Transcript CARDIAC CONTRACTION _ DR SANDEEP R.ppsx

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
Klabunde, Richard E. Cardiovascular Physiology Concepts. Pg.43 ©2005
SARCOMERE




Structural & functional unit of
contraction
Lies between Z lines
Its distance varies – 1.6 2.2Mm
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 Ca +2for 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 calciumSERCA /NCX

Cardiac muscle relxn.
Action Potential to
Excitation-Contraction Coupling
CICR
L-type Ca+2
channel
Calcium removal by
Na/Ca exchanger
Calcium movement from
uptake to release site
Calcium uptake
by SERCA
Force production
http://cvphysiology.com/Arrhythmias/A006.htm
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 Ltype 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)
1
2
3
Intracellular [Ca]
10-7 to 10-5 M
1. Ca++ enters the cell through L-type calcium channels
2. Ca++ stimulates Ca++ release from the SR via RyR
3. Ca++ interacts with contractile proteins to initiate
shortening of the myocyte
Pictorial E-C Coupling
Na+
Ca++
Sarcolemma
Na+ +
Na
Na+/Ca++ Exchanger
Ca++
Ca++
Ca++
Ca++
L-Type Ca++
Channel
Ca++ Ca++
Ca++
SERCA
Ca++
Ca++
Ca++
Ca++
++
Ca Ca++
Ca++
++
Ca
++
++
++
Ca Ca++
Ca Ca ++Ca++
Ca++
Ca
++
Ca Ca++ Ca
++ SR
RyR
Ca++
Ca++Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
Acto-myosin interaction.
Hasenfuss G , Teerlink J R Eur Heart J
2011;eurheartj.ehr026
Interaction Between the "Activated" Actin Filament and the Myosin Cross-BridgesThe "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 forcegenerating, 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 Ca +2is 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
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 betaadrenergic 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 tubulesinhibited 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 forcefrequency 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.
Hasenfuss G , Teerlink J R Eur Heart J
2011;eurheartj.ehr026
Mode of action of cardiac myosin activators.
Hasenfuss G , Teerlink J R Eur Heart J
2011;eurheartj.ehr026
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
Abnormalities in E-C Coupling

CICR - SR


The RyR channel undergoes changes and calcium leaks out.
SR contains less calcium for release during each AP.
Abnormalities in E-C Coupling

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.415 10 January 2002
Overview of E-C Coupling Changes in the Failing Heart
:Regulation of Intracellular Calcium
1. Reduced Ca++ trigger
thru L-type channel
5
2. Reduced RyR function
(Calcium leaks from SR)
3. Decreased sensitivity
of TN-C to Ca++
2
4
1
4. Reduced Ca++ uptake
due to loss of SERCA
function and increased
Plb
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.
1961;24:483-490
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
90:1125-1136, 2001.
MCQ





1.WHAT IS MAXIMAL LENGTH OF SARCOMERE
THAT CAN PRODUCE MAXIMUM FORCE OF
CONTRACTION?
A) 1.6
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