CHAPTER 4 CIRCULATION

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CHAPTER 4 CIRCULATION

• Professor Pan Jing-yun
• Department of Physiology

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SECTION 1 ELECTRICAL ACTIVITY
OF HEART
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I. BIOELECTRICAL PHENOMENA OF
MYOCARDIAL CELL
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• Differences of AP configurations in different
  regions of the heart.
• Fast response potential
• Fast response cells atrium cell and ventricle
  cells working myocardium.
• Fast response automatic cells Purkinje fiber and
  bundle of His.
• Slow response potential
• Slow response cells SA node and AV node.

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• Basic concepts
• Depolarization cations influx ---- Na,
• Ca inward current
• Repolarization cations efflux ---- K
• outward current
• Hyperpolarization Vm ? more negative
• than RMP
• Net current
• inward lt outward repolarization
• inward gt outward depolarization
• inward outward no change in Vm

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TRANSMEMBRANE POTENTIAL OF MYOCARDIAL CELL AND
THEIR IONIC BASIS
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? Typical features Resting membrane
potential (RMP) Action potential (AP)
Phase o (rapid depolarization) Phase
1(rapid initial repolarization) Phase 2
(plateau) Phase 3 (rapid late
repolarization) Phase 4 (resting membrane
potential)
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? Ionic basis for RMP and AP of working
myocardium a. Ionic concentration differences
cross membrane b. Permeability to
ions (conductance)
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? Ionic basis for RMP

• K permeability ?, Ki gt Ko
• RMP ? K equilibrium potential

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? Ionic basis for AP Phase 0 (depolarization)
Stimulation ? partial depolarization ?
threshold potential (-70mV) ?Na Ch.
opening ?Na influx into cell down
electrochemical gradient ? Vm less
negative?0 mV ? 30 mV (overshoot)
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Features of fast Na channel

• (1). Activated and inactivated very
• fast. Speed of depolarization 120-
• 200 V / s
• Fast response potential
• Fast response cell
• Fast channel

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• Regenerative process
• depolarization caused by Na influx
• induces more Na Ch. to open and Na
• influx.
• At same time, Kconductance falls and
• keeps Vm at depolarization state.

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• (2). Voltage dependent
• Activation -70mV
• Inactivation 30mV
• Recovery to reopen from -60mV
• (3). Blocked by TTX

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Phase 1 (rapid repolarization)

• (1) Na Ch. is inactivated at 30mV
• (2) Transient outward current (Ito)
• Koutward current, blocked by
• tetraethylammonium(TEA) and
• 4-aminopyridin.

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• Phase 2 (plateau)
• Ca2 Ch. activation at 40mV ? Ca 2 influx ?
  Ca2 inward current
• IK Ch. Is activated slowly at phase o
• K slowly efflux ? K outward current
• Inward Ca2 current outward K current at
  early stage of plateau
• Inward current lt outward K current at late
  plateau, Vm ? more negative ? repolarization

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• Close of IK1 Ch. at phase o and plateau prevents
  membrane potential from rapid repolarization
• Phase 2 is the integration of inward
• Ca2current and outward Kcurrent.
• The features of Ca2 channel

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• (1).Slow channel, slow inward current, slow
  activation and inactivation and reactivation
• (2).Voltage dependent
• Activated at 40mV, inactivated at 0mV
• (3).Blocked by Mn2 and verapamil
• (4).Low specialty permeability to Na also.

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• Phase 3 (late repolarization)
• Ca2 channel is inactivated.
• ?K efflux via IK channel
• ?K efflux via IK1 channel ??outward
• K current ? Vm ? more and more
• negative ? RMP.

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• Phase 4 (resting stage)
• During Phase 1-3, Na, Ca2 and K
• imbalance outside and inside cell.
• During Phase 4, Na, Ca2 efflux
• against concentration gradient
• K influx against concentration gradient .

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• Na-K pump
• 3 Na out and 2 K in
• Na-Ca2 exchange antiport
• 1 Ca2 out and 3 Na in dependent of
• Na concentration difference inside and
• outside cell.
• Ca2 pump Ca2 out of cell.

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II. Transmembrane potential of rhythmic
cell and their ionic basis

• Automatic fast response cell
• Purkinje cell.
• Automatic slow response cell in S-A
• node and A-V node

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Spontaneous, phase 4 depolarization the
cause of automaticity pacemaker potential
? Maximal repolarization potential at
the end of phase 3. ? Phase 4 depolarizes
automatically and slowly.
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• ? When depolarization reaches
• threshold level, excitation (AP)
• appears.
• .

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1. Slow response cell -- P cell in S-A node
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(1) Features of P cell in S-A node a. Slow
depolarization of phase 0, 7ms, 10V/s
,magnitude 70mV Due to Ca2 channel opening,
blocked by Verapamil or Mn2.b. No distinct
phase 1 and phase 2
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c. Smaller overshoot (15mV)d. Maximum diastolic
potential 70mV, firing level 40mV.f.
Repolarization K outward current.g.
Faster spontaneous phase 4 depolarization.
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(2) Ionic basis for spontaneous phase 4
depolarization in P cell
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a. Inward current, if b. Inward Ca2
current, iCa c. Outward K current, iK
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a. Inward current, if Features of if (a)
Carried by Na, blocked by Cs, but not
TTX (b) Activation at -60mV,full
activation at 100mV (c) Noradrenalin ? ?if
Acetylcholine ??if
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b. Inward Ca2 current, iCa Activation
at -55mV Noradrenalin ? ?if
Acetylcholine ??if Blocked by Ca
ch.blockade
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C. Gradually diminishing outward K
current, Ik
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• With time the inward current (iCa,if )
• gt outward current(Ik), causing phase 4
• diastolic depolarization to reach firing
• level results in a new action potential.

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• 2. Ionic basis of AP of rapid
• response automatic cells
• as the same as that of AP of
• working cells except phase 4.

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Ionic basis of spontaneous phase 4 depolarization
in fast response cell-Purkinje cell
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(1) Gradual increase in inward
current,if(2) Gradually diminishing outward
K current, iK If gt IK ,
depolarization ?threshold potential ? a
new AP
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III. Electrophysiological properties of
cardiac muscle

• Excitability
• Automaticity (autorhythmicity)
• Conductivity.

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?Excitability and its affecting factors

• (1).Excitability 1/threshold strength.
• Affecting factors
• a.Excitation is caused by depolarization
• reaching threshold level, so affecting
• factors are

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1. Excitability and its affecting factors
1).Excitability index 1/threshold
strength.Affecting factors a. Excitation is
caused by depolarization reaching
threshold level, so affecting factors
are
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• (a). RMP level the lower the RMP, the larger the
  distance from RMP to threshold potential, the
  larger the threshold strength needed to induce
  excitation ??excitability, Ko?

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• (b) Threshold level
• Threshold level moves upward,
• the distance between it and RMP
• becomes larger, excitability
• decreases.

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• (c). Behavior of Na channel
• Resting activation inactivation
• stage stage stage
• reactivation
• stage

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Voltage-dependent Na Ch. Resting stage - 90
mV Activation stage - 70mV Inactvation
stage 30mV Reactivation stage -
60mVTime-dependent Na Ch.
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B. Cyclic changes in excitability in a
cardiac cycle

• (a).Effective refractory period (ERP)
• 0 -60mV
• Absolute refractory period (ARP)
• 0 -55mV
• Local response (no AP) -55 -60 mV

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• (b) Relative refractory period (RRP) -60
  -80mV
• Excitability lower than normal, Na channel is
  reactivation, but not fully reactivated.
• Stronger stimulation than normal
• induces a premature potential.

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• (c) Supra-normal period (SNP) -80
• -90mV
• Excitability is higher than normal,
• Vm at this period is less negative than
• normal RMP, and its distance to
• threshold potential is shorter than
• normal. The new AP is still smaller
• than normal.

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• Feature of premature potential
• A propagated AP, but smaller
• than normal AP
• Low speed of phase 0
• Low amplitude of phase 0
• Low conduction
• Shorter duration of AP.

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• The speed and amplitude of depolarization are
  determined by RMP.
• The recovery of ability of Na Ch. to reopen
  depends on membrane potential (Vm).

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Extrasystole and compensatory pause
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? Automaticity (Autorhythmicity)

• ? Index of automaticity
• frequency of discharge of pacemaker cell in
  S-A node. 100/min dominant pacemaker
• A-V junction 50/min,
• Purkinje fiber 25/min
• latent or subordinary pacemaker

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Atrioventricular delay permits optimal
ventricular fillingAtrioventricular(AV)
blockcomplete AV blockAV conduction is affected
by autonomic nerve system
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• S-A node controls latent pacemaker
• due to
• a. S-A node drives latent pacemaker
• b. Overdrive suppression
• (a) The longer overdrive, the stronger
• suppression

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• (b) The larger difference of excitation
• frequency between two pacemakers,
• the stronger suppression.
• Active Na pump 3 Na out, 2 K in ?
  hyperpolarization ? need more time to reach
  firing level.

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? Factors determining automaticity

• Frequency of excitation of pacemaker cell
  determinates the time for maximum diastolic
  potential to reach threshold potential.

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• a. Rate of spontaneous, phase 4
  depolarization.ßreceptor activation, If? HR?
• b. Maximum diastolic potential level , gK? HR?
• c. Threshold potential level

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? Conductivity

• a. Index of conductivity speed of
• conduction of AP
• b. Factors determining conductivity
• of cardiac muscle

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• a. Speed and amplitude of phase 0 depolarization
• (a) ? speed of phase 0 depolarization
• ? ?rate of generation of local
• current ??time for depolarization
• to reach threshold potential ?
• conductivity ?.

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• (b)?amplitude of phase 0 depolarization
• ? ?amplitude of local current ?
• ?distance of depolarization of nearby
• membrane ? ?conductivity.
• (c) Speed and amplitude of phase 0
• depolarization is determined by Vm

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• More negative RMP ? ?speed of Na channel
  opening ? ?speed of phase depolarization ? ?speed
  of local current stimulation to reach to
  threshold potential ? ?speed of conduction

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• More negative RMP ? ?number of Na channel
  opening ? ?amplitude of phase 0 depolarization ?
  ? amplitude of local current ? speed of
  conduction?

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b. ?excitability of nearby membrane area ?
?conductivity

• Local current stimulus conducts to area which is
  in effective refractory period of premature
  potential. The stimulus cant induce a new AP and
  conduction block occurs.

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Local current stimulus conducts to area which is
more negative RMP,excitability decreases and
conductivity also decreases.
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Section 2 Cardiac pump function

• Cardiac cycle
• ? Order of contraction and relaxation
• of atrium and ventricle
• ? Diastole gt systole
• ??HR ? ??diastole, ?systole
• ?HR ? ??diastole, ?systole

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Contraction or relaxation of heart ? changes in
pressure ? opening or closing of valves ?
direction of blood flow
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The opening or closing of valves is a passive
process resulting from pressure differences
across the valves
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I. Mechanical events of the cardiac cycle

• A, Left ventricular ejection and filling
• 1. Atrial systole
• 2. Ventricular systole
• (1) Isovolumic contraction phase
• (2) Rapid ejection phase
• (3) Reduced ejection phase

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• ? Ventricular diastole
• (1) Isovolumic relaxation phase
• (2) Rapid filling phase
• (3) Reduced filling phase

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Importance of rapid ventricular filling.
Primary pump of atrium (a) increase in
ventricular filling (b) decrease in
atrial pressure
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B. Atrial pressure changes of cardiac
cycle a wave, c wave, v wave

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?. Evaluation of cardiac pump function

• Stroke volume EDV ESV, 70ml
• Cardiac output stroke volume heart
• rate 5L / min (4.5 - 6.0)
• Cardiac index cardiac output / area of
• body surface, 3.0 3.5 L / min / m2

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• Ejection fraction (EF)
• SV EDV-ESV
• EF
• EDV EDV
• ESV residue blood volume

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Cardiac work

• pressurevolume work kinetic energya. Stroke
  work
• pressurevolume work / beat Force
  Distance
• FD (PA) D P(AD)
  
• P?V

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Stroke work(g-m) SV(cm3)(1/1000)(MAP
mean atrial P)(13.6g/cm3)Minute cardiac
work(Kg-m/min) SV(g-m)heart rate(1/1000)
b. Kinetic energy 1/2mV2 2-4 of
cardiac work
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Pressure work consumes more oxygen than volume
work
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? Control of cardiac output

• significance
• To meet the need of tissues under
  
• different conditions
• To keep cardiac output balance
• with cardiac filling
• To match the output of the right
• and left ventricle

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• Cardiac output SV HR
• Determinants of stroke volume
• (1)initial length (pre-load)
• (2)contractility
• (3)after-load

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Initial lengthVentricular function curve SV
increases as LVEDV increases at no changes in
other factors.Frank-Starling mechanism(1918)
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EDV is at the left to optimal initial length, SV
increases as EDV increases. This feature means
that ventricle has larger initial length reserve.
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• Sarcomere length 2.0-2.2?m is optimal initial
  length.
• Overlap between thick and thin filements in a
  sarcomere is very well
• Number of cross-bridge linkages is the biggest

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Factors influencing EDV

• a. Venous return blood volume
• b. Duration of filling (diastole)

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a. Venous return blood volume depends on velocity
of venous return, which is determined by
difference between peripheral venous pressure and
end-diastolic pressure.
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b. Duration of filling (diastole) Increase
in HR results in short filling period,
distolic filling decreases, therefore, EDV
decreases.
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• B. contractility1.Sympathetic nerve and
  catecholamine
• ??contractility
• ventricular function curve shifts to
• upward and the left

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Contractility is depended by Number of
activated cross- bridge linkage /total
number of cross-bridge linkage
Intracellular free Ca2 Affinity of
troponin to Ca2
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• Cardiac sympathetic nerve ending
• ? noradrenaline ? binds to ß-
• adrenergic receptor??permeability
• to Ca2 leads to

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• ?Contractility due to ?Ca2i
• ?Ca2 influx ? calcium-induced
• release of calcium ??Release
• Ca2 from sarcoplasmic
• reticulum

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• ?Speed of relaxation during diastole
• a.?Affinity of Ca2 to troponin
• ?dissociation Ca2 from troponin
• b.?Uptake Ca2 of sadrcoplasmic
• reticulum ? ?Ca2i
• c.?Na-Ca2 exchange ? ?Ca2i

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The role of cAMP-dependent protein kinase
Increase in contractile force and speed of
contractionIncrease in the speed of relaxation
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• ? Effect of after-load on cardiac output
• After-load aortic pressure
• ?Aortic pressure ??stroke volume ?
• blood accumulates in ventricle ??EDV?
• recovery of stroke volume by Frank-Starling
  
• mechanism
• recovery of EDV through ?contractility ?
• cardiac work?.

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2. Effect of heart rate on cardiac output

• cardiac output HRSV
• ?HR, ?CO.
• HR gt 200bpm, CO?due to diastole too short, venous
  return too small.

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Autonomic nervous system controls heart rate
Vagal tone Sympathetic tone
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(1)Effect of cardiac vagal nerve?HR Vagal
nerve ending ? ACh binds to M cholinergic
receptor ? ?permeability to K results in
?automaticity of S-A node
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a. More negative maximum diastolic
potential b. ?Speed of phase 4 depolarization
due to ?K efflux during phase 4,
i.e. decrease in diminishing K outward
current
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?conductivity due to ACh ?? Ca2 influx
??amplitude of phase 0 depolarization ? ?
conductivity at A-V junction
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(2) Effects of cardiac sympathetic n Cardiac
sympathetic ending ?NE binds to ßreceptor
??permeability to Ca2 leads to
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?Automaticity ?If at phase 4 in automatic
cell.?Conductivity ?Ca2 influx at
phase 0 in A-V junction ? ?Speed and
amplitude of phase 0 depolarization ? ?
conductivity
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Autonomic nervous system controls heart
rateVagal tone predominates in normal
personIntrinsic heart rate 100 beats/min
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? Cardiac reserve Heart rate reserve
Stroke reserve Diastolic reserve
Systolic reserve
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Measurement of myocardia contractility
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