Cardiac Muscle Contraction and Function

What is stroke volume?

A. Stroke volume. Stroke volume is the volume of blood ejected by the ventricle on each beat (ventricular contraction). It is about 70 mL and is calculated by: SV (mL) = End diastolic volume (EDV) (mL) - End systolic volume (ESV) (mL) Remember that EDV is the volume of blood in the ventricle before ejection. ESV is then the volume of blood in the ventricle after ejection.

What is the ejection fraction?

B. Ejection fraction. Ejection fraction is the fraction of EDV that is ejected in one SV as a percentage. Normal values for left ventricular ejection fraction (EF) are between 55% and 70%. Increases in contractility correlate with increases in EF. EF is calculated by: EF = Stroke volume / End diastolic volume * 100

Greater preloads, or volumes of blood in the ventricle during diastole, result in __________ ventricular pressure.

greater

When EDV is ______________, ventricular muscle length is also nearing its maximum.

increased

What factors are affected by fiber length?

increasing length of fiber increases maximal myocardial fiber tension, Increasing fiber length increases Ca2+-sensitivity of troponin C, Increasing fiber length increases Ca2+ release from sarcoplasmic reticulum

With maximal EDV and preload, ventricular muscle reaches ____ _______________ ___________.

its greatest tension.

The _____ is synonymous with EDV and end diastolic fiber length.

preload

the maximal tension developed by a muscle fiber is correlated with the ________ of that fiber. Increasing the length of a muscle fiber results in what? What is the Lmax for myocardial cells?

On a myocardial cellular level, the maximal tension developed by a muscle fiber is correlated with the length of that fiber. Much like stretching a rubber band results in a bigger "snapback" with greater length, increasing the length of a muscle fiber results in greater overlap of thick and thin filaments and the number of possible cross-bridges between the two. For myocardial cells, the Lmax, or length at which maximal myocardial fiber tension is achieved, is 2.2 μm. This is an important concept when we consider what happens when these fibers are overstretched; e.g. in severe ventricular dilation as would occur in ventricular failure.

What type of nervous stimulation will have a negative inotropic effect? By which mechanism?

Parasympathetic nervous stimulation will have a negative inotropic effect on the atria. Acetylcholine (ACh) binding to muscarinic parasympathetic receptors causes the activation of an inhibitory G protein, decreasing contractility. ACh decreases the inward calcium current and shortens the duration of the action potential by increasing the inward current of K+ into the cell. Less Ca2+ enters during the action potential, less "trigger Ca2+" is present, and less Ca2+ is released from the SR.

When does postextrasystolic potentiation occur?

Postextrasystolic potentiation occurs when an "unexpected," increased amount of Ca2+ enters the SR in between beats due to a premature systole. After an extrasystole, or "extra beat", there is an increase in intracellular calcium, so the beat right after that extrasystole (or premature beat) is more forceful, an effect called post-extrasystolic potentiation. Figure 4 demonstrates the greater tensile force generated in this extra beat as a result of increased Ca2+ release.

Step 5 of cardiac excitation-contraction coupling:

Tension is produced as a result of forming cross-bridges. The magnitude of the tension produced is proportional to the amount of intracellular Ca2+ present. Remember that for cross-bridge cycling to occur, ATP and adequate oxygen must also be present.

Step 1 of cardiac excitation-contraction coupling:

The cardiac action potential is started in the cell membrane and spreads to the inside of the cell via the T-tubules. Calcium enters the cell through L-type calcium channels in the membrane. There is a net inward calcium current from the extracellular to the intracellular fluid.

Step 2 of cardiac excitation-contraction coupling:

The inward current of Ca2+ triggers the release of more Ca2+ from the ryanodine receptors in the sarcoplasmic reticulum. The magnitude of this calcium induced calcium release depends on two factors: 1) how much Ca2+ was previously stored in the SR, and 2) the magnitude of the inward Ca2+ current.

What is the positive/Bowditch staircase?

The positive/Bowditch staircase refers to the fact that when heart rate increases, the tension developed in each beat increases in a stepwise manner (see Figure 4). Because increased heart rate results in greater storage of Ca2+ in the SR, more Ca2+ is released on heartbeats subsequent to the increase, resulting in increased contractile force. With each beat, more Ca2+ enters the SR until it reaches a maximum storage level.

What is the role of the sarcoplasmic reticulum (SR)?

The sarcoplasmic reticulum (SR) stores and releases calcium.

What is the sliding filament model ?

The sliding filament model postulates that forming and breaking cross-bridges between actin and myosin produce tension in the cardiac muscle fiber.

What is aortic pressure or afterload?

The ventricular tension developed is analogous to aortic pressure, or afterload. Because blood flows from areas of high pressure to those of low pressure in the cardiovascular system, when aortic pressure is zero the velocity of shortening of cardiac muscle ("snapping back" after having been "stretched") is maximal.

Sarcomeres have both thick and thin filaments. What are each of these made up of? What are the roles of these components in each filament type?

Thick filaments are made of myosin, the heads of which have ATPase function. Thin filaments include actin, tropomyosin, and troponin. Actin contains a myosin-binding site and forms two twisted strands when it is polymerized. Tropomyosin blocks the myosin-binding site on actin. Troponin contains 3 subunits, one of which binds calcium (troponin C) and removes tropomyosin inhibition of the myosin-actin interaction.

The higher the transmural pressure and the higher the radius (as in ventricular dilation), the higher the wall tension. Why is this important?

Wall tension as it relates to pressure development is important when considering MVO2. Myocardial oxygen consumption is related to the tension able to be developed in the wall, with higher tensions requiring higher rates of MVO2. Thus, tension development is crucial when considering that: ● The heart is a flow limited organ (its function is dependant upon and limited by the maximum coronary artery blood flow) ● The most important disease of the heart and the major cause of death in developed countries (and globally) is ischemic heart disease

What is the Frank-Starling Relationship?

X. FRANK-STARLING RELATIONSHIP The Frank-Starling relationship observes that the volume of blood ejected by the ventricle (stroke volume) is dependent on the volume of blood present in the ventricle at end-diastole (EDV). ● The EDV is determined by how much blood is returned to the heart, or venous return (VR). ● In the steady state (non-pathological), cardiac output must equal venous return. ● Thus, as VR increases, EDV, SV, and CO are all also increased. (Hint: it is useful to explore these relationships mathematically -- VR = CO = SV x HR; SV = EDV - ESV)

Fig. 8: Various changes in pressure-volume loops as a result of increased preload, increased afterload, and increased contractility.

B. Increased Preload. Changes in preload represent changes in VR or EDV. Increases in EDV result in increased stroke volume ejected during systole. C. Increased Afterload. Changes in afterload are due to changes in aortic pressure. In the case of increased afterload, the left ventricle must eject blood against increased aortic pressure, resulting in a longer isovolumetric contraction. Thus, stroke volume decreases and end systolic volume (the blood left in the ventricle after contraction) increases. D. Increased Contractility. Increased contractility means that the ventricle can develop greater tension and pressure than normal. This results in greater stroke volume and ejection fraction and decreased end systolic volume.

What are cardiac glycosides? When are they given and why?

Cardiac glycosides, which include the drug digoxin (digitalis), are positive inotropic agents that inhibit the Na+-K+ ATPase in the myocardial cell membrane. The result of this inhibition is increased intracellular Na+ that inhibits the Na+-Ca2+ exchanger. Thus, the end result of administering a cardiac glycoside is increased intracellular Ca2+ and positive inotropy. Cardiac glycosides are administered in the treatment of congestive heart failure (CHF), in which ventricular contractility is compromised. These drugs counteract the negative inotropy of an affected left or right ventricle, their positive inotropic effects increasing the contractility of that inadequate ventricle.

What is cardiac work or stroke work? What is cardiac minute work? What is it correlated with?

Cardiac work is stroke work, or the work (defined in physics as force times distance) performed in each heart beat. For our purposes, it is more useful to discuss cardiac minute work, or cardiac output times aortic pressure. Cardiac minute work incorporates two dimensions of cardiac work: volume work (CO) and pressure work (aortic pressure or afterload). Myocardial oxygen consumption (MVO2) is correlated with cardiac minute work.

What are sarcomeres?

Contractile units of cardiac muscle

What is contractility? What is Positive inotropy? What is negative inotropy? Which will increase muscle contractility? Which will decrease it?

Contractility (inotropism) is the ability of a myocardial cell to generate force at a given fiber length. Positive inotropy refers to events that result in an increase in force for a given muscle length; negative inotropy refers to events that decrease force for a given length. Positive inotropes increase both the rate of tension development and peak tension, while negative inotropes do the opposite. It may be useful to think of positive and negative inotropes in reference to a preset state of muscle flexion or relaxation. Positive inotropes will increase muscle contractility for that preset state, and negative inotropes will decrease contractility for that state.

Step 4 of cardiac excitation-contraction coupling:

Cross-bridge cycling continues as long as there is adequate intracellular calcium to occupy troponin C binding sites.

Fig. 6: Note the curvilinear relationship between SV and EDV. At the highest EDV (as in pathologic states), the graph curves because the ventricle is not able to handle the increased venous return (remember the Lmax!)..

Figure 6 also highlights the effects of inotropic agents on the heart (inotropy refers to the force of contraction of a muscle, especially cardiac muscle. What do you think the term chronotropy refers to?). Positive inotropic agents result in increased contractility for a given EDV, resulting in an increased EF. By contrast, negative inotropic agents result in decreased contractility for a given EDV and decreased EF. Note that these changes in inotropy create new curves for the relationship between the stroke volume and the end-diastolic volume (preload).

What are the major determinants of MVO2?

Heart rate Preload (EDV) Afterload (e.g. blood pressure) Left ventricular wall tension (T) Left ventricular mass (~H)

Increases in heart rate _____________ contractility. Decreased heart rate _____________ contractility. What would be the effect of more APs in a given time period? How about increased influx of Ca2+? What two phenomena result from increased heart rate?

Increases in heart rate increase contractility. (The reverse is also true, in that decreased heart rate decreases contractility.) More action potentials in a given time period result in an increase of trigger Ca2+ in the myocardial cell. Further, a greater inward flux of Ca2+ begets greater reuptake of Ca2+ into the SR in between action potentials. Two phenomena, the positive or Bowditch staircase and postextrasystolic potentiation, result from increased heart rate.

Step 3 of cardiac excitation-contraction coupling:

Intracellular Ca2+ increases further causing Ca2+ binding to troponin C. This binding moves tropomyosin out of the way so interaction between the actin and myosin heads (cross-bridge cycling) can occur.

Normal Ventricular Pressure-Volume Loop

● 1 → 2. Isovolumetric contraction. Point 1 is the end of diastole. Blood has filled the left left ventricle (EDV is about 140 mL), and the ventricular muscle is relaxed. In moving from Point 1 to Point 2, the left ventricle contracts with all cardiac valves closed, causing a substantial increase in pressure in the left ventricle. ● 2 → 3. Ventricular ejection. When left ventricular pressure becomes greater than aortic pressure (afterload), the aortic valve opens and blood is ejected into the aorta. (Point 2 represents aortic valve opening.) Left ventricular pressure is still high because the ventricle is still actively contracting. The width of the pressure volume loop (from 2 → 3) corresponds to the stroke volume. ● 3 → 4. Isovolumetric relaxation. Point 3 marks when systole ends and the ventricle relaxes. The aortic valve closes when ventricular pressure falls below that of aortic pressure. Volume in the ventricle remains constant because all valves are closed (only ventricular pressure changes). ● 4 → 1. Ventricular filling. Point 4 marks when ventricular pressure falls below atrial pressure, causing the mitral valve to open and blood to pass from the left atrium to the left ventricle. Ventricular muscle is relaxed (passive filling). Fig. 7: Normal ventricular pressure-volume loop. Gold line represents a portion of the systolic pressure-volume curve seen in Figure 6

Concerning O2 consumption:

● Pressure work, or "internal work," is more "costly" than volume work in terms of oxygen consumption in that it is a greater percentage of total cardiac minute work. ● MVO2 is not as directly correlated with cardiac output (volume work) as it is with pressure work. ● In conditions where the heart must overcome a greater afterload (aortic pressure), O2 consumption increases. An example of this is in aortic stenosis, in which MVO2 increases because the left ventricle must generate high pressures to overcome the afterload created by a stenosed (narrowed) aortic valve. A similar phenomenon is seen in systemic hypertension, in which afterload is increased by elevated arterial pressure. ● By contrast, in strenuous exercise (increased CO; increased volume work) MVO2 is increased but not as substantially as in pressure work.

What is cardiac output?

C. Cardiac output. Cardiac output is the total volume of blood ejected per unit of time, designated as liters/minute. An average cardiac output is about 5 L/min in a 70 kg man with a heartbeat of 72 BPM. CO = Stroke volume x Heart rate 5040 mL = 70 ml x 72 beats per minute

The relationship between left ventricular pressure and EDV in systole and diastole. Note that for any increased EDV, ventricular pressure also increased. In diastole, this pressure is passive (no additional contractile force), and in systole this increased pressure is active. You can think of EDV as correlated with end-diastolic fiber length. Greater volumes result in more "stretching" and thus greater tension generated.

It is worth noting for the systolic curve in Figure 5 that as a maximal overlap between muscle fibers is developed at an optimal length, additional increases in length result in less overlap between fibers (and thus less tension generated). To revisit the rubber band analogy: with a certain degree of stretching, the rubber band becomes "stretched out" and can no longer "snap back" to its resting length. The same is true for muscle: after the maximum tension of a muscle is achieved at Lmax, any further increases in length result in reduced tensile force. Cardiac muscle has a high resting tension, meaning that lengthening fibers beyond Lmax is difficult and that increasing fiber length minimally results in a large increase in resting tension. The "working length" of cardiac muscle fibers is 1.9 μm. (Note the small difference between the working length and the Lmax.)

What is the Law of Laplace?

Law of Laplace. The Law of Laplace approximates the heart as a sphere and states that the greater the thickness of the ventricular wall, the greater the pressure that the wall can develop. The equation for the Law of Laplace is given as: P = 2HT / r P is pressure, H is wall thickness (height), T is tension, and r is radius. The Law of Laplace is useful when considering increased afterload, as in systemic hypertension. In response to greater aortic pressure, the wall of the left ventricle will thicken (or hypertrophy) in order to pump against the increased pressure. Note that ventricular hypertrophy can lead to ventricular failure. In addition, if we reconfigure the equation to solve for tension (T), we see that: T = Pr/2H If we ignore the wall thickness for a moment, we see that wall tension is determined by pressure (actually the transmural pressure in the ventricle and the radius of the ventricle). The higher the transmural pressure and the higher the radius (as in ventricular dilation), the higher the wall tension. Why is this important? (Hint: see below).

Nitroglycerin is commonly used to treat angina (chest discomfort associated with a demand/supply mismatch of oxygen to the myocardium). How does it work?

Nitroglycerin, when given sublingually, has its major effect in dilating the venous side of the circulatory system. As you might recall, this is the capacitance side of the system, so venous dilation causes an increase of the blood volume held in the veins, and therefore a significant decrease in venous return to the heart. This cause a decrease in EDV of the heart, a decrease in the "r" of the LaPlace equation, and therefore a decrease in wall tension, which is a major determinant of MVO2.

What would be the effect of decreasing extracullar Na+ on Ca2+ in the cell?

Note that because the Na+- Ca2+ exchanger is dependent on the energy generated by extracellular Na+ flowing down its gradient into the cell, decreases in extracellular Na+ will increase [Ca2+] in the cell, thus increasing contractility by preventing extrusion of the Ca2+ from the cell.

What is the relationship between calcium and inotropy?

Since the concentration of intracellular Ca2+ correlates with inotropy, it makes sense that agents that interfere with the amount of Ca2+ released during excitation-contraction coupling would alter the inotropy of a muscle fiber.

What type of nervous stimulation will have a positive inotropic effect? By which mechanism?

Sympathetic nervous stimulation will have a positive inotropic effect. Cardiac sympathetic stimulation is mediated via β1 receptors, which act through an adenylate cyclase/cAMP pathway to produce increased contractility. In this pathway, both sarcolemmal Ca2+ channels and phospholamban (which regulates the Ca2+ ATPase in the SR) are phosphorylated. Thus, there is a greater inward Ca2+ current into the cell and greater uptake of Ca2+ back into the SR such that 1) relaxation occurs faster and 2) Ca2+ release from the SR increases in subsequent muscle contractions.

What is the FICK principle?

The Fick Principle is used to measure cardiac output and assumes that the cardiac outputs of the left and right ventricles are equal (which, of course, they must be). It is calculated by: Cardiac Output = O2 consumption of whole body / [O2]pulmonary vein - [O2]pulmonary artery Note that O2 consumption for the whole body is in (mL O2/min) and both [O2] are in (mL O2/ mL blood). [O2]pulmonary vein is used to describe the oxygen content of arterial blood, while [O2,]pulmonary artery describes the oxygen content of mixed venous blood.

What is systole? What is diastole? What is EDV? What is the preload?

This relationship between fiber length and tension can be extended macroscopically to ventricular tension. Systole refers to the period of cardiac contraction and diastole the resting period between contractions. End diastolic volume (EDV) refers to the amount of blood in the ventricle after it has filled with blood subsequent to contracting. This volume is best thought of as being "passive pressure," in that it is analogous to water filling up a bucket. As the amount of water in the bucket increases it pushes against the bucket walls, but the bucket itself doesn't change shape (contract) to generate any additional force. The blood that fills the ventricle prior to contraction is known as preload. You can think of preload as the potential "load" of blood to be ejected into the pulmonary arteries or aorta with the next ventricular contraction. It is synonymous with EDV and end diastolic fiber length.

How does cross-bridge cycling end and how do intracellular calcium levels resume?

To end cross-bridge cycling and resume a resting level of intracellular calcium, Ca2+ is taken back into the sarcoplasmic reticulum with a Ca2+ ATPase.

What are T-tubules? What is their function?

Transverse (T) tubules invaginate sarcomeres and function to carry action potentials inside the cell. They are continuous with the cell membrane.