Pressure, Energy, and Flow:

Pressure = pgho P= fluid densityo G= acceleration due to gravityo H= height of the fluid columno The density of a fluid such as mercury or water and the acceleration

due to gravity are constants, so Pressure = Height of a Fluid Column

Energy:o Total Energy (W) = Pressure Potential Energy (P) + Kinetic Energy

(pv^2/2) + Gravitational Potential Energy (pgh) Kinetic Energy only contributes 3%-5%

Flow:o Determined by the different in Total Energy between Point A and

Point B.o In the body, the predominant energy difference causing flow is a

difference in pressure.o Examples:

The left ventricle generates pressure in the Aorta. Pressure in the Right Ventricle is very low. The difference in pressure between the Aorta and the Right Atrium is large. The Aorta is connected to the Right Atrium via Blood Vessel “tubing” that is always filled with blood. Flow occurs from the Aorta, through the Blood Vessels, and to the Right Atrium.

Same reason for the Pulmonary Artery Lungs Left Atrium.

o The physiological affects of gravity are greatest in the veins because they are compliant. When a person is upright, gravity acting on the venous blood column results in stretch of the venous walls and a shift of significant volume from the Thorax to the Lower Body.

o 2/3 of Circulating Blood resides in the Venous System.o No significant shift in arterial blood.

Pressure Difference and Flow:o Blood Flow as a result of Pressure Difference:

Q = (P1-P2)/R Q: Blood Flow per unit time = Cardiac Output (CO) P1: Mean Aortic Pressure P2: Mean Right Atrial Pressure R: Vascular Resistance

Mostly from Arterioles Blood Flow Types: Silent and Noisy Flow

o Silent, Laminar Flow: Highest velocity in the center

Exists because of the concentric layers of blood rubbing against each other with the central layer flowing the fastest.

o Noisy Turbulent Flow Chaotic and disorganized. After the velocity increases enough to create turbulence, the

energy produced goes into making the turbulence and the amount of flow/time (F) increases only very little.

Reynold’s Number: (V)(D)(p)/n V: Velocity D: Diameter P: Density N: Viscosity For SMALL decreases in the Diameter (narrowing) of a

vessel, there are LARGE increases in Velocity, leading to a higher Reynold’s Number.

You can get Turbulence when: Diameter Decreases (narrowing) Rate of Blood Flow Increases (pregnancy,

hyperthyroidism) Cardiac Output Increases (leaky heart valve) Viscosity Increases (Severe Anemia) Usually cause SYSTOLIC murmurs because when the

ventricles contract and push blood out of the Pulmonary and Aortic Valves, the initial velocity of flow through the valves is normally high. It is likely that Reynold’s number will affect the highest velocity (ejection) areas first.

Density of the blood does not change significantly and is not likely to contribute to the development of turbulence.

o Murmurs and Bruits: Murmur: noise from a narrowed heart valve Bruit: noise from a narrowed artery Velocity = Volume/time (Q) / Cross-Sectional Area (A) In a patient with Progressive Narrowing, the Cardiac Output

(Q) at rest will eventually decrease either due to severely compromised left ventricular muscle function or to the extremely high left ventricular pressure load. At this point, velocity will continue to fall and Reynold’s Number may decrease so much that turbulence lessens or disappears (BAD).

Velocity is slowest in the Capillaries because the total cross-sectional area of ALL of the capillaries is the largest – allows for Oxygen Exchange. (Capillaries and LUNGS)

Cardiac Valves:

Atrioventricular Valves:o Tricuspid: Between RA and RVo Mitral (Bicuspid): Between LA and LV

Semilumar Valves:o Pulmonary: Between the RV and the PAo Aortic: between the LV and the Aorta

Valves open when the pressure on the Upstream Side begins to exceed the pressure on the Downstream Side

The Atrioventricular Valves close when Ventricular Pressure increases and exceeds Atrial Pressure.

Pressures on the right are usually much lower than on the left.

The Cardiac Cycle:

SA Node Depolarizes Depolarization spreads through Atrial Musculature Atrial Wall Contraction occurs Tricuspid and Mitral Valves are open Atrial Muscle Contraction increases pressure in the Atria (wave a) Atrial Systole results in a small push of blood from the Atria into the Ventricles called the “Atrial Kick” The wave of Depolarization is delayed in the AV Node Depolarization enters the conduction system and spreads over the ventricles. Ventricular Muscle Contraction begins and force develops ventricular wall The contraction squeezes the blood within the ventricular chamber Blood pressure increases and Mitral/Tricuspid valves close Ventricular pressure continues to increase Isovolumetric Contraction continues until the pressure in the Ventricles outweight the pressure in the Aorta/Pulmonary Vein (all valves remain closed) The Mitral Valve begins to bulge slightly due to the Left Ventricle pressure increase (C-Wave) The Semilunar Valves open Blood flow out is initially rapid Pressure increases in both the Left Ventricle and the Aorta Left Ventricular Ejection begins to wane, aortic blood flow slows, relaxation progresses, and blood leaves the Aorta causing a fall in pressure Ventricular Relaxation continues Blood in the Aortic root momentarily reverses and moves back towards the Aortic Valve, causing it to close When the Aortic Valve closes, the blood in the Aorta bounces against the closed valve, causing vibrations (that manifest as a Notch) Isovolumetric Relaxation begins Intraventricular pressures decrease Tricuspid and Mitral valves open again.

Ventricular Filling:o Early Rapid Filling: 80%o Diastolic Filling: 5%o Atrial Kick: 15%

Contractility:

Shifting function from one curve to another occurs with a change in Myocardial Contractility.

o Y-Axis: Ventricular Performanceo X-Axis: End-Diastolic Volume

What changes Contractility?o Sympathetic Nervous System:

Increased Sympathetic Input Higher (increased) Curveo Treppe: Force-Frequency

Independent affect of Heart Rate is minimal. Unless it is on the AV Node – then it matters.

o Inotropic Agents (Digitalis) Increases Contractility – increases the amount of Calcium in

Heart Muscleo Intrinsic Depressiono Loss of Myocardium (from MI)o Pharmacologic Depression

All anesthetics depress contractility. Ejection Fraction = Stroke Volume/End-Diastolic Volume

o Sympathetic Input increases SV but doesn’t really change EDV, meaning there was an increase in Ejection Fraction, and the line on the graph moves upward.

Heart Sounds:

First Heart Sound:o S1o Low in frequency.

Vibrating valves, oscillations in the blood in the ventricles, vibrations of the ventricular wall.

o Occurs through most of Isovolumetric Contraction.o Caused by Mitral and Tricuspid Valve Closureo Aortic and Pulmonary Valves are OPEN

Second Heart Sound:o S2o Shorter, higher in frequencyo Caused by Aortic and Pulmonary Valve Closure

The blood bounces off of the valves once they snap shut resulting in a Dicrotic Notch.

o Valve Closure Pattern:

Normally, the Pulmonary Valve Closure (P2) is later than the Aortic Valve Closure (A2)

P2 is MORE delayed during Inspiration. P2 is LESS delayed during Expiration

Why does this “split” occur? Intrathoracic pressure drops further below atmospheric

during inspiration. The Intrathoracic pressure is the pressure inside of the chest, but outside of the lungs, heart, and vessels. This drop in pressure below atmospheric pressure (suction) is called Transmural Pressure (P1)

o P1 = Pi-Pe Pe decreases with Inspiration. Pi does not significantly change with

Inspiration. P1 increases with Inspiration.

o Result: Increase in the diameter of the Extrapulmonic Pulmonary Arterial Vessels.

Increases the capacity of the artery. Increase in capacity causes the forward

blood flow in the pulmonary artery to last longer, so the reversal of blood flow in the pulmonary artery during ejection is delayed.

The delay in pulmonary valve closure during inspiration contributes much more to 2 splitting than the earlier closure of the aortic valve.

In Summary:o Decreased Thoracic Pressure Decreased

Pulmonary Artery Impedance Increased Pulmonary Artery Capacitance Increased Venous Return to the Heart Increased Stroke Volume Delayed Pulmonary Valve Closure.

Third Heart Sound:o Caused by Rapid Ventricular Fillingo Found directly after S2o Low pitchedo Not always audibleo Normal in young people, abnormal if age >30-40o Can be caused when blood flow rate and rate of ventricular filling are

high. Anemia, Fever, Pregnancy

o Either the ventricle is dilated, there is hypertrophy of the ventricular wall or both,

Heart disease Fourth Heart Sound:

o Caused by Atrial Contraction at the end of Diastolic Filling Ventricular Hypertrophy Atrial Kick

o Found directly before S1o Always an Abnormal Heart Sound.

Heart Murmurs:

Acquired or Congenital Stenosis (not opening fully) or Regurgitation (not closing fully) Stenosis Murmurs = Turbulence occurs downstream Regurgitation Murmurs = Turbulence occurs upstream

Clinical PhysiologicalSystole S1 S2

Closure of the Atrioventicular Valves to Closure of the Semilunar Valves

Closure of Atrioventricular Valves to Opening of the Atrioventricular Valves

Diastole S2 S1Closure of the Semilunar Valves to Closure of the Atrioventricular Valves

Opening of Atrioventricular Valves to Closing of the Atrioventricular Valves

** Murmurs are based on the Clinical Definitions

Systolic Murmurs: Aortic + Pulmonary Valves are open. Can be normal.o Aortic Stenosis

Narrow Aortic Valve Turbulence occurs downstream, during Ejection. First Sound is Audible and Normal Murmur starts when Ejection starts and

ends towards the end of Ejection when the flow slows down.

Second Sound is Audible and Normal

o Mitral Regurgitation Diastolic Murmurs: Mitral and Tricuspid Valves are open.

o Aortic Regurgitation Valve does not close all the way.

Blood rushes back into the Ventricle from the Aorta Begins at the time of S2 and lasts through Diastole

Turbulence in the Left Ventricle (Upstream) A2 may be diminished or absent. P2 is often obscured by the murmur sound. May also have a Mid-Systolic Murmur because of the large

Diastolic Filling from the Regurgitant Flow plus the usual filling from the Left Atrium. More filling = higher Stroke Volume = large, high velocity flow causing turbulence.

o Mitral Stenosis

Clinical Cardiac Muscle Physiology: Excitation-Contraction Coupling:

o Ca2+-Induced-Ca2+ Release: Ca2+ enters a Cardiac Cell from outside. (L-Type) That Ca2+ triggers the release of more Ca2+ from the Terminal

Cisternae (80% of the Ca2+ comes from Terminal Cisternae) The amount of Ca2+ that enters with each Action Potential +

the amount from the Terminal Cisternae is NOT enough to bind to every Troponin C.

The more Ca2+ the more Troponin C is bound the stronger the contraction.

More available internal Ca2+ is termed an increase in Inotropic State. Inotropic = Contracility

o How can the amount of Ca2+ Entry be enhanced? Sympathetic Input Epinephrine and Norepinephine Beta

Receptor Stimulation More Ca2+ inside of the cell More Ca2+ taken up by the Sarcoplasmic Reticulum More Ca2+ stored in the Terminal Cisternae More forceful contraction.

Example of an increase in the Contractile or Inotropic State.

Increase in Extracellular Ca2+ Concentration (less likely to occur).

o How can Ca2+ leave the Myocyte? Through sarcolemmal channels.

Na+-Ca2+ Exhanger ATP-Dependent Pump

o Relaxation: The same Ca2+ that causes Contraction also causes Relaxation

at the SAME TIME. Ca2+ binds to the sits on the Longitudinal Portion of the

Sarcoplasmic Reticulum Binding activates ATPase ATP powers the pump that begins pumping Ca2+ out of the Myocyte and into the Longitudinal Sarcoplasmic Reticulum

Ca2+ diffuses through the tubules and into the Terminal Cisternae

Catecholamines enhance relaxation. Phospholamban “puts the breaks on Ca2+ uptake” Catecholamines phosphorylation Phospholamban

reduces the breaking action Ca2+ uptake is enhanced.

Cytoplasmic Ca2+ activates Calmodulin Kinase Phosphosphorylation of Phospholamban reduces the breaking action Ca2+ uptake is enhanced.

o Force-Length Relation Narrow length range However, strong correlation between force and length.

As length increases slightly, force increases drastically. Vmax is NOT dependent on length (pre-load)

Vmax = 0 load Highest preload = longest length = highest velocity

o Innervation: Cells do not depend on Nervous Innervation Contraction is initiated by the SA Node The only nerves to the heart are Autonomic, and they only

modulate heart muscle function. The activation of heart cells spreads through low resistance

Gap Junctions.o Contractility:

2 Definitions of Contracility: Change in function without a change in length. Change in force development without a change in pre-

load. Catecholamines increase Contractility Beta-Blockers decrease Contractility Reduced O2 supply decreases Contractility The resting force-muscle length relation does not change with

the inotropic state. The entire line would just move up or down on the graph.

o Frequency of Stimulation: Increasing frequency of stimulation results in “treppe”. Increasing Action Potential Frequency Increasing Ca2+

inside of the cell and increasing the amount of Ca2+ available for release from the Sarcoplasmic Reticulum

With every Action Potential, Extracellular Na+ also enters. An increase in frequency also results in an increase in Na+ ions inside of the cell. These ions reduce the Na+-Ca2+ Exchange (1 Ca2+ out for 3 Na+ in), leading to more Ca2+ inside of the cell.

Ventricular Function:

The Frank-Starling Ventricular Function Curve:o The more Ventricular Filling you have, the more Ventricular Ejection

you have.o The less Ventricular Filling you have, the less Ventricular Ejection you

have.o Y-Axis: Ventricular Performanceo X-Axis: End-Diastolic Volumeo Ventricular Performance can be measured by Stroke Volume or

Cardiac Output: Stroke Volume: the amount of blood

ejected by a ventricle during a single Cardiac Cycle.

Cardiac Output: the amount of blood pumped by the heart per minute.

Stroke Volume x Heart Rate

Ejection Fraction:o Normal: 60% of the EDV

EF: 0.6o The Ejection Fraction is the amount ejected by a ventricle

(Stroke Volume) relative to what was in the ventricle before ejection (End-Diastolic Volume)

o Stroke Volume = End Diastolic Volume – End Systolic Volume Connective Tissue: you get a slight increase in pressure in the

ventricle when you fill the ventricle due only to the stretching of connective tissue and titin, even when the muscle is completely relaxed.

o In Heart Disease, connective tissue and titin remodel, causing stiffness. This alters ventricular filling.

Afterload:o The load on the ventricles after contraction begins and ejection

occurs. You measure the Afterload of the left ventricle by

measuring Aortic Pressure.

You measure the Afterload of the right ventricle by measuring Pulmonary Artery Pressure.

o Example: Increase in Left Ventricular Afterload The Left

Ventricle is then filled with the same amount of blood as it usually is This blood adds to the blood left in the Left Ventricle, increasing End-Systolic Volume. Left Ventricular End-Diastolic Volume increases Increase in Ventricular Performance Increase in Stroke Volume Offset of initial reduced emptying Return of Stroke Volume to normal.

Using the Pressure Volume Loop: A increases D increases AD decreases slightly ESPVR does not shift (no change in contractility)

This can normally happen when a person is exposed to cold temperatures.

Arterioles constrict, peripheral vascular resistance increases, left ventricular afterload increases.

Cardiogenic Shock:

Caused by a large enough Myocardial Infarction resulting in Ventricular Dysfunction and a decrease in Cardiac Output.

o Cardiogenic Shock happens when body tissue perfusion is reduced to below normal levels.

Measurable Variables:o Slow blood flow allows for normal blood hemoglobin O2 Saturation

and Content.o Slow blood flow in the periphery results in more time for O2 to diffuse

out of capillaries, meaning that venous blood leaving these areas has a lower CO2 content. This results in a larger than normal O2 Content difference between Arterial and Venous Blood.

o If blood flow decreases even more drastically, not enough O2 per minute will be delivered to tissues. This causes a shift to Anaerobic Glycolysis. This presents as a decrease in total O2 Consumption.

Therapy: o Restore Coronary Blood Flow Improve Ventricular Functiono Treatment of Cardiogenic Shock using the Fick Principleo Fick Principle:

If we measure the O2 Content of the Pulmonary Artery Blood (V) and compare that to the Aortic Blood (A), the difference is

the same as the steady state difference in the rest of the body because the body is a closed system.

o Cardiac Output = VO2 / (A-V) O2 Difference VO2 = Oxygen Consumption/time

o VO2 = CO x (A-V) O2 Difference

The Peripheral Circulation:

Pulse Pressure = Peak Arterial Systolic Pressure – Diastolic Pressure Mean Arterial Pressure is important for driving the blood through the

circulation.o Mean Pressure = Diastolic Pressure + Pulse Pressure/3o Mean Pressure is determined by:

Cardiac Output Peripheral Runoff Stiffness of the Aorta

Become more stiff with age (connective tissue stiffens) At a given cardiac output and peripheral runoff, the

steady state blood volume and stretch of the aorta in an older person would result in a higher mean aortic pressure than in an younger person.

Q = (P1-P2) / R Q = Blood Flow per Unit Time R = Vascular Resistance

Mostly in Arterioles P1 = Mean Aortic Pressure, Pulmonary Artery Pressure P2 = Mean Right Atrial Pressure, Left Atrial Pressure

Resistance: 8nL/πr^4

oo In a Series:

Additive

Resistance = R1+R2+R3+…o In Parallel:

Reciprocals are additive 1/Resistance = (1/R1)+(1/R2)+(1/R3)+…

Conductance = 1/Resistanceo Conductance in Parallel is additive (C1+C2+C3+…)

Baroreceptor Control:o Short-termo Carotid Sinuso Aortic Archo Root of Right Subclavian and Common Carotid Arteries

Hormonal Regulation:o Renin-Angiotensin-Aldosterone-System (RAAS)

Long-term Renin:

Secreted by Kidney (Juxtaglomerular Cells) Secreted into the bloodstream Secreted if there is less stretch on the kidney cells (low

blood pressure) Secreted if there is direct Sympathetic Stimulation of

Adrenergic Receptors on the cells.o This can be achieved when the Baroreceptor

Response causes increased Sympathetic input. Secreted if there is low plasma Sodium Chloride,

resulting in a decrease in Macula Densa Interstitial Sodium Chloride

The opposite of this can occur, causing deceased Renin levels.

Angiotensinogen (inactive) Angiotensin I (inactive) Angiotensin II (active)

Renin cleaves Angiotensinogen in the Blood Stream Angiotensin I.

Vascular Endothelial Cells produce Angiotensin Converting Enzyme (ACE).

o ACE cleaves Angiotensin I Angiotensin II Angiotensin II:

Potent Direct Vasoconstrictor Stimulates the release of Antidiuretic Hormone from the

Posterior Pituitary Gland.o Increases blood osmolality.o Also happens during dehydration.o Increases water reabsorption in the distal tubule.o Could possibly result in Vasoconstriction

Induces thirst (Angiotensin III)

Directly stimulates the release of Aldosterone from the Adrenal Cortex Increases Na and Water Absorption

Enhances Ca2_+ entry, enhancing Contractility Facilitates Norepinephrine release, which increases

vascular responsiveness to catecholamine. ACE Inhibitors:

ACE inhibitors are being used to treat people with high blood pressure.

ACE Inhibits Angiotensin I Angiotensin IIo Atrial and Brain Natriuretic Peptides:

Atrial Natriuretic Peptide (ANP): Produced by Atrial Cells Blood -- Hormone

Brain Natriuretic Peptide (BNP): Produced by Ventricular Cells Blood -- Hormone

C-Type Natriuretic Peptide (CNP): Produced by Endothelial Cells Act locally in a Paracrine or Autocrine manner on

Vascular Smooth Muscle. Triggers:

Increases in Atrial and Ventricular Wall Tension High Pressure, Chamber Distention

Actions: ANP and BNP levels increase when one goes from

standing to lying down. Ventricular filling increases, causing chamber distention. This results in:

o Peripheral Vasodilation: relaxation of Vascular Smooth Muscle

o Natriuresis: decreased kidney reabsorption of Na, resulting in more Na and Water Excretion

o Inhibition of Renin Secretiono Inhibition of Aldolsterone Production

Actions in Heart Disease: In Aortic Stenosis, you get a back up of blood in the Left

Ventricle, causing an increase in pressure in the chamber. This results in a stiffer chamber and increased filling pressures. This causes a back-up of blood and an increase in the release of both ANP and BNP.

o Reduces myocardial and vascular remodelingo Reduces myocardial apoptosis o Reduces myocardial hypertrophic growtho Reduces myocardial fibrosis

You can measure these levels to determine the prognosis of the heart disease.

Neprilysin: Produced in Vascular Endothelial Cells Produced in tubular cells of the kidney Degrades mostly ANP, some BNP and CNP

o Vascular Endothelial Factors: Smooth Muscle Relaxation (Vasodilation)

NO:o Most important vasodilator.o Rapidly released and then inactivated.o Stimulated by the shear stress of blood flow on

the luminal surface.o There is continued stimulated of NO release.o Can also be stimulated by Thrombin, Serotonin,

ADP, Bradykinin, and Histamine.o NO inhibits clotting.o Can be stimulated by Acetylcholine if it diffuses

through the wall to the endothelium.o NO acts through cGMP to decrease smooth

muscle Ca2+ and relax it locally.o Important in larger arterioles.

Prostacyclin:o Stimulated by the shear stress of blood flow on

the luminal surface.o Relaxes smooth muscle.o Prevents clotting.o Used in Pulmonary Hypertension.

Endothelium-Derived Hyperpolarizing Factors (EDHF)o Opens smooth muscle sarcolemma Ca2+-

activated K+ Channels.o K+ leaves the smooth muscle cells easier cells

become hyperpolarized less likely to contract.o Secretion is increased by shear force, but it also

mediates the effects of bradykinin.o One EDHF is Hydrogen Peroxide.o EDHF’s are more important in the smallest

arterioles. Blood Clotting Effects:

Endothelial cells produce and release Tissue Plasminogen Activator (t-PA) and Plasminogen-Activator Inhibitor Type 1 (PAI-1)

Normal Cells: Produce normal ratio

Abnormal Cells: Produce lower ratio Greater tendency towards thrombosis.

Smooth Muscle Contraction (Vasoconstriction): Reduced production and release of NO is characteristic

of dysfunctional endothelium.o Causes atherosclerotic plaques and

hypercholesterolemia obstruction. Endothelins:

o Produced by Vascular Endothelial Cellso Results in sustained contraction.o Angiotensin II, Norepinephrine, and

Inflammatory Cytokines induce Endothelin release.

o Not a significant player in normal people, but it plays a role in the pathological state.

o One Endothelin Isoform can act in an Autocrine fashion, causing VASODILATION. Multiple factors determine which isoform wins out.

Thromboxane:o Produced by platelet aggregation during vascular

endothelial cell damage. (Atherosclerotic plaques)

o Chemoreceptors: We do not think chemoreceptors influence normal circulation. Chemoreceptors play a key role in regulation of respiration. Carotid Body Low blood pressure vascoconstriction throughout the body

due to sympathetic outflow. This is a survival mechanism during a major drop in blood

pressure.o Local Metabolic Control:

Smooth Muscle Relaxation during increased Cell Metabolism: The harder the organ works, the more relaxed the arterioles

become and the more blood flow increases. This does not involved hormones or nerves. Mechanisms are not clear.

Increase:o Adenosine (ATPADP)o K+ (repeated repolarization)o Lactic Acido PCO2

Decrease:o pHo PO2