Study Guide – Cardiovascular Physiology
General Features of the Cardiovascular System
overview
- functions of the cardiovascular system
- maintenance of homeostasis
- amount of blood flow to each organ must be matched to the needs of the organ
- distribution of blood flow must be adjusted continuously and rapidly
- regulation of body temperature
- variation in blood flow to the skin
- increased temperature leads to increased peripheral blood flow
- transportation of hormones
- anatomical divisions of the cardiovascular system
- systemic circuit: left ventricle to body to right atrium
- pulmonary circuit: right ventricle to lungs to left atrium
- blood volume and distribution of blood between the circuits
- adult human volume
- 4-6 L total
- 70-75 mL blood / kg body weight
- measurement: Evan’s blue dye
- upon injection, binds to plasma proteins in the cardiovascular system
- known volume is injected, and after several minutes, blood sample is drawn and analyzed
- calculation: 
- unequal blood distribution
- systemic: 80-85% of total
- pulmonary: 15-20% of total
autonomics in the nervous system
- parasympathetic
- M2 receptor
- effector: atrial muscle; cardiac nodal tissue (NOT present in ventricles)
- effect: contractile inhibition: slows heart rate, AP conduction velocity, and contractility
- mechanism: anti-β effects (↓ PKA via adenylate cyclase inhibition); ↑gK
- sympathetic
- α1 receptor
- effector: vascular smooth muscle (except coronary, cerebral, pulmonary circulation)
- effect: contraction: targeted vasoconstriction
- mechanism: PKC-induced ↑gCa and ↓gK, giving depolarization
- β1 receptor
- effector: cardiac muscle, nodal tissue
- effect: contractile: increases heart rate, AP conduction velocity, and contractility
- mechanism: PKA-induced ion channel and contractile protein phosphorylation
- β2 receptor
- effector: variable (sometimes present in heart, peripheral vasculature)
- effect: relaxation
- mechanism: PKA activation of Ca2+-dependent gK, giving hyperpolarization
basic anatomy of the systemic circulation
- vascular bed: set of blood vessels supplying blood to a given organ or type of tissue
- organization and order of flow: high to low pressure
- arterial tree: aorta, artery, arteriole, terminal arteriole
- capillary bed
- venous return: venule, vein, vena cava
- structures
- smooth muscle: higher content in high pressure vessels
- elastic tissue: higher content in high pressure vessels
- endothelial cells: line all vessels, including capillaries
- exchange: independent controls of vasoconstriction and vasodilation
- arterioles: regulated by sympathetic innervation
- precapillary sphincters: regulated by O2 tension, CO2 tension
- cross-sectional area
- varies immensely over different levels of circulation
- much larger in capillary beds
- larger area for exchange
- greater time for exchange (increased cross-sectional area means decreased velocity)
- systemic vascular beds: arrangement in parallel
- physiological advantages of parallel arrangement
- blood composition identical in each bed
- arterial pressure identical in each bed
- independent regulation of flow to each bed
- low resistance to flow vs. arrangement in series
- exceptions: arrangement in series
- portal circulations: specialized for point-point delivery of substances (hormones, nutrients)
- glomerular capillary beds: specialized for filtration of blood, reabsorption of salts and water
concepts and terms
- pressure
- pressure: form of energy driving cardiovascular blood flow
- sphygmomanometer: device commonly used to measure blood pressure in humans
- measurement of arterial blood pressure
- arterial blood pressure fluctuates in time, so multiple terms must be used
- systolic pressure: highest pressure achieved during the cardiac cycle (contraction phase)
- diastolic pressure: lowest pressure achieved during the cardiac cycle (relaxation phase)
- pulse pressure: arithmetic difference between systolic, diastolic pressure
- mean arterial blood pressure (MABP): average pressure during an entire cardiac cycle
- can be calculated by a measurement of area under the curve
- can be approximated as 1/3 of the pulse pressure, summed to diastolic pressure
- typical values
- males: 120/80 (systolic/diastolic)
- females: 110/70
- flow
- blood flow (Q): amount of blood flowing through a circuit per unit time
- equation: 
- Q: blood flow
- ΔP: pressure gradient driving flow
- R: resistance to flow
- continuity of flow
- amount of blood flowing through any unique cross-sectional areas are identical
- deviations from continuity indicate disease, acute injury
- velocity of flow
- measurement: flux past a point in a circuit (cm/s)
- varies with cross-sectional area of the flow
- large arteries: 30-50 cm/sec
- capillaries: 0.1 cm/sec
- large veins: 15-20 cm/sec
Physiological Properties of Heart Muscle
automaticity
- automaticity: ability of the heart to spontaneously generate AP necessary for each beat
- pacemaker cells: automatic cells; drive pace of heart beat
- cardiac innervation: autonomic
- heart is not controlled via nerve-induced action potentials, as in α-motor neurons
- autonomic innervation regulates automaticity, force of muscle contraction
conduction or propagation of action potentials
- syncytium: collective; functional organization of heart
- mechanisms of propagation identical to those in unmyleinated neurons, skeletal muscle fibers
- APs pass readily from cell to cell, utilizing numerous gap junctions
- intercalated disc: specialized gap junction permitting local currents to flow from cell to cell
- features and consequences of conduction in the heart
- action potentials from a single cell eventually propagate throughout the entire heart
- all cells undergo excitation, contract during each beat
- not possible to vary force of heart beat by recruitment
- other mechanisms must be utilized
- stimulating electrodes of pacemakers can be placed on any part of the ventricles
- propagation velocity of action potentials varies greatly in different regions of the heart
- nodal tissue: as slow as 0.05 m/s
- ventricular conducting tissue: as fast as 5.0 m/s
contractility of myocardium
- similarities to skeletal muscle
- mechanoenzyme: actin-activated myosin ATPase
- regulation: Ca2+ release from the sarcoplasmic reticulum, binding to troponin C
- tension: attachment and cycling of myosin cross-bridges between thick, thin filaments
- differences from skeletal muscle
- no mechanical coupling between sarcolemma, sarcoplasmic reticulum (CICR still present)
- increased strength is not gained by motor unit recruitment
- Ca2+ entry into cell, Ca2+ release from the SR, Ca2+ SR reuptake are all regulated
- modulation of contractility typically involves regulation (phosphorylation) of these enzymes
- rates of chemical transitions within cross bridge interaction cycle subject to regulation
- contractility
- contractility: ability of the myocardium to develop tension and to shorten
- involves contractile force, rate of force development, and velocity of shortening
distensibility of myocardium
- distensibility: ability to be lengthened or stretched when a force is applied
- factors contributing to resting distensibility
- titin: protein that spans gap between Z line, ends of thick filaments, and gives passive stretch
- slowly-cycling cross bridges: at rest, some cross bridges still bind actin, and give force when stretched
- stretch influence on subsequent contractions
- number of cross bridges interacting with actin is greater at longer lengths
- amount of Ca2+ released from SR during a sarcolemmal action potential increases
- less physical distance between actin, myosin due to volumetric considerations
- thus length of vetricular cells at onset of each contraction affects force of contraction
refractoriness of myocardium
- refractory: unable to respond to an applied stimulus
- refractoriness in the heart
- begins with depolarization (upstroke), ends when membrane potential has repolarized to 50-90% of resting
- time: typically lasts several hundred milliseconds
- consequences
- refractory period lasts into myocardial relaxation phase, allowing relaxation between beats
- permits filling of the ventricles with blood prior to contraction, allowing more efficient pumping
Origin and Conduction of Cardiac Excitation
- anatomy: structures of cardiac conduction
- atria
- sinoatrial (SA) node
- interatrial and internodal tracts
- atrial muscle
- atrioventricular (AV) node
- ventricles
- Bundle of His
- right and left bundle branches
- terminal arborization (Purkinje tissue)
- ventricular muscle
action potential generation and conduction in normal heart
- conduction
- atrial contraction
- pacemaker: site of origin of the cardiac impulse (generally the SA node)
- conduction: originates in the SA node, spreads to AV node and atrial muscle via interatrial pathways
- contraction: virtually synchronous due to short distances of conduction
- AV node
- conduction: propagates through internodal tracts at a highly reduced velocity
- primarily responsible for delay between atrial, ventricular contractions
- ventricular contraction
- conduction: bundle of His through bundle branches, Purkinje system into terminal arborizations and muscle
- contraction: virtually synchronous (range <>
- conduction velocities
- SA node: 0.05 m/s
- internodal tracts: 1.0 m/s
- atrial muscle: 0.3 m/s
- AV node: 0.05 m/s
- His, Purkinje: 3.0 to 5.0 m/s
- ventricular muscle: 0.3 m/s
determinants of conduction velocity
- cell diameter: conduction velocity varies directly with diameter
- His-Purkinje cells: largest diameter cells in the heart, fastest conduction velocity
- mechanism: increased volume of charge carriers lowers axonal Ri
- factors in conduction velocity
- rate of depolarization during upstroke, depolarization phase of AP
- slow conduction: small upstroke velocities (5 V/s in nodal cells)
- fast conduction: large upstroke velocities (500 V/s in Purkinje cells)
- amplitude of AP overshoot (potential reversal)
- slow conduction: virtually no overshoot
- fast conduction: large overshoot (approaching +35 mV)
automaticity
- sinoatrial node: normal site of the cardiac pacemaker
- pacemaker current: analogous to K+ channels in muscle conduction, but with opposite direction
- designation: If (“funny”)
- activation: only activated at very negative potentials
- deactivation: self limiting; turns off as potential increases
- aspects of membrane potential in a cardiac nodal cell
- diastolic depolarization: slow, progressive depolarization in membrane potential
- occurs during diastole (between contractions) in cells exhibiting automaticity
- other names: phase 4 depolarization, pacemaker potential
- threshold potential: potential at which an action potential is initiated 50% of the time
- action potential: transient, propagating change in membrane potential
- results from regenerative increase in inward currents, subsequent activation of outward currents
- slow: APs in nodal cells depolarize slowly
- maximum diastolic potential: most negative membrane potential during diastole (follows end of AP)
- ion channels in a nodal action potential
- diastolic depolarization: inward Na+ (If)
- action potential: inward Ca2+
- repolarization: outward K+
- mechanisms for changing the automaticity of pacemaker cells
- biochemical methods
- alter rate of diastolic depolarization
- increased diastolic depolarization: increased APs
- decreased diastolic depolarization: decreased APs
- examples: caffeine, emotional stress, exercise
- alter threshold potential
- depolarization of threshold potential: decreased APs
- hyperpolarization of threshold potential: increased APs
- examples: certain antiarrhythmic drugs (INa, ICa blockers)
- alter maximum diastolic potential (MDP)
- depolarization of MDP: increased APs
- hyperpolarization of MDP: decreased APs
- physiological methods of decreasing heart rate
- block If (theoretical)
- increase parasympathetic output (M2 receptor agonists)
- decrease sympathetic output (β-blockers)
localization of automaticity
- describing automatic cardiac cells
- true pacemaker: cells in normal hearts that generate the AP leading to the heart beat (usually SA node)
- latent pacemaker: cardiac cells with the capability of automaticity, other than true pacemaker
- normally do not spontaneously generate AP
- cells with greatest degree of automaticity reach threshold first
- other automatic cells are preemptively excited by propagating APs generated by the true pacemaker
- SA node generally has greatest automaticity, dominating other automatic cells
- ectopic pacemaker: automatic cell outside SA node that generates an AP leading to one or more beats
- includes latent pacemakers that have become true pacemakers
- numerous physiological, pathological processes can cause this to occur
- inherent rates of discharge of automatic cells
- in the absence of extrinsic neural, chemical influences:
- SA node: 120 /min
- internodal tract: 80-100 /min
- AV node: 80-100 /min
- His-Purkinje system: 30-50 /min
- greater numbers of If channels in more automatic cells
- mechanisms for shifting the site of automaticity to ectopic regions
- selectively suppress the automaticity of the SA node
- allows the next most automatic cells (usually AV node) to become the (ectopic) pacemaker
- occurs with aging
- selectively enhance the automaticity of latent pacemaker cells
- cells achieve threshold before SA node, thus becoming the (ectopic) pacemaker
- block conduction between SA node, lower heart (e.g. block the SA node)
- SA node will continue to be the atrial pacemaker
- Purkinje cells, in absence of SA control, become ventricular pacemakers
- this causes asynchrony between contraction of the atria, ventricles
- automaticity vs. conduction velocity: two different characteristics of membrane potential
- automaticity: depends on rate of diastolic depolarization
- conduction velocity: depends on cell diameter, upstroke velocity, overshoot
Ionic Currents Underlying Cardiac Membrane Potentials
description of cardiac action potentials
- diastolic depolarization
- not present in atrial, ventricular myocytes
- in all other tissues, automaticity declines with distance from SA node in normal conduction
- characteristics of specific action potentials
- ventricular myocyte action potential
- fast action potential: high upstroke velocity
- no diastolic depolarization (If): steady potential at rest
- refractoriness absolute: persists for most of the action potential
relative: during last stages of repolarization
- Purkinje action potential
- hybrid of ventricular, nodal action potentials
- undergoes diastolic depolarization, but at a lower rate than nodal cells
- bundle branches: longest action potentials
ionic basis for cardiac Em
- phase 0: upstroke, overshoot of the action potential
- atrial, internodal tract, ventricular, and Purkinje cells
- mechanism: fast Na+ channels
- upon triggering, Na+ channels rapidly open to allow influx of Na+ ions, depolarization
- with depolarization, Na+ channels rapidly inactivate, usually closing before ENa is reached
- K+ channels are used to reestablish polarity
- speed: rapid
- velocity of depolarization: 150 to 500 V/sec
- conduction velocity: 0.3 to 5.0 m/s
- variability in upstroke and conduction: Na+ channel inactivation
- as membrane potential becomes less negative, more Na+ channels are inactivated
- at a resting potential of -100 mV, almost all channels are available (closed, but not inactive)
- at a resting potential of -60 mV, almost all channels are unavailable (inactive)
- action potential overshoot (and thus conduction velocity) depends on initial number of available channels
- initial resting depolarization can therefore significantly slow conduction velocity
- tetrodotoxin: selectively blocks Na+ channels, preventing depolarization
- SA and AV nodal cells
- mechanism: slow L-type Ca2+ channels (DHP receptors)
- channels conduct both Ca2+ and Na+, but predominantly Ca2+
- AP triggering causes influx of Ca2+, while depolarization causes inactivation of channels
- K+ channels are used to reestablish polarity
- speed: slow
- both activation and inactivation of Ca2+ channels is slow, so overshoot and conduction is decreased
- velocity of depolarization: 5-10 V/s; overshoot <>
- note: slow L-type Ca2+ channels are found in all non-nodal cells as well
- Ca2+ current contributes to phase 2 (plateau phase)
- slow incoming Ca2+ current maintains depolarized state
- subsequent inactivation allows repolarizing channels to take over, repolarize myocyte
- L-type Ca2+ can also allow contraction in partially depolarized non-nodal cells
- at -60 mV, Na+ channels are almost all inactive
- cells can still undergo a slow action potential utilizing L-type Ca2+ channels
- in this case, contraction is slow and resembles that of nodal tissue
- phase 1: initial rapid repolarization
- mechanism
- inactivation of the fast Na+ current
- activation of the transient outward K+ current (Ito)
- localization
- Purkinje cells: prominent
- SA, AV cells: absent
- phase 2: plateau of the action potential (distinguishing characteristic of cardiac AP)
- mechanisms
- L-type Ca2+ current: flows for 200 msec or longer, maintaining positive membrane potential
- IK: gradually increasing conductance to K+ during the plateau
- during the plateau, L-type ICa dominates
- phase 3: repolarization to resting potential (or maximum diastolic potential)
- three separate mechanisms
- L-type Ca2+ current: eventually slows due to inactivation
- IK: continued increased membrane permeability to K+
- Na+/K+ ATPase: electrogenic effects
- repolarization brings potential back to its diastolic level
- phase 4: resting potential / diastolic depolarization
- non-automatic cells
- effect: steady diastolic resting potential (about -90 mV)
- mechanism: high permeability to K+ via K1 channel
- K1 channel: only open at very negative Em, maintaining polarity
- NOT the same channel as that mediating repolarization
- automatic cells
- effect: progressive diastolic (phase 4) depolarization, resulting in threshold and spontaneous AP trigger
- three mechanisms
- IK channels: time- and voltage-dependent closure, allowing Em to subsequently depolarize
- If channels: specialized channels that activate near maximum diastolic potential
- similar to potassium channels that cause repolarization, but work in the opposite direction
- direct cause of membrane depolarization
- T-type Ca2+ channels: activate near maximum diastolic potential, allowing inward Ca2+ current
- numerous mechanisms may be a consequence of the number of types of cells that can act as pacemakers
TABLE: Summary of Cardiac Action Potentials
| phase | nodal cell | ventricular myocyte | Purkinje cell |
| phase 4: diastole
| ↑ If (Na+) ↑ gCa (T-type ICa) ↓ gK (IK) | high gK (IK1) | ↑ If (Na+) ↑ gCa (T-type ICa) ↓ gK (IK) |
| phase 0: upstroke
| ↑ gCa (L-type ICa) | ↑ gNa (TTX-sensitive) | ↑ gCa (L-type ICa) |
| phase 1: initial repolarization
| --- | ↑ gK (Ito) | ↑ gK (Ito) |
| phase 2: plateau
| --- | ↑ gCa (L-type ICa) ↓ gNa (TTX-sensitive) ↑ gK (IK) | ↑ gCa (L-type ICa) ↓ gNa (TTX-sensitive) ↑ gK (IK) |
| phase 3: repolarization
| ↑↑ gK (IK) | ↑↑ gK (IK) | ↑↑ gK (IK) |
Electrocardiography
theory of electrocardiography
- electrocardiogram: record of electrical changes within the heart as recorded from body surface
- basis of the EKG
- arises from potential differences between regions of the heart during spread of activation
- during activation of the heart, potentials change in a predictable and reproducible pattern
- uneven distribution of cardiac electrical activity can be detected via skin electrodes as potential difference
- model
- potential = (recording – reference)
- depolarization wave movement towards a recording electrode, away from a reference electrode gives (+) ECG
- electrocardiography as a diagnostic tool
- heart rate, rhythm
- pattern of conduction
- site of origin of the pacemaker
- sequence and time required for conduction through the heart
- diseases
- arrythmias
- conduction abnormalities
- hypertrophy (not always bad)
- ischemia
- necrosis
electrocardiography leads
- EKG leads
- lead: any pair of points on the body surface where electrodes are placed to record the EKG
- reference (–) electrode: serves as the reference for potential difference
- recording (+) electrode: number that is shown relative to the reference
- PD = (+) – (–): potential difference (PD) = recording (+) – reference (–)
- interference
- skin potentials are much less (maximum: 1-2 mV) than what would be measured directly on the heart surface
- EKG is thus susceptible to interference from other electrical fields
- external: shield EKG cables and recording devices
- muscular: hold still to maintain 0 mV baseline
- standard limb leads: depolarization movement in the frontal plane (Einthoven’s triangle)
- lead I: measures left arm (+) from right arm (–) 0º
- lead II: measures left leg (+) from right arm (–) +60º
- lead III: measures left leg (+) from left arm (–) +120º
- augmented limb leads: depolarization movement in the frontal plane (supplemental)
- aVF: measures feet from center +90º
- aVR: measures right arm from center -150º
- aVL: measures left arm from center -30º
- reference: average of the other two limb electrodes (e.g. for aVF, reference is shorted left and right arms)
- precordial leads: depolarization movement in the transverse plane (anterior, posterior heart surfaces)
- V1: between ribs 4 and 5, right side of sternum (right ventricle)
- V2: between ribs 4 and 5, left side of sternum (right ventricle, septum)
- V3: curve inferiorly and laterally towards the side of the chest (septum)
- V4: curve inferiorly and laterally towards the side of the chest (septum, left ventricle)
- V5: curve inferiorly and laterally towards the side of the chest (left ventricle)
- V6: side of the chest (left ventricle)
- reference: sum of all three limb leads (thus reference in middle of back)
- does not visualize posterior aspect of the heart very well
- if a problem is suspected there, leads will be placed on the back instead
vector representations of the spread of activation
- patterns
- moving depolarization wave
- towards lead: positive amplitude
- parallel to lead: maximum amplitude
- perpendicular to lead: zero amplitude
- away from lead: negative amplitude
- moving repolarization wave
- towards lead: negative amplitude
- away from lead: positive amplitude
- tissue mass
- increasing: increased amplitude
- decreasing: decreased amplitude
- resting tissue
- uniform depolarization: zero amplitude
- resting potential: zero amplitude
- vector basis of measurement
- formally, EKGs measure surface charge densities
- informally, most think of it as a current wave (spread of activation, or local circuit current)
- ventricles: depolarization from right to left
- myocardium: depolarization from endocardium to epicardium
repolarization from epicardium to endocardium
(i.e. “there and back”)
- mean QRS vector: spatial sum of all instantaneous vectors
- instantaneous vector: direction of charge density movement at a particular moment
- mean QRS vector in young adults is approximately +60º (60º below horizontal)
- conduction velocity and wave magnitude: inverse proportionality
- faster conduction: smaller wave
- slower conduction: larger wave
clinical EKG recording
- lead I electrocardiogram
- idealized lead I electrocardiogram
- P wave: atrial depolarization (positive)
- QRS complex: ventricular depolarization
- Q wave: septal depolarization (negative; may be absent)
- R wave: primary ventricular depolarization (positive)
- S wave: last part of ventricular depolarization (negative)
- T wave: ventricular repolarization (positive)
- waves
- Q wave: septal depolarization
- left bundle branch has branches that course back into, supply septum
- sum of these vectors makes the negative Q wave (not always present)
- R wave: ventricular depolarization (dominated by left ventricle)
- conduction through walls: endocardial à epicardial
- left ventricle is much larger, as is apex
- thus leftward conduction in left ventricle dominates R wave
- S wave: last component of ventricular depolarization (moving away from lead)
- T wave: ventricular repolarization
- endocardium: low number of K+ channels, and thus longer AP
- epicardium: high number of K+ channels, and thus shorter AP
- repolarization of left ventricle moves rightward, causing an upright T wave
- intervals
- P-R interval: corresponds to conduction time from SA node through AV node
- S-T segment: plateau of ventricular action potential; isopotential
- QRS complex: onset of ventricular depolarization
- Q-T interval: period of ventricular depolarization and repolarization
- long QT syndrome: caused by poor ventricular repolarization
- can be due to defective or blocked K+ channels (or high interstitial K+)
- can be due to defective or blocked Na+ channels
- nomenclature: other leads
- theory
- in all leads, Q, R, and S waves are assigned based on polarity and sequence
- in leads other than lead I, QRS waves do not necessarily correspond to identical electrical events
- naming
- Q wave: a negative wave preceding an R wave (sometimes absent)
- R wave: first positive wave in the QRS complex reporting ventricular depolarization
- lead I: reports ventricular depolarization
- V1: reports septal depolarization, which generally moves towards V1
- S wave: negative wave following an R wave
- lead I: final stages of ventricular depolarization
- V1: main phase of ventricular depolarization (moves to the left, away from V1)
reading an ECG
- protocol
- scan the ECG for technical adequacy (noise, signal size)
- measure heart rate, intervals, amplitudes, axis
- identify the rhythm (sinus, supraventricular, ventricular)
- describe abnormalities
- interpret the ECG, listing each abnormality
- compare with previous ECG, if available
- simple estimation of heart rate
- ECG paper
- minor divisions: 40 ms
- major divisions: 200 ms
- estimation
- QRS complex every major division: 300 /min
- QRS complex every two major divisions: 150 /min
- QRS complex every three major divisions: 100 /min
- QRS complex every four major divisions: 75 /min
- QRS complex every five major divisions: 60 /min
- QRS complex every six major divisions: 50 /min
- calculation of the QRS axis
- QRS axis: calculated variable that estimates net direction of depolarization of ventricles
- summation of all vectors generated during ventricular depolarization
- left ventricle is generally the largest tissue mass in normal hearts, so QRS axis usually points in that way
- calculation
- select two leads (typically I and aVF, since their horizontal/vertical direction is easiest for calculation)
- from isopotential, measure amplitudes of Q, R, and S waves
- subtract largest of Q or S wave from R wave
- plot vectors away from center
- direction: based on direction of the lead
- amplitude: based on calculation
- draw lines perpendicular to the end of each vector
- QRS axis: vector from center to the point where perpendicular lines intersect
- normal values: -20º to +110º
- less than -20º left-shifted pregnant, overweight: heart oriented more horizontally
LV hypertrophy: greater depolarization towards the left
- greater than +110º right-shifted thin: heart oriented more vertically
RV hypertrophy: greater depolarization towards the right
- note: angles are relative to lead I, with a positive value corresponding to the direction of right shifting
normal and abnormal 12-lead ECGs
- normal
- sinus rhythm
- rhythm of the heart driven by the sinoatrial node
- marked as regular appearance of a P wave at a constant interval before each QRS complex
- normal
- regular sinus rhythm of 60-100 bpm
- no evidence of pathological processes
- abnormal
- tachycardia: heart rate greater than 100 bpm
- bradycardia: heart rate less than 50 bpm
- atrial fibrillation
- arrhythmia with asynchronous APs arising from multiple ectopic foci in the atria
- seen as irregular baseline, absence of P waves, irregular ventricular rhythm due to irregular AV conduction
- ventricular rhythm
- rhythm of the heart beat driven by an ectopic pacemaker of ventricular origin
- seen as dissociation of P-waves and QRS complexes, and widened QRS complexes
- normal QRS width: less than 120 ms (3 boxes)
- ventricular fibrillation
- arrhythmia with asynchronous APs arising from multiple ectopic foci in the ventricles
- seen as continuous series of up/down deflections of variable amplitude and duration
- left ventricular hypertrophy
- enlargement of the left ventricle, either physiological (athlete) or pathological (hypertensive)
- seen as abnormally large QRS complexes in right or left ventricular leads
- left bundle branch block (LBBB)
- slowed conduction into the left ventricle
- seen as prolonged QRS complex, large R’ waves in left-side leads (I, V5, V6)
- R’ wave: second positive deflection (rabbit ear) caused by sequential ventricular depolarization; can be subtle
- right bundle branch block (RBBB)
- slowed conduction into the right ventricle
- seen as prolonged QRS complex, large R’ waves in right side leads (V1, V2) and/or broad left side S waves
The Heart as a Pump
cardiac valves
- atrioventricular valves: connected to papillary muscles by chordae tendinae
- tricuspid valve: divides right ventricle from right atrium
- bicuspid valve (mitral): divides left ventricle from left atrium
- semilunar valves: each has three cusps
- pulmonic valve: divides pulmonary artery from right ventricle
- aortic valve: divides aorta from left ventricle
- other structures
- sinuses of Valsava: bulges or spaces in arterial walls directly behind valve cusps
- ostia of coronary arteries: within sinus of Valsava in the aorta
- memory device: “ten pin bowling alley” (tricuspid, pulmonic, bicuspid, aortic)
- function: open or close depending on pressure gradient
- valves
- AV valves: close when ventricular pressure is greater than atrial pressure (supported by chordae tendinae)
- semilunar valves: close when arterial pressure is higher than ventricular pressure
- closure
- approximation (coaption): closure of the valve cusps
- insufficiency: failure of valves to fully close
cardiac cycle
- cycle
- ventricular systole: marked by closure of mitral valve, onset of isovolumic contraction
- isovolumetric contraction: ventricle builds tension/pressure, but does not exceed arterial pressure
- ventricular ejection
- rapid ejection: pressure rises to peak, volume drops rapidly
- reduced ejection: pressure falls from peak, volume drops slowly
- ventricular diastole: marked by closure of aortic valve
- isovolumetric relaxation: ventricle loses tension/pressure, aortic valve closes; dichrotic notch
- ventricular filling
- rapid filling: mitral valve reopens, blood rapidly enters ventricles due to atrial buildup (75-80% of filling)
- reduced filling: blood enters more slowly (15-20% of filling)
- atrial systole: contraction causing remaining filling of ventricular volume
- concepts
- dichrotic notch: transient increase in aortic pressure caused by backflow, rebound of blood off valve
- blood pressure
- diastolic: pressure at which aortic valve opens (between isovolumetric, rapid ejection)
- systolic: marked by peak of atrial pressure (between rapid, reduced ejection)
- volume
- end-systolic volume: residual ventricular volume (during isovolumetric relaxation)
- end-diastolic volume: peak of ventricular volume (during isovolumetric contraction)
- directly determines length of individual muscle fibers
- indirectly determines force muscle fibers will develop during subsequent contraction
- filling
- increasing heart rate causes proportional decrease in length of diastole, NOT in filling volume
- rapid filling early in diastole allows filling to remain steady even with increasing heart rate
- only beyond ~180 bpm does rapid filling phase decrease sufficiently to reduce filling volume
- during filling, ventricular pressures are generally less than pressures in great vessels
determinants of ventricular filling
- rate of venous return: greater return à greater filling (aided by ventricular relaxation)
- filling time: greater diastole à greater end-volume
- ventricular distensibility: greater distensibility (compliance) à greater end-volume
- stiff ventricles (e.g. hypertrophy) impairs filling, requiring greater venous pressure
- as ventricular distensibility decreases, atrial contraction becomes a more important contributor
atrial function
- reservoirs: store blood during period that AV valves are closed
- ventricular filling: increasingly important with:
- faster heart rates
- vascular stenosis
- hypertrophied ventricles (decreased distensibility)
- AV valve closure: aid by creating eddy currents that move cusps closer to center of AV orifice
- changes in left atrial pressure during cardiac cycle
- a wave: increasing pressure due to atrial systole
- c wave: transient increase in pressure during isovolumetric contraction (bulging AV valves)
- x descent: results from early ventricular ejection
- during ejection, base of ventricle moves down toward apex
- AV valve, atrium pulled downward, enlarging atrium and reducing pressure
- v wave: increasing pressure due to accumulation of blood within the atrium
- y descent: results from rapid ventricular filling, suction from ventricular relaxation
- left atrial pressure
- contraction: a wave
- ventricular filling/release: c wave, x descent
- atrial filling/release: v wave, y descent
characteristics of ejection
- stroke volume: amount of blood ejected into aorta during a beat
- average: 60-70 mL (60-70% of blood contained within ventricle)
- determinants: primarily force, velocity of ventricular muscle contraction
- end-systolic volume: residual volume contained within ventricle
- ejection fraction: measure of cardiac performance
- corrects for effect of body size on stroke volume
- formula: 
- EDV: end-diastolic volume of the ventricle (maximum volume)
- ESV: end-systolic volume of the ventricle (minimum volume)
- SV: stroke volume (difference)
Regulation of Cardiac Function
key concepts
- preload: extent of diastolic filling (i.e. pre-loading of the ventricle)
- generally, as preload increases, stroke volume increases
- measured as EDV or EDP
- afterload: load (or pressure) against which the heart must work
- generally, as afterload increases, stroke volume decreases
- indicators of afterload
- mean arterial blood pressure
- ventricular wall stress (best indicator)
- regulation
- targets
- heart rate (beats / min)
- stroke volume (mL ejected / beat)
- cardiac output (CO): product of heart rate and stroke volume
- mechanisms
- intrinsic: exist within the heart, and do not involve neural control or circulation
- neural: nerve inputs to the heart
- types: parasympathetic, sympathetic
- targets: heart rate, force, and velocity of muscle contraction
- chemical: naturally-circulating or pharmacologic agents that bind receptors, interact with ion pumps
- heteromeric autoregulation
- changes in muscle length (ventricular volume) alter force of muscular contraction (ventricular pressure)
- mechanism: Frank-Starling mechanism
the Frank-Starling mechanism
- experiment
- design
- canine heart-lung preparation isolated from chemical, neural effects
- effects on cardiac performance studied with varying factors
- findings
- increased ventricular filling
- led to increased contractile force, stroke volume
- extra blood quickly pumped out in subsequent beats
- increased aortic pressure
- less blood pumped into the aorta during the first few transitional beats
- led to increased residual volume of the ventricles, stretched ventricular myocytes
- led to increased contractile force, returning stroke volume to normal
- cardiac performance
- ventricular function vs. chamber dimensions
- y: stroke volume, cardiac output, or stroke work
- x: venous pressure, atrial pressure, or ventricular end-diastolic pressure (VEDP)
- VEDP / VEDV: inputs
- preload: amount of blood and pressure present within the ventricles at the end of diastole
- afterload: pressure against which the heart works
- systemic arterial pressure: good indicator of afterload
- wall stress: best indicator of afterload
- wall stress as the best indicator of afterload
- LaPlace’s Law for spherical wall stress: 
- P: ventricular pressure
- r: chamber radius
- t: wall thickness
- situations where mean arterial blood pressure (MABP) is a poor indicator
- aortic stenosis
- problem: narrowing of the aortic valve opening
- left ventricle must generate blood pressure far in excess of systemic pressure
- dilated cardiomyopathies
- problem: chamber radius is increased, wall thickness decreased relative to normal
- wall stress substantially greater than normal to maintain adequate arterial blood pressure
the basis for the Frank Starling relationship
- alteration in thick/thin filament overlap (minor)
- end-diastolic sarcomere lengths range from 1.8 to 2.3 μm
- below 1.8 μm, there is virtually no tension
- within plateau of length-tension relationship, substantial decreases in tension
- implication: most of variation must involve other mechanisms
- L-type channel-dependent release of Ca2+
- amount of Ca2+ released into myoplasm during EC coupling depends on length
- increased length (distension) leads to increased Ca2+ release, possibly due to:
- increased L-type current, Ca2+ entry into the cell
- increased sensitivity of the SR to the trigger Ca2+ entering the cell
- implication: increased stretch leads to increased Ca2+ and contractility
- alteration in probability of cross bridge binding (most important)
- constant volume system: in striated muscles, as cylinder length increases, diameter decreases
- increased distension leads to smaller distance between actin and myosin, increased rate constant for binding
- implication: increased stretch leads to greater probability of cross bridge formation
implications of the Frank Starling relationship
- systemic venous blood pressure is kept from rising to high levels
- output of the two ventricles is self-correcting
- stroke volume is normal in individuals with chronic hypertension
- work: work = P · ΔV
= mean arterial blood pressure · stroke volume
= MABP · SV
- acute hypertension
- under normal circumstances, MABP is well regulated and relatively constant
- with sudden hypertension, MABP increases, and work is initially constant, so SV decreases
- decreased SV à increased ESV à increased EDV à increased work capacity of the heart
- end result: increased work, increased MABP, normal stroke volume (metabolic burden)
- problem: hypertrophy can occur over time, ultimately leading to heart failure
Neural Regulatory Mechanisms
anatomy of autonomic innervation
- parasympathetic
- preganglionic
- cell bodies: medulla
- axons: project to peripheral ganglia via the vagus (X) verve
- neurotransmitter: acetylcholine
- postganglionic
- cell bodies: peripheral ganglia near or in the heart
- axons: project to targets
- targets: SA node, internodal tracts, atrial muscle, AV node
- ventricles receive virtually no input from parasympathetic nerves
- neurotransmitter: acetylcholine
- receptor: muscarinic (M2)
- function: slows heart rate, conduction velocity
- cardio-inhibitory center (CIC): cell bodies of the preganglionic parasympathetic neurons
- diffuse bilateral center in the medulla
- tends to dominate at rest
- sympathetic
- preganglionic
- cell bodies: lateral horns of the spinal cord, T1 to T6
- axons: synapse in paravertebral chains
- neurotransmitter: acetylcholine
- postganglionic
- cell bodies: paravertebral chains
- axons: project to the heart via the superior, middle, and inferior nerves
- targets: all structures of the heart, including the ventricles
- neurotransmitter: norepinephrine
- receptor: adrenergic (β1)
- cardio-accelerator center (CAC): neuronal control of preganglionic sympathetics
- diffuse bilateral center in the brainstem
- synapse on lateral horn cells
functions of the heart regulated by autonomic nerves
- heart rate
- chronotropism: change in the rate of the heart beat
- positive chronotropism: increased heart rate
- negative chronotropism: decreased heart rate
- mechanism: changes in the rate of diastolic depolarization
- conduction of excitation
- dromotropism: induced changes in action potential conduction velocity
- AV node: functionally most important in controlling conduction velocity
- anything arising from SA node must traverse AV node to control ventricular excitation
- mechanism: changes in the intensity of the depolarizing current (Na+ or Ca2+)
- alters upstroke velocity of the action potential
- alters overshoot of the action potential
- contraction force and velocity
- inotropism: induced changes in myocardial contractile force, resulting in altered stroke volume
- positive inotropy: increase in developed force (or pressure)
- negative inotropy: decrease in developed force (or pressure)
- mechanisms
- change in magnitude of slow Ca2+ current
- modulation of Ca2+ release
- modulation of Ca2+ binding
- modulation of metabolic energy balance
- excitability or irritability
- excitability
- laboratory definition: tendency of the tissue to respond to a stimulus
- clinical definition: tendency of the heart to develop arrythmias
- as such, excitability is often also referred to as irritability
cardiac actions of the parasympathetic nerves
- decreases heart rate
- mechanism: influences diastolic depolarization (phase 0) ionic currents via ACh binding to M2 receptors
- increases membrane K+ conductance (gK), slowing rate of membrane depolarization
- reduces intensity of Na+ current through If channels
- blocks T-type Ca2+ current
- selective effect: targets only atrial walls, AV node
- decreases conduction velocity through AV node
- mechanism
- ACh reduces magnitude of L-type Ca2+ current
- causes decrease in upstroke velocity, overshoot, and thus conduction velocity
- effect: longer time for excitation to traverse AV node, longer P-R interval
- note: can sometimes increase conduction velocity along atrial muscle cells
- ACh-induced increase in membrane gK hyperpolarizes resting membrane potential (-90 to -100 mV)
- increases number of available fast Na+ channels, ultimately increasing conduction velocity
- decreases contractility of atrial muscle cells
- mechanism: decreased amplitude of L-type Ca2+ current (required to initiate Ca2+ release from SR)
- result: negative inotropy, decrease in atrial kick
- selective effects: parasympathetics target atrial walls and AV node, but do not work well in ventricles
- significantly fewer muscarinic receptors in Purkinje cells, ventricular muscle
- significantly less innervation of ventricular cells
cardiac actions of sympathetic nerves
- increases heart rate
- mechanism: influences ionic currents via norepinephrine binding to β1 receptors (PKA-mediated)
- accelerated rate of gK decrease
- increased inward movement of Na+ through If channels
- increased inward Ca2+ channel current through T-type channels
- broad effect: all latent pacemakers receive sympathetic innervation, all have β1 receptors
- increases conduction velocity through AV node
- nodal cells: increase in rate of rise and amount of L-type Ca2+ current
- causes significant increase in AV upstroke, overshoot, and thus conduction velocity
- effect: shorter time for excitation to traverse AV node, shorter P-R interval
- non-nodal cells: mechanism is unclear; may involve hyperpolarization of the threshold potential
- increases contractility of muscle cells
- positive inotropy
- mechanism: upregulation of adenylate cyclase, consequent increase in active PKA
- increase in magnitude, duration of slow L-type Ca2+ current; consequent increase in [Ca2+]i
- increased Ca2+ release from intracellular stores
- increased rate of cross-bridge cycling
- result: increase in atrial kick, and consequent increase in ventricular stroke volume
- increased rate of relaxation
- mechanism: myofibrillar protein phosphorylations (primarily TnI subunit)
- increased rate of cross bridge cycling (length of rate-limiting steps is reduced)
- increased Ca2+ reuptake by SR
- mediated by phosphorylation of phospholamban
- phospholamban: accessory protein to the SR Ca2+ pump
- result: increase in rate of relaxation
- net effect: increase amplitude, reduce duration of cardiac twitch
- increases excitability of cardiac tissue
- mechanism: unclear
- threshold closer to max diastolic potential
- automaticity of latent pacemakers is increased
- problem: hearts subjected to excessive sympathetic innervation tend to develop arrythmias
levels of cardiac autonomic nerve activity in normal humans at rest
- SA node automaticity: 120 beats/minute in absence of outside influence
- normal resting heart rate: 60-80 beats/min
- implication: at rest, heart has a generally parasympathetic tone
TABLE: Summary of Cardiac Effects of Autonomic Nervous System
|
| parasympathetics | sympathetics |
| target | atria | atria, ventricles |
| mechanism | anti-β effects (↓ PKA) | ↑ PKA (protein, channel phosphorylation) |
| chronotropy (heart rate) | decrease (negative chronotropy) ↑ gK ↑ If ↑ ICa | increase (positive chronotropy) accelerated reduction in gK ↓ If ↓ ICa |
| dromotropy (conduction velocity) | decrease (through AV node) ↓ L-type ICa | increase (through AV node) ↑ L-type ICa |
| inotropy (force, speed) | decrease (negative inotropy) ↓ L-type ICa | increase (positive inotropy) ↑ L-type ICa ↑ SR Ca2+ release ↑ SR Ca2+ reuptake speed ↑ cross bridge kinetics |
| excitability (irritability) | decrease ↑ gK | increase mechanism unclear: threshold closer to max diastolic potential, automaticity of latent pacemakers is increased |
Hemodynamics
- hemodynamics: study of the physical factors that produce and affect blood flow
- based on idealized laws developed to quantify flow of liquid through tubes
- quantitatively apply only when liquid is Newtonian in nature (ideal)
- nevertheless, can aid in illustrating general properties on which blood flow is based
physical properties of flow
- pressure
- pressure is form of energy that causes liquid to flow
- flow occurs when pressure exceeds resistance
- resistance is presented by the tube, inertia of the liquid
- pressure can be converted to other forms of energy
- kinetic energy: energy of flow
- heat: byproduct of overcoming resistance to flow
- pressure energy in a tube is a sum of lateral and end pressure
- energy: 
- lateral pressure: pressure exerted on the walls of the container (potential energy)
- end pressure: pressure exerted by energy of flow (kinetic energy)
- note that measurement of flow is measurement of total energy, not just of kinetic energy
- resistance
- determinants
- length of tube: resistance is proportional to tube length
- radius of tube: resistance is inversely exponentially proportional to tube radius
- fluid viscosity: resistance is inversely proportional to viscosity
- measurement
- resistance: 
- L: tube length
- r: tube radius
- η: fluid viscosity
- even a small change in radius will profoundly alter resistance (R is proportional to 1/r4)
- flow
- Poiseluille’s law: 
- Q: flow
- ΔP: pressure gradient
- implications
- flow is directly proportional to size of the pressure gradient and radius of the vessel
- flow is inversely proportional to length of the vessel and viscosity of the fluid
practical applications
- driving force of flow: systemic arterial blood pressure
- physical properties of the vasculature
- parallel arrangement: vascular beds of systemic circulation are arranged in parallel
- pressure in arteries supplying each bed is nearly the same
- same driving force for flow exists at entrance to each bed
- consequently, increased pressure is not efficient in selective flow
- resistance: flow through each vascular bed is primarily determined by net radius of the vessels
- resistance to flow depends on the radius of the vessels
- radius of vessels is primarily determined by contraction/relaxation of circular smooth muscles
- several mechanisms exist to control this
- arterioles: narrow, high resistance vessels located at the end of the arterial tree
- divides systemic circuit into a high pressure region and a low pressure region
- effect: decreases velocity of flow
- increases upstream pressure, decreases downstream pressure
- end result is to increase pressure gradient across the constricted region
vascular resistance
- resistance: 
- ΔP: mean arterial blood pressure (MABP) - RA pressure
- RA pressure is generally close to zero
- ΔP is thus approximated as MABP
- Q: flow
- total peripheral resistance (TPR)
- theory
- ΔP: approximated as MABP, since RA pressure is typically close to 0
- TPR is the primary determinant of MABP
- Q can be thought of as cardiac output (CO)
- equation: 
- MABP: mean arterial blood pressure
- CO: cardiac output
- TPR is less than the largest of the individual resistances
- consequence of parallel arrangement of vascular beds
- resistance in series: 
velocity of flow
- velocity: length of a column of blood passing a point in the circuit per unit time
- velocity is inversely proportional to cross-sectional area of the vessel
- thus as vessel gets bigger, velocity (and kinetic energy) decrease
- implications
- velocity is rapid in arteries and veins, but slow in capillaries
- allows time for exchange of materials across the capillary wall
Bernoulli’s principle
- Bernoulli’s principle: total energy (E = PE + KE) at any point in a system must remain constant
- sum of lateral pressure (PE) and end pressure (KE) must remain constant
- implication: areas of decreased flow receive additional lateral pressure
- arterial aneurism
- bulging of vessel causes reduction in flow and increase in lateral pressure
- as such, aneurisms tend to be unstable and progressive
patterns of blood flow within vessels
- patterns of flow
- streamlined (laminar) flow
- liquid is layered as it flows, and flow occurs without intermixing of the fluid
- each layer (lamella) moves at a different velocity, with greatest velocity at the center
- pattern: ordered, structured, efficient, and quiet
- turbulent flow
- liquid rolls, mixes together as it flows
- pattern: less efficient, requires higher pressure, and is audible
- describing turbulence
- Reynold’s number: 
- v: velocity of flow
- D: diameter of tube
- d: density of liquid
- η: viscosity of liquid
- as Re increases, likelihood of turbulence in flow also increases
- with all else constant, faster flow à increased turbulence
- clinical applications
- abnormal constrictions of dilations of vessels can cause audible downstream turbulence (brutis)
- anemia reduces viscosity of blood, which can result in turbulence
- sphygmomanometry relies on turbulent flow sounds in vessels constricted with a pressure cuff
heart sounds and murmurs
- listening to heart sounds
- stethoscope: that amplifying thingy
- ascultation: the technique of listening for sounds anywhere in circulation
- normal heart sound
- S1: AV valve closure onset of systole “lub”
- S2: SL valve closure onset of diastole “dub”
- heart murmur
- terms
- valvular insufficiency: condition in which blood is able to regurgitate backward through a closed valve
- valvular stenosis: condition in which a valve does not open sufficiently during movement of blood
- findings
- systolic murmur from AV valve: insufficiency (systole: AV valve closes)
- systolic murmur from SL valve: stenosis
- diastolic murmur from AV valve: stenosis (diastole: SL valve closes)
- diastolic murmur from SL valve: insufficiency
LaPlace’s law for wall tension in blood vessels
- LaPlace’s law: T = P · r
- P: intraluminal pressure
- r: radius of vessel
- implications
- pressure is smaller, and radius is far smaller in capillaries than arteries
- as such, the tension is significantly lower, allowing capillary walls to be much thinner
Regulation of Contraction of Vascular Smooth Muscle
- functions of contraction in the cardiovascular system
- reduce the radius of the vessel
- contraction increases resistance to blood flow through the vessel
- arterioles: most important, as they determine TPR
- reduce the capacity of the vessel
- contraction decreases diameter of the lumen, decreasing vessel capacity
- systemic veins: most important, as a reduction in venous capacity causes more blood return to the heart
- increases cardiac output
- increases arterial blood pressure
- reduce the distensibility of the vessel
vascular resistance
- peripheral resistance
- resistance to flow is almost entirely within peripheral vessels, as opposed to the heart
- calculation: depends on pressure gradient (ΔP), flow (Q) across a bed
- total peripheral resistance
- systemic vascular beds arranged in parallel
- inverse of TPR is the sum of the inverses of all vascular beds
- consequence: TPR is less than the resistance of any single vascular bed
- arteriolar smooth muscle: major determinant of TPR
- arterioles
- located at entrance to each capillary
- ideally positioned to control capillary blood flow
- capillaries
- precapillary sphincter: smooth muscle located at the entrance of the capillary
- determines actual blood flow through individual capillary
terms applied to change in vessel radius
- vasoconstriction: decrease in radius of a blood vessel
- types
- passive: recoil due to fall in intraluminal pressure
- active: contraction of smooth muscle in the vessel wall
- contractile factors
- activity in sympathetic adrenergic nerves (primary importance in controlling TPR, capacity, and MABP)
- hormones and neurotransmitters
- exogenous therapeutic agents
- vasodilation: increase in radius of a blood vessel
- types
- passive: stretch due to increase in intraluminal pressure
- active: relaxation of smooth muscle in the vessel wall
- contractile factors
- inhibition of sympathetic adrenergic nerves (important for controlling TPR and MABP)
- therapeutic agents
- local chemical changes produced by tissue metabolism or vascular endothelium
innervation of vascular smooth muscle
- distribution
- all vascular beds receive sympathetic adrenergic innervation
- anatomy
- preganglionic sympathetic: lateral horn of the spinal cord
- postganglionic sympathetic: paravertebral chain
- density of innervation is significantly reduced in:
- brain
- coronary arteries
- pulmonary circulation (determined primarily by local [O2], [CO2])
- sympathetic vasoconstriction: α1 receptors
- vasomotor center: bilateral controller of sympathetic innervation
- located in the medulla
- controls preganglionic sympathetic constrictor neurons in thoracic, lumbar segments (T1-L2)
- sympathetic innervation of smooth muscle contraction
- neurotransmitter: norepinephrine
- receptors: α1 receptors on vascular smooth muscle cells
- distribution
- skin
- skeletal muscle
- bone
- abdominal and pelvic regions (splanchnic vascular beds)
- effect: actively controls TPR and venous capacity
- a tonically-active (3-5 Hz) single set of nerves regulates TPR over a broad range
- increase or decrease of this firing frequency causes resultant changes in TPR, MABP
- sympathetic vasodilation: β2 receptors
- sympathetic innervation of smooth muscle contraction
- neurotransmitter: norepinephrine
- receptors: β2 receptors on vascular smooth muscle cells
- distribution: skeletal muscle beds
- effect: offsets vasoconstriction due to sympathetic adrenergic neurons, to some degree
- beneficial effects in facilitating blood flow to skeletal muscle during exercise
- overall, local [metabolite] dominates, and β2 receptors don’t play that much of a role
regulation of vascular smooth muscle contraction
- local metabolites
- vasodilatory factors
- decreased PO2
- increased PCO2
- decreased pH
- increased adenosine
- increased extracellular [K+]
- increased osmolarity
- increased temperature
- advantage: localized response
- metabolism stimulates changes, leading to increased blood flow on an “as needed” basis
- highly efficient at increasing blood flow to a specific organ or vascular bed
- endothelial cells
- endothelium: single layer of cells lining or comprising the luminal wall of blood vessels
- functions
- formation of a diffusion barrier between circulation and surrounding fluid compartments
- formation of a smooth surface for interaction with blood cells
- modulation and synthesis of numerous blood-borne substances
- modulation or control of contractile state of smooth muscle
- examples
- nitric oxide (NO)
- synthesis and release induced by shear stress across the endothelial surface (mechanism unknown)
- effect: localized vasodilation (reduces velocity of flow, prevents further injury)
- acetylcholine (ACh)
- binds muscarinic receptors on endothelial cells, inducing synthesis and release of NO
- effect: localized vasodilation
- function: unknown
- ACh does not circulate in the blood
- few vessels receive cholinergic innervation
- use as a diagnostic tool
- normal tissues: vasodilate in response to ACh due to interaction with endothelium
- damaged tissues: constrict in response to ACh due to loss of endothelium, interaction with smooth muscle
- other substances
- vasodilation: response to histamine, bradykinin
- vasocontstriction: response to arachidonic acid, stretch
- monoamine oxidase: endothelial enzyme that inactivates norepinephrine and serotonin
- platelet aggregation, blood coagulation: induced by numerous factors released by the endothelium
- myogenic response
- stretch reflex
- effect: contraction in response to simple stretch
- function: allows greater precision in control of flow to a vascular bed
- increasing stimuli for vasodilation (metabolites, pressure) are counteracted by stretch reflex
- at high stimulus intensity, stretch reflex becomes less effective
- mechanism: stretch activation of membrane Ca2+ channels
- inward current depolarizes cell, induces contraction
- self-limiting: stretch-induced contraction reduces cell length, thereby reducing conductance of Ca2+ channels
- atrial natriuretic factor (ANF)
- released by atrial, ventricular myocytes in response to increased EDV
- targets: kidney, adrenal glands, certain regions of the brain
- effects: reduce blood pressure
- diuresis (increased urine output)
- natriuresis (increased Na+ content of the urine)
- vasodilation
- renin-angiotensin-aldosterone system
- pathway: formation of angiotensin II
- renin is secreted in response to:
- reflex activation of sympathetic outflow to the justaglomerular apparatus
- direct release from renal afferent arterioles in response to low blood pressure
- renin catalyzes cleavage of circulating angiotensinogen into angiotensin I
- angiotensin-converting enzyme (ACE) catalyzes cleavage of angiotensin I into angiotensin II
- ACE found primarily in endothelial surfaces of lung vasculature
- angiotensin II: effects to increase blood pressure
- vasoconstrictor
- stimulates Na+ absorption, thereby increasing water retention
- stimulates aldosterone release from the adrenal cortex, which increases Na+ reabsorption by the kidney
- stimulates hypothalamic centers to increase thirst
autoregulation
- autoregulation: maintenance of constant flow regardless of perfusion pressure
- with elevated pressure, flow decreases back to normal due to vasoconstriction
- with reduced pressure, flow increases to normal due to vasodilation
- mechanisms
- myogenic response: appropriate activation of the stretch reflex
- increased local metabolites: appropriate synthesis of metabolites to restore flow rate
reactive hyperemia
- reactive hyperemia: greater than normal volume of blood flow following a period of zero blood flow
- mechanism: abundance of vasodilating agents
- during zero flow, changes in pH, PO2, PCO2, and other metabolites favor vasodilation
- upon restoration, flow is initially greater than normal but recovers once metabolites are cleared
- longer occlusion à longer hyperemia
Neural Regulation of Mean Arterial Blood Pressure
determinants of MABP
- amount of blood in arteries: depends on amount entering vs. amount leaving arterial tree
- CO: cardiac output amount of blood entering arterial tree
- TPR: total peripheral resistance determines blood leaving arterial tree
- cardiac output: depends on heart rate and stroke volume
- HR: heart rate
- SV: stroke volume
- influences on variables in maintaining constant MABP
- cardio-inhibitory center (CI): heart rate and stroke volume (CO)
- cardio-accelerator center (CA): heart rate and stroke volume (CO)
- vasoconstrictor center (VC): total peripheral resistance (TPR)
mechanisms influencing activity of CI, CA, and VC centers
- neural influences from higher centers in the brain
- centers in the cortex, hypothalamus:
- alter output of impulses from CI, CA, and VC centers
- emotional states
- activate centers in the brainstem (CI, CA, VC)
- effect the release of epinephrine from the adrenal glands
- body temperature control centers in the hypothalamus
- influence pool of VC neurons responsible for control of blood flow to the skin
- local chemical effects within the brain
- effects of PCO2
- VC center: highly sensitive to cerebral PCO2 (interstitial fluid)
- 45 mmHg: normal PCO2
- increased PCO2: increase in VC activity effecting vasoconstriction, increase in TPR
- decreased PCO2: decrease in VC activity allowing vasodilation, decrease in TPR
- mechanism
- direct effects on centers due to changes in [H+]
- note: vasoconstriction does not affect brain and heart due to reduced sympathetic innervation
- Cushing’s phenomenon: compensatory increase in MABP in response to increase in brain CO2
- during trauma, blood flow to the brain decreases, CO2 is not cleared as fast, and PCO2 increases
- VC center stimulated, causing systemic vasoconstriction and restoring blood flow to the brain
- note: vascular beds of brain, heart do NOT participate in generalized vasoconstriction (less innervation)
- voluntary hyperventilation
- causes decreased PCO2, effecting a reduced tone in the VC center
- TPR falls, venous capacity increases, and MABP falls
- if MABP falls too much, there is inadequate cerebral blood flow and unconsciousness may result
- CI, CA centers
- increased cerebral PCO2: stimulates both the CA and CI centers
- CI typically dominates, and counterintuitively, HR decreases
- mechanism: direct effects on centers due to changes in [H+]
- effects of PO2
- within brain: small ΔPO2 has little effect; large reductions can cause depressed neural activity
- outside brain: other mechanisms exist by which altered PO2 can stimulate CV system
reflex effects from peripheral neural receptors: arterial baroreceptors
- location and innervation
- carotid sinus baroreceptors: glossopharyngeal (CN IX) nerve
- aortic arch baroreceptors: vagus (CN X) nerve
- mechanism: stretch receptors embedded in vessel walls
- magnitude: effects depend on frequency, duration, and number of active receptors
- tonic activation: some activated during each beat of the cardiac cycle
- frequency: increased discharge, duration with increasing MABP
- recruitment: increased numbers activated with increased MABP
- tonic effects of baroreceptors
- stimulate the CI center
- CI center is tonically active due to constant stimulation by baroreceptors
- inherent SA discharge: 120 beats/min
- normal resting discharge: 60-80 beats/min
- modifying activation
- increasing MABP: increased stimulation, decreased heart rate
- decreasing MABP: decreased stimulation, increased heart rate
- inhibit CA center
- CA center is minimally active due to tonic inhibition by baroreceptors
- modifying activation
- increasing MABP: increased inhibition, decreased heart rate/contraction force
- decreasing MABP: decreased inhibition, increased heart rate/contraction force
- inhibit VC center
- VC center is tonically active, but less than normal due to constant inhibition by baroreceptors
- inherent discharge (normal PCO2) frequency = 10 Hz
- resting discharge rate: frequency = 3-5 Hz
- modifying activation
- increasing MABP: increased inhibition, decreased sympathetic vasoconstriction (vasodilation)
- decreasing MABP: decreased inhibition, increased sympathetic vasoconstriction
TABLE: Summary of Tonic Effects of Baroreceptors
| activity | method | action | effect |
| stimulate CIC | ↓ HR | ↓ CO |
↓ MABP |
| inhibit CAC | ↓ HR, SV | ↓ CO | |
| inhibit VC | vasodilation | ↓ TPR, ↓ CO |
- “buffer” reflexes
- baroreceptors cannot completely prevent any change in arterial pressure
- instead, they provide fast, effective, moment-to-moment regulation of MABP
- with prolonged abnormality, reflexes do adapt to a new standard
- hemorrage: loss of blood directly from the cardiovascular system
- hemorrhage causes a fall in arterial pressure:
- direct loss from the arterial tree
- reduction in blood return to the heart
- response: decreased activity of baroreceptors leading to increased MABP
- CI no longer stimulated, resulting in increased heart rate
- CA no longer inhibited, resulting in increased heart rate and force of contraction
- VC no longer inhibited, resulting in constricted vessels and increased TPR
- function
- mild hemorrhage (<30%>
- severe hemorrhage: prolongs survival time of the organism
- value
- heart is able to pump all blood it receives
- blood is diverted to the brain and heart, which most need blood
- injection of a direct vasoconstrictor drug
- injection of a vasoconstrictor causes constriction of vessels leading to increased TPR, increased MABP
- response: activation of baroreceptors
- CI center activated above normal, slowing heart rate
- CA center further inhibited, reducing heart rate and contraction strength
- VC center further inhibited, reducing constriction and lowering CO
- effect: pharmacologic increase in MABP is moderated
effects on MABP due to stimulation of peripheral chemoreceptors
- structures
- carotid bodies: bilateral structures located at the bifurcation of the common carotid arteries
- aortic bodies: located near the aortic arch
- innervation: glossopharyngeal, vagus nerve
- synapse on CV control centers (especially VC center)
- synapse on respiratory centers
- stimulation
- minimally active at rest
- respond to changes in arterial blood concentrations
- decreases in PO2
- increases in PCO2
- decreases in pH
- effect: increases blood flow to vital organs (brain and heart) when PO2 is low
- stimulates VC center: ↑ TPR gives ↑ MABP
- stimulates CA center: ↑ CO gives ↑ MABP
cardio-pulmonary reflexes
- overview
- receptors: imbedded in walls of the heart, large thoracic vessels, and lungs
- effect: modify vasomotor tone, heart rate, breathing
- innervation: afferents project with the vagus nerve
- ventricular receptors
- activation: greater than normal increases in diastolic or systolic pressure
- effect: strong depressor
- Bezold-Jarisch reflex
- severe depressor response caused by ventricular distension
- results in hypotension, bradycardia, and even fainting (may explain fright response in some)
- hypertension can make a person more susceptible to evoking the reflex
- somatic afferent reflexes
- types of responses
- pressor response: increases in blood pressure and heart rate
- depressor response: decreases in blood pressure and heart rate
- stimulation of somatic afferents generally cause a pressor response
- example: increased BP, heart rate in response to pain
- some have depressor responses, though the mechanism and function is unknown
summary of regulation
- baroreceptor reflex: dominates control
- (+) CI: ↓ HR directly reduces HR (M-ACh)
- (–) VC: ↓ TPR less arterial, venous vasoconstriction (α1 adrenergic)
- (–) CA: ↓ HR, contractility less SA node, myocyte stimulation (β1 adrenergic)
TABLE: Receptors in the Cardiovascular System
|
| location | action |
| M-ACh (M1) | SA node | ↓ heart rate |
| N-ACh (ganglionic) | autonomic ganglia | postganglionic EPSP |
| α1 adrenergic | arterioles, veins | vasoconstriction |
| β1 adrenergic | SA node cardiac muscle cells | ↑ heart rate ↑ contractile strength |
| β2 adrenergic | some arterioles | vasodilation |
| guanylyl cyclase | arterioles | vasodilation |
- receptor affinities
- norepinephrine: strong with α1, β1 (α and β)
- epinephrine: strong with β2, β1 (primarily β)
- mathematical relationships
- influences on stroke volume
- ↑ preload (HR): (–) effect
- ↑ afterload (MABP) (–) effect
- ↑ contractility (β1 stimulation): (+) effect
- reflex can be overridden
- emotions
- Cushing’s phenomenon (central chemoreceptors)
- peripheral chemoreceptors
- cardiopulmonary reflexes
- volume receptors (JGA in the kidney)
- local metabolites
Arterial Blood Pressure and Pulse
measurement of arterial blood pressure
- sphygmomanometry: most common method of measuring arterial blood pressure
- cuff pressure is increased above arterial blood pressure, occluding the pulse
- systolic: spurting of blood into arteries, causing audible turbulence and palpable radial pulses
- diastolic: reestablishment of laminar flow, causing loss of turbulence
- Korotkoff’s sounds: sound of turbulent flow heard during measurement of blood pressure
- average values
- young adult males: 120/80
- young adult females: 110/70
arterial pressure wave
- arterial pulse wave: propagating expansion of the arterial walls
- initiated at the root of the aorta upon ejection of a stroke of blood
- rate: 5-15 m/s (faster than flow velocity of 0.3-0.5 m/s)
- length: 5-7 m (longer than the longest single path in the cardiovascular system)
- can be felt upon palpation of an artery
- partially reflected by arterial bifurcations, small caliber vessels deep in arterial tree
- normally, only arrive back at root after aortic valve has closed
- with stiffened arterial tree, velocity is increased
- can arrive back at root while aortic valve is still open
- increases peak systolic pressure, pulse pressure
Capillary Function
anatomical considerations
- size
- internal diameter: 8 μm or less
- length: 0.5 to 1.0 mm
- density: correlates with metabolic activity of the tissue
- heart muscle: 2500-4000 capillaries / mm3
- skin: 100 capillaries / mm3
- pores: slit-like openings in capillary walls
- found at junctions of endothelial cells
- vary in size and number in different capillaries
- large: liver and marrow (allow passage of proteins in liver, RBCs in marrow)
- small: small (reduce, prevent loss of proteins and cellular elements from the IV space)
- occupy only about 0.02% of capillary surface area
movement of substances across the capillary wall
- diffusion: passive movement across a concentration gradient
- water soluble, fat insoluble: limited to diffusion through pores (inorganic ions, water, glucose, urea)
- fat soluble: can pass across the wall at any point (O2, CO2)
- responsible for vast majority of substance transfer
- filtration/reabsorption: movement due to pressure differences between lumen, interstitial fluid space
- fluid (filtrate) moves through the pores, carrying all solutes small enough to pass through
- mechanism
- pressure components
- hydrostatic pressure: capillary blood pressure (tissue hydrostatic pressure assumed to be zero)
- causes filtration, opposes reabsorption
- declines steadily along the length of the capillary (~32 to ~15 mmHg)
- oncotic pressure: osmotic pressure difference between plasma, interstitial fluid
- develops due to a difference in protein concentration between the fluids
- ~25 mmHg
- capillary exchange
- filtration: initial segment of the capillary (hydrostatic pressure exceeds oncotic, tissue pressures)
- reabsorption: final segment of the capillary (oncotic, tissue pressures exceed hydrostatic pressure)
- responsible for only a small portion of substance transfer, relative to diffusion
- causes of edema
- abnormal, sustained rise in systemic pressure
- reabsorption is reduced, resulting in edema if this exceeds the capacity of the lymphatics to drain fluid
- secondary to several cardiovascular diseases
- decrease in [plasma protein]
- oncotic pressure falls, causing a decrease in the force opposing filtration and promoting reabsorption
- secondary to starvation, kidney diseases, or liver diseases
- abnormally high permeability of the capillary wall
- filtration is increased
- secondary to chemicals such as histamine, bacterial toxins
- obstruction of lymphatic vessels
- drainage of the interstitial fluid space is decreased
- secondary to tumors, surgical complications, or parasites / infections
control of capillary blood flow
- control point: pre-capillary sphincter
- contraction: narrows opening, restricting passage of blood
- relaxation: expands opening, allowing greater passage of blood
- control primarily involves local metabolites rather than nerve activity
- vasomotion: rhythmic contraction and relaxation of pre-capillary sphincters
- spontaneously occurs even during tissue rest, constant metabolism
- due to highly localized changes in metabolite concentration
The Systemic Venous System
effects of gravity on distribution of venous blood
- gravity works against adequate circulation
- standing human: 70% of systemic circulation below the level of the heart
- gravity increases pressure of blood in direct proportion to distance below the heart
- gravity decreases pressure of blood in direct proportion to distance above the heart
- in venous return, gravity is potentially detrimental
- causes distension of systemic veins
- can allow pooling of blood, reducing cardiac output
- pressure alone can drive venous return in the recumbent individual
- pressure at entrance to veins: 15 mmHg
- pressure near RA: ~0 mmHg
- accessory mechanisms are needed for venous return in the upright individual
accessory factors promoting venous return in upright humans
- neurally-induced contraction of venous smooth muscle
- drive: sympathetic adrenergic vasoconstrictor neurons
- venous capacity is kept from increasing, blood does not accumulate
- pumping action of skeletal muscles
- valve: flaps of endothelial tissue that prevent backflow in the veins
- localized primarily to the limbs
- pumping of skeletal muscles causes unidirectional movement back towards the heart
- respiratory pump
- inspiration: drives return towards the heart
- enlarged thorax: fall in intrathoracic pressure
- large veins near the heart are thin enough that this reduces IV pressure
- creates a pressure gradient that favors flow of blood from extrathoracic regions
- descent of the diaphragm: rise in abdominal pressure, further increasing return
- expiration: backflow prevented by valves
venous (jugular) pulse
- external jugular veins: exhibit pulsations in the neck during each beat
- result from transient RA pressure increases
- contraction: a wave
- ventricular filling/release (bulges affect atria): c wave, x descent
- atrial filling/release: v wave, y descent
- especially evident when the head is in a lower position than the feet
- certain valvular defects, cardiac arrhythmias can predictably alter jugular pulse
The Pulmonary Circulation
hemodynamics of the pulmonary circulation
- pressures
- right ventricle systolic: 22-25 mmHg diastolic: 0-5 mmHg
- pulmonary artery: systolic: 22-25 mmHg diastolic: 8-10 mmHg
- pulmonary capillary: 6-8 mmHg
- left atrium: 5-7 mmHg
- flow
- blood flow is necessarily identical to the amount flowing through the systemic system
- driven by a small pressure gradient
- pulmonary arteries are shorter, wider than systemic counterparts
- resistance of pulmonary system is thus quite low
- high distensibility of the pulmonary system: illustrations
- cardiac output
- resting: 5 L/min
- exercising: 25 L/min
- accompanied primarily by enlarging of pulmonary vessels, rather than increase in pulmonary pressure
- surgical removal of one lung
- results in diversion of entire normal cardiac output to one lung
- pulmonary pressure still does not increase, again due to distensibility of the vessels
pulmonary artery (capillary) wedge pressure
- clinically useful
- filling pressure for the left ventricle
- determines left ventricular cell lengths at end-diastole
- difficult measurement to make
- pass a catheter into R side of the heart via systemic veins
- pass it into pulmonary circulation until it wedges in a small vessel
- recorded pressure is close to that of the L atrium
distribution of blood within the lungs
- highly susceptible to gravity
- pressures within circulation are low
- vessels are distensible
- pressure varies with position relative to heart
- apex: above the heart; relatively lower pressure
- base: below the heart; relatively higher pressure
- amount of blood perfusing these regions differs in a resting person, can vary more with upright individual
filtration/reabsorption in the lungs
- normal individuals: alveoli are “dry”
- pulmonary capillary pressure less than plasma oncotic pressure
- interstitial fluid volume remains normal
- pulmonary edema: accumulation of fluid in the interstitium and alveolar space
- commonly caused by left heart failure, which causes blood pooling in the pulmonary circulation
- can also be caused by mitral, aortic valve stenosis
blood volume in lungs
- pulmonary blood volume: 15-20% of total blood volume
- varies slightly with changes in body position
- largest when an individual is recumbent
- smallest when upright
- pulmonary edema manifests more when an individual is recumbent
regulation of pulmonary blood flow
- sympathetic innervation
- sympathetic vasoconstriction
- function: not well understood; may not be important
- local regulatory mechanisms
- hypoxia: vasoconstriction (opposite that in systemic circulation)
- must develop in the air passages, not in the blood
- acts to reduce flow of blood through regions in which O2 supply is inadequate for exchange
- high O2: vasodilation
- can, to some degree, act as a reservoir for blood
- can accept or give up significant quantities of blood
- can aid cardiac filling for a few beats or help maintain appropriate capacity-volume relationship
