---start physio 1.16----

so we're picking up where we stopped yesterday p 9 of the "biophysical 
principals of circulation" handout. Cardiac performance

HEART FAILURE: primarily due to decrease in contractility, which shows up 
as drop in maximum pressure that can be acheived by heart. So 
pressure/volume curve shifts to right. so you can't pump out as much 
blood with each stroke: your stroke volume is going to decrease. so you 
decrease SV because ESV is greater - so, soon, EDV will go up, because 
heart isn't emptying during systole. Now if heart failure were mild, this 
could be a total compensatory measure, compensating for the SV in this 
way (increasing EDV). But with severe heart failure, this compensation 
isn't enough. Ejection fraction goes way down. You end up with a heart 
that is stretched, dilated, not pumping efficiently. this stimulates the 
sympathetic NS which increases the HR but this dosn't compensate enough 
and you do see decreased CO.

Now, during exercise, you get a huge increase in sympathetic outflow 
which increases sympathetic outflow, so pressure volume curve shifts to 
LEFT. So this increases contractility/max pressure. HR goes up too, 
though. So less time is available for filling. EDV decreases due to 
decreased filling time. But, increased contractility means ejection is 
stronger, so SV is not greatly reduced, it's a little reduced. the 
increase in HR is huge, so you see a big increase in CO. this is driven 
by the sympathetic NS. same thing tht causes the increase in 
contractility. now, if you just PACE the heart rapidly with a pacemaker, 
you don't have the sympathetic outflow. what happens? Well:

when you pace muscle faster there is a staircase effect. the amplitude of 
contractions increases until you reach steady state. so there's a minor 
increase in contractility. But the main mechanism is that EDV DECREASES 
as above due to decreased time interval for filling. this of course 
decreases the stroke volume. But the increase in HR balances the decrease 
in SV and you see that the CO doesn't change; this is true over a fairly 
wide range of HR.

starling compensation for an increase in afterload
if contractility isn't changed, but you have an increase in peripheral 
resistance, what happens is BP increases, aortic pressure increases, 
afterload increases, and now heart has to generate more pressure to open 
the valve for ejection. So you end up RAISING the ESV, which in turn 
raises the EDV up to a level at which the stroke volume is exactly 
compensated for. In other words, the stroke volume will remain unchanged 
via this "starling compensation" mechanism. recall from sweeney's lecture 
[argh. people next to me are talking and i can't hear the lecturer. i 
wish everyone would shut up.] the length tensiion stuff. anyway, so, by 
dilating the heart, you can increase the force of contraction and you 
don't lose contractility, so this mechanism causes total compensation - 
everything stays the same.


LA PLACE rlationship./ Law of La Place.

pressure within a vessel of some kind and tension in wall of vessel.
you have an elipsoid vessel

P = T[(1/Ri + 1/Rii)

in sphere: P = 2T/R

in thick walled ventricle
P = 2th/R

(T=tension, t=tensile strength, h=thickness, R = radius)

as thickness decreases, the tension increases and as radius goes up, 
tension goes up.

so in a dilated heart, you have increased tension in the wall. So to do 
external work, you have to generate more tension per muscle cell, so you 
need more oxygen and you have to do more work.

now if you take the ellipsoid and make it a cylinder, you get P = T/R 
because one radius is infinitely larger than the other [huh?][he just 
gave a better explanation of why one radius drops out, but he said it in 
answer to a question that he didn't repeat - eg, he said "yes, that's 
right, thanks for clarifying" and he didn't repeat the point, so I have 
no idea what it was :( and these people are STILL talking. argh.]

now if you make a thick walled cylinder
P = th/R

for a given pressure P, the larger the vessel the more tension in the 
wall, the thinner the wall, the more tension in the wall at a given 
pressure.

Examples: 

NORMAL VENTRICLE:
t=PR/2h
P=100mmHg aka 133 kdyne/sqcm.
R=3.0 cm
h= 1.0 cm
so t=200 kdyne/sq cm.

if you increase the radius, eg DILATE the heart:

h = .7 cm
R= 4.0 cm
P= 100 mmHG
t=380 kdyne/sq cm --> so it's got much more tension

now if it hypertrophies such that

R=4.0 cm
h=1.3 cm
t=205 Kdyne/sq cm
so we can see that HYPERTROPHY is a good compensation for dilation.

NORMAL AORTA
P=133 kdyne/sq cm
R= 0.7 cm
h=0.4 cm
t=233 kdyne/sq cm

if aneurysm exists and it dilates
R=1.5 cm
h=0.2 cm
t=998 kdyne/sq cm and THAT is why aneurysms burst!

p 12 has vessel chart showing radii, wall thickness, etc for aorta, 
arteries, capillaries, venules, veins, and vena cava
this is for people of course (why is EVERYTHING WE LEARN about people? we 
should get MDs also!)

now, thickness/radius measures how well it can support tension. the 
larger the number, the more tension it can support.
elastin and collagen: if you did a length tension curve on these 
substances, elastin you'd see as you change the length, the tension 
changes directly, very springlike. but collagen, as you add tension, the 
molecules uncurl and get longer and become very stiff and then you can't 
lengthen them. now vessels have BOTH of these substances.

AORTA: large radius, thick walled
ARTERY-larger thickness: radius ratio
ARTERIOLES-largest thickness: radius ratio
caps, venules, veins, vc not good at supporting tension. 

see graph volume/pressure of aorta and veins. veins usually mostly 
collapsed, if you increase pressure will increase volume, then reach 
limit - is collagen rich. but aorta looks more like elastin curve...as 
you increase pressure volume increases, and it takes lot of pressure to 
cause volume change because it is already round, not sitting there in 
collapsed state.

in aged aorta elasticity is decreased, it is stiffer, so there is a 
steeper pressure/volume relationship, takes MORE pressure to change 
volume.

smooth muscle prominent in arterioles which are so important in providing 
resistance, regulating blood flow to various capillary beds, and 
maintaining BP.

capillaries have only endothelium, none of other stuff. see handout.

P 13 has diagram of diff kinds of vessels. note the smooth muscle 
(circles along vessel) on arterioles. changes in diameter of these 
vessels regulate total peripheral resistance. the metarterioles feed into 
capillary beds. note the precapillary sphincter which can turn off blood 
flow to the capillary bed. and thoroughfare channels can bypass the 
capillary beds. capillary beds undergo vasomotion - can open and close. 
in skeletal muscle, most of capillary beds stay closed most of the time 
because they are generally undergoing vasomotion.

arteries: sustain pressure changes
veins: sustain volume changes

capillary endothelial types p 14

continuous: small or nonexistent fenestrations; found in tisues requiring 
passage of gases and nutrients required in their own metabolism; found in 
muscle, heart, lungs, cns, fat, CT.

fenestrated: larger endothelial gaps; found in tissues passing materials 
not solely involved in tissue's own metabolism; eg renal glomeruli, 
glands, ciliary body, choroid plexus, intestinal mucosa

discontinuous: very large fenestrations; found in tissues passing large 
discrete components; bone marrow, liver, spleen. bone marrow is making 
blood cells, for example, that need room to pass across the endothelium, 
etc.

note: fenestration = gap between endothelial cells.

HEMODYNAMICS:
VISCOUS NEWTONIAN FLOW
blood flowing in vessels is like any liquid in a tube. molecules tend to 
remain streamlined, not move radially. 
but molecules assume parabolic velocity profile as seen on p 1 of 
hemodynamics handout. because you have many concentric cylindrical 
lamellae - outermost has zero velocity, next one in is moving a bit 
faster, next one in still faster, etc etc. so the more central lamellae 
move faster hence the parabolic profile is due to this velocity gradient. 
newton formalized the mechanism of this occurance by stating that shear 
stress should be proportional to shear strain

stress: force tending to produce deformation
strain: deformation resulting from stress

so he said there is some stress deforming the velocity profile that 
should be proportional with some constant: the coefficient of viscosity.

see equations p 1 - i'm not writing them down.

if you consider the area of the lamella and the tangential force between 
lamellae you have F/A = shear stress; which is proportional to shear 
strain, the velocity gradient.

the less viscous the liquid, the greater the velocity gradient.
shear stress = viscosity contstant * shear strain

POISEUILLE also analyzed this stuff. he found a relationship defining 
flow (note flow is ml/sec - do not confuse w/velocity)

flow Q is determined by pressure differences between two points, the 
length between the points, and the radius of the vessel

Q= P2-P1
   ------
8(coefficient of viscosity)(length)/pi*r^4 (see handout :))

but that huge denominator can bascially be reduced to one variable, R 
resistance

Q = change in P
    -----------
      R

if pressure is fixed, and resistance goes down, flow increases. but in 
arterioles, flow tends to be fixed, and resistance tends to vary. 
dilating arterioles decreases resistance. 

another implication for blood flow in a real system as opposed to rigid 
tube. rigid tube has constant R, so as you increase P, flow increases 
proportionately. at given pressure you get certain flow. now in a vessel, 
as you increase pressure, you also change R, because you increase the 
diameter, so as P increases, R decreases, and flow increases. with 
increased sympathetic tone, vessels constrict and get stiffer, increased 
R, less elasticity, so curve shifts to right, so for given flow, you 
generate much higher pressure.



BERNOULLI'S PRINCIPLE
this is what makes airplanes fly :)

where the velocity of fluid is greatest the lateral pressure against the 
walls is least.

TOTAL ENERGY = potential energy + kinetic energy

energy = PV + 1/2 rho v^2 * V

P pressure
V volume
rho: density
v mean velocity

we're assuming we have no frictional losses in this system.

mean velocity = flow/area
cm/sec = cm^3/sec / cm^2

if you look at liquid flowing in tube, PV = potential energy; 1/2 rho v^2 
* V = kinetic energy. 

so if you have a particular system and you lower the diameter you 
increase velocity, decrease pressure - see handout. a low velocity high 
pressure system becomes a high velocity low pressure system when flow is 
constant if tube is narrowed.
[someone thinks this doesn't make sense. he's saying it does work, and 
that it doesn't make sense to him either.]

say you have an aneurysm. blood is flowing along along aorta. as soon as 
it gets to aneurysm, pressure against it is higher, because blood 
suddenly slows way down - this is another reason why aneurysms burst. the 
increased cross sectional area causes a drop in blood velocity and 
increased pressure on the lateral wall. 

now, with axial streaming, with renal arteries coming off at right angles 
from aorta, you have blood with fewer rbcs going into the renal vessels - 
you get a plasma skimming effect as a consequence of axial streaming - 
the cells concentrate toward the center of the vessel, there's decreased 
viscosity laterally.
in other words, go with the Q (just kidding.)

changes in visocosity p 4.

viscosity is determined using the prefious equation measuring the flow 
through a rigid tube (viscometer) - eg, you know pressure, radius, flow, 
length, you solve for viscosity.

now, as you increase the HCT, you increase viscosity (makes sense.)now, 
how does this effect flow? If viscosity increases, velocity gradient 
should decrease- eg, the velocity profile will blunt, be less deformed. 
also flow Q will decrease per Poiseuille. now, if you look at the 
relative viscosity with different tube radii you can see the fahraeus - 
lindquist effect. as you decrease the tube radius, you reach a point 
where the apparent viscosity drops. what you measure with the smaller 
tubes - the same blood - indicates a lower viscosity than seen in larger 
tube. what does this mean? blood flowing in vessel behaves as previously 
described. but when you get to capillary sized vessl, blood cells take up 
larger proportion of the diameter. so, while you are moving the same 
mass, the blood doesn't have the ability to shear as it would in larger 
vessel. so poiseuille's relation doesn't really hold. now if relative 
viscosity is less, resistance to flow should be less. so this is a Good 
Thing.

now sometimes blood flow is TURBULENT not laminar.
we've been discussing streamlined laminar flow. in the case of laminar 
flow as you increase pressure you increase rate of flow. now, at some 
point, you may start seeing turbulence. at that point, the rate of flow 
trails off with increasing pressure. you need more pressure to increase 
flow when flow is turbulent. REYNOLD'S NUMBER: R = VDrho/mu 

reynolds number is the mean velocity times the tube diameter times the 
fluid density, all divided by the fluid viscosity.

if R reaches 3000 you have a good chance of turbulence forming. so at 
some point on the pressure/flow graph you will see this change.see p 5 
handout.

as you narrow tube diameter, you are favoring the formation of 
turbulence. if you increase the velocity of flow, you are increasing 
chance of turbulence. in normal cardiovascular system there is no 
turbulence. if you have a stenotic aortic valve, that's narrowed, you 
will produce turbulence. you've narrowed the diameter, the blood rushing 
out during ejection is going through narrow opening, velocity is high, 
and when it gets out there in the aorta, there's turbulence and you can 
hear that as a murmur. note that R has no units - it's a unitless number 
empirically derived by this reynold's character.

another thing with an aneurysm...blood flows along, reaches the bulge, 
and you get turbulence forming. that is usually diagnostic of an 
aneurysm. if you hear a murmur in the gut region, you worry about aortic 
aneurysms. some people with these aneurysms can feel the turbulence 
(eeewwwww!!!)

KOROTKOFF SOUNDS
if you listen to your radial artery with a stethoscope, you don't hear 
anything, right? So how do you measure BP? you need to produce turbulent 
flow. you have a cuff around the arm and you increase the pressure on the 
arm by inflating the cuff (note: unless arm is obese, pressure is not 
attenuated by arm, it is directly transmitted to vessel. so if pressure 
in cuff is 120mmHg and arterial pressure is 100, you are occluding the 
vessel)(see p 6). as you allow pressure in cuff to drop, as soon as it 
equals peak pressure in artery, you start hearing turbulence as a pulse 
of turbulent flow gets through with each pulse. this is peak systolic 
pressure. as you continue to decrease the pressure, you open the vessel 
more and more. you start hearing louder and louder sounds as a greater 
volume of turbulent flow passes through. as pressure drops, turbulence 
becomes less and sound gets softer because diameter is widening. when 
cuff pressure drops below diastolic pressure, you no longer have 
turbulence and you know the diastolic pressure because it is now quiet.

ARTERIAL PULSE WAVES:
if you look at the aortic pulse profile, it is much broader than say the 
radial artery, which is higher amplitude and narrower. so the radial 
artery has a lower mean pressure but a higher pulse pressure. so this 
pressure wave is distorted as it travels..why?

pulse reflection. the pulse pressure is not a bolus of blood. it is a 
wave being transmitted through a liquid, like ripples emanating from a 
stone thrown in a pond. as wave moves to shore, it reflects back and 
interferes with the waves still emanating out. well, branching of 
vasculature acts like shoreline. pulse waves kind of "bounce back" and 
interfere. ALSO the has to do with how frequency components are 
transmitted - if you do a fourier analysis of the radial pulse, you can 
break it down into a bunch of sine waves with different  phase 
relationships, different frequencies, etc etc. if you sum them all, you 
get the wave you started with. if any wave is being transmitted through 
some medium, some frequencies will be transmitted better than other 
frequencies (eg, bass through the wall, when your neighbor blasts the 
stereo). the blood dampens higher frequencies. also transmits higher 
frequencies faster. so this contributes to distortion of pulse downstream 
of aorta:

interferece
summing
distortion
dampening
higher frequencies moving faster (changes phase relationships)
------break-----

Dr Kobin (??) Cardiovascular Regulation and maintenance of systemic 
arterial BP

distributed resistance: first page handout has diagram. 
basically, the system supplies blood to different organs, and there are 
mechanisms in place to shunt blood to the organs which need it the most, 
eg muscles during exercise, gut after meal, etc. for this to work well, 
the driving force and arterial BP has to be relatively constant, or the 
valves operating the shunts won't "know" when to open/close. so there are 
many regulatory mechanisms in place to keep arterial BP constant under 
various conditions.

CIRCULATORY SHOCK:
reduced CO leading to arterial BP collapse caused by any of the 
following:
reduced amount of circulating blood (hypovolemia)
sudden increase in volume of vascular system (distributive shock)
inadequate pumping (cardiogenic shock)
obstruction of blood flow in heart or lungs (obstructive shock)

in any case, shock is severe and prolonged. 
a model for shock is something reaction
when you change from supine to upright there is a change in blood 
pressure

this is an acute situation - very important in clinical practice - the 
something reaction is a good test of the importance of 

but we aren't going to see this in our practice [what??]
I don't understand this man, sorry

Arterial pressure control mechanisms:

keep in mind that the mechanisms operate on difffernt time scales. We'll 
talk about each one individually, but you should be able tos ee the chart 
shows that some things operate over seconds and some over days or minutes 
or hours, or whatever.

[not only does this guy have a confusing accent, the people around me 
STILL will not shut the F*CK up and it's making me crazy.]

Arterial BP is determined by total peripheral resistance and cardiac 
output.
cardiac output we know consists of product of HR and SV, and SV is 
comprised of contractility and filling of heart, determined by total 
blood volume and venous return. so all of htese things are important and 
we'll discuss them as well as total peripheral resistance.

NEURAL REGULATION:

seehandout
these regulations are the first line of defense against vascular 
collapse. the central nervous system acts as a black box. on the one side 
are the afferents with receptors, etc, which feed into to the brain and 
cord, and the info is processed and it affects the efferent outflow to 
the heart, to the kidney, to the adrenal, to splanchnic viscera, to blood 
vessels. 

on afferent side, most important aspect are the arterial baroreceptors. 
they are located at two distinct sides of the arterial end of the system. 
they detect changes in arterial BP and send info to brain. 

another important group of receptors is the carotid body chemoreceptors, 
located in specific location, which function to notice changs in blood 
pH, CO2 level, O2 level.  in fact they are theonly sensors in our body 
providing info about oxygenation of blood to the brain. 

then there are other receptors in the low pressure side of the system, in 
the atria and large veins in thorax, sensitive to stretching of the 
vessels/atria - tell CNS the volume of blood filling them. 

other somatic and visceral:
also there are other receptors: pain receps, pressure receps, stretch 
receptors, general chemoreceptors

so, efferent side: 
parasympathetics: vagus and sacral efferent system. 
sympathetics

the principal transmitter of PSNS is ACH
SNS uses NOREPI and EPI

so both psns and sns consist of two neurons, one in CNS and one in 
peripheral ganglion. so there are pregang Sym neurons and postgang symp 
neurons. structurally there is a difference in efferent pathways in that 
for parasymp the ganglion is usually within the innervated tissue, 
whereas that isn't the case with the SNS, where ganglia are located in 
chain along cord.

arterial baroreceptors:

location:
pressure receptors: many in carotid sinus of internal carotid artery
these receptors are more excited the higher the pressure. if pressure 
bottoms out they are not excited any more.
see chart on right side showing what these pressure receptors do under 
varying pressure...as pressure drops, they generate fewer and fewer APs. 


those are the MAIN nts, not all of them.


major pathways of arterial baroreceptor reflex is outlined in handout - 
take a look... goes to ganglion, goes to medulla to second order cell - 
then to rostral ventrolateral medulla, where info is integrated and 
outflow to cord and back to heart, basically is what it looks like to me.


what's special about the reflex pathway is that this system 
(baroreceptors of carotid) is always active. you see continuous input to 
the medulla, so there is constant inhibitory outflow to the sympathetics. 
so this provides a constant inhibition to sympathetic outflow which 
varies with BP.

when BP drops, we have reducd activity in the pathway, reduced inhibitory 
outflow, we get increased sympathetic outflow to increase BP

another part of the pathway affects the heart rate. the same input acts 
on neurons controlling the vagus nerve. ACH is released tothe heart 
causing slowing of the heart. when baroreceptors are activated, it has an 
inhibitory effect on the heart rate.

[i wish the guy would talk with his mouth facing us instead of the 
screen]

the arterial CHEMORECEPTOR is located in the carotid body and aortic 
body, sensitive to pH changes and O2 changes. these organs have the 
highest blood flow per volume of all tissue in the body, and consume a 
lot of O2 and are very sensitive to it.very much like afferent pathway 
for arterial baroreceps, this pathway is also going to brainstem, and 
paths are sl different, not going to describe them in more detail but we 
will be talking about these receptors in connection w/respiratory 
regulation. the main effect is that these cause vasoconstriction and 
slowing of heart rate. (is that right? they cause vasoCONSTRICTION? hmmm) 
vasoconstriction will increase BP and slow heart which probably helps it 
operate during times of reduced oxygenation.

supraspinal centers of circulatory regulation:
looking at same system as in previous slide but from side. the important 
part ot focus on is the rostral ventrolateral medulla, with the vasomotor 
nucleus.

the point of this, you don't need to know all the pathways, but this site 
is the driving force for central neural regulation of tone of sympathetic 
system. many pathways are integrated here to produce appropriate signals. 
those pathways not only originate in periphery but come from 
hypothalamus, midbrain, etc. emotionally induced changes in 
cardiovascular system occur also, something about change in osmolarity. 
if a lesion destroys this partof the medulla, you're a goner, man.

circulatory response to valsalva maneuver;
you attempt to expire against an occluded airway in this test. this 
increases pressure in the thorax thereby reducing return of blood to the 
heart. it's like sudden loss of circulation. what you see is the arterial 
BP initially increases due to mechanical influences, then it drops quite 
a bit, and without neural regulation it would bottom out, but within a 
few heart beats, it rises again, because there is rapid vasoconstriction 
even though there is much reduced CO the BP is maintained. then when you 
stop the maneuver, you see a huge SURGE in BP regulated and brought back 
to normal rapidly. see, now you're allowing blood back into heart, on a 
background of tremendous vasoconstriction. the point being that when 
measuring the pressure at this point you can measure the regulation which 
occured during the maneuver.

moving on to renal regulation

			decreased arterial pressure
				/				\
            renin				decreased renal output of Na+ and H2O
           (kidney)                       |
 renin substrate--->ATI            increased blood volume
                    /                    |
                   /  (converting enz)   | 
         angiotensin II                  |
            |                      increased venous return and cardiac 
output
         vasoconstriction                        /
            \                                   /
               INCREASED ARTERIAL PRESSURE

angiotensin has it's own receptors and causes constriction of smooth 
muscle in vessels, but AT also has other effects besides direct art. 
vasoconstriction. it wil act directly on postganglionic sympathetic 
neurons, exciting them and causing vasoconstriction. also will cause 
increased aldosterone production by adrenal cortex, decreasing Na+ and 
water excretion. also causes increased secretion of vasopressin, causing 
increased water intake et al.
recall vasopressin is the same as ADH. it also causes direct 
vasoconstriction as a minimal effect, it's released from posterior 
pituitary and goes into circulation and in particular affects sites with 
no blood brain barrier. it causes increased thirst by affecting certain 
sites in the brain.

it also affects the kidney, reducing excretion of Na+/H2O. also there is 
negative feedback. increased level of AT II in circulation inhibits renin 
release. so there is a self limiting mechanism; you can't infinitely 
produce angiotensin.

regulation of aldosterone secretion...

----end---