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CVD > Pathophysiology of CVD > Flashcards

Pathophysiology of CVD Flashcards

1
Q

What are the most typical types of CVD?

A
  • Coronary artery disease or ischemic heart disease includes angina, myocardial infarction and sudden death
  • Stroke: poor blood flow to the brain (ischemic and haemorrhagic)
  • TIA: transient ischemic attack (resolved within 24hrs)
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2
Q

What are 4 facts about the cardiovascular system?

A
  • A ‘closed circuit’ perfusion system
  • Delivers nutrients
  • Removes waste products
  • Operates at both high & low pressure simultaneously
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3
Q

What does an artery have?

A
  • Thick walls, elastic structure so resistant to high pressure
  • Muscle layer under which is controlled by nervous system (varies in diameter)
  • Generally high pressures
  • Predominant target for CVD (atheroma develop in arteries and aneurysm and stroke originate in arteries)
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4
Q

What does a vein have?

A
  • Generally larger diameter, no muscle, limited elasticity with limited scope for control of diameter
  • Holding most of the blood in the body
  • Generally lower pressures
  • Contains valves to prevent back flow
  • Largely free of CVD (atheroma do not develop in low pressure vessels)
  • Subject to peripheral vascular disease associated with diabetes
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5
Q

What does a capillary have?

A
  • Very narrow, thin walled, no muscle, allow nutrient exchange across endothelium, no muscle or elastic fibres
  • Very low pressure
  • Free of CVD but targets for microvascular disease associated with diabetes
  • Leads to capillary loss; more insidious than CVD as capillary loss is gradual and progressive, losing exchange SA
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6
Q

What is the first step of atheroma formation?

A

Damage to the endothelial cells, which may result from factors such as hypertension, hyperlipidemia or smoking, results in abnormal expression of adhesion molecules

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7
Q

What is the second step of atheroma formation?

A

This increases binding of various leukocytes, particularly monocytes and T-lymphocytes to migrate into the intima of the vessel.

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8
Q

What is the third step of atheroma formation?

A

Inflammatory mediators cause monocytes and T-lymphocytes to migrate into the intima of the vessel.

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9
Q

What is the fourth step of atheroma formation?

A

Meanwhile, LDL moves into the vessel wall at site of injury and becomes oxidised and activated macrophages accumulate oxidised LDL, forming foam cells which are the base of the atherosclerotic plaque.

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10
Q

What is the fifth step of atheroma formation?

A

Another important component to the development is proliferation and migration of smooth muscle cells to the intima of the vessel and become incorporated in the plaque.

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11
Q

Can atheroma be resolved?

A
  • They may be reversible
  • Babies as young as 9 months develop fatty streaks but they resolve
  • Hard to tell as we only see the ones causing harm
  • Atheroma tend to form at bifurcations or narrowing of arteries (changes in flow) these change with age/increasing size
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12
Q

What are platelets involved in?

A

Haemostasis (clot formation) and also contribute to atheroma formation

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13
Q

What is platelet activation triggered by?

A

Exposure to collagen, Thrombin, ADP, Von Willibrands Factor (vWF)

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14
Q

How does platelet adhesion work?

A

Platelets adhere to subendothelial tissue to stop the loss of blood from a damaged vessel. Following endothelial damage, von Willebrand factor (vWF) is released from the endothelium, serving as the “glue” that promotes platelet adherence to the injured vessel/ Platelet adhesion to the damaged vascular wall is mediated primarily through the interaction of vWF and platelet receptors

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15
Q

When does platelet activation occur?

A

When platelets adhere to the damaged vascular wall and in response to humoral factors (epinephrine, ADP, thrombin) bind to platelet receptors

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16
Q

What does platelet activation cause?

A
  • Platelets to change shape, form pseudopodia, and release potent regulatory factors.
  • The release of alpha-granule contents (e.g. fibrinogen) and initiates a feedforward mechanism in which more platelets are recruited to the site of injury.
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17
Q

What happens during the activation phase with platelets?

A

Platelets also express specific receptors (Gp IIb/IIIa receptors) on their surface. These receptors serve as an important site for binding fibrinogen, which allows platelets to bind together to form the platelet plug.

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18
Q

What is platelet aggregation?

A

The process where activated platelets bind to one another and is the final step in platelet plug formation.

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19
Q

How do heterogeneous particles flow in blood?

A

They adopt an axial flow

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20
Q

What does blood plasma form?

A

A thin sleeve of lubricant between the cells and vessel walls, hence flow of cells through larger vessels is very low resistance

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21
Q

Where do the smallest cells travel?

A

At the margins of the column of cells, lowest mass therefore are pushed to the extremities

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22
Q

Where do largest cells travel?

A

Closest to the centre of the tube, have the greatest surface area and subject to greatest forces

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23
Q

What happens when flow meets an obstacle in a blood vessel?

A

Turbulent flow requires ‘more work’ to move the column of blood, axial flow is disrupted and resistance to flow in the circulation increases

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24
Q

What happens to the flow when there is an atheroma?

A

The flow is disrupted and the flow becomes turbulent

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25
Q

What happens when the flow becomes turbulent?

A

Horizontal flow decreases, therefore particles start to sediment in the slow-flow regions which is a reason why atheroma starts to ‘migrate’ downstream of the original point of damage

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26
Q

What happens as there are greater degrees of artery occlusion?

A

Decreased oxygen and substrate delivery downstream of the atheroma as flow decreases (e.g. 40% decrease in flow decreases peak delivery of O2 and glucose)

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27
Q

What is the most common example clinically?

A

Narrowing of coronary arteries leading to reduced flow leading to pain on exertion

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28
Q

What is angina?

A

Acute condition triggered on exertion due to the increased oxygen demand of the heart

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29
Q

What are symptoms of angina?

A

Intense and transient chest pain

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30
Q

What is the cause of angina?

A
  • Partially-occluded coronary artery: blood flow sufficient at rest.
  • On exertion, oxygen becomes limiting and pain occurs as a result of oxygen deprivation
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31
Q

What is the treatment for angina?

A

Oral glyceryl trinitrate (GTN) - Generates rapid release of exogenous nitric oxide (NO)

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32
Q

What is the mechanism behind the treatment?

A
  • Dilation of the diseased coronary artery, more oxygenated blood is delivered. Heart function improves (pain subsides)
  • Demand also falls, as you tend to stop exertion.
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33
Q

How does NO work?

A

Acts on smooth muscle cells by increasing cGMP levels, making the muscle relax, widening the diameter of the blood vessel, very quickly

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34
Q

How can atheroma alter the structure of the artery wall?

A

It is not elastic anymore so harder to regulate blood pressure

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35
Q

What does data suggest regarding elasticity?

A

If measured as pulse-wave velocity, it could be an indicator of progression of CVD, but only works for widespread disease. It would not register focal disease (in one artery)

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36
Q

What is CVD characterised by?

A

Narrowing of arteries

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37
Q

What is CVD likely to be due to?

A

Normal consequence of the ageing process

38
Q

What are endothelial cells?

A

A single layer of cells lining lumen of all blood vessels

39
Q

What do endothelial cells provide?

A

A barrier, regulate both acute and chronic blood flow, local inflammation and vascular cell proliferation

40
Q

Describe the endothelial?

A
  • Highly active metabolic and endocrine organ

- Maintains vascular homeostasis and control local homeostasis

41
Q

What do endothelial cells have?

A
  • Sensors and release mediators

- Production and release of vasoactive, thromboregulatory and growth factors, adhesion molecules

42
Q

What do endothelial factors include?

A
  • Nitric oxide (NO)
  • Endothelin-I (ET-I)
  • Endothelium Depolarisation Factor (EDF)
  • Angiotensin II
  • Thromboxane A2
  • Prostacyclin
43
Q

What is the normal regulatory functions of endothelium and what is involved?

A
  • Vasodilation (NO, PGI2, EDHF, BK, C-NP)
  • Thrombolysis (tPA, Protein C, TF-I, vWF)
  • Platelet disaggregation (NO, PGI2)
  • Antiproliferation (NO, PGI2, TGF-beta, Hep)
  • Lipolysis (LPL)
44
Q

What is the dysfunction regulatory functions of endothelium and what is involved?

A
  • Vasoconstriction (ROS, ET-1, TxA2, A-II, PGH2)
  • Thrombosis (PAI-1, TF-alpha, Tx-A2)
  • Adhesion molecules (CAMs, P,E Selectins)
  • Growth factors (ET-1, A-II, PDGF, ILGF, ILs)
  • Inflammation (ROS, NFkB)
45
Q

How is NO produced?

A

Continually by the endothelium

46
Q

What are the roles of NO?

A
  • It causes vascular smooth muscle (VSM) relaxation
  • inhibits platelet aggregation
  • inhibits vascular smooth muscle proliferation
  • inhibits the production of adhesion molecules.
47
Q

What is NO?

A
  • Nitric oxide

- most potent vasodilator secreted by the endothelium

48
Q

How is NO synthesised?

A

In the endothelium by the enzyme nitric oxide synthase (eNOS), which cleaves NO from the amino acid L-arginine

49
Q

After synthesis, where does NO diffuse to?

A

Rapidly diffuses from the endothelium into vascular smooth muscle where it leads to relaxation

50
Q

What is nitric oxide synthase and production of NO regulated by?

A
  • Shear stress and by several receptor-bound agonists

- Shear stress is most important stimulus for the production of NO under normal conditions.

51
Q

What happens during exercise?

A

Shear stress increases due to increased cardiac output and increased blood flow to the exercising skeletal muscle, which leads to greater production of NO, which causes greater vasodilation—known as flow-mediated dilation.

52
Q

What is the equation of NO production?

A

Arginine + O2 + NADPH –> (through NOS) –> Citrulline + NO + NADP+

53
Q

What is the first step in NO synthesis?

A

When endothelial cells are activated by a receptor-mediated agonist, such as acetylcholine or bradykinin, or mechanical stimuli, such as shear stress, Ca2+ is transiently released from intracellular stores via a second messenger cascade involving inositol triphosphate, resulting in Ca2+-calmodulin complex-dependent activation of eNOS

54
Q

What is the second step in NO synthesis?

A

Agonists stimulate eNOS activity by raising intracellular calcium concentrations, which promote the formation of calcium–calmodulin complexes. In turn, the calcium–calmodulin complex stimulates eNOS activity and NO production rate.

55
Q

What is the third step in NO synthesis?

A

Agonists can increase intracellular concentration by two main mechanisms: activating receptor-operated channels that lead to an influx of calcium or causing the release of calcium from the endoplasmic reticulum.

56
Q

What is the fourth step in NO synthesis?

A

The release of calcium from the endoplasmic reticulum occurs when agonist binding activates a membrane-bound enzyme (phospholipase C), which catalyzes the formation of inositol triphosphate (IP3).

57
Q

What is the fifth step in NO synthesis?

A

The IP3 then causes the release calcium from the endoplasmic reticulum.

58
Q

What is the sixth step in NO synthesis?

A

Agonist-mediated vasodilation leads to NO release primarily in large arteries. Nitric oxide activity is diminished under conditions of high oxidative stress

59
Q

What are the three subtypes of nitric oxide synthase?

A
  • Neuronal NOS (nNOS)
  • Endothelial NOS (eNOS)
  • Inducible NOS (iNOS)
60
Q

Where are the 3 subtypes under normal conditions?

A
  • eNOS is localised in endothelium and muscle cells
  • nNOS is present in neurons AND associated with nuclei and mitochondria
  • iNOS is ONLY found in immune cells
61
Q

What does eNOS derived NO cause?

A

Dilation of vessels by relaxing the smooth muscle cells and its activity continuously stimulated by shear stress in order to maintain basal production of NO

62
Q

Describe nitric oxide synthase?

A
  • Multi component enzymes
  • Haem-containing
  • Require Fe2+, Zn2+, Ca2+-calmodulin and BH4 (tetrahydrobiopterin) as constituents
  • Reducing equivalent cascade transfers electrons via NADPH, FAD and FMN
  • Can be inhibited by CN- and CO as they compete with O2 at Fe2+ in haem
  • Separating the two components (uncoupling) will inhibit activity of eNOS
63
Q

Why might uncoupling of NOS occur?

A
  • Diabetes
  • Smoking
  • Hypertension
  • Atherosclerosis
  • High nitrate consumption (e.g. GTN in heart failure)
64
Q

What does eNOS uncoupling lead to?

A
  • Leads to endothelial dysfunction
  • Caused mainly due to reduced bioavailability of Nitric Oxide
  • “oxidative stress” can lead to endothelial dysfunction
65
Q

What is endothelial dysfunction?

A
  • a condition in which the endothelial layer (the inner lining) of the small arteries fails to function normally. As a result, several bad things can happen to the tissues supplied by those arteries.
  • Major factor for atherosclerosis
  • It is also a physiological process and takes place gradually through ageing and menopause
66
Q

What does NO availability depend on?

A
  • Levels of eNOS in the endothelial cells
  • Dimerisation of eNOS (uncoupling prevents NO and increases superoxide)
  • Availability of substrate L-arginine
  • Availability of eNOS co-factors which include NADPH and tetrahydrobiopterin (BH4)
  • Absence of NO inactivators such as ROS and especially superoxide
67
Q

How is exogenous nitrate different to endogenous?

A

Nitrate-nitrite-NO pathway as an alternative pathway to classical L-arginine-nitric oxide synthase (NOS) pathway for NO production

68
Q

What happens to both exogenous and endogenous nitrate?

A

It undergoes reduction to nitrite (by facultative anaerobic bacteria on the dorsal surface o the tongue) and then to NO (in various tissues) either chemically (low pH) or enzymatically (xanthine oxidoreductase, myoglobin, cytochrome P450, mito electron transport chain complexes) reduced further to NO

69
Q

What is beetroot rich in?

A

Dietary nitrates, which your body can convert to nitric oxide

70
Q

What might beetroot do to blood pressure?

A

Reduce it through the vasodilation effects of nitrate

71
Q

What does the data suggest with beetroot and blood pressure?

A
  • reduction ≈5mmHg (=corresponds to 14% stroke mortality risk reduction and 9% CVD mortality)
  • Both diastolic & systolic pressure decreased
72
Q

What does nitrate supplementation acutely reduce?

A
  • BP and the O2 cost of submaximal exercise

- These effects are maintained for at least 15 days if supplementation is continued

73
Q

What is the acceptable daily intake of dietary nitrate?

A
  • There may be potential toxicity of nitrate
  • Reaction with amines to form nitrosamines
  • Potential initiation of cancer
  • Weight‐based guide to the ‘acceptable daily intake’ (ADI) of dietary nitrate in mg, mmol and ‘nitrate units’ (1 Nitrate unit = 1 mmol). ADI = 3.7 mg kg−1, and 62 mg nitrate = 1 mmol
74
Q

How might vegetable rich diets protect against CVD?

A

Via inorganic nitrate/NO

75
Q

What is step 1 in CVD protection from vegetables?

A

Ingestion of vegetables

76
Q

What is step 2 in CVD protection from vegetables?

A

Produces systemic NO3-

77
Q

What is step 3 in CVD protection from vegetables?

A

Through anaerobic bacteria in oral cavity and tissue nitrate reductase enzymes systemic NO2- is formed

78
Q

What is step 4 in CVD protection from vegetables?

A

There are many possible NO2- reduction pathways including protons and polyphenols  NO (which also is formed through classical L-arginine pathway)

79
Q

What is step 5 in CVD protection from vegetables?

A

Which leads to CV protection through

a. Smooth muscle contraction, smooth muscle cell proliferation
b. Platelet adhesion and aggregation, activity of inflammatory markers

80
Q

What did Oggioni (2018) find?

A

No significant improvement of cardiac output at rest and during exercise and BP at rest and during exercise when older adults consume dietary nitrate

81
Q

How can we assess cardiovascular health/disease state?

A
  • Mortality outcome
  • Measurement of risk factors such as blood lipids (total Chol, LDL-Chol, TG, HDL), Inflammation markers, adhesion factors
  • Functionality of endothelium, vasculature
82
Q

What is the principle of flow mediated dilate measurement?

A

dilation of the brachial artery in response to shear stress caused by an increase in blood flow

83
Q

What is 1% reduction in FMD associated with?

A

13% increase in CVD risk

84
Q

Why is FMD technically challenging?

A

o FMD requires at least 100 supervised practice scans to be competent
o Regular practice (100 scans per year) to maintain competence (Corretti et al., 2002)

85
Q

What is the first step of FMD?

A

Baseline:

  • A pneumatic cuff on the left forearm (the wrist).
  • The brachial artery is imaged 10-15 cm below the shoulder at rest for 30 seconds to acquire the baseline diameter with FMD
86
Q

What is the second step of FMD?

A

Occlusion
- After baseline known, the pneumatic cuff positioned around the wrist is then inflated to 220mmHg (suprasystolic pressure) during 5 min.

87
Q

What is the third step of FMD?

A

Maximum dilation
- After the interval of 5 min, the cuff is deflated to achieve reactive hyperaemia. The artery is imaged by ultrasound device and the dilation of artery FMD-1 during 2 min.

88
Q

What is FMD defined by?

A

Maximum diameter after occlusion divided by the baseline diameter

89
Q

What is reactive hyperaemia?

A

The transient increase in organ blood flow that occurs following a brief period of ischemia (e.g., arterial occlusion).

90
Q

What does FMD measurement reflect?

A

Nitric oxide (NO) production, and growing evidence has shown that endothelial function assessed by FMD can serve as an independent predictor of cardiovascular events

91
Q

What is FMD considered to be?

A

The gold standard to determine vascular elasticity

CVD (12 decks)

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