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LSS 1 - Thorax anatomy, Respiratory and Circulatory system > CVS Lecture 15/16/17 - Hypertension, Atherosclerosis and Vascular Endothelium > Flashcards

CVS Lecture 15/16/17 - Hypertension, Atherosclerosis and Vascular Endothelium Flashcards

1
Q

What is hypertension?

A

Not a disease, but on a scale -> number one risk factor for death; can be defined as level of BP above which investigation and treatment do more good than harm -> 140/90

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2
Q

How is BP distributed in populations?

A

Unimodal and any distinction between normal/abnormal is arbitrary -> no threshold for BP risk

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3
Q

What happens to BP with age?

A

Mean BP rises with age, PP does too -> majority of people >60y would be expected to be hypertensive by current definitions

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4
Q

What are the classifications of hypertension?

A
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5
Q

What are some genetic and environmental factors that affect primary hypertension risk?

A

Genetics -> monogenic (rare), complex polygenic (common); Environment -> dietary salt, obesity/overweight, lack of exercise, alcohol, prenatal environment, pregnancy, other exposures

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6
Q

What are some monogenic disease causes of hypertension?

A

Liddle’s syndrome, apparent mineralocorticoid excess

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7
Q

What are some complex polygenic causes of hypertension?

A

Multiple genes with small effects, interactions with sex, other genes, environment

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8
Q

What are the haemodynamics of hypertension?

A

Increased TPR, reduced arterial compliance (higher PP), normal CO, normal blood volume/ECV, central shift in blood volume (2ry to reduced venous compliance)

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9
Q

What causes the elevated TPR in hypertension?

A

Active vasoconstriction, structural narrowing of arteries -> growth and remodelling, loss of capillaries -> rarefaction

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10
Q

What is isolated systolic hypertension?

A

SBP >140, BP condition of ppl over 60, due to increasing stiffness of medium/large arteries -> pulse wave reflected and is greater by the time it reaches the brachial artery

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11
Q

What are the primary causes of primary hypertension?

A

Kidney -> key role in BP regulation (salt intake evidence); SNS -> evidence linking high activity to development of hypertension; Endocrine/paracrine factors -> inconsistent evidence

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12
Q

What are some pieces of evidence for kidneys as a cause of hypertension?

A

Exerts major influence on BP through reg of Na/H2O/ECF volume; impaired renal function/blood flow is commonest cause of hypertension; almost all monogenic causes affect renal Na excretion; salt intake is strongly linked with BP of human popn; animals with reduced Na handling develop hypertension

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13
Q

What are the major risks attributable to elevated BP?

A

Increased risk of CHD, stroke, peripheral vascular disease/atheromatous disease, HF, atrial fibrillation, dementia/cognitive impairment, retinopathy

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14
Q

What is hypertension associated with in the heart?

A

Commonly associated with increase in left ventricular wall mass and changes in chamber size

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15
Q

How are hypertension and CHF related?

A

Prevalence of CHF is increasing and hypertension increases risk 2-3x, and also accounts for 25% of all cases of CHF and precedes 90% of CHF cases, with elderly CHF attributable to hypertension

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16
Q

What are some effects of hypertension on vessels?

A

Hypertrophy in large arteries and acceleration of atherosclerosis; also may cause arterial rupture/dilations (aneurysms) leading to thrombosis or haemorrhage

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17
Q

How does hypertension affect the eye?

A

Retina has microvascular damage, with thickening of small arteries, arteriolar narrowing, vasospasm, impaired perfusion, increased leakage into surrounding tissue, haemorrhage, AV nipping and hard exudates

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18
Q

How does hypertension affect the microvasculature?

A

Reduction in capillary density -> impaired perfusion, increased PVR; elevated capillary pressure -> damage and leakage

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19
Q

How does hypertension affect the kidney?

A

Renal dysfunction is common (increased excretion of albumin), extreme accelerated hypertension can lead to progressive renal failure -> decline GFR with age

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20
Q

What are the modifiable risk factors for atherosclerosis?

A

Smoking, lipids, BP, diabetes, obesity, lack of exercise -> all greatly related, and multiply each other

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21
Q

What are the non-modifiable risk factors for atherosclerosis?

A

Age, sex, genetic background

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22
Q

What is the organisation of the artery wall?

A
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23
Q

Where do atherosclerosis develop in the artery wall?

A

LDL are deposited in the subintimal space and bind to proteoglycans and sets up a chronic inflammatory action

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24
Q

How do atherosclerosis progress?

A

Chronic inflammatory response leads to increase in SM cells, macrophages iniltrating and causing mild inflammation -> pick up lipid and become overwhelmed by the fat that they take up, so they die and there is a build up of fat in the artery wall -> abscess wall response in the artery which produces a thick fibrous cap which settles OR like an abscess popping, inflammatory response is driven by the fat and eats through the wall, forming an occlusive clot, haemorrhage or repair response

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25
Q

How does an atherosclerosis develop over time in an individual?

A

Lesion progression and in 40-50s there is a window of opportunity for primary prevention by changing life-style or risk managment -> after 60+ when complications arise, there is a window of clinical intervention, where secondary prevention occurs: catheter based interventions, revascularisation surgery, treatment of HF

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26
Q

What are the main cell types involved in atherosclerosis?

A

Vascular endothelial cells, platelets, monocytes/macrohpages, VSMC, T cells

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27
Q

What is the role of vascular endothelial cells in atherosclerosis?

A

Barrier function to lipoproteins, leukocyte recruitment

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28
Q

What is the role of platelets in atherosclerosis?

A

Thrombus generation, cytokine and growth factor release

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29
Q

What is the role of monocytes/macrophages in atherosclerosis?

A

Foam cell formation, cytokine and growth factor release, major source of free radicals, metalloproteinases

30
Q

What is the role of VSMC in atherosclerosis?

A

Migration and proliferation, collagen synthesis, remodelling and fibrous cap formation

31
Q

What is the role of T cells in atherosclerosis?

A

Macrophage activation

32
Q

How do macrophages affect atherosclerosis formation?

A

Main inflammatory cells, derived from blood monocytes, subtypes are regulated by combinations of transcription factors binding to regulatory sequences

33
Q

What are the 2 types of macrophages?

A

Resident: normally homeostatic, suppressed inflammatory activity, alveolar resident macrophages (surfactant lipid homeostasis), osteoclasts (Ca PO4[3-] homeostasis), spleen (iron homeostasis). Inflammatory: adapted to kill MO’s

34
Q

What are the 2 types of lipoproteins?

A

LDLs -> bad cholesterol, synthesised in liver, carries cholesterol from liver to rest of body including arteries. HDL’s -> good cholesterol, carries cholesterol from peripheral tissues including arteries back to liver

35
Q

What are oxidised/modified LDLs?

A

Due to actions of free radicals on LDL, not one single substance with families of high inflammatory and toxic forms of LDL found in vessel walls

36
Q

What is the structure of LDL?

A

Monolayer of P/L and on inside is TG

37
Q

How is LDL trapped in the subendothelium?

A

LDL leaks through the epithelial barrier by uncertain mechanisms, trapped by binding to proteoglycans in the sub endothelial layer, and is then susceptible to modification

38
Q

How is the LDL modified when trapped in the subendothelium?

A

Oxidation -> chemically represents partial burning, where LDL becomes oxidatively modified by free radicals and then oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation

39
Q

What is familial hyperlipidaemia?

A

Autosomal genetic disease -> recessive generates massive blood cholesterol due to failure to clear LDL from blood, forming xanthomas and early atherosclerosis-> LDL receptor expression and cholesterol synthesis is negatively regulated by intracellular cholesterol -> statins (HMG-CoA reductase inhibitor) lower plasma cholesterol

40
Q

What is the scavenger receptor?

A

Hoovers up oxidised LDL in atherosclerotic lesions and macrophages -> was a pathogen detector which recognises OxLDL as such and phagocytoses it

41
Q

What are the 2 pathways that can occur after arterial Ox-LDL is deposited?

A

x

42
Q

What is the macrophage scavenger receptor A?

A

CD204, binds to -> oxLDL, GPB, dead cells

43
Q

What is the macrophage scavenger receptor B?

A

CD36 binds to -> oxLDL, malaria parasites and dead cells

44
Q

What do the macrophages do within plaques?

A

Generate free radicals that further oxidise LDL; phagocytose/scavenge modified lipoproteins and become foam cells; become activated by modified lipoproteins/free intracellular cholesterol to express/secrete: cytokine mediators to recruit more monocytes, chemoattractants and growth factors for VSMC, proteinases that degrade tissue, tissue factor that stimulates coagulation upon contact with blood; die by apoptosis, contributing to the lipid-rich core of the plaque

45
Q

What are the 2 main oxidative enzymes that modify LDLs?

A

NADPH oxidase -> superoxide O2- (to kill bacteria). Myeloperoxidase -> HOCl (bleach from ROS and Cl-), HONOO (peroxynitrite)

46
Q

Which cytokines and chemokines are expressed by plaque macrophages?

A

CytoK-> IL-1 (upregulates VCAM-1), VCAM-1 (mediates tight monocyte binding). ChemoK -> MCP-1 which binds to monocyte GPCR = CCR2. Both form a positive feedback loop leading to self-perpetuating inflammation and deficiency in either of these molecules causes a decrease in atherosclerosis

47
Q

What are the growth factors that recruit VSMC by macrophages?

A

Platelet derived growth factor -> VSMC chemotaxis, VSMC survival, VSMC division. Transforming growth factor beta -> increased collagen synthesis and matrix deposition

48
Q

How are the VSMC different in atherosclerotic scenarios?

A

Increased matrix deposition and decreased contractile filaments -> synthetic cells

49
Q

How do macrophages proteolyse ECM?

A

Metalloproteinases -> 28 homologous enzymes, activate each other by proteolysis which degrade collagen -> have a catalytic mechanism based on Zn

50
Q

What happens when the plaque erodes/ruptures?

A

MMPs break up the collagen holding the plaque, causing it to rupture -> Occlusive thrombosis can occur due to blood coagulation at site of rupture causing cessation of blood flow

51
Q

What are the characteristics of vulnerable and stable plaques?

A

Large soft eccentric lipid rich necrotic core, thin fibrous cap, reduced VSMC and collagen content, increased VSMC apoptosis and inflitrate of activated macrophages expressing MMPs

52
Q

How does macrophage apoptosis occur?

A

OxLDL derived metabolites are toxic and macrophage foam cells have protective systems that maintain survival in the face of toxic lipid loading -> once overwhelmed, macrophages die via apoptosis which releases tissue factor and toxic lipids into central death zone (lipid necrotic core) -> thrombogenic and toxic material accumulates, walled off until plaque rupture causes it to meet blood

53
Q

What is nuclear factor kappa B (NFkB)?

A

Transcription factor, master regulator of inflammation -> activated by numerous inflammatory stimuli (scavenger/toll-like/cytokine receptors), switches on numerous inflammatory genes (MMP, inducible NOS)

54
Q

Summarise macrophages in atherosclerosis

A

Carotid for stroke, coronary for MI, iliac/femoral artery for limb ischemia

55
Q

What is the basic structure of blood vessels?

A

3 layers (not capillaries and venules) -> tunica intima (endothelium), tunica media (VSMC), tunica adventitia (vasa vasorum, nerves)

56
Q

What is the vascular endothelium?

A

Surface separating blood from other tissues -> very extensive SA and weight -> formed by monolayer of endothelial cells which are very flat, thin

57
Q

What are endothelial cells?

A

Very flat, about 1-2 micrometres thick and 10-20 micrometres in diameter -> not all endothelial cells are the same; live a long life with low proliferation rate (unless angiogenesis required) and they regulate essential function of blood vessels

58
Q

What do endothelial cells do?

A

Thrombosis and haemostasis (procoagulant factors, antithrombotic factors), angiogenesis (matrix products and growth factors), vascular tone and permeability (vasodilator/constrictor factrs), inflammation (adhesion molecules, inflammatory mediators)

59
Q

What is the endothelium state normally?

A

Resting state -> which when activated can tip the balance towards one side but can become deactivated once the problem is corrected -> HOWEVER atherosclerosis is a chronic tipping of the scales towards the pro-inflammatory, pro-thrombotic and pro-angiogenic side

60
Q

How are leukocytes recruited in atherosclerosis?

A

Leukocytes adhere to activated endothelium of large arteries and get stuck in subendothelial space -> newly formed post-capillary venules at base of developing lesions provide a further portal for leukocyte entry

61
Q

What are endothelial junctions?

A

Have transmembrane proteins which bind to each other to maintain a barrier and control transmigration across the endothelium

62
Q

Why does atherosclerosis occur more commonly in arteries rather than capillaries and venules?

A

Capillaries are just surrounded by basement membrane and pericytes (venules have more pericytes) BUT arteries have 3 thick layers, rich in cells and ECM so the WBC get stuck in the tunica media where they form the atherosclerotic plaque

63
Q

How permeable is the vascular endothelium?

A

It regulates flux of fluids and molecules from blood to tissues and vice versa -> increased permeability leads to increased leakage of plasma proteins through the junctions into the subendothelial space

64
Q

What happens when there is chronic activation of endothelium causing the vessel to become more permeable?

A

LDL diffuse through vessels into the vessel wall and become oxidised and then are taken up by macrophages, forming foam cells, which leads to chronic inflammation

65
Q

How does blood flow affect atherosclerosis development?

A

Develop mostly at bifurcations -> blood flow signals to endothelium (laminar/turbulent) -> laminar promotes quiescent pathways and formation of NO; Turbulent flow -> activates pro-thrombotic, coagulation and downregulate NO production

66
Q

What is angiogenesis?

A

Formation of new blood vessels by sprouting from pre-existing vessles -> hypoxia is a trigger, which produces growth factors (VEGF) and activates existing capillaries to form sprouts which then migrate towards source of hypoxia by maintaining connection with original blood vessels

67
Q

What is the Janus paradox?

A

Angiogenesis promotes plaque growth, by growth factors causing angiogenesis but capillaries are very thin and rupture causing haemorrhage so are BAD. Therapeutic angiogenesis prevents damage post-ischemia, by causing angiogenesis before occlusion causes tissue death so GOOD

68
Q

What is senescence?

A

Growth arrest that halts the proliferation of ageing/damaged cells -> which prevents transmission of damage to daughter cells: replicative senescence is limited proliferative capacity of human cells and response to stress and damage. Can also be pro-inflammatory and contribute to many diseases,

69
Q

What do senescent cells do?

A

Have distinctive morphology and acquire specific markers -> found in atherosclerotic lesions induced by CV risk factors (oxidative stress) with proinflammatory and prothrombotic phenotypes so contribute to atherosclerosis plaque progression and complications

70
Q

What is the inflammation model of atherosclerosis?

A
71
Q

What is important about red wine to help with atherosclerosis?

A

Contains resveratrol which has a hormetic action -> by promoting endothelial protective pathways and anti-aging compound and reduces vascular cell senescence

LSS 1 - Thorax anatomy, Respiratory and Circulatory system (27 decks)

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