CARDIOVASCULAR

MHR

GEORGE 0
Automaticity and Rhythmicity of the Heart

Automaticity = initiate contraction independent of external stimuli.

Rhythmicity = regular beats
Cause Due to presence of Pacemaker cells → generate spontaneous & regular action potentials.
• SAN cells (90-105/min Normal pacemaker (fastest)→
o Vagal tone →↓ SAN rate
• AV node cells (60/min) in failure of SAN
• Purkinje cells (40/min) in failure of AVN. (idioventricular rhythm)

Pacemaker potential “slow response action potential”

• In (SA node) and (AV node): 3 phases
Phase Ionic changes
Phase 4 At – 60 mv:
Pre-potential A- Opening of funny Na+ channels→Causes inward Na+ (HCN?)
B- Activation of Na+-Ca++ exchanger due to spontaneous release of Ca++ from SR
• → move 1 Ca++ out for 3 Na+ in → Causes inward Na+
At -50 mv: Opening of T-type Ca++ channels →Cause inward Ca++
Phase 0 At -40 mV = firing level
Depolarization 1. Closure of funny channels & T-type Ca++ channels
2. Opening of L-type Ca++ channels Causes inward Ca++ current→ cause slow depolarization
3. Gradual opening of DRK+ channels
Phase 3 1. Opening of DRK+ channels →cause outward K+
Repolarization 2. Closure of L-type Ca++ channels
3. Repolarization to -60 mV→ cause inactivation of K channel & Activation of funny channel

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Factors affecting rate of SA nodal discharge= chronotropy= heart rate (rhythmicity)

1. Autonomic ‫الرسم‬

Sympathetic ↑ HR Parasympathetic ↓ HR
Mechanism: Mechanism:
✓ Sympathetic (norepinephrine) ✓ Vagus (acetylcholine)
✓ Bind β1 receptors →↑ c-AMP → ✓ Bind muscarinic receptors →↓ c-AMP→
✓ ↑ funny current ✓ ↓ funny current.
1. Earlier depolarization starts earlier 1. Delayed depolarization
2. ↑slope of phase 4. 2. ↓slope of phase 4.
Reach threshold in shorter time Reach threshold in longer time
Acetylcholine activates K+ channels (KAch)
• Vagal tone→↓ SAN rate
2. Catecholamines →↑ HR
3. ↑Body Temperature 10 (fever) →↑ HR 10 beats/min.
4. Ca++ channel blocking drugs → → ↓ HR
5. Extracellular K+
o Hyperkalemia →↑ conductance → ↓ slope of phase 4 → ↓ HR

Conduction of Action Potentials

Velocity of conduction depends on

1- Number of gap junction (↓ conductance ability in hypoxia or ↑free Ca++ )
2- Amplitude & speed of upstroke of A.P.
Factors affecting rate of conduction

Sympathetic Parasympathetic
→↑ conductance → ↑ velocity Vice versa , Digitalis→↓ velocity
Pathway = initiation of cardiac electrical activity ??? Via pacemaker cells in specialized system
SAN in right atrium ,
Action potentials Conducted through Atrial myocytes (0.5 m/sec) or 3 Internodal bundles (1 m/sec)
AV node =at lower posterior atrial septum
• only pathway between atria & ventricles
• Slow Conduction (0.05 m/sec) due to Few gap junctions & Slow upstroke
A- Importance: Allow ventricular filling & Protect ventricles from abnormal high rhythm
Bundle of His & branches on each side of ventricular septum (2 m/sec.)
Purkinje fibers rapid conduction= (4 m/sec) →Allows coordinated contraction ventricular myocytes 0.5

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 Resting membrane potential
determined by Concentration gradient, Permeability, pumps)
Causes of RMP = -90 mv
1- Efflux of K+ via inward rectifying potassium channels (conduct inward current in hyperpolarization
2- Influx of Na+ and Ca++ with low permeability
3- Na+-K+ ATPase: Pumps 3 Na+ out for 2 K+ in
Maintenance of ionic concentrations:
During RMP During action potential
1. Continuous leak of K+ to outside (Equilibrium of K+= -94 mv) 1. More Na+ & Ca++ in
2. Continuous little leak of Na+ to inside (Equilibrium of Na+ = +61 2. More K+ out
• To maintain ionic concentrations:
Na+-K+ ATPase Ca++-ATPase Na+-Ca++ exchanger
Pump 3 Na+ out Pump Ca++ Exchange 3 Na+ for 1 Ca++
for 2 K+ in out Operate in both directions depending on
• Concentration gradient for these ions
Digitalis ??

Cardiac Myocyte Action potential (Non-pacemaker Action Potential)

firing level (-65
Phase Ionic change
Phase 4 (RMP) K+ moves out via IRK
Phase 0 Depolarization 1. Inactivation of IRK
from -90 to + 20mv 2. Opening of voltage gated Na+-channels: inward Na+ (Fast response )
Phase 1 rapid small 1. Closure of voltage gated Na+ channels
repolarization 2. Opening of special K+ channels
3. Opening of Cl- channels
Phase 2 Plateau (around Balance between
zero mV) 1. Outward positive via DRK+ channels
200 msec 2. Inward positive via
A- Long lasting Ca++ channels
B- ↑Activity of Na+-Ca++ exchanger: Move 1 Ca++ out for 3 Na+ in
Phase 3 Rapid late 1. Closure of long-lasting Ca++ & ↓ activity of Na+-Ca++ exchanger
repolarization 2. Delayed rectifier K+ channels → causes outward K+
As membrane potential approaches RMP:
• Closure of DRK
• ↑Activity of inwardly rectifying K+ channels: →to reach -90 mV

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 Relationship between Action potential &mechanical response

• Contraction after start of depolarization

maximum at end of plateau
• Relaxation First half with Repolarization (phase 3)

Excitability changes during action potential

Absolute refractory period (ARP) Relative refractory supernormal period

period (RRP)
Response No response to nay stimulus Respond to supra- Respond to weaker
Cause: inactivation of Na+ ch threshold stimulus. stimulus → arrhythmias

Phase Phases 0, 1, 2, and part of phase 3 Follows ARP Follows RRP

to -50 mv) to -75 mv. to fully repolarization

o Refractory period in cardiac myocytes is much longer than skeletal myocytes: due to presence of plateau.
o Importance of refractory period: Prevents tetanic contractions (not suitable for pumping) As it occupies
whole systole and early diastole

Effect of ischemia on electrical activity of the heart

1. Ischemia cause accumulation of K+ in ECF, due to:

A- Opening of KATP channels & Inhibition of Na+-K+ ATPase pump
2. Accumulation of K+ in ECF cause Membrane depolarization
3. Membrane depolarization →↓decreased number of active Na+ channels →↓Slope of phase 0.
4. ↓Slope of phase 0 & ↑intracellular Ca++→↓conduction velocity

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 Mechanical Properties (Excitation contraction coupling)
1- Membrane depolarization → open L-type Ca++ channels
2- Ca++ entry → open ryanodine sensitive- calcium channel on SR “Calcium- induced Calcium release”
3- Ca++ binds Troponin-C →contraction
4- Relaxation via removal of calcium from cytoplasm:
a. SERCA→ actively reuptake Ca++
b. Na+-Ca++ exchanger: move Ca++ out
c. Calcium pump
5- Force of cardiac contraction (notropic state) depends mainly on Ca++

Regulation of Contractility (inotropic state) of cardiac myocytes

Positive inotropic mechanisms Negative Inotropic Mechanisms:

Sympathetic (norepinephrine) or catecholamines → Parasympathetic (acetylcholine) →
✓ bind β1 receptors →↑c-AMP→ ✓ Bind muscarinic receptors (M2) → ↓c-AMP
✓ Activates Protein Kinase → phosphorylates
a. L-type Ca++ channel
b. calcium release channel on SR

Glucagon hormone →↑c-AMP Adenosine: inhibits production of c-AMP

↑ ECF Ca++ →↑Ca++ entry. Hypoxia (ischemia) →↓ATP
Drugs: Drugs:
• Digitalis→ inhibits Na+-K+ ATPase →↑ Na+. • Calcium channel blockers (dihydropyridine)
Na+-Ca++ exchanger move 3Na+ out for inhibit L-type Ca++ channels →↓ Ca++ entry
1Ca++ in. →↑Ca++ inside myocytes. • Anesthetic drugs.
• Xanthine (caffeine)→ inhibit breakdown of
c-AMP→↑c-AMP conc.

Regulation of Myocyte Relaxation (lusitropy)

1- Sympathetic / catecholamine → bind β1 receptors →↑ c-AMP →activate protein kinase
a. ↑Activation of SERCA → rapid removal of Ca++
b. ↓binding of Troponin to Ca++.
• Sympathetic causes strong contraction ad rapid relaxation
2- Ischemia → ↓activity of Ca pump →↑ intracellular Ca++→ inhibits relaxation.
• Myocardial ischemia causes weak contraction and poor relaxation.

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Performance of Isolated Cardiac Muscle

Indicators of performance (ability of the muscle to contract to achieve its goal

1- Degree of shortening: (on length-tension relationship)
o At certain length (preload) (point 1) → muscle start isometric contraction
→ tension increase till reaches afterload (point 2)
o Then Contraction becomes isotonic to point 3
o Degree of shortening (line 2 → 3)
2- Velocity of shortening (on load-velocity relationship)

Factors affect the performance of isolated cardiac muscle (4)

Preload, Afterload , Inotropic state , Frequency of contraction

1. Effect of changes in afterload:
A- On degree of shortening: (inverse relation). ↓by ↑afterload
B- On velocity: inverse relation
Zero velocity Maximum velocity (Vmax)
When load ≥ maximum tension When load is zero
(Contraction remains isometric).

2. Effect of changes in preload:

A- On degree of shortening direct relation
B- On velocity
o ↑preload → shifts load-velocity curve upwards and right →↑ velocity

3. Effect of changes in inotropic state: positive inotropic

A- On degree of shortening shifts active length-tension relationship upwards and left.
B- On velocity → Shifts load-velocity curve upwards and right→↑ velocity
Vmax: ↑
4. Effect of ↑frequency: staircase phenomenon” or “treppe”
o ↑frequency → ↑ force of contractions till reach plateau
o Cause: Ca++accumulation

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PHASES OF CARDIAC CYCLE
Atrial systole Isovolumetric Rapid ejection Reduced
(late diastole) Contraction Phase phase Ejection Phase
Duration 0.1 s 0.05 s 0.1 s 0.15 s
Evacuate 20%
Ventricular ↑ to 130 m (EDV) Constant ↓rapidly ↓ to 60 ml (ESV)
volume
Ventricular ↑ ↑ rapidly ↑ ↓
pressure To 9 in LT ventricle To 80 in LT ventricle To 120 in LT ventricle Momentum
To 4 in RT ventricle To 10 in RT ventricle To 25 in RT ventricle keeps blood
moving forwards

Valves
AV valves Opened Sudden closure Closed Closed
Semilunar valves Closed Closed Opened Opened

Heart sounds 4th , not heard 1st 1st (continue)

Aortic ↓ ↓ to minimum ↑ ↓catacrotic
Pulmonary = 80 mmHg (aorta) To 120 mmHg Near end of this
pressure = 10 mmHg To 25 mmHg phase: dicrotic
notch” ?
Atrial pressure + ve a wave + ve C wave -ve X- wave +ve V wave
Cause Limited blood flow back Bulging of cusps downward pull of Due to ↑ VR
into veins due to cusps
contraction of cardiac
muscle around orifices
ECG P wave precedes this QRS complex ….. Beginning of T
phase wave

Isovolumetric Relaxation Phase Rapid Filling Phase Reduced filling Phase

Duration 0.1 s 0.1 s 0.2 s

Ventricular Constant ↑ rapidly ↑slowly
volume 80% of blood pass from atria to ventricle (passive)
Ventricular ↓ ↓as ventricles relax to Little rise
pressure accommodate more blood
Valves
AV valves closed Opening
Semilunar valves Sudden closure Closed

Heart sounds 2nd 3rd Not heard (except in

children)
Aortic Dicrotic wave due to bouncing of ↓ As blood flow to periphery
Pulmonary blood upward due to elasticity of
‘pressure the valve
Atrial pressure +ve V wave -ve y wave Little rise ?
Cause Due to ↑VR Due to Rapid flow of blood
from atria to ventricle

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Ventricular pressure-volume relationship: Pressure-Volume Loop

• End-diastolic pressure-volume relationship EDPVR = Passive length-tension relationship

➢ ↑EDV → ↑end diastolic pressure
• End-systolic pressure-volume relationship ESPVR= Active length-tension relationship
➢ Starling law: “within limits, ↑EDV → ↑maximum ESP
➢ Slope on the inotropic state
point “1” Mitral valve open (ESV)
Line “1-2” filling phase
(Ventricular volume ↑
Ventricular pressure ↑)
point “2” Mitral valve close (EDV)
o Ventricle contract isometric
Point 2 Mitral valve closes
Line “2-3” isometric contraction phase
Ventricular volume constant
ventricular pressure ↑
Point “3” Aortic valve opens
o With opening of aortic valve,
Point “3” Aortic valve opens
Line “3-4” ejection phase
Ventricular volume ↓
ventricular pressure ↑to maximum then starts to ↓
point “4 Aortic valve closes
o Ventricular start isometric relaxation
point “4 Aortic valve closes
Line “4-1” isometric relaxation phase
ventricular volume constant & ventricular pressure ↓)
point “1 Mitral valve open
Width of loop = stroke volume (SV).
stroke work: = stroke volume X mean aortic pressure (afterload)

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 CONTROL OF CARDIAC OUTPUT: determined by

1. Heart rate (HR)

2. Stroke volume (SV): depend on preload, afterload, inotropic state
Effect of heart rate on cardiac output
A- Changes in HR are more important than changes in SV.
• Cause: In untrained person, HR ↑100% to 200% during exercise
B- Heart rate controlled by many factors mainly autonomic
Doubling HR alone from 70 to 140 beat/min ↓ SV (due to shortening of diastolic time & filling)
(by artificial pacemaker or arrhythmias) → → no change in CO
↑HR alone > 150/min→ Marked↓ in SV →↓ CO.
(↑HR cannot compensate for ↓in SV)
↓HR alone < 60/min→ ↓ CO
(↑SV cannot compensate for ↓ HR)
(Limited capacity)

C- During exercise (in physiology) Doubling HR → doubling CO due to ↑ SV

Regulation of Stroke Volume = EDV - ESV. affected by:

Preload: affects mainly EDV. Afterload: affects mainly ESV. Inotropy: affects mainly ESV.
Effect of changes in preload on SV
A- Preload degree of stretching (sarcomere length) before contraction.
• Measured by EDV
• EDV depends on VR.
B- ↑VR→↑ EDV→↑ SV = direct relation = Starling’s law=
“heterometric autoregulation” → matches SV with VR.
C- In pressure-volume loop
• Ventricle start contraction at higher EDV (2a) and reach the same ESV = ↑ width → ↑SV.
D-in performance of isolated cardiac muscle
↑preload →↑ amount and velocity of shortening
D- Factors affecting preload:
1. ↑VR (most important factor )
2. Strong Atrial contraction →↑preload.
3. ↑Heart rate → ↓diastolic time →↓preload
4. ↓Ventricular compliance (myocardial infarction) →↑slope of EDVPR→ ↓ preload

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Effect of Afterload on Stroke Volume
➢ Afterload= aortic pressure for left ventricle/ pulmonary pressure for right ventricle
➢ ↑afterload → shifts relationship between EDV and SV downward →↓ SV
➢ In Pressure-volume loop:
• Ventricle start contraction at the same EDV and
reach higher ESV = ↓SV
➢ in performance of isolated cardiac muscle:
↑afterload → ↓ amount and velocity of shortening →↓SV

Effect of Inotropic State on Stroke Volume

➢ + ve inotropic → shifts relationship between EDV and SV upward → ↑SV
➢ In pressure-volume loop:
• + ve inotropic shifts ESPVR upwards & left
• Ventricle start contraction at the same EDV and reach lower ESV
➢ in performance of isolated cardiac muscle: + ve inotropic →↑ amount and velocity

Cardiac Function Curve

Relation between (RAP) and (CO)
Mechanism:↑ RAP →↑CO independent of external stimuli = (heterometric autoregulation) = Starling’s law=
intrinsic mechanism
Limit curve reaches a plateau at 13 L/min
Slope of the curve increases with Slope of the curve decreases with
• ↑Heart rate (sympathetic) • ↓Heart rate (parasympathetic).
• ↑Inotropy (sympathetic • ↓Inotropy (myocardial ischemia).
• ↓Afterload (peripheral VD & ↓ABP). • ↑Afterload (hypertension).
Result: higher CO , exceed 13 l/min. Result: lower CO , ↓ below13 l/min.
“Hyper-effective heart” “Hypo-effective heart”

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Myocardial Oxygen Consumption (MVO2)
= 8 ml O2/ min/100 gm tissue to regenerate ATP
6 ml needed to regenerate ATP for 2ml by other cellular activities and ionic pumps
contraction & relaxation. (basal oxygen consumption)

Factors affecting myocardial oxygen consumption

1- Heart rate: → increase in MVO2
2- Inotropy: → ↑in MVO2.
3- Afterload: → ↑in MVO2.
4- Preload: →smaller ↑in MVO2.
• Anginal pain: worsen by ↑HR or ABP and not worsen by ↑preload
• Necessary to prevent tachycardia & hypertension in case of coronary insufficiency.

Cardiac Reserve
maximum % increase in CO above normal.
Cardiac reserve
In normal young adult 400 %→ CO↑ from 5 to 25 L/min (during exercise)
In well-trained athletes 600 % (35 l/min)
In elderly people 200%
In heart failure zero %.

Cardiac reserve depends on

1- Heart rate reserve: Maximal HR = 220 – age in years
2- Stroke volume reserve
• SV: ↑ from 70 up to 200 ml during exercise via ↑EDV (Starling’s mechanism).
↓ESV (positive inotropic).
3. Cardiac hypertrophy (↑size of the heart):
Volume overload hypertrophy Pressure overload hypertrophy
↑ ventricular thickness ↑ ventricular thickness
↑ventricular volume (EDV) without ↑ in ventricular volume
Eccentric hypertrophy Concentric hypertrophy
Cause: Exposure to high preload (performance Cause: Exposure to high afterload (e.g.
of endurance exercise (moderate intensity, e.g. performance of strength training, or untreated
long-distance runners) hypertension).
Benefit: ↑ ability of the heart to pump greater Benefit: ↑ ability of the heart to pump With
volume. greater strength
Disadvantage: ↓ventricular compliance

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Arrangement of circulatory system?
2 pumps (circulation)
Pulmonary circulation Systemic circulation

Series arrangement of pulmonary & systemic circulations ensure that

• Blood pumped by right ventricle = blood pumped the left ventricle into
Parallel arrangement in systemic circulation→ ↑or ↓blood supply to a particular organ except the liver
• Receives blood supply from aorta (parallel) And also from venous blood of GIT (series)

Define??
Preload Afterload
Stretching of cardiac muscle by load before Load added to the muscle after start of contraction=
contraction → generates passive tension →The muscle generate active tension to move the
afterload.

Length-Tension Relationship in Cardiac Muscle

Passive length-tension relationship Active length-tension relationship= Starling Law

Stretching of cardiac muscle →↑passive tension Stretching of cardiac muscle →↑active tension within
limits

CARDIAC CYCLE
Period during which the heart complete one systole & diastole
60
Duration of each cycle = HR (75)
= 0.8 sec
Atria Ventricle
Systole 0.1 0.3
Diastole 0.7 0.5
• Atrial & ventricular diastole for 0.4 s
• Atrial systole before ventricular systole
• Atrial systole coincides with last 0.1 sec of ventricular diastole (late diastole)
• ↑HR → ↓duration of cycle (Shortening affects diastole more than systole)

Heart rate 75 / min Heart rate 200 / min

Duration of cardiac cycle 0.8 0.3

Duration of ventricular systole 0.3 0.15

Duration of ventricular diastole 0.5 0.15

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AORTIC PRESSURE curve (record of aortic pressure during cardiac cycle)
Anacrotic limb Catacrotic limb
Diacrotic Notch= Diacrotic wave Remaining of catacrotic
Incisura limb

Aortic ↑ to 120 mmHg Sharp small drop ↑ (bouncing of ↓ to reaches 80 mmHg

Pressure blood up by closed
valve)

Coincide Rapid ejection End of reduced Isovolumetric

with phase ejection phase relaxation phase

Right atrial pressure curve (jugular venous pulse= JVP)

• No valves exist between right atrium and internal jugular vein

Cause
Positive A wave Atrial contraction
Negative X wave Flow of blood from atria to ventricle

Positive C wave Bulging of cusps during isovolumetric contraction phase

Negative X- wave Downward pull of cusps during rapid ejection phase

Positive V wave ↑VR
Negative y wave ventricular filling phase

Relationship between JVP and ECG, carotid pulse and heart sounds.

o “a” wave follows P wave of ECG.

o “c” wave follows QRS complex of ECG
o “x\” wave occurs with carotid pulse= normally jugular veins collapse with carotid pulsation.

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 heard with: Closure of valve & Very rapid turbulent Blood flow
HEART SOUNDS

first heart sound (S1) Second heart sound (S2)

Causes Sudden closure of A-V valves Sudden closure of semilunar valves

Timing Isovolumetric contraction phase Isovolumetric relaxation
Characters low pitched high-pitched
Duration Long Shorter
Best Mitral component: Aortic component
heard • At left 5th intercostal space in mid- At 2nd right intercostal space parasternal
clavicular line Pulmonary Components
Tricuspid components: at: 2nd left intercostal space parasternal
• At left lower end of sternum
Splitting Mitral valve closes before tricuspid valve Aortic valve closes before pulmonary valve,
Cause: left ventricular ejection ends before
As time interval between 2 components is right ventricular ejection
very short→ normally heard as a single Splitting of 2nd sound: ↑ during inspiration.
sound (physiological splitting

Third heart sound (S3 Fourth heart sound (S4)

Cause Rapid flow of blood Rapid flow of blood

Timing Rapid filling phase Atrial systole
Characters Non-audible except in children Non-audible

• End Diastolic Volume = volume of blood at end of diastole.

• ESV: volume of blood at end of Systole.
• Stroke volume: volume of blood pumped by each ventricle/ beat
• Cardiac Output: volume of blood pumped by each ventricle /min.
• Cardiac index: CO/ m2
• Cardiac Output in Various Conditions:
Increased in Decreased in
Exercise (700%) Rapid arrhythmia
Excitement & anxiety (100%) Heart failure
Pregnancy standing from supine position

= normally > 55%

Heart failure with reduced heart failure with normal ejection fraction
Importance index of
ejection fraction Due to ↓ ventricular compliance→↓ EDV
contractility

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GEORGE 0