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Discuss how the brain’s blood flow is controlled under normal circumstances. (25)
The brain uses ~20% of available oxygen for normal function, making tight regulation of blood flow and oxygen delivery critical for survival. In a normal physiological state, total blood flow to the brain is remarkably constant due in part to the prominent contribution of large arteries to vascular resistance. In addition, parenchymal arterioles have considerable basal tone and also contribute significantly to vascular resistance in the brain . The high metabolic demand of neuronal tissue requires tight coordination between neuronal activity and blood flow within the brain parenchyma, known as functional hyperemia. However, in order for flow to increase to areas within the brain that demand it, upstream vessels must dilate in order to avoid reductions in downstream microvascularpressure . Therefore, coordinated flow responses occur in the brain, likely due to conducted or flow-mediated vasodilation from distal to proximal arterial segments and to myogenic mechanisms that increase flow in response to decreased pressure. ? Only use symbols where indicated (2.5)
Cerebral HemodynamicsBrain blood flow can be modeled from a physical standpoint as flow in a tube with the assumptions that flow is steady, laminar, and uniform through thinned-walled (the wall is ;10% of the lumen) non-distensible tubes. These assumptions do not apply to large arteries that have thick walls or in the microcirculation in which flow is non-Newtonian . Ohm’s law states that flow is proportional to the difference in inflow and outflow pressure (?P) divided by the resistance to flow (R): flow = ?P/R. In the brain, ?P is cerebral perfusion pressure (CPP), the difference between intra-arterial pressure and the pressure in veins. Venous pressure is normally low (2–5 mmHg) and is influenced directly by intracranial pressure (ICP). Therefore, ?P is calculated as the difference in CPP and either venous pressure or ICP, whichever is greater. Blood flow is also estimated by Poiseuielle’s law that states that flow is directly related to ?P, blood viscosity, and the length of the vessel (assumed to be constant) and inversely related to radius to the fourth power: flow = (8 × ? × L)/r4 . Thus, radius is the most powerful determinant of blood flow and even small changes in lumen diameter have significant effects on cerebral blood flow, and it is by this mechanism that vascular resistance can change rapidly to alter regional and global cerebral blood flow ? source of information not acknowledged (5)
Autoregulation of Cerebral Blood Flow
Autoregulation of cerebral blood flow is the ability of the brain to maintain relatively constant blood flow despite changes in perfusion pressure .Autoregulation is present in many vascular beds, but is particularly well-developed in the brain, likely due to the need for a constant blood supply and water homeostasis. In normotensive adults, cerebral blood flow is maintained at ~50 mL per 100 g of brain tissue per minute, provided CPP is in the range of ~60 to 160 mmHg . Above and below this limit, autoregulation is lost and cerebral blood flow becomes dependent on mean arterial pressure in a linear fashion . When CPP falls below the lower limit of autoregulation, cerebral ischemia ensues . The reduction in cerebral blood flow is compensated for by an increase in oxygen extraction from the blood . Clinical signs or symptoms of ischemia are not seen until the decrease in perfusion exceeds the ability of increased oxygen extraction to meet metabolic needs. At this point, clinical signs of hypoperfusion occur, including dizziness, altered mental status, and eventually irreversible tissue damage (infarction) . ?
The mechanisms of autoregulation in the brain are not completely understood and likely differ with increases vs. decreases in pressure. Although a role for neuronal involvement in autoregulation is appealing, studies have shown that cerebral blood flow autoregulation is preserved in sympathetically and parasympatheticallydenervated animals, indicating that a major contribution of extrinsic neurogenic factors to autoregulation of cerebral blood flow is unlikely. Recently, a role for neuronal nitric oxide in modulating cerebral blood flow autoregulation has been shown, suggesting that although extrinsic innervation may not be involved, intrinsic innervation may have a role .Biproducts of metabolism have also been proposed to have a role in autoregulation . Reductions in cerebral blood flow stimulate release of vasoactive substances from the brain that cause arterial dilatation. Candidates for these vasoactive substances include H+, K+, O2, adenosine, and others. Autoregulation of cerebral blood flow when pressure fluctuates at the high end of the autoregulatory curve is most likely due to the myogenic behavior of the cerebral smooth muscle that constrict in response to elevated pressure and dilate in response to decreased pressure . The important contribution of myogenic activity to autoregulation is demonstrated in vitro in isolated and pressurized cerebral arteries that constrict in a response to increased pressure and dilate in response to decreased pressure . Autoregulation at pressures below the myogenic pressure range likely involves hypoxia and release of metabolic factors . ?
The importance of autoregulation in normal brain function is highlighted by the fact that significant brain injury occurs when autoregulatory mechanisms are lost. For example, during acute hypertension at pressures above the autoregulatory limit, the myogenic constriction of vascular smooth muscle is overcome by the excessive intravascular pressure and forced dilatation of cerebral vessels occurs . The loss of myogenic tone during forced dilatation decreases cerebrovascular resistance, a result that can produce a large increase in cerebral blood flow (300–400%), known as autoregulatory breakthrough (Figure 1). In addition, decreased cerebrovascular resistance increases hydrostatic pressure on the cerebral endothelium, causing edema formation , the underlying cause of conditions such as hypertensive encephalopathy, posterior reversible encephalopathy syndrome (PRES), and eclampsia . × not necessary

Tracing of CBF (in laser Doppler units) and ABP (in mmHg) in response to increasing doses of PE. In this experiment, CBF increased four times greater than baseline as ABP increased from 140 to 210 mmHg, demonstrating autoregulatory breakthrough. Used
Although uncommon since the advent of effective antihypertensive therapy, hypertensive encephalopathy occurs as a result of a sudden, sustained rise in blood pressure sufficient to exceed the upper limit of cerebral blood flow autoregulation (;160 mmHg) . Early studies on the reaction of cerebral vessels to high blood pressure produced the concept of hypertensive vasospasm. Acute hypertensive encephalopathy was thought the result of spasm—;defined as an uncontrolled vasoconstriction—;of the cerebral arteries, causing brain tissue ischemia . This concept originated from the observations of Byrom who produced experimental renal hypertension and found ~90% of hypertensive rats with neurologic manifestations showed multiple cortical spots of trypan blue extravasation, whereas rats without cerebral symptoms appeared to have normal cerebrovascular permeability. He also noted what he called an alternating vasoconstriction/vasodilation in the pial vessels, a phenomenon known as a “sausage-string” appearance. This observation led him to the conclusion that cerebral vasospasm caused ischemia and edema formation in response to acute hypertension. Byrom later modified his view and referred to a finding in the mesenteric circulation that vessels with this “sausage-string” appearance had protein leakage in the dilated parts of the vessels only . Since then, it has been established that high blood pressure results in increased cerebral blood flow and “breakthrough of autoregulation” . Further experiments confirmed that loss of myogenic vasoconstriction during forced dilatation rather than spasm is the critical event in hypertensive encephalopathy × not relevant
Segmental Vascular Resistance
In peripheral circulations, small arterioles (;100 ?m diameter) are typically the major site of vascular resistance . However, in the brain, both large arteries and small arterioles contribute significantly to vascular resistance. Direct measure of the pressure gradient across different segments of the cerebral circulation found that the large extracranial vessels (internal carotid and vertebral) and intracranial pial vessels contribute ~50% of cerebral vascular resistance . Large artery resistance in the brain is likely important to provide constant blood flow under conditions that change blood flow locally, e.g., metabolism. Large artery resistance also attenuates changes in downstream microvascular pressure during increases in systemic arterial pressure. Thus, segmental vascular resistance in the brain is a protective mechanism that helps provide constant blood flow in an organ with high metabolic demand without pathologically increasing hydrostatic pressure that can cause vasogenic edema. ? mostly irrelevant material. Definition came at the end of the answer (1)
Neural–Astrocyte Regulation
Unlike pial arteries and arterioles, parenchymal arterioles are in close association with astrocytes and, to a lesser extent, neurons. Both these cell types may have a role in controlling local blood flow . Subcortical microvessels are innervated from within the brain parenchyma and are unique in that the majority of vericosities adjoin astrocytic end-feet surrounding arterioles and thus does not have conventional neurovascular junctions . Neurons whose cell bodies are from within the subcortical brain regions (e.g., nucleus basalis, locus ceruleus, raphe nucleus) project to cortical microvessels to control local blood flow by release of neurotransmitter (e.g., ACH, norepinephrine, 5HT) (Figure 2). Release of neurotransmitter stimulates receptors on smooth muscle, endothelium, or astrocytes to cause constriction or dilation, thereby regulating local blood flow in concert with neuronal demand . It has been known for some time that astrocytes can release vasoactive factors . Evidence for the involvement of astrocytes in local control of blood flow in vivo has recently emerged. Their close opposition to microvessels, encasing almost the entire parenchymal arterioles and capillaries with little neuronal contact, makes astrocytic involvement likely at this level . Studies in brain slices, in which the entire neurovascular unit is intact, showed that direct electrical stimulation of neuronal processes raises calcium in astrocytic end-feet and causes dilation of nearby arterioles . Stimulation of astrocytes also raises calcium in end-feet and has a similar vasoactive effect on parenchymal arterioles; however, whether dilation or constriction occurs seems to depend on the level of calcium and, not surprisingly, resting tone . It has been proposed that an elevation in astrocyte calcium releases vasoactive factors, including K+, 20-HETE, and PGE2 . However, a weakness of the brain slice preparation is that it does not allow for arterioles to be pressurized or have flow. Thus, the role of the myogenic response, which may significantly modify any astrocytic-derived signals in vivo is not known. ? mostly irrelevant material. (1.5)

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Summary of the regulation of cortical microvessels from cells located in subcortical areas and within the cerebral cortex. The possibility that interneurons also induce the release of vasoactive molecules from astrocytes is not included for clarity purposes. × diagram not necessary
Effect of Oxygen
The brain has a very high metabolic demand for oxygen compared to other organs, and thus, it is not surprising that acute hypoxia is a potent dilator in the cerebral circulation that produces marked increases in cerebral blood flow . In general, blood flow does not change in the brain until tissue PO2 falls below ~50 mmHg, below which cerebral blood flow increases substantially . As hypoxia decreases PO2 further, cerebral blood flow can rise up to 400% of resting levels . Increases in cerebral blood flow do not change metabolism, but hemoglobin saturation falls from ~100% at PO2;70 mmHg to ~50% at PO2;50 mmHg . Acute hypoxia causes an increase in cerebral blood flow via direct effects on vascular cells of cerebral arteries and arterioles. Hypoxia-induced drop in ATP levels opens KATP channels on smooth muscle, causing hyperpolarization and vasodilation .In addition, hypoxia rapidly increases nitric oxide and adenosine production locally, also promoting vasodilation Chronic hypoxia increases cerebral blood flow throughh an effect on capillary density ? (1) source not acknowledged
Effect of Carbon Dioxide
Carbon dioxide (CO2) has a profound and reversible effect on cerebral blood flow, such that hypercapnia causes marked dilation of cerebral arteries and arterioles and increased blood flow, whereas hypocapnia causes constriction and decreased blood flow. The potent vasodilator effect of CO2 is demonstrated by the finding that in humans 5% CO2 inhalation causes an increase in cerebral blood flow by 50% and 7% CO2 inhalation causes a 100% increase in cerebral blood flow Although several mechanisms involved in hypercapnic vasodilation have been proposed, the major mechanism appears to be related to a direct effect of extracellular H+ on vascular smooth muscle This is supported by findings that neither bicarbonate ion nor changes in PCO2 alone affect cerebral artery diameter Other proposed mechanisms involved in the response to changes in PCO2 include vasodilator prostanoids and nitric oxide; however, the involvement of these mediators appears to be species-specific × source not acknowledged (1)
Describe the relationship between the ECG and the cardiac cycle (25)
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The period of time that begins with contraction of the atria and ends with ventricular relaxation is known as the cardiac cycle. The period of contraction that the heart undergoes while it pumps blood into circulation is called systole. The period of relaxation that occurs as the chambers fill with blood is called diastole. Both the atria and ventricles undergo systole and diastole, and it is essential that these components be carefully regulated and coordinated to ensure blood is pumped efficiently to the body. Your doctor may suggest you get an electrocardiogram — also called an EKG or ECG — to check for signs of heart disease. It’s a test that records the electrical activity of your ticker through small electrode patches that a technician attaches to the skin of your chest, arms, and legs.

Check your heart rhythm
See if you have poor blood flow to your heart muscle (this is called ischemia)
Diagnose a heart attackCheck on things that are abnormal, such as thickened heart muscle
How Should I Prepare?
Some things you can do to get yourself ready:
Avoid oily or greasy skin creams and lotions the day of the test because they can keep the electrodes from making contact with your skin.



What Happens During an Electrocardiogram?
A technician will attach 10 electrodes with adhesive pads to the skin of your chest, arms, and legs. If you’re a guy, you may need to have your chest hair shaved to allow a better connection.

During the test you’ll lie flat while a computer creates a picture, on graph paper, of the electrical impulses that move through your heart. This is called a “resting” EKG, although the same test may be used to check your heart while you exercise.


Your doctor will keep your EKG patterns on file so that he can compare them to tests you get in the future.

Types of EKG Tests
Besides the standard EKG, your doctor may recommend other kinds: 
Holter monitor. It’s a portable EKG that checks the electrical activity of your heart for 1 to 2 days, 24-hours a day. Your doctor may suggest it if he suspects you have an abnormal heart rhythm, you have palpitations, or don’t have enough blood flow to your heart muscle.

Like the standard EKG, it’s painless. The electrodes from the monitor are taped to your skin. Once they’re in place, you can go home and do all of your normal activities except shower. Your doctor will ask you to keep a diary of what you did and any symptoms you notice.

Event monitor. Your doctor may suggest this device if you only get symptoms now and then. When you push a button, it will record and store your heart’s electrical activity for a few minutes. You may need to wear it for weeks or sometimes months.

Each time you notice symptoms, you should try to get a reading on the monitor. The info is sent on the phone to your doctor, who will analyze it.

Signal-averaged electrocardiogram. It checks to see if you’re at high risk of getting a condition called heart arrhythmia, which can lead to cardiac arrest. The test is done in a similar way as a standard EKG, but it uses sophisticated technology to analyze your risk.

Figure 1. The cardiac cycle begins with atrial systole and progresses to ventricular systole, atrial diastole, and ventricular diastole, when the cycle begins again. Correlations to the ECG are highlighted.

Pressures and Flow
Fluids, whether gases or liquids, are materials that flow according to pressure gradients—that is, they move from regions that are higher in pressure to regions that are lower in pressure. Accordingly, when the heart chambers are relaxed (diastole), blood will flow into the atria from the veins, which are higher in pressure. As blood flows into the atria, the pressure will rise, so the blood will initially move passively from the atria into the ventricles. When the action potential triggers the muscles in the atria to contract (atrial systole), the pressure within the atria rises further, pumping blood into the ventricles. During ventricular systole, pressure rises in the ventricles, pumping blood into the pulmonary trunk from the right ventricle and into the aorta from the left ventricle. Again, as you consider this flow and relate it to the conduction pathway, the elegance of the system should become apparent.

Phases of the Cardiac Cycle

Atrial Systole and Diastole
Contraction of the atria follows depolarization, represented by the P wave of the ECG. As the atrial muscles contract from the superior portion of the atria toward the atrioventricular septum, pressure rises within the atria and blood is pumped into the ventricles through the open atrioventricular (tricuspid, and mitral or bicuspid) valves. At the start of atrial systole, the ventricles are normally filled with approximately 70–80 percent of their capacity due to inflow during diastole. Atrial contraction, also referred to as the “atrial kick,” contributes the remaining 20–30 percent of filling (see the image below). Atrial systole lasts approximately 100 ms and ends prior to ventricular systole, as the atrial muscle returns to diastole.

Ventricular Systole
Ventricular systole (see image below) follows the depolarization of the ventricles and is represented by the QRS complex in the ECG. It may be conveniently divided into two phases, lasting a total of 270 ms. At the end of atrial systole and just prior to atrial contraction, the ventricles contain approximately 130 mL blood in a resting adult in a standing position. This volume is known as the end diastolic volume (EDV) or preload.

Initially, as the muscles in the ventricle contract, the pressure of the blood within the chamber rises, but it is not yet high enough to open the semilunar (pulmonary and aortic) valves and be ejected from the heart. However, blood pressure quickly rises above that of the atria that are now relaxed and in diastole. This increase in pressure causes blood to flow back toward the atria, closing the tricuspid and mitral valves. Since blood is not being ejected from the ventricles at this early stage, the volume of blood within the chamber remains constant. Consequently, this initial phase of ventricular systole is known as isovolumic contraction, also called isovolumetric contraction (see image below).

In the second phase of ventricular systole, the ventricular ejection phase, the contraction of the ventricular muscle has raised the pressure within the ventricle to the point that it is greater than the pressures in the pulmonary trunk and the aorta. Blood is pumped from the heart, pushing open the pulmonary and aortic semilunar valves. Pressure generated by the left ventricle will be appreciably greater than the pressure generated by the right ventricle, since the existing pressure in the aorta will be so much higher. Nevertheless, both ventricles pump the same amount of blood. This quantity is referred to as stroke volume. Stroke volume will normally be in the range of 70–80 mL. Since ventricular systole began with an EDV of approximately 130 mL of blood, this means that there is still 50–60 mL of blood remaining in the ventricle following contraction. This volume of blood is known as the end systolic volume (ESV).

Ventricular Diastole
Ventricular relaxation, or diastole, follows repolarization of the ventricles and is represented by the T wave of the ECG. It too is divided into two distinct phases and lasts approximately 430 ms.During the early phase of ventricular diastole, as the ventricular muscle relaxes, pressure on the remaining blood within the ventricle begins to fall. When pressure within the ventricles drops below pressure in both the pulmonary trunk and aorta, blood flows back toward the heart, producing the dicrotic notch (small dip) seen in blood pressure tracings. The semilunar valves close to prevent backflow into the heart. Since the atrioventricular valves remain closed at this point, there is no change in the volume of blood in the ventricle, so the early phase of ventricular diastole is called the isovolumic ventricular relaxation phase, also called isovolumetric ventricular relaxation phase (see image below).

In the second phase of ventricular diastole, called late ventricular diastole, as the ventricular muscle relaxes, pressure on the blood within the ventricles drops even further. Eventually, it drops below the pressure in the atria. When this occurs, blood flows from the atria into the ventricles, pushing open the tricuspid and mitral valves. As pressure drops within the ventricles, blood flows from the major veins into the relaxed atria and from there into the ventricles. Both chambers are in diastole, the atrioventricular valves are open, and the semilunar valves remain closed (see image below). The cardiac cycle is complete. Figure 2 illustrates the relationship between the cardiac cycle and the ECG.

Figure 2. Initially, both the atria and ventricles are relaxed (diastole). The P wave represents depolarization of the atria and is followed by atrial contraction (systole). Atrial systole extends until the QRS complex, at which point, the atria relax. The QRS complex represents depolarization of the ventricles and is followed by ventricular contraction. The T wave represents the repolarization of the ventricles and marks the beginning of ventricular relaxation.

Heart Sounds
One of the simplest, yet effective, diagnostic techniques applied to assess the state of a patient’s heart is auscultation using a stethoscope.

In a normal, healthy heart, there are only two audible heart sounds: S1 and S2. S1 is the sound created by the closing of the atrioventricular valves during ventricular contraction and is normally described as a “lub,” or first heart sound. The second heart sound, S2, is the sound of the closing of the semilunar valves during ventricular diastole and is described as a “dub” (Figure 3). In both cases, as the valves close, the openings within the atrioventricular septum guarded by the valves will become reduced, and blood flow through the opening will become more turbulent until the valves are fully closed. There is a third heart sound, S3, but it is rarely heard in healthy individuals. It may be the sound of blood flowing into the atria, or blood sloshing back and forth in the ventricle, or even tensing of the chordae tendineae. S3 may be heard in youth, some athletes, and pregnant women. If the sound is heard later in life, it may indicate congestive heart failure, warranting further tests. Some cardiologists refer to the collective S1, S2, and S3 sounds as the “Kentucky gallop,” because they mimic those produced by a galloping horse. The fourth heart sound, S4, results from the contraction of the atria pushing blood into a stiff or hypertrophic ventricle, indicating failure of the left ventricle. S4 occurs prior to S1 and the collective sounds S4, S1, and S2 are referred to by some cardiologists as the “Tennessee gallop,” because of their similarity to the sound produced by a galloping horse with a different gait. A few individuals may have both S3 and S4, and this combined sound is referred to as S7.


The term murmur is used to describe an unusual sound coming from the heart that is caused by the turbulent flow of blood. Murmurs are graded on a scale of 1 to 6, with 1 being the most common, the most difficult sound to detect, and the least serious. The most severe is a 6. Phonocardiograms or auscultograms can be used to record both normal and abnormal sounds using specialized electronic stethoscopes.

During auscultation, it is common practice for the clinician to ask the patient to breathe deeply. This procedure not only allows for listening to airflow, but it may also amplify heart murmurs. Inhalation increases blood flow into the right side of the heart and may increase the amplitude of right-sided heart murmurs. Expiration partially restricts blood flow into the left side of the heart and may amplify left-sided heart murmurs. Figure 4 indicates proper placement of the bell of the stethoscope to facilitate auscultation.


The cardiac cycle comprises a complete relaxation and contraction of both the atria and ventricles, and lasts approximately 0.8 seconds. Beginning with all chambers in diastole, blood flows passively from the veins into the atria and past the atrioventricular valves into the ventricles. The atria begin to contract (atrial systole), following depolarization of the atria, and pump blood into the ventricles. The ventricles begin to contract (ventricular systole), raising pressure within the ventricles. When ventricular pressure rises above the pressure in the atria, blood flows toward the atria, producing the first heart sound, S1 or lub. As pressure in the ventricles rises above two major arteries, blood pushes open the two semilunar valves and moves into the pulmonary trunk and aorta in the ventricular ejection phase. Following ventricular repolarization, the ventricles begin to relax (ventricular diastole), and pressure within the ventricles drops. As ventricular pressure drops, there is a tendency for blood to flow back into the atria from the major arteries, producing the dicrotic notch in the ECG and closing the two semilunar valves. The second heart sound, S2 or dub, occurs when the semilunar valves close. When the pressure falls below that of the atria, blood moves from the atria into the ventricles, opening the atrioventricular valves and marking one complete heart cycle. The valves prevent backflow of blood. Failure of the valves to operate properly produces turbulent blood flow within the heart; the resulting heart murmur can often be heard with a stethoscope.
cardiac cycle period of time between the onset of atrial contraction (atrial systole) and ventricular relaxation (ventricular diastole)
diastole:: period of time when the heart muscle is relaxed and the chambers fill with blood
end diastolic volume (EDV): (also, preload) the amount of blood in the ventricles at the end of atrial systole just prior to ventricular contraction
end systolic volume (ESV): amount of blood remaining in each ventricle following systole
heart sounds: sounds heard via auscultation with a stethoscope of the closing of the atrioventricular valves (“lub”) and semilunar valves (“dub”)
isovolumic contraction: also, isovolumetric contraction) initial phase of ventricular contraction in which tension and pressure in the ventricle increase, but no blood is pumped or ejected from the heart
isovolumic ventricular relaxation phase: initial phase of the ventricular diastole when pressure in the ventricles drops below pressure in the two major arteries, the pulmonary trunk, and the aorta, and blood attempts to flow back into the ventricles, producing the dicrotic notch of the ECG and closing the two semilunar valves
murmur: unusual heart sound detected by auscultation; typically related to septal or valve defects
preload: (also, end diastolic volume) amount of blood in the ventricles at the end of atrial systole just prior to ventricular contraction
systole: period of time when the heart muscle is contracting
ventricular ejection phase: second phase of ventricular systole during which blood is pumped from the ventricle
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