The black loop represents normal cardiac physiology.

Phases—left ventricle:
Isovolumetric contraction—period between mitral valve closing and aortic valve opening; period of highest O2
consumption
Systolic ejection—period between aortic valve opening and closing
Isovolumetric relaxation—period between aortic valve closing and mitral valve opening
Rapid filling—period just after mitral valve opening
Reduced filling—period just before mitral valve closing
Heart sounds:
S1—mitral and tricuspid valve closure. Loudest
at mitral area.

S2—aortic and pulmonary valve closure.

Loudest at left upper sternal border.

S3—in early diastole during rapid ventricular

filling phase. Associated with filling pressures
(eg, mitral regurgitation, HF) and more
common in dilated ventricles (but can be
normal in children, young adults, and pregnant
women).

S4—in late diastole (“atrial kick”). Best heard

at apex with patient in left lateral decubitus
position. High atrial pressure. Associated with
ventricular noncompliance (eg, hypertrophy).
Left atrium must push against stiff LV wall.
Consider abnormal, regardless of patient age.

Jugular venous pulse (JVP):

A wave—atrial contraction. Absent in atrial
fibrillation (AF).

C wave—RV contraction (closed tricuspid valve

bulging into atrium).

x descent—downward displacement of closed

tricuspid valve during rapid ventricular
ejection phase. Reduced or absent in tricuspid
regurgitation and right HF because pressure
gradients are reduced.

V wave—right atrial pressure due to filling

(“villing”) against closed tricuspid valve.

Y descent—RA emptying into RV. Prominent in

constrictive pericarditis, absent in cardiac
tamponade.
Atrioventricular block
(Heart block)
Last updated: Dec 10, 2019
QBANK SESSION
CLINICAL SCIENCES
LEARNED

Summary
Atrioventricular block (AV block) is characterized by an interrupted or delayed conduction between
the atria and the ventricles. AV blocks are divided into three different degrees depending on the extent of
the delay or interruption. First-degree blocks are identifiable on ECG by a prolonged PR interval. Most
patients with first-degree block are asymptomatic, and the condition is usually an incidental
finding. Second-degree AV blocks are further divided into two different subtypes. Mobitz type I, or
Wenckebach, blocks exhibit a progressive prolongation of the PR interval that culminates in a non-
conducted P wave (“dropped beat”). Most patients with Mobitz type I blocks are asymptomatic. The
Mobitz type II block generates dropped QRS complexes at regular intervals (e.g. 2:1, 3:1, or 3:2), often
leading to bradycardia. Symptoms of patients with Mobitz type II block range from fatigue
to dyspnea, chest pain, and/or syncope. This fixed second-degree block frequently progresses to a third-
degree block. A third-degree AV block involves total interruption of the electrical impulse between
the atria and ventricles. The complete absence of conduction results in a ventricular escape mechanism,
which may be dangerously slow and result in life-threatening bradycardia or Stokes-Adams attacks.
Therefore, a third-degree AV block is an absolute indication for pacemaker placement.

NOTES
FEEDBACK

Etiology
• Physiological: ↑ vagal tone
• Pathophysiological
o Idiopathic fibrosis of the conduction system

o Ischemic heart disease

o Cardiomyopathy (e.g., due to amyloidosis or sarcoidosis)

o Infections (e.g., Lyme disease, bacterial endocarditis)

o Hyperkalemia (> 6.3 mEq/L)

• Iatrogenic
o Side effect of certain drugs (e.g.,beta blockers, calcium channel blockers, digitalis)

o Cardiac interventions (e.g., surgery, alcohol septal ablation)

References:[1][2]
NOTES
FEEDBACK

First-degree AV block
Definition
• PR interval > 200 ms

• No interruption in atrial to ventricular conduction

• Rate of SA node = heart rate

Characteristics
• May be found in healthy individuals, e.g., in athletes with ↑ vagal tone
• Usually asymptomatic
• Often discovered incidentally on ECG

Treatment
• Clinical assessment for underlying diseases (e.g., structural heart diseases,
electrolyte imbalances)
• Usually no specific treatment necessary

• Follow-ups to evaluate progression of the disease

• Pacemaker

o If the patient also exhibits wide QRS complexes on ECG → identify the level of AV
block (within or below the bundle of His) using intracardiac electrogram → if
conduction time from the bundle of His to the ventricles is > 100 ms: pacemaker
placement
o Symptomatic patients: unpleasant awareness of the heartbeat due to loss of
atrioventricular synchrony (pacemaker syndrome)
References:[3][4][5]
NOTES
FEEDBACK

Second-degree AV block
Mobitz type I/Wenckebach
Definition
• Progressive lengthening of the PR interval until a beat is dropped; regular atrial
impulse does not reach the ventricles (a normal P wave is not followed by a QRS-
complex)
• Rate of SA node > heart rate; mostly regular rhythm separated by short pauses,
which may lead to bradycardia

Symptoms/clinical findings
• Usually asymptomatic
• May present with symptoms of reduced cardiac output, resulting in hypoperfusion
(e.g., dizziness, syncope) and bradycardia
• Irregular pulse

Treatment
• Asymptomatic patients
o Clinical assessment for underlying diseases (e.g., structural heart diseases,
electrolyte imbalances)
o Usually no specific treatment necessary

o Follow-ups (ECG and cardiac monitoring) to evaluate progression of the disease

• Symptomatic patients

o Hemodynamically stable

§ Monitoring with transcutaneous pacing pads

§ If symptoms not reversible → placement of a permanent pacemaker
o Hemodynamically unstable

§ Atropine
§ Temporary cardiac pacing (if not responsive to atropine)

Mobitz type II
Definition
• Single or intermittent non-conducted P waves without QRS complexes
 • The PR interval remains constant.
• The conduction of atrial impulses to the ventricles follows regular patterns:
o 2:1 block: regular AV block that inhibits conduction of every other
atrial depolarization (P wave) to the ventricles (heart rate = ½ SA node rate)
o 3:1 block: regular AV block with 3 atrial depolarizations but only 1 atrial impulse
that reach the ventricles (heart rate = ⅓ SA node rate)
o 3:2 block: regular AV block with 3 atrial depolarizations but only 2 atrial impulses
that reach the ventricles (heart rate = ⅔ SA node rate)

Symptoms/clinical findings
• Bradycardia → ↓ cardiac output

o Fatigue

o Dyspnea

o Chest pain

o Dizziness, syncope

Treatment
• Hemodynamically stable patients:

o Monitoring with transcutaneous pacing pads

o Clinical assessment for underlying diseases (e.g., structural heart diseases,

electrolyte imbalances)
o If symptoms are not reversible → placement of a permanent pacemaker

• Hemodynamically unstable patients:

o Atropine

o Temporary cardiac pacing

The second-degree AV block Mobitz type II may progress to a third-degree block and is an unstable
condition that requires monitoring and treatment!
References:[1][4][6][7]
NOTES
FEEDBACK

Third-degree AV block
Definition
• Third-degree AV block is a complete block with no conduction between
the atria and ventricles.
• AV dissociation: on ECG, P waves and QRS complexes have their own regular
rhythm but bear no relationship to each other
• A ventricular escape mechanism is generated by sites that are usually located near
the AV node or near the bundle of His.
o The more distant the site of impulse generation:

§ The slower the ventricular escape mechanism

§ The wider and more deformed the QRS complex
§ Block proximal to bundle of His: narrow QRS complexes
§ Block distal to bundle of His: wide QRS complexes
§ The worse the prognosis
• Sudden onset of a third-degree AV block results in asystole, which lasts until the
ventricular escape mechanism takes over. This asystole may lead to Stokes-
Adams attacks.

Symptoms/clinical findings
Symptoms depend on:
• Rate of ventricular escape mechanism
o Bradycardia (< 40 bpm) with cerebral hypoperfusion (fatigue,
irritability, apathy, dizziness, syncope, cognitive impairment), heart
failure, dyspnea
• Length of asystole
o Nausea, dizziness

o Stokes-Adams attacks

o Cardiac arrest

Treatment
 • Hemodynamically stable patients:
o Monitoring with transcutaneous pacing pads

o Clinical assessment for underlying diseases (e.g., structural heart diseases,

electrolyte imbalances)
o No reversible causes → placement of a permanent pacemaker

• Hemodynamically unstable patients:

o Temporary transcutaneous or transvenous cardiac pacing

§ In the event of low blood pressure, administer dopamine.

§ In the event of heart failure, administer dobutamine.

Cardiac physiology
Last updated: Jun 03, 2020
QBANK SESSION
LEARNED

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.
NOTES
FEEDBACK

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: Q1 = 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.
NOTES
FEEDBACK

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

MAXIMIZE TABLETABLE QUIZ
Valvular Pressure-volume loop Time-pressure curves
disease

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

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

Mitral stenosis • The pressure-volume loop is narrower and • LA pressure > LV

flatter than the normal pressure-volume loop. pressure during diastole
• ↑ LA pressure
• ↓ LV end-diastolic volume
• ↓ Stroke volume
• ↓ LV end-systolic volume

Aortic • The pressure-volume loop is rounder and taller • ↑ Pulse pressure

regurgitation than the normal pressure-volume loop.
• ↑ LV end-diastolic volume and pressure
• ↑ Stroke volume
• No true isovolumetric relaxation

Aortic stenosis • The pressure-volume loop is narrower and • LV blood pressure > aortic pressure
taller than the normal pressure-volume loop. during systole
• ↑ LV end-systolic pressure
• No change in end-diastolic volume
• ↓ Stroke volume
• ↑ LV end-systolic volume
• ↑ LV end-diastolic pressure
The width of the volume-pressure loop is the SV (the difference between EDV and ESV).
NOTES
FEEDBACK

Conduction system of the heart

Definition: the collection of nodes and specialized conduction cells that initiate and coordinate
contraction of the heart muscle

MAXIMIZE TABLETABLE QUIZ

Name Anatomic localization Characteristics Frequency

Sinoatrial node • Upper wall of • Natural pacemaker center of ca. 60–

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

Atrioventricular • Within the AV • Receives impulses from the SA node and ca. 40–
node septum (superior passes these impulses to the bundle of His 50/min
and medial to the
• Has the slowest conduction velocity
opening of
the coronary sinus in • Delays conduction for 60–120 ms (allowing
the right atrium) 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)
 Name Anatomic localization Characteristics Frequency

Bundle of His • Directly below • Receives impulses from the AV node ca. 30–
the cardiac skeleton, • Splits into left and right bundle 40/min
within the branches (Tawara branches) → the right
membranous part of bundle travels to the right ventricle; the left
the interventricular bundle splits into an anterior and
septum 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 • Conduct cardiac AP faster than any other ca. 30–
Purkinje fibers fibers in the cardiac cells 40/min
subendocardium • Ensure synchronized contraction of the
ventricles
• 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.
NOTES
FEEDBACK

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

MAXIMIZE TABLETABLE QUIZ

Name Definition Location Direction of Activatio

flow n phase
(affected
tissue)

Calci L-type voltage- • Long-acting, high- • Cell • Influx of • Plateau

um gated calcium voltage channels membrane of car extracellul phase
chan channel that are responsible diomyocytes ar (myoca
nels (i Ca) for electromechani Ca2+ into rdium)
cal coupling the cytopl • Upstrok
• Activation asm e phase
via depolarization ( (SV
- 40 mV) triggers node)
Ca2+ influx into the
cells, which in turn
stimulates the
release of Ca2+ from
the SR.

T-type voltage- • A voltage-gated • Cell • Influx of • During

gated calcium calcium membrane of extracellul the
channel channel that is cardiac ar middle
opened by low- pacemaker cells Ca2+ into of
voltage depolarizati the cytopl phase 4
on potentials asm (SV
node)

Ryanodine • Ca2+ channel that • Membrane of SR • Transport • Plateau

receptor opens after binding Ca2+ from phase
of SR to (myoca
Ca2+ (i.e., calcium- the cytopl rdium)
induced Ca2+ releas asm
e)
 Calci SERCA (sarcopl • Ca2+ pumps and • Membrane of SR • Efflux of • Plateau
um asmic Ca2+- exchangers that are Ca2+ from phase
pum ATPase) responsible for the cytopl (myoca
ps terminating a asm into rdium)
contraction the SR

Na+/Ca2+ • Cell • Efflux of

exchanger membrane of car Ca2+ from
diomyocytes the cytopl
asm into
extracellul
ar space

Other cation channels

All of these channels are located in the cell membrane.
MAXIMIZE TABLETABLE QUIZ

Name Definition Direction of Activation phase (affected

flow tissue)

Funny channels (HCN, If) • Nonselective cation • Extracellul • Upstroke phase (sinus node)
channels (e.g., for ar →
Na+, K+) in intracellul
pacemaker cells that ar
open as the
membrane potential
becomes more
negative
(hyperpolarized)

Fast sodium channels (INa) • Na+ channels that • Depolarization (myocardium

rapidly open and )
close
following depolariza
tion

Potassiu Inward rectifier • K+ channels that • Intracellul • Resting

m K+ channels open during ar → potential (primarily myocard
channels the resting extracellul ium; sinus node)
potential (below −70 ar
mV) and stabilize
the resting
potential of
the cardiomyocytes

Delayed • K+ channels that can • Repolarization (sinus node

rectifier be rapidly (IKr) or and myocardium)
K+ channels(IKr a slowly (IKs) activated
nd IKs) upon depolarization
The long plateau phase of the Ca2+ channels allows the myocardium to contract and pump blood
effectively.

Cardiac action potential

MAXIMIZE TABLETABLE QUIZ

Myocardial action Pacemaker action potential (SA

potential (myocardium, bundle of node and AV node)
His, Purkinje fibers)

Phase 0 • Upstroke: An action potential from • Upstroke: At TMP -40 mV (threshold

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

Phase 1 • Inactivation of voltage-gated • Absent

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

Phase 2 • K+ efflux through delayed rectifier • Absent

(plateau phase) K+ channels and Ca2+ influx through
voltage-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.
 Myocardial action Pacemaker action potential (SA
potential (myocardium, bundle of node and AV node)
His, Purkinje fibers)

Phase 3 • Inactivation of voltage-gated • Closure of voltage-

(rapid repolarization) Ca2+ channels gated Ca2+ channels and
• K+ efflux through delayed • Opening of delayed
rectifier K+ channels continues: rectifier K+ channels → K+ efflux (TMP
Persistent outflow of returns to -60 mV)
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).

Phase 4 • Resting membrane potential stable • No resting phase (unstable membrane

(resting phase) at -90 mV due to a constant potential)
outward flow of K+ through inward o Gradual Na+/K+ entry via funny
rectifier channels channels If (funny
• Na+ and Ca2+ channels closed current or pacemaker current) →
slow
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.

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)!
NOTES
FEEDBACK

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

MAXIMIZE TABLETABLE QUIZ

 Site of Nerves Effect Mechanism of action
innerva
tion

Sympathetic stimul • Atria • Fibers from • ↑ Heart • Activation of beta1 adrenergic

ation and the sympathetic rate, receptors (Gs protein-coupled) of
ventri cervical trunk conduct the heart by epinephrine and nor
cles ion, epinephrine → ↑
(superior,
middle, and contrac activity of adenylyl cyclase → ↑
inferior cardiac tility, intracellular cAMP concentration
and in SA node cardiomyocytes,
nerve)
relaxati which then:
on 1. Increases the conductance of
funny sodium channels
and L-type calcium
channels → ↑ influx of
cations during
spontaneous depolarization
→ faster attainment of
the threshold
potential during phase
4 of pacemaker action
potential for initiating the
rhythmic cardiac action
potential → ↑ heart
rate (positive chronotropic)
2. Activates protein kinase
A (PKA), which leads to two
effects:
§ Phosphorylation of L-
type Ca2+ channels in AV
node → increased
Ca2+ entry →
increased Ca2+-
induced Ca2+ release
during action
potential → increased
contraction and
conduction
(positive dromotropic a
nd inotropic)
§ Phosphorylation of phosp
holamban
→ activation
of sarcoplasmic
reticulum Ca2+-ATPase
(SERCA) → increased
transport of Ca2+ back
into sarcoplasmic
reticulum after a
contraction → faster
 Site of Nerves Effect Mechanism of action
innerva
tion

relaxation
(positive lusitropic)

Parasympathetic sti • Atria • Branches of • ↓ Heart • Exerts its action on

mulation the vagus rate an the heart through parasympatheti
nerve d atrial c muscarinic ACh
o Cervical contrac receptors (subtype M2) on SA
cardiac tility and AV node cardiomyocytes
branches o Activation
of M2 receptors on SA
o Thoracic
cardiac node (negative chronotropi
branches c)
§ Reduces the conductance
of funny sodium channels
via adenylyl cyclase,
decreasing cAMP →
↓ pacemaker
current (lengthens the
rate of depolarization in
the
slow depolarization phase
)
§ Increases conductance of
the slow potassium
channels
→ hyperpolarization of
the resting membrane
potential (harder to
overcome)
 Site of Nerves Effect Mechanism of action
innerva
tion

o Vagal fibers innervate

the AV
node (negative dromotropic
): slows cardiac action
potential propagation (can
result in complete AV block)

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.

NOTES
FEEDBACK

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)

MAXIMIZE TABLETABLE QUIZ

Factors that increase SV Factors that decrease SV

Preload • ↑ Venous return • ↓ Venous return

o During inspiration o During expiration
o When changing from upright to supine position o When changing
from supine to upright
o ↑ Skeletal muscle pump activity
position
o ↑ Venous tone (increased sympathetic activity)
o Nitroglycerin (venous
o ↑ Circulating blood volume (e.g., infusions) vasodilatation)
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 • ↑ Systemic and/or

to vasodilators such as hydralazine, ACE peripheral vascular
inhibitors, angiotensin II receptor blockers) resistance (e.g., due to
and/or pulmonary vascular resistance (e.g., due chronic hypertension)
to vasodilators such as phosphodiesterase inhibitors) • Aortic valve stenosis
 Factors that increase SV Factors that decrease SV

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

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

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.
Summary
The cerebrovascular system comprises the vessels that transport blood to and from the brain. The brain's arterial
supply is provided by a pair of internal carotid arteries and a pair of vertebral arteries, the latter of which unite to form
the basilar artery. The anterior cerebral artery, a branch of the internal carotid artery, perfuses the
anteromedial cerebral cortex; the middle cerebral artery, also a branch of the internal carotid artery, perfuses
the lateral cerebral cortex; and the posterior cerebral artery, a branch of the basilar artery, perfuses
the medial and lateral portions of the posterior cerebral cortex. The internal carotid arteries, the anterior cerebral
arteries, and the posterior cerebral arteries anastomose through the anterior and posterior communicating arteries to
form the circle of Willis, a vascular circuit surrounding the optic chiasm and pituitary stalk. The circle of Willis provides
an alternative channel for blood flow in case of vascular occlusion and equalizes blood flow between the cerebral
hemispheres. The cerebral hemispheres are drained by superficial cerebral veins (superior cerebral veins, middle
cerebral veins, inferior cerebral veins) and deep cerebral veins (great cerebral vein, basal vein), which empty into
the dural venous sinuses. Brain perfusion is regulated by the partial pressure of carbon dioxide (PaCO2). The
interruption of perfusion due to occlusion or hemorrhage of the cerebral vessels results in a stroke, which manifests
with focal neurologic deficits in the body parts controlled by the affected brain territory.
NOTES
FEEDBACK

Arterial supply
The arterial supply of the brain is provided by the internal carotid arteries and the vertebral arteries, which are
derivatives of the branches of the aortic arch.
Internal carotid arteries (ICA)
• A terminal branch of the common carotid artery
• Course:
o Neck: lies within the carotid sheath and enters the cranium through the carotid canal

o Cranium: lies on the roof of the cavernous sinus, in close proximity to CN VI

• Only has intracranial branches:

o Caroticotympanic artery (the first intracranial branch of the internal carotid artery that enters
the middle ear cavity and anastomoses with the inferior tympanic artery)
o Artery of the pterygoid canal (Vidian artery)

o Meningohypophyseal trunk (posterior trunk;

o Inferolateral trunk

o Ophthalmic artery

o Superior pituitary artery

o Posterior communicating artery: anastomosis in Circle of Willis

o Anterior choroidal artery

o Terminal branches:

§ Middle cerebral artery: supplies lateral cerebrum

 § Anterior cerebral artery: supplies anterior cerebrum

Vertebral arteries
• Arise from the subclavian arteries
• Course:
o Neck: The vertebral arteries pass through the foramina in the transverse processes of
the cervical vertebrae and enter the cranium through the foramen magnum.
o Cranium: The right and left vertebral arteries unite at the midline of the anterior surface of
the pons to form the basilar artery.
• Branches:
o Anterior spinal artery and posterior spinal arteries: supply spinal cord

o Posterior inferior cerebellar arteries (PICA): terminal branches that supply inferior cerebellum

References:[1][2]
NOTES
FEEDBACK

Circle of Willis
• Definition: a vascular circuit formed by the anastomoses between branches of the internal
carotid arteries (anterior circulation) and vertebral arteries (posterior circulation) around
the optic chiasm and pituitary stalk
• Consists of paired:
o Internal carotid arteries (proximal to the origin of the middle cerebral arteries)

o Anterior cerebral arteries (terminal branches of the internal carotids)

o Posterior cerebral arteries (terminal branches of the vertebral arteries)

• Two anastomoses
o Anterior communicating artery: connects the two anterior cerebral arteries

o Posterior communicating artery (branch of internal carotid artery): connects the ICA to
the posterior cerebral artery
• Functional significance
 o The circuit provides alternative channels to bypass a potential site of vascular occlusion.

o Equalizes arterial flow to both cerebral hemispheres

Most saccular cerebral aneurysms, also known as berry aneurysms, occur in the anterior circulation of the brain,
usually at the junction of the anterior cerebral artery and the anterior communicating artery in the circle of Willis. They
are the most common cause of nontraumatic subarachnoid hemorrhage.

References:[3][4]
NOTES
FEEDBACK

Cerebral arterial territories

MAXIMIZE TABLETABLE QUIZ

Artery Arterial territory Main Features of stroke

branches

Anterior circu Anteri • Anteromedial cortex, • Anterior • Contralateral hemiplegia (lower

lation or including: communi limbs affected more severely)
Branches of cereb o Medial portion of cating • Minimal hemisensory loss (lower
the internal ral the frontal artery limbs affected more severely)
carotid artery artery and parietal lobes: • Ophthal
(ACA) • Dysarthria
motor and sensory mic
supply of the artery • Aphasia
lower extremities • Anterior • Abulia (lack of motivation)
o Anterior limb of choroidal • Limb apraxia
the internal artery (se
capsule e below) • Urinary incontinence

o Corpus callosum
o Basal ganglia
.
Artery Arterial territory Main Features of stroke
branches

Middl • Lateral cortex, • Lenticulo • Contralateral hemiplegia

e including: striate • Contralateral hemisensory loss
cereb o Lateral portion of arteries
ral • Gaze deviation towards the side
the frontal
artery of infarction
and parietal lobes:
(MCA) motor and sensory • Hemineglect (right MCA territory;
cortex of the face nondominant hemisphere)
and upper • Contralateral homonymous
extremities hemianopia without macular
o Temporal sparing
lobe: Wernicke • Broca aphasia (inferior
area frontal gyrus of dominant
o Frontal lobe: Broca hemisphere)
area • Wernicke aphasia (superior
• Lenticulostriate temporal gyrus of dominant
arteries supply deeper hemisphere)
structures of the
brain:
o Putamen, globus
pallidus
o Parts of
the internal
capsule and cauda
te nucleus

Anteri • Optic tract and lateral • • Triad of:

or geniculate nuclei o Hemiparesis or hemiplegia (in
choroi • Hippocampus and late cluding dysarthria)
dal ral thalamus
artery o Hemisensory loss
• Posterior limb of o Homonymous hemianopsia
the internal capsule
 Artery Arterial territory Main Features of stroke
branches

Posterior circ Poste • Posteroinferior cortex • Several • Contralateral hemisensory loss

ulation rior o Occipital lobes branches • Contralateral homonymous
Branch of cereb to the hemianopia with macular sparing
the basilar ral o Posteromedial cortical
artery artery aspect of lobes • Memory deficits
(PCA) the temporal lobes and chor • Vertigo, nausea
o Thalamus oid
plexus • Left PCA: alexia without
agraphia, anomic aphasia,
visual agnosia
• Right PCA: prosopagnosia

References:[5][6][7]
NOTES
FEEDBACK

Venous drainage
The cerebral hemispheres are drained by superficial and deep cerebral veins, which empty into the dural venous
sinuses.
Superficial cerebral veins
MAXIMIZE TABLETABLE QUIZ

Superficial veins Bridging vein Draining venous sinus

Drain the white matter

Superior cerebral veins Superior anastomotic vein Superiorsagittal sinus

Middle cerebral veins Inferior anastomotic vein Cavernous sinus

Inferior cerebral veins Cavernous and transverse venous sinuses

Deep cerebral veins

Deep cerebral veins drain the cerebral medulla and drain into the straight sinus.
• Medullary veins: drain the gray matter
• Subependymal veins: receive blood from the medullary veins
• Basal vein (vein of Rosenthal): paired paramedian veins that receive blood from the temporal
lobe and drain into the great cerebral vein
 • Great cerebral vein (vein of Galen): receives blood from the deep veins
Dural venous sinuses
• The dural venous sinuses drain blood from cerebral veins and CSF from the arachnoid
granulations into the internal jugular vein.
• They are located intracranially between the two layers of dura mater (endosteal layer
and meningeal layer).

MAXIMIZE TABLETABLE QUIZ

Venous sinus Characteristics

Superior sagittal • Located at the midline

sinus • Terminates at the confluence of sinuses
• Drains blood from cortical veins of the cerebral hemispheres
• Main location of cerebral fluid return via arachnoid granulations

Inferior sagittal • Located at the midline

sinus • Joined by the great cerebral vein of Galen before draining into the straight sinus
• Drains blood from the medial surface of the cerebral hemispheres

Straight sinus • Located at the midline

• Terminates at the confluence of sinuses

Occipital sinus • Located posteriorly

• Drains into the confluence of sinuses

Confluence of • Formed by the union of the superior sagittal sinus, straight sinus, and occipital sinus
sinuses • Located posteriorly
• Drains into left and right transverse sinus

Superior petrosal • Located laterally

sinus • Drains into the transverse sinus
(paired)
• Drains blood from the inner ear structures via the labyrinthine vein

Transverse sinus • Located laterally along the edge of the tentorium cerebelli
(paired) • Drains into the sigmoid sinus
 Venous sinus Characteristics

Inferior petrosal • Located laterally

sinus • Drains the cavernous sinus into the internal jugular vein
(paired)
• Drains blood from the medulla, pons, and inferior surface of the cerebellum

Sigmoid sinus • Located laterally

(paired) • Continuation of transverse sinus that arches downward in an S-shaped groove into
the internal jugular vein

Sphenoparietal • Located anteriorly

sinus • Drains into the cavernous sinus
(paired)

Cavernous sinus • Located anteriorly on each side of the sella turcica (pituitary fossa)
(paired) • Structures running through these sinuses include:
o Medially: internal carotid artery and abducens nerve (VI)
o Laterally: oculomotor nerve (III), trochlear nerve (IV), ophthalmic nerve (V1),
and maxillary nerve (V2)
• Receives the superior ophthalmic vein
• Drains into the petrosal sinuses

Basilar venous • Lies over the basilar part of the occipital bone (the clivus)
plexus • Connected with the cavernous and petrosal sinuses and the
(paired) internal vertebral (epidural) venous plexus.

Brain veins run in the subarachnoid space, have no valves to allow bidirectional blood flow, and have no muscular layer
in the vessel wall!
References:[8][3][9][10][11][12][13]
NOTES
FEEDBACK

Physiology
• Cerebral perfusion is modulated by the partial pressure of carbon dioxide (pCO2)

o Increased pCO2 → vasodilation → increased cerebral blood flow

o Decreased pCO2 → vasoconstriction → decreased cerebral blood flow

• Therapeutic hyperventilation reduces pCO2 → decreases cerebral blood flow →

lower intracranial pressure (e.g., used in acute cerebral edema)
 • Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) - intracranial pressure (ICP)

o Decreased blood pressure or increased ICP → decreased cerebral perfusion

o CPP of 0 indicates no brain perfusion (brain death)

o Hypoxemia increases CPP if pO2 < 50 mm Hg

o CPP linearly increases with pCO2 until pCO2 > 90 mm Hg

References:[14][15]
NOTES
FEEDBACK

Clinical significance
• Arterial conditions:
o Stroke

o Cerebral aneurysms

o Subarachnoid hemorrhage

o Epidural hematoma

o Intraparenchymal hemorrhage

o Trigeminal neuralgia (compression of superior cerebellar artery)

o Hydrostatic cerebral edema (e.g., in severe hypertension)

• Venous conditions:
o Cerebral venous thrombosis

o Cavernous sinus syndrome

o Subdural hematoma (caused by ruptured bridging veins)

Summary
The circulatory system, which is also called the vascular system or cardiovascular system, consists of
the systemic circulation, pulmonary circulation, the heart, and the lymphatic system. Blood flow through
the circulatory system is generated by the heart. Vascular resistance is the amount of resistance in the
systematic circulation that must be overcome to create blood flow. The Poiseuille equation describes the
relationship between vascular resistance, the length and radius of the vessel, and the viscosity of blood.
Blood pressure is generated by the heart, creating a pulsatile blood flow that leads to systolic blood
pressure (maximum pressure reached during a cardiac cycle) and diastolic blood pressure (minimum
pressure reached during a cardiac cycle) within the circulatory system. The pressure gradient across
the circulatory system drives the blood flow from high pressure to low pressure. Blood pressure regulation
involves a complex interaction of various sensors (baroreceptors, volume receptors, chemoreceptors) and
mechanisms, including the autonomic nervous system, the renin-angiotensin-aldosterone system (RAAS),
and atrial reflex and diuresis reflex. Perfusion is the passage of the blood through the circulatory system to
the capillary bed to deliver oxygen and nutrients to the tissue and remove waste products (e.g., removal of
CO2 to the lungs, removal of urea to the kidneys). Perfusion levels differ in organs and fluctuate depending
on the activity (e.g., rest, physical activity). Autoregulatory mechanisms (myogenic autoregulation, local
metabolite production), as well as central regulatory mechanisms, modulate perfusion levels in organs.
The exchange of substances in the microcirculation occurs via diffusion, filtration, and
reabsorption. Capillary fluid exchange is described by the Starling equation, which states that the net fluid
flow is dependent on the capillary and interstitial hydrostatic pressures, oncotic pressures, and the vascular
permeability to fluid and proteins.
The heart and cardiac physiology, as well as the lymphatic system, are discussed in separate learning
cards.
NOTES
FEEDBACK

Circulatory system
• Systemic circulation: Oxygenated blood flows from the left ventricle into
the systemic circulation and, after passing through the capillary bed, flows back in a
deoxygenated state to the right atrium of the heart to restart the process.
o Left atrium → mitral valve → left ventricle→ aortic valve →
aorta→ arteries → arterioles → capillary beds → veins → superior vena cava (SVC)
and inferior vena cava (IVC) → right atrium
• Pulmonary circulation: Deoxygenated blood in the right heart flows into the lungs,
where it is oxygenated and returned to the left atrium.
o Right atrium → tricuspid valve → right ventricle → pulmonary valve → pulmonary
trunk → pulmonary arteries
→ lungs
→ four pulmonary veins
→ left atrium

• Heart: connects systemic circulation and pulmonary circulation

o See heart and cardiac physiology for details.

• Lymphatic system: a network of lymphatic vessels that transport lymph toward

the heart (see lymphatic drainage for details)
NOTES
FEEDBACK

Hemodynamics
Pressure, flow, and resistance
• The relationship between pressure, flow, and resistance in the circulatory system is
expressed as ΔP = Q x R
o ΔP = pressure gradient

o Q = blood flow
 o R = vascular resistance

Blood flow
• Blood flow is driven by cardiac activity pumping blood through the circulatory
system.
• Volume of blood returning to the heart per minute = cardiac output (CO)

o Rate of blood flow = blood flow / total cross-sectional area of the blood vessel

o The rate of blood flow (blood velocity cm/s) is inversely proportional to the
total cross-sectional area of the blood vessel.
Capillaries have the largest total cross-sectional area of all blood vessels (i.e., 4500–6000 cm2 compared
to 3–5 cm2 in the aorta) and, thus, the slowest blood velocity (0.03 cm/s) compared to the aorta (40 cm/s).
Laminar and turbulent blood flow
Blood flow in vessels is either laminar or turbulent depending on the smoothness of the blood vessel walls,
the viscosity of the blood, the blood velocity, and the diameter of the lumen.
• Laminar blood flow
o Definition: a layered flow pattern

o Effect: The layer with the highest velocity flows in the center of the vessel lumen.

o Low Reynolds number

o Occurrence: throughout the vascular system

• Turbulent blood flow

o Definition: a chaotic flow pattern

o Effects

§ Increases vascular resistance

§ Promotes thrombus formation
§ Creates murmurs (e.g., bruits in a stenotic vessel)
o High Reynolds number

o Occurrence

§ Vessels with a large diameter (e.g., aorta)

§ High viscosity
§ Low viscosity (e.g., anemia)
§ Vascular bifurcations
§ Vascular stenosis
 Vascular resistance
• Definition: resistance offered by the circulatory system that must be overcome to
create blood flow (R = ΔP / Q)
• Vascular resistance comprises:
o Total peripheral resistance (TPR): the amount of resistance to blood flow in the
systemic circulation = (MAP - CVP) / CO
§ ↑ TPR in vasoconstriction of arterioles (e.g., in hemorrhage, ↑ vasopressor)
→ ↑ afterload and ↓ venous return → ↓ CO
§ ↓ TPR in vasodilation of arterioles (e.g., in exercise, AV
shunts) → ↓ afterload and ↑ venous return → ↑ CO
o Pulmonary vascular resistance

Poiseuille equation
• This equation describes the relationship between systemic vascular resistance (R)
and the length of the vessel (L), the radius of the vessel (r), and the viscosity of blood
(η).
• Resistance to flow: R = 8ηL/(πr4)
o Systemic vascular resistance is inversely proportional to vessel radius to
the 4th power.
§ ↓ Vessel radius (i.e., vasoconstriction) → ↑ systemic vascular resistance → ↓
blood flow → ↑ pressure upstream (i.e., MAP) and ↓ pressure downstream (i.e.,
in capillaries)
§ ↑ Vessel radius (i.e., vasodilation) → ↓ systemic vascular resistance → ↑
blood flow → ↓ MAP and ↑ capillary pressure
o Systemic vascular resistance is proportional to blood viscosity, which is primarily
determined by hematocrit.
§ ↑ Viscosity (e.g., polycythemia, hyperproteinemia) → ↑ systemic vascular
resistance
§ ↓ Viscosity (e.g., anemia) → ↓ resistance
o Systemic vascular resistance is proportional to blood vessel length.

Vascular stenosis (e.g., coronary artery disease) increases systemic vascular resistance significantly! When
the length of the vessel and viscosity of the blood remain constant, the relationship between systemic
vascular resistance and the radius of the vessel can be simplified to R ∼ 1/r4. So, if there is a 50% reduction
in radius, R = 1/(0.5 x r)^4 → 1/(0.0625 x r4) → 16/r4, there is a 16x increase in resistance (1600%).

Serial and parallel circuits

The total resistance in blood vessels depends on whether these vessels are arranged as serial or parallel
circuits.
MAXIMIZE TABLETABLE QUIZ

Serial circuit Parallel circuit

Definition • Total resistance is the sum of individual • Total resistance is the sum of reciprocals of
resistors (Rx = R1 + R2 + R3 ...+ RN). individual resistors (Rx = 1/R1 + 1/R2 + 1/R3...+
• Total resistance is greater than individual 1/RN)
resistors. • Total resistance can be smaller than
• Blood flow is the same in each vessel in a individual resistors.
series circuit. • Pressure is the same in each vessel in a
parallel network.

Examples • An artery gives rise to two or more • An artery gives rise to two or more branches
branches in series (e.g., artery branches parallel to each other (e.g., capillaries in
into arterioles). a capillary bed).

Arterioles account for most of the TPR and, thus, are the blood vessels that contribute the most to blood
pressure regulation.
Pressure
• Blood pressure is generated by the pumping of the heart, which results in pulsatile
blood flow (ΔP = Q x R).
o The ΔP drives blood flow from high pressure to low pressure.

• Systolic blood pressure: maximum pressure reached during a cardiac cycle

• Diastolic blood pressure: minimum pressure reached during a cardiac cycle
• Mean arterial pressure (MAP): simplified value of systolic and diastolic blood
pressure
o MAP = ⅓ systolic pressure + ⅔ diastolic pressure

o MAP = CO × TPR

• Pulse pressure: the difference between diastolic blood pressure (DP)

and systolic blood pressure (SP) of the heart cycle (SP - DP)
o Normally: 30–40 mm Hg
 o Directly proportional to SV and inversely proportional to arterial compliance

§ Low/narrow pulse pressure due to ↓ SV (e.g., congestive heart

failure, shock, cardiac tamponade, aortic stenosis)
§ High/wide pulse pressure due to ↑ SV (e.g., exercise, hyperthyroidism, aortic
regurgitation) or stiff arteries
Wall tension
• Definition: the force within vessel walls that counteracts vessel rupture during
expansion, thus holding the vascular wall together
• Laplace's law
o Equation: σt = (Ptm × r) / h

§ Units: σt = wall tension (mm Hg); Ptm = transmural pressure (mm Hg); r =
inner radius (cm); h = wall thickness (cm)
o Increases in wall tension are proportional to increases in pressure across the vessel
wall (transmural pressure).

• Wall tension increases with decreasing wall thickness, increasing transmural

pressure and/or increasing the inner diameter.
• Given a constant transmural pressure, the smaller the vascular radius and thicker the
vascular wall, the less wall tension generated.
Vessels of the high-pressure system (arteries) have thick vessel walls and smaller internal diameters that
enable them to withstand high internal pressures, while vessels of the low-pressure system (veins) have
thin vascular walls and larger diameters.
Blood vessel elasticity
• Definition: the ability of a blood vessel to return to its original shape after
expanding
Vascular compliance
• Definition: the ability of a vessel to expand in response to changes in pressure
• Equation: C = ΔV/ΔP
o Units: C = compliance (mL/mm Hg); ΔV = change in volume (mL); ΔP = change in
pressure (mm Hg)
• Greater compliance: greater increase in vascular volume during an increase in
pressure (e.g., elastic arteries)
• Less compliance: less increase in vascular volume during an increase in pressure
(e.g., muscular arteries)
Vascular elastance
 • Definition: the ability of a vessel to adapt to intraluminal pressure in response to
changes in volume (i.e., the reciprocal of compliance)
• Equation: E' = ΔP/ΔV
o Units: E' = elastance (mm Hg/mL); C = compliance (mL/mm Hg); ΔP = change in
pressure (mm Hg); ΔV = change in volume (mL)
• Greater elastance: greater change in blood pressure during blood volume change
• Less elastance: less change in blood pressure during blood volume change
Compliance is mainly determined by the muscle tone of vessel walls. Arterioles, which are abundant
in smooth muscle, have low compliance and are, therefore, considered resistance vessels. Veins are less
abundant in smooth muscle, have much higher compliance, and are considered capacitance vessels.
NOTES
FEEDBACK

Blood pressure regulation

Sensors of blood flow regulation
Baroreceptors
• Definition: stretch-sensitive nerve endings that detect and regulate blood pressure
in systemic circulation via signaling to the autonomic nervous system
• Location: wall of the carotid sinus, aortic arch, atria, and venae cavae
• Mechanism of action: baroreceptor reflex
o Baroreceptors detect ↓ BP → ↓ firing frequency of baroreceptors → ↓ signaling to
the brain stem (vasomotor center) → ↓ parasympathetic stimulation
and ↑ sympathetic innervation → vasoconstriction → ↑ HR, SV, and BP
o Baroreceptors detect ↑ BP → ↑ firing frequency of baroreceptors → triggering
of baroreceptor reflex in brain stem (vasomotor center)
→ ↑ parasympathetic stimulation and ↓ sympathetic innervation → vasodilatation
→ ↓ HR, SV, and BP
• Only suitable for making short-term changes in blood pressure because their activity
(i.e., their firing frequency) adapts to a new blood pressure level within a few days.
• A component of Cushing reflex (hypertension, bradycardia, and respiratory
depression)
Volume receptors
• Definition: specialized receptors that detect blood flow changes in the pulmonary
circulation and regulate blood flow through the autonomic nervous system, atrial
natriuretic peptide (ANP), and antidiuretic hormone (ADH)
• Location: atria, pulmonary artery, and cardiac atria (low-pressure system)
• Mechanism of action: See atrial reflex and diuresis reflex.
 Chemoreceptors
• Definition: specialized receptors that detect changes in pH and respiratory gases
and regulate pH level, O2, and CO2 concentrations through respiration
• Types
o Peripheral chemoreceptors

§ Location: carotid body and aortic body

§ Function: measure PaO2 (< 60 mm Hg), CO2, and pH
o Central chemoreceptors

§ Location: medulla oblongata

§ Function: measure PaCO2 and pH
• Mechanisms of action
o ↑ CO2, ↓ O2, and ↓ pH → ↑ sympathetic innervation

o Modulate breathing via the respiratory center in the medulla

If the baroreceptors of the carotid sinus are too sensitive, even small stimuli, such as turning the head or
the pressure of a shirt collar, can lead to excessive blood pressure reduction and even fainting. This is
referred to as carotid sinus syndrome.
Carotid massage, which stimulates the baroreceptors in the carotid sinus, is an effective way of reducing
the heart rate by increasing the refractory period of the AV node.
Central blood pressure regulation
• Localization: solitary nucleus in the medulla oblongata
• Receives information (afferents) via:
o The glossopharyngeal nerve (IX): from carotid sinus baroreceptor and carotid body
chemoreceptor
o The vagus nerve (X): from aortic chemoreceptor, aortic baroreceptor, and
atrial volume receptors
• Sends information (efferents) via:
o Sympathetic cervical chain and sympathetic fibers: to blood vessels, SA node,
and AV node
o Parasympathetic vagus nerve: to AV node and SA node

MAXIMIZE TABLETABLE QUIZ

Sympathetic stimulation Parasympathetic stimulation

Arteries • Arterial constriction • Arterial vasodilatation via the release of nitric

→ ↑ peripheral vascular resistance oxide (NO) only in coronary arteries and vessels of
the penis (erection)
 Sympathetic stimulation Parasympathetic stimulation

Veins • Venous constriction • Venous dilatation → ↓ preload → ↓ stroke volume

→ ↑ preload → ↑ stroke volume

Heart • ↑ Contractility • ↓ Heart rate

• ↑ Heart rate

Atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH)

regulation
Atrial reflex
• Definition: a physiologic reflex characterized by an increased heart rate in response
to atrial distention (increased venous return to the heart). It is mediated by stretch
receptors in the atria.
• Mechanisms of action
o ↑ Volume → atrial stretching

1. Release of atrial natriuretic peptide (ANP) from cardiomyocytes

→ ↑ excretion of NaCl and water by

the kidneys, vasodilation of veins and arteries (↓ preload and ↓ afterload), and
inhibition of renin
2. ↑ Parasympathetic innervation and ↓ sympathetic innervation
o ↓ Volume → less atrial stretching

1. ↓ Release of ANP → ↓ excretion of NaCl and water by the kidneys

2. ↓ Parasympathetic innervation and ↑ sympathetic innervation

Diuresis reflex (= Gauer-Henry reflex)

• Definition: a physiological reflex that adapts ADH release in
the hypothalamus according to blood pressure
• Mechanisms of action
o ↑ BP: Atrial stretch receptors inhibit ADH release via afferent vagal fibers → ↑
water excretion by the kidneys
o ↓ BP: ↑ ADH release → ↓ water excretion by the kidneys

Renal regulation
• Mechanism of action: release of renin from the juxtaglomerular cells → activation
of RAAS → direct vasoconstriction and ↑ extracellular volume (↑ sodium and water
reabsorption, ↓ K+, ↑ pH)
• RAAS is stimulated by:
 o Hyponatremia

o Decreased blood osmolality

o Decreased renal blood flow

The RAAS plays a key role in long-term blood pressure regulation and is, therefore, an ideal target for the
treatment of arterial hypertension. While beta blockers decrease renin release by the kidneys, the
conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) can be influenced
by ACE inhibitors (e.g., ramipril, enalapril). The effect of angiotensin II on target cell receptors can be
inhibited by AT1 receptor antagonists (e.g., candesartan, losartan).
NOTES
FEEDBACK

Perfusion
Perfusion
Definition: the passage of the blood through the circulatory system to the capillary bed to deliver oxygen
and nutrients to the tissue and remove waste products (e.g., removal of CO2 to the lungs)
MAXIMIZE TABLETABLE QUIZ

Perfusion levels of various organs

Organs % of cardiac output at rest % of cardiac output during exercise

Viscera (hepatic-splanchnic circulation) 24 1

Skeletal muscle 20 88

Kidneys 19 1

Brain 13 3

Other organs 10 1

Skin 8 2

Heart muscle 3 4

Regulation of organ perfusion

Although blood pressure is the main determinant of perfusion, various other mechanisms maintain
constant blood flow within organs.
Autoregulation
• Myogenic autoregulation: Myocytes in the walls of arteries and arterioles react to
changes in blood pressure to maintain constant blood flow in the blood vessels.

o Mechanism of action: ↑ BP → ↑ transmural pressure in arteries and arterioles

 → stretch-activated ion channels opening up
in myocytes → myocyte depolarization and subsequent Ca2+ influx → smooth
muscle contraction → vasoconstriction
o Sites of action: almost all organs (especially the kidneys and brain) except
the lungs
• Local metabolites
o Mechanism of action: the release of vasoactive substances

§ NO: produced in endothelium by NO-synthase from arginine → vasodilation

§ NO production is triggered by:
§ Increased BP
§ Activation of endothelial receptors by binding of vasoactive substances
(e.g., serotonin, bradykinin) → increased release of NO
§ Other substances: kinin, histamine, serotonin, prostaglandins, thromboxane
o Sites of action: arteries and arterioles

Central regulation
• Mechanisms
o Sympathetic innervation

o Catecholamines from adrenal medulla

• Receptors
o Alpha-1 receptors → vasoconstriction

o Beta-2 receptors → vasodilation

• Differing effects of catecholamines

o Epinephrine: acts on both receptor types but has a greater affinity for beta-2
receptors
§ Low concentrations: stronger effect on beta-2 receptors → vasodilation
§ High concentrations: stronger effect on alpha-1 receptors → vasoconstriction
o Norepinephrine: mainly acts on alpha-1 receptors → vasoconstriction

Autoregulation of specific organs

• Heart
o Local metabolic autoregulation: Adenosine and NO cause vasodilation of
the coronary arteries to increase blood flow and oxygen delivery to
the myocardium.
 o Has the highest arteriovenous O2 difference of all organs (O2 extraction at rest ∼
60–80%)
o During exercise, there is limited capacity to increase myocardial oxygen extraction
(small coronary flow reserve).
• Lungs
o Adjustment of vascular perfusion to ventilation

o Hypoventilation (hypoxia) causes vasoconstriction (Euler-Liljestrand

mechanism).
• Kidneys
o Myogenic autoregulation

o Tubuloglomerular feedback

• Brain
o Local metabolic autoregulation (CO2, pH) → vasodilation

o Myogenic autoregulation

• Skeletal muscle
o At rest: sympathetic innervation

o During exercise: local metabolic and chemical autoregulation, e.g., lactate,

CO2, adenosine, K+, H+
o Blood flow can be increased (20–30 times) during exercise

• Skin

o Perfusion levels are determined by how much is needed for thermoregulation

(via capillaries and arteriovenous anastomoses).
o Mainly sympathetic innervation

The lungs are the only organs in which hypoxia causes vasoconstriction. This is to ensure that perfusion
only occurs in areas that are well ventilated. In all other organs, hypoxia leads to vasodilation to improve
perfusion and maintain oxygen supply.
Hypoperfusion of vital organs (e.g., hypovolemic shock, cardiogenic shock) is detected
by baroreceptors and volume receptors, leading to an increase in sympathetic tone. Autoregulatory
mechanisms are then triggered and lead to centralization of blood flow away from the extremities (skeletal
muscle, skin), the GI tract, and other internal organs to maintain perfusion of the heart and brain. In
addition, vasoconstriction of precapillary resistance vessels raises systemic vascular resistance and
reduces hydrostatic pressure in capillaries, increasing the reabsorption of interstitial fluids into vessels.
To remember the local metabolites used in autoregulation of skeletal muscle, think
“CHALK”: CO2, H+, Adenosine, Lactate, K+.
NOTES
FEEDBACK
Capillary fluid exchange
Definitions
• Hydrostatic pressure: the pressure exerted by any fluid on the wall of an enclosed
space

o Intravascular hydrostatic pressure: the force exerted by the blood confined

within blood vessel walls (e.g., capillary hydrostatic pressure)
§ Drives fluid out of capillaries and into the interstitium
• Osmotic pressure: the minimum pressure needed to prevent the flow of a solvent
across a semi-permeable membrane
o Determined by concentration gradients: Solvent from a lower concentration
solution is drawn across a semi-permeable membrane (via osmosis) into a higher
concentration solution.
o Directly proportional to the concentration of solute in the solvent

o Opposes hydrostatic pressure

• Oncotic pressure (colloid osmotic pressure): an intravascular osmotic

pressure generated by proteins (especially albumin)
o Keeps intravascular fluid within blood vessels and opposes intravascular hydrostatic
pressure

Starling forces
For information on the Starling equation for the glomerulus see measurement of renal
function in physiology of the kidney.
• Four Starling forces determine the net flow of fluid between
the capillaries and interstitium.

o Capillary hydrostatic pressure (Pc): drives fluid out of the capillary

o Interstitial hydrostatic pressure (Pi): attenuates filtration or drives fluid

into capillaries
o Plasma colloid (oncotic) pressure (πc): drives fluid into the capillary

o Interstitial fluid colloid osmotic pressure (πi): drives fluid out of the capillary

• Net fluid flow = Jv = Kf [(Pc - Pi) - σ(πc - πi)]

o Kf = coefficient for vessel permeability to fluid

o σ = Staverman reflection coefficient for vessel permeability to protein

• Net filtration (capillary fluid exchange)

o Depends on the hydrostatic pressure gradient (Pc - Pi) and the oncotic
pressure gradient (πc - πi)
 o Filtration of fluid out of the capillary usually occurs on the arterial side of
the capillary bed, mostly because of pressure from the arterial circulation
(increased Pc) and high plasma fluid levels (decreased πc).
o Filtration of fluid into the capillary usually occurs on the venous side of the capillary
bed, mostly because of capillary flow resistance (decreased Pc) and higher
relative plasma protein levels following water filtration into
the interstitium (increased πc).
o Outward filtration volume (arterial side) = inward filtration volume (venous side) +
10%
§ 10% of the filtered fluid is returned via lymphatics rather than blood vessels.
Edema is caused by the net movement of fluid into the interstitium if there is an increase
in capillary hydrostatic pressure (due to heart failure or Na+ retention) or a decrease in oncotic
pressure (due to cirrhosis, nephrotic syndrome).
Burns affect vessel permeability (increased Kf) and can, therefore, result in the formation of edema.