CARDIAC CONTRACTION & RELAXATION

CARDIAC CONTRACTION & RELAXATION
Dr Sandeep .R

HISTORY Ringer first discovered the dependency of the beating
heart on extracellular Ca2+ (1882). Ebashi (1976) and Weber & Murray (1973) initially described the importance of the sarcoplasmic reticulum (SR) in skeletal muscle Fabiato (1985) introduced the concept of CICR in the heart

Organization of Cardiac Cells
A cardiac cell, or myocyte, is composed of many contractile units called sarcomeres. Each myocyte is separated by intercalated discs, which provide a low resistance junction for depolarization currents (ions) to move from cell to cell. Within each sarcomere are the contractile proteins which create shortening of the cell. Each sarcomere is bounded by 2 z-lines. The thick filaments, or myosin, interact with the thin filaments, which are composed of actin, troponin, and tropomyosin, during excitation-contraction coupling to create force production and shortening. Klabunde, Richard E. Cardiovascular Physiology Concepts. Pg.43 ©2005

SARCOMERE Structural & functional unit of contraction
Lies between Z lines Its distance varies – Mm Maximum force of contraction is produced at a distance of 2.2 Mm

SARCOMERE Sarcomere –bet. Two Z lines I BAND –Only thin filament A BAND- Both thick& thin filaments H zone – only myosin M line – centre point of sarcomere

Components of excitation contraction coupling
Sarcolemma (1) SR coupling in the form of dyads by means of the T-tubule (2) Caveolae (3) Intercalated disc 4)Ankyrins

SARCOPLASMIC RETICULUM
The SR is an intracellular membrane-bounded compartment comprised of terminal, longitudinal, and corbular components The free walls of the terminal cisternae are apposed to the walls of the T-tubules and form the dyadic cleft The RyR2 receptors- located in the walls of the terminal cisternae (feet) and face the dyadic cleft Longitudinal SR is fairly homogenous and contains primarily the SR Ca2+-ATPase proteins, SERCA2 &phospholamban SR calcium is transported from the tubular lumen of the SR to the terminal cisternae, where it is stored mostly bound to calsequestrin.

Transverse Tubules and the Sarcoplasmic Reticulum
The transverse (T) tubules are an extensive network of muscle cell membrane (sarcolemmal membrane) that invaginates deep into the muscle fiber. The T tubules are responsible for carrying depolarization from action potentials at the muscle cell surface to the interior of the fiber The sarcoplasmic reticulum is an internal tubular structure, which is the site of storage and release of Ca2+ for excitation-contraction coupling

SARCOPLASMIC RETICULUM
Junctional SR Longitudinal SR

MYOFILAMENTS

MYOSIN The myosin molecule consists of two heavy chains with a globular head, a long -helical tail, and four myosin light chains 500,000 Da Transduction of chemical to mechanical energy and work is the function of myosin ATPase, located in the myosin heads. Two myosin light chains (the alkali or essential light chain [MLC1] and the phosphorylatable or regulatory light chain [MLC2]), are associated with each myosin head and confer stability to the thick filament.

ARRANGEMENT OF THICK AND THIN FILAMENTS
Myosin molecules arranged in apolarized manner , leaving globular portions projecting outward So that they can interact with actin to generate force & shortening

MYOSIN

TITIN Titin is the largest protein which is extraordinarily long, flexible, and slender. Titin molecule extends from the Z-line, stopping just short of the M-line It has two distinct segments: 1) An inextensible anchoring segment 2) An extensible elastic segment that stretches as sarcomere length increases.

Titin – functions 1) It tethers the myosin molecule to the Z-line, thereby stabilizing the contractile proteins 2) As it stretches and relaxes, its elasticity explains the stress-strain relation of cardiac and skeletal muscle. 3) Increased diastolic stretch of titin as the sarcomere length of cardiac muscle is increased causes the enfolded part of the titin molecule to straighten This stretched molecular spring then contracts more vigorously in systole 4) Titin may transduce mechanical stretch into growth signals.

MYOSIN BINDING PROTEIN C
Myosin-binding protein C runs at approximately right angles to the myosin molecules to tether myosin molecules by linking the structures that lie around subfragments of the myosin heads. This binding protein, which stabilizes the myosin head, itself flexes and extends at the level of the light chains Defects in the binding protein C may be involved in some types of hypertrophic cardiomyopathy.

Thin Filaments The backbone -helical double-stranded actin
Tropomyosin is a long, flexible, double-stranded (largely -helix) protein that lies in the groove between the actin strands and inhibits the interaction between actin and myosin The troponin complex is composed of 1)A calcium-binding subunit- troponin C (TnC) 2) An inhibitory subunit to actin- troponin I (TnI) 3) A tropomyosin-binding subunit- troponin T (TnT)

EXCITATION CONTRACTION COUPLING
The cascade of biological processes that begins with the cardiac action potential and ends with myocyte contraction & relaxation

Influx of extracellular calcium
Calcium-induced calcium release (CICR) – Ryanodine receptor Activation of actin myosin cross bridges Cardiac muscle contrn. Decrease in intracellular calcium- SERCA /NCX Cardiac muscle relxn.

Action Potential to Excitation-Contraction Coupling
CICR L-type Ca+2 channel Calcium removal by Na/Ca exchanger Calcium movement into the cell during phase 2 begins the process of excitation-contraction coupling Brief overview Calcium enters the cell through L-type channels located in the T-tubules of the sarcolemma Calcium-induced calcium release (CICR) occurs when the “trigger” calcium from L-type channels is sensed by the ryanodine receptors (RyR). This causes Ca release from the sarcoplasmic reticulum (SR). Ca interacts with troponin-C (TN-C), causing troponin-I (TN-I) to uncover a myosin binding site on actin Intracellular Ca is reabsorbed into SR via the sarco-endoplasmic reticulum Ca ATPase (SERCA) pump and removed from the cell via other means such as Na/Ca exchanger and an ATP dependent Ca pump. As intracellular Ca decreases, Ca dissociates from TN-C and the binding site on actin is inhibited. ATP is required to unbind myosin from actin and reset the sarcomere to its normal length. Calcium movement from uptake to release site Calcium uptake by SERCA Force production

CALCIUM ENTRY

Calcium sparks (localized [Ca2+]i transients) are the elementary SR Ca2+ release events that trigger E–C coupling in heart muscle. The basis for the generally accepted local control theory of E–C coupling is that Ca2+ sparks are triggered by a local [Ca2+]i established in the region of the RyR2s by the opening of a single L-type Ca2+ channel. The amplitude of Ca2+ sparks is determined by SR Ca2+ load and gating properties of the RyR2

Factors responsible for the [Ca2+]i transient amplitude include
(1) the calcium current (ICa), primarily caused by Ca2+ influx through the L- type Ca2+ channel, but in small part caused by reverse mode NCX (2) SR [Ca2+]i content (3) the efficiency of E–C coupling (4) intracellular Ca2+ buffers The decline of the [Ca2+]i transient is caused by (1) Ca2+ reuptake into SR by SERCA2 (a process modulated by a phosphorylatable regulatory protein termed phospholamban) (2) Ca2+ extrusion from the cell by the NCX (3) Ca2+ extrusion from the cell by the sarcolemmal Ca2+-ATPase (4) Ca2+ accumulation by mitochondria (5) Ca2+ binding to intracellular buffers (including fluorescent indicators that are used in experimental systems to measure the transient).

Calcium release & uptake
Ryanodine Receptors The calcium release channel is part of the complex structure known as the ryanodine receptor, so called because it coincidentally binds the potent insecticide ryanodine; it is often abbreviated to RyR2 to indicate the cardiac isoform. Ryanodine receptors have a dual function, both containing the calcium release channels of the SR and acting as scaffolding proteins that localize numerous key regulatory proteins to the junctional complexes. These proteins include the important stabilizing protein (technical term: FKBP-12.6) that responds to phosphorylation to coordinate opening of neighboring ryanodine calcium channels by the process of coupled gating.

Calcium Induced Calcium Release (CICR)
Intracellular [Ca] 10-7 to 10-5 M 1 2 3 1. Ca enters the cell through voltage controlled L-type channels located in the T-tubules of the sarcolemma 2. Ca entry further stimulates Ca release from the SR via sensing by the RyR. Intracellular Ca concentrations increase about 100x, from 10-7 to 10-5 M. 3. The rise in intracellular Ca, caused by CICR from the SR, allows Ca to bind to TN-C in a concentration dependent manner. Ca++ enters the cell through L-type calcium channels Ca++ stimulates Ca++ release from the SR via RyR Ca++ interacts with contractile proteins to initiate shortening of the myocyte

Pictorial E-C Coupling
Na+ Na+ Sarcolemma Na+ Ca++ Na+/Ca++ Exchanger Ca++ L-Type Ca++ Channel Ca++ Ca++ Plb Ca++ Ca++ Ca++ SERCA Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ The L-Type (“long lasting”) Ca Channel is a voltage controlled gate located in the T-tubules of the sarcolemma. Ca enters the cell through this channel during phase 2 of the action potential. This Ca stimulates further Ca release from the SR via the RyR. This process is referred to as calcium induced calcium release (CICR). Once contraction is complete, Ca is dissociates from TN-C and is reabsorbed by the SR via the SERCA pump. Phosphorlyation of phospholamban (Plb) increases the activity of SERCA. Phosphorylation occurs when a phosphate group binds to a molecule. Ca is also removed through the Na/Ca exchanger in a ratio of 3 Na ions for each Ca ion. An ATP dependent Ca pump also helps remove Ca from the cell. Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ SR Ca++ Ca++ RyR Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++

Acto-myosin interaction.
Acto-myosin interaction. The myosin head carrying the ATPase site combines with actin to produce force. Calcium binding to troponin C (TnC) results in a conformational change of tropomyosin, troponin I (TnI), and troponin T (TnT), allowing the myosin head to attach to actin, facilitating the acto-myosin cross-bridge to cycle (see also Figures 2 and 6). Hasenfuss G , Teerlink J R Eur Heart J 2011;eurheartj.ehr026

Interaction Between the "Activated" Actin Filament and the Myosin Cross-Bridges-
The "Walk-Along" Theory of Contraction The head attaches to an active site, this causes forces between the head and arm of its cross-bridge. this causes the head to tilt toward the arm and to drag the actin filament along with it. This tilt of the head is called the power stroke. Then, immediately after tilting, the head automatically breaks away from the active site. Next, the head returns to its extended direction. In this position, it combines with a new active site farther down along the actin filament; then the head tilts again to cause a new power stroke, and the actin filament moves another step

A, At the beginning of the cycle, no ATP is bound to myosin, and myosin is tightly attached to actin in a "rigor" position. In rapidly contracting muscle, this state is very brief. However, in the absence of ATP, this state is permanent (i.e., rigor mortis

B, The binding of ATP to a cleft on the back of the myosin head produces a conformational change in myosin that decreases its affinity for actin; thus, myosin is released from the original actin-binding site. C,

C, The cleft closes around the bound ATP molecule, producing a further conformational change that causes myosin to be displaced toward the plus end of actin. ATP is hydrolyzed to ADP and Pi, which remain attached to myosin

D, Myosin binds to a new site on actin (toward the plus end), constituting the force-generating, or power, stroke. Each cross-bridge cycle "walks" the myosin head 10 nanometers along the actin filament

E, ADP is released, and myosin is returned to its original state with no nucleotides bound
(A). Cross-bridge cycling continues, with myosin "walking" toward the plus end of the actin filament, as long as Ca2+ is bound to troponin C.

CROSS BRIDGE CYCLE

muscle contraction occurs by a sliding filament mechanism
This is caused by forces generated by interaction of the cross-bridges from the myosin filaments with the actin filaments.

Mitochondria Mitochondria comprise approximately 35% of ventricular myocyte volume and according to their cellular location are designated as either subsarcolemmal or interfibrillar. Mitochondria are the sites of oxidative phosphorylation and ATP generation Although they have the capacity to buffer large amounts of Ca2+ and are a potential source of activator calcium, classical teaching is that their contribution to E–C coupling is minimal in view of the short time constants involved In addition, the ability to accumulate large amounts of Ca2+ under pathological conditions (eg, ischemia) can help protect against myocyte Ca2+ overload; however, Ca2+ accumulation by mitochondria ultimately slows ATP production

NO NO is produced by the myocardium and regulates cardiac function through both vascular-dependent and independent effects NO's positive effects on relaxation or lusitropy are likely to be caused by (cGMP)-mediated reduction in myofilament Ca2+ sensitivity Mitochondrial NO reduces maximal venous oxygen (MVO2) consumption and increases mechanical efficiency (stroke work/MVO2), suggesting that NO regulates energy production as well influencing consumption NOS III- T tubule caveole – cgmp mediated lusiotropy NOS I – cardiac SR – modulates Ca 2+ homeostasis

DIASTOLE Diastole is the summation of processes by which the heart loses its ability to generate force and shorten and returns to its precontractile state. Diastolic properties of the ventricle are complex and multifactorial. Diastole occurs in a series of energy-consuming steps beginning with release of calcium from troponin C Detachment of actin–myosin crossbridges SERCA2a-induced calcium sequestration into the SR, NCX-induced extrusion of calcium from the cytoplasm Return of the sarcomere to its resting length.

DIASTOLE Adequate ATP must be present for these processes to occur at a sufficient rate and extent. The P–V relationship during early diastole reflects the lusitropic (relaxation) state of the heart, analogous to the inotropic (contraction) state measured during systole The rate of LV relaxation can be estimated from the maximal rate of pressure decay (–dP/dtmax) and indices (eg, relaxation half-time [RT1/2]) that are related to the time necessary for ventricular relaxation,

CALCIUM UPTAKE -SERCA Calcium uptake is mediated by SERCA ATPase in the sarcoplasmic reticulum. This is an active process and for each ATP -2 Ca2+ taken up This uptake is regulated by phospholamban Phosphorylated phospholamban activates SERCA Calcium taken up is stored in the junctional SR with calsequesterin and calreticulin SERCA down regulated in heart failure

SR Calcium Uptake Phospholamban SR removes Ca++ through an ATP dependent pump (SERCA) Disinhibition of phospholamban increases the rate of calcium uptake Cytosolic Ca++ decreases and Ca++ is removed from TN-C Excess Ca++ is removed from the cell by other processes Ca entry diminishes near the end of the AP. CICR stops and Ca uptake begins through SERCA. Phosphorylation of phospholamban removes its inhibitory effects and increases the activity of SERCA. This pump uptakes intracellular Ca, which is released from TN-C, and stores it in the SR for release during subsequent contractions. Intracellular Ca can also be removed by an ATP dependent Ca pump or by the Na/Ca Exchanger.

Turning Off Calcium Release: Role of Calmodulin Kinase
Calmodulin is activated when calcium binds to its high-affinity binding sites to become calcium-calmodulin (CaM) . The latter in turn also activates the calmodulin kinase II (CaMKII) system. Activation of CaM closes the previously open L channels to help shut off calcium ion entry into the cell. Effects of CaMKII - complex and appear to play a physiologic role in acute beta-adrenergic stimulation. There is a converse pathologic role especially in chronic heart failure, when the major effects appear to include (1) increased inflow of the slow sodium current (2) promotion of calcium leak through the ryanodine receptors to promote release of calcium ions (3) enhancement of calcium entry into the SR by stimulation of the Ca uptake pump, SERCA. The overall effect is calcium dysregulation, especially in chronic beta- adrenergic stimulation .

Sarcolemmal Control of Calcium and Sodium Ions
L&T type calcium channels T – denotes transient Ca2+ entry L type channels seen in myocardium and T tubules- inhibited by CCB Ltype- activation causes entry of Ca2+ It is inactivated by 1) increasing depolarization 2)rising intracellular Ca2+

Ion exchangers & pumps The calcium homeostasis is maintained by Na/Ca exchanger which pumps calcium out This removes 25% of intracellular calcium At times there is reverse transport of Na and Ca that occurs during rapid depolarization increasing the Ca intracellularily Na /K pump Na entry during rapid depolarization and during calcium exchange is maintained by this pump which extrudes 3 Na and takes in 2 K.

FACTORS AFFECTING LV CHAMBER STIFFNESS
Physical properties of the LV LV chamber volume and mass . Composition of the LV wall Viscosity Stress relaxation Intrinsic factors Myocardial relaxation Coronary turgor Extrinsic factors Pericardial restraint RV interaction Atrial contraction Pleural and mediastinal pressure

Factors affecting ventricular relaxation
First, the cytosolic calcium level must fall to cause the relaxation phase, a process requiring ATP and phosphorylation of phospholamban for uptake of calcium into the SR Second, the inherent viscoelastic properties of the myocardium are of importance Third, increased phosphorylation of troponin I enhances the rate of relaxation Fourth, relaxation is influenced by the systolic load

Measurement of Isovolumic Relaxation
The rate of isovolumic relaxation is best measured by negative dP/dtmax during invasive catheterization Tau, the time constant of relaxation, describes the rate of fall of LV pressure during isovolumic relaxation and also requires invasive techniques for precise determination Tau is increased as the systolic LV pressure rises. Other indices of isovolumic relaxation can be obtained echocardiographically or from tissue Doppler measurements to monitor the peak rate of wall thinning

Diastolic suction LV suction by active relaxation could increase the pressure gradient from left atrium to left ventricle during the early filling phase is now well supported by data The suction effect can be found by carefully comparing LV and left atrial pressures, and it occurs especially in the early diastolic phase of rapid filling as a result of the LV elastic recoil In early diastole, myosin is pulled into the space between the two anchoring segments of titin to lower the intraventricular pressure to below that in the atrium Ventricular suction, by propagating a dominant backward pressure wave, is also responsible for diastolic coronary filling and attenuated in LV hypertrophy

Beta adrenergic signal system
Beta 1 ,beta 2(20%) & beta 3 Predominant is beta 1 It acts through G protein coupled

TACHYPHYLAXIS Prolonged beta stimulation Activation of Gi
Stimulate B arrestin Downregulation of beta 1 receptor

PARASYMPATHETIC

Contractile Function Versus Loading Conditions
Contractile function or contractility is the inherent capacity of the myocardium to contract independently of changes in the preload or afterload. At a molecular level, an increased contraction is called ionotropic effect An increased contractile function is often associated with enhanced rates of relaxation called the lusitropic effect. Factors that increase contractile function include exercise, adrenergic stimulation, digitalis, and other inotropic agents

Preload Any change in the contractile state should be independent of the loading conditions. The preload is the load present before contraction has started, at the end of diastole The preload reflects the venous filling pressure that fills the left atrium, which in turn fills the left ventricle during diastole. When the preload increases, the left ventricle distends during diastole, and the stroke volume rises according to Starling's law Clinically ,preload is assesed by the PCWP and the LVEDP

FRANK STARLING’S LAW The force of contraction is directly proportional to the lenghth of the muscle fibre upto a physiological limit 1918, Related venous pressure in the right atrium to the heart volume in dog heart – lung preparation Increased diastolic filling – STARLINGS LAW Increased ionotropic state – FRANK’S findings It is due to 1)E nhanced calcium binding to troponin I 2) Narrower interfilament gaps at long sarcomere length 3)Increased SR calcium release and uptake at increased length

Afterload This is the systolic load on the left ventricle after it has started to contract In the nonfailing heart, the left ventricle can overcome any physiologic acute increase in load Chronically, however, the left ventricle must hypertrophy to overcome sustained arterial hypertension or significant aortic stenosis Arterial blood pressure can be taken as the afterload

Anrep Effect Abrupt Increase in Afterload
When the aortic pressure is elevated abruptly, a positive inotropic effect rapidly follows. Proposed mechanism - increased LV wall tension could increase cytosolic sodium and then, by Na+/Ca2+ exchange, the cytosolic calcium increases

WALL STRESS A more exact definition of the afterload is the wall stress during LV ejection First, the bigger the left ventricle and the greater its radius, the more is the wall stress. Second, at any given radius (LV size), the greater the pressure developed by the left ventricle, the greater the wall stress.

BOWDITCH STAIRCASE PHENOMENON
An increased heart rate progressively enhances the force of ventricular contraction, even in an isolated papillary muscle preparation (Bowditch staircase phenomenon) Alternative names are the treppe (German, steps) phenomenon, positive inotropic effect of activation, and force- frequency relationship Conversely, a decreased heart rate has a negative staircase effect. When stimulation becomes too rapid, force decreases

Optimal measurement of LV function should assess LV twist motion, which results from apical counterclockwise and basal clockwise rotation of the left ventricle, both essential for generation of LV pumping power. The extent of the twist can now be measured noninvasively by speckle tracking echocardiography, which closely correlates with dP/dtmax in a variety of experimental conditions and is superior to the global ejection fraction

CONTRACTION OF RIGHT VENTRICLE
RV contraction is sequential, starting with the contraction of the inlet and trabeculated myocardium and ending with the contraction of the infundibulum (approximately 25 to 50 ms apart Contraction of the infundibulum is of longer duration than contraction of the inflow region. The RV contracts by 3 separate mechanisms: (1) Inward movement of the free wall, which produces a bellows effect (2) Contraction of the longitudinal fibers, which shortens the long axis and draws the tricuspid annulus toward the apex (3) Traction on the free wall at the points of attachment secondary to LV contraction.

LV CONTRACTION

Shortening of the RV is greater longitudinally than radially.
In contrast to the LV, twisting and rotational movements do not contribute significantly to RV contraction. Moreover, because of the higher surface-to- volume ratio of the RV, a smaller inward motion is required to eject the same stroke volume.

APPLIED PHYSIOLOGY 1) IONOTROPES
2) CHANGES IN E-C DURING HEART FAILURE 3) MUTATIONS AFFECTING CONTRACTILE PROTEINS

Inotropic mechanisms and current inotropic interventions.
Inotropic mechanisms and current inotropic interventions. Activation of the β-adrenoceptor stimulates adenylyl cyclase to produce cAMP, which activates protein kinase A (PKA) to phosphorylate intracellular calcium-cycling proteins. Phosphodiesterases (PDEs) degrade cAMP. Phosphodiesterases are inhibited by Phosphodiesterase inhibitors. Digitalis inhibits transport of three sodium ions for two potassium ions through Na/K-ATPase. Calcium sensitizers increase the affinity of troponin C for calcium. Hasenfuss G , Teerlink J R Eur Heart J 2011;eurheartj.ehr026

Mode of action of cardiac myosin activators.
Mode of action of cardiac myosin activators. The agents promote actin-dependent phosphate release (Pi–release) moving the cross-bridge into its strongly bound force-producing state (see text). A, actin; M, myosin. Hasenfuss G , Teerlink J R Eur Heart J 2011;eurheartj.ehr026

Future inotropic compounds: the ryanodine receptor (RyR) stabilizers reduce sarcoplasmic reticulum leak through the ryanodine receptor and reconstitute ryanodine receptor channel function. Istaroxime inhibits sodium-potassium-ATPase and stimulates SERCA2a. Cardiac myosin activators promote transition of cross-bridges from the weakly to the strongly bound force-producing state. Energetic modulators improve myocardial energetics through switching from fatty acid to glucose oxidation or by other mechanisms including means to increase the cellular phosphorylation potential. Virus-mediated sarcoplasmic reticulum calcium pump gene transfer (AV-SERCA) increases sarcoplasmic reticulum calcium uptake. Nitroxyl (HNO) may increase sarcoplasmic reticulum calcium uptake by modification of sarcoplasmic reticulum calcium pump and/or phospholamban (PL). Hasenfuss G , Teerlink J R Eur Heart J 2011;eurheartj.ehr026

Ryanodine 2 mutation causes – CPVT,ARVD2
Calsequestrin mutation causes –AR variety of CPVT FKBP mutation can cause cardiomyopathy

Abnormalities in E-C Coupling
CICR – Ion Channels Channels operate differently and conductances change, possibly due to the effect of heart failure on membrane characteristics Less Ca++ may move across membrane during each AP

CICR - SR The RyR channel undergoes changes and calcium leaks out. SR contains less calcium for release during each AP.

Phospholamban Plb protein levels increase due the continued stimulation by the sympathetic nervous system. SERCA2 protein levels decrease This will lead to elevated diastolic calcium levels Donald M. Bers.”Cardiac excitation-contraction coupling” Nature Vol January 2002

Overview of E-C Coupling Changes in the Failing Heart :Regulation of Intracellular Calcium
1. Reduced Ca++ trigger thru L-type channel 2. Reduced RyR function (Calcium leaks from SR) 5 3. Decreased sensitivity of TN-C to Ca++ 2 4 4. Reduced Ca++ uptake due to loss of SERCA function and increased Plb 1 5. Increased Na/Ca exchanger function 3

BIBILOGRAPHY 1.HURST’S THE HEART ,13TH EDITION,VOLUME 1
2.BRAUNWALD HEART DISEASES,9TH EDITION 3.CARDIAC EXCITATION CONTRACTION COUPLING ;ROLE OF MEMBRANE POTENTIAL IN REGULATION OF CONTRACTION : Am J Physiol Heart Circ Physiol 280: H1928– H1944, 2001 4. Ludwig W. Eichna, RICHARD J. BING and K. KAKO ;Contractile Proteins of Heart Muscle in Man Circulation ;24: 5. Olga M. Hernandez, Philippe R. Housmans and James D. Potter thin filament regulation contraction and relaxation as a result of alterations in Invited Review: Pathophysiology of cardiac muscleJ Appl Physiol 90: , 2001.

1.WHAT IS MAXIMAL LENGTH OF SARCOMERE THAT CAN PRODUCE MAXIMUM FORCE OF CONTRACTION?
B) 1.8 C) 2.0 D) 2.2

2.CALCIUM RELEASE FROM SR IS MEDIATED BY
1) SERCA 2A 2) PHOSPHOLAMBAN 3) CALMODULIN 4) RYANODINE

3.SUDDEN INCREASE IN AFTERLOAD CAN INCREASE THE FORCE OF CONTRACTION
1) TREPPE PHENOMENON 2) STARLINGS LAW 3) ANREP EFFECT 4) MARY’S LAW

4. RV CONTRACTION IS A) TWISTING B)CLOCKWISE COUNTERCLOCKWISE C) SEQUENTIAL D) ROTATIONAL

5.WHICH OCCURS LAST IN RV CONTRACTION?
A) CONTRACTION OF SEPTUM B) CONTRACTION OF INLET C) CONTRACTION OF INFUNDIBULAM D) CONTRACTION OF APEX

6.CHANGES IN EC COUPLING DURING HEART FAILURE ARE ALL EXCEPT
A)DECREASE IN L Ca CHANNELS B) INCREASED PHOSPHORYLATION OF RYANODINE C)DECREASED PHOSPHOLAMBAN D)DECREASED SERCA 2A

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