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Life Support Systems (LSS) > Cardiovascular System 2 > Flashcards

Cardiovascular System 2 Flashcards

1
Q

What does aspirin do?

A

It irreversibly inhibits COX enzymes. It inactivates COX 1 and switches the function of COX 2 to generate protective lipids.

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2
Q

Why are thromboxane A2 levels depleted by aspirin but prostacyclin levels aren’t?

A

TXA2 is mainly produced in platelets rather than endothelial cells.
Prostacyclin is mainly produced in endothelial cells, which contain nuclei and hence can produce more COXs to produce prostacyclin (replacing the enzymes inhibited by aspirin).

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3
Q

What properties does resting endothelium have (laminar blood flow)?

A

Anti-inflammatory, anti-thrombotic, anti-proliferative.

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4
Q

What properties does activated endothelium have (turbulent blood flow)?

A

Pro-inflammatory, pro-thrombotic, pro-angiogenic.

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5
Q

What is the main difference in the structure of capillaries and post-capillary venules?

A

In capillaries, the endothelial cells are surrounded by basement membrane and precapillary cells (pericytes).
Post-capillary venules have more pericytes.

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6
Q

Why does turbulent flow cause the activation of endothelial cells?

A

Stable flow downregulates the expression of DNA methyltransferases (DNMTs), which allows the promotion of antiatherogenic genes to remain demethylated, enabling their expression.
Disturbed flow upregulates DNMTs.

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7
Q

What does phospholipase C do?

A

Causes PIP2 to be converted into IP3 and DAG.

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8
Q

How is arachidonic acid produced?

A

DAG is converted into it by DAG lipase.

Phospholipids from plasma membrane converted into it by phospholipase A2.

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9
Q

How does prostacyclin (PGI2) cause relaxation of vascular smooth muscle cells?

A

It binds to IP1 receptor on VSMC. This activates adenyl cyclase, converting ATP into cAMP. cAMP inhibits myosin light chain kinase.

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10
Q

What is the precursor for prostacyclin?

A

PGH2 - produced from arachidonic acid by COX1 and COX2 (COX enzymes).

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11
Q

How is NO produced in endothelial cells?

A

IP3 causes Ca2+ influx from ER. Ca2+ upregulates eNOS (endothelial nitric oxide synthase). eNOS converts L-Arg + O2 to L-Cit + NO.

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12
Q

How does NO cause relaxation of VSMCs?

A

NO diffuses into the VSMC and activates guanylyl cyclase, which converts GTP to cGMP. cGMP upregulates PKG. PKG activates potassium channels, causing K+ efflux and hyperpolarising the membrane.

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13
Q

How is TXA2 produced?

A

PGH2 is converted into it by thromboxane synthase.

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14
Q

How does TXA2 cause contraction of VSMCs?

A

It diffuses out of the endothelial cell (though the apical and basement membrane). It binds to TP beta receptors on the VSMC. PLC migrates along membrane and converts PIP2 into DAG and IP3. IP3 causes Ca2+ from extracellular space and SER. Ca2+ upregulates MLCK.

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15
Q

How does TXA2 activate platelets?

A

Binds to TB alpha receptors on platelets. Platelet activates and produces more TXA2. Positive feedback potentiates response and platelets aggregate.

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16
Q

Where is ACE?

A

It is expressed on endothelial cells in renal/pulmonary circulation.

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17
Q

How does angiotensin II cause contraction of VSMCs?

A

It diffuses across endothelial cells and binds to AT1 receptors on VSMCs. PLC converts PIP2, resulting in IP3 formation, resulting in Ca2+ influx and MLCK upregulation.

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18
Q

Other than angiotensin II production, how else does ACE induce vasodilation?

A

It metabolises bradykinin, reducing NO-mediated vasodilation.

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19
Q

How is endothelin 1 produced?

A

Endothelium cell nucleus produces big endothelin 1. Endothelin converting enzyme, ECE, produces endothelin-1.

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20
Q

How does endothelin 1 cause contraction of VSMCs?

A

Binds to ETalpha and beta receptors on VSMC, causing PLC to convert PIP2 into IP3 causing Ca2+ influx causing MLCK upregulation…

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21
Q

How does endothelin 1 cause relaxation of VSMC?

A

It binds to ET beta on endothelial cell. Upregulates eNOS, resulting in NO production. Resultant hyperpolarisation from activation of K+ channels.

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22
Q

Is endothelin’s relaxatory or contractatory effect greater?

A

Contraction is greater.

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23
Q

How does angiotensin II increase blood pressure?

A

Increases water reabsorption and vasoconstriction.

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24
Q

How does atrial natriuretic peptide (ANP) cause vasodilation?

A

Antagonist of big endothelin 1 production.

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25
Q

What is isolated systolic hypertension?

A

Systolic BP is greater than or equal to 140mmHg, but diastolic is 90 or less.
Caused by increasing stiffness in medium/large arteries.

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26
Q

What treatment is used for hypertension?

A

ACE inhibitors (ACEi) and angiotensin receptor blockers.
Beta-blockers, which block B1 receptors on the heart, reducing contractility and CO.
Also block B1 receptors on kidneys, reducing activity of RAAS and renin excretion.
Calcium channel blockers. Major mechanism for VSMCs, minor mechanism for heart.

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27
Q

What is von Willebrand Factor (vWF)?

A

A giant adhesive plasma protein (the biggest soluble protein in the blood). Has binding sites for collagen, platelets and factor VIII. It is usually curled up in the blood, hiding the binding sites. When it binds to collagen, the flow of blood uncurls it.

28
Q

When endothelium is damaged, what is the blood exposed to?

A

Collagen and tissue factor.

29
Q

What is primary haemostasis?

A

Where VWF binds to collagen and it is uncurled, exposing its binding sites to platelets. This activates platelets. The platelets discharge, releasing more VWF, capturing more platelets. Fibrinogen holds it all together.
This is a PRIMARY HAEMOSTATIC PLUG. Sufficient for small vessels.

30
Q

What do activated platelets do?

A

They change shape, expose phospholipid and present new or activated proteins on their surface.
The bind to VWF, allowing secondary binding to collagen. Binds to other platelets by fibrinogen. They also produce ADP and TXA2 which have receptors on the platelet surface (POSITIVE FEEDBACK).

31
Q

What is secondary haemostasis (coagulation)?

A

It is the formation of a fibrin mesh. Components mostly made in liver, however FVIII and VWF are made in endothelial cells. Collagen is not required.

32
Q

What is a zymogen?

A

An inactive substance which is converted into an enzyme when activated by another enzyme.

33
Q

What triggers coagulation?

A

FVIIa binds to its cofactor, tissue factor. A TF-FVIIa complex is the trigger of coagulation.

34
Q

What are the immediate downstream consequences of a TF-FVIIa complex?

A

FIX and FX become FIXa and FXa respectively. Zymogens –> proteinases.

35
Q

What does FXa do?

A

Causes FII (prothrombin) to be converted into THROMBIN.

36
Q

What does thrombin do?

A

It activates FVIII and FV. These form complexes with FIXa and FXa respectively, as well as phospholipid from platelets and calcium ions.
It also cleaves fibrinogen to produce fibrin.

37
Q

What does tissue factor pathway inhibitor (TFPI) do?

A

It binds to TF, FVIIa and FXa, sequestering them to prevent a coagulation cascade.
Coagulation will only happen if the trigger is great enough to overcome the damping.

38
Q

Describe direct inhibition of haemostasis.

A

Antithrombin is present, a direct inhibitor of thrombin. Heparin make antithrombin more reactive and helps the 2 molecules come together.
TFPI.

39
Q

Describe indirect inhibition of haemostasis.

A

Inhibition of thrombin generation by the protein C anticoagulant system. (Protein S is a cofactor of protein C).
Thrombomodulin (TM) binds thrombin and directs it to cleave protein C into its active form. Protein C breaks down FVa and FVIIIa.

40
Q

Why can’t coagulation propagate to undamaged endothelium?

A

Free thrombin is bound to thrombomodulin and heparins.

41
Q

How is a clot broken down?

A

Plasminogen and tissue plasminogen activator (tPA) meet on fibrin. Plasminogen is converted into plasmin, which targets fibrin. It breaks down fibrin to form fibrin degradation products. Antiplasmin is a regulator.

42
Q

Define abnormal bleeding.

A

Spontaneous, out of proportion to the trauma/injury, unduly prolonged, restarts after appearing to stop.

43
Q

Describe problems with primary haemostasis.

A

Deficiency or defective collagen (steroid therapy, age, scurvy).
Von Willebrand disease (genetic deficiency).
Platelets (aspirin and other drugs. Thrombocytopenia).

44
Q

Describe problems with coagulation.

A

Haemophilia A = no FVIII.
Haemophilia B = no FIX.
Haemophilia = failure to generate enough fibrin to stabilise platelet plug. Plug falls apart. Genetic.
No thrombin burst.

45
Q

How does liver disease cause problems with coagulation?

A

Most coagulation factors are made in the liver.

46
Q

What is disseminated intravascular coagulation (DIC)?

A

Sepsis causes activation of tissue factor inside vasculature. Consumes and depletes coagulation factors and platelets. Activation of fibrinolysis depletes fibrinogen. Consequences: widespread bleeding. Deposition of fibrin in vessels causes organ failure.

47
Q

Describe defects in fibrinolysis.

A

Deficient antiplasmin (genetic). Anticoagulant excess, eg. heparin administration.

48
Q

What does a thrombus in an artery or vein cause?

A

Artery: stroke, MI, limb ischaemia.
Vein: pain and swelling.

49
Q

What is Virchow’s triad?

A

There are 3 contributory causes to thrombosis:
Blood
Vessel wall
Blood flow

50
Q

What is factor V Leiden?

A

Increase in activity (hypercoagulation) due to activated protein C resistance.

51
Q

Define thrombophilia.

A

Increased risk of thrombosis. Thrombosis at a young age. Multiple thromboses, idiopathic thrombosis. Thrombosis while anticoagulated.

52
Q

What is the equation for ejection fraction and what are the normal ranges.

A 
SV/EDV. 
55% or more is normal
45-54% mildly reduced
30-44% moderately reduced
<30% severely reduced.
53
Q

What can be used to measure SV?

A

Transthoracic echocardiogram (ultrasound).

54
Q

Describe left heart failure.

A

Ejection or filling issue. Backs up into lungs, causing congestion. Respiratory symptoms (SoB, coughing, wheezing).

55
Q

Describe right heart failure.

A

Ejection or filling issue. Increased afterload of pulmonary circulation (pulmonary hypertension). Often secondary to left heart failure.

56
Q

What is HF with reduced EF (HFrEF)?

A

Abnormal systolic function. Impaired contraction of ventricles. Weakness caused by damage or destruction of ventricular myocytes. Leads to higher diastolic pressures.

57
Q

What is HF with preserved EF (HFpEF)?

A

Abnormal diastolic function. Normal contraction of ventricle. Increased stiffness means reduced relaxation or filling. Since EDV is inherently reduced, reduced SV is masked when looking at EF.

58
Q

Give 6 causes of heart failure.

A

Valve disease (reduces filling -AV- or ejection -SL).
IHD: ischaemia of heart tissue due to narrowing of coronary vessels
MI: significant occlusion leads to death of heart muscle
Hypertension: increases afterload
Dilated cardiomyopathy: reduces generatable pressure
Hypertrophic cardiomyopathy: reduces volume + filling

59
Q

Give 3 signs of heart failure.

A

Raised jugular venous pressure (JVP).
Pitting oedema (usually in lower extremities) (indentation visible for short period).
Ascites: fluid accumulation in peritoneal cavity.

60
Q

What is B-type natriuretic peptide (BNP)?

A

It is released from ventricular myocytes in response to stretch. Causes vasodilation of microvessels, reduced aldosterone secretion, reduced sodium reabsorption and inhibits renin secretion.
Reduced ECF –> reduced pressure

61
Q

What BNP levels are indicative of heart failure?

A

> 100pg/mL (<70 years old) or >300pg/mL (>70 years old)

62
Q

What medication can be given to treat heart failure?

A

ACE inhibitors, beta blockers, diuretics.

63
Q

Explain the beneficial and pathological responses to heart failure.

A

Beneficial: NP system. Natriuretic peptides.
Pathological: RAAS –> angiotensin II. Caused by less renal perfusion (lower BP). Results in raised BP, increased sympathetic tone, more sodium and water in blood and more aldosterone.

64
Q

What are the main inflammatory cells in atherosclerosis?

A

Macrophages, derived from blood monocytes.

65
Q

What happens to LDL which migrates through endothelial barrier?

A

It’s trapped by binding to sticky matrix of carbohydrates (proteoglycans). The LDLs are then oxidised by free radicals. Oxidised LDL is then phagocytosed by macrophages, causing chronic inflammation.

66
Q

Give 2 examples of oxidative enzymes possessed by macrophages which can modify LDLs.

A

NADPH oxidase, myeloperoxidase.

67
Q

What is nuclear factor kappa B (NFkB)?

A

A transcription factor which is the master regulator of inflammation - upregulated in foam cells by oxidised LDLs.
Codes for chemokines and cytokines.
Cytokines: IL-1 upregulates VCAM-1, VCAM-1 mediates tight monocyte binding.
Chemokines draw in monocytes by chemotaxis: MCP-1 binds to CCR2 on monocytes.
Result is more monocytes, more foam cells.
POSITIVE FEEDBACK.

Life Support Systems (LSS) (6 decks)

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