Regulation of Cardiac Function (LeGrice) Flashcards
What are the factors governing cardiac output?
Describe the pressure-volume loop
1) Normal
2) Effect of Preload
3) Effect of Afterload
4) Effect of inotropic state
Define
1) Preload
2) Afterload
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction
Afterload is the pressure against which the heart must work to eject blood during systole. In other words, it is the end load against which the heart contracts to eject blood.
Define
1) Inotropy
2) Chronotropy
- Inotropy is contractility of myocardium (calcium!)
- Chronotropy is firing rate of SA node (heart rate)
Define
1) Lusitropy
2) Dromotropy
- Lusitropy is relaxation of myocardium (calcium removal)
- Dromotropy is conduction velocity of AV node
Describe the Trigger that results in myocardium to contract
Trigger for Contraction
Calcium is the trigger for contraction in cardiac muscle.
- Depolarization of cardiac cell membrane opens L-type Ca2+ channels in T-tubules, and Ca2+ enters cell cytoplasm.
- Ca2+ then binds to r_yanodine (RyR2) receptors_ on junctional sarcoplasmic reticulum (SR), opening calcium release channels so more Ca2+ enters cell cytoplasm.
- As a result, concentration of Ca2+ rises rapidly in cytoplasm. This Ca2+ binds to regulatory protein troponin C, unmasking active sites on thin filaments, thus enabling cross bridge cycling to occur.
Contraction ceases with removal of Ca2+ from the cytoplasm.
- This mainly involves calcium pumps in SR membrane (sarcoendoplasmic reticulum calcium ATPase) (SERCA).
- This highly effective calcium pump transfers Ca2+ into SR, where it is transported to storage sites in junctional SR.
- In addition, Ca2+ ions can be extruded from cell by Na/Ca exchangers in cell membrane.
- This process is passive, relying on sodium gradient generated by Na/K pump to drive calcium ions out of the cell.
- Finally, there is evidence for active calcium pumping by sarcolemma.
The operation of these mechanisms ensures that cytoplasmic [Ca2+] is normally maintained at very low levels during diastole.
Describe the role of Calcium as a Strength Modulator for Contraction= Inotropic State
Strength Modulator for Contraction (Inotropic State)
In cardiac muscle, calcium is not only trigger for contraction, but also modulates the strength of contraction.
Cardiac inotropic state (force generated at a given sarcomere length) depends on:
-
Magnitude and rate of calcium release from SR on activation
- Release depends on amount of calcium stored in SR
- Store depends in turn depends on balance between different fluxes
- Affinity of Troponin-C for Ca2+ ions (sarcomere length-dependent Ca2+ sensitivity for troponin-C).
Describe the Step by step Effect of Sympathetic Activation (Inotropic State)
Effect of Sympathetic Activation (b1)
- G protein Gs stimulates adenylate cyclase, leading to increased levels of second messenger cyclic AMP.
- Increased cAMP results in increased cAMP-dependent protein kinase A.
- This leads to phosphorylation of:
- L-type Ca2+ channels,
- Phospholamban,
- Ryanodine receptors,
- Troponin I, and other proteins.
- These phosphorylations lead to:
- Increased opening of L-type calcium channels,
- Stimulation of SR and cell membrane Ca2+ pumps,
- Faster Ca2+ kinetics,
- Faster X-bridge cycling.
Overall, these changes lead to marked increases in magnitude and rate of calcium release from SR on activation (and more rapid uptake of calcium into SR after contraction). Therefore, activation of the adenylate cyclase system is associated with more vigorous and more rapid contraction (and relaxation).
Describe the Effect of Parasympathetic Activation (Inotropic State)
Effect of Parasympathetic Activation (M2)
Activation of Gi has opposite effect.
- Gi inhibits adenylate cyclase, leading to decreased levels of cAMP.
- In addition, Gi directly opens K+ channels, via bg subunit, which results in decreased action potential duration.
These changes have a negative inotropic effect in cardiac myocytes.
Describe the Force and Sacromere-Length Relationship in Cardiac Muscle
+ compare the differences between skeletal and cardiac muscle sarcomere-length relationship
For cardiac muscle, relationship between sarcomere length and force generated in a fixed length (isometric) contraction is shown.
- Passive force-length relationship reflects force applied to stretch resting muscle to any given length.
- Active force-length relationship indicates total force generated during contraction at any sarcomere length.
Two points should be noted when comparing cardiac muscle and skeletal muscle:
- 1) Force-length relationship for cardiac muscle has no descending limb. This is because:
- Cardiac connective tissue has high passive stiffness, which limits sarcomere lengths to <2.3-2.4µm
- 2) Force-sarcomere length relationship for cardiac muscle has much steeper ascending limb.
- At sarcomere length of 1.6µm, no force is generated in cardiac muscle. Whereas in skeletal muscle, force generated at 1.6µm is ~80% peak force generated at 2.25µm. This is because:
- There is different actin-myosin overlap effects.
- Greater than that simply due to actin-myosin overlap effects, there is incresed sensitivity of length-dependent affinity of troponin C for Ca2+ in cardiac muscle.
- At sarcomere length of 1.6µm, no force is generated in cardiac muscle. Whereas in skeletal muscle, force generated at 1.6µm is ~80% peak force generated at 2.25µm. This is because:
What are some Effects of Hypoxic States on the Heart?
Mechanical performance of cardiac cells depends on maintenance of cellular calcium homeostasis, which is, in turn, dependent on function of SR calcium pump and Na/K pump.
If oxygen supply is reduced relative to oxygen demand, ATP stores are rapidly depleted and operation of these pumps is impaired. As a result:
-
Reduced Na+/K+ pump
- Reduced Na+ & K+ transmembrane concentration gradients
- Hyperkalaemia ( Increased [K+]o)
- Reduced resting membrane potential
- Reduced action potential upstroke speed and magnitude
- Shortened APD
- Reduced Na+/Ca2+ exchange
- Reduced myosin head detachment (ATP required for relaxation)
-
Reduced sarcolemmal Ca2+ extrusion
- Increased cytoplasmic Ca2+ in diastole
- Impaired ventricular filling and relaxation
- Electrical instability
- Increased cytoplasmic Ca2+ in diastole
- _Reduced pH (local acidosis) i_mpacting on systolic mechanical function
- H+ competes with Ca2+ binding site on troponin-C
- (reduced inotropic state) (reduced strength of contraction)
- Reduced nexus junction coupling (slows conduction)
Overall, describe the heart motion when it contacts
When you look at the inside and outside surface of the heart, it shows that the inside contracts more than the outside
Ejection is all about thickening of the ventricular wall (not the whole heart)
Describe the Anatomical Structure and Layout of Cardiac Myocytes
Cellular Architecture
Cellular architecture of the heart is complex.
- Left ventricle resembles a truncated thick-walled ellipsoid, to which right ventricle is appended.
- Myocytes are organized and coupled within extensive extracellular connective tissue network.
At any point in left or right ventricles, cardiac myocytes have a principal orientation (myofibre orientation) varying across wall. For instance, in LV free wall:
- Myocyte orientation is -60° with respect to circumferential axis at epicardium (outer surface),
- It is aligned with circumferential axis at myocardium (centre of ventricular wall),
- It is near longitudinal +90° at endocardium (subendocardial regions nearest LV cavity).
Describe the Heart Wall Motion and Deformation During Cardiac Cycle (During Systole and Diastole)
Summary
3D patterns of heart wall motion and deformation (changes in dimension and shape) that occur throughout cardiac cycle cannot simply be associated with axial length changes of myocytes. Nonetheless, 3D heart wall motion and deformation that occurs in normal heart beat is highly repeatable and ensures that right and left ventricles operate as an extremely efficient pump.
During systole, there is complex 3D pattern of hear wall motion and deformation in normal left ventricle:
- There are circumferential and longitudinal shortening, while ventricular wall thickens radially
- Dimensional changes are greatest at endocardial surface and least at epicardial surface.
- Circumferential shortening is greater than longitudinal shortening.
- Therefore, shortening in myofibre direction (along sarcomere axis) is remarkably uniform across ventricular wall.
- There is significant torsional deformation with apex twisting counter-clockwise relative to base.
- There are also important local shear deformations that involve slippage or relative movement of layers of cells.
Combined effect is that a very large proportion of blood stored in LV at end-diastole is ejected during systole.
- Normal LV ejection fraction is >50% at rest and may increase to 85% in exercise.
- Dimensional changes necessary to produce such effective voiding of LV cavity could not be achieved by sarcomere shortening alone. It involves complex 3D pattern of hear wall motion and deformation.
Left Ventricular Deformation During Diastole
During diastole, hear wall motion and deformation is reversed. Particularly during early diastole, energy released from elastic elements in myocardium contributes to efficient filling of ventricles.
Describe the Progession To failure in spontaneously hypertensive rat (SHR)
Describe the effect of Structural Heart Disease/Hypertension on Cardiac function/pumping
In structural heart disease (myocardial infarction and heart failure) and hypertension, remodeling of ventricles occurs, which leads to changes in cardiac geometry and myocyte arrangement, which then reduce effectiveness of mechanical function of heart.
- For instance, systemic hypertension leads to L_V myocyte hypertrophy_ and wall thickening.
- Moreover, there is a marked i_ncrease in collagen density_ throughout LV (importance of collage location rather than amount, i.e. location at cleavage planes, so merges layers of different orientations).
- This increases LV stiffness in diastole, which then reduces effectiveness of cardiac filling.
- Circumferential and longitudinal s_hortening decreas_e (likely as a result of impaired slippage or shearing between layers of cells), but ejection fraction is maintained initially by increased torsional deformation.
- However, systolic failure generally occurs if hypertension is sustained.
- Effectiveness of mechanical function is reduced (heart can no longer reorganize itself via layers through cycle).
- Ventricular cavity volume enlarges progressively and ejection fraction declines.
Describe the Sympathetic Regulation of Cardiac Function (not intracellular)
Sympathetic Regulation Of Cardiac Function (b1)
Response of heart to sympathetic nerve stimulation is mediated by noradrenaline, released from adrenergic nerve terminals. In myocardium, this binds predominantly to b1 adrenergic receptors.
Rate
- Cardiac sympathetic stimulation increases HR.
- HR response to a step change in sympathetic stimulation is relatively slow.
- There is a latency of 1-3 seconds and 30 seconds taken to reach steady state.
Rhythm
- Sympathetic stimulation reduces cardiac action potential duration.
- It accelerates impulse propagation through AV node, and it may also facilitate pacemaker activity of cells in AV node.
Contractility
- Cardiac sympathetic stimulation increases inotropic state of both atria and ventricles.
- Effects of cardiac stellate ganglion stimulation were first demonstrated using left ventricular function plot. Graded stellate ganglion stimulation produced “family” of LV function curves.
Left and right fibres
- L_eft sympathetic_ fibres have more effect on contractility than right fibres.
- Right sympathetic fibres have relatively more effect on heart rate than left fibres.
Cardiac cycle dynamics (LV pump function)
- Pressure due to atrial contraction is increased
- Rate of ventricular pressure development is increased, as is peak ventricular pressure.
- Initial acceleration of blood ejected from ventricle is increased, as is maximum level of aortic flow
- Ventricular end-systolic volume is reduced, so SV increases
- Rapid filling occurs faster, which sustains ventricular filling to some extent, despite reduction in diastolic interval. In addition, shortening of systolic interval provides a small relative contribution toward maintenance of cardiac filling.
What causes the change in HR between breathing in/out?
HR is being kept low by the parasympathetic nervous system. The fastest way the HR goes up is via the parasympathetic nervous system.
Therefore changes in the HR during breathing must be controlled by the parasympathetic nervous system
Neurological Regulation**: **Relative Roles Of Cardiac Sympathetic And Parasympathetic Nerves
Although sympathetic and parasympathetic division of autonomic nervous system normally act synergistically to effect alterations in cardiac performance, it should not be presumed that their effect is simply additive.
Describe the Determinants of Myocardial Oxygen Supply
Determinants of Myocardial Oxygen Supply
1) Perfusion pressure
- Aortic pressure
- Extravascular compression
2) Impendence
- Impedence
- Perfusion pressure
3) Local regulation
Coronary Circulation
- Left and right coronary arteries arise from aortic root, and divide to form a system of arteries embedded in epicardial surface of the heart. Most coronary venous blood returns to heart through coronary sinus and anterior cardiac veins, which drain into right atrium.
- Coronary vasculature is very dense. Coronary blood vessels are distributed widely throughout the myocardium and are in close physical contact with muscle cells which they supply. There is a separate capillary for each myocyte (coronary microcirculation).
There are two main consequences of this structure:
- A large proportion of oxygen in blood entering the coronary circulation is extracted.
- Coronary blood vessels (particularly in left ventricle) are affected by wall forces generated during contraction. Systolic vascular compression is greatest in subendocardial layers of the LV.
2) Coronary Blood Flow
Qc is coronary blood flow; CaO2 and CvO2 are coronary arterial and coronary mixed venous oxygen contents.
In order to increase myocardial oxygen supply (MVdotO2 ):
- Increase _arterial oxygen conten_t (oxygen concentration) ( CaO2 )
- Increase coronary oxygen extraction (60-75%) (little extra available)
- Increase coronary blood flow
Under normal circumstances, arterial blood is near completely saturated, while oxygen extraction from coronary circulation is substantial (60-75%). Therefore, oxygen supply must be matched to demand mainly by changes in coronary blood flow.
Describe the Determinants of Coronary Blood Flow
1) Mechanical Factor
Coronary blood flow (Q) is determined by perfusion pressure and instantaneous resistance (impedance) to flow (Q=DP/R).
In left ventricle, following coronary blood flow pattern is seen:
- During isovolumetric contraction, there is a sudden and almost complete cessation of Q due to compression of vessels.
- Over systole, there is some recovery, but Q is still relatively low.
- During isovolumetric relaxation, Q rebounds when extravascular compression is released.
- After that over diastole, compressive forces are much reduced and intrinsic coronary vascular resistance is “unmasked.” Therefore, _Q increase_s and follows variation in aortic pressure at root of aorta (driving flow).
A similar pattern can be seen in the right ventricle but the changes are less dramatic presumably because compressive wall forces are less.
In LV subendocardium, it is assumed that compressive stresses acting on blood vessels are closely related to pressure in ventricular cavity. Therefore, subendocardial LV blood flow is determined by difference between aortic and LV pressures, so diastolic interval sets relative duration of blood flow to LV subendocardium.
2) Coronary Blood Flow And Metabolism
Coronary vascular resistance is predominantly controlled by local factors at microvascular level (figure next page), which in turn linked to balance of oxygen supply and demand.
3) Neural And Hormonal Influences
There are both a and ß2 receptors in coronary vessels, which mediate vasoconstriction and vasodilatation respectively.
- Sympathetic nervous system acts directly on coronary circulation to cause vasoconstriction. This provides a vasoconstrictor tone under normal conditions.
- However, in stress situations, it tends to be overridden by a concurrent increase in oxygen demand working through metabolites to cause vasodilatation.
- Parasympathetic activation can be seen to cause a transient vasodilatation.
Describe the Diastrolic Pressre Time Index and the Tension Time Index
Diastolic pressure time index (DPTI) is subendocardial blood flow (oxygen supply)
Tension time index (TTI) is oxygen demand
The balance between the white and the shaded is teh balance between demand and supply. In a healthy heart, DPTI > TTI (supply > demand)
Endocardial viability ratio (EVR) represents myocardial oxygen supply-demand balance. In healthy heart, EVR is normally 1 or more, hence DPTI>TTI (supply>demand)
