Pathophysiology of CVD

• What is CVD


  •       A non-communicable disease

  •       It is not a single condition.

  •       Includes all the diseases of the cardiovascular system: heart and blood vessels (arteries, veins and capillaries)

  –      also called heart or circulatory disease

  •       Involving increasing narrowing and/or blockage of the arteries – reducing blood flow, which is needed for oxygen + nutrients.

  • A disease of age, risk increases as age does
• Examples of Cardiovascular Diseases (CVDs)


  • Coronary heart disease (CHD) - blood vessels supplying the heart muscle
  • Cerebrovascular disease - blood vessels supplying the brain tissue
  • Peripheral arterial disease - blood vessels supplying the periphery arms and legs
  • Rheumatic heart disease - damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria (often discovered too late)
  • Congenital heart diseases - malformations of heart structure existing at birth = heart not working
  • Deep vein thrombosis and pulmonary embolism - blot clots in the leg vein which can dislodge and move to heart or lung
• Most typical types of CVD


  • Coronary artery disease (CAD) or ischemic heart disease (IHD)
  • Stroke
  • Transient ischemic attack (TIA)
• Coronary artery disease (CAD) or ischemic heart disease (IHD) includes


  • Impairment of O2

  - Angina (temporary)

  - Myocardial infarction (lack of blood flow round the heart muscles – if not solved quickly can = necrosis) and sudden death as a consequence.
• Coronary artery disease (CAD) or ischemic heart disease (IHD)


  • Angina (temporary)
  • Myocardial infarction (lack of blood flow round the heart muscles – if not solved quickly can = necrosis) and sudden death as a consequence
• Stroke


  • Poor blood flow to the brain
• Examples of Stroke

  • Ischemic stroke (oxygen, 30 day recovery rate, 12% death rate)
  • Haemorrhagic stroke (vessels rupture + blood bleeds into the tissue – more people die from this compared to ischemic – 30% death rate)
• Transient ischemic attack (TIA)


  Mild form, mini-stroke, temporary blockage (typically resolved within 24h)
• What is a consequence of us living so long


  CVD is a consequence of increasing lifespan

  we live longer than our genetics were designed to
• CVD and gender


  •      Increasing age = increasing incidence

  •       Women rates are lower than men, this is more pronounced at younger age.

  •       The risk of CVD gap between genders gets smaller as age increases as differences are linked to reduced oestrogen production when women become menopausal.

  -As women get older, their risk for CVD increases
• What are the benefits of oestrogen

  -        Oestrogen protects against oxidative stress, lowers fibrosis, increases angiogenesis and vasodilation, anti – apoptotic

  -       Menopause results in women exposed to higher risk of CVD. 

  
• CVD in UK


  • Cardiovascular disease accounts for 1:4 deaths in the UK each year
  • But rates are falling
  • There is significant regional variation in incidence of disease: even within single cities
  • Higher survival for the more affluent - due to diet, education, smoking exercise?
• SES and CVD study 


  AIM: Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study.

  FINDINGS: Higher level of education in high income and middle-income countries shows higher incidence compared to lower level of education in low-income of and mortality from cardiovascular disease, but better overall risk factor profiles.
• What is the CV system?

  -       A ‘closed circuit’ perfusion system

  -       Delivers nutrients.

  -       Removes waste products.

  -       Operates at both high (left side) & Low pressure (right side.

  -       Simultaneously!

  
• Whats the cardiovascular sytem made up of?


  • Artery
  • Veins
  • Capillarys
• Artery 


  •       STRUCTURE: Thick walled, elastic structures, to resist high pressure. Have muscle layer under nervous system control – can vary diameter. Generally high pressures + relax.

  •       Predominant target for CVD – atheroma develops in arteries, and aneurysm and stroke originate in arteries

  
• Vein


  •       STRUCTURE: Generally, larger diameter, no muscle, limited elasticity with limited scope for control of diameter. 

  •       For the ‘capacitance vessels’ holding most of the blood in the body. 

  •       Generally low pressures. Also contains valves to prevent ‘back-flow’.

  •       Largely free of CVD (atheroma do not develop in ‘low pressure’ vessels). 

  •       But subject to peripheral vascular disease associated with diabetes

  
• CAPILLARY


  •      STRUCTURE: Very narrow, thin walled – no muscle, allow nutrient exchange across an endothelium. No muscle or elastic fibres. 

  •       Very low pressure.

  •       Free of cardiovascular disease as such BUT are the targets for microvascular disease associated with diabetes. 

  •       Leads to capillary loss. More insidious than CVD as capillary loss is gradual and progressive – losing exchange surface area.

   

  
• Atheroma Formation


  The process of plaque buildup in arteries
• Atheroma Formation


  1. Trigger stimulates trigger

  2. Environment of high lipids, oxidised LDL, BP = high stress and inflammatory environment

  3. Trigger (from stress) damages endothelial lining + function, triggering expression of inflammatory markers

  4. Monocytes levels increase due to increased permeability of endothelium, changing to macrophages, foam cells form as lipids accumulate

  5. Cytokine release = inflammatory signalling, this recruits more inflammatory cells + fibroblasts = increase in growth of plaque

  6. Fibroblasts proliferate quick and embeds foam cells + hardens = blockage
• Atheroma formation

  
• Atheroma in babies


  •       Atheroma may be ‘reversible’ in babies.

  •       Babies as little as 9 months old develop fatty streaks, BUT they resolve

  •       We ONLY see the atheroma that cause harm in adults, its irreversible in adults.
• Where does atheroma form?


  •       Atheroma tend to form at bifurcations or narrowing of arteries (changes in flow) these change with age/increasing size

  •       Perhaps ‘adults’ present with fixed dimensions within the cardiovascular system = irrevesible

  •       The disruption in flow does not change.
• Platelets


  •       Platelets involved in Haemostasis – clot formation.

  •       ALSO contribute to atheroma formation

  •       Activation is triggered by exposure to collagen, Thrombin, ADP, Von Willibrands Factor (vWF), etc.

  •       Platelets ‘Help’ to migrate and enlarge a plaque in the ‘downstream’ direction of flow.
• Platelets in action


  Platelets are trying to repair, but are causing more damage.

  
• Blood cells and flow


  -       With such a mix of cell types and sizes, this affects flow as the largest cells are trapped in the middle, smallest cells travel on the outside. 

  -       Heterogeneous particles flowing in a tube adopt ‘axial flow.

  
• HOW IS blood FLOW DISRUPTED BY OBSTRUCTION

  If there’s a blockage, the diameter decreases, resulting in the heart working harder to pump the cells through = increased blood pressure.

  
• Atheroma & Axial Flow


  • Effects of modest changes in diameter of arteries in early atherosclerosis are modest but progressive.

  -       Greater degrees of artery occlusion decreases both oxygen and substrate deliver downstream of the atheroma as flow decreases (eg. 40% decrease in flow decreases peak delivery of O2 and glucose 40%)
• Angina


  -       Angina is an acute condition triggered on exertion (physical activity = need more O2)

  -       Increasing oxygen demand of the heart

  -       Symptoms include intense, transient chest pain

  
  

  CAUSE: Partially blocked coronary artery: blood flow sufficient at rest.

  On exertion, oxygen becomes limiting and pain occurs as a result of oxygen deprivation
• Treatment of angina


  Oral glyceryl trinitrate (GTN) – spray is very quick acting.

  -       Generates rapid release of exogenous nitric oxide (NO)
• Mechanism of NO


  Dilation of the diseased coronary artery, more oxygenated blood is delivered. 

  -       Heart function improves (pain subsides).

  -       Demand for O2 also falls, as you tend to stop exertion.

  Spray is doner for NO, NO taken up by the muscles cells = quick relaxation of muscle cells, results in more oxygenated blood to be delivered.

  
• Summary of atherosclerosis


  •       Cardiovascular disease characterised by a narrowing of arteries

  •       Likely a normal consequence of the aging process

  •       Normal physiological response to continual damage stimulus

  •       Arterial narrowing has local and systemic effects

  •       Can change mechanical character of arteries

  •       Exacerbates the declines associated with aging
• Endothelial cells are a single layer of cells lining the lumen of all blood vessels.
• Function of endothelial cells

  -       Provide a barrier, regulate both acute and chronic blood flow, local inflammation (have mechanisms that can sense inflammation + act on it), and vascular cell proliferation.

  -       Endothel is a highly active metabolic and endocrine organ.

  -       Maintain vascular homeostasis (balance of dilation constriction of vessels) and control local homeostasis (of inflammation etc).

  -       Endothelial cells have sensors and release mediators.

  -       Production and release of vasoactive, thromboregulatory and growth factors, adhesion molecules.
• Important endothelial factors 


  -       Nitric oxide (NO)

  -       Endothelin-I (ET-I)

  -       Endothelium Depolarisation Factor (EDF)

  -       Angiotensin II

  -       Thromboxane A2

  -       Prostacyclin
• Synthesis of Nitric Oxide


  •       Nitric oxide is an important signalling molecule (by making the cells relax).

  •       NO has a short duration.

  •       NO is produced in endothelium cells + requires Nitric Oxide Synthase (which produces citrulline, Nom NADP+, Arginine, O2, NADPH).

  •       Synthesised from Arginine.

  
  

  - If there’s high shear stress e.g obstacles in vessels, it stimulates NO production = relaxation of blood vessel.

  - NO is the main driver for equilibrium of blood vessel dilation.
• NO production in arteries

  A) Intima

  
• How is NO produced?


  Nitric oxide (NO) is produced through the oxidation of L-arginine by the enzyme nitric oxide synthase (NOS).

  It requries Arginine + O2 + NADPH --> citrulline + NO + NADP+
• What happens when blood pressure increases?

  High shear = increases NO = reduced sheer = reduced NO (is an equilibrium)
• When does uncoupling of NOS occur?

  Diabetes, smoking, hypertension, atherosclerosis, high nitrate consumption (e.g. GTN in heart failure)