-infarction
Congestive heart failure
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Cardiogenic shock
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 embolisation
Myocardial wall rupture
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Due to low BP
Mural thrombosis
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Due to reduction in functioning muscle
Tamponade (fluid in pericardial sac)
Papillary muscle rupture, ventricular aneurysm
MI - Rupture
MI - Aneurysm
MI Pain
• Severe chest pain is the
usual main symptom
• May travel…
• Into jaw
• down left arm
• down both arms
• Sweating, nausea, feel faint
Reperfusion Strategies
Treatment Overview
Reperfusion Strategies
Stroke : Introduction

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A sudden onset of focal neurological deficit with
signs and symptoms lasting greater than 24
hours (or resulting in death) where the cause is
thought to be vascular (WHO)
 <24 h is a Transient Ischaemic Attack (TIA)
UK
 150,000 strokes/year in UK (50,000 deaths)
 1 every 3 minutes
 1,000 people under 30
rd commonest specific cause of death
 3
 Most common cause of disability
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250,000 living with disability caused by stroke
Stroke : Introduction
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USA
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600,000 - 700,000 people in the US have a stroke
each year
3rd leading cause of death (after CHD and cancer)
Incidence to double in 50 years (ageing
population)?
10% of strokes are immediately fatal
25% of stroke victims die within one year
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25% recover fully
Remainder have varying degrees of disabilities
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55% within 5 years
Most common cause of disability in adults
Direct Costs of Stroke totals $28.3 Billion/yr
Total Costs of Stroke totals $43.3 Billion/yr
Stroke : 10% of all-cause mortality
Tuberculosis
Diarrhoea
Perinatal causes
3%
Chronic obstructive pulmonary
disease
5%
HIV/AIDS
Respiratory infections
3%
Malaria
2%
Other causes
4%
27%
5%
7%
Coronary heart
disease
9%
Accidents
Stroke
10%
Cancer
13%
12%
1.0–2.0/1,000 people in USA
2.0–2.5/1,000 in Western Europe
3.0–3.5/1,000 in Eastern Europe
American Stroke AssociationHeart . Disease and Stroke Statistics 2004
Stroke : Risk Factors
Non- modifiable
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Race - e.g Afro-Americans increased risk
Inherited - family history of stroke
History of stroke or myocardial infarction
Age...
14
12
Men
 Women

% of population
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12,0
11,5
10
8
6,6 6,3
6
4
2
3,1 3,0
2,1
0,4 0,3
1,1 0,8
1,2
35-44
45-54
0
20-34
55-64
65-74
75+
Age
NHANES: 1999-2002 CDC/NCHS and NHLBI
Stroke : Risk Factors
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Modifiable
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Major
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Hypertension
Diabetes
Dyslipidaemia
Smoking
Risk for embolic events in heart/carotid disease
Other
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Obesity; Insulin resistance; Decreased physical activity;
Increased alcohol consumption; Heart disease (CHD,
CHF); Vasculitis; Migraine; Hypothyroidism; Sleep
apnoea syndrome; Haematological disorders
(Hypercoagulation or emboli); Predisposition for
thrombotic events (Hyperhomocysteinemia, female
hormones).
10yr Stroke Risk, Adults 55 yr old
according to basic Risk Factors
Estimated 10-Year Rate (%)
(Framingham Heart Study)
30
27
25
22.4
19.1
20
14.8
15
8.4
10
5
2.6
6.3
5.4
4
3.5
2
1.1
0
A
B
C
Men
Systolic BP
Diabetes
Smoking
Previous Atr Fib
Previous CVD
D
E
F
Women
A
B
C
D
E
F
95-105 130-148 130-148 130-148 130-148 130-148 mmHg
no
no
yes
yes
yes
yes
no
no
yes
yes
yes
yes
no
no
no
no
yes
yes
no
no
no
no
no
yes
Stroke 1991;22:312-318
Stroke : Types
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Ischaemic
Lack of circulating blood
deprives the neurones
of oxygen/nourishment
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Thrombotic
Embolic
Global, Hypotensive
Haemorrhagic
Extravascular release of
blood  local or
generalised pressure
injury
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Intracerebral (within the
brain)
Subarachnoid (between
the brain and the skull)
Stroke : Ischaemic vs Haemorrhagic
• Incidence –
• 88% (Ischaemic) vs 12% (Haemorrhagic)
• 30-day mortality –
• 10% (Ischaemic) vs 35% (Haemorrhagic)
Stroke : Ischaemic vs Haemorrhagic
Acute Ischaemic Injury
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Occlusion of a large vessel (such as MCA) is rarely
complete
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Progression and extent of ischaemic injury…
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Effect on Cerebral Blood Flow (CBF) depends on the degree
of obstruction, and collateral circulation
Rate & duration of the ischaemic event
Collateral circulation in the involved area of the brain
Systemic circulation & arterial blood pressure
Coagulation abnormalities
Temperature
Glucose
At macroscopic tissue level, can think of...
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CBF & Ischaemic Thresholds
Ischaemic Penumbra and Window of Opportunity
Macroscopic Factors
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CBF & Ischemic Thresholds
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Normal CBF  50-60 ml/100g/min
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Varies in different regions of the brain
CBF 20-30ml/100g/min  Loss of
electrical activity
CBF 10 ml/100g/min  Neuronal
death
Ischaemic Penumbra & Window
of Opportunity
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Ischaemic zone surrounds central
core of infarction
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CBF 25% to 50% normal and loss of
blood flow autoregulation
Viability of that brain tissue
preserved if perfusion is restored
within 2 to 4 hours?
Microscopic Injury Mechanisms
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Development of microcirculatory disturbances
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Excitotoxicity
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Formation of micro thrombi
Accumulation of noxious metabolites
Interaction of endothelial cells with neutrophils & platelets
Neutrophils trigger neuronal necrosis
Ischaemia  depletion of neuronal energy stores
 failure of active membrane ion pumps
increased extracellular glutamate (+ aspartate)
opening of Ca++ channels
influx of Ca++, Na+ and Cl- and efflux of K+
 irreversible neuronal damage
Apoptosis triggered by ischaemia, ~ 2 hours
Coagulation Necrosis, evolves over 6 - 12 hours
 physical/chemical/osmotic damage to cell memb
Haemodynamic Crisis: ‘Hypotensive Stroke’
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An event causing abrupt
drop in blood pressure
results in critical
compromise of CBF
and cerebral perfusion
Sites affected by
critically low CBF are
located at the end of an
arterial tree
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Hence the term
“watershed or boundary
zone infarct”
Hippocampus, Cerebral/
Cerebellar cortexes
sensitive
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Abundance of glutamate
Complications of Restoring Blood Flow
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Arterial occlusion causes ischaemia of vascular
walls in addition to effects on neurones
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Hemorrhage (red infarcts) result when the
fragile “ischaemic” or “injured” vessels rupture
after sudden restoration of blood flow
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Vasogenic oedema can also occur following
sudden restoration of blood flow to an
ischaemic area
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Disruption of BBB  increased permeability