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What are the components of myofibrils in myocytes?
actin (thin filaments), myosin (thick filaments), titin (structural proteins), troponins/tropomyosin (regulatory proteins)
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What is the sarcomere?
functional unit of contraction; Z-disc to Z-disc
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What are the components of the troponin complex?
- TnC- binds to Ca2+
- TnI- inhibits actin unless Ca2+ is bound to TnC
- TnT- distributes TnI effects
- Tropomyosin- supports actin
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What is the clinical significance of the troponin complex?
elevated serum troponins indicate heart injury from myocarditis, ischemia, toxic injury
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Give a very general overview of myocardial cell contraction.
cell depolarizes--> Ca2+ enters cell--> Ca2+ triggers release of more Ca2+ from SR--> increased cytosolic Ca2+ leads to TnC binding and release of TnI inhibition--> actin and myosin filaments contact one another--> cross-bridge cycling--> myocyte contracts--> Ca2+ re-sequestered in SR--> myocyte relaxes
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Describe excitation-contraction coupling at the cellular level.
- 1. depolarization by entrance of Na+
- 2. Increased conductance across L-type Ca2+ channels
- 3. increased Ca2+ entry into cells triggers Ryanodine receptor
- 4. increased Ca2+ release from SR
- 5. Increased cytosolic Ca2+
- 6. Ca2+ binds TnC and releases inhibition by TnI
- 7. Meromyosin heads activated by hydrolysis of ATP
- 8. Cross-bridge-cycling b/w myosin and actin
- 9. Z-lines move closer, creating tension, eventual shortening
- 10. Ca2+ is actively returned to SR by SERCA--> relaxation
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___________ is the prime regulator of the strength of contraction of the cardiomyocyte; this is called ___________.
Calcium availability; inotropy (contractility)
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Describe the functions and regulation of SERCA.
- SERCA (sarcoendoplastic reticulum calcium ATPase) is a pump that moves calcium back into the sarcoplasmic reticulum following contraction, leading to relaxation by an active process.
- SERCA is regulated by/inhibited by phospholamban when it (plb) is not phosphorylated.
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Describe the functions and regulation of phospholamban.
- Phospholamban is a membrane protein that depresses/inhibits the activity of SERCA, preventing reuptake of calcium into the SR and relaxation.
- Phospholamban is only active when it is phosphorylated by protein kinase A, which is activated by cAMP when NE binds to beta-receptors.
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Sympathetic activation leads to ________ inotropy and _________ lusitropy by...
increased; increased; activating cAMP (protein kinase A) and allowing more Ca2+ into the cell--> + inotropy and by activating cAMP (protein kinase A phosphorylates phospholamban, deactivating it), allowing faster reuptake of calcium by SERCA--> + lusitropy
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What effect does a positive inotrope or positive inotropic stimulus/drug have on cardiomyocytes?
increases the strength of cardiomyocyte contraction
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What are examples of positive inotropic stimuli/drugs? (4)
sympathetic activation, catecholamines, digoxin, pimobendan
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What is the function of the Na+CA2+ exchanger?
removes Ca2+ and takes up Na+ into the cell during relaxation of the cardiomyocyte (minor since most of the Ca2+ comes from the SR and most returns to the SR via SERCA)
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In this intact heart, velocity of shortening is inversely related to _________.
afterload
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Describe in general terms the process of excitation-contractin coupling at the level of the intact heart.
- 1. [isovolumetric relaxation- end of T wave- repolarization] ventricle actively relaxes; IV pressure drops
- 2. atria fill and pressure in atria exceeds that of the ventricles
- 3. AV valve opens and rapid ventricular filling begins; passive early filling
- 4. [diastasis] mid-diastol, ventricular filling rate is markedly reduced
- 5. [end P wave- atrial depolarization] end of diastole, atria actively contract, creating EDV
- 6. [isovolumetric contraction- end QRS complex- ventricular depolarization] AV vales close/semilunar valves still closed; myocardium contracts and rapidly builds pressure
- 7. ventricular pressure eventually exceeds aortic pressure, causing aortic valve to open and blood to be ejected; muscle shortening
- 8. mid-to-late systole, ejection rate is slower; atria have begun to fill again
- 9. ejection ends, semilunar valves close; repeat cycle
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What is cardiac inotropism?
the inherent rate at which actin and myosin interact; aka contractility/contractile force; depends on availability of Ca2+
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How is inotropy measured in a muscle strip experiment?
estimated by measuring the maximum velocity of contraction that can be achieved from a minimally afterloaded muscle strip with preload/stretch kept constant.
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What are some causes of decreased inotropy? (3)
hypoxia, metabolic acidosis, most anesthetic agents
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What are some causes of increased inotropy? (5)
sympathetic activation, addition of calcium salts, positive inotropic drugs (digitalis glycosides), calcium-sensitizing drugs, drugs that block phosphodiesterases
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What are physiologic mechanisms by which inotropy can be increased at the cellular level? (3)
add calcium salts, sympathetic activation, catecholamines, and stimulation of histamine receptors in the myocardium
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What are pharmalogical methods of increasing inotropy at the cellular level? (3)
digitalis glycosides (raises cytosolic calcium by blocking Na+K+ATPase pump and activating Na+Ca++ exchanger), pimobendan (calcium-sensitizing drug), drugs that block phosphodiesterase (PDE inactivates cAMP, which allows calcium channels to stay open normally)
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How does changing the preload modify the sensitivity of actin and myosin to calcium?
changing preload changes the amount that the muscle is stretched, therefore changing the number of cross-brdges between myosin and actin prior to contraction; by stretching muscle to an optimal length (fewer cross bridges to start out), you can cause a more vigorous contraction of the sarcomere
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For the same preload, peak well tension is reduced when ____________.
inotropy is depressed (general anesthesia, hypoxia, etc)
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What is preload?
the stretch of the ventricular myocytes prior to ejection; end-diastolic volume
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What are the factors that can affect preload/EDV? (3 definitely, 2 somewhat)
venous pressure (in the ventricle), plasma volume, distensibility of the ventricle; also maybe heart rhythm b/c diastolic filling depends on diastolic interval and rhythm regularity, maybe atrial contraction
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What is the significance of preload/EDV?
positive determinant of ventricular systolic function--> increased EDV leads to increased force of contraction; the normal ventricle is highly preload sensitive--> decreased preload leads to decreased SV and CO
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What is afterload?
wall tension that must be developed to overcome impedance to ejection of blood (aortic diastolic blood pressure and impedance of arterial system= if overcome, aortic valve opens and shortening can occur to eject blood into aorta)
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How is afterload measured in the muscle strip experiments?
represented by the weight that must be moved following stimulation and muscle contraction; the weight that must be overcome for the muscle to shorten
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When does afterload reach its maximum in the intact heart?
- just before the aortic valve opens and shortening occurs to eject blood from the ventricle, afterload reaches its maximum
- according to LaPlace Relationship: tension(afterload) is proportional to (pressure x radius)/wall thickness
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How might afterload be estimated in the intact LV?
- a very crude estimate of afterload is the intraluminal pressure at the onset of ejection, ie. diastolic blood pressure; they come about this estimate because of the LaPlace relationship:
- tension is proportional to (pressure x radius)/ wall thickness
- in a normal heart we assume radius and thickness are negligible.
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How does a dilated/thin-walled ventricle affect afterload in a diseased heart?
- higher afterload (radius gets larger, thickness gets smaller)
- tension(afterload) is proportional to (pressure x radius)/wall thickness
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How does a thickened/hypertrophied ventricular wall affect afterload in a diseased heart?
- reduced afterload (radius decreases, thickness increases)
- tension(afterload) is proportional to (pressure x radius)/wall thickness
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What is the relationship between increased afterload and ventricular shortening and ejection fraction?
- higher afterload--> reduced velocity of shortening and reduced extent of LV shortening (increase in wall tension and oxygen usage)
- With increased afterload, there is an increase in tension required to force open the aortic valve; for each beat you have so much energy to develop tension and shorten--> if you're using more energy to develop tension b/c there is more resistance, then you have less energy to actually shorten.
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How does hypertension affect the afterload on the ventricle?
- hypertension leads to increased afterload
- tension(afterload) is proportional to (pressure x radius)/wall thickness
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What are the physical factors that affect afterload? (3)
aortic distensibility, peripheral vascular resistance, reflected waves of blood
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What is Treppe?
A phenomenon in cardiac muscle that occurs if a number of stimuli of the same intensity are sent into the muscle after a quiescent period--> the first few contractions of the series show a successive increase in amplitude (strength) [increased contractility with increased frequency].
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With treppe, a shortened filling time could decrease ________.
preload
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It is difficult to differentiate treppe from __________ in the intact ventricle.
increased sympathetic traffic
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Stroke volume depends on... (3)
contractility/inotropy, preload, and afterload
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What is the equation for ejection fraction? What is the normal value in SA?
EF = SV/ EDV (>0.5)
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What is the equation for shortening fraction? What is the normal value in SA?
SF= (Dd-Ds)/Dd (>0.25)
- Dd= end diastolic ventricular diameter
- Ds= end systolic ventricular diameter
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What is ejection fraction?
the fraction of blood you started with [in the ventricle] that gets ejected with each beat
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What is the Frank-Starling Law of the Heart?
in hearts with normal ventricular distensibility, an increase in venous pressure (increased stretch) leads to an increase in cardiac output (increase SV/force of contraction).
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How does the frank-starling law of the heart relate to what is happening at the level of the sarcomere?
the more stretch of the sarcomere (increased preload- to an optimal point), the farther apart the Z-discs are, the more force can be generated; with low preload, there is a lot of overlap b/w actin and myosin (Z-discs closer together to start out), less force is generated and SV decreases.
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How does the frank-starling relationship change in a patient with significant blood loss?
- with a lower body blood volume, preload is automatically lower (hypotension)--> less stretch and force generated--> less stroke volume
- The F-S curve would shift down and to the right
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How does heart failure affect the frank-starling relationship?
with heart failure there is reduced inotropy and therefore, reduced contractility--> EF and SV are low; F-S curve is low and to the right
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How does increased intropy affect the frank-starling relationship?
increased intropy, increased contractility and increased tension--> for the same preload, you will have increased force of contraction and SV; F-S curve would shift upward and to the left
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How does dilated cardiomyopathy affect the frank-starling relationship?
dilated cardiomyopathy is systolic dysfunction, so for any preload, shortening fraction and SV are low; the F-S relationship is depressed and the curve is low and to the right
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Oxygen consumption by the myocardium depends on... (3)
heart rate, myocardial tension (afterload, BP), contractile state
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What types of drugs reduce oxygen demand of the heart? (2)
beta-adrenergic blockers (decrease effect of NE, effectively decreasing HR, BP, etc.), drugs that slow HR
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When does coronary flow occur during the cardiac cycle and why?
mainly during diastole b/c during systole, wall tension is very high, so there is more resistance to flow in the coronary vessels
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How do we estimate ejection fraction in patients?
shortening fraction
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Clinically, what stages of the cardiac cycle constitute diastole?
aortic valve closure, through filling, until the mitral valve closes
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What part of the cardiac cycle constitutes diastasis?
early passive filling of the ventricles (majority of filling occurs during this period); E wave on PW Doppler
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What occurs at end-diastole?
atrial contraction/atrial kick (minority of filling, but at high HR can make up to 50% of filling); A wave on PW Doppler
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The tension in the ventricular wall at end-diastole determines ___________.
preload
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Isovolumetric relaxation occurs from _________ to __________ of the cardiac cycle.
aortic valve closure; mitral valve opening
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___________ corresponds to the peak negative pressure drop (peak negative dP/dT).
Isovolumetric relaxation
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Doppler echo measures...
direction, velocity, and quality of blood flow within a discrete sample volume (usually inflow and outflow tract)
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_________ immediately precedes active contraction, which is visible on a velocity profile from PW Doppler.
Depolarization
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The ____________ tells us about overall diastolic function of the ventricle.
diastolic pressure to volume relationship
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How do you estimate ventricular compliance/distensibility for any given EDV?
LV diastolic pressure on y-axis, LV diastolic diameter (volume) on x-axis; draw a tangent to the slope at EDV...the slope of the line= compliance/distensibility [stiffer lung--> smaller slope to tangent]
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Describe the distribution of sympathetic and parasympathetic innervation to the heart.
parasympathetic predominantly affects the SA node, AV node, and atria; sympathetic innervation is widely distributed throughout the heart
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What is chronotropy?
rate, controlled by the SA node
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What is dromotropy?
conduction, controlled by the AV node and Bundle of His-Purkinje system
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What is bathmotropy?
electrical excitability
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What is lusitropy?
relaxation
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What receptor is phenylephrine an agonist of?
alpha 1 adrenergic
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What receptor is isoproterenol an agonist of?
beta1 and beta 2 adrenergic
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What receptor is dopamine (and dobutamine) an agonist of?
alpha and beta adrenergic
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What receptor is ephedrine an agonist of?
beta and alpha adrenergic
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How does Prazosin affect the autonomic NS?
alpha 1 antagonist
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What kind of drugs are atropine and glycopyrrolate?
muscarinic receptor blockers
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What are the main energy substrates of the myocardium during aerobic and anaerobic work?
aerobic: long-chain fatty acids- metabolized using oxygen by the process of beta-oxidation within mitochondria
anaerobic: glucose by glycolysis as a consequence of ischemia, creating lactate as a by-product
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What is the significance of an increase in lactate concentration in coronary sinus blood?
it is a marker for anaerobic metabolism in the heart, ie. ischemia.
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Describe the major sympathetic signaling pathway of the heart and the steps it involves.
- Signal: NE
- Receptors: beta adrenergic
- Second messengers: cAMP, protein kinase A
- 1. NE released from sympathetic nn.
- 2. NE binds beta receptor
- 3. G stimulatory protein (Gs)is activated
- 4. Gs is a positive regulator of adenylate cyclase, which splits ATP into the second messenger, cAMP
- 5. cAMP phosphorylates Ca2+ channel by activating protein kinase A--> channel opens
- 6. more Ca2+ enters the cell, triggering more Ca2+ release from the SR
- 7. increase in heart contractility (+inotropy)
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Describe the minor sympathetic signaling pathway of the heart and the steps it involves.
- Signal: NE
- Receptor: alpha adrenergic
- Second messenger: inositol triphosphate (IP3)
- 1. NE released from sympathetic nn.
- 2. NE binds to alpha receptor
- 3. NE activates phospholipase C, which generates the second messenger, IP3
- 4. IP3 causes increased release of Ca2+ from the SR
- 5. Increased heart contractility (+inotropy)
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Describe the parasympathetic signaling pathway of the heart and the steps it involves.
- Signal: Acetylcholine
- Receptor: muscarinic receptors
- Second messenger: cGMP
- 1. Ach released from vagus n.
- 2. Ach binds muscarinic receptors
- 3. G inhibitory protein (Gi) is activated
- 4. Gi is a negative regulator of adenylate cyclase, blocking production of cAMP
- 5. Decrease in Ca2+ entry to cell, decreased contractility of atria (-inotropy)
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