Download Normal Heart Pumping: When the ventricles are in diastole they

Normal Heart Pumping:
 When the ventricles are in diastole they fill with blood.
 When the ventricles are in systole they are contracting to eject blood.
o 50 to 60 percent of the blood is ejected from the Ventricles.
 See Image labeled “Normal Heart” below if this is confusing
Systolic Heart Failure:
 Larger ventricular chamber leads to stretched ventricles
 Stretched ventricles = weaker contraction
 Weaker contraction = less blood ejection
 If confused see Image below labeled Systolic Heart Failure
Diastolic Heart Failure
 The walls of the ventricles are enlarged/stiff
 This leads to a decrease in the amount of fluid the ventricles can hold
 Though the force of contraction is the same, there is less fluid to kick out.
Excitation Contraction:
 Depolarization Ca Released from SR  Myocyte Contraction Ca Uptake into SR
Myocyte Relaxes
 Pictures worth a thousand on this one:
Role of Calcium
 Step 1- ATP binds to myosin. ATP serves two roles. A. Serves as an allosteric regulator
causing myosin to release from actin. B. Provides and energy source for conformational
change of myosin. This is what is called “crossbridge energization”
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Step 2- Breakdown of ATP to ADP and inorganic phosphate occurs on the myosin head.
Head pivots to a 90 degree angle to the thick and thin filaments into the cocked position.
This causes tip of myosin to move along the actin filament so it lines up with a a new
actin monomer two monomers further along the actin filament.
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Step 3- The cocked myosin heads binds to a new position on actin filament.
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Step 4. Phosphate release from the myosin head triggering the POWERSTROKE. This
is where the force is developed. This is a conformational change in which the myosin
heads bends 45 degrees and pulls the actin filament toward the tail of the myosin
molecule.
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Step 5. The dissociation of ADP from myosin completes the cycle. As long as more
ATP is present, this cycle continues until calcium is resequestered and intracellular
calcium levels decrease.
Labs:
 Troponin (T or I) - the most sensitive and specific test for myocardial damage released
during MI from the cytosolic pool of the myocytes.
o Approximate peak release in 12 hours in MI
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Creatin kinase (CK) is relatively specific when skeletal muscle damage is not present.
o CK has two subunits –
 CK-M (muscle),
 CK-B (brain) and mitochondrial CKmi
o CK-MM (CK-1) - skeletal muscle 95%, heart 42%, smooth muscle 2 – 3%
o CK-MB (CK2) – skeletal muscle 3%, heart 28%, smooth muscle 1 – 5%
o CK-BB (CK-3) – skeletal muscle 1%, heart 1%, smooth muscle 87%
 Approximate peak release in 10 to 24 hours.
 Myoglobin (2 hours) has low specificity for MI – it is high when muscle tissue is
damaged but it lacks specificity.
Re-uptake of Calcium in the SR:
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The rate of myocardial relaxation is referred to as “lusitropy”
Key proteins that  intracellular Ca2+:
o Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA)
o Na+/Ca2+ Exchanger (NCX)
o Sarcolemmal Ca2+-ATPase
Calcium Control:
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Amount of Ca2+ released by the SR is determined by:
o Size of the inward Ca2+ current
o Amount of Ca2+ previously stored in the SR
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The greater the intracellular calcium concentration, the more the calcium that is bound to
TnC and the more the force that is generated between actin and myosin.
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Conversely the Sympathetic System plays a role in providing a positive lucotropy in
order to increase relaxation and allow more filling time for the ventricles.
Sympathetic Effects on Excitation of the Heart:
1. Phos of L-type Ca channels by catecholamines increases channels probability of opening
and the average time the channel remains open once activated.
2. Phos of ryanodine receptor increases the amount of Ca released by the SR. This is part of
the fight or flight response allowing for sudden increases in inotropy and CO during
exercise or stress.
Essentially: Greater intracellular calcium leads to more calcium bound to TnC which leads to
more force is generated between actin and myosin. Also, increased TnC affinity for calcium
means that at any given calcium concentration, there is greater force generated.
Sympathetic Effects on Relaxation of the Heart
1. PLB inhibits SERCA, but phosphorylation by catecholamines causes removes the
inhibitory effect and SERCA pumps Ca into SR more rapidly.
2. When the SR pump runs faster, more Ca2+ is stored in the SR and less is returned to the
extracellular space. This leads to a greater amount of Ca that can be released during the
subsequent contraction.
3. Calcium binding to TnC can be modulated by PKA phosphorylation of TnI, which
increases calcium dissociation from TnC.
HR effect on Contractility:
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 HR
 contractility
 HR
 contractility
Referred to as the “Treppe” or Bowditch Effect
Drug Side Note: Digoxin
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Cardiac glycosides inhibit Na+-K+ ATPase
Intracellular Na+ concentrations rise
Higher intracellular Na+ alters function of Na+-Ca2+ exchanger
This leads to a rise in intracellular Ca2+
 muscle tension
Intrinsic Causes of Heart Failure

For example, defects in PLB are a cause of multiple forms of cardiomyopathy in humans
leading to systolic dysfunction and HF.
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In systolic heart failure, ECC can be impaired at several different sites.
o First, there can be decreased influx of calcium into the cell through L-type
calcium channels (resulting from impaired signal transduction), which decreases
subsequent calcium release by the SR.
o There can also be a decrease in TN-C affinity for calcium, so that a given increase
in calcium in the vicinity of the troponin complex has less of an activating effect
on cardiac contraction.
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In some forms of diastolic heart failure, there is evidence that the function of the SR
ATP-dependent calcium pump is impaired.
o This defect would retard the rate of calcium uptake by the SR and reduce the rate
of relaxation, leading to diastolic dysfunction.
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TensionTension is the same as force. The two elements that contribute are:
o Elastic element- PASSIVE or resting tension
o Contractile element- ACTIVE tension
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LengthThe length of the muscle fibers influences force
o Starling relationship: tension (active and passive) vs. length
o  sarcomere length  Ca2+ sensitivity of the myofilaments
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Myosin- Contractile Component
o Causes active tension
Titin
o Elastic elements
o Passive Tension
Passive tension is an important factor in cardiac muscle because it is part of the diastolic
wall tension that determines the extent of filling of the heart and its subsequent stroke
volume.
Recent evidence suggests that increased sarcomere length increases Ca sensitivity of
TnC, thereby increasing Ca binding leading to increased force.
Heart Failure Effects:
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Systolic Dysfunction:
o LV contractility is depressed
o End-systolic pressure-volume line is displaced downward and to the right
o  capacity to eject blood into the high pressure aorta
o Ejection fraction is DEPRESSED
o End-diastolic pressure is NORMAL
Diastolic Dysfunction:
o Diastolic pressure-volume line is displaced upward and to the left
o  capacity to fill ventricle at low atrial pressures
o Ejection fraction is NORMAL
o End-diastolic pressure is ELEVATED
Excitation/Contraction/Relaxation Coupling
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Two sources of Ca2+ during EC coupling
o Extracellular is 20%;
o SR is 80%
Three pathways for restoration of low [Ca++]i
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o Sacroplasmic Ca2+-ATPase
o Plasma membrane Na+-Ca++ exchanger
o Plasma membrane Ca2+-ATPase
 cAMP activation (phosphorylation) of protein kinase A (PKA)
Enhanced by  -adrenergic agonists
o Mediated by Gs
Reduced by M2 cholinergic agonists
o Mediated by Gi
PKA phosphorylation
o Inotropy
o Lusitropy
Diastolic Heart Failure
Normal Heart
Systolic Heart Failure