Heart Failure Physiology Flashcards
Describe
Ventricular myocytes
Atrial Myocytes
Ventricular - brickshaped, 150x20x12 um
Atrial - smaller, more spnindle shaped; <10u in diameter; <100um in length
The on and off switch for contraction
SR
What are ryanodine receptors
Ca2+ release channels concentrated at the part of SR in close apposition with T tubules
parts of SR
1 terminal cisternae / junctional SR
2 longitudinal/ free/ network SR
What is SERCA/ SR Ca-ATPase
ATP-consuming Ca2+ pump that faciliates calcium uptake from the sarcoplasm
Calsequestrin
Calcium buffering proteins
Caveolae
Caveolin , RYR
small invaginations of sarcolemma
Scaffolding preoteins
How many mitochondria in a ventricular myocyte?
8000
How is the mitochondira in myocytes during Calcium overload?
there is a electrochemical gradient favoring the entry of calcium in the mitochondria - but this is kept to a level by the Na/Ca exhanger to pump calcium out, but this will increase Na inside the mitochondria so the Na/H exchanger regulates this - but there is a consequence since H+ influx uses ATP.
Instead of these protons being used to make more ATP (F0-F1 ATP synthase) they were used to extrude Na and Ca
So in Calcium overload- calcium can diminish gradient at expense of ATP production thus hampering recovery from stress; also elevated Ca facilitate opening of the mitochondrial permeability transistion pore releasing Mmatrix to cytosol and result to death of mitochondria; release of ROS
Two chief contractile proteins
actin and myosin
Titin is
a giant molecule, largest protein to be described
1 - tethers myosis and thick filaments to Z line; stabilizing sacromere
2- its elasticity contribute to the stress-strain relationship; aid in early diastolic filling
3- limits overstretching of sarcomeres at end diastolic volume
4 - transduces mechanical stretch to growth signals
Musle LIM protein (MLP)
attached to z line at end of titin, stretch sensor that transmits signals that result in myocyte growth pattern
MLP is defective in what condition
dilated cardiomyopathies
Crossbridge cycle events
A - Rigor state B- Weak binding state C - ATP hydrolysis D- strong binding state E- Powerstroke;
Crossbridge cycle: ADP released ; vacant empty pocket
Rigor state
Binding of ATP to the pocket produces
Weak binding state
ATP hydrolysis results to
alteration of actin binding domain; favoring release from actin, head binds to adjacent actin; “cocked”
Strong binding state
Phosphate is released; myosin head strongly attaches to induce powerstroke
Troponin C
Troponin I
Troponin T
- Calcium binding
- binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place
- binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
B myosin heavy chain (B-MHC)
slower ATPase rate, predominant in adult humans
Defects in myosin, myosin binding protein C, other myofilament proteins linked to
familial hypertrophic cardiomyopathy
In vascular smooth muscle, contraction is activated by
Calcium dependent myosin light chain kinase (MLCK)
preload is
sarcomere length at end of diastole
Frank-Sterling effect
the more diastolic filling of the heart, the greater the strength of each heartbeat
A great diastolic end volume would increase contractile strength and increase stroke volume
why does the Frank-Starling effect occur
as the myocardium is stretched due to greater volume, there is increase in sarcomere length, increase in myofilament calcium sensitiviy - hence stronger contraction
what happens in isovolumetric contraction ?
sarcomeres do not shorten but cross bridges are developing force
main entry of Ca in cells
voltage gated L-type calcium channels (3/4) vs Ca influx
TOtal SR content is sum of Ca SR plus Ca bound to?
calsequestrin - local reservoir of buffered Calcium
mediates SR release of calcium
RYR channels -functions as ca channel and scaffolding protein
Can stabilize RSR gating
calmodulin, FKBP, kinases, CAMKII
When is SR Calcium release turns off?
When calcium in SR drops by approx 50%
What breaks the positive feedback of Ca release?
1 closure of RYR channels by binding to CaM
2 Ryr2 gating is sensitive to luminal CaSR
3 Calcium flux through RyR falls and junctional Ca also falls
Versatile mediator of Calcium signaling
Calmodulin
Calcium is transported in the SR by
SERCA
cardiac myocytes (SERCA2a)
1 ATP - 2 Ca ions
A reduction in SERCA expression or function can be sean in
heart failure or energetic limitations
slower rates of cardiac relaxation
what is PLB
Phospolamban - a single transmembrane pass protein that binds directly to SERCA2a -this reduces the affinity of SERCA for cytosolic Ca- weaker uptake
What happens when PLB is phosphorylated by CaMKII
The inhibitory effect of PLB is relieved leading to increased SERCA uptake - cardiac relaxation (lusitropic effect) and increased SR Ca content - stronger contraction
2 types of sarcolemmal Ca channels
T-type
L-type - predominate in ventricular myocytes
T (transient) type channels
- open at more negative voltage
- short bursts of opening
- do not interact with Calcium antagonist drugs
- doesnt participate in excitation-contraction coupling
- seen in neonatal ventricular myocytes, purkinje fibers, pacemaker cells
L-type / long lasting Calcium channels
- at T-tubules & jSR sites
- inhibited by Verapamil, Diltiazem, Dihydropyridines
- facilitates rapid sympathetic activation of changes in Ica
Important contributor to plateau phase of cardiac action potential
InwardCalcium
Voltage gated cardia Na is mainly carried by
Nav 1.5 cardiac isoform
near intercalated discs
Is sodium participating in the plateau phase?
yes - late sodium current - ultra slow voltage independent inactivation / activation
Consequence of inrease Na
acquired long QT syndrome
Cause sodium and calcium loading of myocytes
CaMKII is upregulated and chronically activated in
ischemia reperfusion, heart failure , ROS; LQT3 Syndrome;Brugada like syndrome
(Ca overload)
NCX is
responsible for extruding most of the Ca entered by Ica and NCX;
-reversible
Main mechanism for extruding Na from the cell is
NaKATPase
Order of agonist activity in B1 and B2 receptors
B1 isproterenol > E = NE
B2 isoproterenol > E > NE
Relative potencies of alpha agonists are
NE >E> Isoproterenol
Gs - cAMP
Gi - (cholinergic & vagal)
Gs- chronotropic, inotropic lusitropic , dromotrophic
Gi - inhibit adenylyl cyclase - slow HR, limit cAMP
AC5 and 6 - cardiac myocytes
Potent direct adenylyl cyclase inhibitor-
PDE inhibitor -
Forskolin
IBMX
5 main determinants of ventricular mechanical performance
preload afterload contractility lusitropy HR
Normal pressure in LA
8-15 mmHg
physiologic systole
-start of isovolumetric contraction to peak of ejection phase
Physiologic diastole
- as calcium is taken back to SR , myocyte relaxation dominates; LV starts to fall
Cardiologic systole
- longer than physiologic
- M1 to A2
When is S3 heard
prodiastole
