Download Lecture 11- Cardiac Output and Venous Return Cardiac Output

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Lecture 11- Cardiac Output and Venous Return
Cardiac Output- The quantity of blood pumped into the aorta each minute by the heart
Venous Return- The quantity of blood flowing from the veins into the right atrium each minute
Venous return and cardiac output must equal each other
Cardiac Function Curves- *
In the Frank-Starling curve, we said that increasing EDV would lead to an increase in Preload.
This increased preload led to increased ventricular filling, increased myocyte stretch and
increased cardiac function
In cardiac function curves, we say that increasing right atrial pressure increases preload,
resulting in increased cardiac output or increased stroke volume
Factors that improve pump functionIncreased sympathetic activity (which increases heart rate by increasing the Funny Current, leading to an
increase in intracellular calcium), decreased parasympathetic activity, physiologic hypertrophy (exercise)
Factors that impair pump functionHypertension (which causes increased afterload), abnormal rates and rhythms, Coronary artery disease,
Congenital heart disease
Venous ReturnThe venous return to the heart is the sum of all the local blood flows through all the individual tissue
segments of the peripheral circulation
Venous pressure is much lower than arterial pressure. The arterial to venous pressure is what drives
blood flow through the circulatory system
Veins have a high capacitance so small increases in venous pressure causes veins to swell with a minimal
increase in resistance
Coronary Artery Bypass Grafts: Occluded coronary arteries can be bypassed by grafting, in reverse
orientation, the Saphenous vein around the blockage
Central Venous Pressure- *
Sympathetic nerve activity on veins lead to increased tone on the
veins. Increased venous tones mean the compliance of the veins is
decreased. As a result, we see an increase in central venous pressure.
This means more blood is returned to the heart, leading to an increase in EDV which (by Frank-Starling)
leads to increased stroke volume. Central Venous Pressure is directly related to volume and inversely
related to compliance, so increased tone (/decreased compliance) means we will achieve a greater
Central Venous Pressure at a lower venous volume
When you are reclining, venous pressure in the legs is less than the Central Venous Pressure in the
thorax. When you stand up, venous pressure in the legs rises rapidly, while the Central Venous Pressure
in the thorax plummets
Orthostatic Hypotension: When you go from sitting to standing, blood pools in your veins. This
decreases venous return to the heart, which means EDV is lowered, meaning there is decreased preload.
If preload is down, cardiac output is down. If cardiac output is down, blood pressure is down. If blood
pressure is down, cerebral perfusion is down, and you feel light headed. [Normally the baroreflex
detects low blood pressure, and increases heart rate and stroke volume, while at the same time
increasing peripheral vasoconstriction]
Skeletal Muscle Pump: Relaxed skeletal muscle allows blood to pool in the veins with high capacitance.
Contraction of skeletal muscle compresses veins, expelling blood along
Respiration: The Respiratory Pump- *
Inspiring decreases the pressure in the thorax. More negative pressure in the thorax allows the Inferior
Vena Cava and the Superior Vena Cava to expand. Blood is sucked back to the heart more rapidly.
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Increased venous return leads to increased right atrial pressure which means more blood is shot into the
right ventricle which means more blood must be pushed out to the lungs. This is why there is a slight
delay in the closure of the pulmonic valve
Expiring or Valsalvaing: I exhale against the glottis. This increases extrapleural pressure. This decreases
transmural pressure which causes the Vena Cava to collapse. This decreases venous return, causing a
reflex response
Exercise increases the rate of skeletal muscle contraction (forcing blood back to the heart) and it
increases the rate of respiration and depth of respiration (blood is sucked up faster back to the heart).
More venous return leads to increased cardiac output
Left Heart Output and Right Heart OutputThey must match. Venous return determines right atrial pressure. Right atrial pressure determines how
much blood is pumped to the lungs, then back to the left ventricle. Left Ventricular EDV is a very
important determinant of cardiac output. So, venous return (leading to Right Atrial pressure) supports
cardiac output…and cardiac output creates venous return
Left heart failure causes pulmonary edema
Right heart failure causes fluid buildup in the Right Atrium and systemic veins leading to jugular venous
distention and peripheral edema
A Refresher on the Cardiac Cycle-
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Left Ventricular Diastole
Time (msec)
0
Electrocardiogram
(ECG)
100
200
300
400
500
600
700
800
Pressure in the left atrium is higher
than that in the left ventricle
(ventricle is filling)
QRS
complex
T
P
P
120
The mitral valve is consequently
open (valve movement is passive).
90
Dicrotic notch
Pressure
(mm Hg)
60
Left
venticular
pressure
30
Left atrial
pressure
0
Pressure in the aorta is higher than
that in the left ventricle.
S1
Heart sounds
S2
S3
S4
The aortic semilunar
consequently closed.
valve
is
135
Left
ventricular
volume (mL)
65
Atrial
systole
Ventricular
systole
Ventricular
diastole
Atrial
systole
Blood is flowing from atrium to ventricle
and from aorta (and arteries) to veins
via capillaries. As a consequence,
pressure in the aorta is falling.
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Aortic Regurgitation- *
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Mitral Regurgitation- *
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Aortic Stenosis- *
SoundsAortic Regurgitation
Mitral Stenosis-*
Mitral Regurgitation
Aortic Stenosis
Mitral Stenosis
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12- Cardiac Function in Disease
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Potassium Levels in the Blood and its EffectsPotassium is usually high in the cell and lower in the plasma
Hyperkalemia: Intracellular potassium levels remain normal, but extracellular plasma concentrations
become elevated . This prevents the efflux of potassium from the cell because the gradient is not as
significant. This causes the membrane potential to become more positive/less negative
Also, the slope of Phase 4 Depolarization is less steep. Remember, the slope of Phase 4
Deoplarization is caused by the influx of sodium via the funny channel. When potassium levels in the
blood are high, the membrane potential is already a little positive, so the gradient for sodium to move
into the cell is reduced
Hyperkalemia increases maximum diastolic potential (it makes the cell more positive, shifting up the
slope on Phase 4)
Essentially, hyperkalemia reduces the heart rate and acts very similar to parasympathetics
Reduced potassium efflux (as a result of Hyperkalemia) increases membrane potential (the membrane
becomes a little more positive)
Depolarization of cardiac cells occurs with hyperkalemia, but depolarization occurs
slower. This causes widening of the QRS complex
Because the membrane potential is more positive, the cell depolarizes.
Once those channels open via potassium they are occupied, and cant be opened
with sodium. This means depolarization is less rapid (less steep slope) and
repolarization begins sooner and at a steeper rate
Repolarization is potassium exiting the cell. In hyperkalemia, potassium
is already high outside the cell. Why would more go out? Well, it turns out the
Inward Rectifying Current that the potassium relies on simply functions better
under high potassium settings. This better function leads to more rapid repolarization.
On the EKG, the T wave happens earlier and is more pronounced ('Tent-shape effect')
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Mitral Stenosis-
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Aortic Stenosis-
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Mitral RegurgitationWhen the left ventricle begins to contract, you start losing volume back to the left atrium
The tall V wave is blood flowing back into the left atrium
Stroke volume is huge, but only a fraction of it is going to the aorta. Cardiac output is reduced
Because cardiac output is down, systolic pressure is down
There is no lub-dub sound, because the valves are not closing. The sound is constant throughout
because turbulent flow is consistent and constant
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Atrial RegurgitationThe aortic valve opens earlier because diastolic pressure is lower. Because some blood goes systemic
and some comes back into the Left Ventricle. So blood has two paths where it can go, pressure drops
more rapidly and to a lower level. Because diastolic pressure is then lower, the aortic valve opens earlier
than it normally would
Abnormal murmur is heard due to turbulent flow of blood back into the Left Ventricle
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Lecture 13 & 14- Microcirculation I and II
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CapillariesCapillary diameter is barely bigger than RBCs. The individual cross sectional area of capillaries is
extremely small, but the total cross sectional area of Capillaries is far and away the largest in the body.
Velocity of blood flow depends on the total cross sectional area, so the large total cross sectional area
means that blood flow velocity is very slow through the capillaries
Diffusion and Bulk Flow account for most capillary exchange. Diffusion is from high concentration to low
concentration through fenestrations. Bulk Flow is driven by blood pressure, and again is through
fenestrations/pores and intercellular junctions
The metarteriole regulates blood flow into the capillary beds. Capillaries lack smooth muscle so they are
incapable of active constriction
Fick's LawUsed to describe capillary diffusion. A greater surface area or a greater concentration gradient or a
decreased membrane thickness leads to a faster rate of capillary diffusion.
In pulmonary congestion, were there is fluid in the alveoli, oxygen and carbon dioxide in the lungs have
to diffuse a greater distance (now across fluid instead of just dead space), so there's issues
Hydrostatic Pressure- (P)
Blood enters a capillary at high pressure from the arteriole side, forcing fluid out of the capillary and into
the interstitium
Osmotic Pressure- (π)
Blood proteins (albumin and globulins) trap and hold large volumes of water in the capillary
The Krough CylinderIn skeletal muscle, at rest, few capillaries are open and there is a large intercapillary distance. During
activity, more capillaries dilate, so the distance between capillaries decreases. Thus, the radius of the
functional Krough Cylinder decreases as more capillaries are recruited (which increases the levels of
oxygen in the exercising muscles because diffusion distances decreases as cylinders have smaller radii)
Fluid FluxFiltration: Out of the capillary into the interstium
Absorption: Out of the interstium into the capillary
The net filtration pressure= [(PC - Pi) - (πC - πi)] High pressure in the capillary will cause a net flow out
of the capillary, into the interstitum. High interstitial pressure will result in fluid reabsorption. Fluid
leaving the capillary is positive (out). Fluid entering the capillary is negative (in)A + net filtration pressure
means fluid is leaving the capillary. A - net filtration pressure means reabsorption
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Sprained Ankle:
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Lymphatics-
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How is lymphatic fluid pumped throughout the body: the Skeletal Muscle Pump, the Respiratory Pump,
the Peristaltic Action of the GI tract, the Pulsation of arteries that are adjacent to the lymph vessels
EdemaNormally fluid that leaks into the interstitum is returned via the lymphatics. Edema is the accumulation
of fluid in the interstitum
An increase in capillary hydrostatic pressure (P) pushes fluid out of the capillaries
A decrease in plasma protein concentration would lead to more fluid escaping the vasculature
An increase in interstitial proteins pulls fluid into the interstitium
Two causes of Edema: Filtration > Absorption
or Inadequate drainage of lymph
Left Heart Failure: In left heart failure, blood backs up into the left atria, and then further back into the
pulmonary capillaries. This causes increased hydrostatic pressure in the pulmonary capillaries, so fluid is
forced out of the capillaries, leading to pulmonary edema
Right Heart Failure: The right ventricle fails, blood backs up into the systemic veins, increasing central
venous pressure. Hydrostatic pressure increases throughout the lower extremities and abdominal
viscera, causing ascites
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Kwashiorkor: Starvation leads to lack of dietary protein. This means there's less albumin in the plasma.
This leads to a decreased osmotic pressure in the capillaries (c). That causes Ascites.
Nephrotic Syndrome: Renal disease in which protein is lost in the urine
Pregnancy: The mother cannot synthesize plasma proteins fast enough to keep up with fetal demands,
so fluid leaks from the capillaries into the interstitial space, causing edema
Dehydration: There is a deficit of salt and water, leading to increased osmotic pressure/blood proteins in
the capillaries. This draws fluid into the capillaries, depleting interstitial fluid. This leads to reduced
turgor or 'not springy skin' when pinched
Inflammation: An immune response leads to the release of histamine and cytokines, both of which are
vasodilators. These increase the number of open capillaries which increases filtration
Elephantiasis: Extreme edema that occurs when lymph vessels become blocked by filarial worms
(transmitted by black flies and mosquitoes)
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Lecture 15- Using Exercise to Integrate Control of the Cardiovascular System
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Heart RateThis figure represents the relationship between heart rate and increasing work load. Work load is
expressed as the oxygen consumption required to perform the work. Heart rate is under the influence of
the autonomic nervous system (individuals with heart transplantation and quadriplegia do not have
autonomic innervation to the heart; however, the individual with quadriplegia has intact cardiac
parasympathetic innervation)
Decreases in cardiac parasympathetic efferent activity and/or increases in cardiac sympathetic efferent
activity increase heart rate. At the onset of exercise, there is a centrally mediated simultaneous
activation of the cardiovascular and motor centers (central command), causing an initial rapid increase
in heart rate due to withdrawal of parasympathetic efferent activity. Once heart rate reaches - 100
beats/min, there is a further increase in heart rate due to activation of cardiac sympathetic efferent
activity
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Stroke VolumeStroke volume is a function of: Venous return, Cardiac sympathetic efferent activity, Circulating
catecholamines and Afterload
During exercise, venous return increases because of an increase in the activity of the muscle venous
pump. Consequently, end-diastolic volume increases and causes a stronger systolic contraction of the
ventricle, in accordance with the Frank-Starling law. During exercise, cardiac sympathetic efferent
activity also increases. Stroke volume increases during exercise, reaching a maximum at 40-45% of the
oxygen uptake at maximum exercise (VO2max). Finally, stroke volume can also increase slightly because
of the effect of circulating catecholamines activating beta 1-adrenergic receptors on the myocardium
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Physiological v Pathological HypertrophyPathological Hypertrophy- Thickened wall without an increase in the size of the ventricle
Physiological Hypertrophy- Thickened wall while ventricular volume also increases. This does not result
in an increase in wall stress, so Cardiac Output actually increases
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Myocardial O2 ConsumptionChanges in stroke volume have smaller
effects on Myocardial VO2
consumption than do changes in
heart rate, aortic pressure and
inotropy
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Lecture 16 and 17- Special Circulations I and II: Local Control of Blood Flow
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Metabolic Theory:
Increased tissue metabolism (increased tissue activity) leads to increased metabolite production. These
metabolites act decrease arterioles resistance by increasing vasodilation, resulting in increased blood
flow
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Myogenic Theory:
Remember, Pressure= Flow x Resistance
Increased arterial pressure leads to increased arteriolar pressure leading to increased arteriolar wall
stretch. When vascular smooth muscle is stretched, it depolarizes. Depolarization increases calcium
entry and promotes contraction of the smooth muscle. Smooth muscle contraction leads to increased
arteriolar resistance, and this helps maintain blood flow (because remember pressure=flow x resistance)
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Autoregulation of Blood FlowAutoregulation is the intrinsic ability of an organ to maintain a constant blood flow despite changes in
perfusion pressure (remember, Perfusion Pressure = MAP - Central Venous Pressure). The
autoregulatory range is the range of pressure over which there is little if any change in blood flow. The
three organs where we normally see flat curves (because these organs need consistent levels of blood)
are the Brain, the Kidneys, and Coronary vessels
Example, blood flow to an organ is too low. In order to increase blood flow
to that organ, we use a myogenic or a metabolic mechanism to decrease
the resistance of the vessel, which allows blood to flow more freely
Blood flow to an organ is proportional to its metabolic activity. Increased
tissue metabolism leads to increased production of vasoactive metabolites . This
production of things like Adenosine, Lactate, CO2, H+,etc cause vasodilation which leads to increased
blood flow to that organ. We call this 'Functional Hyperemia' or 'Active Hyperemia'
Reactive Hyperemia, on the other hand is this- A transient bout of ischemia (ischemic stroke, torniquet
after a snake bite, etc) cause tissue hypoxia because there is no blood flow to that organ. Vasoactive
metabolites build up on the other side of the occlusion, and once blood flow is returned to the occluded
tissues, vasoactive metabolites rush in as well. So not only is blood flow returned, but there are also
vasodilatory metabolites rushing in which causes even more blood flow to the organ. The longer the
period of occlusion, the greater the post-surge above the baseline
How do we protect capillaries from surges in arterial pressure? Stretch-induced contraction
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Coronary CirculationDuring Diastole: Epicardial coronary vessels (those that run along the outer surface of the heart) and
subendocardial vessels (those that run along the internal surface of the heart) remain patent/open. This
allows blood from the vessels to flow down into the more center of the heart. Most myocardial blood
flow occurs during diastole
During Systole: Subendocardial coronary vessels are compressed due to the high intraventricular
pressures → blood flow in the subendocardium nearly stops because blood is forced back towards the
surface of the heart and eventually the aorta. This is why subendocardial regions are more succeptible
to ischemic injury when coronary artery disease or reduced aortic pressure is present
At rest, the heart extracts 70-80% of oxygen its presented with. Skeletal muscle extracts much less, but
when we start to exercise, skeletal muscle dramatically increases the amount it extracts
Coronary Reserve: When the demand for cardiac output increases, say for something like running, the
Coronary Flow Reserve provides the increased blood flow to the heart to meet the increased myocardial
activity
At rest, in the heart, 20% of precapillary coronary sphincters are open. All of them cycle between open
and closed. During maximal exercise, all precapillary sphincters are in the open position and net
coronary flow is 100% of maximum. (Sphincters are composed of smooth muscle and are regulated by
local metabolite concentrations)
An example of Active Hyperemia in the Heart: Increased metabolic activity, insufficient coronary blood
flow, or decreased myocardial PO2 all cause the release of Adenosine. Adenosine induces coronary
vasodilation which leads to increased coronary blood flow. Coronary blood flow can now keep up with
Myocardial O2 consumption
Intrinsic Control: Increased coronary blood flow causes shear stress. Shear stress causes the release of
nitric oxide from the endothelium. NO activates Guanylate Cyclase, which becomes cGMP, which
activates PKG which phosphoralizes MLK (inhibiting smooth muscle contraction) and SERCA (increasing
the reuptake of Calcium) leading to vasodilation
Extrinsic Control: Sympathetic nerve activity on cardiac β-1 adrenergic receptors increases heart rate
and contractility. This increases myocardial work, increasing metabolite production, leading to
vasodilation. On the flip side, sympathetic nerve activity on coronary α-1 receptors leads to
vasoconstriction. So, sympathetic nerves can modulate coronary blood flow, but their influence is
overridden by local control (i.e., intrinsic mechanisms)
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Cerebral CirculationIntolerant of ischemia. Shuts down with anoxia. Interruption of flow for 4-5 min can cause organ failure
and death
Regional Blood Flow Patterns: Cerebral blood flow is tightly coupled to oxygen consumption. Normally,
increased metabolic activity leads to increased blood flow and resultant tissue expansion. The cranium
wouldn’t allow that in the brain, so blood flow simply increases to areas of the brain where the most
neurons are most active. Total flow is always constant. This is an example of Active Hyperemia
Cerebral blood flow is very sensitive to small changes in PCO2. Remember, CO2 is a vasodilator. So when
you exercise and increase metabolite production, you increase CO2 levels and actually increase cerebral
blood flow (this is also why blowing into a paper bag works). If you blow off too much CO2
(hyperventilation) your cerebral blood flow decreases and you become lightheaded
Arterial blood gas for PO2 should be high (~98), but PCO2 is still potent at low (~40)
In chronic hypertension, cerebral vascular resistance increases to allow for normal capillary perfusion
pressures. Overtime, this contraction causes the vascular smooth muscle to hypertrophy, causing a
decrease in luminal diameter. This impairment of autoregulation slows down the ability of cerebral
vessels to vasodilate. So, say there were a decrease in blood flow, the vessel would normally dilate, but
now it cant
Cushing's Reflex: An increase in intracranial pressure (tumor, trauma) compresses brain vasculature.
Brain perfusion is decreased and hypoxia occurs. When the pons and medulla sense hypoxia, they
activate the sympathetic autonomic control centers. The heart beats harder and arterial blood pressure
rises, causing an increase in cerebral blood flow. One problem, this increases microvasculature pressure.
Now there is increased hydrostatic pressure, fluid is forced out of capillaries, cerebral edema occurs, ICP
rises, bang your dead
Cerebral Blood flow is controlled almost exclusively by local metabolites. Co2 is the key
Myogenic control plays an autoregulatory role
Sympathetic neural control is minor
Splanchnic CirculationLiver, Spleen, Stomach, Pancreas, Small Intestines, Colon
The portal vein drains most blood from these organs to the liver, where the blood is filtered
Local Controls of Splanchnic Blood Flow: Increased blood flow following a meal may be triggered by
metabolites, GI hormones, products of digestion, etc. Poorly understood mechanism
Central Controls: The parasympthetic nervous system increases blood flow both in anticipation and
while digesting a meal (classic “rest-and-digest” response), while the sympathetic nervous system
constricts all splanchnic vascular beds during “fight-or-flight” responses
Almost 15% of blood in the body is held in this system. In mild sympathetic stimulation, flow is
decreased to the organs. In strong stimulation (i.e. vigorous exercise) there is a decrease in splanchnic
flow 75% and venoconstriction forces 250 ml of blood from the splanchnic organs
In Intense Sympathetic stimulation (Hypovolemic Shock) you cut off an arm. Blood volume decreases.
The ventricles don’t fill up as much, so cardiac output drops. This leads to a decrease in arterial pressure.
Baroreceptors pick this up and increase sympathetic outflow. Increased sympathetics cause a decrease
in Sphlanchnic blood flow. No blood to these organs means the integrity of the intestinal lining is
compromised. Materials from the gut enter circulation and you go into septic shock
Normally the splanchnic circulation is a venous reservoir for blood. In cases of long-term sympathetic
activity (stress), you increase sympathetic tone on the veins, so venous volume drops, meaning arterial
volume has to rise. This is what we call hypertension
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Cutaneous CirculationIn a cold environment, vessels in the dermis constrict, forcing blood away from the skin, trying to keep
heat in the body
In a warm environment, vessels dilate incredibly largely. In fact, during severe heat stress nearly 60% of
cardiac output is compromised of blood flow to the skin (skin has enormous vasodilatory capacity)
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Lecture 18- Systolic Heart Failure
The following graph represents the Frank-Starling relationship for the Left Ventricle in a patient with a
Myocardial Infarction
Increased capillary wedge pressure- MI impairs stroke volume. This means ESV in the
ventricle is elevated because not as much blood is ejected with each contraction. So,
pressure builds up in the Left Ventricle. Well, that means pressure also builds up in the
Left Atrium in order to maintain the pressure gradient between the LV and LA
Decreased ejection fraction- Not as much blood is ejected because the myocytes are
dead
Decreased pulse pressure- (Pulse Pressure= Systolic- Diastolic). Stroke volume correlates
directly with systolic pressure. In a patient with an MI, stroke volume is reduced. This means Systolic
pressure is decreased. And this means that pulse pressure is decreased
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This graph shows the MI patient, after being administered Digoxin/ Digitalis
Digoxin inhibits Na/K ATPase. This causes Na levels in the cell to rise. In addition
to Na staying high inside the cell, thanks to the busted transporter, calcium
levels inside the myocyte stay high. This leads to increased muscle tension and a
positive inotropic effect (increased contractility)
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EKG Differences in a patient with an MI
ST Segment Elevation- Indicative of current or recent coronary
ischemia. Ischemia means there is less oxygen available. This
means the ATPase gets shut down. So, the membrane is now
permanently closer to a depolarized state
Q Waves- Depolarization occurs from endocardium to
ectocardium. Negative deflections are caused by depolarization
moving away from a lead. Q waves are indicative of necrotic
tissue (probably from a previous MI) because necrotic tissue
cannot polarize or depolarize. So it cannot send out a depolarization cascade, meaning the Q wave is
increased in that patient because it doesn’t have equal depolarization from all aspects of the heart
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Pulmonary Capillary Wedge PressureThe wedge is wedged in the pulmonary artery
It is measuring Left Atrial pressure
There is not too much of a difference in pressure between the
Pulmonary arteryCapillary BedPulmonary Vein Left Atrium, so
measuring in the pulmonary artery gives you a fairly good estimation of
what pressure is in the left atrium
Why is Left Atrium pressure Increased? He had an MI. This impairs heart
function, and decreases Stroke Volume. He's not ejecting as much as
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what was filled. Decreased stroke volume means more blood is left in the ventricle, causing an increase
in ESV. That causes Left Ventricle pressure to increase. In order to maintain the pressure gradient, Left
Atrium pressure must increase in order to get blood into the Left Ventricle
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Pulmonary Edema is caused byHigh hydrostatic pressure in the capillaries forces fluid out of pulmonary capillaries and the fluid
accumulates in the alveoli
Fluid in the alveoli increases the distribution distance, so there is decreased O2 diffusion in the
alveoli
This leads to hypoxemia (which is low PO2)
Hypoxemia causes hypoxia (good blood flow, but there is not enough O2 in the blood)(whereas
Ischemia= O2 levels in the blood are good, but there is reduction of blood flow)
Hypoxia leads to hypoxic vasoconstriction: Shunting of blood away from the fluid-filled alveoli
If you have capillary damage, then you may begin to release protein into the
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Dyspnea and OthopneaDyspnea is shortness of breath and difficulty breathing, related to the accumulation of pulmonary
interstitial fluid
Orthopnea is dyspnea is precipitated by lying down
In a standing patient, blood pools in the lower extremities in the veins which are very compliant. When
you lie down, blood is now distributed throughout all the veins, not just those in the lower extremities.
Since there is more blood in the veins near the heart, lying down increases venous return. This causes an
increase in Right Atrial pressure. This leads to an increase in Right Ventricle end diastolic volume. This
increases pulmonary arterial and capillary pressure, which in turn worsens pulmonary venous
congestion
Usually when sitting, your venous return is, say, 10. When you stand up, gravity sucks blood down into
your legs, and now your venous return is 2. Because there is not as much venous return, we have the
opposite of the Frank-Starling mechanism, so we have decreased stretch, decreased stroke volume,
decreased cardiac output, decreased blood pressure. The baroreceptors sense this drop in pressure,
then they increase heart rate, increase venous return (although not above what venous return was
when you were sitting, because gravity is still in play), increase contractility, increase peripheral
vasoconstriction and increase venoconstriction
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Short-Term Compensatory Changes in response to lowered MAPNormally, we can increase mean arterial pressure by a cardiac component or by a vascular component.
In a patient with an MI, the baroreflex is inhibited because even when nerves signal the heart to
increase heart rate and cardiac output, the heart muscle is so damaged that it cannot increase
contractility. So, the only way to increase mean arterial pressure to normal levels is by sympathetic
nerve activity causing an increase in vascular resistance. Great, but now you've increased afterload, so
an already dead heart has to work harder to pump blood out against resisted vessels
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HypertrophyConcentric hypertrophy: Seen in patients who have hypertrophy due to increased vascular resistance
Eccentric hypertrophy: Seen in patients who have ventricular hypertrophy/ dilation due to volume
overload. In patients with an MI, there is systolic dysfunction. This means more blood is left in the heart
after systole (increased ESV). In order to accompany the more blood, the ventricle dilates or
hypertrophies. This increases the chamber diameter, decreases wall thickness, and increases wall stress
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Heart SoundsIn a patient with an MI, you hear a 3rd heart sound during early diastole
3rd heart sound may occur during early diastole when there is rapid,
turbulent filling of a dilated ventricle
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Long-term Compensatory Changes to a low MAPThese would all be hormonal changes in order to cope long-term
Decreased arterial pressure is detected and leads to increased
sympathetic activity. Increased sympathetic activity leads to
increased release of Angiotensin II, Aldosterone, and Vasopressin,
all of which increase systemic vascular resistance and increase
blood volume. Increased blood volume leads to increased venous pressure,
which over time pushes fluid into the lungs, causing pulmonary edema and systemic edema
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Lecture 19- Diastolic Heart Failure
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Chronic HypertensionChronic hypertension leads to increased afterload. In order to create
enough pressure to force blood into the aorta, the left ventricle must
work harder, and create more pressure. As per the equation, this
would increase wall stress. But by thickening the wall
(concentric Left Ventricle hypertrophy), we actually counterbalance
the increased Left Ventricle pressure, so wall stress in a chronically
hypertensive patient does not increases that much
Hypertrophy does cause a ventricle to become less compliant (Compliance= ∆V/ ∆P)
Decrease in ventricular diameter leads to less filling. Ejection fraction is still fine, it just fills less during
diastole, so stroke volume is decreased
Two Types of Left Ventricle Hypertrophy1.Hypertension: Due to pressure overload. This leads to symptomatic heart failure with normal ejection
fraction. End diastolic volume decreases because the lumen of the ventricle is smaller. So stroke volume
is less (Frank-Starling). But decreased EDV and decreased Stroke Volume, both reduced to the same
degree, means that the the percentage of available blood actually being ejected is normal (Ejection
fraction)
2. MI: Due to volume overload. This leads to symptomatic heart failure with low ejection fraction
because the heart muscle is not strong enough to eject the increased ESV present in the ventricle
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Heart Sounds for a patient with Diastolic Failure4th heart sound during atrial contraction
Produced when atrium contracts against and tries to fill a
non-compliant ventricle (i.e., stiff ventricle) as occurs with
ventricular hypertrophy
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Heart Rate in a Healthy PersonAt rest there is higher parasympathetic tone than sympathetic tone. This keeps the heart rate at ~80
If we block sympathetic and parasympathetic stimulation to the heart (β-adrenergic and muscarinic
receptor blockade), the heart rate jumps up to ~105
At onset of exercise there is rapid parasympathetic withdrawal ('Vagal Withdrawl') that causes HR to rise
Removal of parasympathetic activity allows HR to rise. Once it gets above 100 beats/min, the
sympathetics kick in and any increase is due to a rise in efferent sympathetic nerve activity and
circulating catecholamines
Heart Rate in a Heart Failure SubjectParasympathetic activity is depressed, while sympathetic activity is increased
Sympathetic nerves release high levels of norepi. You would think that would jump heart rate, but there
is actually down regulation of β-adrenergic receptors in heart failure patients which is the body's way of
buffering the barrage of norepi that’s hitting β-adrenergic receptors
There is a decrease in Intrinsic HR in heart failure patients, for unknown reasons
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Patient with heart failure: Higher resting heart rate, due to decreased parasympathetic tone and
increased sympathetic tone
Patient with heart failure: Slower increase in heart rate at a given workload, due to decreased reserve
for parasympathetic withdrawal (we've already removed most of it, we can't remove a lot more) or
decreased reserve for sympathetic activation, and attentuated β-adrenergic responsiveness
Patient with heart failure: Maximal heart rate is markedly lower, due to decreased sympathetic reserve
(the sympathetics are already on. So theyre starting at a higher baseline. If we want to jump up heart
rate to 10, but we have already used up 5 points of sympathetic stimulation to begin with, we don’t
have as much ammo to ramp things up if we need to), attenuated β-adrenergic responsiveness, and
decreased exercise tolerance
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Stroke Volume and Responses to Exercise-
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Concentric Hypertrophy increases myocardial O2 consumption
Less blood is pumped out, but it still requires the same amount of oxygen---------------The mass of the Left Ventricle increases to normalize wall stress. This increased mass
requires more myocardial O2 consumption. Wall stress is normalized, but….
Left Ventricle compliance is decreased
Left Ventricle filling pressure is increased
EDV and Stroke Volume are decreased
So, systolic function is fine, but stroke volume and cardiac output are both decreased because the heart
can only eject the amount of blood it receives during filling
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Mean Arterial Pressure= Cardiac Output x Peripheral Resistance
Cardiac output in patients with heart failure is decreased. The amount of depreciation is more
pronounced the more that workload increases (workload up, CO down)
Peripheral resistance in patients with heart failure is higher, due to the baroreflex. Because they have a
markedly lower maximal heart rate, CO is down and heart rate is down. The body responds by increasing
peripheral vascular resistance
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Systolic Arterial Pressure: Decreased in heart failure patient because stroke volume is markedly
decreased (systolic pressure is reliant on stroke volume)
Mean Arterial Pressure: Decreased in heart failure patient. This is because in a heart failure patient, the
decrease in systolic pressure is greater than the increase in diastolic pressure. As a result of a lowered
MAP, there is decreased perfusion pressure of skeletal muscle during exercise. This stimulates the
baroreflex and metaboreflex, both of which increase peripheral resistance
Diastolic Arterial Pressure: Increased in heart failure patients because peripheral resistance in heart
failure patients remains relatively high (a key determinant of diastolic pressure is peripheral resistance)
Skeletal Muscle Blood FlowPatients with heart failure typically have exercise intolerance. This may be because
Blood flow to skeletal muscle is reduced (due to the increased sympathetic efferent activity which
causes vasoconstriction). This decreases the perfusion pressure
Also, in heart failure there is increased O2 extraction which leads to a decreased extraction reserve. In
heart failure, skeletal muscle begins to extract oxygen from the blood at a much lower workload. When
the workload increases, there isn't lots of oxygen left in the blood to keep up because we pulled it all out
much earlier in the game ----------------------------------------------------------------------------
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Lecture 20- Genetic Disorders of the Circulatory System
Collagen and Elastin are responsible for the unique stretch properties of arteries
Windkessel Effect: Wall deformation acts as pressure reservoir
Anisotrophy : Forces are moved in specific directions
Viscoelastic: Both resists stretch, and stretches; also creeps in response to a force
Hysteresis: Identical force doesn’t produce identical stretch
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Collagen Vascular PropertiesAs the artery is stretched at a specific blood pressure, it increases in diameter. When the pressure
returns back to normal levels, the artery maintains a greater diameter than when pressure was low. It's
kind of like putting a weight on a rubber band, which stretches the band, but when you remove the
weight the band is still stretched
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Collagen and Its LocationType III Collagen in the adventitia of most arteries. Type III Collagen is also in the intima media of large
vessels such as the aorta
Collagen by itself has left-handed helical structure. When we twist three collagen proteins together,
they form a right-handed triple helix called tropocollagen. Tropocollagen has the structure of Gly-X-Y .
X is frequently Proline
Y is frequently Lysine
The process of cross-linking collagen molecules is dependent on Vitamin C
Tropocollagen/ Collagen triple helices are bundled together into Fibrils
Fibrillin protein (Chromosome 15) connects collagen sheets (outside cell layers) to cell membranes –
forming layers in the artery
Anchor is necessary for collagen tension & normal function
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Erlers-Danlos SyndromeA group of genetically heterogeneous disease characterized by skin, joint and internal organ fragility
Most EDS mutations involve mutations of proteins that are involved in Extracellular Matrix
formation
EDS Type IV (Vascular EDS)- Autosomal dominant, COL 3A1 gene on Chromosome 2q31. Decreased or
defective type III collagen, making it not as effective. Vascular-thin translucent skin, extensive bruising,
small joint hypermobility, high risk for arterial and bowel rupture, placenta rupture (pregnancy),
Characteristic facial appearance with thin lips & philtrum, thin nose, small chin, and large eyes.
Commonly will see arterial rupture in the 3rd or 4th decade
Most common arteries to undergo aneurysm and dissection are visceral arteries and illiofemoral
arteries
Heritable Disorders of Connective Tissues (HDCT)Hundreds of different conditions, and all are clinically distinct based on different mutations in the same
gene
Marfan’s Syndrome- Autosomal dominant, mutation of the Fibrillin 1 gene on Chromosome 15. Patients
have ligamentous laxity and joint hypermobility, scoliosis and kyphosis of the spine. Pectus excavatum
or Pectus carinatum, Ectopia lentis (dislocation of the lens of the eye), Gluacoma and cataracts
In the heart, mitral valve prolapse and dilation of the ascending aorta/ aortic dissection are
common
The key finding in Marfan's Syndrome is stiff aortic walls. Why?......
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Fibrillins are in microfibrills that are widely distributed in extracellular multi-molecular
complexes, and are important because they allow connective tissue to be elastic. Marfan mutations
affect the structural integrity of fibrillin or it’s ability to participate in cellular complexes. So, tissues
don’t adhere well and normal forces across arterial walls result in shear , leading to aortic dissection.
In addition to aortic dissections, collagen sheets are not anchored well and do not undergo
effective repair, which results in degeneration of heart valves (particularly aorta and mitral) that lead to
murmurs & insufficiency
Familial Hypercholesterolemia Cholesterol and LDLs are deposited around the iris (corneal arcus), around the eye (xanthoma) and in
tissues especially the Achilles
LDLs are 'Balls of Lipid' composed of Cholesterol, phospholipid & apo B-100 on surface with a
cholesterol ester in core. Larger, “fluffy” LDLs= less atherogenic , Smaller, dense LDL = More atherogenic
Normally receptors on the liver binds to the ApoB-100 on LDL molecules and the LDL are
ingested into the liver via clarithin coated pits, then digested by lysosomes, and then the lipids are
processed
Defects in the ApoB LDL receptor result in decreased LDL clearance from circulation and
increased plasma levels of LDLs
There are 4 classes of LDL Receptor deficitsClass I - Null synthesis
Class II - Transport defect, Intracellular transport from ER to Golgi blocked
Class III - Binding defect, Proteins are synthesized & transported to cell surface, but binding of LDL is
defective
Class IV - Uptake defect, Surface proteins bind LDL normally but receptors do not cluster in coated pits
When there are lots of LDL molecules floating around in the blood plasma, they bypass the epithelium of
blood vessels and get under the surface. Here, the LDL molecules are ingested by phagocytosis and
stored in foam cells. These foam cells build up, forming an atheroma
Blood passing through these narrowed vessels leads to bruits
A fibrous cap forms over the atheroma inside the vessel. If this cap ruptures, the vessel throws a
clot and can lead to vascular obstruction
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