mmh study guide

8/8/2019 MMH Study Guide

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MMH Study Guide

1Lecture 1: General Concepts

y Anatomy-o Theheart is made up of two sides, a right side and a left side which do not communicate

directly, except abnormally in some forms of congenital heart disease.

o Each side is made of an atrium and a ventricle separated by atrio-ventricular valvesnamed tricuspid on the right side and mitral on the left side.

o Each atrium receives blood from veins, the venae cavae on the right side and thepulmonary veins on the left side, and ejects this blood into the corresponding ventricle.

o Each ventricleejects blood into an artery, the pulmonary artery on the right side and theaorta on the left side. Reverse flow from the artery is prevented by a valve between the

ventricle and the artery.

o The first branches of the aorta are the coronary arteries, which provide theheart withblood supply.

y Structure-o Myocardium- cardiac muscle made of cardiac myocytes; major part of thehearto Endocardium- Endothelial layer separating the myocardium from the bloodo Pericardium- protective sheet surrounding the myocardium; anti-chaffingo Coronary arteries- arteries from the aorta supplying blood to the myocardium; issue:

cholesterol buildup can lead to a heart attack.

o Capillaries- microvessels between the cardiac myocyteso Subendocardium- deep myocardial layers, adjacent to theendocardium; more abstracto Subepicardium- superficial myocardial layers, adjacent to the pericardium; more

abstract


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2y Pathophysiological importance of the structures-

o Myocardium- Cardiomyopathy: describes any form of dysfunctional myocardium (ischemic,

hypertensive, congenital, valvular). Any impairment in the myocardial

contraction results in altered cardiac function. Insufficient cardiac function is

defined as heart failure.

o Pericardium- Pericarditis: Inflammation of the pericardium, usually of viral origin. Induces

strong pain that mimics a heart attack. Because the pericardium is fibrous and

rigid, any effusion will compress the myocardium and impair its function.

y Pump function of theheart- Theheart ejects blood from the thick-walled left ventricle to bepropelled through the body, ultimately to reach theperipheral circulation where oxygen is

removed to nourish the various organs and tissues.The deoxygenated venous blood flows back

to the right side of theheart to beejected from the right ventricle to the lungs, where it is

oxygenated before it is directed toward the left atrium and ventricle.

y Diastole- The ventricle relaxes; Passive system (image on left)y Systole- The ventricle contracts (image on right)


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3y Cardiac myocytes are physically bound by intercalated disks

o Gapjunctions: tight coupling between myocytes by the connexons for easy passage ofsmall molecules and current

o Desmosomes: protein complex that is linked to the sarcomeres by desmin, whichpromotes force transfer.

y Coordinated contraction of the cardiac muscle- when one myocite contracts, they all do.Thehearts eliptical sphere shape makes it easier to eject blood.

y Systemic vasculatureo Conductance vessels- large arteries with low resistance, used as conduits to carry

oxygenated blood towards the organs.Ex- the aorta, femoral, carotid, etc.

o Resistance vessels- Arterioles with thick muscular walls and high resistance, directingthe blood flow to the organs that need oxygen.Constitute the peripheral vascular

resistance. Important because generates pressure and you do not need blood

everywhere all the time.

o Capillaries- exchange vessels made of an endothelial layer without muscular cells, whereoxygen leaves the blood and enters the tissues by diffusion.

o eins- low-pressure, large-capacitance system containing most of the blood volume,constitute the venous capacitance system, returning the blood flow to the right side of

theheart.

y Principle of conductance vesselso Pressure in conductor (aorta) must push blood even when LV is at a low pressure. If

diastole gets higher, elastin/collagen system is not working.

y Principle of resistance vessels- using physics principles, the blood vessels constrict and dilate in amanner so as to haveeither series or parallel resistance, affecting blood flow. (series being

R1+R2+R3 while parallel being


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4y Blood pressure drops in resistance vessels-

y The coronary arteries-The coronary arteries are the leading cause ofheart diseaseo The LV receives blood from the left coronary artery, that divides in two main branches

The left anterior descending artery (LAD) supplies most of the anterior part ofthe myocardium

The circumflex artery supplies the lateral and posterior part.

o The right ventricle receives blood from the right coronary arteryo The posterior descending artery can originate from either the right or left coronary

artery right or left dominant.


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5y The sarcomere is the fundamental contractive unit of the cardiac myocyte; actin over myosin

o It is limited on each side by the Z line, on which actin filaments are attached.o Myosin filaments originate from the middle of the sarcomere, orM line, but do not

attach directly to the Z line.

o The A band represents the zone of overlap between actin and myosino The I band represents the zone which contains only actin filamentso The H band represents the zone which contains only myosin filaments.o Myosin filaments are indirectly connected to the Z line by the macromoleculeTitin,

which limits the maximal stretch of the sarcomere the whole cardiac myocyte.

y Other aspects of the sarcomere-o Tropomodulin- caps actin filamento Nebulette- attaches actin filament to Z lineo MyBPC- attaches myosin to Titin

y The morphological aspect of the sarcomere depends on the contractile stateo Contraction is passive while relaxation requires energy and ATP

y Cardiac conduction systemo TheSino-Atrial Node is the natural pace-maker of thehearto From this node, the current diffuses through both atriao The current cannot diffuse freely to the ventricles, atria and ventricles are separated

by fibrous tissue.

o The only point ofelectrical transmission is the atrio-ventricular node, which slows downthe current to avoid simultaneous contraction of atria and ventricles.

o The AV node distributes the current to the His bundle, which separates in one right andtwo left branches.

o The bundles separate in multiplePurkinje fibers that distribute the currentsimultaneously to the different parts of the myocardium.


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6Lecture 2: Physiology of contraction and relaxation

y There are seven phases of contraction and relaxationo Atrial contractiono Isovolumic contractiono Maximal ejectiono Reduced ejection/start of relaxationo Isovolumic relaxationo Rapid fillingo Slow filling

y Description of processA. The atrium contracts to finish the left ventricular fillingB. The left ventricle starts contracting, which rapidly closes the atrio-ventricular valve.

The contraction is isovolumic because the aortic or pulmonary valve is still closed

C. The pressure in the ventricle becomes superior to that in the aorta or thepulmonary artery, and therefore the corresponding valve opens.Pressure keeps

rising in the ventricle while it ejects blood.

D. The ventricle starts to relax while it keeps ejecting. Its pressure gradually decreasesbut it still superior to that in the aorta or the pulmonary artery.

E. The pressure in the ventricle becomes inferior to that in the aorta or pulmonaryartery, and the corresponding valve closes, Pressure inside the ventricle rapidly

drops but remains higher than that in the atrium.

F. Pressure in the ventricle becomes smaller than that in the atrium, and the atrio-ventricular valve spontaneously opens. Because of the atrio-ventricular pressure

gradient, the ventricle rapidly fills.

G. The atrio-ventricular gradient fades because pressure starts to rise in the fillingventricle, while it decreases in theemptying


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7

y Cardiac Soundso S1- the mitral valve (M1) and tricuspid valve (T1) closeo S2- The aortic valve (A2) and the pulmonary valve (P2) closeo The ventricle rapidly fills (rushing blood can be physiolocial when cardiac output is

increased)

o S4- Late filling by the atrial contraction (when ventricular relaxation is decreased,therefore this sound is abnormal)

o *the systole is between S1 and S2, the diastole is between S2 and S1.y Determinants of cardiac function- The main function of the myocardium is to maintain the

cardiac output.The cardiac output is the product ofheart ratex stroke volume.

o Theheart rate is determined by the firing rate of the sino-atrial node. It can beaccelerated by chatecholamines or slowed down by acetylcholine through

neurohumoral regulation.

o The stroke volume is determined by changes in pressure and volume in ventricularcavity.


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8y Determinants of cardiac output:CO = HR xSV (Cardiac output = heart ratex stroke volume)

o Heart rate- firing rate of the sino-atrial node pace-maker; can be adapted by changes inthe firing frequency (chronotropy)

It is obvious that an increased heart rate will increase the cardiac output for aconstant stroke volume

In addition, an increase in heart rate induces an increase in force developmentdue to an accumulation of cytosolic Ca

2+.This property is called the Bowditch

phenomenon. Basically beating faster = beating harder because of increased

calcium.

o Stroke volume- (end-diatolic volume end-systolic volume); can be adapted by changesin pressures (preload and afterload) and volumes (inotropy and lusitropy)

Pressure is mainly determined by:y The preload or the pressure with which theheart is filled.y The afterload or the pressure against which theheart ejects

*These pressure parameters are independent of the myocardium

Volume is mainly determined by:y The inotropy or contractile capacity of the myocardiumy The lusitropy or relaxation capacity of the myocardium

y Physiological pressure/volume relation


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9y Preload and afterload areessentially independent of the myocardial contractility.They are

controlled by the vasculature. However, a poor contractile performance (such as heart failure)

will modify the loading conditions as a consequence.

o Preload represents the pressure with which theheart is filled. Increased preload resultsin increased developed pressure and also stretches the sarcomeres leading to increased

contractile force.Thus, increased preload will increase the stroke volume.

o Afterload represents the pressure against which theheart ejects. Increasing theafterload is generally progressive (iehypertension) so theheart tends to compensate for

a long period of time, but eventually increasing the afterload will decrease the stroke

volume by not allowing enough blood to escape theheart.


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10y Inotropy and Lusitrope are mainly controlled by the force of actin-myosin interaction in the

sarcomere.The amplitude of this contractile force is modulated by calcium. However, external

factors such as fibrosis after myocardial infarction can modify the capacity of theheart to eject

or relax.

o Inotropy- inotropy corresponds to the modulation of the cardiac ability to contract inorder to eject more or less blood during systole (contractibility)

o Increased inotropy is thehearts ability to beat stronger, thus, there is a smaller endsystolic volume and a lower heart rate (ex- exercise).Negative intropy shows that the

heart cannot pump as hard, thus it must pump more times to make up for it, putting

even more stress on theheart (ex- heart disease).

oLusitropy corresponds to modulation of the cardiac ability to relax in order to receivemore or less blood during diastole (relaxibility). Increased lusitropy is a positive thing,

as the capacity of theheart to relax is greater and theheart thus is easier to fill.Thus,

theheart has the same pressure, it isjust has a bigger capacity of theheart.Negative

lusitropy is bad, decreasing thehearts ability to pump as hard and thus decreasing

stroke volume.


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11y The volume/pressure relationship determines the cardiac work

o External work- good work; work needed to propel the blood into the vasculature.Thisis mostly stroke work needed for ejection, not kinetic work.Catecholamine stimulation

increases external work.

o Internal work- keep at minimum as it is considered bad work; work done inside thewall to contract the muscle. Heart failure increases internal work.

y Catecholamineso Epinephrine (adrenaline)-

Released by the adrenal medulla (systemic) Binds best to adrenergic receptors, resulting in increased cardiac output and

decreased arterial resistance.

Contains a methyl group that is attached to the nitrogeno Norepinephrine (noradrenaline)-

Released by the stellate ganglion (paracrine) Binds best to adrenergic receptors, resulting in increased arterial resistance Contains a hydrogen atom attached to the nitrogen (one less methyl than ep).

y Acetylcholineo Released by the vagal nerveo Binds to muscarinic receptorso Decreases heart rate (negative chronotrypy) and decreases AV conduction (negative

dromotropy)

o Decreases inotropyy Adrenergic receptors

o 1- smooth muscle cell contraction- vasoconstriction; stimulation of cell growth/prolif.o 2- negative feed-back inhibition of sympathetic drive in CNSo 1- positive inotropy, lusitropy, and chronotropy.o 2- positive inotropy and chronotropy, vasodialation/relaxation


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MMH Study Guide

12Lecture 3: Electrophysiology

y Cell polarizationo The membrane potential is an electrical potential resulting from a difference in charge

distribution on both sides of the plasma membrane.

o The cell is rich in K+ and poor in Na+, and the opposite is true in theextracellular area.Through theNa+/K+ pump, the cell extrudes Na+ and accumulates K+.

o As K+ tends to leave the cell spontaneously easily and Na+ tends to enter the cell slowlyspontaneously, there are more positive charges outside than inside the cell, causing the

plasma membrane to develop a membrane potential.

o The cardiac myocitehas a resting potential of -85 mVy K+, Na+, and Ca2+ balance of the cell at rest

o K+ and Na+ determine the membrane potential whileCa2+ determines cell contraction.o At rest, the cell is rich in K+ and poor in Na+, with the opposite being true outside of the

cell.

o At rest, the plasma membrane is impermeable to Ca2+.y The action potential is a sequence of depolarization-repolarizaion that leads to cardiac cell

contraction. It is controlled by the influx or efflux of specific ions during a specific period of time.

The action potential is transmitted from one cell to the next by a domino effect. It has five

phases:

o Phase 0- influx ofNa+ (INa); induces membrane depolarizationo Phase 1- Efflux of K+ (Ito); Limits theNa+ spikeo Phase 2- Influx ofCa2+ (ICa); Ca2+enters the cell to trigger theCa2+-induced Ca2+ releaseo Phase 3- Efflux of K+ (Ik); Repolarization startso Phase4- Restoration of the resting potential through theNa+/K+ pump


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13y Variations in the action potential

o In the conduction system, the action potential shows a sharp Phase 1 and a short Phase2 because speed of transmission matters.

o In the cardiomyocytes, the action potential shows a small Phase 1 and a prolongedPhase 2 becauseCa

2+ influx matters

o Ito dictates the difference between the action potentials; the more Ito channels, the morepotential channels

y Ion channels must, in order to work properly, have two characteristics- spedificity and gating.Their activity can be stimulated by phosphorylation (a mechanism particularly important for the

Ca2+ channel) and by ligands (a mechanism particularly important for the K+ channel).The

channel alternates between rest, activation, and inactivation.The current intensity is

determined by the number of open channels.

o General structure of an ion channel: Selectivity filter: determines the ion that crosses the channel Activation gate: opens to start the current Inactivation gate: closes to interrupt the current Voltage sensor: determines at which potential the channel opens and closes


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14y Ca2+ channel activity can be modulated by phosphorylation.The stimulation of the -adrenergic

receptors by catecholamines increases the intropy by increasing theCa2+

current through the L-

typeCa2+

channel (L for long-acting), thereby increasing theCa2+

-induced Ca2+

release.

y K+ channel activity can be modulated by ligand binding.Stimulation of the muscarinic receptorby acetylcholine decreases the chronotropy by increasing the K+ current, thereby

hyperpolarizing the membrane.

y Cardiac pace-makero The initiation of the action potential lies in the automatic pace-maker activity of theSA

node, in which there is spontaneous depolarization.The whole function of theSA node

relies on this automaticity, which is translated into a repetitive and spontaneous firing

of action potentials.

o The automaticity relies on specific cells in theSA node, the pacemaker cells or P cells.y Currents in theSA node- The shape of the action potential in theSA node is totally different

from the shape described in the conduction system and in myocytes because the ion channels

expressed in theP cells are different from other cardiac cells.

o ICa is an inward Ca2+ current depolarizing theP cells through a T-typeCa2+ channel (T fortransient).Catecholamines through the -adrenergic receptor accelerate the

depolarization of ICa and therefore accelerateheart rate (positive chronotropy)

o IK is a rectifier potassium current that repolarizes the cells after the ICa. Acetylcholinethrough the muscarinic receptor increases the repolarization of IK and therefore

decreases heart rate (negative chronotropy).

y If(funny current) is an inward sodium current specific of theSA node that destabilizes theresting potential and therefore underlies the automaticity of theP cells.

y Theelectrocardiogram- The cardiac electrical impulse is generated in theSA node, rapidlyconducted through the atria to the AV node, where it undergoes filtration and delay.Thenfollows another phase of rapid conduction through the His bundle and its branches, finally

leading to excitation-contraction coupling in the ventricular myocyte.The whole sequence is

monitored externally by theelectrocardiogram.

o If the current is going to theelectrode, the wave will be positive.o If the current is going away from theelectrode, the wave will be negative.o The size of the wave is proportional to the intensity of the current.


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15y General profile of an EKG

o P wave- atrial depolarizationo QRS complex- Depolarization of both ventricleso T wave- Ventricular repolarizationo PR interval- slow-down in the AV nodeo ST interval Isoelectric phase 2 of the action potential

y Generation of theEKG wave

y The shape of the waves depends on the localization of theelectrodeso The intensity of the current is proportional to the ventricular mass.o V1 to V3 see mainly the right ventricle, the complex is globally negative.o V4 to V6 see mainly the left ventricle, the complex is globally positive.o Therefore, the shape in V1 to V6 will vary in case of right or left ventricular hypertrophy.


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16y Arrhythmias

o Sinus tachycardia- SA node firing at more than 100 times per minute (positivechronotropy).This can be caused by exercise, stress, and most forms ofheart disease

(especially heart failure).The only way you can detect it is if you know the speed of the

paper.

o Sinus bradycardia- SA node firing less than 60 times per minute (negative chronotropy).This can be seen in athletes hearts, sleep, or during vagal stimulation (cause of

syncope).

o SA block- absence of firing from theSA node. A whole depolarization is missing.This canbe caused by fibrosis and by aging. It can be temporary (one beat is missing) or

complete (no firing at all), which is followed by a relay from the AV node.

o Atrial fibrillation- High-frequency firing from the atrium, which prevents normal atrialcontraction and therefore impairs ventricular filling. Ventricular beat is irregular.Caused

by atrial dilation in many forms ofheart disease and aging. Accumulation of blood in the

non-contracting atrium is a cause of thrombosis (coagulation) and embolism

(dissemination of the blood clot in the circulation).

o AV block- Conduction defect in the AV node with downstream relay to conduct theventricular impulse.The atrium remains under control of theSA node.Can be congenital

or caused by ischemia. A resynchronization of atria and ventricle is needed.


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17y Arrhythmias are not necessarily abnormal

o The Hering-Breuer reflex- the cardiac rhythm is irregular during the respiratory cycleo Exercise-induced tachycardia- catecholaminergic stimulation can increase theheart rate

to a maximum rate: 220-age

o Vagal bradycardia- cholinergic stimulation in the athletes heart can decrease theheartrate under 60.

y The Hering-Breuer Reflex- During inspiration, the venous return is impaired by the inflation ofthe lungs, which decreases the ventricular stroke volume (SV).TO maintain the cardiac output

(CO), theheart rate (HR) must increase becauseCO = SV x HR.Therefore, lung inflation creates a

reflex that decreases acetylcholine discharge from the vagal nerve, thereby inducing a relative

increase in adrenergic activity and a resulting increase in heart rate.


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18Lecture 4: Calcium and contraction

y The principle ofCa2+-induced Ca2+ releaseo The action potential is propagated by a depolarization of the plasma membrane, which

opens theCa2+

channel and creates an inward Ca2+

current (ICa)

o This Ca2+ channel is particularly abundant on theT tubule, an intracellular extension ofthe plasma membrane.The intracellular part of it is wrapped by theextremity of the

sarcoplasmic reticulum.

o The cisterna contains a Ca2+ binding site that binds theCa2+ ions crossing theCa2+ L-typechannel in theT tubules

o Stimulation of theCa2+ binding site triggers the release ofCa2+ from the sarcoplasmicreticulum through a specific channel called the ryanodine receptor which initiates

cardiac contraction.

o Cardiac relaxation is initiated by a reuptake ofCa2+ in the sarcoplasmic reticulum bySERCA.

y Mechanisms ofCa2+ influx in the cardiac cytosolo TheDHP receptoro The ryanodine receptor

*these two channels are called receptors because they bind specific drugs

y TheCa2+-induced Ca2+ release is coupled by theT tubules.There are three advantages of this:o Excitation-contraction coupling- The t tubules increase the surface of the plasma

membrane by 30%, which increases the density ofDHP receptors and therefore the

speed ofexcitation-contraction coupling.

o Receptor coupling- The tight coupling between DHP receptors on theT tubule andryanodine receptors on the sarcoplasmic reticulum optimizes the coupling between

C

a2+ entry (through theD

HP

receptor) andC

a2+ release (through the ryanodinereceptor)

o SR coupling- the deep invaginations of theT tubule inside the cell allows a synchronizedrelease ofCa2+ from theentire sarcoplasmic reticulum compartment.


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19y Mechanisms ofCa2+ reuptake

o The sarcoplasmic reticulum Ca2+ ATPase (SERCA)- pumps Ca2+ back inside thesarcoplasmic reticulum which represents about 90% of the reuptake mechanisms.This

pump requires ATP to overcome theCa2+ gradient.

o The sarcolemmal Na+/Ca2+exchanger- Pumps Ca2+ out of the cell through an exchangewithNa+, which represents about 5% of the reuptake mechanisms.Theexchanger

doesnt use ATP becauseNa+

follows its spontaneous electrochemical gradient which

provides theenergy, but thereafter Na+has to be pumped back outside the cell by the

Na+/K

+-ATPase, which requires ATP.

o The mitochondrial Na+/Ca2+exchanger- pumps Ca2+ in the mitochondria through anexchange withNa

+, which represents about 4% of the reuptake mechanisms.

o The sarcolemmal Ca2+ ATPase- pumps Ca2+ back in theextracellular area whichrepresents about 1% of the reuptake mechanisms.This pump requires ATP to overcome

theCa2+ gradient.

y Structure of the ryanodine receptoro The foot links the sarcoplasmic membrane to theT tubuleo The transmembrane subunit is theCa2+ channel in itselfo This channel is activated by caffeine whichempties theSR ofCa2+ and therefore

increases contraction strength.

o Opening of the channel results from an alignment of two subunits.y Structure ofSERCA- TheCa2+ reuptake in theSR is done by SERCA

o It exists in two main isoforms: SERCA 1- in fast-twitch skeletal muscles SERCA 2a- in heart and slow-twitch skeletal muscles SERCA 2b- in smooth muscle cells

y Role of phospholambano The reuptake by SERCA is modulated by phospholamban.Phospholamban is an inhibitor

ofSERCA. Inhibition is relieved by phosphorylation of the pentamer, which thereby

activates SERCA activity to fasten relaxation.This is one of the molecular mechanisms of

positive lusitropy.

o Phospholamban is phosphorylated by: Protein kinase A upon -adrenergic stimulation (explains the lusitropic effect of

catecholamines)

Calcium-calmodulin protein kinase, activated when cytosolic [Ca2+] is increased.y

Role of calsequestrin- calsequestrin is a highly-charged storage protein mainly expressed in thecisterna of the sarcoplasmic reticulum. Its increased expression increases the pool of releasable

Ca2+.

y Structure of contractile proteinso Actin filaments slide to shorten the sarcomere.o Myosin is the molecular motor moving actin.


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20y Myosin structure - Each myosin molecule is made of two heavy chains and four light chains

o Theheavy chains areembedded in the body of the filament at oneend and form theheads that emerge from the filament at the other end in a spiral fashion.Thehead

contains the myosin ATPase responsible for actin-myosin dissociation.Trypsin digestion

separates theheavy chains in light and heavy meromyosin.

o The light chains are two different types.MLC-1 or ELC participates in the interactionwith actin and is indispensable for the protein function.MLC-2 or RLC is a regulatory

subunit that controls the intensity of contraction.There are two ofeachMLC-1 and

MLC-2 per myosin molecule.

y Actin structureo Actin polymerizes into a filament which represent sthethin filament of the sarcomere

attached to the Z line.

o In the sarcomere, two actin filaments are twisted around each other like two strings ofbeads that follow the spiral of myosin heads.

o Theextremity of the actin filament is capped by tropomodulin, which prevents excessivegrowth of actin.

y Structure of tropomyosin- tropomyosin is a twisting backbone supporting the actin filaments.o Tropomysoin is made of two peptide chains bound in a coiled-coil structure.o In the sarcomere, tropomyosin inhibits the actin-myosin interaction.Through

cooperative interaction with the troponins, this inhibition is relieved when Ca2+

increases, which allows Ca2+

to activate muscle contraction.

y Structure of troponinso Tropinin C (C=calcium) is a dumbbell-shaped protein which allows TnC to recognize a

rise in Ca2+ as a signal to activate muscle contraction.

o Troponin I (I=inhibitory) is an inhibitor of actin-myosin interaction that inducescooperative interactions in the thin filament to reduceCa2+ affinity for TnC, and

thereby initiates relaxation.

o Troponin T (T=Tropomyosin) glues the whole troponin complex together and links it totropomyosin. Upon TnC stimulation, TnT moves the tropomyosin filament to allow

actin-myosin interaction.

y The crossbridge cycleo The cycle is initiated by the binding to TnC of theCa2+ released from the sarcoplasmic

reticulum and is followed by four steps:

The myosin head attaches to actin

The power stroke bends the myosin head and actin slides ATP binds to the myosin head, which is thereby released from actin ATP is hydrolyzed, whichenergizes the myosin head to bind actin


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21y Molecular basis of the crossbridge cycle

o In diastole, ATP binds to myosin, which cannot interact with actin becausetropomyosinis in the way and because ATP induces a weak actin-myosin binding. ATP is

rapidly hydrolyzed into ADP + Pi by the myosin ATPase, whichextends the myosin head.

o Upon Ca2+stimulation, the troponincomplex moves tropomyosin.The myosin head isstill extended.The ADP resulting from ATPhydrolysis creates a strong actin-myosin

binding, and Pi is released.

o De-energized myosin bends its head to come back to a rest position and thereby createsthe power stroke that slides the actin filament (rigor state, or maximal sliding).The

change in conformation extrudes ADP.

o ATP binds to the myosin head, restores a weak actin-myosin bond and re-extends themyosin head. ATP is rapidly hydrolyzed by the myosin ATPase. A new cycle can be

repeated ifTnCstill binds Ca2+. IfCa

2+reuptake by SERCA has begun, tropomyosincomes

back to original position and the actin-myosin complex remains in a relaxed state

y Integrated view ofCa2+ metabolism- Ca2+ is both the trigger and theeffector of contraction.o Ca2+ metabolism is largely controlled by ATP, which maintains cardiac cell relaxation.o Modification ofCa2+metabolism by catecholamines explains their positive inotropic,

lusitropic, and chronotropic effects.

y Theeffects of catecholamines on Ca2+ metabolismo Positive chronotropy- activates Ica by phosphorylating theT-typeCa2+ channel in theSA

node, which increases the firing rate.

o Positive inotropy- activates Ica by phosphorylating the L-typeCa2+ channel in theTtubules, which increases the release ofCa

2+from the ryanodine receptor and activates

MLS-2 by phosphorylation which stimulates the myosin power stroke.

o Positive lusitropy- activates actin-myosin dissociation by phosphorylation ofTnl andactivates Ca

2+reuptake by phosphorylation of phospholamban.


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22Lecture 5: Metabolism

y Cardiac metabolism is determined by workload, substrates, and oxygeno Workload- due to its constant contractile activity, theheart requires a considerable

amount of ATP to feed the ATPase activities of the myosin head, SERCA and theNa+/K

+

pump.

o Substrates- to sustain its energy supply, theheart is a metabolic omnivore, using everysubstrate that provides ATP.Substrates interact witheach other to coordinate the

metabolic activity.The two main substrates for theheart are fatty acids in fasting

conditions and glucose in fed condition.Theheart also uses lactate during exercise.

o Oxygen- a sufficient supply of ATP can be achieved only through oxidativephosphorylation, which requires an aerobic metabolism. In conditions of oxygen

deprivation (ischemia), theheart must shift toward an anaerobic metabolism, which

provides far less ATP per mole of substrate.

y Glycolysis is the only source of anaerobic ATP; the regulatory steps of glycolysis are:o Glucose uptake through specific transporters (GLUT)o Glocose phosphorylation throughhexokinase (HK)o Hexose phosphate phosphorylation through phosphofructokinase (PFK-1)o Triose phosphate oxidation through glyceraldehyde-3-phosphate dehydrogenase

(GAPDH).

o Pyruvate oxidation through pyruvate dehydrogenase (PDH)o Glycolysis can be fed from glycogen which is regulated by glycogen phosphorylase.

y Phosphofructo-1-kinase catalyzes the transformation of fructo 6-phosphate into fructose 1,6-biphosphate which marks the first irreversible step of glycolysis in itself. It is the main regulatory

step in the glycolytic pathway and is a sensor of glucose needs as a function of oxygen

availability, workload, and substrate availability.o It is regulated by theenergetic status: inhibited by ATP and activated by AMP.o It is activated by fructose 2,6 biphosphate upon -adrenergic stimulation or insulin

stimulation

o It is inhibited by citrate when fatty acids or lactate are oxidized.y Glycogen metabolism- glycogen is the cardiac storage form of glucose

o Glycogen synthesis stimulated by alternative substrates and breakdown is stimulated bycatecholamines.

o The main roles of glycogen are an emergency fuel for ATP production in conditions ofsevere oxygen deprivation and a rapidly mobilized source ofenergy upon adrenergic

stimulation.o The metabolism is controlled by two enzymes: glycogen synthase (synthesis) and

glycogen phosphorylase (breakdown).


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23y Effects of fatty acid on glucose metabolism

y Fatty acid metabolism- Fatty acids are the main source ofenergy for thehearto Most abundant fatty acids are oleic acid and palmitic acid.o Need to be activated as fatty acyty-CoA to be releasef from theFABP, which requires

ATP and are transferred to the mitochondria.

o Transfer into the mitochondria is performed through a specific carrier, CPT, which is theregulated step of fatty acid metabolism.

o Inside the mitochondria, fatty acids are degraded through the -oxidation into acetyl-CoA units that enter the tricarboxylic acid (Krebs) cycle.

y ATP production relies on two basic mechanisms:o Proton production, which is essentially made by the tricarboxylic acid cycle and the -

oxidation and, in smaller amounts, by GAPDH and lactate dehydrogenase.

o Proton accumulation and transfer through the mitochondrial membrane.o As the Krebs cycle is the common mechanism and is cyclical, its activity can be rapidly

adapted to the ATP demand.


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24y Overview of the Krebs Cycle

o 2 carbons are lost that generateCO2o 8 protons are produced that generate 11 ATP through oxidative phosphorylationo 1 ATP is produced from GTPo It is a cycle, so there is no accumulation ofend-producto It can be accelerated by Ca2+ whichenters the mitochondria through theCa2+/Na+

exchanger.

y Protons generated by glycolysis in the cytosol are transferred inside the mitochondria by themalate-aspartate shuttle.

y All the proteins of theelectron transport chain are organized in four multi-protein complexesthat cross the inner mitochondrial membrane to extrude protons from one side to the other. It

can easily be released and can migrate to the cytosol in damaged cells where it is the main

trigger of the mitochondrial pathway of apoptosis.

y The role of creatine phosphate- it is the shuttle ofhigh-energy phosphates between their pointof synthesis (mitochondria) and their point of utilization (cytosol and sarcomere). It is

synthesized upon phosphylation of creatine by ATP by theenzyme creatine phosphokinase

(CPK).CPK is expressed on the outer surface of the inner mitochondrial membrane to transfer

thehigh-energy phosphate from ATP to Cr.

y Anaerobic metabolism- provides far less ATP per mole of substrate. In the case of ATP depletion,its degredation products trigger emergency mechanisms:

o Adenosine decreases energy demand by a negative chronotropic and inotropic effect.o AMP-dependent protein kinase optimizes energy production from glucose, the only

endogenous anaerobic source of ATP.


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25y Effects of adenosine- adenosine binds to the spec. receptor A1 in cardiac & A2 in vascular tissue.

o Receptor A1 Stimulates an adenosine-dependent K+ channel in theSA and AV nodes which

results in bradycardia (negative chronotropy) and negative dromotropy (speed

of impulse)

Blocks the L-typeCa2+ channel which results in a negative inotropy Triggers ischemic preconditioning (cardioprotective mechanism against

ischemia)

o Receptor A2 Induces vasodilation of the coronary arteries to improve oxygen and substate

supply (coronary flow reserve).This is the main mechanism through which an

atheroscierotic artery maintains coronary flow.

y AMP-dependent protein kinase (AMPK) is a metabolite-sensing kinase, activated by changes inenergy status resulting from:

o Increased workloado Decreased substrate supplyo Decreased oxygen supply*overall, AMPK activates glucose metabolism. It also stimulates fatty acid oxidation by

inhibiting the production of malonyl-CoA.


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26Lecture 6 (partial): Signal transduction and gene expression

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