Cardio1- Myocardial Contraction

actin (thin filaments), myosin (thick filaments), titin (structural proteins), troponins/tropomyosin (regulatory proteins)

functional unit of contraction; Z-disc to Z-disc

• TnC- binds to Ca2+
• TnI- inhibits actin unless Ca2+ is bound to TnC
• TnT- distributes TnI effects
• Tropomyosin- supports actin

elevated serum troponins indicate heart injury from myocarditis, ischemia, toxic injury

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

• 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

Calcium availability; inotropy (contractility)

• 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.

• 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.

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

increases the strength of cardiomyocyte contraction

sympathetic activation, catecholamines, digoxin, pimobendan

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)

afterload

• 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

the inherent rate at which actin and myosin interact; aka contractility/contractile force; depends on availability of Ca2+

estimated by measuring the maximum velocity of contraction that can be achieved from a minimally afterloaded muscle strip with preload/stretch kept constant.

hypoxia, metabolic acidosis, most anesthetic agents

sympathetic activation, addition of calcium salts, positive inotropic drugs (digitalis glycosides), calcium-sensitizing drugs, drugs that block phosphodiesterases

add calcium salts, sympathetic activation, catecholamines, and stimulation of histamine receptors in the myocardium

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)

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

inotropy is depressed (general anesthesia, hypoxia, etc)

the stretch of the ventricular myocytes prior to ejection; end-diastolic volume

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

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

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)

represented by the weight that must be moved following stimulation and muscle contraction; the weight that must be overcome for the muscle to shorten

• 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

• 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.

• higher afterload (radius gets larger, thickness gets smaller)
• tension(afterload) is proportional to (pressure x radius)/wall thickness

• reduced afterload (radius decreases, thickness increases)
• tension(afterload) is proportional to (pressure x radius)/wall thickness

• 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.

• hypertension leads to increased afterload
• tension(afterload) is proportional to (pressure x radius)/wall thickness

aortic distensibility, peripheral vascular resistance, reflected waves of blood

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].

preload

increased sympathetic traffic

contractility/inotropy, preload, and afterload

EF = SV/ EDV (>0.5)

SF= (Dd-Ds)/Dd (>0.25)

• Dd= end diastolic ventricular diameter
• Ds= end systolic ventricular diameter

the fraction of blood you started with [in the ventricle] that gets ejected with each beat

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).

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.

• 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

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

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

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

heart rate, myocardial tension (afterload, BP), contractile state

beta-adrenergic blockers (decrease effect of NE, effectively decreasing HR, BP, etc.), drugs that slow HR

mainly during diastole b/c during systole, wall tension is very high, so there is more resistance to flow in the coronary vessels

shortening fraction

aortic valve closure, through filling, until the mitral valve closes

early passive filling of the ventricles (majority of filling occurs during this period); E wave on PW Doppler

atrial contraction/atrial kick (minority of filling, but at high HR can make up to 50% of filling); A wave on PW Doppler

preload

aortic valve closure; mitral valve opening

Isovolumetric relaxation

direction, velocity, and quality of blood flow within a discrete sample volume (usually inflow and outflow tract)

Depolarization

diastolic pressure to volume relationship

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]

parasympathetic predominantly affects the SA node, AV node, and atria; sympathetic innervation is widely distributed throughout the heart

rate, controlled by the SA node

conduction, controlled by the AV node and Bundle of His-Purkinje system

electrical excitability

relaxation

alpha 1 adrenergic

beta1 and beta 2 adrenergic

alpha and beta adrenergic

beta and alpha adrenergic

alpha 1 antagonist

muscarinic receptor blockers

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

it is a marker for anaerobic metabolism in the heart, ie. ischemia.

• 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)

• 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)

• 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)