Contractility

Question 1

systole - defined

Answer 1

*left ventricle (and right ventricle) contract
*sending blood out the pulmonic and aortic valves

Question 2

diastole - defined

Answer 2

*left ventricle (and right ventricle) relax
*ventricles allow themselves to fill with blood to prepare for the next heartbeat

Question 3

LV ejection fraction (EF) - defined

Answer 3

*EF is an index of ventricular contractility (how much blood the left ventricle ejects in 1 heartbeat)
*normal EF is > 50% (generally 50-70%)

*in essence: EF = (amount of blood pumped out of the ventricle) / (total amount of blood in ventricle)

Question 4

LV ejection fraction - formula

Answer 4

EF = SV / EDV

note: SV = EDV - ESV

EDV = end diastolic volume (represents when the LV has the most blood in it)
ESV = end systolic volume
SV = stroke volume

Question 5

stroke volume (SV) - formula

Answer 5

SV = EDV - ESV

EDV = end diastolic volume
ESV = end systolic volume

Question 6

gold standard test used to measure LV ejection fraction

Answer 6

cardiac MRI

Question 7

cardiac output - defined

Answer 7

*the amount of fluid pumped through the heart in 1 minute (measured in L/min)

-note: organs receive different amounts of cardiac output (ex. brain receives 15%, kidneys receive 20-25%, heart receives 5%)
-normal range: 4-8 L/min (but there is significant variation related to body size)

Question 8

cardiac output - formula

Answer 8

CO = SV x HR

CO: cardiac output (measured in L/min)
SV: stroke volume (SV = EDV - ESV)
HR: heart rate

Question 9

cardiac index

Answer 9

*a measure used in many intensive care settings to account for body size by normalizing the cardiac output relative to body surface area
*cardiac index = CO / body surface area
*normal cardiac index ranges from 2.5 L/min/m2 to 4.5 L/min/m2

note: a cardiac index < 1 L/min/m2 is not compatible with life

Question 10

a cardiac index < ? is incompatible with life?

Answer 10

cardiac index < 1 L/min/m2 is not compatible with life

Question 11

Swan-Ganz catheter

Answer 11

*small tube, typically placed in someone’s jugular vein or subclavian vein
*allows for the direct measurement of pressure and obtain blood samples throughout the right-sided circulation system
*used to calculate cardiac output (based on Fick Principle)

Question 12

Fick Principle as a measure of cardiac output

Answer 12

CO = (rate of O2 consumption) / (arterial O2 content - venous O2 content)

Question 13

examples of how different factors can affect CO using Fick Principle

Answer 13

*if the rate of O2 consumption increases (exercise, increased metabolism, etc), the cardiac output increases
*if cardiac output decreases (and metabolism remains the same), then the cells/tissues of the body get their oxygen by attempting to extract more oxygen from the bloodstream

Question 14

Fick Principle: obtaining the measures

Answer 14

*arterial O2 content: measured from a peripheral artery
*venous O2 content: measured from the pulmonary artery (via the Swan-Ganz catheter)
*a commonly used value for rate of O2 consumption at rest is 125 mL O2/min/m2
*however, OXYGEN CONTENT can be DIRECTLY CALCULATED using:
([Hb] x 1.34 x O2 sat) + 0.003(PaO2)

Question 15

thermodilution method for measuring CO

Answer 15

*measures CO (using Swan-Ganz catheter) by extrapolating flow based on the change in temperature at distal post after injection of a cooled solution at a more proximal port

Question 16

factors that affect stroke volume

Answer 16

*contractility: increase in contractility increases SV
*preload: increase in preload increases SV
*afterload: DECREASE in afterload increases SV

Question 17

sarcomeres in the heart - general principles

Answer 17

*sarcomeres are the heart’s building blocks
*many sarcomeres are contained within a single muscle cell
*muscle cells are organized into myofibrils, which are themselves organized into muscle fibers
*muscle fibers are organized into different regions of the heart, such as the endocardium, myocardium, and epicardium

Question 18

sarcomeres - bands & filaments

Answer 18

*recall: myosin is the thick filaments, and actin is the thin filaments
*I band: actin + titin
*H band: myosin only
*A band: actin-myosin overlap + myosin only
*with contraction, both the H and I bands narrow, but the A band stays the same

Question 19

sarcomere electron micrograph

Answer 19

Question 20

troponin complex

Answer 20

*composed of troponin C, troponin I, and troponin T
*when calcium becomes bound to specific sites in the troponin complex, a series of protein structural changes such that tropomyosin is rolled away from myosin-binding sites on actin, allowing myosin to attach to the thin filament and SHORTEN THE SARCOMERE, which produces force

Question 21

troponin C

Answer 21

*binds to calcium ions to produce a conformational change in troponin I
*part of the troponin complex

Question 22

troponin T

Answer 22

*binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
*part of the troponin complex

Question 23

troponin I

Answer 23

*binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place
*part of the troponin complex

Question 24

actin and myosin cross-links during contraction

Answer 24

*for most circumstances, the more actin-myosin cross-links, the more force is generated
*actin-myosin will continue to form cross-links until enough force has been generated for the sarcomere to shorten
*if only 1 actin-myosin cross-link is needed to generate sufficient force to shorten, then it will obviously shorten faster than if 4 actin-myosin cross-links were needed

Question 25

titin: contraction & relaxation

Answer 25

*during contraction, titin gets compressed like a spring as myosin travels down the actin filament
*during relaxation, the potential energy stored in the spring of titin gets released as the myosin dissociates from actin, and results in the RECOIL of the left ventricle (causes the pressure in the left ventricle to decrease such that it is lower than the left atrial pressure, so that the LV is sucking blood in)

Question 26

sarcolemma

Answer 26

*myocardial cell membrane
*has deep invaginations with the purpose to get extra-cellular fluid (containing CALCIUM) as close to the sarcomere & sarcoplasmic reticulum as possible
*the sarcoplasmic reticulum contains calcium used to contract the heart muscle, but MOST of the contraction is generated from the extra-cellular fluid

Question 27

microphysiology of CONTRACTION in the heart

Answer 27

1. as depolarization travels down the cell membrane, the voltage-gated calcium channel opens (allowing extra-cellular calcium to flow into the cell)
2. calcium from the voltage-gated calcium channel activates the ryanodine calcium channel (of the sarcoplasmic reticulum)
3. calcium from both the voltage-gated calcium channel and ryanodine calcium channel bind to troponin, allowing for myosin-actin cross-bridging and subsequent sarcomere contraction

Question 28

microphysiology of RELAXATION in the heart

Answer 28

1. both the voltage-gated calcium and the ryanodine calcium channel are closed
2. using ATP, the SERCA-2 ATPase on the sarcoplasmic reticulum (SR) transports calcium BACK INTO THE SR
3. using the energy stored in the sodium gradient between the intra- and extra-cellular environments (extra- concentration > intra), sodium goes down its gradient in order to move calcium against its gradient and get CALCIUM OUT OF THE CELL (allow one sodium into cell to get one calcium out)
4. with calcium removed, troponin prevents myosin-actin cross-bridge formation, preventing contraction (ie. allowing relaxation)

Question 29

microphysiologic ways to increase contractility

Answer 29

1. allow more calcium channels to open for more calcium to enter the myocyte
2. increase SERCA-2 activity to allow sarcoplasmic reticulum to hold more calcium (such that it can release more calcium)
3. make it easier for troponin-C to move out of the way to allow for more actin-myosin cross-links to form

Question 30

beta-1 receptor and increases in contractility

Answer 30

*the binding of an agonist (epinephrine) to the beta-1 adrenergic receptor increases contractility/relaxation in several ways:
1. increased influx of calcium ions (by phosphorylation of calcium channel)
2. increased removal of calcium ions for relaxation by phosphorylation of phospholamban (which prevents it from inhibits SERCA-2)
3. phosphorylation of troponin-I results in a faster relaxation (more difficult for it to bind to calcium; as such, breaks up actin-myosin cross-links)

Question 31

beta-1 receptor agonists

Answer 31

*epinephrine
*norepinephrine
*isoproteronol
*dopamine
*dobutamine

Question 32

beta-1 receptor antagonists

Answer 32

beta blockers (metoprolol, carvedilol)

Question 33

effects of a phosphodiesterase inhibitor on the beta-1 receptor

Answer 33

*cAMP is broken down by phosphodiesterase
*inhibition of phosphodiesterase allows cAMP to stick around longer (allowing for increased beta-1 activity)
*ex. milrinone

Question 34

heart rate and contractility - Bowditch Effect (Force Frequency)

Answer 34

*at higher heart rates, there is less time for the Na/K ATPase pump to restore electrolyte gradients
*as a result, the intra-cellular calcium increases because there is less time for the Ca/Na exchanger to remove calcium from the cell
*more calcium will be removed by SERCA, which means more calcium will be released by the sarcoplasmic reticulum
*NET RESULT: INCREASED HEART RATE → INCREASED CONTRACTILITY

Question 35

calcium and contractility - general principles

Answer 35

*higher intra-cellular calcium means more actin-myosin cross-bridges
*in general, more actin-myosin cross-bridges results in more force being generated
*high heart rate increases intra-cellular calcium (Bowditch Effect)
*inhibition of Na/K ATPase inhibits the Na/Ca exchanger, thus increasing intra-cellular calcium

Question 36

mavacemten

Answer 36

*a novel myosin inhibitor
*reduces cardiac contraction by stabilizing the state of relaxation of beta-cardiac myosin

Question 37

omecamtiv

Answer 37

*a novel myosin activator
*enhances cardiac contraction