CARDIOVASCULAR PHYSIOLOGY

LECTURE 1

Organization of the cardiovascular system. Heart – morpho-functional features.

Properties of the myocardium: Cardiac electrophysiology - excitability.

Prof. Ana-Maria Zagrean

Physiology Division
CARDIOVASCULAR PHYSIOLOGY

Organization of the cardiovascular system. Heart – morpho functional

features.

Properties of the myocardium: Cardiac electrophysiology – excitability,

automatism and conductivity. Mechanical properties of the heart: Working
myocardium - Myocardial contractility and relaxation.

Electrocardiogram

Cardiac cycle. Analysis of cardiac activity – Polygram.

Heart as a pump – cardiac performance. Particularities of the cardiac
muscle metabolism. Heart activity regulation - intrinsic mechanisms.

Hemodynamics – morpho-functional properties of blood vessels. Blood

flow. Vascular resistance. Blood pressure. Arterial pressure.
Venous pressure. Microcirculation and its regulation. Lymphatic circulation.
Coronary circulation.

Cardiovascular system regulation.

 The need for a competitive circulatory system

• Isolated/single cells vs. multicellular organisms

• Connection between external - internal milieu: from simple

diffusion to complex, highly regulated, circulatory systems
Cardiovascular System - an interplay of fast and complex mechanisms to
maintain body homeostasis and adaptive capacity

1) Heart: a dual pump circulating blood

2) Blood

3) Vessels of systemic and

pulmonary circulations

4) Integrated regulatory system to

adapt to the changing circumstances
 Components of the cardiovascular system
and their function:
1. the heart consists in two pumps, operating in series, requiring equalization of
their outputs (5 L/min)
Left heart (LH) – main pump
Right heart (RH) – boost pump
2. the blood
3. a vascular system (two serial circuits):
-systemic / pulmonary circulation
-high-pressure / low-pressure
-vessels (arteries, veins, capillaries) respond with changes in blood flow to
changing metabolic demands
-angiogenesis: self-repairing/self-expanding capacity of endothelial cells

4. an integrated regulatory system to adapt to variable demands:

- intrinsic: automatism
- systemic: nervous system & endocrine system
- local/metabolic regulation
! Coupling of blood tissue perfusion with the level of activity/metabolic rate
e.g., increase in muscular metabolic rate during physical activity
muscular blood perfusion - resting conditions – 4 ml/100g/min
- physical activity - 80 ml/100g/min
 1. Primary roles of the circulatory system:
Transport system function

(1) - Nutrition, growth and repair

transport between all parts of the body of nutrients,
metabolic products, respiratory gases (O2, CO2):
relation CO2 → pH → homeostasis

(2) - Maintenance of circulatory parameters:

-cardiac output - 5 L/min at rest, for an adult;

capacity to increase 5 fold during exercise
-blood pressure
-blood volume
-blood fluidity/viscosity
 2. Secondary roles of the circulatory system:

(1) fast chemical signaling to cells by means of circulating hormones, neurotransmitters,

signaling molecules, including the ones secreted by itself
(2) dissipation of heat by delivery of heat from the core to the surface of the body
(3) mediation of inflammatory and host defense responses against invading
microorganisms - ‘channel’ for the immune response/defense mechanisms:
immune cells, antibodies, clotting proteins
(4) secretory function of the circulatory system:
- Atrial Natriuretic Peptide (ANP):
- released by atrial fibers as a response to heart overload
- powerful vasodilator, reduces circulatory water & Na+ → reduces blood pressure
- Nitric oxide - NO (Endothelial Derived Relaxing Factor):
vasodilator, inhibits platelets adherence & aggregation
- Endothelial Derived Hyperpolarizing Factor
- Endothelin (ET): vasoconstrictor on ETA, ETB2 receptors
- Prostaglandins (PGs) - PGE2, PGI2 (prostacyclin): increase Na+ excretion by the
kidneys, vasodilators
Cooperation between different components of the cardiovascular system
- example of adaptation to variable demands during heavy exercise
All components of the cardiovascular system cooperate
for serving its functions and maintain body homeostasis

Life-threatening human diseases are caused by failure of:

- the heart as a pump (e.g., congestive heart failure),

- the blood as an effective liquid organ (e.g., thrombosis and
embolism),
- the vasculature either as a competent container (e.g., hemorrhage)
or as an efficient distribution system (e.g., atherosclerosis),
- the interactions among all these components can by itself elicit or
aggravate many human pathological processes.
 Heart – morphological data

- Weight  300 g

- Longitudinal diam.=100-120 mm
- Transversal diam. = 80 -100 mm

- Measurement methods:
- clinical: aria of cardiac dullness
- echocardiography
- radiology
 Morphological components of the heart
- Pericardium:
thin-walled membranous cavity surrounding the heart;
small volume of pericardial fluid in the space between its two surfaces.

- Myocardium:
working myocardium,
peacemaker cells & cardiac conduction system (excitoconductive system)

- Fibrous skeleton
- 4 intracardiac valves that ensure the
one-way blood flow through the heart:
2 AV valves: Right (tricuspid)
Left (mitral)
2 semilunar valves: Aortic & Pulmonary
- chordae tendineae

- Endocardium
- Coronary circulation
The cardiac muscle: myocardium
Excito-conductive system (1%)
- Peacemaker cells
- Conductive system

Working myocardium (99%)

-involuntary contraction
-striated in appearance (sarcomeres
and myofilaments similar to skeletal
muscle ones);
-small cells, electrical and mechanical
cell-to-cell communication (syncytium)
-mechanical performance
 Myocardial cell (MC) structure

-Sarcolema
T tubules & terminal cisterns
continuous with the cell membrane, carry
the AP; more developed in the ventricles

-Sarcoplasmic reticulum (SR)

in close proximity to the contractile
elements; site of storage and release of
Calcium
 Myocardial cell (MC) structure

Sarcomere:
contractile unit of the MC
between 2 Z lines
contains: thin filaments
- actin, troponin, tropomyosin
thick filaments
- myosin
Intercalated disks:
paracellular connections
hold the cells (desmosomes)
connect them electrically (gap junctions),
→ heart behaves as an electrical
syncytium
(sync, synch: informal for synchronization)

Mitochondria
more than in the skeletal muscle
 Myocardial properties
1. Excitability - bathmotropia
2. Automaticity & rhythmic activity - chronotropia
3. Conductibility - dromotropia
4. Contractility - inotropia
5. Relaxation - lusitropia
Different cardiac cells serve different and
very specialized functions, but all are
electrically active/excitable.
The heart’s electrical signal normally
originates in a group of cells located at the
junction between vena cava and the right
atrium (SA node) that depolarize
spontaneously; it then spreads throughout
the heart from cell to cell.
Because the excitation of cardiac myocytes triggers contraction, a process called
excitation-contraction coupling, the propagation of action potentials must be
carefully timed to synchronize ventricular contraction and thereby optimize the
ejection of blood.
 Myocardial Excitability
• Excitability
-is the capacity to respond to a stimulus with a minimum threshold intensity
-depends on ionic gradients across the polarized cell membrane,
maintained through the action of the membrane ion transport system (ionic
channels, pumps, exchangers).

• Heart is an excitable tissue capable of generating and responding to

electrical signals

• The action potential (AP) generated in the heart propagates through

specialized conducting pathways or cell-to-cell within the working
myocardium, that generate the force of contraction.

• AP displays different appearances within the different types of cardiac cells.

Based on the speed of the upstroke, AP are either slow (sinoatrial and
atrioventricular nodes) or fast (atrial myocytes, Purkinje fibers, and
ventricular myocytes).
→ Heart contains cells that generate spontaneously APs =
Pacemaker Cells (exhibits automaticity)
→ slow response AP → induce a pace, rhythm…
→ Working myocardium – respond to electrical stimuli
→ fast response AP → contraction, mecanical activity

Cardiac action potentials (APs) have

distinctive shapes at different sites.
 Electrophysiology of cardiac cells – pacemaker cells

The cardiac AP starts in specialized muscle cells with intrinsic pacemaker

activity, or automaticity, located in the sinoatrial node (SAN), within the right
atrium (RA). APs then propagates in an orderly fashion throughout the heart.

SAN’ cells depolarize spontaneously and fire APs at a regular, intrinsic rate
ranging from 60 - 100 times/minute for an adult individual at rest. This rate can
be modulated by parasympathetic and sympathetic neural inputs.
 AP conduction in the heart
Cardiac cells are electrically coupled through gap junctions, thus spontaneous
AP originating in the SAN propagates from cell-to-cell throughout the right atrial
muscle and spread to the left atrium.
 The cardiac AP conducts from cell to cell via gap junctions

The electrical influence of one cardiac cell on another depends on the

voltage difference between the cells and on the resistance of the gap
junction connecting them and permits electrical current to flow - Ohm’s law.

When RAB is very small (i.e., when

the cells are tightly coupled), the gap
junctions are minimal barriers to the
flow of depolarizing current.

An AP conducting from left to right causes intracellular current to flow from fully
depolarized cells on the left, through gap junctions, and into cell A. Depolarization
of cell A causes current to flow from cell A to cell B (IAB). Part of IAB discharges the
capacitance of cell B (depolarizing cell B), and part flows downstream to cell C.
 Conduction in the heart – gap junctions and currents flow

Depolarization with Na+ and Ca2+ inflow (cell A) produces a flow of positive charge
= intracellular current that discharges the membrane capacitance of the next cell
connected through gap junctions (cell B), thereby depolarizing it and releasing
extracellular positive charges that had been associated with the membrane
(capacitative current).
The movement of this extracellular positive charge (from cell B to cell A) constitutes
the extracellular current.
The intracellular and extracellular currents are equal and opposite.
The flow of this extracellular current in the heart gives rise to an instantaneous
electrical vector, which changes with time. Each point on an electrocardiogram
is the sum of the many such electrical vectors, generated by the cells of the heart.
 AP conduction in the heart

About 0.1 sec after its origination in SAN, AP arrives at the atrioventricular
node (AVN), then, because of the presence of a fibrous atrioventricular ring,
spreads directly through the only available pathway towards the ventricles – the
His-Purkinje fiber system (bundle of His), a network of specialized conducting
cells that carries the AP to the muscle of both ventricles.
 Underlying APs are 4 major time-dependent and voltage-
gated membrane currents

The myocytes in each region of the heart have a characteristic set of channels,
to support distinctive APs:

1.The Na+ current (INa) is responsible for the rapid depolarizing phase of the
AP in atrial and ventricular muscle and in Purkinje fibers.

2. The Ca2+ current (ICa) is responsible for the rapid depolarizing phase of the
action potential in the SA node and AV node; it also occurs during the plateau
phase (phase 2) of the AP in the working myocardium contributing to its
contraction.
3. The K+ current (IK) is responsible for the repolarizing phase of the AP in all
cardiomyocytes.

4. The pacemaker current (If) is responsible, in part, for pacemaker activity in

SA nodal cells, AV nodal cells and Purkinje fibers.
Channels in heart muscle carry numerous other ionic currents.
 Diversity of the cardiac ion channels

While the cellular and organ-level function corelates with the classical
channels described, important subtleties in the detailed function can depend
on the additional channel subtypes that may be expressed at varying
levels (channelopathies) and that can change under stress or during
disease.

- Along with the Nav1.5 “cardiac” Na+ channel, Nav1.4, normally found in
skeletal muscle can be expressed in the heart.

- In addition to the L-type Ca2+ channel, cardiac myocytes may also

express the T-type Ca2+ channel, mainly in heart diseases (L - long lasting,
T - transitory).

- Ventricular and atrial myocytes may express K+ channels in a diversity

much greater than classically described. Moreover, the subtypes of K+
channels often changes in disease processes.
Cardiac Ion Channels
Two electrogenic transporters also carry current across
plasma membranes:
NCX1 - type 1 Na-Ca exchanger - normally moves 3 Na+ into the cell in order to
extrude 1 Ca2+, using the electrochemical gradient for Na+ as an energy
source/driving force for transport → produces an inward depolarizing current.
This electrochemical gradient transiently reverses early during the cardiac AP (due to
the positive Vm), when the Na-Ca exchanger may be able to reverse and mediate
entry of Ca2+ and a net outward current.
Later during the AP, the Na-Ca exchanger returns to its original direction of operation
(i.e., Ca2+ extrusion and inward current).
During the plateau phase of the AP, the inward current mediated by the Na-Ca
exchanger tends to prolong the action potential.

Na-K pump - normally moves 2 K+ into the cell for 3 Na+ transported out of the cell,
using ATP → produces an outward or hyperpolarizing current.
Cardiotonic drugs (digoxin, ouabain) inhibit the Na-K pump and thereby cause an
increase in [Na+]i, thus reduce the outward current carried by the pump and therefore
depolarize the cell.
The changes in membrane potential (Vm) during the cardiac AP are
divided into separate phases, with particularities in the SA node and
ventricular muscle (working myocardium).
Phase 0 - the upstroke of the AP.
- Slow upstroke due only to ICA (pacemaker cells),
- Fast upstroke due to both ICA and INa

Phase 1 - the rapid repolarization component of the AP

- due to almost total inactivation of INa or ICa and may also depend on the
activation of a minor K+ current, called Ito (for transient outward current).

Phase 2 - the plateau phase of the AP, prominent in ventricular muscle.

- depends on the continued entry of Ca2+ or Na+ ions through their major channels
and on a minor membrane current due to the Na-Ca exchanger NCX1.
Phase 3 - the repolarization phase of the AP.
- depends on IK

Phase 4 - the electrical diastolic phase of the AP.

- Vm during phase 4 is termed the diastolic potential;
- in SA and AV nodal cells, changes in IK, ICa, and If produce pacemaker activity
during phase 4.
- Purkinje fibers also exhibit pacemaker activity but use only If.
- Atrial and ventricular muscle have no time-dependent currents during phase 4.
Principal ionic currents & channels that generate AP in a cardiac cell
AP Phases 1
2
0

Membrane Potential (mV)

0 3
-50

4 4
-100
0 50 100 150 200 250 300 ms
AP Phases:
0- depolarization/upstroke of the AP; 1-initial repolarization;
2-plateau; 3-repolarization; 4- resting membrane potential
The Na+ current is the largest current in the heart
Abundant (200 Na+ channels / µm2 of membrane) in ventricular and atrial
muscle, Purkinje fibers, and specialized conduction pathways of the atria.
Current through Na+ channels (INa) is not present in SA or AV nodal cells.
Voltage-gated Na+ channel has both α and β1 subunits.
The α subunit (Nav1.5) - specific for the cardiac Na+ channel, has several
phosphorylation sites that make it sensitive to cAMP-dependent protein kinase
(PKA) which stimulates the cardiac Na+ channel

The Na+ channels:

- closed at the negative resting potentials of the ventricular muscle cells,

- rapidly activate (in 0.1 - 0.2 ms) in response to local depolarization produced
by conducted APs → massive inward current → rapid upstroke of the cardiac
AP (phase 0).
-close if Vm remains at a positive level, a time-dependent process known as
inactivation (slower than activation, but still rapid, half-time, ~1 ms), partly
responsible for the rapid repolarization of the AP (phase 1).
-at the potentials maintained during the plateau of the cardiac AP, slightly + to 0 mV during
phase 2, a very small but important component of this current remains (INa, late), and
contribute to prolong phase 2; also can contribute to myocytes’ proarrhythmic behavior.
 The Na+ current

The regenerative spread of the conducted AP depends in large part

on the magnitude of Na+ current (INa).

Na+ current activates INa in neighboring cells and also activates

other membrane currents in the same cell, including ICa and IK.

In cardiac myocytes the depolarization, initiated by Nav1.5,

activates the L-type cardiac Ca2+ channel (Cav1.2), which greatly
prolongs the depolarizing phase of the cardiac AP due to its long-
duration opening events.

Local anesthetic antiarrhythmic drugs, such as lidocaine, work by

partially blocking INa.

Note that during AP [Na+]i increases by only 0.02%

 The Ca2+ current in the heart passes primarily through
L-type Ca2+ channels
The Ca2+ current (ICa) is present in all cardiac myocytes:
-L-type Ca2+ channel (Cav1.2) is the dominant one in the heart.
activation ~ 1 ms; inactivation ~ 10-20 ms
are dihydropyridine receptors
pharmacologically blocked by: nifedipin, verapamil, diltiazem
-T-type Ca2+ channels is present but in smaller amounts.
In the SA node, the role of ICa is to contribute to pacemaker activity.
In both the SA and AV nodes, ICa is the inward current source that is
responsible for the upstrokes (phase 0) of the SA & AV nodal slower APs
→ the speed of the conducted APs is much slower than that of any other
cardiac tissue
→ electrical delay between atrial contraction and ventricular contraction
that permits more time for the atria to empty blood into the ventricles.
 The Ca2+ current

ICa sums with INa during the upstroke of the APs of the ventricular
and atrial muscle and the Purkinje fibers → it increases the
velocity of the conducted AP

ICa participate in Phase 2 (plateau phase) of AP in atrial and

ventricular muscle → long refractory period of the AP

In atrial and ventricular muscle cells, the Ca2+ entering via L-type
Ca2+ channels activates the release of Ca2+ from the sarcoplasmic
reticulum (SR) by calcium-induced Ca2+ release
 Sarcoplasmic
Reticulum Ca2+

Ca2+ dependent Ca2+

releasing channel
(ryanodine receptor)

T (transverse) tubule

L-type Ca2+ channel

(Cav1.2. dihydropiridine
receptors)

Sarcoplasmic
Reticulum (SR)
 K+ Currents
IK
- repolarization currents present in all cardiac myocytes
- very small at negative potentials
- with depolarization slowly activates (20-200 ms), but does not inactivate
- responsible for repolarizing the membrane at the end of AP, during
Phase 3 of the AP
- deactivating at the diastolic membrane voltage

Ito
- early transient outward K current (A-type)
- activated by depolarization; rapidly inactivates
- contributes to Phase 1 of the AP

IK 1 inward rectifying K channel

- responsible for the resting membrane potential (Phase 4)
 K+ Currents
G-protein activated K+ current
-vagal nerv stim. of SAN & AVN→ Ach→ muscarinic receptor M2 →
G-protein (bg subunit) → GIRK K channels: outward K current →
hyperpolarization → slows pacemaker rate & slows AP conduction
through AVN

KATP current:
-ATP-sensitive channels, present in abundance, activated by low intracellular
[ATP]; low probability to open at normal [ATP] ~ 5 mM
-K currents dependent on ATP/ADP ratio; high activity/hypoxia→
ATP & ADP → K channels activation & K+ outflow
-possible role in electrical regulation of contractile behavior by coupling
cellular metabolism & membrane excitability; cardioprotection
Note that the [K+]i changes just by 0.001% during AP.
 Pacemaker Current If

- found in SAN & AVN cells and in Purkinje fibers

- slow activation (100 ms) by hyperpolarization at the end of Phase 3
(“f” from funny); they do not conduct at positive potentials
- Produces an inward, depolarizing current of Na+
- If through a nonspecific cation channel (permeable for Na & K) called
HCN (hyperpolarization-activated cyclic nucleotide (AMPc, GMPc)-
gated channels)
- If current is not the only current that contributes to pacemaker activity;
in SA and AV nodal cells, ICa and IK also contribute significantly to the
phase 4 depolarization.
 Cardiac ion channels and their modulation

The membrane currents involved in the membrane potential and

AP phases:

- are under the control of local and circulating agents:

acetylcholine, epinephrine, and norepinephrine

- are targets for therapeutic agents designed to modulate the

heart’s rhythm: Ca2+ channel blockers
β-adrenergic blockers.
Local anesthetic antiarrhythmic drugs (lidocaine)
 Different cardiac tissues uniquely combine ionic
currents to produce distinctive action potentials

- cell specific combination of various currents, both voltage-gated/time-dependent

currents and “background” currents, present in each cell type.

-Goldman-Hodgkin-Katz (GHK) equation describes Vm in terms of the conductances’

for the different ions (GNa, GK, GCa, GCl) relative to the total membrane conductance
(Gm) and the equilibrium potentials (ENa, EK, ECa, ECl):

-As the relative contribution of a particular membrane

current becomes dominant, Vm approaches the
equilibrium potential for that membrane current.
-How fast Vm changes during AP depends on the
magnitude of each of the currents.
-Each current independently affect the shape of AP,
but the voltage- and time dependent currents interact
with one another because they affect, and are
affected by Vm.
 PNa+
AP

0
Membrane Potential (mV)

10

PCa2+
PK+
-50
1.0

-100
0.1

0 0.15 0.30
Time (sec.)
 Major Ion Channels Involved in Purkinje and Ventricular
Myocyte Membrane Potentials
Voltage
(V)-Gated
or Ligand
Name (L)-Gated Functional Role
Voltage-gated Na+ V Phase 0 of action potential (permits influx of Na+)
channel (fast, INa)
Voltage-gated Ca2+ V Contributes to phase 2 of action potential (permits influx of Ca++
channel (slow, ICa) when membrane is depolarized); β-adrenergic agents increase
the probability of channel opening and raise Ca2+ influx;
Acetylcholine (ACh) lowers the probability of channel opening
Inward rectifying K+ V Maintains resting membrane potential (phase 4) by permitting
channel (IK1) outflux of K+ at highly negative membrane potentials
Outward (transient) V Contributes briefly to phase 1 by transiently permitting outflow of
rectifying K+ K+ at positive membrane potentials
channel (Ito)
Outward (delayed) V Cause phase 3 of action potential by permitting outflow of K+
rectifying K+ after a delay when membrane depolarizes; IKr channel is also
channels (iKr, iKs) called HERG channel (‘r’ for rapid, ‘s’ for slow).
G protein–activated L G protein–operated channel, opened by ACh and adenosine
K+ channel (iK.G, (ado); this channel hyperpolarizes membrane during phase 4
iK.ACh, iK.ado) and shortens phase 2
Events associated with the
ventricular action potential
 Cardiac AP - Refractory periods
Once a ventricular muscle cell is activated electrically, it is refractory to
additional activation because the inward currents (INa and ICa) that are
responsible for activation are largely inactivated by the membrane
depolarization → effective/absolute refractory period.
During the effective refractory period, an additional electrical stimulus has
no effect on the AP.
The relative refractory period begins at the end of the plateau, when the
cell begins to repolarize as IK increases in magnitude and ICa and INa begin
to recover from inactivation.
During this period, an additional electrical stimulus can produce an AP, but
a smaller one than usual.
Refractoriness provides the heart with a measure of electrical safety
because it prevents extraneous pacemakers (which may arise
pathologically) from triggering ectopic beats.

An extrasystolic contraction would make the heart a less efficient pump.

Refractoriness also prevents tetanus (perpetual systole and no further
contractions).
 Cardiac AP - Refractory periods

0
Membrane Potential (mV)

-50 RRP
ERP

-100
0 50 100 150 200 250 300 ms

ERP/ARP - Effective/Absolute Refractory Period;

RRP - Relative Refractory Period
Changes in action potential amplitude and slope of the upstroke as
premature (P) action potentials are initiated at different stages of the
relative refractory period of the preceding excitation in a fast-response
fiber (bar = 100 msec).
 Premature contraction
early

delayed

Compensatory pause

P- premature contraction
AP – electrical activity
Contraction – mechanical activity
 CARDIOVASCULAR PHYSIOLOGY BIBLIOGRAPHY
-LECTURES
Medical Physiology 3rd Edition - W. Boron & E. Boulpaep
-PRACTICALS
Cardiovascular System Physiology. A Practical Approach - A-M. Zagrean et al., 2020

Lecture 1 bibliography from Boron & Boulpaep, Medical Physiology

Organization of the cardiovascular system (Boron, Ch. 17, p. 410-412)

Cardiac electrophysiology (Boron, Ch. 21, p. 483-493)
 CARDIOVASCULAR PHYSIOLOGY

LECTURE 2

Organization of the cardiovascular system.

Cardiac electrophysiology - Properties of the myocardium:
Automatism, Conductivity, Contractility and Relaxation.

Prof. Ana-Maria Zagrean

Physiology Division
 Myocardial properties

1. Excitability - bathmotropia
2. Automaticity & rhythmic activity - chronotropia
3. Conductibility - dromotropia
4. Contractility - inotropia
5. Relaxation - lusitropia
 Heart Automaticity and Rhythmicity

• Automaticity and rhythmic activity (chronotropia) - the intrinsic

property of myocardial cells with automatism (pacemaker cells) to
spontaneously and rhythmically generate a propagated depolarization /
action potential (AP), at regular rate, in the absence of an external
stimulus*
* heart of human fetus start to beat (22 days) before development of nerves

• Conductibility (dromotropia) – the ability of myocardial cells to transmit

electrical impulses generated from the heart peacemaker, from one cell to
another, within the myocardial syncytium;
The hierarchy of the pacemakers of the heart
Pacemaker activity = spontaneous time-dependent depolarization of the cell
membrane leading to an AP in an otherwise quiescent cell.

The normal heart has three intrinsic pacemaking tissues: the SA node, the AV
node, and the Purkinje fibers.
Any cardiac cell with pacemaker activity can initiate the heartbeat, but the
pacemaker with the highest frequency (SAN) will be the one to trigger an AP that will
propagate through the heart.
 SA node is the primary pacemaker of the heart

The heart’s AP normally spontaneously originates in SA node and propagates

throughout the heart from cell to cell, to synchronize ventricular contraction
and optimize the ejection of blood.
The automatism of the heart - Pacemaker cells
- organized in a specialized excitatory & conductive system
- anatomically distinct: smaller, few contractile fibers

- electrogenic system: EXCITABILITY, AUTOMATISM

generate AP spontaneously, rhythmically
- set the rate of the heart beat: CONDUCTIVITY

rapidly conduct APs throughout the heart

generate rhythmical contraction
Cardiac pacemaker and conductive system (excito-conductive system):

1) a sinoatrial node (SAN),

-located in the superior posterolateral wall of the RA; ellipsoid shape: 15/3/1 mm
-with the highest automaticity, discharging at an intrinsic rate of 60÷100 discharges/min.
The depolarization generated by the SA node consecutively suppresses the spontaneous
depolarization of other cardiac structures, and determines the sinus rhythm and a heart rate
of about 70 beats/minute, in physiological conditions.

P cells of the SAN:

- are stable oscillators whose currents are always varying with
time, and they do not have a constant resting potential;
- membrane permeability to Na and Ca during diastole; inward
Ca current during upstroke (phase 0) of AP.
Cardiac pacemaker and conductive system
(excito-conductive system):

2) Internodal & interatrial pathways

3) an atrio-ventricular (AV) node (40 discharges/min),

-located just above the AV ring,
-slows the current conduction with about 0.1 sec
-is the secondary site of origin of the electrical signal in
the heart
-its intrinsic activity depends on the interaction of IK, ICa,
and If.
-inward Ca current during upstroke of AP

4) the AV bundle of His-Purkinje,

-represents the only normal electrical atrio-ventricular
connection, and continues with its left and right
branches within the left and right ventricular myocardium
-intercalated disks, gap junctions
-in case of an accessory AV pathways - reentry loops
 Organization of the A-V node

AV node is composed of three functional

regions:
1. the AN region - the transitional zone
between the atrium and the remainder of the
node;
2. the N region - the middle part of the AV
node
3. the NH region, in which the nodal fibers
gradually merge with the bundle of His

Normally, the AV node and bundle of His are the

only pathways along which the cardiac impulse
travels from atria to ventricles
- accessory AV pathways - reentry loops

AN - atrio-nodal, N – nodal, NH – nodal-Hiss regions

The numbers represent the interval of time (sec)
from the origin of the impulse in the sinus node.
 Specialized excitatory & conductive system
5) Purkinje system:
-slowest intrinsic pacemaker rate (20-30 beats/min or less)
-distributed subendocardial within the ventricular walls, with the fastest conduction
velocity of the AP
-INa is large →conduct APs rapidly (rapid upstroke)
-distribute to the endocardium, causes ventricles to contract, from bottom up, pushing
blood out top of heart
Two fundamental principles underlie pacemaker activity:

1 - inward or depolarizing membrane currents interact with outward or

hyperpolarizing membrane currents to establish regular cycles of
spontaneous depolarization and repolarization.

2 - in a particular cell, these currents interact during phase 4 within a

narrow range of diastolic potentials:
between −70 and −50 mV in SA and AV nodal cells,
between −90 and −65 mV in Purkinje fibers.
Membrane currents in the SA node cells
The interactions among 3 time-dependent and
voltage-gated membrane currents (ICa, IK, and If)
control the intrinsic rhythmicity of the SA node.

The sum of a decreasing outward current (IK)

and two increasing inward currents (ICa and If)
produces the slow pacemaker depolarization
(phase 4) associated with the SA node.

The maximum diastolic potential (i.e., the most

negative Vm) of the SA nodal cells occurs during
phase 4 of the AP  −60 ÷ −70 mV.

As Vm rises toward −55 mV, ICa becomes increasingly activated and eventually
becomes regenerative, producing the upstroke of AP. This depolarization rapidly turns
off/deactivates If, and the whole process begins again.

Contribution of the Na-Ca exchanger NCX (the Ca2+ clock):

- the time-dependent subcellular Ca2+ release (Ca2+ sparks) from the SR in SA and AV
nodal cells → subcellular Ca2+ sparks activate an inward (depolarizing) INCX.
 Action Potential (AP) in pacemaker cells

Phases of SAN action potential.

The records in this figure are idealized. IK, INa,
ICa, and If are currents through K+, Na+, Ca2+,
and nonselective cation channels, respectively.
 Action Potential (AP) in pacemaker cells
-membrane permeability to Na+ and Ca2+ during diastole → unstable resting
membrane potential → slow diastolic depolarization after each repolarization

-inward Ca2+ current during upstroke of AP (phase 0 / depolarization).

The slow diastolic depolarization results from the

hyperpolarization-triggered cationic influx through
the non-selective ‘funny’ channels (If), that
raises the membrane potential from -60 mV up to
the -40 mV value of threshold potential, thus
triggering an AP.
 Action Potential (AP) in pacemaker cells

Slow diastolic depolarization (SDD), occurs during diastole and

represents phase 4 of the AP:
when the K+ outflow gradually diminish, Na+ inflow starts through the
funny channels, and Ca2+ inflow occurs through T-type calcium channels
(T from transient).

Mechanism:
1. Na influx through funny (slow) Na+ channels
2. Ca influx through T-type Ca channel
3. Decreased K+ efflux

phase 4
Non-selective ‘funny’ channels - Pacemaker Current If
- found in SAN & AVN cells and in Purkinje fibers
- are nonspecific cation channels (permeable for Na+ & K+)
- slow activation by hyperpolarization at the end of repolarization
(phase 3)
-“f” from funny, as it is activated by hyperpolarization and not by
depolarization
-produces a slow, inward, depolarizing current (slow Na+ influx)
AP in the pacemaker cell (SA node)
Upstroke - phase 0, depolarization:
• From the threshold membrane potential of – 40 mV to +10 ÷ +20 mV

Mechanism:
• Inward Ca2+ current through L-type Ca2+ channels (L from long-lasting)
→ increased Ca2+ conductance (ICa) → positive values of the membrane
potential

AP in the pacemaker cells is called

slow AP as the Ca2+ dependent phase 0
upstroke is slower than the fast
Na+-dependent upstroke of the AP
in the working myocardium.
AP in the pacemaker cell
Repolarization (phase 3):
• from membrane potential (+20 mv) to (-60 mv)

Mechanism:
• increase K+ efflux

phase 3
Myocardial conductivity (dromotropia)
 Spreading of excitation from SA node to the entire cardiac tissue

Chronotropic effect:
on the firing rate of SAN;
positive/negative
Dromotropic effects:
on conduction velocity, especially in AVN;
positive/negative
The myocardial conductivity is needed for an efficient pumping

Atria contraction precedes ventricles contraction, because of AV nodal delay:

- the impulse travels rather slowly through AV node (0.1 sec) & penetrating part of
the AV bundle (0,04 sec) (cause of the delay: less gap junctions…)

Both atria and ventricles should contract as a unit

-the impulse spreads so rapidly through the conducting system that all myocardial cells
in the atria and ventricles, respectively, contract at about the same time.
 Conduction velocity
• Reflects the time required for excitation to spread from SAN to the entire
cardiac tissue
• Fastest in the Purkinje system, slowest in AVN (important for ventricular
filling…)
– 0.02 to 0.1 m/sec in SA & AV nodes; AV delay: ~ 0.1 sec
– 1 m/sec. in internodal & interatrial anterior pathways
– 0.3-0.5 m/sec in A & V muscle (Endocardium → Epicardium)
– 1.5 - 4 m/sec in Purkinje fibers
longer fibers, distributed in 1/3 of ventricular volume
gap junctions (no., permeability…), direct connection with myocytes
fast Na currents, “regenerative spread of conducted AP” → rapid conduction
of cardiac impulse
 AP conduction in the heart
Atrial activation
Step 1: AP generated in the SAN is propagated and depolarize the atria,
following a general axis from right to left and downward.

Ventricular activation completes in ~100 ms:

Step 2: The septum depolarizes from left to right.
Step 3: The anteroseptal region depolarizes.
Step 4: The myocardium always depolarizes from the endocardium
(the cells lining the ventricles) toward the epicardium (cells on the outer
surface of the heart). The left ventricle depolarizes at the apex while the
Purkinje fibers are still in the process of conducting the action potential
toward the base of the left ventricle.
Step 5: Depolarization spreads from the apex toward the base, carried by
the Purkinje fibers. This spread to the base begins even as the signal in the
apex is still spreading from the endocardium to the epicardium. The last
region to depolarize is the posterobasal region of the left ventricle.
Step 6: The ventricles are fully depolarized.
 AP conduction in the heart

Ventricular muscle has three major time- and voltage gated membrane
currents: INa, ICa, and IK, and has no If (normally does not show no
pacemaker activity).

Ventricular AP:
-starts from a resting potential of −80 mV,
-rapid upstroke results from the activation of INa by an external
stimulus
-Ca2+ current is of particular importance to ventricular muscle because it
provides the Ca2+ influx that activates the release of Ca2+ from the SR.
The rapid repolarization (phase 1), the plateau (phase 2), and the
repolarization (phase 3) all appear to be governed by mechanisms similar to
those found in the Purkinje fibers.
However, the plateau phase is prolonged in ventricular muscle because the
inward and outward currents are rather stable during that time.
Distribution of the nervous fibers
 Autonomic effects on automatism and conduction
velocity

PS vagal innervation
Ach mediated
Muscarinic receptors on SAN, atria, AVN
Negative chronotropic effect: ↓ If , delayed slow depolarization
↓ heart rate (sinus bradycardia)
Negative dromotropic effect: ↓ inward Ca current
↓ conduction velocity through AVN
AP are conducted more slowly from A to V
S innervation
norepinephrine mediated (also epinephrine - adrenal medulla)
b1 receptors
Positive chronotropic effect: ↑ If , ↑ heart rate (sinus tachycardia)
Positive dromotropic effect: ↑ inward Ca current
↑ conduction velocity through AVN
! ventricular filling
Acetylcholine modulate pacemaker activity and conduction velocity

Acetylcholine (ACh)

-released from the vagus nerve (parasympathetic) onto the SA and AV

nodes
-slows the intrinsic pacemaker activity by all three mechanisms:
1. ACh decreases If in the SA node, reducing the steepness of the phase 4
depolarization
2. ACh opens GIRK channels, increasing relative K+ conductance and
making the maximum diastolic potential of SA nodal cells more negative
3. ACh reduces ICa in the SA node, thereby reducing the steepness of the
phase 4 depolarization and also moving the threshold to more positive
values.

→ all three effects cooperate to lengthen the time for the SA node to depolarize to
threshold; the net effect is to lower the heart rate.

ACh has similar effects on currents in the AV and SA nodes. In AV node Ach
slows conduction velocity by inhibition of ICa that also makes the threshold more
positive for AV nodal cells. Because it is more difficult for one cell to depolarize its
neighbors to threshold, conduction velocity falls.
Modulation of pacemaker activity to
decrease the heart rate:

A. Prolonged slow depolarization,

lengthening the time necessary for Vm to
reach threshold → diastole is longer and
the heart rate falls
B. Hyperpolarization (Vm starts phase 4 at
a more negative potential and thus takes
longer to reach threshold)
C. Threshold shift towards a more
positive value (Vm requires a longer time to
reach a more positive threshold)

A combination of these mechanisms could

have either a negative or positive
chronotropic effect.
Catecholamines modulate pacemaker activity, conduction velocity
and contractility
- Norepinephrine (NE), from sympathetic innervation; epinephrine (E) from the
adrenal medulla
- in pacemaker cells act through β1-adrenergic receptors, to produce an increase in
heart rate by:
1) increase If in the nodal cells, thereby increasing the steepness of the
phase 4 depolarization
2) increase ICa in all myocardial cells.
- in the SA and AV nodal cells steepens the phase 4 depolarization and also
makes the threshold more negative
- produce shorter APs as a result of the actions on specific currents.
-in atrial and ventricular muscle, NE, E cause an increase in the strength of
contraction (positive inotropic effect) through:
1) increased ICa (i.e., Ca2+ influx) leads to a greater local increase in [Ca2+]i and
also a greater Ca2+-induced Ca2+ release from the SR.
2) increase the sensitivity of the SR Ca2+-release channel to cytoplasmic Ca2+
3) enhance Ca2+ pumping into the SR by stimulation of the SERCA Ca2+ pump,
thereby increasing Ca2+ stores for later release.
4) the increased ICa presents more Ca2+ to SERCA, so that SR Ca2+ stores
increase over time → more Ca2+ available to troponin C, enabling a more
forceful contraction
Modulation of the heart rate by autonomous
nervous system
 Effect of vagal stimulation on heart activity and vagal escape.

PS fibers (from vagal nerve) are mainly supplying the atriums, SA node, and AV node.

Excessive vagal stimulation → heart stops beating (diastolic cardiac arrest). After a
short time (a few seconds), the ventricles begin to beat again at a much slower rate -
vagal escape due to acetylcholine depletion, S stimulation and manifestation of the
idioventricular rhythm.

In clinics, parasympathetic stimulation and decrease in the heart rate is obtained

through vagal maneuvers, such as Valsalva maneuver, carotid sinus massage,
oculo–depressor reflex (Dagnini–Aschner), and viscero–vagal reflex, with therapeutic
(e.g., supraventricular tachycardia - SVT) and diagnostic values for arrhythmias.
 Vagal maneuvers

Valsalva reflex is obtained by asking the person to inhale, and then to have a
forced expiratory effort while having the glottis closed. The maneuver increases
the intrathoracic pressure. By opening the airways, intrathoracic pressure
diminishes, the raised transmural pressure stretches the aorta, resulting in aortic
baroreceptors stimulation, and reflex activation of the vagus nerve.
Massage of the carotid sinus, located at the bifurcation of the carotid artery,
directly stretches the carotid sinus wall, consecutively stimulating the
baroreceptors, that further signal to the brainstem centers to stimulate the vagus
nerve, slowing the heart rate.
The oculo-depressor (Dagnini-Aschner) reflex is used in clinics for decreasing
the heart rate, stopping an episode of paroxistic atrial tachycardia, or for
arrhythmias differential diagnostics purposes. To initiate this reflex, pressure is
applied over the eyelids for 15-20 seconds to successively stimulate the trigeminal
receptors, the dorsal vagal nucleus and the vagal nerve.

Viscero-vagal reflex - the heart rate falls up to the cardiac arrest, due to the
powerful stimulation of the vagus receptors from the gut/internal organs. In clinics,
this vagal stimulation can happen during surgery.
Vagal maneuvers increase parasympathetic activity and decrease
ventricular rate.
In case of atrial tachycardia (atrial flutter, atrial fibrillation) →ventricular rate may
become so high that the effectiveness of the ventricles’ pumping is hindered.

Because all impulses activating the ventricles must pass through the AV node, use
of ACh to slow impulse conduction through the AV node can slow the ventricular
rate.

Valsalva maneuver: opening of the airway allows intrathoracic pressure to fall →

the increased transmural pressure stretches the aorta →aortic baroreceptors
stimulation → reflex activation of the vagus nerve

Massage of the bifurcation of the carotid artery in the neck directly stretches the
wall of the carotid sinus, thereby stimulating the baroreceptors.

Note that digitalis compounds may also be used to treat supraventricular tachycardias
because these drugs may increase vagal tone and decrease sympathetic tone, thereby
slowing the conduction of atrial impulses through the AV node.

Patients with congestive heart failure may have a low baseline vagal tone and a high baseline
sympathetic tone. In these patients, digitalis-like drugs increase myocardial contractility and
cardiac output, causing a reflex increase in vagal tone.
 Myocardial properties

1. Excitability - bathmotropia
2. Automaticity & rhythmic activity - chronotropia
3. Conductibility - dromotropia
4. Contractility - inotropia
5. Relaxation - lusitropia
 Myocardial contractility – myocardial cell structure
Cardiac myocytes are shorter then the skeletal ones, branched, interconnected
from end to end by intercalated disks (desmosomes, gap junctions) in a
mechanical and electrical syncytium:
AP generated in the sinoatrial node travel in the entire heart in ~ 0.22 sec
Contraction of a cardiac muscle cell ~ 0.3 sec

Sarcolema -T tubules & terminal cisternae Triad and its role in the
- sarcoplasmic reticulum (SR) excitation-contraction coupling
 Myocardial contractility – myocardial cell structure

-Transverse T-tubule
-particular to myocardium: radial, but also axial T tubules
-invagination of the sarcolemma; extension of extracellular fluid…
-more developed in the ventricles;
-scanty in atrial & Purkinje cells
-oriented at the Z lines
-enable fast impulse transmission / almost simultaneously
stimulation of myofibrils

-Sarcoplasmic reticulum
-developed from ER, important as Ca2+ store
-closed set of anastomosing tubules wandering through the myofibrils:
• network SR (important for Ca2+ re-uptake by Ca-ATPase pumps, inhibited by
phospholamban)
• junctional SR (close to sarcolemma/T-tubules, Ca2+ store)
• corbular SR (sac-like expansion) along the SR network, in I band (Ca2+ storage
enabled by calsequestrin)
 Myocardial contractility – myocardial cell structure

• Sarcoplasm: contains myoglobin (3.4 g/l), an O2 store, which is

50% saturated at pO2=5 mmHg; it facilitates the diffusion of O2
through the sarcoplasm

• Single central nucleus

• Mitochondria: up to 30% of the volume of the heart

→ great oxidative capacity

• Rich capillary supply: ~ 1 capillary / myocardial cell; short diffusion

distances

• Cardiac myocytes receive sympathetic and parasympathetic

innervation that modulate cardiac muscle function.
 Myocardial contractility – myocardial cell structure

Sarcomere - contractile unit, located between two Z lines, 1.8-2 mm in resting

myocytes, give the striated appearance, contains myofibrillary proteins:
- contractil: myosin (thick), actin (thin); each myosin is surrounded by 6 actin filam.
- regulatory: tropomyosin, troponin complex
- accesory, non-contractile cytoskeletal filaments:
titin/connectin, tropomodulin, nebulin
Cardiac sarcomere: major components

Troponin C (TnC): binds to Ca2+ to produce a conformational change in TnI

Troponin T (TnT): binds to tropomyosin, interlocking them to form a troponin-
tropomyosin complex
Troponin I (TnI): binds to actin and cover its myosin binding sites, to hold the troponin-
tropomyosin complex in place and to inhibit A-M binding and contraction.
TnI phosphorylation by beta1 agonists accelerates relaxation
 Cardiac sarcomere and contraction

Actin has ATP and Ca2+ /Mg2+ binding sites; interaction with tropomyosin-
troponin complex; present myosin binding sites

Myosin - ATP-ase activity, interact with actin

Contraction = shortening of the sarcomeres; sliding filament mechanism

(repeated making and breaking of crossbridges between A & M filaments, in
the presence of ATP).
The crossbridges are the heads of the myosin molecules, which change
their angles by binding to the actin sites, after tropomyosin Ca-dependent
displacement.
 Cardiac muscle is generally similar to skeletal muscle in the interaction
of the actin and myosin during cross-bridge cycling, the resynthesis of ATP,
and the termination of contraction/relaxation.
Excitation-Contraction Coupling in Cardiac Muscle
STEPS:

1. AP from SAN travels through gap junctions in adjacent myocytes/

conductive tissue. AP spreads over cell membranes and deep into the
T tubules

2. AP-triggered voltage change opens L-type Ca channel on cardiac

myocytes membrane → inward Ca current (during the AP’s plateau)

3. ↑ [Ca2+]i (10%) triggers the Ca-induced Ca2+ release from SR Ca

channels (ryanodine receptors) → critical dependence of cardiac
contraction on extracellular Ca2+

4. ↑↑ [Ca2+ ]i (90%) from SR stores → Ca2+ binds to troponin C →

tropomyosin is moved out and release the myosin binding sites on the
actin filaments → promotes actin-myosin interaction and contraction
 Excitation-Contraction Coupling in Cardiac Muscle

5. Myosin cross-bridges bind to the underlying actin → one direction

movement of the myosin head, which pulls the actin filament toward the
center of the sarcomere
6. Actin & myosin binding → myocardial cells contract, developing a tension
proportional to [Ca]i
7. Late stage of AP phase 2 (plateau): influx of Ca2+ through L-type Ca2+
channels decreases → less Ca2+ released by the SR - prevent a further
increase in [Ca2+]i
8. Relaxation occurs when [Ca2+]i is restored/decreased to resting values by
-Ca-ATPase pump (SERCA)- disinhibited by phospholamban phosphorylation
-sarcolemmal Ca pump
-electrogenic 3Na-1Ca antiporter
9. ATP is needed for relaxation, to release myosin from the actin (if not →
rigor status). Partial hydrolysis of ATP and release of ADP energizes the
myosin head for another cross-bridge cycle.
AP plateau: opening of the voltage-
dependent L-type Ca2+ channels.
Ca2+ influx is small but critical for the
opening of SR Ca2+ channels.

Ca2+ release from the SR increases [Ca2+]i

to allow contraction.

Relaxation occurs as the [Ca2+]i is

lowered from the combined actions of the
sarcolemmal 3Na+-1Ca2+ antiporter, Ca2+
uptake by the SR and Ca2+ extrusion by the
sarcolemmal Ca2+ pump.

AP in cardiac muscle (≈0.3 sec) overlaps

the contraction, resulting in a long
refractory period; modulation of L-type
Ca2+ channel can be used as an alternative
strategy to increase the force of contraction
 Myocardial relaxation and intracellular Ca2+

(1) Extrusion of Ca2+ into the Extracellular Fluid

! Even during the plateau of AP the myocyte extrudes some Ca2+.

After the membrane potential returns to more negative values, the

extrusion processes trigger a [Ca2+ ]i fall.

The cells extrude all the Ca2+ that enters the cytosol from the
extracellular fluid through L-type Ca2+ channels.

Ca2+ extrusion into the extracellular fluid occurs by

(1) sarcolemmal Na-Ca exchanger (NCX1), which operates
at relatively high levels of [Ca2+ ]i;
Effect of cardiac glycosides (digitalis) to ↑ [Ca2+ ]i

(2) a sarcolemmal Ca2+ pump, which may function at even

low levels of [Ca2+]i, but contributes only modestly to relaxation.
 Myocardial relaxation and intracellular Ca2+

(2) Re-uptake of Ca2+ into the SR

Even during the plateau of AP, some of the
Ca2+ accumulating in the cytoplasm is
sequestered into the SR by the Ca2+ pump
SERCA. Regulated by phospholamban.

(3) Dissociation of Ca2+ from Troponin C

As [Ca2+ ]i falls, Ca2+ dissociates from

troponin C, blocking actin-myosin
interactions and causing relaxation.

β1-Adrenergic agonists accelerate

relaxation by promoting phosphorylation of
troponin I, which in turn enhances the
dissociation of Ca2+ from troponin C.
 Phospholamban effect on heart activity

Phospholamban, an integral SR membrane protein with a single

transmembrane segment, is an important regulator of SR Ca-pump
(SERCA).

Its phosphorylation by any of several kinases (like protein kinase A – PKA,

secondary to β1-adrenergic stimulation) relieves phospholamban's inhibition
of SERCA, allowing Ca2+ resequestration in the SR to accelerate.

The net effect of its phosphorylation is an increase in the rate of cardiac

muscle relaxation. Also, a positive inotropic effect (more Ca available in the
SR).
 What is specific to cardiac muscle

APs that propagate between adjacent cardiac myocytes through gap

junctions initiate contraction of cardiac muscle.

Cardiac contraction requires Ca2+ entry through L-type Ca2+ channels,

that will locally determine important Ca-induced Ca release

The regulatory protein troponin C (TNNC1 subtype) has just a single,

active low-affinity Ca2+ binding site, rather than the two high-affinity and
two low-affinity sites of troponin C TNNC2 in skeletal muscle.

Note the importance of SR Ca2+ pump activity and its inhibition by the
regulatory protein phospholamban.
When phospholamban is phosphorylated by cAMP-dependent protein
kinase (PKA), its ability to inhibit the SR Ca2+ pump is lost.
Thus, activators of PKA, such as epinephrine, may enhance the rate of
cardiac myocyte relaxation.
 What is specific to cardiac muscle
• In cardiac muscle, the strength of contraction is not regulated by frequency
summation or multiple-fiber summation possible, but through modulating
the contractile force generated during each individual muscle twitch.
• The contractile force is enhanced (positive inotropic effect) by:
- modulating the magnitude of the rise in [Ca2+ ]i :
Norepinephrine (NE) acts on β-type adrenergic receptor to increase
cAMP, activate PKA and phosphorylate the L-type Ca2+ channels,
thereby increasing Ca2+ influx and contractile force.
- cAMP pathway also increase the Ca2+ sensitivity of the contractile
apparatus by phosphorylating one or more of the regulatory proteins.
- NE increase the Ca2+ permeability of voltage-gated Na+ channels
- prolongation of AP through inhibition of K channels increase Ca2+
inflow
• The contractile force is decreased (negative inotropic effect) by:
Ach acts on muscarinic receptors, increase cGMP →
phosphorylation of L-type Ca2+ channels at distinct sites →
decrease in Ca2+ influx during the cardiac AP → decrease in the force
of contraction.
Lecture 1 bibliography from Boron & Boulpaep, Medical Physiology

Organization of the cardiovascular system (Boron, Ch. 17, p. 410-412)

Cardiac electrophysiology (Boron, Ch. 21, p. 483-493)
Cardiac muscle (Ch. 9, p. 242-243 and Ch. 22, p. 517-519)
CARDIOVASCULAR PHYSIOLOGY

Lecture 3

Electrocardiogram (ECG)

Prof. Ana-Maria Zagrean

Physiology Division
 Electrocardiogram (ECG)

- non-invasive method to record time-dependent electrical vectors of the

heart representing the sum of the extracellular signals produced by the
movement of APs through cardiac myocytes, using electrodes attached
to the skin.

- detects the dynamic of electro-mechanic events

- the rate and regularity of heartbeats,
- the size and position of the chambers,
- the presence of any damage to the heart,
- the effects of drugs, ionic changes etc.
 Electrocardiogram (ECG)
Electrodes are connected to (+)/(–) side of a
voltmeter.

A standard 12-lead ECG is obtained using 10

electrodes: 2 electrodes on the upper extremities,
2 on the lower extremities, and 6 on standard
locations across the chest.

Fluctuations of extracellular voltage recorded by

one lead, between one (+) and one (–) electrode,
are called waves.

The electrodes on the extremities generate the

6 limb leads (3 standard and 3 augmented), and
the chest electrodes produce the 6 precordial
leads.

ECG machine has amplifiers and filters to

reduce the electrical noise/artifacts.
 Instantaneous potentials develop on the surface of a cardiac
muscle mass that has been depolarized in its center.

Voltmeter

In a lead, one electrode is

treated as the positive side of a
voltmeter and one or more
electrodes as the negative side
→ a lead records the fluctuation
in voltage difference between (+)
and (-) electrodes.

Myocardium extracellular surface

 From AP to ECG
Recordings of electrical activity in isolated muscular fibers

o Extracellular side of o
- + the cell membrane
- +
1 ++++++++ 5 -----------

2 ---++++++ 6 +++ -------

3 -----++++ 7
++++-----
8
4
----------- ++++++++
depolarization repolarization
+/- Deflections correspond to the recorded +/- waves
(+) wave when the depolarization moves towards the positive/exploratory electrode
Recordings of electrical activity in isolated muscular fibers
ECG traces show the sum of all the electrical potentials
generated by all the cells of the heart at any moment

Monophasic AP  110 mV recorded

directly at the heart muscle membrane

heart
during normal cardiac function, showing
rapid depolarization and then repolarization

Tissue fluids conduct electricity…

skin
Electrocardiogram trace recorded
simultaneously with AP in the heart.
QRS complex voltage (from the top of the R
wave to the bottom of the S wave)
 1 - 1.5 mV, when ECGs recorded from
electrodes on the two arms or on one arm
and one leg (standard leads).
 3 - 4 mV, when ECGs recorded with one
electrode placed on the thorax directly over
the ventricles and a second electrode is
placed elsewhere on the body, remote from
the heart (precordial leads)
 Action Potentials in the Heart

subendocardium

subepicardium

The different waveforms for each of the specialized

cells found in the heart are shown. The latency shown
approximates that normally found in the healthy heart.
Timing of ECG waves compared with intracellular recordings of cardiac APs.
Subepicardial and apical myocytes (dashed trace) have shorter action potential durations
than subendocardial and basal myocytes, so they repolarize first. This causes the T wave
to be upright.
 Electrical conduction in the heart
The movement of charge/the spreading wave of electrical activity in the heart has
both a three-dimensional direction and a magnitude → the signal measured on
an ECG is a vector.
Properties of an electrical dipole.
(a) Two diffuse groups of opposite charge can be represented by a dipole; that is, two points
of opposite charge, like the terminals of a battery.
(b) Equipotential lines around a dipole. The zero potential runs across the middle of the dipole
(c) Resolution of dipole vector (red arrow) into two components at right angles. The length of
the red arrow represents vector magnitude d. The voltage difference v1 detected by Lead I
depends on angle θ (v1 = d cosine θ). If v1 and v2 are drawn the same lengths as the R
waves in Leads I and aVF, respectively, the electrical axis of the heart equals θ.
 Standard 12-lead ECG
The ECG recording from a single lead shows how that lead views
the time-dependent changes in voltage of the heart.
ECG leads classification
- polarity
- bipolar: - 3 Bipolar Limb Leads I, II, III (Standard Leads): LI, LII, LIII
utilize a positive and a negative electrode between which electrical
potentials are measured.
- unipolar: - 6 Chest Leads (Precordial Leads): V1→ V6
the positive recording electrode is placed on the anterior
surface of the chest directly over the heart, and the negative
electrode (indifferent electrode), is connected through equal
electrical resistances to the right arm, left arm, and left leg all
at the same time
- 3 Augmented Limb Leads (aVL, aVR, aVF)
two of the limbs are connected through electrical resistances
to the negative terminal of the electrocardiograph, and the
third limb is connected to the positive terminal.
- direction
- frontal plane - 6 limb leads: 3 standard bipolar leads, 3 augmented leads
- horizontal plane - 6 chest leads: precordial leads
ECG Leads

The projections of the lead vectors

of the 12-lead ECG system in three
orthogonal planes when one
assumes the volume conductor to
be spherical homogeneous and the
cardiac source centrally located.
Conventions / Rules, for recording and interpreting an ECG
Rules: standard bipolar limb Leads I, II and III

Right arm Left arm

- I +
-

II III

Left leg
+
Rules: standard bipolar & augmented unipolar limb leads

Einthoven triangle

(-) LI (+)
(-) + + (-)

LII aVF LIII

+
+
+

( ) ( )
Frontal plane leads - Einthoven's Triangle

Each of the 6 frontal plane

leads has a negative '-’ and
positive '+' orientation.

Lead I (and to a lesser extent

Leads aVR and aVL) are right
→ left in orientation.

Lead aVF (and to a lesser

extent Leads II and III) are
superior → inferior in
orientation.
 Frontal Plane Leads

-120 -60

-150 -30

180 0
aVF
30

120 90 60
Bipolar Standard Leads:
• Lead I - from the right arm to the left arm
• Lead II - from the right arm to the left leg
• Lead III - from the left arm to the left leg
Augmented Unipolar Limb Leads:

aVR lead - the positive terminal is on the right arm; inverted !

aVL lead - the positive terminal is on the left arm;
aVF lead - the positive terminal is on the left leg.
Precordial / chest leads
in transverse plane (Wilson)

Unipolar Precordial Leads:

• V1 - 4th intercostal space to the right of sternum
• V2 - 4th intercostal space to the left of sternum
• V3 - halfway between V2 and V4
• V4 - 5th intercostal space in the left mid-clavicular line
• V5 - 5th intercostal space in the left anterior axillary line
• V6 - 5th intercostal space in the left mid axillary line
Two-cell model of the ECG demonstrates that the wave of depolarization
behaves like a vector, with both magnitude and direction

When the wave of depolarization When a lead is perpendicular to When the wave of depolarization
moves toward the positive lead, the wave of depolarization, the moves away from the positive
there is a positive deflection in the measured deflection on that lead electrode, a negative deflection is
is isoelectric. recorded.
extracellular voltage difference.
 ECG
- a direct measurement of the rate, rhythm, and time-dependent electrical
vector of the heart
- provides fundamental information about the origin and conduction of the
cardiac action potential within the heart.
 The normal electrocardiogram

“Lead II”

Right Arm 0.12-0.2s 0.35 - 0.44 s

PR QT

Atrial muscle T
depolarization P
Left Leg
Q S
Ventricular
Ventricular muscle muscle
depolarization repolarization
 The normal electrocardiogram

Lead I

Cardiac cycle duration

Ventricular
depolarization
Atrial
depolarization Ventricular
repolarization

Atrial contraction Cardiac cycle duration

Ventricles contract
Normal ECG consists in 3 waves:
– P wave = Represents atrial depolarization
• Atria begin to contract about 0.1 sec after P wave begins
– QRS complex = Represents ventricular depolarization
• Why is it a larger signal than the P wave?
• Ventricular contraction shortly after the peak of the R wave
– T wave = Indicates ventricular repolarization
• Why do we not see a wave corresponding to atrial
repolarization?
The normal electrocardiogram
Waves:
P wave – Atrial depolarization
(P from primus – Latin)
QRS complex – Ventricular
depolarization
q or Q – first negative wave
R or r – first positive wave;
R’ – if second positive wave
s – second negative wave
T wave – Ventricular
repolarization (T from
terminus – Latin)
Segments: PR, ST, TP
Intervals: PR, QT, ST
Nomenclature and durations of ECG

The various waves of the ECG are named P, Q, R, S, T, and U:

• P wave: a small, usually positive, deflection before the QRS complex
• QRS complex: a group of waves that may include a Q wave, an R wave,
and an S wave; not every QRS complex consists of all three waves
• Q wave: the initial negative wave of the QRS complex
• R wave: the first positive wave of the QRS complex, or the single wave if the
entire complex is positive
• S wave: the negative wave following the R wave
• QS wave: the single wave if the entire complex is negative
• R’ wave: extra positive wave, if the entire complex contains more than two
or three deflections
• S’ wave: extra negative wave, if the entire complex contains more than two
or three deflections
• T wave: a deflection that occurs after the QRS complex and the following
isoelectric segment (i.e., the ST segment that we define later)
• U wave: a small deflection sometimes seen after the T wave (usually of same sign
as the T wave)
 Nomenclature and durations of ECG
We use upper- and lower-case letters as an estimate of the amplitude of Q, R, and S
waves:
Capital letters Q, R, S are used for deflections of relatively large amplitude.
Lowercase letters q, r, s are used for deflections of relatively small amplitude. For
instance: an rS complex indicates a small R wave followed by a large S wave.

(from www.ecgwaves.com)
 Nomenclature and durations of ECG

The various intervals are

PR interval: measured from the beginning of the P wave to the
beginning of the QRS complex; normal duration is 0.12 - 0.2 s (three to
five small boxes on the recording)
QRS interval: measured from the beginning to the end of the QRS
complex, as defined previously; normal duration is <0.12 s
QT interval: measured from the beginning of the QRS complex to the
end of the T wave; the QT interval is an index of the length of the overall
ventricular action potential; duration depends on heart rate because the
AP shortens with increased heart rate
RR interval: the interval between two consecutive QRS complexes;
duration is equal to the duration of the cardiac cycle
ST segment: from the end of QRS complex to the beginning of T wave
Conduction pathways through the heart.
Spreading wave of depolarization.
Correlation between the ECG and the electrical events in the heart

Wave of repolarization
(the ventricular myocytes
that depolarize last are
the first to repolarize)

Spreading wave of depolarization

Different parts of the heart activate sequentially → the time-dependent changes
in the electrical vector of the heart in different regions generate ECG waves.

Start of ECG Cycle

Early P Wave

Dark red - depolarization

 Later in P Wave
The P wave reflects the atrial depolarization.

Dark red - depolarization

Early QRS

Dark red - depolarization

Light blue - repolarization
 Later in QRS

The QRS complex corresponds

to ventricular depolarization.

Dark red - depolarization

Light blue - repolarization
S-T Segment

Dark red - depolarization

Early T Wave

Dark red - depolarization

Light blue - repolarization
 Later in T-Wave

T wave reflects ventricular

repolarization.

Dark red - depolarization

Light blue - repolarization
 Back to where it started

R ECG paper has a grid of small 1-mm square boxes

and larger 5-mm square boxes.
P T
The vertical axis is calibrated at 0.1 mV / 1 mm;
the horizontal (time) axis, at 0.04 s /1 mm (small
Q S box) or 0.2 s / 5 mm (large box) → 5 large boxes
correspond to 1 second.
Changes in size and angle of cardiac dipole (straight arrows) with time during
ventricular excitation. Charges refer to extracellular, not intracellular, fluid. Pale
pink areas are myocytes at resting potential, so they carry a positive
extracellular charge. Red areas are depolarized myocytes with negative
extracellular charge. The cardiac dipole rotates anticlockwise and waxes and
wanes over ~90 ms. The electrical axis here is ~40° below the horizontal.

The direction of the largest dipole

in the frontal plane is called the
electrical axis of the heart.
The generation of the ECG signal in the Einthoven limb leads.
The generation of the ECG signal in the Einthoven limb leads.
 ECG

aVR

Lead I

Lead II
Einthoven's triangle, illustrating Magnitude and direction of the QRS
the voltmeter connections for complexes in limb leads I, II, and III
standard limb leads I, II, and III. when the mean electrical axis (Q) is
60 degrees (A), 120 degrees (B), and
0 degrees (C).
Leads and electrical vectors of the heart

• The inferior leads (leads II, III and aVF) show the electrical activity
from the inferior region (wall) of the heart - the apex of the left ventricle.

• The lateral leads (I, aVL, V5 and V6) look at the electrical activity
from the lateral wall of the heart.

• The anterior leads, V1 through V6, and represent the anterior wall
of the heart.

The lateral and anterior leads record events from the left wall and front walls
of the left ventricle, respectively.

aVR is rarely used for diagnostic information, but indicates if the ECG leads
were placed correctly on the patient.

The right ventricle has very little muscle mass→ it leaves only a small imprint
on the ECG, making it more difficult to diagnose changes in the right
ventricle.
Normal ECG
 ECG Analysis

1. Check ECG calibration

2. Heart rate (frequency )
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart (QRS axis)
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS duration,
QT interval)
 ECG Analysis – Normal ECG

1. Check ECG calibration

2. Heart rate (frequency)
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS duration,
QT interval)
 How to record an ECG? Calibration

• Put electrodes on the skin, on arms, legs and chest in order to record in
different leads (don’t forget the ground electrode)
• Standardization of the recording:
calibration lines on the recording paper:
horizontal lines: 10 small divisions upward/downward =+/-1 mV
vertical lines: 0.04 sec = 1 smaller interval (1 mm)
for a paper speed of 25 mm/sec
Calibration
 ECG Analysis – Normal ECG

1. Check ECG calibration

2. Heart rate (frequency)
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS duration,
QT interval)
 Heart rate (HR)

• HR – number of beats / min

• Normal HR ~ 60-100 beats/min
• If the normal interval between 2 successive QRS
complexes (RR interval) is 0.83 sec, then
HR = 60/0.83=72 beats/min

• Methods of determination: direct method

quick method
 Direct Method for HR determination

The direct method is to measure the number of seconds between waves

of the same type, for example, the R-R interval. The quotient of 60
divided by the interval in seconds is the heart rate in beats/minute.

HR = 60 s / R-R interval (s) = 60 / 0.04 s x no. of div. for R-R interval

If 60 s = 1500 div. of 0,04 s → HR = 1500 div./ no. of div. for R-R
(1 s = 25 divisions (small squares) of 0.04 s for a recording at 25 mm/s )

R-R interval = duration of the cardiac cycle

25mm/s

75 b/m
 Quick method for HR determination

R R

0.04 s, for 25 mm/sec

Measure the number of large boxes that form the R-R interval.

HR of 300, 150, 100, 75, 60, 50, corresponds to an interval of one, two, three,
four, five, or six large boxes.
Rate = 300/(number of large boxes)
Ex: four large boxes separate the R waves, the heart rate is 75 beats/min.
 ECG Analysis – Normal ECG

1. Check ECG calibration

2. Heart rate (frequency)
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS duration,
QT interval)
 Heart Rhythm
Normal Sinusal Rhythm (SR): impulses originate at S-A node at
normal rate → all complexes normal, evenly spaced.
Criteria for sinusal rhythm:
1. P before every QRS complex in at least one lead
2. P wave in Lead II: amplitude less than 2.5 mm; duration less than
0.11 sec
3. P-R Interval ~ 0,12 - 0,21 sec
4. Heart rate (frequency) ~ 60-100 beats/min, regulated (var. < 10%)
5. P wave electrical axis ~ 0º ÷ +90º (close to +45º ÷ +60º)

• Other heart rhythms: jonctional/nodal rhythm, ventricular rhythm (see below)

 Electrocardiographic Rhythm Strip
Determining the cardiac “rhythm” requires observation over a longer time
interval than that used to obtain the ECG traces.
The rhythm strip below shows leads V , II, and V obtained simultaneously
1 5

for an extended period.

CARDIOVASCULAR PHYSIOLOGY

Lecture 4
Electrocardiogram (ECG)

Prof. Ana-Maria Zagrean

 Analysis of Normal ECG
1. Check ECG calibration
2. Heart rate (frequency )
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS
duration, QT interval)
 Electrical axis of the heart

Electrical axis for a given electrical potential is

represented as a vector:
– vector = an arrow that points in the direction of the
electrical potential generated by the current flow, with
the arrowhead in the positive direction.
– by convention, the length of the arrow is drawn
proportional to the voltage of the potential
– the summated vector of the generated potential at
any particular instant is called instantaneous mean
vector
Projection of a vector with different orientations on a segment

Connection between the aspect of the recorded wave and the

orientation of the vector relative to the positive electrode
 Electrical axis of the heart: QRS axis

• QRS electric axis (mean vector)

denotes the average direction of the
electric activity throughout ventricular
activation: the direction of the electric
axis denote the instantaneous direction
of the electric heart vector.

• The normal range of the electric axis

lies between
-30° and +90 ÷ +120° in the frontal plane
+30° and -30° in the transverse plane
Electrical axis in the frontal plane

Extreme LAD

Extreme Left axis

deviation (LAD)
RAD
Important LAD

Extreme RAD Small LAD

Right axis
deviation
(RAD) Normal
Small RAD
 Geometric method
Measurement of the magnitude of the wave projected onto at least two leads in
the frontal plane, usually limb leads

Step 1: Measure the height of the wave on the ECG records in two leads (number of
boxes). A positive deflection is one that rises above the baseline, and a negative
deflection is one that falls below the baseline.

Step 2: Mark the height of the measured deflections on the corresponding lead lines on
a circle of axes. Starting at the center of the circle, mark a positive deflection toward the
arrowhead and a negative deflection toward the tail (origin) of the arrow.

Step 3: Draw lines perpendicular to the lead axes through each of your two marks.

Step 4: Connect the center of the circle of axes (tail of the vector) to the intersection of
the two perpendicular lines (head of the vector).

Step 5: Estimate the axis of the vector that corresponds to the R wave, using the
“angle” scale of the circle of axes
In a normal heart, the average direction of the vector during
spread of the depolarization wave through the ventricles
(mean QRS vector) is about +59 degrees.
Qualitative inspection method.
When the wave is isoelectric (i.e., no deflection, or equal positive and
negative deflections), then the electrical vector responsible for that projection
must be perpendicular to the isoelectric lead.

Step 1:
Identify a lead in which the wave of interest is isoelectric (or nearly
isoelectric).
The vector must be perpendicular (or nearly perpendicular) to that lead.
Because the leads in the frontal plane define axes every 30 degrees, every
lead has another lead to which it is perpendicular.

Step 2:
Identify a lead in which the wave is largely positive.
The vector must lie roughly in the same direction as the orientation of that
lead.

If the wave of interest is not isoelectric in any lead, then find two leads onto
which the projections are of similar magnitude and sign.
The vector has an axis halfway between those two leads.
QRS axis in the normal range: -30o ÷ + 90o

Lead aVF is the isoelectric lead.

The two perpendiculars to aVF are

0o and 180o.

Lead I is positive (i.e., oriented to

the left).

Therefore, the axis has to be 0o.

To determine how much of the voltage in vector A will be recorded in
lead I, a line perpendicular to the axis of lead I is drawn from the tip of
vector A to the lead I axis → projected vector (B) along the lead I axis,
with the arrow toward the positive end of the lead I axis, which means
that the record momentarily being recorded in the electrocardiogram of
lead I is positive.
C – projected vector along the L II axis
D – projected vector along the L III axis
The ventricular vectors and QRS complexes: 0.01 second after onset of ventricular depolarization (A); 0.02
second after onset of depolarization (B); 0.035 second after onset of depolarization (C); 0.05 second after onset
of depolarization (D); and after depolarization of the ventricles is complete, 0.06 second after onset (E).
Einthoven’s law:
If the three standard limb leads (I,II,III) are placed
correctly, the sum of the voltages in leads I and III
equals the voltage in lead II

LI + LIII = LII
QRS axis in augmented unipolar limb leads
QRS axis in the horizontal plane
 T wave axis

T wave – ventricles repolarization

T wave duration ~ 0.15 sec.; axis: +30 , +60 degrees)

QRS and T vectorcardiograms:
- vector increases and decreases in length because of increasing and
decreasing voltage of the vector.
- vector changes direction because of changes in the average direction of the
electrical potential from the heart.
 P wave axis

P wave - depolarization of the atria

Spread of depolarization through the atrial muscle is much slower than in the
ventricles (atria have no Purkinje system for fast conduction of the depolarization
signal).

Repolarization begins in SA node →atrial repolarization vector is backward to

the vector of depolarization, and it is almost always totally obscured by the
large ventricular QRS complex.
 Analysis of Normal ECG
1. Check ECG calibration
2. Heart rate (frequency)
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS
duration, QT interval)
ECG Measurement of waves, segments, intervals

Waves: P, QRS, T, U

Segments – isoelectric lines on ECG:

no potentials are recorded when the
ventricular muscle is either completely
polarized or completely depolarized.
PQ(R), ST, TP

Intervals – segments + waves

PQ(R), ST, QT
ECG Measurement of waves, segments, intervals
 P wave: atrial depolarization wave
- amplitude < 2.5 mm in lead II
- duration < 0.11 s in lead II (atrial depolarization duration)
- axis: between 0o ÷ +75o (+45o and +60o)
- morphology: rounded, symmetrical, usually positive wave, except aVR
- abnormal P waves: right atrial hypertrophy (pulmonary P), left atrial
hypertrophy (mitral P)…
 QRS
• Ventricular depolarization wave
• QRS duration ~ 0.06 - 0.10 s (how long it takes for the wave of
depolarization to spread throughout the ventricles)
• q <0.04s, <25% R, reflects normal septal activation in the
lateral leads (LI, aVL, V5, V6).
Intrinsecoid Deflection (ID) in precordial leads

ID ID_
ID = R wave peak time, measured from
the beginning of the QRS complex to
– definition: the peak of the R wave.

– up to 0,02 sec for V1,2 ID reflects the depolarization vector

from the endocardium to the epicardium
– up to 0,05 sec for V4-6
Prolonged ID in bundle branch block
and ventricular hypertrophy.
ID>0.05 s in left ventricle hypertrophy
 T wave: ventricular repolarization
- amplitude:
~ 1/3 R, but it is considered normal within the ¼ R – ½ R interval
- duration ~ 0.15 s
- axis: +30 ÷ +60 degrees
- morphology: rounded, asymmetrical wave.
Wave U
• Amplitude usually < 1/3 T wave amplitude in same lead
• direction - the same as T wave direction in the same lead
• more prominent at slow HR, best seen in the right precordial leads.
• origin of the U wave
- related to afterdepolarizations which interrupt or follow repolarization
- also possible due to delayed repolarization of papillary muscles
 Analysis of Normal ECG
1. Check ECG calibration
2. Heart rate (frequency)
3. Rhythm of the heart: "normal sinus rhythm"
4. Electrical axis of the heart
5. Measurement of waves, segments, intervals
- the sizes of the voltage changes
- the duration and temporal relationships of the various components
6. Conduction analysis (PR interval, QRS
duration, QT interval)
 Conduction Analysis
"Normal" conduction implies normal sino-atrial (SA), atrio-ventricular
(AV), and intraventricular (IV) conduction:
• PR interval= 0.12 - 0.20 s (how long it takes the AP to conduct
through the AV node before activating the ventricles)
• QRS complex ~ 0.06 – 0.10 s (ventricular depolarization)
• QT segment - gets shorter as the heart rate increases, which
reflects the shorter AP that are observed at high rates.
• QT interval (how long the ventricles remain depolarized; rough
measure of the duration of the overall “ventricular” AP).
~ 45% RR
0.33 s ÷ 0.46 s
depends on HR → corrected QT (QTc)
(Bazett formula)
+90
+75
+150
+90
+30
0
 Pathologic ECG
Vector analysis - Axis determination
Left axis deviation
Right axis deviation

Abnormal Voltages of the QRS complex

Increased voltage (att. to electrode location)
Decreased voltage
Prolonged QRS
Cardiac rhythms – cardiac arrhythmias
Tachycardia
Bradycardia
Sinus arrhythmia

Myocardial infarction
 Pathologic ECG
Vector analysis - Axis determination
Left axis deviation
Right axis deviation

Abnormal Voltages of the QRS complex

Increased voltage (att. to electrode location)
Decreased voltage
Prolonged QRS
Cardiac rhythms – cardiac arrhythmias
Tachycardia
Bradycardia
Sinus arrhythmia

Myocardial infarction
 Vector analysis - Axis determination

Deviation of the electric axis

• to the right = increased electric activity in the RV due to

increased RV mass (e.g. severe pulmonary hypertension).

• to the left = increased electric activity in the LV due to

increased LV mass (e.g. hypertension, aortic stenosis, etc.).
Axis in the left axis deviation (LAD) range

Lead aVR is the smallest and

isoelectric lead.

The two perpendiculars are -

60o and +120o.

Leads II and III are mostly

negative (i.e., moving away
from the + left leg)

The axis, therefore, is -60o.

Axis deviation – left ventricle hypertrophy
Axis in the right axis deviation (RAD) range

Lead aVR is closest to being

isoelectric (slightly more
positive than negative)

The two perpendiculars are -

60o and +120o.

Lead I is mostly negative; lead

III is mostly positive.

Therefore the axis is close to

+120o. Because aVR is slightly
more positive, the axis is
slightly beyond +120o (i.e.,
closer to the positive right arm
for aVR).
Axis deviation – right ventricle hypertrophy
 Pathologic ECG

Vector analysis - Axis determination

Left axis deviation
Right axis deviation
Abnormal QRS complex
Increased voltage (attention to electrode location)
Decreased voltage
Prolonged QRS

Cardiac rhythms
Tachycardia
Bradycardia
Sinus arrhythmia

Myocardial infarction
 Abnormal Voltages of QRS complex
• Increases:
- If sum of the voltages of QRS [S-R] of the 3 standard leads
is > 4 mV → high voltage ECG
- ex. Cardiac muscle hypertrophy

• Decreases:
- cardiac myopathies
- diminished muscle mass – ex. after myocardial infarctions
(delay of impulse conduction and reduced voltages)
-‘short-circuits’ of the heart electrical potentials through
pericardial fluid, pleural effusions
- pulmonary emphysema
• >0.12 s
• A widened QRS duration occurs in the setting of
-a right bundle branch block,
-a left bundle branch block,
-a non-specific intraventricular conduction delay
-during ventricular arrhythmias (ventricular tachycardia)
 Pathologic ECG
Vector analysis - Axis determination
Normal axis
Left axis deviation
Right axis deviation
Abnormal Voltages of the QRS complex
Increased voltage (att to electrode location)
Decreased voltage
Prolonged QRS
Cardiac rhythms - Arrhythmias
Tachycardia
Bradycardia
Sinus arrhythmia

Myocardial infarction
 Cardiac Arrhythmias

Any change in cardiac rhythm from the normal sinus rhythm

is defined as an arrhythmia.
Can be normal/adaptive or pathological.

Causes of the cardiac arrhythmias:

1. Abnormal rhythmicity of the pacemaker
2. Shift of the pacemaker from the sinus node to another place in
the heart
3. Blocks at different points in the spread of the impulse through
the heart
4. Abnormal pathways of impulse transmission through the heart
5. Spontaneous generation of impulses in almost any part of the
heart
 Abnormal Sinus Rhythms
• Sinus tachycardia (fast heart rate driven by the sinus node, in an adult
person >100 beats /min) is determined by increased body temperature (18
beats/°C, up to 40.5°C), stimulation of the heart by the sympathetic nerves (in
frightened or startled individuals, during normal exercise);
rarely, can be pathological – ex. in patients with acute hyperthyroidism

• Bradycardia: - slow heart rate, def. as fewer than 60 beats/minute

- in athletes; after vagal stimulation

• Sinus arrhythmia with respiratory cycle results from cyclic variations in

the sympathetic and parasympathetic tone, that influence the SA node
- results mainly from "spillover" of signals from the medullary respiratory center
into the adjacent vasomotor center during inspiratory and expiratory cycles of
respiration
→ alternate increase and decrease in the number of impulses transmitted
through the sympathetic and vagus nerves to the heart
→ increased HR during inspiration and decreased HR during expiration:
5% for normal/quiet respiration, up to 30% for deep respiration.
- when loss, is a sign of autonomic system dysfunction, as in diabetes.
Other heart rhythms:
Junctional / Nodal rhythm: superior / middle / inferior part of AV node

https://ecgwaves.com
Other heart rhythms:
Ventricular rhythm:
- if 3 or more beats have a ventricular origin
- ventricular rate between 20-40 beats/min
- regular rhythm
- wide QRS complex with secondary ST-T
changes (discordant ST-T)
- typically occurs in AV dissociation
(3rd degree complete AV block)

Accelerated ventricular rhythm (idioventricular rhythm):

- ventricular rate between 60-100 beats/min (compete / alternate with sinusal rhythm)
- in most cases has a regular rhythm
- wide QRS complex with secondary ST-T changes (discordant ST-T)
- typically occurs after reperfusion (post-ischemia/post-hypoxia - good prognostic
marker for restoration of coronary blood flow); occurs also secondary to drugs,
electrolyte disorders etc.
 Conduction abnormalities are a major cause
of arrhythmias
-can occur at any point in the conduction pathway
-partial or complete.
-multiple causes
1) abnormal depolarization
2) abnormal anatomy.

1) If a tissue is injured (stretch, anoxia), an altered balance of ionic currents can lead to
a depolarization that partially inactivates INa and ICa, slowing the spread of current
slowing conduction → the tissue may become less excitable
→ partial conduction block
or completely inexcitable →complete conduction block.

2) The presence of an aberrant conduction pathway, reflecting abnormal anatomy -

an accessory conduction pathway that rapidly transmits AP from the
atria to the ventricles, bypassing the AV node, which normally imposes a conduction
delay.
Patients with the common Wolff-Parkinson-White (WPW) syndrome have a bypass
pathway called the bundle of Kent.
The existence of a second pathway between the atria and ventricles predisposes to
supraventricular arrhythmias.
Abnormal conduction
Accessory pathways (Wolff-Parkinson-White)
Kent pathway - NSA to the ventricle base
James pathways - NSA. to Hiss bundle
Mahaim pathway - Hiss b. to the ventricle base
 Partial or Incomplete Conduction Block
1) slowed conduction
- the tissue conducts all the impulses, but more slowly than normal, unusually long PR
interval
2) intermittent block, in which the tissue conducts some impulses but not others.
3) unidirectional block

1) First-degree AV block reflects a slowing of conduction through the AV node.

2) Second-degree AV block: incomplete (i.e., intermittent) coupling of the atria to the ventricles.
These are 2 types:
Mobitz type I block (or Wenckebach block), the PR interval gradually lengthens from one cycle
to the next until the AV node fails completely, skipping a ventricular depolarization; every third or
fourth atrial beat fail to conduct to the ventricles.
Mobitz type II block, the PR interval is constant from beat to beat, but every nth ventricular
depolarization is missing.
 Partial or Incomplete Conduction Block

Rate-dependent block - bundle branches

- a form of intermittent conduction block, in the large branches of the His-Purkinje
fiber system.
When the heart rate exceeds a critical level, the ventricular conduction system
fails, presumably because a part of the conducting system lacks sufficient time to
repolarize → the impulse is left to spread slowly and inefficiently through the
ventricles by conducting from one myocyte to the next → the resulting contraction
loses some efficiency.
Such a failure, intermittent or continuous, is known as a bundle branch block
and appears on the ECG as an intermittently wide QRS complex.

Right bundle branch Left bundle branch

block is visible in the block is visible in the V5
V1 or V2 precordial or V6 leads.
leads
Bundle branch Blocks
Right Left
Complete Conduction Block or third-degree AV block – medical emergency!

- complete block at the AV node stops any supraventricular electrical impulse from
triggering a ventricular contraction → atria and ventricles beat under control of its
own pacemakers = AV dissociation.

The only ventricular pacemakers that are available to initiate cardiac contraction are
the Purkinje fiber cells (unreliable and slow) → fall of cardiac output and blood
pressure.
Treatment: placement of an artificial ventricular pacemaker.

On an ECG, complete block appears as regularly spaced P waves (SA node properly
triggers the atria) and as irregularly spaced QRS and T waves that have a low
frequency and no fixed relationship to the P waves
 Progressive stages of heart block and the ECG

(a) First-degree block; the PR

interval is prolonged (>200 ms).
(b) Second-degree block (Mobitz
type 1 or Wenckebach);
progressive prolongation of the
PR interval until a P wave fails
to conduct to the ventricle.
(c) Second-degree block (Mobitz
type 2); several P waves are
present (in this case 2) for
every QRS.
(d) Third-degree block (complete
heart block); QRS complexes
are unrelated to P waves.
3) Unidirectional block

- a conduction defect that is essential for re-entry

- a type of partial conduction block: impulses travel in one direction but
not in the opposite one.
- may arise as a result of a local depolarization or may be due to
pathological changes in functional anatomy, as an asymmetric
anatomical lesion
Re-Entry- re-entrant excitation or circus movement, a major cause of clinical arrhythmias
It occurs when a wave of depolarization travels in an apparently endless circle.
Re-entry has three requirements:
(1) a closed conduction loop,
(2) a region of unidirectional block (at least briefly),
(3) a sufficiently slow conduction of action potentials around the loop.

Normal cardiac tissue can

conduct impulses in both
directions.

If this re-entrant movement (steps 2 → 5 → 2,

and so on) continues, the frequency of re-
entry will generally outpace the SA nodal
pacemaker (frequency of step 1) and is often
responsible for diverse tachyarrhythmias
because the fastest pacemaker sets the heart
rate.
Re-entry excitation may be responsible for
atrial and ventricular tachycardia, atrial
and ventricular fibrillation, and many other
arrhythmias.
Re-entry can occur in big loops or in small
loops consisting entirely of myocardial cells.
Accessory Conduction Pathways - Wolff-Parkinson-White (WPW) syndrome
- an accessory conduction pathway provides a short circuit (i.e., bundle of Kent)
around the delay in the AV node.
- the fast accessory pathway is composed of muscle cells.
- it conducts the AP directly from the atria to the ventricular septum, depolarizing
some of the septal muscle earlier than if the depolarization had reached it via the
normal, slower AV nodal pathway→ ventricular depolarization is more spread out in
time than is normal, giving rise to a wider QRS complex.
- the general direction of ventricular depolarization is reversed→ the events normally
underlying the Q wave of the QRS complex have an axis opposite to normal one →
early depolarization / pre-excitation, appears as a small, positive delta wave at
the beginning of the QRS complex
WPW syndrome + re-entry → supraventricular tachycardia
Paroxysmal supraventricular tachycardia (PSVT)
- a regular tachycardia; ventricular rate usually exceeding 150 beats/min.
- because ventricular depolarization still occurs via the normal conducting pathways,
the QRS complex appears normal.
- if, during an episode of PSVT, the conduction direction for re-entry is in the reverse
direction (i.e., down the accessory pathway and back up through the AV node), the
QRS shape may be unusual → wide and bizarre QRS complexes
- a small number of people with WPW syndrome have more than one accessory
pathway, so that multiple re-entry loops are possible
Fibrillation: many regions of re-entrant electrical activity are present →electrical chaos
that is not associated with useful contraction.
Atrial fibrillation
- a wandering re-entry loop within the atria moves wildly and rapidly, generating a rapid
succession of APs (500 per minute) → the fastest pacemaker in the heart, outpacing
the SA node and bombarding the AV node.
- AV node cannot repolarize fast enough to pass along all of these impulses→ irregular
appearance of QRS complexes without any detectable P waves, still the ventricular
rate can be quite high.
- the baseline between QRS may appear straight or show small, rapid fluctuations.
- atrial fibrillation is well tolerated as the atria function mainly as a booster pump.
- attempts to convert the rhythm back to normal sinus rhythm: electrical or chemical
means, or, when not possible, to slow conduction through the AV node:
-digitalis: increase PS and decrease S stimulation to the AV node, decreasing
the speed of AV conduction and thus reducing the ventricular rate.
-β-adrenergic blockers or Ca2+ channel blockers are also used to control
ventricular rate.
Ventricular fibrillation is a life-threatening medical emergency.

The heart cannot generate cardiac output because the ventricles are not able
to pump blood without a coordinated ventricular depolarization.
Altered automaticity can originate from the sinus node or from an ectopic locus

Depolarization-Dependent Triggered Activity

- a positive shift in the maximum diastolic potential brings Vm closer to the threshold for an AP →
induce automaticity (otherwise with no pacemaker activity).
- depends on the interaction of the Ca2+ current (ICa) and the repolarizing K+ current (IK). → an
accelerated pacemaker depolarization in the SA or AV nodal cells
- it can also increase the intrinsic pacemaker rate in Purkinje fiber cells, which normally have a very
slow pacemaker.
-is particularly dramatic in nonpacemaker tissues (e.g., ventricular muscle),
which normally exhibit no diastolic depolarization.

During the repolarization phase, INa remains inactivated because the

cell is so depolarized. On the other hand, Ica has had enough time to recover from inactivation and
because the cell is still depolarized, triggers a slow, positive
deflection in Vm known as an early afterdepolarization (EAD).
Eventually, IK increases and returns Vm toward the resting potential. Such EADs may trigger an
extrasystole.

Isolated ventricular extrasystoles (premature ventricular contractions -PVCs) may occur in normal
individuals.
Alterations in cellular Ca2+ metabolism may increase the tendency of a prolonged AP to produce
an extrasystole.
! Drugs used to treat arrhythmias can become arrhythmogenic by producing EADs (quinidine by
inhibiting Na+ channels and some K+ channels prolongs the ventricular muscle AP)
Altered automaticity can originate from the sinus node or from an ectopic locus

Abnormal automaticity in ventricular muscle.

The prolonged AP keeps INa inactivated but permits ICa and IK to interact and thereby
produce a spontaneous depolarization - the early afterdepolarization.
Altered automaticity can originate from the sinus node or from an ectopic locus

More than one extrasystole, a run of

extrasystoles, is pathological.

A run of three or more ventricular

extrasystoles is the minimal
requirement for diagnosis of
ventricular tachycardia (120-150
beats/min or faster).

This arrhythmia is life-threatening

(can degenerate into ventricular
fibrillation, the heart cannot
pump blood effectively).
The afterdepolarization reaches threshold,
triggering a sequence of several slow pacemaker-
like APs that generate extrasystoles.
Long QT Syndrome (LQTS)

- prolonged ventricular AP
- patients prone to ventricular arrhythmias, susceptible to a form of ventricular
tachycardia called torsades de pointes (“twisting of the points”) in which the QRS
complexes appear to spiral around the baseline, constantly changing their axes and
amplitude.
- can be
-congenital (mutations of cardiac Na+ or K+ channels.
-acquired (more common)
electrolyte disturbances, especially hypokalemia and hypocalcemia
prescribed or over-the-counter medications (antiarrhythmic drugs,
tricyclic antidepressants, some nonsedating antihistamines
when they are taken together with certain antibiotics,
notably erythromycin).
Ca2+ overload and metabolic changes can cause arrhythmias

Ca2+ Overload
Causes: digitalis intoxication; injury-related cellular depolarization.
When [Ca2+]i increases, causes the SR to sequester too much Ca2+ → overloaded
SR begins to cyclically and spontaneously dump Ca2+ and then take it back up.
The Ca2+ release may be large enough to stimulate a Ca2+-activated nonselective
cation channel and the Na-Ca exchanger.
These current sources combine to produce Iti, a transient inward current that
produces a delayed afterdepolarization (DAD).
When it is large enough, Iti can depolarize the cell beyond threshold and produce a
spontaneous action potential.

Metabolism-Dependent Conduction Changes

During ischemia and anoxia→ fall in [ATP]i activates the ATP-sensitive K+ channel
(KATP), which is plentiful in cardiac myocytes.
When [ATP]i falls sufficiently, KATP is less inhibited, K+ goes out and the cells tend to
become less excitable.
The activation of this channel may explain, in part, the slowing or blocking of
conduction that may occur during ischemia or in the periinfarction period.
Electromechanical Dissociation
Rarely, patients being resuscitated from cardiac arrest exhibit
electromechanical dissociation in which the heart’s ECG activity is not
accompanied by the pumping of blood (absence of detectable pulse).

Causes frequently not understood, or known (ex. a large pericardial

effusion may manifest normal electrical activity, but the fluid between the
heart and the pericardium may press in on the heart (cardiac tamponade)
and prevent effective pumping).
 Pathologic ECG
Vector analysis - Axis determination
Normal axis
Left axis deviation
Right axis deviation
Abnormal Voltages of the QRS complex
Increased voltage (att to electrode location)
Decreased voltage
Prolonged QRS
Cardiac rhythms - Arrhythmias
Tachycardia
Bradycardia
Sinus arrhythmia

Myocardial infarction
Myocardial Infarction
 Myocardial Infarction
-The first electrical change associated with an acute myocardial infarction is
peaking of the T waves, followed soon after by T-wave inversion.
These T-wave changes are not specific for infarction and are reversible if blood
flow is restored.

-The next change, more characteristic of an acute myocardial infarction, is

elevation of the ST segment (myocytes closest to the epicardium become
depolarized by the cellular anoxic injury, but they are still electrically coupled).
ST elevation can be also determined by brief periods of coronary artery spasm.
 Myocardial Infarction

With irreversible ischemic cell death, the ECG typically shows the evolution
of deep Q waves.
Deep Q wave is a large negative deflection at the beginning of the QRS
complex, develops only in those leads overlying or near the region of the
infarction and indicates an area of myocardium that has become electrically
silent (APs cannot propagate into the infarcted area → the net vector of the
remaining areas of ventricular depolarization points away from this area).
Examples:
- an inferior wall infarction inscribes deep Q waves in leads II, III, and aVF.
- an infarction affecting the large muscular anterior wall of the heart will
inscribe deep Q waves in some of the precordial leads (V1 through V6).

Not all infarctions create deep Q waves; the only visible changes may be
T-wave inversion and ST-segment depression. Clinically, these infarctions
behave like incomplete infarctions, and patients are at risk of a second,
completing event.
Effect of myocardial ischemia on ventricle extracellular charge distribution and the ECG
CARDIOVASCULAR PHYSIOLOGY

LECTURE 5

Cardiac cycle
Analysis of cardiac activity - Polygram

Ana-Maria Zagrean MD, PhD

 The Cardiac Cycle (CC)
- definitions:
the sequence of electrical and mechanical events that
repeats with every heartbeat

the period of time from the beginning of one heartbeat to the

beginning of the next one

a sequence of filling and pumping

- the duration of the cardiac cycle is the reciprocal of the heart rate:

- CC duration is dependent on HR
= 0.8 s for a HR = 75 beats/min
= 1 s for a HR = 60 beats/min
The Cardiac Cycle

The valves control the one way direction

of blood flow; also, the chordae
tendineae prevent the AV valves from
turning inside-out.
- the atria fill, then contract (atrial
systole), pumping blood via the AV valves
into the ventricles.
- then the ventricles contract (ventricular
systole), causing the AV valves to shut
and the semicircular valves to open,
allowing blood out of the heart
(normally, A and V do not contract at
the same time).
- this is followed by relaxation (diastole)
of the ventricles, and the semilunar
valves shut.
The cycles then repeats itself…
 The Cardiac Cycle
The closing and opening of the cardiac valves define 4 main phases of the CC
1. Inflow phase: the inlet AV valve is open and the outlet semilunar valve is closed;
AV valve closure terminates phase 1
2. Isovolumetric contraction: both valves are closed, with no blood flow; semilunar
valve opening terminates phase 2.
3. Outflow phase: the outlet semilunar valve is open and the inlet AV valve is closed;
Semilunar valve closing terminates phase 3
4. Isovolumetric relaxation: both valves are closed, with no blood flow; AV valve
opening terminates phase 4
2+3 = systole (ventricles contract), about 0.3 sec for a HR =75 beats /min
4+1 = diastole (ventricles relax), about 0.5 sec from a CC of 0.8 sec, HR=75 beats/min
 The Cardiac Cycle

AS: pumping the blood into V during the last part of the VD
VS: isovolumic contraction
VS: rapid ventricular ejection
VS: reduced ventricular ejection
VD: isovolumic ventricular relaxation
VD: rapid ventricular filling
VD: slow/reduced ventricular filling (diastasis)
AD: during all the VS and part of the VD
(A for atrial, V for ventricular, S for systole, D for diastole)
The Cardiac Cycle
Changes in ventricular volumes, pressures and flow during the phases of the cardiac cycle

The placement of
catheters used for
pressure measurements
in the right heart.
 Atrial Systole

- immediately following the P wave on the ECG

- 0.1 sec at a HR of 75 b/min

- functional significance:
Atrium = primer pump for the ventricle: contributes to,
but is not essential for ventricular filling (<20% from stroke
volume in a person at rest, and up to 40% during heavy exercise)

- causes the 4th heart sound (phonocardiogram)

- venous pulse: a wave (jugulogram)

 Isovolumic Isovolumic Rapid inflow
contraction Ejection relaxation Diastasis Atrial systole

120 AoC
Volume (ml) Presure (mmHg)

100
Aortic pressure
80
60
AoO MO
40 MC
Atrial pressure
20 a c v
0
Ventricular pres.
130
90
Ventricular volume
50

S2 Electrocardiogram
S1 S3 S4 S1

Phonocardiogram

Polygram: events of the cardiac

cycle for left ventricular function
 Atrial Diastole

- 0,7 sec for 75 beats/min

- changes in diastolic intra-atrial pressure:
- physiological changes: c and v waves
- pathological changes (valves pathology)
 Isovolumic Isovolumic Rapid inflow
contraction Ejection relaxation Diastasis Atrial systole

120 AoC
Volume (ml) Presure (mmHg)

100
Aortic pressure
80
60
AoO MO
40 MC
Atrial pressure
20 a c v a c v
0
Ventricular pres.
130
90
Ventricular volume
50

S2 Electrocardiogram
S1 S3 S4 S1

Phonocardiogram

Polygram: events of the cardiac

cycle for left ventricular function
 Ventriculare systole
- 0,27 s;
- phases:
1. isovolumic contraction
AV valves close, V contracts with closed valves
increase in intraventricular pressure that will
cause opening of semilunar valves
2. rapid ejection; 70% ejection
accelerated decrease in ventricular volume
3. decreased/slow ejection; 30% ejection
slow decrease in ventricular volume
decrease ventricular and aortic pressures
- results in ejection of 70 ml of blood = stroke volume
(leaving another 50 ml in the ventricle – end systolic volume)
Isovolumic ventricular Ventricular
contraction ejection

When PLV > 80 mmHg

PRV > 8 mmHg
Ventricles are closed
Rapid (1/3; 70%) ejection
chambers
Slow (2/3; 30%) ejection
 Isovolumic Isovolumic Rapid inflow
contraction Ejection relaxation Diastasis Atrial systole

120 AoC
Volume (ml) Presure (mmHg)

100
Aortic pressure
80
60
AoO MO
40 MC
Atrial pressure
20 a c v
0
Ventricular pres.
130
90
Ventricular volume
50

S2 Electrocardiogram
S1 S3 S4 S1

Phonocardiogram

Polygram: events of the cardiac

cycle for left ventricular function
 Ventricular diastole

- 0,53 s (decreases with increase in HR)

- phases:
- isovolumic relaxation (all valves closed, pressure
falls rapidly in the ventricle)
- rapid ventricular filling
- slow ventricular filling (diastasis)
- late ventricular filling determined by atrial systole
Isovolumic Ventricular
relaxation filling
 Isovolumic Isovolumic Rapid inflow
contraction Ejection relaxation Diastasis Atrial systole

120 AoC
Volume (ml) Presure (mmHg)

100
Aortic pressure
80
60
AoO MO
40 MC
Atrial pressure
20 a c v
0
Ventricular pres.
130
90
Ventricular volume
50

S2 Electrocardiogram
S1 S3 S4 S1

Phonocardiogram

Polygram: events of the cardiac

cycle for left ventricular function
The Cardiac Cycle
Comparison of the dynamics of the left and right ventricles
Comparison of the dynamics of the left and right ventricles
Mechanical, electrical, and acoustic events
in the cardiac cycle.
Here the cardiac cycle begins with atrial
contraction (AS)

Phase 1 of the CC has three subparts:

-rapid ventricular filling,
-decreased/slow ventricular filling,
-atrial systole (last stage of ventricular filling);

Phase 3 has two subparts:

-rapid and decreased/slow ventricular ejection
 Polygram - Analysis of cardiac activity

Electrical activity – measured by electrocardiography

Mechanical activity – evaluated by:

1. Phonocardiography: record of the heart sounds
2. Atrial pressure curve and venous pressure: recorded at
jugular vein level (jugulogram)
3. Aortic pressure curve: recorded at carotid artery level
(carotidogram)
4. Ventricular volume: evaluated by apexocardiogram
 Heart sounds and phonocardiography
Heart sounds are relatively brief, discrete auditory vibrations of varying
intensity (loudness), frequency (pitch), and quality (timbre).
The first heart sound identifies the onset of ventricular systole, and the
second heart sound identifies the onset of diastole.
These two auscultatory events establish a framework within which other
heart sounds and murmurs can be placed and timed.
Listening to the sounds of the body with the aid of a stethoscope is called
auscultation. The stethoscope can detect leaks in the valves that permit jets of
blood to flow backward across the valvular orifice (i.e., regurgitation) as well as
stenotic lesions that narrow the valve opening, forcing the blood to pass through a
narrower space (i.e., stenosis). During certain parts of the cardiac cycle, blood passing
through either regurgitant or stenotic lesions makes characteristic sounds that are
called murmurs.

Phonocardiogram: the recording of the auscultatory cardiac activity,

using a transducer placed on the thorax.
The movement of the valve leaflets can be detected by echocardiography.
 Chest Surface Areas for Auscultation of Normal Heart Sounds

The primary aortic area: 2nd right intercostal space, adjacent to the sternum.
The secondary aortic area: 3rd left intercostal space, adjacent to the sternum
(known as Erb area).
The pulmonary area: 2nd left intercostal space
The tricuspid area: 4th & 5th intercostal spaces, adjacent to the left sternal border.
The mitral area at the cardiac apex: 5th left intercostal space, on the
medioclavicular line.
The first heart sound
(S1) – systolic sound

• the “lub”
• appears at 0.02 – 0.04 sec after the beginning of the
QRS complex
• vibrations are low in pitch and relatively long-lasting
- lasts ~ 0.12-0.15 sec;
• frequency ~ 30-100 Hz;
• produced, in this order, by:
closing of the mitral valve → closing of the tricuspid valve →
opening of the pulmonary valve → opening of the aortic valve.
 The second heart sound (S2) – diastolic sound
• the “dub”
• appears in the terminal period of the T wave
• lasts 0.08 – 0.12 s
• produced, in this order, by: closing of the aortic valve, closing
of the pulmonic valve, opening of the tricuspid valve, opening of
the mitral valve.
• heard like a rapid snap because these valves close rapidly,
and the surroundings vibrate for a short period
• physiologic splitting that varies with respiration (wider
splitting with inspiration)
Split S2 Inspiration Expiration

Normal or physiologic
 Split S2
• Audible respiratory splitting means > 0.03 sec difference in the
timing of the aortic (A2) and pulmonic (P2) components of the
second heart sound.
• Splitting of S2 is best heard over the 2nd left intercostal space
• The normal P2 is often softer than A2 and rarely audible at apex
• Inspiration accentuates the splitting of S2.

Split S2 Inspiration Expiration

Normal or physiologic
 The third heart sound (S3)
• occurs in early diastole (at the beginning of the middle third of diastole)
when rapid filling of the ventricles results in recoil of ventricular walls that
have a limited distensibility
• lasts 0.02-0.04 sec
• protodiastolic sound or gallop
A gallop rhythm is a grouping of three heart sounds that together
sound like hoofs of a galloping horse. The addition of an S3 to the
physiological S1 and S2 creates a three-sound sequence, S1-S2-S3, that is
termed a protodiastolic gallop or ventricular gallop.
• it is normal in children and individuals with a thin thoracic wall
• occasionally heard as a weak, rumbling sound
The fourth heart sound (S4) – presystolic sound:

• appears at 0.04 s after the P wave (late diastolic)

• lasts 0.04-0.10 s
• caused by the blood flow that hits the ventricular wall
during the atrial systole.
• physiological only in small children, if heard in other
conditions it is a sign of reduced ventricular compliance.
• addition of an S4 produces another three-sound sequence,
S4-S1-S2, which is a presystolic gallop rhythm or atrial
gallop
• during tachycardia S4-S1 can fuse, producing a
summation gallop
EC=ejection click: most common early systolic sound;
Results from abrupt halting of semilunar valves
OS=opening snap: high-frequency early diastolic sound
(occurs 50-100 msec after A2) associated with mitral
stenosis (stiffening of the mitral valve); sound due to abrupt
deceleration of mitral leaflets sound with associated murmur.
Phonocardiogram

The duration of S1, S2 is slightly more

than 0.10 sec.
S1 ~ 0.14 sec
S2 ~ 0.11 sec.
(the semilunar valves are more taut than
the A-V valves, so that they vibrate for a
shorter time than do the A-V valves).
The audible range of frequency (pitch) in
the first and second heart sounds:
~40 cycles/sec→up above 500 cycles/sec
 Polygram - Analysis of Cardiac activity

Electrical activity – measured by electrocardiography

Mechanical activity – evaluated by:

1. Phonocardiography: record of the heart sounds
2. Atrial pressure curve and venous pressure: recorded at
jugular vein level (jugulogram)
3. Aortic pressure curve: recorded at carotid artery level
(carotidogram)
4. Ventricular volume: evaluated by apexocardiogram
 Pressure waves in veins
• Systemic veins have pressure waves - venous pulse:
(1) retrograde action of the heartbeat during the cardiac cycle,
(2) the respiratory cycle
(3) the contraction of skeletal muscles.
• Jugular vein, has a complex pulse wave synchronized to the
cardiac cycle:
3 peaks, labeled a, c, and v
3 minima, labeled av, x, and y.
 Pressure transients in the jugular vein
pulse reflect events in the cardiac cycle:

• a peak - caused by the contraction of the right atrium.

• av minimum is due to relaxation of the right atrium and closure of the
tricuspid valve.
• c peak reflects the pressure rise in the right ventricle early during systole
and the resultant protruding of the tricuspid valve-which has just closed-into
the right atrium.
• x minimum occurs as the ventricle contracts and shortens during the
ejection phase, later in systole. The shortening heart-with tricuspid valve still
closed-pulls on and therefore elongates the veins, lowering their pressure.
• v peak is related to filling of the right atrium against a closed tricuspid valve,
which causes right atrial pressure to slowly rise. As the tricuspid valve
opens, the v peak begins to decline.
• y minimum reflects a fall in right atrial pressure during rapid ventricular
filling, as blood leaves the right atrium through an open tricuspid valve and
enters the right ventricle. The increase in venous pressure after the y
minimum occurs as venous return continues in the face of reduced
ventricular filling.
 Effect of the Respiratory Cycle

• During inspiration, the diaphragm descends, causing intrathoracic

pressure (and therefore the pressure inside the thoracic vessels) to
decrease and intra-abdominal pressure to increase → the venous
return from the head and upper extremities transiently increases, as
low-pressure vessels literally draw blood into the thoracic cavity.
• Simultaneously, the venous flow decreases from the lower
extremities because of the relatively high pressure of the abdominal
veins during inspiration.
• Therefore, during inspiration, pressure in the jugular vein falls while
pressure in the femoral vein rises.
Venous pressure changes:

In A, the time scale is a single cardiac

cycle. The relative heights of the
peaks and valleys are variable.

In B, the time scale surrounds one

protracted inspiration (i.e., several
heartbeats); the y-axis in the lower
panel shows the mean jugular venous
pressure.

1 mmHg = 1.36 cmH2O

1 cmH2O = 0.735 mmHg

In C, venous pressure in the saphenous

vein at the ankle in man during exercise
and changes in posture
Polygram - Analysis of cardiac activity

Electrical activity – measured by electrocardiography

Mechanical activity – evaluated by:

1. Phonocardiography: record of the heart sounds
2. Atrial pressure curve and venous pressure: recorded at
jugular vein level (jugulogram)
3. Aortic pressure curve: recorded at carotid artery level
(carotidogram)
4. Ventricular volume: evaluated by apexocardiogram
 Polygram: events of the cardiac cycle for the left ventricul
Isovolumic Isovolumic Rapid inflow
contraction Ejection relaxation Diastasis Atrial systole

120 AoC
Volume (ml) Presure (mmHg)

100
Aortic pressure
80
60
40 MC Ao MO Atrial pressure
20 O
a c v
0
Ventricular pres.
130
90
Ventricular volume
50

S2 Electrocardiogram
S1 S3 S4 S1

Phonocardiogram
Sphygmogram - recording of the peripheral pulse

Arterial system converts the intermittent cardiac output into a

continuous capillary flow.

The arterial pulse wave represents the rhythmic expansion of

arterial walls synchronous with the left ventricular contraction.

The velocity of the pulse wave as it travels down the arteries is

3-5 m/sec for large elastic arteries, and 14-15 m/sec for the
small, less compliant vessels.

The velocity of the pulse wave increases with age because of

the high rigidity of the vessels.
Cardiac cycle causes flow waves in aorta and peripheral vessels
With the closing & opening of
pulmonary and aortic valves, blood
flow and blood velocity across these
valves oscillate from near zero, when
the valves are closed, to high values,
when the valves are open.
Blood flow in the aortic arch oscillates
between slightly negative and highly
positive values.
Pressure in the aortic arch typically
oscillates between ~ 80 - 120 mm Hg.
Phasic changes in pressure and flow
also occur in the peripheral arteries.
Arterial pressure is usually measured in
a large artery, such as the brachial
artery → the measured systolic and
diastolic arterial pressures, as well as
the pulse pressure and mean arterial
pressure, closely approximate the
corresponding aortic pressures.

Flow (A) and pressure (B) profiles in the aorta and smaller vessels.
 Carotidogram – a particular sphygmogram, recording the pressure
changes in the carotid artery during one cycle of the heart.

ECG

Phonocardiogram

Carotidogram
 Carotidogram
E point - the opening of the aortic valve and the beginning of ejection
from the left ventricle.
The arterial pressure increases sharply as the blood enters the aorta
faster than it flows away to the periphery → ascending slope of the
carotid pressure curve is called the anacrotic limb.

The small a wave produced by the left atrial systole precedes the E point.

The P point (percussion wave), represents the pressure peak - in early systole
(rapid ejection). A second, smaller peak -tidal wave, represents a reflected
wave from the periphery. An anacrotic notch lies between the two waves.
 Carotidogram
After the aortic pressure curve reaches its peak, it begins to decline -
catacrotic limb, as ventricular ejection slows down (slow ejection).

During the initial phase of ventricular relaxation, there is a brief

reversal of blood flow from the compliant central arteries back toward
the ventricle → aortic valves close → a notch (dicrotic notch/incisure)
on the descending limb of the aortic pressure curve, associated with
transient reversal of blood flow.
Types of carotid pulses
 Polygram - Analysis of cardiac activity

Electrical activity – measured by electrocardiography

Mechanical activity – evaluated by:

1. Phonocardiography: record of the heart sounds
2. Atrial pressure curve and venous pressure: recorded at
jugular vein level (jugulogram)
3. Aortic pressure curve: recorded at carotid artery level
(carotidogram)
4. Ventricular volume: evaluated by apexocardiogram
 Apexcardiogram

The apex beat, or the point of maximum impulse, is the

furthermost point outwards (laterally) and downwards (inferiorly)
from the sternum at which the cardiac impulse can be felt.
The cardiac impulse is the result of the heart rotating, moving
forward, and striking against the chest wall during systole.

The apexcardiogram records the relative displacement of the

thoracic wall, with a transducer placed in the specific area where
the apex beat is felt, which is in the 5th intercostal space on the
mid-clavicular line.

The apexcardiogram, like the carotidogram, gives information

about the left side of the heart.
 Apexcardiogram
• a wave - generated by the atrial
systole (after the middle of the P wave
on ECG).
• c point marks the beginning of the
isovolumetric contraction.
• E point represents the end of the
isovolumetric contraction, the opening
of the aortic valves, and the beginning
of the ejection period.
There is a slow descending plateau
phase between E and H points that
represent the ejection phase (rapid
and slow).
• with point H, the isovolumetric
relaxation starts.
• Point O (opening) marks the opening
of the mitral valve.
• F (filling) point represents the rapid
filling phase, corresponds to the third
sound on the phonocardiogram.
ATRIAL SYSTOLE (The end of ventricular diastole)

Heart:
During atrial systole the atrium contracts and tops off the volume in the
ventricle with only a small amount of blood. Atrial contraction is
complete before the ventricle begins to contract.

Atrial pressure:
The "a" wave occurs when the atrium contracts, increasing atrial
pressure (yellow). Blood arriving at the heart cannot enter the atrium so
it flows back up the jugular vein, causing the first discernible wave in
the jugular venous pulse. Atrial pressure drops when the atria stop
contracting.

ECG:
An impulse arising from the SA node results in depolarization and
contraction of the atria. The P wave is due to this atrial depolarization.
The PR segment is electrically quiet as the depolarization proceeds to
the AV node. This brief pause before contraction allows the ventricles to
fill completely with blood.

Heart sounds:
A fourth heart sound (S4) is abnormal and is associated with the end of
atrial emptying after atrial contraction. It occurs with hypertrophic
congestive heart failure, massive pulmonary embolism or tricuspid
incompetence.
 ISOVOLUMETRIC CONTRACTION
The beginning of systole
Heart:
The atrioventricular (AV) valves close at the beginning of this phase.
Electrically, ventricular systole is defined as the interval between the QRS
complex and the end of the T wave (the Q-T interval).
Mechanically, ventricular systole is defined as the interval between the
closing of the AV valves and the opening of the semilunar valves (aortic
and pulmonary valves).
Pressures & Volume:
The AV valves close when the pressure in the ventricles (red) exceeds the
pressure in the atria (yellow). As the ventricles contract isovolumetrically -
- their volume does not change (white
white ) -- the pressure inside increases,
approaching the pressure in the aorta and pulmonary arteries (green).
ECG:
The electrical impulse propagates from the AV node through the His
bundle and Purkinje system to allow the ventricles to contract from the
apex of the heart towards the base.
The QRS complex is due to ventricular depolarization, and it marks the
beginning of ventricular systole. It is so large that it masks the underlying
atrial repolarization signal.
Heart sounds:
The first heart sound (S1, "lub") is due to the closing AV valves and
associated blood turbulence.
 RAPID EJECTION

Heart:
The semilunar (aortic and pulmonary) valves open at the beginning of
this phase.

Pressures & Volume:

While the ventricles continue contracting, the pressure in the ventricles
(red) exceeds the pressure in the aorta and pulmonary arteries
(green); the semilunar valves open, blood exits the ventricles, and
the volume in the ventricles decreases rapidly ( white
white). As more
blood enters the arteries, pressure there builds until the flow of
blood reaches a peak.
The "c" wave of atrial pressure is not normally discernible in the
jugular venous pulse. Right ventricular contraction pushes the
tricuspid valve into the atrium and increases atrial pressure,
creating a small wave into the jugular vein. It is normally
simultaneous with the carotid pulse.
ECG:

Heart sounds:
REDUCED EJECTION
The end of systole
Heart:
At the end of this phase the semilunar (aortic and pulmonary) valves
close.

Pressures & Volume:

After the peak in ventricular and arterial pressures (red and green),
blood flow out of the ventricles decreases and ventricular volume
decreases more slowly (white
white ).
When the pressure in the ventricles falls below the pressure in the
arteries, blood in the arteries begins to flow back toward the ventricles
and causes the semilunar valves to close. This marks the end of
ventricular systole mechanically.

ECG:
The T wave is due to ventricular repolarization. The end of the T wave
marks the end of ventricular systole electrically.

Heart sounds:
ISOVOLUMETRIC RELAXATION
The beginning of diastole
Heart:
At the beginning of this phase the AV valves are closed.

Pressures & Volume:

Throughout this and the previous two phases, the atrium in diastole
has been filling with blood on top of the closed AV valve, causing atrial
pressure to rise gradually (yellow).
The "v" wave is due to the back flow of blood after it hits the closed
AV valve. It is the second discernible wave of the jugular venous pulse.
The pressure in the ventricles (red) continues to drop.
Ventricular volume (white
white ) is at a minimum and is ready to be filled
again with blood.
ECG:

Heart sounds:
The second heart sound (S2, "dup") occurs when the semilunar (aortic
and pulmonary) valves close. S2 is normally split because the aortic
valve closes slightly earlier than the pulmonary valve.
RAPID VENTRICULAR FILLING

Heart:
Once the AV valves open, blood that has accumulated in the atria
flows rapidly into the ventricles.

Pressures & Volume:

Ventricular volume ( white
white) increases rapidly as blood flows from the
atria into the ventricles.

ECG:

Heart sounds:
A third heart sound (S3) is usually abnormal and is due to rapid
passive ventricular filling.
It occurs in dilated congestive heart failure, myocardial infarction, or
mitral incompetence.
REDUCED VENTRICULAR FILLING
(DIASTASIS)
Heart:

Pressures & Volume:

Ventricular volume ( white
white ) increases more slowly now. The

ventricles continue to fill with blood until they are nearly full.

ECG:

Heart sounds: