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

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

Flashcards in CVS Lecture 15/16/17 - Hypertension, Atherosclerosis and Vascular Endothelium Deck (71):
1

What is hypertension?

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

2

How is BP distributed in populations?

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

3

What happens to BP with age?

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

4

What are the classifications of hypertension?

5

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

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

6

What are some monogenic disease causes of hypertension?

Liddle's syndrome, apparent mineralocorticoid excess

7

What are some complex polygenic causes of hypertension?

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

8

What are the haemodynamics of hypertension?

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

9

What causes the elevated TPR in hypertension?

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

10

What is isolated systolic hypertension?

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

11

What are the primary causes of primary hypertension?

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

12

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

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

13

What are the major risks attributable to elevated BP?

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

14

What is hypertension associated with in the heart?

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

15

How are hypertension and CHF related?

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

16

What are some effects of hypertension on vessels?

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

17

How does hypertension affect the eye?

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

18

How does hypertension affect the microvasculature?

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

19

How does hypertension affect the kidney?

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

20

What are the modifiable risk factors for atherosclerosis?

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

21

What are the non-modifiable risk factors for atherosclerosis?

Age, sex, genetic background

22

What is the organisation of the artery wall?

23

Where do atherosclerosis develop in the artery wall?

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

24

How do atherosclerosis progress?

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

25

How does an atherosclerosis develop over time in an individual?

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

26

What are the main cell types involved in atherosclerosis?

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

27

What is the role of vascular endothelial cells in atherosclerosis?

Barrier function to lipoproteins, leukocyte recruitment

28

What is the role of platelets in atherosclerosis?

Thrombus generation, cytokine and growth factor release

29

What is the role of monocytes/macrophages in atherosclerosis?

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

30

What is the role of VSMC in atherosclerosis?

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

31

What is the role of T cells in atherosclerosis?

Macrophage activation

32

How do macrophages affect atherosclerosis formation?

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

33

What are the 2 types of macrophages?

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

What are the 2 types of lipoproteins?

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

What are oxidised/modified LDLs?

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

What is the structure of LDL?

Monolayer of P/L and on inside is TG

37

How is LDL trapped in the subendothelium?

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

How is the LDL modified when trapped in the subendothelium?

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

What is familial hyperlipidaemia?

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

What is the scavenger receptor?

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

41

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

x

42

What is the macrophage scavenger receptor A?

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

43

What is the macrophage scavenger receptor B?

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

44

What do the macrophages do within plaques?

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

What are the 2 main oxidative enzymes that modify LDLs?

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

46

Which cytokines and chemokines are expressed by plaque macrophages?

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

What are the growth factors that recruit VSMC by macrophages?

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

48

How are the VSMC different in atherosclerotic scenarios?

Increased matrix deposition and decreased contractile filaments -> synthetic cells

49

How do macrophages proteolyse ECM?

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

50

What happens when the plaque erodes/ruptures?

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

What are the characteristics of vulnerable and stable plaques?

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

How does macrophage apoptosis occur?

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

What is nuclear factor kappa B (NFkB)?

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

Summarise macrophages in atherosclerosis

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

55

What is the basic structure of blood vessels?

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

56

What is the vascular endothelium?

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

57

What are endothelial cells?

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

What do endothelial cells do?

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

What is the endothelium state normally?

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

How are leukocytes recruited in atherosclerosis?

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

What are endothelial junctions?

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

62

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

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

How permeable is the vascular endothelium?

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

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

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

How does blood flow affect atherosclerosis development?

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

What is angiogenesis?

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

What is the Janus paradox?

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

What is senescence?

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

What do senescent cells do?

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

What is the inflammation model of atherosclerosis?

71

What is important about red wine to help with atherosclerosis?

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

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