Normal heart sounds

Normal heart sounds are associated with heart valves closing, causing changes in red blood flow.

[edit] S1

The first heart tone, or S1, forms the "lubb" of "lubb-dub" or "lubb-dup" and is composed of components M1 and T1.
Normaly M1 precedes T1 slightly. It is caused by the sudden block of reverse blood flow due to closure of the
atrioventricular valves, i.e. mitral and tricuspid, at the beginning of ventricular contraction, or systole. When the
ventricles begin to contract, so do the papillary muscles in each ventricle. The papillary muscles are attached to the
tricuspid and mitral valves via chordae tendineae, which bring the cusps of the valve closed (chorda tendinae also
prevent the valves from blowing into the atria as ventricular pressure rises due to contraction). The closing of the
inlet valves prevents regurgitation of blood from the ventricles back into the atria. The S1 sound results from
reverberation within the blood associated with the sudden block of flow reversal by the valves. [1]

[edit] S2

The second heart tone, or S2, forms the "dub" of "lubb-dub" or "lubb-dup" and is composed of components A2 and
P2. Normally A2 precedes P2 especially during inspiration when a split of S2 can be heard. It is caused by the sudden
block of reversing blood flow due to closure of the aortic valve and pulmonary valve at the end of ventricular
systole, i.e beginning of ventricular diastole. As the left ventricle empties, its pressure falls below the pressure in the
aorta, aortic blood flow quickly reverses back toward the left ventricle, catching the aortic valve leaflets and is
stopped by aortic (outlet) valve closure. Similarly, as the pressure in the right ventricle falls below the pressure in
the pulmonary artery, the pulmonary (outlet) valve closes. The S2 sound results from reverberation within the blood
associated with the sudden block of flow reversal.

A split S2 can be associated with several different cardiovascular conditions.

[edit] Extra heart sounds

The rarer extra heart sounds form gallop rhythms and are heard in both normal and abnormal situations.

[edit] S3

Rarely, there may be a third heart sound also called a protodiastolic gallop, ventricular gallop, or informally the
"Kentucky" gallop as an onomatopoeic reference to the rhythm and stress of S1 followed by S2 and S3 together
(S1=ken; S2=tuc; S3=ky). It occurs at the beginning of diastole after S2 and is lower in pitch than S1 or S2 as it is
not of valvular origin. The third heart sound is benign in youth and some trained athletes, but if it re-emerges later in
life it may signal cardiac problems like a failing left ventricle as in dilated congestive heart failure (CHF). S3 is
thought to be caused by the oscillation of blood back and forth between the walls of the ventricles initiated by
inrushing blood from the atria. The reason the third heart sound does not occur until the middle third of diastole is
probably because during the early part of diastole, the ventricles are not filled sufficiently to create enough tension
for reverberation. It may also be a result of tensing of the chordae tendineae during rapid filling and expansion of the
ventricle. In other words, an S3 heart sound indicates increased volume of blood within the ventricle. An S3 heart
sound is best heard with the bell-side of the stethoscope (used for lower frequency sounds). A left-sided S3 is best
heard at the apex of the heart, which is normally located in the 5th left intercostal space at the midclavicular line. A
right-sided S3 is best heard at the lower-left sternal border. The way to distinguish between a left and right-sided S3
is to observe whether it increases in intensity with inspiration or expiration. A right-sided S3 will increase on
inspiration whereas a left-sided S3 will increase on expiration.
[edit] S4

Main article: Fourth heart sound

The rare fourth heart sound is sometimes audible in healthy children and again in trained athletes, but when audible
in an adult is called a presystolic gallop or atrial gallop. This gallop is produced by the sound of blood being
forced into a stiff/hypertrophic ventricle. It is a sign of a pathologic state, usually a failing left ventricle, but can also
be heard in other conditions such as restrictive cardiomyopathy. The sound occurs just after atrial contraction ("atrial
kick") at the end of diastole and immediately before S1, producing a rhythm sometimes referred to as the
"Tennessee" gallop where S4 represents the "tenn-" syllable. The combined presence of S3 and S4 is a quadruple
gallop. At rapid heart rates, S3 and S4 may merge to produce a summation gallop.

Cardiac cycle is the term referring to all or any of the events related to the flow or blood pressure that occurs from
the beginning of one heartbeat to the beginning of the next.[1] The frequency of the cardiac cycle is the heart rate.
Every single 'beat' of the heart involves five major stages: First, "Late diastole" which is when the semilunar valves
close, the Av valves open and the whole heart is relaxed. Second, "Atrial systole" when atria is contracting, AV
valves open and blood flows from atrium to the ventricle. Third, "Isovolumic ventricular contraction" it is when the
ventricles begin to contract, AV valves close, as well as the semilunar valves and there is no change in volume.
Fourth, "ventricular ejection", Ventricles are empty, they are still contracting and the semilunar valves are open. The
fifth stage is: "Isovolumic ventricular relaxation", Pressure decreases, no blood is entering the ventricles, ventricles
stop contracting and begin to relax, semilunars are shut because blood in the aorta is pushing them shut. Throughout
the cardiac cycle, the blood pressure increases and decreases. The cardiac cycle is coordinated by a series of
electrical impulses that are produced by specialized heart cells found within the sino-atrial node and the
atrioventricular node. The cardiac muscle is composed of myocytes which initiate their own contraction without
help of external nerves (with the exception of modifying the heart rate due to metabolic demand). Under normal
circumstances, each cycle takes approximately one second.

Atrial systole
Atrial systole

Atrial systole is the contraction of the heart muscle (myocardia) of the left and right atria. Normally, both atria
contract at the same time. The term systole is synonymous with contraction (movement or shortening) of a muscle.
Electrical systole is the electrical activity that stimulates the myocardium of the chambers of the heart to make them
contract. This is soon followed by Mechanical systole, which is the mechanical contraction of the heart.

As the atria contract, the blood pressure in each atrium increases, forcing additional blood into the ventricles. The
additional flow of blood is called atrial kick.

70% of the blood flows passively down to the ventricles, so the atria do not have to contract a great amount.[2]

Atrial kick is absent if there is loss of normal electrical conduction in the heart, such as during atrial fibrillation,
atrial flutter, and complete heart block. Atrial kick is also different in character depending on the condition of the
heart, such as stiff heart, which is found in patients with diastolic dysfunction.

[edit] Detection of atrial systole

Electrical systole of the atria begins with the onset of the P wave on the ECG. The wave of bipolarization (or
depolarization) that stimulates both atria to contract at the same time is due to sinoatrial node which is located on the
upper wall of the right atrium. 30% of the ventricles are filled during this phase
[edit] Ventricular systole
Ventricular systole

Ventricular systole is the contraction of the muscles (myocardia) of the left and right ventricles.

At the later part of the ejection phase, although the ventricular pressure falls below the aortic pressure, the aortic
valve remains patent because of the inertial energy of the ejected blood.[3]

The graph of aortic pressure throughout the cardiac cycle displays a small dip which coincides with the aortic valve
closure. The dip in the graph is immediately followed by a brief rise then gradual decline. The small rise in the graph
is known as the "dicrotic notch" or "incisure", and represents a transient increase in aortic pressure. Just as the
ventricles enter into diastole, the brief reversal of flow from the aorta back into the left ventricle causes the aortic
valves to shut. This results in the slight increase in aortic pressure caused by the elastic recoil of the semilunar
valves and aorta.[4] [5] [6]

[edit] Detection of ventricular systole

[edit] Heart sounds

Main article: Heart sounds

The closing of the mitral and tricuspid valves (known together as the atrioventricular valves) at the beginning of
ventricular systole cause the first part of the "lub-dub" sound made by the heart as it beats. Formally, this sound is
known as the First Heart Tone, or S1. This first heart tone is created by the closure of mitral and tricuspid valve and
is actually a two component sound, M1, T1.

The second part of the "lub-dub" (the Second Heart Tone, or S2), is caused by the closure of the aortic and
pulmonary valves at the end of ventricular systole. As the left ventricle empties, its pressure falls below the pressure
in the aorta, and the aortic valve closes. Similarly, as the pressure in the right ventricle falls below the pressure in the
pulmonary artery, the pulmonary valve closes. The second heart sound is also two components, A2, P2. The aortic
valve closes earlier than the pulmonary valve and they are audibly separated from each other in the second heart
sound. This "splitting" of S2 is only audible during inhalation.

[edit] Electrocardiogram

In an electrocardiogram, electrical systole of the ventricles begins at the beginning of the QRS complex.

[edit] Diastole
Cardiac diastole

Cardiac Diastole is the period of time when the heart relaxes after contraction in preparation for refilling with
circulating blood. Ventricular diastole is when the ventricles are relaxing, while atrial diastole is when the atria
are relaxing. Together they are known as complete cardiac diastole.

During ventricular diastole, the pressure in the (left and right) ventricles drops from the peak that it reaches in
systole. When the pressure in the left ventricle drops to below the pressure in the left atrium, the mitral valve opens,
and the left ventricle fills with blood that was accumulating in the left atrium. Likewise, when the pressure in the
right ventricle drops below that in the right atrium, the tricuspid valve opens, and the right ventricle fills with blood
that was accumulating in the right atrium. During diastole the pressure within the myocardium is lower than that in
aorta, allowing blood to circulate in the heart itself via the coronary arteries.
[edit] Regulation of the cardiac cycle
Cardiac muscle has automaticity, which means that it is self-exciting. This is in contrast with skeletal muscle, which
requires either conscious or reflex nervous stimuli for excitation. The heart's rhythmic contractions occur
spontaneously, although the rate of contraction can be changed by nervous or hormonal influences, exercise and
emotions. For example, the sympathetic nerves to heart accelerate heart rate and the vagus nerve decelerates heart
rate.

The rhythmic sequence of contractions is coordinated by the sinoatrial (SA) and atrioventricular (AV) nodes. The
sinoatrial node, often known as the cardiac pacemaker, is located in the upper wall of the right atrium and is
responsible for the wave of electrical stimulation that initiates atrial contraction by creating an action potential. Once
the wave reaches the AV node, situated in the lower right atrium, it is delayed there before being conducted through
the bundles of His and back up the Purkinje fibers, leading to a contraction of the ventricles. The delay at the AV
node allows enough time for all of the blood in the atria to fill their respective ventricles. In the event of severe
pathology, the AV node can also act as a pacemaker; this is usually not the case because their rate of spontaneous
firing is considerably lower than that of the pacemaker cells in the SA node and hence is overridden.

Murmurs
Heart murmurs are produced as a result of turbulent flow of blood, turbulence sufficient to produce
audible noise. They are usually heard as a whooshing sound. The term murmur only refers to a sound
believed to originate within blood flow through or near the heart; rapid blood velocity is necessary to
produce a murmur. Yet most heart problems do not produce any murmur and most valve problems also
do not produce an audible murmur.

The following paragraphs overview the murmurs most commonly heard in adults who do not have major
congenital heart abnormalities.

 Regurgitation through the mitral valve is by far the most commonly heard murmur, sometimes
fairly loud to a practiced ear, even though the volume of regurgitant blood flow may be quite
small. Yet, though obvious using echocardiography visualization, probably about 20% of cases of
mitral regurgitation do not produce an audible murmur.
 Stenosis of the aortic valve is typically the next most common heart murmur, a systolic ejection
murmur. This is more common in older adults or in those individuals having a two, not a three
leaflet aortic valve.

 Regurgitation through the aortic valve, if marked, is sometimes audible to a practiced ear with a
high quality, especially electronically amplified, stethoscope. Generally, this is a very rarely
heard murmur, even though aortic valve regurgitation is not so rare. Aortic regurgitation, though
obvious using echocardiography visualization, usually does not produce an audible murmur.

 Stenosis of the mitral valve, if severe, also rarely produces an audible, low frequency soft
rumbling murmur, best recognized by a practiced ear using a high quality, especially
electronically amplified, stethoscope.

 Either regurgitation through, or stenosis of, the tricuspid or pulmonary valves essentially never
produces audible murmurs.

 Other audible murmurs are associated with abnormal openings between the left ventricle and
right heart or from the aortic or pulmonary arteries back into a lower pressure heart chamber.
Coronary anatomy
The coronary arteries' ostia and their proximal segments. The proximal portion of right coronary artery
and its ostium can be seen at the lower left (of the image). The left main coronary artery and its ostium
are seen on the right (of the image). An aortic valve that, due to rheumatic heart disease, has a severe
stenosis is seen at the centre (of the image). The pulmonary trunk is seen at the lower right (of the image).
Autopsy specimen.

The exact anatomy of the myocardial blood supply system varies considerably from person to person. A
full evaluation of the coronary arteries requires cardiac catheterization or CT coronary angiography.

In general there are two main coronary arteries, the left and right.

 Right coronary artery

 Left coronary artery

Both of these arteries originate from the beginning (root) of the aorta, immediately above the aortic valve.
As discussed below, the left coronary artery originates from the left aortic sinus, while the right coronary
artery originates from the right aortic sinus.

[edit] Variations

Four percent of people have a third, the posterior coronary artery. In rare cases, a person will have one
coronary artery that runs around the root of the aorta.

Occasionally, a coronary artery will exist as a double structure (i. e. there are two arteries, parallel to each
other, where ordinarily there would be one).

[edit] Coronary artery dominance

The artery that supplies the posterior descending artery (PDA)[1] (a.k.a. posterior interventricular artery)
determines the coronary dominance.[2]

 If the posterior descending artery (PDA) (a.k.a. posterior interventricular artery) is supplied by
the right coronary artery (RCA), then the coronary circulation can be classified as "right-
dominant".
 If the posterior descending artery (PDA) is supplied by the circumflex artery (CX), a branch of
the left artery, then the coronary circulation can be classified as "left-dominant".

 If the posterior descending artery (PDA) is supplied by both the right coronary artery (RCA) and
the circumflex artery, then the coronary circulation can be classified as "co-dominant".

Approximately 70% of the general population are right-dominant, 20% are co-dominant, and 10% are
left-dominant.[2]
[edit] Blood supply of the papillary muscles
The papillary muscles tether the mitral valve (the valve between the left atrium and the left ventricle) and
the tricuspid valve (the valve between the right atrium and the right ventricle) to the wall of the heart. If
the papillary muscles are not functioning properly, the mitral valve may leak during contraction of the left
ventricle. This causes some of the blood to travel "in reverse", from the left ventricle to the left atrium,
instead of forward to the aorta and the rest of the body. This leaking of blood to the left atrium is known
as mitral regurgitation. Similarly, the leaking of blood from the right ventricle through the tricuspid valve
and into the right atrium can also occur, and this is described as tricuspid insufficiency or tricuspid
regurgitation.

The anterolateral papillary muscle more frequently receives two blood supplies: left anterior descending
(LAD) artery and the left circumflex artery (LCX).[3] It is therefore more frequently resistant to coronary
ischemia (insufficiency of oxygen-rich blood). On the other hand, the posteromedial papillary muscle is
usually supplied only by the PDA.[3] This makes the posteromedial papillary muscle significantly more
susceptible to ischemia. The clinical significance of this is that a myocardial infarction involving the PDA
is more likely to cause mitral regurgitation.

[edit] Coronary flow

During contraction of the ventricular myocardium (systole), the subendocardial coronary vessels (the
vessels that enter the myocardium) are compressed due to the high intraventricular pressures. However,
the epicardial coronary vessels (the vessels that run along the outer surface of the heart) remain patent.
Because of this, blood flow in the subendocardium stops. As a result most myocardial perfusion occurs
during heart relaxation (diastole) when the subendocardial coronary vessels are patent and under low
pressure. This contributes to the filling difficulties of the coronary arteries. Compression remains the
same. Failure of oxygen delivery caused by a decrease in blood flow in front of increased oxygen demand
of the heart results in tissue ischemia, a condition of oxygen debt. Brief ischemia is associated with
intense chest pain, known as angina. Severe ischemia can cause the heart muscle to die of oxygen
starvation, called a myocardial infarction. Chronic moderate ischemia causes contraction of the heart to
weaken, known as myocardial hibernation.

In addition to metabolism, the coronary circulation possesses unique pharmacologic characteristics.

Prominent among these is its reactivity to adrenergic stimulation. The majority of vasculature in the body
constricts to norepinephrine, a sympathetic neurotransmitter the body uses to increase blood pressure. In
the coronary circulation, norepinephrine elicits vasodilation, due to the predominance of beta-adrenergic
receptors in the coronary circulation. Agonists of alpha-receptors, such as phenylephrine, elicit very little
constriction in the coronary circulation.

[edit] Anastomoses
When two arteries of the coronary circulation join, dual blood flow to a certain area of the myocardium
occurs. These junctions are called anastomoses. If one coronary artery is obstructed by an atheroma, the
second artery is still able to supply oxygenated blood to the myocardium. However this can only occur if
the atheroma progresses slowly, giving the anastomoses a chance to proliferate. Under the most common
configuration of coronary arteries, there exist two anastomoses on the posterior side of the heart. More
superiorly, there is an anastomosis between the circumflex artery (a branch of the left coronary artery)
and the right coronary artery. More inferiorly, there is an anastomosis between the anterior
interventricular artery (a branch of the left coronary artery) and the posterior interventricular artery (a
branch of the right coronary artery).

Low arterial pressure

Main article: Hypotension

Blood pressure that is too low is known as hypotension. The similarity in pronunciation with hypertension
can cause confusion. Hypotension is a medical concern only if it causes signs or symptoms, such as
dizziness, fainting, or in extreme cases, shock.[17]

When arterial pressure and blood flow decrease beyond a certain point, the perfusion of the brain
becomes critically decreased (i.e., the blood supply is not sufficient), causing lightheadedness, dizziness,
weakness or fainting.

Sometimes the arterial pressure drops significantly when a patient stands up from sitting. This is known
as orthostatic hypotension (postural hypotension); gravity reduces the rate of blood return from the body
veins below the heart back to the heart, thus reducing stroke volume and cardiac output.

When people are healthy, the veins below their heart quickly constrict and the heart rate increases to
minimize and compensate for the gravity effect. This is carried out involuntarily by the autonomic
nervous system. The system usually requires a few seconds to fully adjust and if the compensations are
too slow or inadequate, the individual will suffer reduced blood flow to the brain, dizziness and potential
blackout. Increases in G-loading, such as routinely experienced by aerobatic or combat pilots 'pulling Gs',
greatly increases this effect. Repositioning the body perpendicular to gravity largely eliminates the
problem.

Other causes of low arterial pressure include:

 Sepsis
 Hemorrhage - blood loss

 Toxins including toxic doses of BP medicine

 Hormonal abnormalities, such as Addison's disease

Shock is a complex condition which leads to critically decreased perfusion. The usual mechanisms are
loss of blood volume, pooling of blood within the veins reducing adequate return to the heart and/or low
effective heart pumping. Low arterial pressure, especially low pulse pressure, is a sign of shock and
contributes to and reflects decreased perfusion.

If there is a significant difference in the pressure from one arm to the other, that may indicate a narrowing
(for example, due to aortic coarctation, aortic dissection, thrombosis or embolism) of an artery.
Overall Effect

The balance of Starling forces in the lung is generally stated as favouring reabsorption because of the
clinical fact that the lungs are generally ‘dry’ and clearly need to be to facilitate gas exchange. Under
normal conditions, there is a small net outward movement of fluid. This is estimated as equal to the
pulmonary lymph flow rate. The flow is usually small (eg 10 to 20 mls/min) which is only about 2% of
the pulmonary blood flow. So despite the net outward hydrostatic pressure gradient and the high
reflection coefficient which limits the effectiveness of the oncotic pressure in opposing outward fluid
movement, the measured low lymph flow means that the balance of forces is clearly to minimise loss of
fluid into the interstitium.

The large surface area and thin capillary walls which assist efficient gas exchange also facilitate filtration
from the capillaries to the interstitium. The interstitial fluid move towards the hilum along the spaces
beside the vessels and the airways. The interstitial hydrostatic pressure probably becomes more negative
as the hilum is approached. The excess filtrate is removed by the pulmonary lymphatics. Lymphatic flow
is promoted by the rhythmic external compression that occurs during the ventilatory cycle and by the
presence of one way valves.

The Starling equation is not very useful clinically because it is not possible to measure all six of the
unknown values. In particular, bedside determination of the interstitial hydrostatic & oncotic pressures
and the reflection coefficient is not possible. The clinician is limited to assessments based on plasma
protein concentration (as index of capillary oncotic pressure) and values obtainable from use of a
pulmonary artery catheter (eg wedge pressure as estimate of left atrial pressure & mean pulmonary
venous pressure). A clinical examination and a chest xray are much more useful in assessing &
monitoring pulmonary oedema.

Safety Factors Preventing Pulmonary Oedema

For pulmonary oedema to occur, excess fluid must first accumulate in the interstitium (interstitial
oedema), then must move into the alveoli (alveolar flooding). The lung is relatively resistant to the onset
of pulmonary oedema and this is usually ascribed to several safety factors:

 Increased lymph flow: Increased fluid filtration causes increased lymph flow which tends to remove the
fluid.
 Decrease in interstitial oncotic pressure (oncotic buffering mechanism): When filtration increases, the
albumin loss in the filtrate decreases. This combined with the increased lymph flow washes the albumin
out of the interstitium and interstitial oncotic pressure decreases. This protection does not work if the
capillary membrane is damaged eg by septic mediators.

 High interstitial compliance: A large volume of fluid can accumulate in the gel of the interstitium without
much pressure rise. Finally, the interstial tissues become full of fluid, the pressure rises and alveolar
flooding occurs. This has been called the bathtub effect: the analogy is that the tub can take a lot of fluid
but there comes a point when it is full and suddenly overflows.
These safety mechanisms are quite effective especially in preventing pulmonary oedema associated with
rises in capillary hydrostatic pressure. It has been estimated that the capillary hydrostatic pressure can rise
to three times normal before alveolar flooding occurs. Surfactant assists in the prevention of alveolar
flooding also.

Inhalation of tobacco smoke causes several immediate responses within the heart and blood
vessels. Within one minute the heart rate begins to rise, increasing by as much as 30 percent
during the first 10 minutes of smoking. Carbon monoxide in tobacco smoke exerts its negative
effects by reducing the blood’s ability to carry oxygen.[86]

Smoking also increases the chance of heart disease, stroke, atherosclerosis, and peripheral
vascular disease. Several ingredients of tobacco lead to the narrowing of blood vessels,
increasing the likelihood of a blockage, and thus a heart attack or stroke. According to a study by
an international team of researchers, people under 40 are five times more likely to have a heart
attack if they smoke.[87]

Latest research of the American biologists have determined that cigarette smoke also influences
the process of cell division in the cardiac muscle and changes heart's shape.[88]

The usage of tobacco has also been linked to Buerger's disease (thromboangiitis obliterans) the
acute inflammation and thrombosis (clotting) of arteries and veins of the hands and feet.[citation
needed]

The current Surgeon General’s Report concluded that there is no risk-free level of exposure to
secondhand smoke. Even short exposures to secondhand smoke can cause blood platelets to
become stickier, damage the lining of blood vessels, decrease coronary flow velocity reserves,
and reduce heart rate variability, potentially increasing the risk of heart attack. New research
indicates that private research conducted by cigarette company Philip Morris in the 1980s
showed that secondhand smoke was toxic, yet the company suppressed the finding during the
next two decades.[77]

Smoking tends to increase blood cholesterol levels. Furthermore, the ratio of high-density lipoprotein
(the "good" cholesterol) to low-density lipoprotein (the "bad" cholesterol) tends to be lower in smokers
compared to non-smokers. Smoking also raises the levels of fibrinogen and increases platelet production
(both involved in blood clotting) which makes the blood viscous. Carbon monoxide binds to
haemoglobin (the oxygen-carrying component in red blood cells), resulting in a much stabler complex
than haemoglobin bound with oxygen or carbon dioxide—the result is permanent loss of blood cell
functionality. Blood cells are naturally recycled after a certain period of time, allowing for the creation of
new, functional erythrocytes. However, if carbon monoxide exposure reaches a certain point before
they can be recycled, hypoxia (and later death) occurs. All these factors make smokers more at risk of
developing various forms of arteriosclerosis. As the arteriosclerosis progresses, blood flows less easily
through rigid and narrowed blood vessels, making the blood more likely to form a thrombosis (clot).
Sudden blockage of a blood vessel may lead to an infarction (e.g. stroke). However, it is also worth
noting that the effects of smoking on the heart may be more subtle. These conditions may develop
gradually given the smoking-healing cycle (the human body heals itself between periods of smoking),
and therefore a smoker may develop less significant disorders such as worsening or maintenance of
unpleasant dermatological conditions, e.g. eczema, due to reduced blood supply. Smoking also increases
blood pressure and weakens blood vessels.[92]

Atherosclerosis develops from low-density lipoprotein molecules (LDL) becoming oxidized (ldl-
ox) by free radicals, particularly oxygen free radicals (ROS). Blood in arteries contains plenty of
oxygen and is where atherosclerosis develops. Blood in veins contains little oxygen where
atherosclerosis rarely develops. When oxidized LDL comes in contact with an artery wall, a
series of reactions occur to repair the damage to the artery wall caused by oxidized LDL. The
LDL molecule is globular shaped with a hollow core to carry cholesterol throughout the body to
generate brain tissues, vitamin D, and so on. Cholesterol does not dissolve in water. Blood is
70% water. Cholesterol can move in the bloodstream only by being transported by LDL.

The body's immune system responds to the damage to the artery wall caused by oxidized LDL
by sending specialized white blood cells (macrophages and T-lymphocytes) to absorb the
oxidized-LDL forming specialized foam cells. Unfortunately, these white blood cells are not able
to process the oxidized-LDL, and ultimately grow then rupture, depositing a greater amount of
oxidized cholesterol into the artery wall. This triggers more white blood cells, continuing the
cycle.

Eventually, the artery becomes inflamed. The cholesterol plaque causes the muscle cells to
enlarge and form a hard cover over the affected area. This hard cover is what causes a narrowing
of the artery, reduces the blood flow and increases blood pressure.

Coronary heart disease1 - estimated number of patients in Scotland consulting a GP or practice nurse
at least once in the financial year 2007/08 2, 3 per 1,000 patients registered
Illustration of the relationship between age and 30-day mortality after acute
myocardial infarction. Data from the GUSTO-I trial (Lee et al., 1995) were
analyzed with age as a linear, continuous variable (thick line) and with a
dichotomized version of age (<65 years versus >65 years). With the
dichotomized version of age, there is an unnaturally big step between age
64 and age 65, and no difference in predicted risk among patients younger
than 64 and among those older than 65 years of age.
Stroke1 - estimated number of patients in Scotland consulting a GP or practice nurse at least once in
the financial year 2007/08 2, 3 per 1,000 patients registered

Cerebral circulation refers to the movement of blood through the network of blood vessels
supplying the brain. The arteries deliver oxygenated blood, glucose and other nutrients to the
brain and the veins carry deoxygenated blood back to the heart, removing carbon dioxide, lactic
acid, and other metabolic products. Since the brain is very vulnerable to compromises in its
blood supply, the cerebral circulatory system has many safeguards. Failure of these safeguards
results in cerebrovascular accidents, commonly known as strokes. The amount of blood that the
cerebral circulation carries is known as cerebral blood flow. The presence of gravitational fields
or accelerations also determine variations in the movement and distribution of blood in the brain,
such as when suspended upside-down.

The following description is based on idealized human cerebral circulation. The pattern of
circulation and its nomenclature vary between organisms.

[edit] Cranial arteries

There are two main pairs of arteries that supply the cerebral arteries and the cerebellum:

 Internal carotid arteries: These large arteries are the left and right branches of the
common carotid arteries in the neck which enter the skull, as opposed to the external
carotid branches which supply the facial tissues. The internal carotid artery branches into
the anterior cerebral artery and continues to form the middle cerebral artery
 Vertebral arteries. These smaller arteries branch from the subclavian arteries which
primarily supply the shoulders, lateral chest and arms. Within the cranium the two
 vertebral arteries fuse into the basilar artery, which supplies the midbrain, cerebellum,
and usually branches into the posterior cerebral artery.

Both internal carotid arteries, within and along the floor of the cerebral vault, are interconnected
via the anterior communicating artery. Additionally, both internal carotid arteries are
interconnected with the basilar artery via bilateral posterior communicating arteries.

The Circle of Willis, long considered to be an important anatomic vascular formation, provides
backup circulation to the brain. In case one of the supply arteries is occluded, the Circle of Willis
provides interconnections between the internal carotid arteries and basilar artery along the floor
of the cerebral vault, providing blood to tissues that would otherwise become ischemic.

[edit] Cerebral venous drainage

The venous drainage of the cerebrum can be separated into two subdivisions: superficial and
deep. The superficial system is composed of dural venous sinuses, which have wall composed of
dura mater as opposed to a traditional vein. The dural sinuses are, therefore located on the
surface of the cerebrum. The most prominent of these sinuses is the Superior sagittal sinus which
flows in the sagittal plane under the midline of the cerebral vault, posteriorly and inferiorly to the
torcula, forming the Confluence of sinuses, where the superficial drainage joins with the sinus
the primarily drains the deep venous system. From here, two transverse sinuses bifurcate and
travel laterally and inferiorly in an S-shaped curve that form the sigmoid sinuses which go on to
form the two jugular veins. In the neck, the jugular veins parallel the upward course of the
carotid arteries and drain blood into the vena cava. The deep venous drainage is primarily
composed of traditional veins inside the deep structures of the brain, which join behind the
midbrain to form the Vein of Galen. This vein merges with the Inferior sagittal sinus to form the
Straight sinus which then joins the superficial venous system mentioned above at the Confluence
of sinuses.

Cerebral blood flow, or CBF, is the blood supply to the brain in a given time.[1] In an adult,
CBF is typically 750 millitres per minute or 15% of the cardiac output. This equates to 50 to 54
millilitres of blood per 100 grams of brain tissue per minute.[2][3][4] CBF is tightly regulated to
meet the brain's metabolic demands.[2][5] Too much blood (a condition known as hyperemia) can
raise intracranial pressure (ICP), which can compress and damage delicate brain tissue. Too little
blood flow (ischemia) results if blood flow to the brain is below 18 to 20 ml per 100 g per
minute, and tissue death occurs if flow dips below 8 to 10 ml per 100 g per minute. In brain
tissue, a biochemical cascade known as the ischemic cascade is triggered when the tissue
becomes ischemic, potentially resulting in damage to and death of brain cells. Medical
professionals must take steps to maintain proper CBF in patients who have conditions like shock,
stroke, and traumatic brain injury.

Cerebral blood flow is determined by a number of factors, such as viscosity of blood, how
dilated blood vessels are, and the net pressure of the flow of blood into the brain, known as
cerebral perfusion pressure, which is determined by the body's blood pressure and intracranial
pressure. Cerebral blood vessels are able to change the flow of blood through them by altering
their diameters in a process called autoregulation; they constrict when systemic blood pressure is
raised and dilate when it is lowered[6] Arterioles also constrict and dilate in response to different
chemical concentrations. For example, they dilate in response to higher levels of carbon dioxide
in the blood.[6]

CBF is equal to the cerebral perfusion pressure (CPP) divided by the cerebrovascular resistance
(CVR):[7]

CBF = CPP / CVR

Control of CBF is considered in terms of the factors affecting CPP and the factors affecting
CVR. CVR is controlled by four major mechanisms:

1. Metabolic control (or 'metabolic autoregulation')

2. Pressure autoregulation
3. Chemical control (by arterial pCO2 and pO2)
4. Neural control

Functional magnetic resonance imaging and positron emission tomography are neuroimaging
techniques that can both be used to measure CBF. These techniques are also used to measure
regional CBF (rCBF) within a specific brain region.

The ischemic (ischaemic) cascade is a series of biochemical reactions that take place in the brain and
other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply).[1] This is typically
secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due
to the activation of chemicals produced during and after ischemia. [2] The ischemic cascade usually goes
on for two to three hours but can last for days, even after normal blood flow returns. [3]

A cascade is a series of events in which one event triggers the next, in a linear fashion. Thus "ischemic
cascade" is actually a misnomer, since in it events are not always linear: in some cases they are circular,
and sometimes one event can cause or be caused by multiple events. [4] In addition, cells receiving
different amounts of blood may go through different chemical processes. Despite these facts, the ischemic
cascade can be generally characterized as follows:

1. Lack of oxygen causes the neuron's normal process for making ATP for energy to fail.
2. The cell switches to anaerobic metabolism, producing lactic acid.

3. ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions,
including calcium (Ca++), to flow into the cell.

4. The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get
too high.

5. The presence of calcium triggers the release of the excitatory amino acid neurotransmitter
glutamate.
 6. Glutamate stimulates AMPA receptors and Ca++-permeable NMDA receptors, which open to
allow more calcium into cells.

7. Excess calcium entry overexcites cells and causes the generation of harmful chemicals like free
radicals, reactive oxygen species and calcium-dependent enzymes such as calpain, endonucleases,
ATPases, and phospholipases in a process called excitotoxicity.[5][6] Calcium can also cause the
release of more glutamate.

8. As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more
ions and harmful chemicals flow into the cell.

9. Mitochondria break down, releasing toxins and apoptotic factors into the cell.

10. The caspase-dependent apoptosis cascade is initiated, causing cells to "commit suicide."

11. If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment
around it. Toxins poison nearby neurons, and glutamate can overexcite them.

12. If and when the brain is reperfused, a number of factors lead to reperfusion injury.

13. An inflammatory response is mounted, and phagocytic cells engulf damaged but still viable
tissue.

14. Harmful chemicals damage the blood brain barrier.

15. Cerebral edema (swelling of the brain) occurs due to leakage of large molecules like albumins
from blood vessels through the damaged blood brain barrier. These large molecules pull water
into the brain tissue after them by osmosis. This "vasogenic edema" causes compression of and
damage to brain tissue.

The fact that the ischemic cascade involves a number of steps has led doctors to suspect that
neuroprotectants such as calcium channel blockers or glutamate antagonists could be produced to
interrupt the cascade at a single one of the steps, blocking the downstream effects. Though initial trials for
such neuroprotective drugs led many to be hopeful, until recently, human clinical trials with
neuroprotectants such as NMDA receptor antagonists were unsuccessful.