Cardio1- Myocardial Contraction

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  1. What are the components of myofibrils in myocytes?
    actin (thin filaments), myosin (thick filaments), titin (structural proteins), troponins/tropomyosin (regulatory proteins)
  2. What is the sarcomere?
    functional unit of contraction; Z-disc to Z-disc
  3. 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
  4. What is the clinical significance of the troponin complex?
    elevated serum troponins indicate heart injury from myocarditis, ischemia, toxic injury
  5. 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
  6. 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
  7. ___________ is the prime regulator of the strength of contraction of the cardiomyocyte; this is called ___________.
    Calcium availability; inotropy (contractility)
  8. 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.
  9. 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.
  10. 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
  11. What effect does a positive inotrope or positive inotropic stimulus/drug have on cardiomyocytes?
    increases the strength of cardiomyocyte contraction
  12. What are examples of positive inotropic stimuli/drugs? (4)
    sympathetic activation, catecholamines, digoxin, pimobendan
  13. 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)
  14. In this intact heart, velocity of shortening is inversely related to _________.
    afterload
  15. 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
  16. What is cardiac inotropism?
    the inherent rate at which actin and myosin interact; aka contractility/contractile force; depends on availability of Ca2+
  17. 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.
  18. What are some causes of decreased inotropy? (3)
    hypoxia, metabolic acidosis, most anesthetic agents
  19. 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
  20. 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
  21. 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)
  22. 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
  23. For the same preload, peak well tension is reduced when ____________.
    inotropy is depressed (general anesthesia, hypoxia, etc)
  24. What is  preload?
    the stretch of the ventricular myocytes prior to ejection; end-diastolic volume
  25. 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
  26. 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
  27. 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)
  28. 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
  29. 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
  30. 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.
  31. 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
  32. 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
  33. 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.
  34. How does hypertension affect the afterload on the ventricle?
    • hypertension leads to increased afterload
    • tension(afterload) is proportional to (pressure x radius)/wall thickness
  35. What are the physical factors that affect afterload? (3)
    aortic distensibility, peripheral vascular resistance, reflected waves of blood
  36. 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].
  37. With treppe, a shortened filling time could decrease ________.
    preload
  38. It is difficult to differentiate treppe from __________ in the intact ventricle.
    increased sympathetic traffic
  39. Stroke volume depends on... (3)
    contractility/inotropy, preload, and afterload
  40. What is the equation for ejection fraction? What is the normal value in SA?
    EF = SV/ EDV (>0.5)
  41. 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
  42. What is ejection fraction?
    the fraction of blood you started with [in the ventricle] that gets ejected with each beat
  43. 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).
  44. 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.
  45. 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
  46. 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
  47. 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
  48. 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
  49. Oxygen consumption by the myocardium depends on... (3)
    heart rate, myocardial tension (afterload, BP), contractile state
  50. 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
  51. 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
  52. How do we estimate ejection fraction in patients?
    shortening fraction
  53. Clinically, what stages of the cardiac cycle constitute diastole?
    aortic valve closure, through filling, until the mitral valve closes
  54. 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
  55. 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
  56. The tension in the ventricular wall at end-diastole determines ___________.
    preload
  57. Isovolumetric relaxation occurs from _________ to __________ of the cardiac cycle.
    aortic valve closure; mitral valve opening
  58. ___________ corresponds to the peak negative pressure drop (peak negative dP/dT).
    Isovolumetric relaxation
  59. Doppler echo measures...
    direction, velocity, and quality of blood flow within a discrete sample volume (usually inflow and outflow tract)
  60. _________ immediately precedes active contraction, which is visible on a velocity profile from PW Doppler.
    Depolarization
  61. The ____________ tells us about overall diastolic function of the ventricle.
    diastolic pressure to volume relationship
  62. 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]
  63. 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
  64. What is chronotropy?
    rate, controlled by the SA node
  65. What is dromotropy?
    conduction, controlled by the AV node and Bundle of His-Purkinje system
  66. What is bathmotropy?
    electrical excitability
  67. What is lusitropy?
    relaxation
  68. What receptor is phenylephrine an agonist of?
    alpha 1 adrenergic
  69. What receptor is isoproterenol an agonist of?
    beta1 and beta 2 adrenergic
  70. What receptor is dopamine (and dobutamine) an agonist of?
    alpha and beta adrenergic
  71. What receptor is ephedrine an agonist of?
    beta and alpha adrenergic
  72. How does Prazosin affect the autonomic NS?
    alpha 1 antagonist
  73. What kind of drugs are atropine and glycopyrrolate?
    muscarinic receptor blockers
  74. 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
  75. 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.
  76. 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)
  77. 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)
  78. 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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Cardio1- Myocardial Contraction
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vetmed cardio1
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