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Chapter 12
Lecture Outline*
Cardiovascular Physiology
Eric P. Widmaier
Boston University
Hershel Raff
Medical College of Wisconsin
Kevin T. Strang
University of Wisconsin - Madison
*See PowerPoint Image Slides for all
figures and tables pre-inserted into
PowerPoint without notes.
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
1
System Overview
• The three principal components that make up
the circulatory system are:
– the heart (the pump)
– the blood vessels (the pipes)
– the blood (the fluid to be moved)
• The cardiovascular system function is
impacted by the endocrine system, nervous
system and kidneys.
2
Blood
Blood is made of “formed elements”
i.e., cells and cell fragments and
plasma (which is mostly water).
Plasma carries blood cells, proteins,
nutrients, metabolic wastes, and
other molecules being transported
around the body.
Fig. 12-1
3
System
Overview
There are 2 “loops” in the
cardiovascular system:
Systemic and pulmonary.
The pulmonary loop
carries oxygen-poor
blood to the lungs and
back to the heart.
The systemic loop carries
blood from the heart to
the rest of the body.
This is considered a
“closed system,” i.e.,
leaks are bad.
Fig. 12-2
4
Blood Vessels
• Blood vessels can be divided into arteries (muscular and
conduit), arterioles, capillaries, venules and veins.
• In general, arteries carry oxygenated blood and veins carry
deoxygenated blood.
• The exception to this is the pulmonary arteries carry
deoxygenated blood to the lungs to get oxygenated and the
pulmonary veins carry oxygenated blood to the heart to get
sent to the rest of the body.
• All arteries carry blood away from the heart. All veins carry
blood to the heart.
5
Pressure, Flow and Resistance
• Pressure is the force exerted and we measure this in mm Hg.
• Flow is the volume moved and it is measured in mL/min
(volume moved in the time).
• Resistance is how difficult it is for blood to flow between two
points at any given pressure difference. Resistance is the
measure of the friction that impedes flow.
• The basic equation relating these variables is:
F = DP/R
• If you increase resistance you decrease flow if pressure stays
the same.
6
Resistance
• Three things contribute to the resistance:
1. Blood viscosity
(affected by volume and # of RBC)
2. Total blood vessel length
(how much tubing is needed)
3. Blood vessel diameter
(relaxed vessels decrease, vasoconstricted vessels
increase; this is the biggest contributor to minute-tominute control of resistance in the vascular system)
7
Pressure, Flow, and
Resistance
Fig. 12-4
Fig. 12-5
8
The Heart Anatomy
Fig. 12-6
9
Heart Layers
• Epicardium:
This is the most superficial (outer) layer. It is the visceral layer
of the serous pericardium.
• Myocardium:
The middle layer of the heart muscle. It is composed of cardiac
muscle and forms the bulk of the heart mass. This is the layer
that contracts.
• Endocardium:
The inner layer, it is of endothelium which rests on a thin layer
of connective tissue. It is continuous with the lining of the
blood vessels entering and leaving the heart.
10
Heart Valves
Fig. 12-7
11
Cardiac Muscle
• The cardiac muscle cells of the myocardium are arranged in
layers that are tightly bound together and completely encircle
the blood-filled chambers.
• When the walls of a chamber contract, they come together like
a squeezing fist and exert pressure on the blood they enclose.
• Every heart cell contracts with every beat of the heart, so these
cells do not get much rest.
• The heart has only a limited ability to replace its muscle cells.
Recent experiments suggest that only about 1 percent of heart
muscle cells are replaced per year. This is why heart attacks
that result in myocyte death are so hard to fix.
12
Cardiac Communication
• Approximately 1 percent of cardiac cells do not function in
contraction, but have specialized features that are essential for
normal heart excitation.
• These cells constitute a network known as the conducting system
of the heart and are in electrical contact with the cardiac muscle
cells via gap junctions.
• The conducting system initiates the heartbeat and helps spread
the impulse rapidly throughout the heart.
• Certain cells in the atria secrete the peptide hormone called atrial
natriuretic peptide (regulates the concentration of Na+ in the
extracellular fluid).
13
Innervation of the Heart
• The heart is innervated by both sympathetic and
parasympathetic nerve fibers.
• The SNS innervates the entire heart muscle and node cells and
release NE, whereas the PSNS innervates the node cells and
release primarily acetylcholine.
• The receptors for NE on cardiac muscle are mainly betaadrenergic. The hormone epinephrine, from the adrenal
medulla, binds to the same receptors as NE and exerts the
same actions on the heart.
• The receptors for acetylcholine are of the muscarinic type.
14
Innervation of the Heart
Fig. 12-9
15
Blood Supply
• The blood being pumped through the heart chambers does not
exchange nutrients and metabolic end products with the
myocardial cells.
• They receive their blood supply via arteries that branch from the
aorta. The arteries supplying the myocardium are the coronary
arteries, and the blood flowing through them is the coronary blood
flow.
• The coronary arteries exit from behind the aortic valve cusps in
the very first part of the aorta and lead to a branching network of
small arteries, arterioles, capillaries, venules, and veins similar to
those in other organs.
• Most of the cardiac veins drain into a single large vein, the
coronary sinus, which empties into the right atrium.
16
Heartbeat Coordination
Fig. 12-10
17
Excitation of the Heart
• The signal starts in the SA node (normal rate is about 75 signals
per minute).
• The wave of depolarization travels through the internodal pathway
(via gap junctions) to the AV node. The signal then has a .1 s
delay to allow the atria to contract and totally fill the ventricles
before they contract.
• Then the wave of depolarization travels through the AV bundle
(bundle of His) down towards the purkinji fibers which go to the
apex of the ventricular septum then turn upwards.
• The purkinji fibers also supply the papillary muscles which tell
them to contract before the rest of the atria to help prevent
backflow through the valves.
18
Sequence of Excitation
Fig. 12-11
19
Cardiac Action
Potential
Fig. 12-12
20
Node Cells
• Node cells have automaticity and are found in the
Sinoatrial node (SA), the Atrioventricular node (AV),
the atrioventricular bundle, the purkinjie fibers (found
in the walls of the ventricles), and AV bundle branches.
• In a healthy heart the SA node is the pacemaker and
controls the electrical impulses which cause
contraction. Any damage to the SA node or to the heart
walls can damage this circuit and cause problems.
21
Excitation of the SA Node
Fig. 12-13
22
Clinical Issues
• Arrhythmias are the uncoordinated atrial and ventricular
contractions caused by a defect in the conduction system.
• A fibrillation is a rapid and irregular (usually out of phase)
contraction where the SA node is no longer controlling heart rate.
• An atrial fibrillation can cause clotting and inefficient filling of the
ventricles.
• A ventricular fibrillation is more life threatening. The ventricles
pump without filling and if the rhythm is not rapidly reestablished
then circulation stops and brain death occurs.
• Defibrillation is the application of an electrical stimulus to shock the
heart back into a normal SA rhythm. For chronic issues people can
have “pacemakers” implanted. This is a device that delivers the
electrical stimulus rather than the SA node.
23
Clinical Issues - cont.
• An ectopic focus is an abnormal pacemaker that takes over the
conduction system usually because it goes faster than the SA node.
•
If the SA node is damaged the AV node (~60 beats per minute) can
take over. This is still adequate for normal circulation.
• Premature contraction is called extrasystole. The preventricular
contractions (PVCs) are the most problematic.
• Damage to the AV node results in a heart block. The AV node is the
only communication between the atria and ventricles. There are
degrees of this; a total block means the ventricles beat at their
intrinsic rate (purkinji fibers), but this is too slow to maintain
circulation. A partial block means the impulse is slow but does get
through. A pacemaker must be used to treat this.
• Most of these abnormalities can be seen on an electrocardiogram.
24
The Electrocardiogram
Fig. 12-14
25
Electrocardiogram
• A graphic record of the heart’s electrical
activity.
• The leads must be placed correctly to get a
proper reading.
• The reading is a composite of the electrical
activity not a single action potential.
26
EKGs
• The P wave is the result of the depolarization wave
from the SA node to the AV node. Atria contract .1
second after P wave starts.
• The QRS complex is the result of the ventricular
depolarization and precedes ventricular contraction.
• The T wave is caused by ventricular repolarization.
• The atrial repolarization is obscured by the QRS
complex.
27
Electrocardiograms
Fig. 12-16
28
Excitation-Contraction Coupling
• A small amount of extracellular calcium enters
the cell through L-type calcium channels
during the plateau of the action potential.
• This calcium binds to ryanodine receptors on
the sarcoplasmic reticulum membrane and
triggers the release of a larger quantity of
calcium.
29
Refractory Period of the Heart
Fig. 12-17
30
Cardiac Cycle
• The cardiac cycle is all the events involved
with the blood flow through the heart during
one heart beat.
• Systole is the contraction phase.
• Diastole is the relaxation phase.
31
Mechanical Events of the Cardiac Cycle
Fig. 12-18 32
Cardiac Cycle
Fig. 12-19 33
Pulmonary Circulation Pressures
Fig. 12-20
34
Clinical Issues
• Abnormal heart sounds are called heart murmurs.
• Blood flow should be silent as long as it is smoothly
flowing. If it hits anything that obstructs it, it will
become turbulent and generate sound that can be heard
with a stethoscope.
• Most causes of heart murmurs in adults are valve
problems. If the valve is incompetent (doesn’t close
right) then a swishing sound is heard. If the valve is
stenotic a high pitched sound or a click can be heard.
35
Heart Sounds
Fig. 12-21
36
Cardiac Output
• Cardiac output is the amount of blood pumped
out of each ventricle in one minute.
• It is the product of heart rate (HR) and stroke
volume (SV).
• CO=HR x SV
• Normal cardiac output is 5.25 L/min.
37
Regulation of Heart Rate
• In a healthy system SV is fairly constant. If blood volume
drops or if the heart weakens, then SV declines and CO is
maintained by increasing HR.
• CO= SV x HR
• Things that increase HR are positive chronotropic factors.
• Things that decrease HR are negative chronotropic factors.
• Heart rate is also controlled by the input from the nervous
system: SNS increases heart rate; PSNS decreases heart
rate.
38
Control of Heart Rate
Fig. 12-22
39
Stroke Volume
• SV is the difference between the end diastolic
volume and the end systolic volume.
• SV= EDV-ESV
• So with every beat the heart pumps about 60%
of the blood in its chambers or 70 mL.
• This is important to preload, afterload and
contractility of the heart.
40
Starlings Law
• Starlings law says that the critical factor controlling stroke
volume is preload.
• Preload is the degree to which the cardiac muscle cells are
stretched before they contract. You want an optimal
length/tension relationship for maximal force generation, so
overextension leads to inefficient pumping.
• The most important factor in causing stretch is the amount of
blood in the ventricles. The amount of blood in the ventricles is
controlled by venous return.
• This controls the end diastolic volume (EDV).
• A slow heart rate, exercise (anything that increases venous
return or slows heart rate increases EDV).
41
Frank-Starling Mechanism
Fig. 12-24 42
Stroke Volume
• Anything that increases EDV or increases the force
of the ventricular contraction can increase SV.
• The ventricles are never completely empty of
blood, so a more forceful contraction will expel
more blood with each pump.
• Extrinsic controls of SV include:
− Sympathetic drive to ventricular muscle fibers
− (NE at Beta1 receptors in cardiac muscle cells)
− Hormonal control
− (Thyroid hormones can increase the force of contraction)
43
Control of Stroke Volume
Fig. 12-25
44
Ejection Fraction
• One way to quantify contractility is through the
ejection fraction (EF), defined as the ratio of stroke
volume (SV) to end-diastolic volume (EDV):
• EF = SV/EDV
• Expressed as a percentage, the ejection fraction
normally averages between 50 and 75 percent under
resting conditions.
• Increased contractility causes an increased ejection
fraction.
45
Preload and Afterload
• Preload is proportional to the amount of ventricular
myocardial fiber stretch just before systole (EDV).
• Afterload is the pressure that the ventricles must
overcome to force open the aortic and pulmonary
valves.
• Anything that increases systemic or pulmonary
arterial pressure can increase afterload.
(ex. Hypertension)
46
Measurement of Cardiac Function
• Human cardiac output can be measured by a variety of methods.
• Echocardiography: Echocardiography is a noninvasive technique
that uses ultrasonic waves. This technique can detect the
abnormal functioning of cardiac valves or contractions of the
cardiac walls, and can also be used to measure ejection fraction.
• Cardiac angiography: requires the temporary threading of a thin,
flexible tube called a catheter through an artery or vein into the
heart. A liquid containing radio-opaque contrast material is then
injected through the catheter during high-speed x-ray
videography. This technique is useful for evaluating cardiac
function and for identifying narrowed coronary arteries
47
The Vascular System
• The vascular system are the “pipes” that carry the blood. The
arteries and veins both have vascular smooth muscle cells,
endothelial cells, and advential fibroblasts, but the composition
of each type varies in amounts.
• The types of structures involved are:
• Arteries
‒
‒
‒
‒
Elastic arteries (conduit)
Muscular arteries
Arterioles
Capillaries
• Veins
‒ Venules
48
The Vascular System
Fig. 12-29
49
Arteries
Compliance = Δvolume/Δ pressure
The higher the compliance of a
structure, the more easily it can
be stretched.
Arteries are often called
pressure reservoirs because
of the elastic recoil. They are
not as compliant as veins.
Fig. 12-30
50
Elastic Arteries
• These are conduit vessels that are near the heart which carry
blood for circulation.
• The major example of an elastic artery is the aorta.
• These are large lumen vessels (low resistance) that contain
more elastin than the muscular arteries.
• This allows them to be “pressure reservoirs” ‒‒ they expand
and contract (recoil) as blood is ejected by the heart. This
allows blood flow to be continuous.
• Atherosclerosis and arteriosclerosis affect the ability to
function properly. Furthermore, if pressure becomes too
great over time, the walls either remodel or weaken. If they
weaken they can burst.
51
Muscular Arteries
• These arteries deliver blood to specific organs
(mesenteric artery, renal artery etc.).
• They have proportionally the thickest media (most
smooth muscle) and are very active in vasoconstriction.
• These arteries can play a large role in the regulation of
blood pressure.
‒ For example, the mesenteric artery carries ~25 % of the CO, so
alterations in its diameter would have a large effect.
52
Arterial Blood Pressure
Fig. 12-31
53
Measurement of Systemic Arterial Pressure
Fig. 12-32
54
Pressures
• The average blood pressure is considered to be
120/80 mm Hg.
• Blood pressure of about 140/90 mm Hg is
considered hypertensive.
• Either the systolic or diastolic can be elevated
independent of the other number. Hypertension
is a disease that affects millions of patients.
55
Pulse Pressure
• The difference between systolic pressure and diastolic pressure
(120 – 80 = 40 mmHg in the example) is called the pulse pressure.
• It can be felt as a pulsation or throb in the arteries of the wrist or
neck with each heartbeat.
• The most important factors determining the magnitude of the pulse
pressure are:
(1) Stroke volume
(2) Speed of ejection of the stroke volume
(3) Arterial compliance
• A decrease in arterial compliance occurs in arteriosclerosis
(stiffening of the arteries).
56
Arterioles
• These are the smallest arteries. Their function is
controlled by neural, hormonal, and local chemicals.
• They control minute-to-minute blood flow into the
capillary beds. If they contract, blood flow is diverted
away from their tissues; if they dilate, then blood
flow to the tissue increases.
• The smaller ones, which directly lead into the
capillary beds, are usually just a single layer of
smooth muscle which spirals around the endothelium.
• These vessels have an impact on blood pressure.
57
Flow – Pressure Relationship
• F = ΔP/R
• So, if you increase resistance by
vasoconstriction and keep pressure the same,
then flow to a tissue decreases.
• If you need to increase flow to a tissue, then
you either increase the pressure or vasodilate
to decrease resistance.
58
Arterioles
Fig. 12-33
59
Local Controls
Fig. 12-34
60
Extrinsic Controls
Fig. 12-35
61
Endothelial Cells and Vascular
Smooth Muscle
• Endothelial cells secrete several paracrine
agents that diffuse to the adjacent vascular
smooth muscle and induce either relaxation or
contraction.
• One of the most important is nitric oxide (NO).
• NO causes vasodilation and is critical to
proper vessel tone.
62
Autoregulation
• Autoregulation is the automatic adjustment of
blood flow to each tissue in proportion to that
tissue’s requirement at any instant.
• This is regulated by local factors and
independent of systemic factors. This is
controlled by modifying the diameter of the
local arterioles. There is metabolic and
myogenic control of this system.
63
Arteriolar Control in Specific Organs
Fig. 12-36
64
Types of Capillaries
• Capillaries are the smallest blood vessels. This is
where gas and nutrient exchange happens by
diffusion out of the blood into the tissues (or back
into the blood).
• There are 3 types of capillaries:
– Continuous capillary: found in skin, muscle, most
common kind have tight junctions.
– Fenestrated capillary: more permeable — intestines,
hormone-producing tissues, kidneys, etc.
– Sinusoidal capillary: only one with an incomplete
basement membrane; these are found in the liver, bone
marrow and lymphoid tissues.
65
Capillaries
Fig. 12-37
66
Anatomy of Capillary Network
Fig. 12-38
67
Velocity of Capillary Blood Flow
Velocity is slowest in the capillary
beds because they have a greater
cross-sectional area.
Fig. 12-39
68
Diffusion Across the Capillary Wall: Exchanges
of Nutrients and Metabolic End Products
Fig. 12-40
69
Bulk Flow Across the Capillary Wall:
Distribution of the Extracellular Fluid
Fig. 12-41
70
Fluid Movement
• The direction fluid moves at the capillaries is dependent
on the difference between the net hydrostatic pressure
and the net colloid osmotic pressure.
• Hydrostatic pressure is the force exerted by the fluid
pressing against a wall. In the capillaries it is the same
as the capillary blood pressure.
• In capillaries the pressure tends to force fluid out
(filtration), especially on the arterial end where pressure
is higher.
71
Osmotic Pressure
• Colloid osmotic pressure (oncotic) is the force
that opposes the hydrostatic pressure.
• It is created by the large nondiffusible
molecules, like plasma proteins.
• It does not vary from one end of the capillaries
to the other, like hydrostatic force.
72
Net Filtration Pressure
• NFP=(HPc –HPif) – (OPc- OPif)
• So if HP exceeds OP, then fluid leaves the
capillaries (filtered). If OP is greater than HP, it
enters the capillaries (reabsorbed).
• Generally the amount of fluid lost and not
regained is about 1.5 ml/min. This is picked up by
the lymph system and returned to the circulation.
73
Veins
Fig. 12-44
74
Venous System
• Venules vary in structure as they progress away
from the capillaries.
• Veins have all three distinct layers (tunics). The
walls are thinner than arteries, so they often
appear collapsed in Histological slides.
• Veins also have less smooth muscle and more
elastin than arteries.
• Veins are highly distensible, so they are called
capacitance vessels that act as blood reservoirs.
75
Varicose Veins
• Remember that veins have one-way valves that
prevent the backflow of blood.
• Varicose veins are veins that have become
dilated and tortuous because of incompetent
(leaky) valves.
• About 15% of adults suffer from this condition,
mainly in the lower limbs.
76
Venous Pressure
• Blood pressure in veins is ~15 mm Hg. This is not sufficient to
move blood back to the heart. So there are the “pumps”:
1. Respiratory pump: Pressure changes in the central cavity due
to the pressure changes due to breathing. This helps to propel
blood back to the heart.
2. Muscular pump: When muscles contract they squeeze the
veins. This results in blood moving forward and being
prevented from backflow by the veins. This moves blood
toward the heart.
• The smooth muscle in the veins is under SNS control and contract
when stimulated, similar to the arterial smooth muscle. This
causes contraction and a narrowing of the lumen.
77
Determinants of Venous Pressure
Fig. 12-46
78
The Lymphatic System
• The lymphatic system is made up of lymphatic
vessels and lymphatic tissue.
• The purpose is to collect the fluid lost from the
capillaries and return it to the circulation and
then house the phagocytes and lymphocytes that
play a role in the immune system.
• Lymphatic vessels can take up cells, proteins,
debris etc., unlike blood vessels. They detour
into lymph nodes where the lymph is cleaned and
examined by immune cells for pathogens etc.
79
The Lymphatic System
Fig. 12-47
80
Mechanism of Lymph Flow
• The smooth muscle in the wall of the
lymphatics exerts a pumplike action, and the
lymphatic vessels have valves similar to those
in veins.
81
Clinical Issues
• If lymph nodes become overwhelmed they can become
swollen and painful. These are called “swollen glands.”
• Some infected lymph nodes become visible and are called
buboes. These are a prominent symptom of the bubonic
plague (also known as the Black Death—killed ¼ of the
population of Europe in the Middle Ages and still makes
appearance in the United States in the western parts).
• These are also a site where metastasizing cancers live and
spread. This is why we biopsy them for breast cancer etc.
Those nodes are swollen but not usually painful.
82
Lymphoid Tissues
• Have two very important roles:
1. House and provide a proliferation site for
lymphocytes
2. Give a surveillance site to examine and clean the
lymph fluid
• The principle lymph organs in the body are the lymph
nodes. These cluster along the lymph vessels and are
usually embedded in connective tissue. Large clusters
occur in the regions where vessels cluster to become
trunks.
83
CO = HR x SV
SV = EDV-ESV
MAP = CO x TPR
84
Integrative Cardiovascular Function:
Regulation of Systemic Arterial Pressure
Fig. 12-51 85
Arterial Baroreceptors
Fig. 12-53
86
The Medullary Cardiovascular Center
Fig. 12-55
87
Operation of
the Arterial
Baroreceptor
Reflex
Fig. 12-56
88
Other Baroreceptors
• Large systemic veins, the pulmonary vessels,
and the walls of the heart also contain
baroreceptors.
89
Blood Volume and Long-Term Regulation of Arterial Pressure
Fig. 12-57
90
Other Cardiovascular Reflexes
and Responses
• Blood pressure is affected by arterial
concentrations of oxygen and carbon dioxide,
blood flow to the brain, pain, sexual activity,
and stress.
91
Hypotension
• Low blood pressure is called hypotension.
• Some people just run low, and that is normal.
• Orthostatic hypotension is a temporary drop in
blood pressure when standing up from a prone
or reclining position. Also called postural
hypotension.
• This is due to blood pooling in the extremities
and the SNS not signaling the lower vessels to
constrict and send the blood back toward the
heart.
92
The Upright Posture
Fig. 12-60
93
Other Forms of Hypotension
• Chronic hypotension may indicate poor
nutrition, low viscosity of the blood, or
Addison’s disease.
• Hemorrhage is also a major cause of
hypotension.
• Acute hypotension is one of the most
important signs of circulatory shock.
94
Hemorrhage
and Other
Causes of
Hypotension
Fig. 12-58
95
Circulatory Shock
• This is a condition in which there is inadequate
blood flow to meet tissue needs.
• There are 3 types:
1. Hypovolemic shock
2. Vascular shock
3. Cardiogenic shock
96
Hypovolemic Shock
• This form of shock is the most common.
• It results from a large loss of blood, so there is a
drop in blood volume.
• This usually follows hemorrhage, severe
vomiting, severe diarrhea, and extensive burns.
• If blood volume drops, then heart rate increases to
try to compensate (clinical signs include a weak,
thready pulse).
• You must replace the fluids lost to maintain blood
flow.
97
Vascular Shock
• Blood volume is normal, but circulation is poor due to
abnormal expansion of the vascular bed caused by extreme
vasodilation. This is a huge drop is TPR which leads to a
drop in MAP.
• The most common cause is a loss of vasomotor tone
associated with anaphylaxis (allergic reaction; anaphylactic
shock), a loss of nervous system regulation (neurogenic
shock), and septicimia (septic shock; a bacterial infection).
• Transient vascular shock may happen if you sunbathe too
long. The sun heats your skin, which then vasodilates and
allows blood to pool. When you stand up you are dizzy
because your brain isn’t getting enough oxygen. It passes
once the vessels constrict and get blood back into
circulation.
98
Cardiogenic Shock
• This is pump failure. The heart can not sustain
adequate circulation.
• This is usually the result of myocardial damage
following a severe MI or multiple MIs.
99
Exercise
Blood flow goes to the areas it is
needed most at any given time.
During exercise blood is shunted
as depicted in the diagram. Note
that brain blood flow is always
maintained. Flow is diverted to
and from skeletal muscles, GI,
and the heart and kidneys, but
they always maintain the minimal
flow.
Fig. 12-61
100
Maximal Oxygen Consumption and Training
Fig. 12-64
101
Hypertension
• Hypertension is chronically elevated blood pressure. It is usually
a “silent” killer because most people don’t know that they have it
until it has caused significant damage.
• Prolonged hypertension is the major cause of heart failure, renal
failure, stroke, and vascular disease.
• There are two major forms of hypertension—primary (essential)
and secondary. About 90% have primary hypertension and there
usually isn’t one thing we can pinpoint as the cause. Secondary is
the result of a disease, usually a tumor of the adrenal medulla. It
resolves with surgery. It can also be a sign of Cushing’s disease,
physical obstruction of the renal arteries, kidney disease,
arteriosclerosis, hyperthyroidism.
102
Essential Hypertension
• Factors that are involved in the development of hypertension include:
–
–
–
–
–
–
Diet: high Na+, high cholesterol etc.
Obesity
Age (clinical signs appear ~40)
Gender (males get it more than females until menopause)
Diabetes mellitus
Genetics (runs in families, black more prevalent [salt sensitive forms] than
whites)
– Stress
– Smoking
• We can not cure it. We can manage it with diet, exercise, life-style
changes, and medication.
• We treat it with diuretics, beta blockers, calcium channel blockers, ACE
inhibitors, and AT1 receptor antagonists.
103
Hypertension
104
Heart Failure
Fig. 12-65
105
Coronary Artery Disease and Heart Attacks
Fig. 12-66
106
Plasma
• Plasma consists of a number of inorganic and
organic substances dissolved in water,
including proteins such as albumin, globulins,
and fibrinogen.
• Plasma is about 90% water and carries
electrolytes and nutrients (glucose, amino
acids, vitamins), as well as wastes (urea,
bilirubin, creatine), gases (O2 and CO2), and
hormones.
107
The Blood Cells
Fig. 12-70
108
Erythrocytes
Fig. 12-67
109
Erythrocytes (Red Blood Cells)
• They function in oxygen and carbon dioxide transport.
Biconcave disk in shape with a flexible membrane.
They have a large surface area which favors diffusion.
• No nucleus nor organelles
– No mitochondria
– No DNA, RNA (so no division of mature RBCs)
• Enzymes
– Glycolytic enzymes
– Carbonic anhydrase
• Hemoglobin (binds oxygen and carbon dioxide)
110
Erythrocytes
• RBCs have a short life span and only last about
120 days.
• RBCs are synthesized in red bone marrow by
the process called Erythropoiesis.
• They are filtered by the spleen and the liver.
• Erythropoietin (hormone from the kidneys)
triggers differentiation of stem cells to
erythrocytes
111
Leukocytes & Platelets
Fig. 12-71
112
Leukocytes
• Leukocytes (white blood cells) function in the
defense of the body.
• They can be divided into granulocytes and
agranulocytes.
– Granulocytes—cytoplasmic granules
• Neutrophils
• Eosinophils
• Basophils
– Agranulocytes—no cytoplasmic granules
• Monocytes
• Lymphocytes
113
WBC Functions
• Neutrophils:
– Phagocytic
– Numbers increase during infections
• Eosinophils:
– Defend against parasitic worms
– Granules contain toxic molecules that attack parasites
• Basophils:
– Non-phagocytic
– Contribute to allergic reactions
• Histamine
• Monocytes:
– Phagocytic
– Migrate to tissues and become macrophages
• Lymphocytes:
– B cells
– T cells
114
Requirements for Erythrocyte
Production
• Iron
– Component of hemoglobin (heme portion)
– Normal hemoglobin content of blood
• Men: 13–18 gram / dL
• Women: 12–16 gram / dL
• Folic acid
– Necessary for DNA replication, thus cell proliferation
• Vitamin B12
– Necessary for DNA replication, thus cell proliferation
115
RBC Production
Fig. 12-69
116
Regulation of Blood Cell Production
117
Clinical Issues
• Renal dialysis patients whose kidneys have failed have
too little erythropoietin and need to have synthetic forms
administered to maintain normal RBC counts.
• Athletes who abuse this synthetic form (to increase
stamina) can die from the blood becoming too viscous
which results in clotting, stroke and heart failure.
• Testosterone also enhances RBC production by increasing
EPO production (hence men have higher hematocrit than
women) so people on hormone replacement need to be
very careful with dosing.
118
Anemia
• Anemia is defined as a decrease in the oxygen-carrying capacity
of blood.
• Dietary anemia
– Iron: iron-deficiency anemia
– Vitamin B12: pernicious anemia
• Hemorrhagic anemia
– Bleeding
• Hemolytic anemia
– Malaria
– Sickle cell anemia
• Aplastic anemia
– Bone marrow defect
• Renal anemia
– Kidney disease
119
Filtering and Destruction of Erythrocytes
• The spleen filters and removes old erythrocytes, and
the liver metabolizes byproducts from breakdown of
erythrocytes.
• Iron is recycled for the synthesis of new hemoglobin.
• Iron is transported in the blood bound to transferrin
to the red bone marrow.
• Iron is stored bound to ferritin in the liver, spleen
and small intestines.
120
Spleen
• Spleen macrophages filter blood by phagocytosis of
old fragile RBCs.
• Hemoglobin is then catabolized and the iron is
removed. Heme is converted into bilirubin.
• Bilirubin is released into the bloodstream and
travels to the liver for further metabolism. Products
of bilirubin catabolism are secreted in bile to the
intestinal tract or released into the bloodstream and
excreted in the urine.
121
Platelets
• Platelets are cytoplasmic fragments derived from
megakaryocytes, also called thrombocytes.
• As cell fragments there are no organelles, but they
do have granules and are important in blood
clotting.
• The granules contain secretory products:
– ADP
– Serotonin
– Epinephrine
122
Hemostasis
• Hemostasis is the physiological mechanisms
that stop bleeding.
• Hemostasis is a 3-step process:
1. Vascular spasm
2. Formation of platelet plug
3. Blood coagulation
123
Fig. 12-72
124
Vascular Spasm
• Vascular spasm results from damage to the blood
vessel. The damaged tissue secretes factors that
cause contraction.
• Vessels constrict to minimize blood loss (this is
protective to maintain BP).
• Endothelial layer becomes sticky to aid in the
clotting process.
125
Formation of a Platelet Plug
• The platelet plug forms around site of vessel
damage and is started by the sticky endothelium at
the damaged site.
• The plug results in a decreased blood loss
(maintains BP).
• The plug formation is necessary for production of
a blood clot.
126
Formation of a Platelet Plug
Fig. 12-73
127
Formation of a Blood Clot
• Clotting = coagulation
– Blood converted into solid gel called clot or
thrombus
• Occurs around platelet plug
• Dominant hemostatic defense mechanism
128
Blood Coagulation: Clot Formation
Fig. 12-75
Fig. 12-74
129
Clotting Cascade
Fig. 12-76
130
Clotting Factors
• Clotting factors are produced by the liver and
secreted into blood in inactive forms which are
activated during the clotting cascade.
• Plasma without clotting factors is called serum.
• Hemophilia is a genetic disorder, characterized
by deficiencies in clotting factors, usually
Factor VIII.
131
Dissolving Blood Clots
Dissolved Clot
Fig. 12-79
132
Anticlotting Systems
Fig. 12-78
Fig. 12-79
133
Plasminogen Activators
• Plasminogen activators convert plasminogen to
plasmin.
• We can use recombinant tissue plasminogen activator
(TPA).
• TPA can be given to dissolve clots that are
obstructing flow in coronary arteries, pulmonary
arteries and cerebral arteries. It is often used to treat
stroke patients if they arrive soon enough to the
hospital.
134
Role of Coagulation Factors in Clot
Formation Disorders
• Hemophilia
– Genetic disorder caused by deficiency of gene
for specific coagulation factor
• Von Willebrand’s disease
– Reduced levels of vWf
– Decreases platelet plug formation
• Vitamin K deficiencies
– Decreased synthesis of clotting factors
135
Aspirin as an Anticoagulant
• Low doses—anticoagulant
– Inhibits formation of thromboxane A2
• High doses
– Inhibits formation of prostacyclin
136
Clot Controllers
• To prevent the clot from becoming unnecessarily large (don’t
want to completely clog arteries), there is swift removal of
clotting factors and inhibition of active clotting factors.
• Also most of the thrombin is bound to the fibrin threads. This
prevents systemic clotting. Unbound thrombin is inactivated by
Antithrombin III and protein C.
• Heparin is an anticoagulant contained in mast cells and basophils
as well as being found on the surface of endothelial cells. This
inhibits thrombin by enhancing Antithrombin III and clotting by
inhibiting the intrinsic pathway.
• Heparin is also given in synthetic versions to prevent clots in
high risk patients.
137
Endothelial Cells
• Normally endothelial cells are smooth and
intact and prevent platelets from adhering.
• They also secrete NO and prostacyclin, which
prevent platelet aggregation.
• Inappropriate clotting causes serious problems
including stroke, heart attacks, tissue ischemia
and death.
138
Causes and treatments
• Anything that roughens up the endothelium can cause inappropriate
clotting. Things like inflammation and altherosclerosis, diabetes and
hypertension (diabetes and hypertension both result in endothelial
cells’ dysfunction and death).
• Slow-moving blood (too high hematocrit), bed-ridden patients, long
flight with no movement of the lower limbs, all allow clotting
factors to accumulate.
• Aspirin, heparin and warfarin are all used clinically to prevent clots.
Aspirin is an antiprostaglandin that inhibits the formation of TxA2.
Heparin is injected clinically. Warfarin (originally a rat poison) is
taken orally and is called coumadin. This is a mainstay for people
with atrial fibrillation.
139
Clotting Disorders
• Thromboembolic disorders, which result from
inappropriate clot formation.
• Bleeding disorders, which are caused by the
prevention of normal clotting functions.
• Disseminated intravascular coagulation
disorders, which involve widespread clotting
and severe bleeding.
140
Thromboembolic Conditions
• A thrombus is a clot that forms and persists in an unbroken
blood vessel.
• It can block the vessel if it is large enough. This leads to
ischemia and tissue death downstream from the clot. This is
a cause of fatal heart attacks.
• Embolus or emboli is a clot that is free-floating in the blood
stream. This is a problem since it can wedge in a vessel
(referred to as an embolism).
• Pulmonary embolisms impair the body’s ability to get
enough oxygen, while cerebral embolisms cause strokes.
141
Bleeding Disorders
• Thrombocytopenia is characterized by a lack of
platelets, which causes spontaneous bleeding in small
blood vessels.
• Even normal movement causes internal hemorrhaging
(petechiae) in the skin.
• Anything that affects bone marrow can cause this.
For example chemotherapy, irradiation etc. The only
treatment is platelet transfusions.
142
Bleeding Disorders
• Impaired liver function causes a lack of
procoagulants. This can be treated with
vitamin K shots (newborns) if that is deficient.
• Severe cases like total impairment of liver
function associated with cirrhosis and hepatitis
can require transfusions.
143
Role of the Liver
Fig. 12-77
144
Hemophilia
• These are a genetic X-linked disorders seen primarily in men.
• Hemophilia A or classical hemophilia is a lack of factor VIII
(~77% of cases).
• Hemophilia B is a lack of factor IX.
• Hemophilia C can be seen in both sexes and is mild. It is a lack of
factor XI. It is mild because IX (which is activated by XI) can also
be activated by VII.
• Symptoms occur early in life and can be disabling. Bleeds can
impair joint function. It is treated by transfusions of plasma and
injections of purified clotting factors. This is expensive to treat and
inconvenient to the patient. Surgery, simple dental procedures etc.,
can be life-threatening.
145
Transfusions
• Loss of 15-30% of the blood volume can can cause weakness and
pallor. Loss of 30% of the blood volume and more results in severe
shock and is fatal unless it is replaced.
• To replace blood volume there are several options:
1. Whole blood transfusions are routine when loss is rapid and
substantial.
2. Packed red cells are preferred when you just need to restore oxygen
carrying capacity.
3. Plasma can also be given alone and you can give platelets alone.
• When blood is donated it is mixed with an anticoagulant (usually
something to prevent Ca2+ ions binding) and the shelf life at 4˚C is
35 days. Blood is often separated into its components. There are
often shortages because the blood supply depends on donors.
146