Cardiac physiology

Summary

The heart pumps blood through the circulatory system and supplies the body with blood. Cardiac
activity can be assessed with measurable parameters, including heart rate, stroke volume,
and cardiac output. The cardiac cycle consists of two phases: systole, in which blood is pumped
from the heart, and diastole, in which the heart fills with blood. The conduction system is made
up of a collection of nodes and specialized conduction cells that initiate and coordinate the
contraction of the myocardium. Pacemaker cells (e.g., sinus node) of the conduction system of
the heart autonomously and spontaneously generate an action potential (AP). The conduction
system transmits the AP throughout the myocardium, and the electrical excitation of
the myocardium results in its contraction. A phase of relaxation (refractory period) prevents
immediate re-excitation. The Frank-Starling mechanism maintains cardiac output by
increasing myocardial contractility and thus stroke volume, in response to an
increased preload (end-diastolic volume). The autonomic nervous system is able to regulate
the heart rate as well as cardiac excitability, conductivity, relaxation, and contractility.
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Overview

The main task of the heart is to supply the body with blood. This activity can be assessed with
measurable parameters, including heart rate, stroke volume, and cardiac output.
Definitions

• Heart rate (HR)

o The number of heart contractions per minute (bpm)
o Normal heart rate at rest: 60–100 bpm
• Stroke volume (SV): the volume of blood pumped by the left or right ventricle in a single heartbeat
o SV = end-diastolic volume (EDV) − end-systolic volume (ESV)
• Ejection fraction (EF): the proportion of EDV ejected from the ventricle
o EF = SV / EDV = (EDV - ESV)/EDV
o Normally 50–70%
o Serves as an index of myocardial contractility: e.g., ↓ myocardial contractility → ↓ EF (seen in systolic
heart failure, where EF is < 40%)
• Venous return: the rate at which blood flows back to the heart, which typically equals cardiac
output (see preload)
• Cardiac output: the volume of blood the heart pumps through the circulatory system per minute (∼ 5
L/min at rest)
o Cardiac output (CO) = heart rate (HR) × stroke volume (SV)
o Measurement
▪ Via Fick principle: Cardiac output is proportional to the quotient of the total body oxygen consumption
and the difference in oxygen content of arterial blood and mixed venous blood.
▪ Cardiac output (CO) = oxygen consumption rate/arteriovenous oxygen
difference = (O2 consumption)/(arterial O2 content − venous O2 content)
▪ Via mean arterial pressure (MAP): MAP = cardiac output (CO) × total peripheral resistance (TPR)
▪ Mean arterial pressure (MAP) = 1⁄3 systolic blood pressure (SP) + ⅔ diastolic blood pressure (DP) = (SP +
2 x DP)/3
o As HR increases, diastole is shortened, which decreases CO due to less filling time.
• Volumetric flow rate: the volume of blood that flows across a valve per second
o Volumetric flow rate (Q) = average flow velocity (v) x cross-sectional area occupied by the blood (A)
▪ The amount of fluid entering the system must equal the amount leaving the system: Q 1 = Q2 so A1v1 =
A2v2 (discharge at section 1 = discharge at section 2)
▪ Used to calculate flow across stenotic valves, vessels of different diameters, etc.
• Cardiac blood pressures
o Right atrium: < 5 mm Hg
o Right ventricle (pulmonary artery pressure): 25/5 mm Hg
o Left atrium (pulmonary capillary wedge pressure): < 12 mm Hg
o Left ventricle: 130/10 mm Hg

During exercise, a healthy young adult can increase their CO to approx. 4–5 times the resting
rate of 5 L/min, to approx. 20–25 L/min. This increase in CO is achieved through a significant
increase in HR and a slight increase in SV. The increased HR shortens the filling time (diastole),
which limits the increase in SV. As the HR reaches ≥ 160/bpm, maximum CO is therefore
reached and begins to decrease, as SV declines faster than HR increases.
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 Cardiac cycle

The cardiac cycle can be divided into two phases: systole, in which blood is pumped from
the heart, and diastole, in which the heart fills with blood. Systole and diastole are each
subdivided into two further phases, resulting in a total of four phases of heart action. Depending
on the phase, pressure and volume in the ventricles and atria change, with the pressure in the left
ventricle changing the most and the pressure in the atria the least.
Systole
1.) Isovolumetric contraction

• Main function: ventricular contraction

• Follows ventricular filling
• Occurs in early systole, directly after the atrioventricular valves (AV valves) close and before
the semilunar valves open (all valves are closed)
• Ventricle contracts (i.e., pressure increases) with no corresponding ventricular volume change
o LV pressure: 8 mm Hg → ∼ 80 mm Hg (when aortic and pulmonary valves open passively)
o LV volume: remains ∼ 150 mL
o RV pressure: 5 mm Hg → 25 mm Hg
o RV volume: ∼ 150 mL
• The period of highest O2 consumption

2.) Systolic ejection

• Main function: Blood is pumped from the ventricles into the circulation and lungs.
• Follows isovolumetric contraction
• Occurs between the opening and closing of the aortic valve and pulmonary valve
• Ventricles contract (i.e., pressure increases) to eject blood, which decreases the ventricular volume
o Pressure: first increases from ∼ 80 mm Hg to 120 mm Hg and then decreases until aortic and pulmonary
valves close
o Volume: ejection of ∼ 90 mL SV (150 mL → 60 mL)

Diastole
3.) Isovolumetric relaxation

• Main function: ventricular relaxation

• Follows systolic ejection
• Occurs between aortic valve closing and mitral valve opening
• All valves closed (volume remains constant)
o Dicrotic notch: slight increase of aortic pressure in the early diastole that corresponds to closure of
the aortic valve
• The ventricles relax (i.e., pressure decreases) with no corresponding ventricular volume change until
ventricular pressure is lower than atrial pressure and atrioventricular valves open
o Pressure: decreases to ∼ 10 mm Hg in the left atrium and ∼ 5 mm Hg in the right atrium
o Volume: remains at ∼ 60 mL
• Coronary blood flow peaks during early diastole at the point when the pressure differential between the
aorta and the ventricle is the greatest.
o The coronary arteries fill with blood during diastole because they are compressed during
ventricular systole.

4.) Ventricular filling

Main function: ventricles fill with blood

Rapid filling

• Follows isovolumetric relaxation

• Occurs in early diastole; immediately after mitral valve opening
• Blood flows passively from the atria to the ventricles.
• The largest volume of ventricular filling occurs during this phase.

Reduced filling

• Follows rapid filling

• Occurs in late diastole; immediately before atrioventricular valves close
o LV pressure: ∼ 8 mm Hg; RV pressure: ∼ 5 mm Hg (2–8 mm Hg)
o LV and RV volume: ventricles fill with ∼ 90 mL (60 mL → 150 mL)

During isovolumetric contraction and relaxation, all heart valves are closed. There are no periods
in which all heart valves are open!
During states of increased heart rate (e.g., during exercise), the duration of diastole decreases so
that there is less time for the coronary arteries to fill with blood and supply the heart with
 oxygen. Patients with narrow coronary arteries, e.g., due to atherosclerosis, will, therefore,
experience chest pain (angina pectoris) during exertion!
Left ventricular pressure-volume diagram

• Used to: measure cardiac performance

• Shape: roughly rectangular; each loop is formed in a counter-clockwise direction
• Course
o (1) End-diastolic state: closure of the atrioventricular valve and the beginning of systole (the LV is filled
with blood)
o (1 → 2) Isovolumetric contraction: With the atrioventricular and semilunar valves closed, contraction
increases the internal pressure of the left ventricle; ventricular volume is left unchanged.
o (2) Opening of the semilunar valve when the ventricular pressure exceeds the aortic and pulmonary
arterial pressure
o (2 → 3) Ejection phase: The ventricle pumps out the stroke volume.
o (3) Closure of the semilunar valve when the ventricular pressure falls below the aortic and pulmonary
arterial pressure
o (3 → 4) Isovolumetric relaxation: the beginning of diastole, when the ventricle relaxes and all the valves
are closed
o (4) Opening of the atrioventricular valve when the ventricular pressure falls below the atrial pressure
o (4 → 1) Filling phase: The ventricles receive blood from the atria and a new cardiac cycle begins.

Physiological changes in valvular disease

Valvular disease Pressure-volume loop Time-pressure curves

• The pressure-volume loop is rounder and flatter than a • Tall V-wave

Mitral
normal pressure-volume loop.
regurgitation
• ↑ LV end-diastolic volume and pressure
• ↑ Stroke volume
• No isovolumetric contraction
• No isovolumetric relaxation
• ↓ End-systolic volume

Mitral stenosis• The pressure-volume loop is narrower and flatter than the • LA pressure > LV pressure
normal pressure-volume loop during diastole
• ↑ LA pressure
• ↓ End-diastolic volume
• ↓ Stroke volume
Valvular disease Pressure-volume loop Time-pressure curves

• ↓ End-systolic volume

Aortic • The pressure-volume loop is rounder and taller than the • ↑ Pulse pressure
regurgitation normal pressure-volume loop
• ↑ End-diastolic volume
• ↑ Stroke volume
• No true isovolumetric relaxation

Aortic stenosis• The pressure-volume loop is narrower and taller than the • LV blood pressure > aortic
normal pressure-volume loop pressure during systole
• ↑ LV pressure
• No change in end-diastolic volume
• ↓ Stroke volume
• ↑ End-systolic volume
• ↑ End-diastolic pressure

The width of the volume-pressure loop is the SV (the difference between EDV and ESV).
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Conduction system of the heart

Definition: the collection of nodes and specialized conduction cells that initiate
and coordinate contraction of the heart muscle
 Name Anatomic localization Characteristics Frequency

• Upper wall of the right • Natural pacemaker center of the heart with specialized ca. 60–
Sinoatrial node
atrium (at the junction pacemaker cells 80/min
where the SVC enters) • Spontaneously generates electrical impulses that initiate a
heartbeat
• Influenced by autonomic nervous system
• Supplied by sinus node artery (branch of the right coronary
artery)

• Within the AV septum • Receives impulses from the SA node and passes these ca. 40–
Atrioventricular
(superior and medial to the impulses to the bundle of His 50/min
node
opening of the coronary • Has the slowest conduction velocity
sinus in the right atrium) • Delays conduction for 60–120 ms (allowing the ventricles to
fill with blood; without this delay, the atria and ventricles
would contract at the same time)
• Supplied by the AV nodal artery (posterior descending
artery of right coronary artery)

Bundle of His • Directly below the cardiac• Receives impulses from the AV node ca. 30–
skeleton, within the • Splits into left and right bundle branches (Tawara branches) 40/min
membranous part of the → the right bundle travels to the right ventricle; the left
interventricular septum bundle splits into an anterior and a posterior branch to
supply the left ventricle → terminate into terminal
conducting fibers (Purkinje fibers) of the left and right
ventricle
• Prevents retrograde conduction
• Filters high-frequency action potentials so that high atrial
rates (e.g., in atrial fibrillation) are not conducted to
the myocardium

• Terminal conducting fibers• Conduct cardiac AP faster than any other cardiac cells
ca. 30–
Purkinje fibers in the subendocardium • Ensure synchronized contraction of the ventricles
40/min
• Purkinje fibers have a long refractory period.
• Form functional syncytium: forward incoming stimuli very
quickly via gap junctions to allow coordinated contraction

Normal course of electrical conduction

SA node (pacemaker) creates an action potential → signal spreads
across atria and causes their contraction → signal reaches AV node and
is slowed down → AV node conducts the signal to bundle of His down the
 interventricular septum to Purkinje fibers in myocardium → they carry the signal
across the ventricles → the ventricles contract (electromechanical coupling)

The electrical activity of the heart can be recorded through electrocardiography.

See ECG for an overview of ECGs and their interpretation.
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Heart excitation

Overview

1. Pacemaker cells (e.g., sinus node) of the conduction system of the heart autonomously
and spontaneously generate an action potential (AP).

2. The conduction system transmits the AP throughout the myocardium.

3. The electrical excitation of the myocardium results in its contraction

(see electromechanical coupling and filament sliding theory in muscle tissue).

4. The phase of relaxation prevents immediate re-excitation (refractory period).

Cardiac calcium channels and calcium pumps

Other cation channels

All of these channels are located in the cell membrane.

 Name Definition Direction of Activation phase (affected tissue)
flow

• Nonselective cation channels (e.g.,• Extracellular• Upstroke phase (sinus node)

Funny channels (HCN, If)
for Na+, K+) in pacemaker cells that →
open as the membrane potential intracellular
becomes more negative
(hyperpolarized)

• Na+ channels that rapidly open and • Depolarization (myocardium)

Fast sodium channels (INa)
close following depolarization

Inward rectifier• K+ channels that open during • Intracellular• Resting

Potassium
K+ channels the resting potential (below −70 → potential (primarily myocardium;
channels
mV) and stabilize the resting extracellular sinus node)
potential of the cardiomyocytes

Delayed rectifier• K+ channels that can be rapidly (IKr) • Repolarization (sinus node
K+ channels(IKr and or slowly (IKs) activated and myocardium)
IKs) upon depolarization
 Myocardial action Pacemaker action potential (SA node and AV
potential (myocardium, bundle of His, Purkinje node)
fibers)

• Upstroke: An action potential from a • Upstroke: At TMP -40 mV (threshold potential of

Phase 0
pacemaker cell or pacemaker cells), L-type Ca2+ channels open →
(upstroke adjacent cardiomyocyte causes the TMP increases to +40 mV
and depolarization) transmembrane potential (TMP) to rise • No rapid depolarization phase because
above −90 mV. fast voltage-gated Na+ channels are inactivated
• Depolarization: Fast voltage-gated in pacemaker cells → results in slower
Na+ channels open at -65 mV → rapid Na+ influx conduction velocity between atria and ventricles
into the cell → TMP rises further until slightly
above 0 mV

•Inactivation of voltage-gated Na+ channels • Absent

Phase 1
•Transient K+ channels start to open (outward
(early repolarization) flow of K+ returns TMP to 0 mV)

• K+ efflux through delayed rectifier • Absent

Phase 2
K channels and Ca influx through voltage-
+ 2+

(plateau phase) gated L-type Ca2+ channels, which

triggers Ca2+ release from the sarcoplasmic
reticulum (i.e., Ca2+-induced Ca2+ release) →
contraction of the myocyte
• TMP is maintained at a plateau just below 0
mV.

•Inactivation of voltage-gated Ca2+ channels • Closure of voltage-gated Ca2+ channels and

Phase 3
•K+ efflux through delayed • Opening of delayed rectifier K+ channels →
(rapid repolarization) rectifier K+ channels continues: Persistent K+ efflux (TMP returns to -60 mV)
outflow of K+ exceeds Ca2+ inflow and brings
TMP back to -90 mV.
• The sarcolemmal Na+-Ca2+ exchanger, Ca2+-
ATPase, and Na+-K+-ATPase restore normal
transmembrane ionic concentration gradients
(Na+ and Ca2+ ions return to extracellular space,
K+ to intracellular space).

• Resting membrane potential stable at -90 • No resting phase (unstable membrane potential)
Phase 4
mV due to a constant outward flow of o Gradual Na+/K+ entry via funny channels If (funny
(resting phase) K+ through inward rectifier channels current or pacemaker current) → slow
• Na+ and Ca2+ channels closed spontaneous depolarization (TMP raises above -
60 mV); no external action potential needed
(automaticity of SA and AV nodes)
▪ At TMP -50 mV: T-type Ca2+ channels open.
 The long plateau phase of the Ca 2+ channels allows the myocardium to contract

and pump blood effectively.

Cardiac action potential

Pacemaker cells have no stable resting membrane potential. Their
special hyperpolarization-activated cation channels (funny channels) ensure a
spontaneous new depolarization at the end of each repolarization and are
responsible for the automaticity of the heart conduction system!
In sympathetic stimulation, more If channels open, increasing the heart rate.

Upstroke and depolarization of a pacemaker cell are caused by the opening of

voltage-activated L-type calcium channels. In other muscle cells and neurons,
upstroke and depolarization are caused by fast sodium channels!

The duration of action potentials differs in the various structures of

the conduction system and increases from the sinus node to the Purkinje
fibers!

Refractory period

• Effective refractory period (ERP): a recovery period immediately after

stimulation, during which a second stimulus cannot generate a new AP in a
depolarized cardiomyocyte. The Na+ channels are in an inactivated state until
the cell fully repolarizes (phases 1–3).
o See 'Refractory period' in resting potential and action potential for details.
• Phases (determined based on the number of sodium channels ready to be
reactivated)
o Absolute refractory period: time interval in which no new AP can be generated
because fast Na+ channels are deactivated (plateau phase)
o Relative refractory period: time interval in which some Na+ channels can be
reactivated but have a higher threshold potential; only a strong impulse can
trigger a new, low amplitude AP
• Effect
o Ensures sufficient time for chamber emptying (during systole) and refilling
(during diastole) before the next contraction
o Prevents re-excitation of cardiomyocytes during this period to avoid circulatory
excitation, which would lead to arrhythmia and tetany of cardiac muscle

The firing frequency of the SA node is faster than that of other pacemaker sites
(e.g., AV node). The SA node activates these sites before they can activate
themselves (overdrive suppression).

The plateau phase of the myocardial action potential is longer than the actual
contraction. This allows the heart muscle to relax after each contraction and
prevents permanent contraction (tetany)!

Heterogeneity of the refractory period within the myocardium (in which some
cells are in the absolute refractory period, relative refractory period, or resting
potential state) renders individuals more susceptible
to arrhythmias (e.g., ventricular fibrillation) when exposed to
an inappropriately-timed stimulus.

During cardioversion, shock delivery must be synchronized with the R

wave on ECG (indicating depolarization) and avoided during the relative
refractory period (T waves, indicating repolarization)!

Regulation of cardiac activity

Adaptation to short-term changes is provided by the Frank-Starling
mechanism. Long-term changes in cardiac activity are regulated by
the autonomic nervous system.

Frank-Starling mechanism

• Definition: a law that describes the relationship between end-diastolic volume and
cardiac stroke volume
o Cardiac contractility is directly related to the wall tension of the myocardium.
▪ An increase in end-diastolic volume (preload) will cause the myocardium to stretch (↑
end-diastolic length of cardiac muscle fibers), which increases contractility (↑ force of
contraction) and results in increased stroke volume in order to maintain cardiac
output.
▪ This relationship between end-diastolic volume and stroke volume is shown in
the Frank-Starling curve.
• Aim: maintain CO by modulating contractility and SV
o Stroke volume of both ventricles should remain the same.

Because the afterload is chronically increased in chronic hypertension, the left

ventricle undergoes hypertrophy to decrease left ventricular wall stress (↑ LV
wall thickness → ↓ LV wall stress).

An increase in preload leads to an increase in stroke volume; an increase

in afterload leads to a decrease in stroke volume!

Autonomic innervation of the heart

The autonomic nervous system is able to regulate heart rate, excitability,
conductivity, relaxation, and contractility. Sympathetic fibers innervate both
the atria and ventricles. Parasympathetic fibers only innervate the atria.
 Definition: modulation of cardiac action by sympathetic and/or parasympathetic nerve
fibers

• Function: long-term regulation of cardiac action

o Chronotropy: any influence on the heart rate
o Dromotropy: any influence on the conductivity of myocardium
o Inotropy: any influence on the force of myocardial contraction
o Lusitropy: any influence on the rate of relaxation of the myocardium
o Bathmotropy: any influence on the excitability of the myocardium

Persistent epinephrine surges and long-lasting sympathetic activity can damage

blood vessel endothelium, increase blood pressure, and increase the risk
of heart attack and stroke.

Initially, a diminished ejection fraction can be compensated by

increased sympathetic tone, RAAS activation, ADH release, and the Frank-
Starling mechanism. In the long term, however, these mechanisms increase
cardiac work and lead to heart failure. Antihypertensive drugs target these
mechanisms.
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▪ Factors that increase SV Factors that decrease SV

• ↑ Venous return • ↓ Venous return

Preload
o During inspiration o During expiration
o When changing from upright to supine position o When changing from supine to
o ↑ Skeletal muscle pump activity upright position
o ↑ Venous tone (increased sympathetic activity) o Nitroglycerin (venous vasodilatation)
o ↑ Circulating blood volume (e.g., infusions) o Inferior vena cava obstruction
during pregnancy or due to Valsalva
maneuver
o Due to ACE inhibitors or angiotensin
II receptor blockers
o Hemorrhage
• Tricuspid and mitral valve
stenosis (↓ ventricular inflow)
• Aortic
stenosis (↑ diastolic ventricular
pressure → ↓ ventricular filling)
• Atrial tachycardia (e.g., atrial
fibrillation ↓ ventricular filling time)

Afterload• ↓ Systemic vascular resistance (e.g., due to vasodilators such • ↑ Systemic and/or
as hydralazine, ACE inhibitors, angiotensin II receptor blockers) peripheral vascular resistance (e.g.,
and/or pulmonary vascular resistance (e.g., due to vasodilators such due to chronic hypertension)
as phosphodiesterase inhibitors) • Aortic valve stenosis

Myocardial• ↑ Myocardial contractility (↑ inotropy) • ↓ Myocardial

o Sympathetic innervation (β1-receptor activation)
contractility contractility (↓ inotropy)
o Catecholamines (e.g., epinephrine, norepinephrine, dopamine) through βo1- Parasympathetic stimulation
receptor activation o Acetylcholine
o High levels of blood and intracellular calcium o β1-receptor blockers: inhibition
o Thyroid hormones of adenylyl cyclase → ↓ cAMP →
o Decreased extracellular Na+ (because subsequently, the activity of ↓ cAMP-dependent protein kinase
the Na+/Ca2+ exchanger will decrease) A (PKA) activity
o Digitalis: inhibition of Na+/K+ pump → increased intracellular Na+ → o Nondihydropyridine Ca2+ channel
decreased Na /Ca exchanger activity → increased intracellular Ca
+ 2+ 2+
blockers: See effects in calcium
channel blockers.
o Systolic heart failure
o Hypoxia
o Hypercapnia
 o Hyperkalemia
o Acidosis

Factors that affect cardiac output

• Preload: the extent to which heart muscle fibers are stretched before the onset
of systole; depends on end-diastolic ventricular volume (EDV), which changes
according to:
o Venous constriction: ↑ venous tone → ↑ venous blood return to
the heart → ↑ EDV → ↑ preload
o Circulating blood volume: ↑ circulating blood volume → ↑ venous blood return to
the heart → ↑ EDV → ↑ preload
• Afterload: the force against which the ventricle contracts to eject blood during systole
o Afterload is primarily determined by the mean arterial pressure (MAP) in the aorta,
which is influenced by total peripheral resistance.
o ↑ Afterload → ↑ left ventricular pressure → ↑ left ventricular wall stress
o According to Laplace's law, ↑ left ventricular pressure → ↑ left ventricular wall stress
▪ Left ventricular (LV) wall stress = (LV pressure × radius)/ (2×LV wall thickness)

Valsalva maneuver

• Definition: forceful exhalation against a closed airway

• Technique: four phases
o Phase 1 (start strain) & phase 2 (continued strain): increased intrathoracic pressure →
decreases venous return/ventricular preload → decreased cardiac output
o Phase 3 (release of strain) & phase 4 (recovery phase): reduced intrathoracic pressure
→ reduced afterload → increased stroke volume → increased cardiac output
• Applications:

o Treatment of supraventricular tachycardia (e.g., AVNRT)

o Diagnostic tool to:

▪ Evaluate conditions of the heart: augments heart sounds on physical exam (e.g., earlier
click in mitral valve prolapse and louder murmur in hypertrophic obstructive
cardiomyopathy)

▪ Test for hernia (increased intraabdominal pressure → bulging)

o Measure to normalize middle-ear pressure (e.g., in diving)

Myocardial oxygen demand increases with an increase in HR, myocardial

contractility, afterload, or diameter of the ventricle.

Clinical significance

• Electrocardiography
• Cardiac examination
• Heart failure
• Overview of cardiac arrhythmias
• Cardiomyopathy
• Antiarrhythmic drugs
• Sympathomimetic drugs
• Sympatholytic drugs
• Parasympathomimetic drugs
• Parasympatholytic drugs
• Shock
• Syncope