Cardiac physiology

Question 1

Identify major anatomic structures of the heart and describe cardiac cycle:

Answer 1

inferior and superior vena cava - right atrium- tricuspid valve (Atrioventricular)- right ventricle - (semilunar) pulmonary valve- pulmonary artery - lungs- pulmonary veins - left atrium- mitroid valve ( AV) - left ventricle - Aortic Valve ( semilunar valve) - aorta - body

Question 2

Describe cellular physiology of cardiac cell;

Answer 2

Conductive cells contain a series of sodium ion channels that allow a normal and slow influx of sodium ions that causes the membrane potential to rise slowly from an initial value of −60 mV up to about –40
mV. The resulting movement of sodium ions creates spontaneous depolarization (or prepotential depolarization).

Action potential in cardiac contractile cells
There is a rapid depolarization, followed by a plateau phase and then repolarization. This phenomenon accounts for the long refractory periods required for the cardiac muscle cells to pump blood effectively
before they are capable of firing for a second time. These cardiac myocytes normally do not initiate their own electrical potential, although they are capable of doing so, but rather wait for an impulse to reach

Propagation of action potential
Cardiomyocytes are interconnected from end to end by intercalated disks, which contain:
-Desmosomes: which connect cardiomyocytes mechanically
-Gap junctions: which connect cardiomyocytes electrically (allow passage of ions and propagation of action potential)

Question 3

Describe pathophysiology of the heart failure and methodology to assess cardiac function in preclinical models of cardiac diseases

Answer 3

Heart failure is a structural and functional impairment of the ventricular filling or ejection of the blood, therefore the heart cannot meet the body’s oxygen demands (or can meet the demands only at the cost of increased filling pressure).
Ejection fraction (EF) is a paramenter used to measure cardiac outcome and and refers to the percent of blood pumped by the ventricle with each contraction. EF (%) = (EDV-ESV)/EDV *100
Normal EF = 50-75%
NB! Heart failure is common also with normal EF when diastolic dysfunction is the main problem leading to low stroke volume. In this category few pharmacological treatments
exists.
HF with reduced EF (HFrEF)
HF with preserved EF (HFpEF)

MI model
Tac model
cardiometabolic desease model

Question 4

Identify factors that affect cardiac function:

Answer 4

Baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and
other locations, including pulmonary vessels and the right side of the heart itself. Chemoreceptors: sensitive to changes in O2, CO2, H+ and lactic acid
With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers
decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers
increase sympathetic stimulation and decrease parasympathetic stimulation.
Factors increasing HR:
Sympathetic neurotransmitters (NE)
Thyroid hormones
Calcium
Caffeine and nicotine
Factors decreasing HR:
Electrolyte imbalance (Na+, K+, H+)

Kidney function,
other endocrine function like adrenergic

Liver function

Question 5

Reflect on mechanism of action of drugs used to treat patients with cardiovascular diseases:

Answer 5

Reflect on mechanism of action of drugs used to treat patients with cardiovascular diseases:β-Adrenergic receptor Blockers:
Reduced mortality and improved cardiac function in CVD patients even in HFrEF
Decreaded HR, conduction velocity and relaxation
Reduced cardiac remodelling
Hypertension: Decrease in blood pressure by reducing cardiac contractile force and cardiac
output.
Blood vessels: little direct effect, minor vasoconstriction due to Beta 2 AR block
New generation of Beta blockers can block alpha adrenergic signaling and promote vasorelaxation (i.e. Nebivolol, Carvedilol).

Drugs that affect cardiac function directly:
-cardiac glycosides (digitalis) or other inotropic drugs (adrenergic agonists)
-autonomic neurotransmitters (adrenaline, noradrenaline, acetyl choline)
-antiarrhytmic drugs (Ca2+ channel blockers, i.e. dihydropiridines)
Drugs that affect cardiac function indirectly:
-action on vascular system i.e. AngII or nitrate
-drugs used in HF such as diuretics or ACE inhibitors
-Calcium antagonists
-Vascular system : RAS system, Hypertension
-Atherosclerosis: dyslipidemia, Lipid lowering drugs (i.e statins)

Question 6

Review the vascular system and mechanisms of blood pressure regulation:

Answer 6

veins :Lower pressure from blood
Thin walls
Large lumen
( they have valves)

Artery : Thick walls
small lumen

Question 7

kinds of cells in the heart ?

Answer 7

Myocardial conducting cells These cells
initiate and propagate the action potential that is conducted throughout the heart to initiate contraction needed to propel the blood.
Myocardial contractile cells propagate the
electrical impulse (action potential) and by
contracting they propel blood throughout the body

Question 8

Ach and NE effects in cardiac plexus?

Answer 8

ACh= extends repolarization period (lowers the resting membrane potential )
NE= shortens repolarization period

Question 9

The conduction system of the heart?

Answer 9

The components of the cardiac conduction system include:
-sinoatrial (SA) node: located in the superior and posterior walls of the right atrium in close proximity to the orifice of the superior vena cava -atrioventricular node: located in the inferior portion of the right atrium within the
atrioventricular septum
-atrioventricular bundle (bundle of Hiss),
the atrioventricular bundle branches supply the left and right ventricles.
-Purkinje cells: from the apex of the heart toward the atrioventricular septum and the base of the heart

Question 10

calcium signaling and EC coupling:

Answer 10

Na+ goes in - L- voltage gated Ca+ channel (DHPR)- Ca+ inside- ryanodine Ca+ activated Ca+ channel in ER- Ca+ increases significantly - troponin activated no longer covered by tropomyosin -SERCA replenishes the Ca+ in SR

PLN ( phospholamban) - inhibits SERCA but stops when phosphorilated

Question 11

what affects Contractiltity of the heart and how?

Answer 11

Positive inotropic factors: increase contractiltity. Sympathetic stimulation
Drugs: Beta adrenergic agonists (e.g. isoproterenol), digitalis (digoxin)
Hormones: Thyroid hormones and glucagon
Calcium
Negative inotropic factors: decrease contractility. Parasympathetic stimulation
Hypoxia
Acidosis
Hyperkalemia
Drugs: Beta blockers, Ca2+ channel blockers

Question 12

Cardiac output?

Answer 12

Cardiac output (CO) represents the amount of blood that is propelled by each ventricle in one minute. This is calculated by multiplying the amount of blood pumped by the ventricle (Stroke volume , SV) by
the number of contraction per minute (heart rate, HR).
CO = SV * HR
Echocardiogrphy and Pressure-Volume catheter are the common methodology used in clinical and preclinical to measure end diastolic volume (EDV) and end systolic volume (ESV) which allow the measurement of stroke volume as follows:
SV = EDV-ESV

Question 13

what do you know about afterload?

Answer 13

Afterload refers to the tension that the ventricles must develop to pump blood effectively against the resistance in the vascular system.
Any condition that increases resistance requires a greater afterload to force open the semilunar valves
and pump the blood. Damage to the valves, such as stenosis, which makes them harder to open will also increase afterload. Any decrease in resistance decreases the afterload.
Increased afterload: increased vascular resistance or semilunar valve damage
Decrease afterload: decreased vascular resistance
Animal model of pressure overload: Transverse aortic constriction (TAC)

Question 14

what do you know about preload?

Answer 14

Preload refers to end diastolic volume (EDV) of the ventricle and represent the load needed to fill the ventricle with blood. The greater the preload the greater is contractility (Frank starling law). Increased preload: Increased venous return, fast filling time
Venous return is determined by activity of the skeletal muscles, blood volume, and changes in peripheral circulation. Venous return determines preload and the atrial reflex.
Decrease preload: similar to negative inotropic factors (decreased thyroid hormones, decreased Ca2+,
high or low K+, high or low Na+, hypoxia, abnormal pH balance, drugs blocking Ca2+ channels
Animal model: Cardiometabolic diseases, kidney failure, hypertension

Question 15

Hallmarks of cardiomyopathy upon cardiac injury?

Answer 15

Cardiac remodeling:
* Hypertrophy
* Fibrosis
* Inflammation
Functional impairment:
* Systolic dysfunction
(HFrEF)
* Diastolic disfunction
(HFpEF)

Question 16

Digitalis

Answer 16

closes Na+-K+pumps - Na+ goes up in the cell- Ca+ channels open -more Ca+ inside

inotropy up

Question 17

Cardiac remodeling following injury?

Answer 17

Unlike other tissues, damaged
cardiac muscle cells have extremely
limited abilities to repair themselves
or to replace dead cells via mitosis
(regeneration), as fibrotic scar is
produced by the heart to repair
injuries.
-reparative fibrosis which replaces
myocardial areas where
cardiomyocytes have undergone cell
death (i.e. ischemic events)
-reactive fibrosis which is driven by
a series of stimuli (e.g., pressure
overload, inflammation, metabolic
dysfunction, aging) and mediators
(e.g., AngII, PDGF, TGF-b,
and CTGF)
Reparative fibrosis
Reactive fibrosis
Myocardial injury
Fibroblasts Myofibroblasts* Matrifibrocytes
Tcf21 +
Periostin +
Acta 2+
α-SMA +
Phase I Phase II Phase III
Biomarkers
Lymphocytes
Macrophages
TGF-β Ang II Pro-inflammatory cytokines
PDGF CTGF
Mast cells
Pro-fibrotic
factors

Question 18

describe cardiovascular diseases.

Answer 18

U wave = heard rate lower than 60

MI causes cell damage which results in increased membrane potential of cardiomyocytes of LV wall
(ST segment up)

HF with reduced EF (HFrEF)
HF with preserved EF (HFpEF)

congestive heart failure has reduced ejection fraction EF
enlarged heart, chest conjestion, exess of fluid in the lungs, shortness of breath , swelling in legs and feet, edema

due to sympathetic activation an RAAS activation

impaired filling of the heart , contractile disfunction, ventricular dilation , cardiomyocyte slippage, Arrhythmia, pulmonary conjestion, ECM extracelular matrix turnover increased, collagen deposition increased, inflamatory cell infiltration increased , cardiomyocyte hypertrophy, E-C coupling deteriorating , cell apoptosis up but autophagy down , oxidative metabolism down

CHF following myocardial infarction

HFrEF
↓CO ↓ BP
↑ RAS
↑ Sympathetic nervous system (↑ E, NE)
↑ cardiac
remodelling
↓ β-AR density !!!!
either Lysosome – permanent reduction of b- adrenergic receptors in heart failure to compensate or back out

Question 19

Identify the mechanisms responsible for cardiac cycle and E-C coupling in cardiomyocytes

Answer 19

SA node, AV node , bundle of hiss , pukinjee cells

Action Potential: The cardiac action potential, initiated by the electrical signals, propagates along the cardiomyocyte’s sarcolemma (cell membrane).

T-Tubules and Sarcoplasmic Reticulum (SR): T-tubules are invaginations of the sarcolemma that allow the action potential to penetrate deep into the cardiomyocyte. Adjacent to the T-tubules is the SR, a specialized organelle that stores calcium ions (Ca2+).

Calcium Release: The depolarization of the T-tubules triggers the opening of voltage-gated calcium channels (L-type calcium channels) in the sarcolemma. This influx of calcium ions causes a larger release of calcium from the SR through the ryanodine receptors (RyR). This process is known as calcium-induced calcium release (CICR).

Myofilament Contraction: The released calcium ions bind to troponin-C on the myofilaments, allowing myosin and actin to interact and initiate muscle contraction. This results in the shortening of sarcomeres and the contraction of the cardiomyocyte.

Relaxation: Relaxation occurs when calcium ions are actively pumped back into the SR (by the sarcoplasmic reticulum calcium ATPase, SERCA) and expelled from the cell (by the sodium-calcium exchanger, NCX). This reduces intracellular calcium levels and allows the myofilaments to relax.

Question 20

Explain electrophysiology in cardiomyocytes .

Answer 20

Action potential in cardiac conductive cells (SA node)

slow influx of sodium ( prepotential) ( Na+) - rapid influx of Calcium (Ca+) ( depolarization) - outflux of K+Potassium ( repolarization )

action potential in contractile cells

Na+ , Ca+ closed - TMP stable at -90 mV

Fast Na+ channels open - rapid Na+ influx TMP more than 0 mV

Transient K+ channels open and K+ efflux returns TMP to 0 mV

Efflux of K+ is electricaly balanced by influx of Ca+ through the L-type Ca+ channels

Ca+ channels close but K+ rectifier channels remain open and TMP returns to -90 mV

Question 21

Identify mechanisms that regulate blood pressure.

Answer 21

Baroreceptor reflexes
Baroreceptors are stretch receptors that sense changes in arterial pressure. Located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary
vessels and the right side of the heart itself. Negative feedback loop: increased Mean arterial pressure (MAP) causes vasodilatation and bradycardia (parasympathetic
stimulation), whereas decreased MAP causes vasoconstriction and tachycardia (sympathetic stimulation)
Chemoreceptors: sensitive to changes in O2, CO2, H+ and lactic acid
A fall of PO2 and rise of PCO2 or a fall of pH increases tachycardia and rate and sympathetic tone

Question 22

Identify mechanisms that regulate hemodynamics, coagulation and thrombosis

Answer 22

coagulation pathways
Intrinsic Pathway:

Activation: The intrinsic pathway is initiated when damage to the endothelial cells lining the blood vessels exposes collagen fibers. This exposure activates factor XII (also known as Hageman factor).

Cascade: Factor XII activates factor XI, which then activates factor IX in the presence of factor VIII (also known as antihemophilic factor A). This series of activations amplifies the coagulation response.

Common Pathway: Factor IXa, along with factor VIIIa, activates factor X to form factor Xa. This is where the intrinsic pathway and extrinsic pathway converge.

Extrinsic Pathway:

Activation: The extrinsic pathway is initiated when there is tissue damage and release of tissue factor (also known as factor III or thromboplastin) outside the blood vessels. Tissue factor interacts with factor VII, forming the tissue factor-factor VIIa complex.

Cascade: The tissue factor-factor VIIa complex activates factor X directly.

Common Pathway: Factor Xa generated from the extrinsic pathway also enters the common pathway.

Common Pathway:

Prothrombin Activation: Factor Xa, along with other cofactors, activates prothrombin (factor II) to form thrombin (factor IIa). Thrombin is a central enzyme in the coagulation cascade.

Fibrin Formation: Thrombin converts soluble fibrinogen into insoluble strands of fibrin. Fibrin strands then aggregate to form a stable blood clot.

Clot Stabilization: Factor XIIIa cross-links the fibrin strands, further stabilizing the clot.

Clot Retraction: The clot contracts and retracts, pulling the edges of the damaged blood vessel closer together.

Clot Dissolution: Once tissue repair is complete, the clot must be dissolved. This is accomplished by the fibrinolytic system, which involves the conversion of plasminogen to plasmin, an enzyme that breaks down fibrin.

Anticoagulants
Paracrine factors:, prostacyclin (PG2) and NO promote vasodilation and inhibits platelet adhesion and activation
Anticoagulant factors:
TF pathway inhibitor (TFPI)
Antithombin III (AT III): heparin enhance the binding of AT III to Factor Xa to thrombin, thus inhibiting common pathway of coagulation
Trombomodulin: glycosamminoglycan produced by EC, which binds Thrombin and remove it from circulation
Protein C: together with cofactor protein S, inactivates cofactors Va and VIIa inhibiting coagulation
Anticoagulant drugs:
Heparin, low molecular weight heparin (LMWHs)
Warfarin: vitamin K inhibitor (inhibits the formation of clotting factors II VII, IX, X)

1. Plasminogen Activation:

Plasminogen is an inactive precursor of plasmin, the enzyme that breaks down fibrin. Plasminogen is present in the blood.
Plasminogen is converted into its active form, plasmin, through the action of various enzymes called plasminogen activators. Two important types of plasminogen activators are tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).
2. Generation of Plasmin:

Plasminogen activators, such as t-PA, bind to fibrin within the blood clot and convert plasminogen into plasmin specifically at the site of the clot.
Plasminogen activators are typically released by endothelial cells lining the blood vessels.
3. Action of Plasmin:

Plasmin is a proteolytic enzyme that specifically targets fibrin, the major component of blood clots.
Plasmin cleaves fibrin into smaller fragments, known as fibrin degradation products (FDPs) or fibrinogen degradation products (D-dimers). These fragments are soluble in the blood and can be cleared away more easily.
4. Fibrinolysis Inhibition:

Fibrinolysis is a tightly regulated process to prevent excessive bleeding. One of the main inhibitors of fibrinolysis is plasminogen activator inhibitor-1 (PAI-1), which inhibits the action of t-PA.
Alpha-2 antiplasmin is another inhibitor that directly inhibits plasmin activity by binding to it.
5. Clearance of Fibrin Degradation Products:

The soluble fibrin degradation products (FDPs or D-dimers) are cleared from the bloodstream by various mechanisms, including the liver and kidneys.

Primarly process to prevent blood clot formation and ensure that the blood stays liquid
Secondary process to breakdown blood clots formed following inhury, medication or other causes

Antifibrinolytic drugs (bleeding): Tranexamic acid (inhibits plasminogen activation)

Question 23

Identify pathologic factors that are associated with cardiovascular diseases.

Answer 23

Hallmarks of cardiomyopathy upon cardiac injury , Cardiac remodeling:
* Hypertrophy
* Fibrosis
* Inflammation
Functional impairment:
* Systolic dysfunction
(HFrEF)
* Diastolic disfunction
(HFpEF)

Question 24

Discuss the mechanism of action of common drugs used to treat cardiovascular diseases.

Answer 24

b- adrenergic receptor inhibitors - inotropy down

Question 25

Compare and characterize different preclinical models of cardiovascular diseases and cardiac remodeling.

Answer 25

Common Models:

Transgenic mice overexpressing specific genes (e.g., hypertrophic cardiomyopathy models).
Knockout mice lacking key cardiac proteins (e.g., cardiomyocyte-specific deletion of receptors).
Induction of myocardial infarction (MI) by surgical ligation or ischemia-reperfusion.
Pressure overload models (e.g.,transverse aortic constriction (TAC) ) to induce hypertrophy and heart failure.

Question 26

Compare and reflect on different state-of-the-art methodologies used in vitro and in vivo to assess cardiovascular function.

Answer 26

Electrocardiogram (ECG)

cardiomyocytes isolation and Ca2+ signaling measurements
Langerhoffs perfusion system for cardiomyocyte isolation, line confocal microscopy , Ca+ signaling can be measured

Question 27

Reflect on pulmonary manifestations of heart failure.

Answer 27

1. Pulmonary Edema:2. Dyspnea (Shortness of Breath):3. Cough:4. Wheezing:5. Pleural Effusion:6. Decreased Oxygen Saturation:7. Cyanosis:8. Pulmonary Hypertension:8. Pulmonary Hypertension:

Question 28

describe coronary flow in systole and diastole.

Answer 28

in systole it is low,
in diastole it rapidly increases

Question 29

how is the Metabolism of cardiomyocytes regulated?

Answer 29

In adult cardiomyocytes, mitochondria are the major cellular powerhouse and produce >95% of the cell’s
energy in the form of ATP.
Cardiac muscle undergoes aerobic respiration patterns, primarily metabolizing within mitochondria lipids
and carbohydrates to release energy in the form of ATP. Myoglobin, lipids, and glycogen are all stored within the cytoplasm and provide additional nutrient supply.
O2 consumption in myocardium:
The heart has a very high basal oxygen consumption (8-10 ml O2/min/100 g)
O2 consumption increases during cardiac activity
and wall stress leading to increased coronary
blood flow

heart is 300g approximately

Answer 30

Blockade of Potassium Channels (IKr):

Many Q-T prolonging drugs, such as certain antiarrhythmics and some medications used for other purposes, primarily block the rapid component of the delayed rectifier potassium current (IKr). IKr is responsible for the repolarization phase (phase 3) of the cardiac action potential.
By inhibiting IKr, these drugs delay the repolarization of the cardiomyocytes, prolonging the time it takes for the ventricles to return to their resting state.
This delay in repolarization can lead to a prolonged Q-T interval on the electrocardiogram (ECG).
Blockade of Calcium Channels (ICaL):

Some drugs that prolong the Q-T interval also block L-type calcium channels (ICaL). These channels are responsible for calcium entry into cardiomyocytes during the action potential’s plateau phase (phase 2).
Blocking ICaL reduces the calcium influx into cardiomyocytes, which can lead to a slower

Drugs that prolong the cardiac action potential (Q-T interval) e.g. by blocking Ca2+ channels

Paradox: may have pro-arrhtytmic effect due to formation of early afterdepolarizations (mostly in combination with other drugs or in patients with hereditary prolonged Q-T)

Question 31

Propagation of action potential?

Answer 31

Propagation of action potential
Cardiomyocytes are interconnected from end to end by intercalated disks, which contain:
-Desmosomes: which connect cardiomyocytes mechanically
-Gap junctions: which connect cardiomyocytes electrically (allow passage of ions and propagation of action potential)

Question 32

Electrocardiogram (ECG):

Answer 32

traces the direction of the electrical vectors generated by the difference of intracellular current (generated by the opening of ion channel) and extracellular current (generated by
the movement of extracellular positive charge from neighbor cell)

ECG – detect the movement of positive ions

Question 33

why the resistance in the systemic circualtion is much more than that of the pulmonary ?

Answer 33

because of the increased surface alnd length of this circulation

Question 34

Factors affecting HR:

Answer 34

-Autonomic innervation
-Hormones
-Fitness levels
-Age

Question 35

Factors affecting SV:

Answer 35

-Heart size
-Fitness levels
-Gender
-Contractility
-Duration of contractility
-Preload (EDV)
-Afterload (resistance)

Question 36

what is afterload?

Answer 36

Afterload refers to the tension that the ventricles must develop to pump blood effectively against the resistance in the vascular system.
Any condition that increases resistance requires a greater afterload to force open the semilunar valves
and pump the blood. Damage to the valves, such as stenosis, which makes them harder to open will also increase afterload. Any decrease in resistance decreases the afterload.
Increased afterload: increased vascular resistance or semilunar valve damage
Decrease afterload: decreased vascular resistance
Animal model of pressure overload: Transverse aortic constriction (TAC)

Question 37

what is preload?

Answer 37

Preload refers to end diastolic volume (EDV) of the ventricle and represent the load needed to fill the ventricle with blood. In healthy individual the greater the preload the greater is contractility (Frank starling law).
Increased preload: Increased venous return, fast filling time
Venous return is determined by activity of the skeletal muscles, blood volume, and changes in peripheral circulation. Venous return determines preload and the atrial reflex.
Decrease preload: similar to negative inotropic factors (decreased thyroid hormones, decreased Ca2+,
high or low K+, high or low Na+, hypoxia, abnormal pH balance, drugs blocking Ca2+ channels
Animal model: Cardiometabolic diseases, kidney failure, hypertension

Question 38

what is Starling law in healthy and failing hearts?

Answer 38

in the case of a failing heart

Flattened curve:
More venous return and filling pressure is required to increase contractility and SV
Increased fluid retention

Question 39

what do b- adrenergic receptor blockers do to the heart ?

Answer 39

inotropy down, Serca function down , all other receptors like Ryr2 and DHPR function down - ISC Ca+ down - conduction velocity and heart rate down

Question 40

what do you know about blood vessels ?

Answer 40

Arteries and veins transport blood in two distinct circuits: the systemic circuit and the pulmonary
circuit. Systemic arteries provide blood rich in oxygen to the body’s tissues. The blood returned to the heart through systemic veins has less
oxygen.
In the pulmonary circuit, arteries carry blood low in oxygen exclusively to the lungs for gas
exchange. Pulmonary veins then return freshly
oxygenated blood from the lungs to the heart to be pumped back out into systemic circulation.

arteries :Thick walls
small lumen

veins:Lower pressure from blood
Thin walls
Large lumen

Question 41

Hemorragic shock : what is it and how to stop it ?

Answer 41

Hypovolemic shock:
* SAP : lower than 90 and MAP is lower than 70 mm Hg
* Subject in moist pale skin with rapid and weak pulse
Compensatory response:
* Baroreceptor activation (enhanced sympathetic and decreases parasympathetic)
* Chemoreceptors activation: vasoconstriction and tachicardia
* Increased adrenalin and noradrenalin release from adrenal medulla
* Increase of HR leads to increased CO only if venous return also improves
Hemostasis (hemorrage prevention) can be achieved through:
* Vasoconstriction
* Increased Tissue pressure
* Formation of platelets plug (capillary bleeding)
* Coagulation of clot formation

Question 42

What do you know about Atherosclerosis.

Answer 42

Blood vessels transport blood throughout the body to provide O2, nutrients and other substances that are exchanged with body cells.
Blood vessel occlusion (e.g. myocardial infarct) results in tissue injury following ischemia/hypoxia.
Animal model: transgenic APO E KO mice

Question 43

Atherosclerotic lesion progression :

Answer 43

1.Fatty streak formation
2. stable plaque / fibroatheroma
3. Vulnerable plaque / Thrombus formation

Question 44

Anticoagulants

Answer 44

Paracrine factors:, prostacyclin (PG2) and NO promote vasodilation and inhibits platelet adhesion and activation
Anticoagulant factors:
TF pathway inhibitor (TFPI)
Antithombin III (AT III): heparin enhance the binding of AT III to Factor Xa to thrombin, thus inhibiting common pathway of coagulation
Trombomodulin: glycosamminoglycan produced by EC, which binds Thrombin and remove it from circulation
Protein C: together with cofactor protein S, inactivates cofactors Va and VIIa inhibiting coagulation
Anticoagulant drugs:
Heparin, low molecular weight heparin (LMWHs)
Warfarin: vitamin K inhibitor (inhibits the formation of clotting factors II VII, IX, X)

Question 45

Platelet adhesion and activation

Answer 45

Patelets mantain the integrity of the circulation by healing damaged blood vessels
* Adhesion following vascular damage
* Shape change (from smooth discs to spiny sphere)
* Secretion of granule contents (platelets agonists i.e. ADP, PDGF)
* Biosynthesis of mediators (Thromboxane A2)
* Aggregation
* Ehance platelets activation by exposure of acidic phospholipid (thrombin formation)
Antiplatelets drugs
* Aspirin: inhibits COX and reduces TXA2
* Clopidogrel: inhibits ADP induced aggregation

Question 46

Nitric Oxide (NO) signaling in cardiovascular tissues.

Answer 46

Nitric Oxide synthase (NOS) produces NO from arginine in endothelial cells. NO activates
the soluble guanylyl cyclase in VSMC causing vasodilation.
Dietary nitrate: external source of NO

NO is produced by ROS from arginine to citrulline to NO when O2 is present and from NO-3 to NO-2 to NO without oxigen

Question 47

how do we get NO from food ?

Answer 47

1. Ingestion of green leafy
   vegetables
   provides
   dietary nitrate to the body
2. Nitrate is
   quickly
   absorbed in the small intestine, and enters the bloodstream
3. Nitrate is
   concentrate from the blood by the salivary glands
   and enters the oral cavity, and reduced to Nitrite by commensal bacteria
4. Nitrite is further reduced to NO in the acid environment of the stomach or by
   hemeproteins
   (myoglobin, hemoglobin) nitrite-reductases
   (under hypoxia)
5. NO from dietary
   nitrate and from NO
   synthase* has beneficial cardiometabolic effect