LV Function: Heart as a Pump

Question 1

Describe the cellular ultrastructure of the myocardium important for contraction.

Answer 1

Myofibrils made of thick and thin filaments (sarcomeres in series)
o Sarcomere length varies between 2.2 to 1.8 microns
Myosin thick filaments
o Heads that interact with thin actin filaments
Titian
o Giant molecule attaching myosin to Z line
o Long, flexible
o Provides elasticity to myocyte
Actin thin filaments
o Arise from each Z line, overlap with myosin thick filaments
o Contain troponin = interacts with myosin heads

Question 2

Explain the process of calcium activation and its control of contraction of the myocyte.

Answer 2

• AP conducted down invaginations of sarcolemma
• Changes membrane permeability to Ca2+ → inward flow of Ca2+
• Triggers main Ca2+ release from sarcoplasmic reticulum
• Ca2+ binds troponin C → conformational change in troponin C
• Positions actin and myosin filaments → initiates contraction

Cross-bridge cycling
o ATP binds, myosin head dissociates from actin
o ATP hydrolysis → cocks myosin head
o Head binds adjacent actin
o Phosphate released → Power stroke: actin displaced about 10 nanometers
o ADP released, myocin head back to original state (rigor state)
• Ca2+ reduced by ATP-driven pumps (Na+/Ca2+ exchanger)
o Occurs quickly (Ca2+ declines before force of myocyte is maximal)
o Relaxation rate = controlled by rate of detachment from actin and myocin (not Ca2+-dependent process)
• Higher Ca2+ concentrations → greater force contraction

Theories:
o More Ca2+ recruits more cross-bridge cycling
o More Ca2+ activates more troponin control systems
o ATPase may respond in graded fashion to Ca2+ concentration
o Ca2+ may change light chain phosphorylation
o Ca2+ release may increase with increasing preload
o Number of cross-bridge cycles my depend on preload by changes in cell shape

Question 3

Measuring cardiac contractility

Answer 3

Force generation 
•	LV pressure generation
•	Rate of pressure generation
Stroke work
•	End systolic pressure volume relation
•	Cardiac output and stroke volume
•	Ejection fraction (SV/LV EDV) = most commonly used technique!

Question 4

Discuss the effects of length changes on myocardial cellular force development and whole chamber force development.

Answer 4

• Increase length = increase preload → greater force of contraction

Ventricular fiber orientation
o Fibers positioned as counter-wound helices
o Change orientation based on transmural location in LV wall
• Endocardial fibers: right-handed helix
• Epicardial fibers: left-handed helix
o Surface fibers oriented to long axis; midwall fibers are circumferential
o Myocytes bound together in sheets and sheet motion rather than myocyte thickening defines much of what is “radial thickening”
o Rotation of apex is counterclockwise, but rotation of base is clockwise

Question 5

Describe the concepts of preload and afterload, both at the cellular level and at the whole heart level.

Answer 5

Afterload: force against which single muscle cell must contract
o Important in controlling amount of output cardiac chamber must generate
o Increase afterload → decrease in velocity of contraction
• Velocity correlates with amount of force generated
o Estimated by Law of Laplace:
• End Systolic wall stress = (BP x r) / (2 x wall thickness)
• Defines afterload better than simply BP alone

Preload: heart can adjust preload to afterload to generate more force
o Clinically measured:
• LV end diastolic pressure
• Pulmonary capillary wedge pressure
• Non-invasive measurements of filling pressure
• LV end diastolic volume
• LV end diastolic dimension

Rate of stimulation (Treppe or Bowditch Effect)
o As increase HR, increase force development
o But if increase HR too much, start to decrease force development
o Peak contractile force: 150-180 stimuli per minute

Question 6

Describe the Frank-Starling mechanism of whole heart performance and how it helps explain ventricular function.

Answer 6

• Describes effect of enhanced preload and effect of increasing inotropy (force of muscle contraction) on ventricular performance
• Can plot Starling curves on graph of preload (LV end diastolic volume) vs Cardiac output
• With cardiac damage, decreased CO → curve shifts downward and to right

Question 7

Explain what adrenergic stimulation does to myocardial function and how it affects pressure volume loops and Frank-Starling curves

Answer 7

Beta-adrenergic agonist
o Another way to deal with increased afterload
o Stimulate beta-adrenergic receptor → G protein stimulation of adenyl cyclase → increase cAMP
o Stimulates PKA:
• Stimulates metabolism (glycolysis, lipolysis, citrate cycle)
• Phosphorylation of Ca2+ channel protein → increased inward flow of Ca2+
o Net result: increase rate of contraction, force development, rate of relaxation

P-V loops:
o Enhanced contractility → increase in stroke volume, reduction in end-systolic volume, greater stroke work by heart

Question 8

Describe the pressure volume loop and also understand what loading conditions do to change the pressure volume loop

Answer 8

• Describes events of cardiac cycle by plotting LV volume vs LV pressure
• Stroke Work = Volume x pressure
Increase Preload:
o Increase volume of venous return to heart → heart fills to greater volume
o Stroke volume increases to compensate increased filling
o So: increase preload→ greater CO (higher stroke volume and stroke work)

Increase afterload:
o Initially: decline in ejection
o Stroke volume drops
o Heart ejects to higher end-systolic volume than normal
o Venous return continues
o Preload augmentation occurs over next few beats
o Heart begins to fill to greater volume → ejection returns to normal stroke volume
o Heart pumps in state of enhanced preload and increased afterload

Question 9

Define the concept of ejection fraction and how it relates to the time volume curve of performance of the left ventricle.

Answer 9

• Highly useful, non-invasive measure of ventricular performance
• (LVEDV – LVESV) / LVEDV or SV/LVEDV
• Not a measure of pure contractility
o Highly “load dependent”
o High preload or contractility → increases EF
o High afterload or decreased contractility → decreases EF

Question 10

List ways that cardiac function changes: global, regional, and synchronous.

Answer 10

• Many disease states do not affect heart uniformly
• Changes in shape or wall thickness → affect performance of individual cells
Ischemic heart disease:
o Reduced global performance
o Regional effects:
• Ischemic zone: cells die or no longer function
• Border zone: cells under higher preload and afterload due to stretch and tethering effects
• Cells at distance: unaffected or hyperdynamic (adrenergic stimulation)
• Gradually affected by changes over time

Change in synchrony of contraction
o Diseases of electrical activation → change sequence of contraction
o Result: dyssynchrony
o Reduces pump performance