MB2080: Topic 6 - Atherosclerosis, Stroke & Mitochondrial Disease

Arterial wall anatomy

• tunica externa — elastic/collagen fibres

• tunica media — contains smooth muscle cells

• tunica intima — consists of endothelial cells

Functional role of arterial wall layers

• adventitia — structure

• media — contractile function to regulate vascular tone

• intima — smooth surface for blood flow

Atherosclerosis

the build-up of fibrous and fatty material inside arterial walls and is the underlying condition that causes coronary heart disease and other cardiovascular diseases

Significance of atherosclerosis

• CVD is the no.1 cause of death globally

• ~17.9M people died from CVDs in 2019, 32% of global deaths

• ~85% of CVD deaths are due to either coronary heart disease or stroke

Atherosclerosis symptoms

• absent for many years?

• angina (chest pain)

• heart attack

• claudication

• stroke

Claudication

cramping pain in leg during exercise (non-cerebral, non-coronary = ‘peripheral arterial disease’)

Atherosclerosis as a cause of stroke

caused by a build up in the carotid arteries

Peripheral arterial disease

non-cerebral, non-coronary atherosclerosis which affects blood flow to the limbs

Atheroma

a fatty deposit made up of cholesterol, waste, endothelial and smooth muscle cells as well as inflammatory leukocytes, restricting blood flow

Diapedesis

passage of immune cells into the arterial wall

Macrophage Function in Atherogenesis

• penetration

• activation

Macrophage penetration in atherogenesis

leukocytes respond to chemotactic stimuli and penetrate the endothelial surface and enter into the arterial lamina

Macrophage activation in atherogenesis

• once inside the intima, the mononuclear phagocyte undergoes activation

• expresses scavenger receptors that can internalise modified LDL

• promotes foam cell formation

Molecular mediators of atherogenesis

• Adhesion molecules (e.g. VCAM-1) — cause binding of inflammatory leukocytes to the endothelium

• Chemoattractants (e.g. MCP-1) — cause direct migration of leukocytes into the intima

• Activators (e.g. M-CSF) — cause expression of scavenger receptors, releasing cytokines and stimulating macrophage proliferation

Label the atherosclerotic plaque

1. Lipid core

2. Lumen

3. Intima

4. Fibrous cap

5. Shoulder

6. Media

7. Elastic laminae

8. Internal elastic laminae

9. external elastic laminae

Lipid core formation

Overloaded foam cells die from necrosis or apoptosis, releasing their lipid content into the intima, forming the lipid core

Most common cause of acute coronary syndromes

thrombosis of disrupted atheroma

Thrombosis of atheroma

formation of a blood clot caused by the weakening of the fibrous cap

Inflammatory cells effect on collagen of the fibrous cap

• inhibit the ability for smooth muscle cells to synthesize new collagen

• release proteolytic enzyme that degrade collagen and other connective tissue

• weakening the fibrous cap over time

Tissue factor

a potent procoagulant produced by inflammatory cells, partly responsible for thrombosis of ruptured plaque

Ischaemia

restriction of blood flow to tissues, causing a shortage of oxygen and nutrients required for cell metabolism

Consequence of ischaemia

• cell damage

• cell death

• release of proteins: enzymes, troponin

Risk factors of atherosclerosis

• drugs

• sugar

• alcohol

• smoking

Primary prevention

preventing onset of disease by addressing risk factors and reducing them by altering behaviour, exposure or enhancing resistance

Secondary prevention

detection and treatment of pre-clinical changes to prevent progression

Examples of secondary preventors of CVD

• statins

• aspirin

• angiotensin II inhibitors

• ACEi

• ARB

• diureitcs

• beta blockers

Cardiac interventions

• valve repair

• bypass graft

• stents

• heart transplant

Bypass graft

healthy blood vessel is taken from another part of the body and attached above and below the blockage to create a new route for blood flow

Stent

small mesh tube inserted into vessels to hold it open for improved blood flow

Stent procedure

• stent with balloon is inserted into partially blocked artery

• balloon inflated to expand state and open up the vessel

• balloon is removed, expanded stent is left in the artery, keeping it open

Neurodegeneration

progressive damage or death of neurons leading to gradual deterioration of the bodily functions controlled by the affected part of the nervous system

Stroke

occurs when blood flow to the brain is cut off leading to acute neurodegeneration

Types of strokes (and prevalence)

• Ischaemic stroke (80%)

• Haemorrhagic (20%)

Ischaemic stroke

blockage in the blood supply feeding the brain with oxygenated blood (area of brain becomes blood deprived)

Haemorrhagic stroke

break in blood vessel (aneurysm) in brain — area of bleeding in the brain

UK stroke prevalence

• 250-400 strokes per 100,000 people

• 3rd cause of death

• 1st cause of disability

Clinical symptoms of stroke

• sudden or gradual onset one-sided limb weakness/paralysis

• confusion, loss of speech/vision

• headache

• loss of consciousness

• cognitive impairment

Types of cognitive impairment caused by stroke

• amnesia

• inattention

• confusion

• depression

• mood & behaviour changes

Transient Ischaemic Attack

transient episode of neurological dysfunction without acute tissue death

Primary cause of stroke-induced cell death

excessive amounts of glutamate

Core pathology of stroke

rapid necrotic cell death mainly due to excess NMDA

Penumbra pathology of stroke

slower apoptotic cell death due to more moderate NMDA receptor hyperactivity

How does post-stroke depression differ from primary depression

• more cognitive impairment

• increased irritability

• more psychomotor slowing

• more mood liability

Excitotoxic hypothesis

excess amino acids results in prolonged depolarisation of receptive neurons which in some way leads to their eventual damage or death (excitotoxic lesions)

Events following stroke

• excitotoxicity

• inflammation

• increased sodium ions retention

• microglia

• blood-brain barrier breakdown

• oedema formation

Stroke treatment methods

• pharmacological

• thrombolysis

• aspirin

• modifiable risk factors

• physiotherapy

• stem cells

Limitations of NMDA receptor antagonists

• glutamate plays a crucial role in normal cell physiology and survival — this is disrupted by NMDA receptor antagonists

• difficult to administer the antagonists to the core of the stroke

Thrombolysis

break down of blood clots to restore blood flow to blocked organs or limbs

Major limitation of t-PA

needs to be administered within 3 hours of a stroke

Surgical intervention for thrombolysis

• carotid endarterectomy

• intra-arterial clot removal

Aspirin for stroke treatment

• prevents recurring strokes

• reducing severity of stroke

Modifiable stroke risk factors

• high blood pressure

• smoking

• physical inactivity

• obesity

Physiotherapy for stroke treatment

• Improve motility/avoid injury

• Everyday activities

• Independent living

• Exercise, manipulation, massage, skills training, electrical treatment

Mitochondrial disease

a group chronic, genetic disorders caused by dysfunctional mitochondria

Features of mtDNA

• 16,569 bp

• polyploidy

• codes 13 polypeptides, 22 tRNAS, 2 rRNAs

• maternal inheritance

• polycistronic

Mitochondrial disease prevelance

• children: prevalence >6.2/100,000 births

• much higher in consanguineous communities

• adults: 1 in 4300 affected or at risk

• mtDNA mutations in 75% clin affected adults

• 152 births per annum at risk of tranmission in UK (778 US)

• no cure

• progressive nature

Features of mtDNA mutations

• either homoplasic or heteroplasmic

• cellular threshold for biochemical effect to be seen

• maternal inheritance

Homoplasmy

all mtDNA copies within a cell are identical

Heteroplasmy

mixed populations of mtDNA within a cell

MELAS

Mitochondria Encephalomyopathy Lactic Acidosis and Stroke-like episodes

Clinical symptoms of MELAS

• migraine

• limb weakness

• neuro deficit

• stroke like radiol

• hearing loss

• diabetes cardiomyopathy

MERRF

Myoclonic Epilepsy and Ragged Red Fibres — caused by mtDNA 80-90s lysine tRNA mutation

MERRF symptoms

• encephalomyopathy

• ataxia

• muscle weakness

• hearing loss

• lactic acidosis

• cardiomyopathy

MNGIE

Myoneurogastrointenstinal Encephalomyopathy (caused by mutation in thymidine phosphorylase) — nDNA

Mitochondrial donation

the transfer of the nuclear chromosomal DNA from an oocyte or zygote from a woman with pathogenic mtDNA mutation into an enucleated, recipient donor oocyte or zygote

Potential therapeutic interventions for mitochondrial disease

• increasing mitochondria biogenesis to restore OXPHOS function

• promoting respiratory efficiency or mitochondria protein synthesis

• restoring mtDNA homeostasis

• shifting mtDNA heteroplasmy by genome editing