Chapter 22: Part 3

Question 1

Wat is excitation-contraction (EC) en wat is het verschil tussen EC in ventricular myocytes en skeletal muscle?

Answer 1

• Excitation-contraction (EC) coupling in cardiac ventricular myocytes is similar to EC coupling in skeletal muscle. One major difference is that, in the case of skeletal muscle, the initiating event is the arrival of an action potential at the neuromuscular junction, the release of acetylcholine, and the initiation of an end-plate potential. In the ventricular myocyte, action potentials in adjacent myocytes depolarize the target cell through gap junctions and thereby generate an action potential.
• As in a skeletal muscle fiber, the depolarization of the plasma membrane in the ventricular myocyte invades T tubules that run radially to the long axis of the myocyte. Unlike skeletal muscle cells, cardiac myocytes also have axial T tubules that run parallel to the long axis of the cell and interconnect adjacent radial T tubules.
• the L-type Ca 2+ channels (Cav1.2, dihydropyridine receptors) in the T-tubule membrane activate the Ca 2+ -release channels made up of four RYR2 molecules in the sarcoplasmic reticulum (SR) membrane.

Question 2

Waarom stopt het hart met beaten when u place it in a Ca 2+ -free solution?

Answer 2

In cardiac muscle, Ca 2+ entry through the L-type Ca 2+ channel Cav1.2 is essential for raising [Ca 2+ ] i in the vicinity of the RYR2 on the SR. A subset of Cav1.2 channels may be part of caveolae. This trigger Ca 2+ activates an adjacent cluster of RYRs in concert, causing them to release Ca 2+ locally into the cytoplasm by Ca 2+ -induced Ca 2+ release (CICR). In the CICR coupling mechanism, the action of this Ca 2+ is analogous to that of a neurotransmitter or chemical messenger that diffuses across a synapse to activate an agonist-gated channel, but in this case the synapse is the intracellular diffusion gap of ~15 nm between plasma-membrane Cav channels and RYR channels on the SR membrane. The CICR mechanism is a robust amplification system whereby the local influx of Ca 2+ from small clusters of L-type Cav channels in the plasma membrane triggers the coordinated release of Ca 2+ from the high-capacity Ca 2+ stores of the SR. Such single CICR events can raise [Ca 2+ ] i to as high as 10 µM in microdomains of ~1 µm in diameter. These localized increases in [Ca 2+ ] i appear as calcium sparks N9-3 when they are monitored with a Ca 2+ -sensitive dye by confocal microscopy. If many L-type Ca 2+ channels open simultaneously in ventricular myocytes, the spatial and temporal summation of many elementary Ca 2+ sparks leads to a global increase in [Ca 2+ ] i . The time course of this global [Ca 2+ ] i increase in ventricular myocytes lasts longer than that of the action potential because the RYR Ca 2+ -release channels remain open for a longer time than L-type Ca 2+ channels.

Question 3

Wat gebeurd er bij depolarization-induced activation of L-type Cav channels on the plasma membrane
in atrial cells?

Answer 3

In atrial cells, depolarization-induced activation of L-type Cav channels on the plasma membrane triggers Ca 2+ release from RYR channels in the peripheral SR (i.e., closest to the plasma membrane), eliciting subsurface Ca 2+ sparks. These peripheral Ca 2+ sparks then activate a wave of CICR that propagates inwardly throughout the central SR network of the atrial myocyte.

Question 4

Wat gebeurd er nadat [Ca 2+ ] i increases?

Answer 4

fter [Ca 2+ ] i increases, Ca 2+ binds to the cardiac isoform of troponin C (TNNC1), and the Ca 2+ -TNNC1 complex releases the inhibition of the cardiac isoform of troponin I (TNNI3) on actin. As a result, the tropomyosin (TPM1) filaments bound to cardiac troponin T (TNNT2) on the thin filament shift out of the way, allowing myosin to interact with active sites on the actin. ATP fuels the subsequent cross-bridge cycling. Because the heart can never rest, cardiac myocytes have a very high density of mitochondria and thus are capable of sustaining very high rates of oxidative phosphorylation (i.e., ATP synthesis).

Question 5

Waar zorgt de cross-bridge cycling voor?

Answer 5

The cross-bridge cycling causes thick filaments to slide past thin filaments, generating tension. The time course of cardiac tension development is delayed relative to the time course of the global surge in [Ca 2+ ] i.

Question 6

Wat is the length parameter voor ventricular myocytes?

Answer 6

For heart muscle, which wraps around the ventricle, the length parameter can be either the ventricular volume, which is analogous to whole-muscle length, or the sarcomere length. The sarcomere, stretching from one Z line to another, is the functional unit in both skeletal and cardiac muscle.

Question 7

Wat gebeurd er met het afnemen van het fase 2 plateau van de cardiale actiepotentiaal?

Answer 7

Met het afnemen van het fase 2 plateau van de cardiale actiepotentiaal, neemt de instroom van Ca 2+ via L-type Ca 2+ kanalen af, wat de afgifte van Ca 2+ door de SR vermindert.

Op zichzelf kan het stoppen van Ca 2+ intrede en afgifte alleen een verdere stijging van [Ca 2+ ] i voorkomen.

Question 8

Op welke processen hangt de feitelijke ontspanning van de contractiele eiwitten af?

Answer 8

(1) extrusie van Ca 2+ in de extracellulaire vloeistof (ECF)

(2) heropname van Ca 2+ uit het cytosol door de SR

(3) opname van Ca 2+ uit het cytosol in de mitochondriën

(4) dissociatie van Ca 2+ uit troponine C. Processen 2 en 4 zijn sterk gereguleerd.

Question 9

Wat gebeurd er nadat the membrane potential returns to more negative values?

Answer 9

After the membrane potential returns to more negative values, Ca 2+ extrusion gains the upper hand and [Ca 2+ ] i falls. In the steady state (i.e., during the course of several action potentials), the cell must extrude all the Ca 2+ that enters the cytosol from the ECF through L-type Ca 2+ channels.

Question 10

Hoe wordt Ca 2+ into the ECF extrusiated?

Answer 10

(1) a sarcolemmal Na-Ca exchanger (NCX1), which operates at relatively high levels of [Ca 2+ ] i

(2) a sarcolemmal Ca pump (cardiac subtypes 1, 2, and 4 of plasma-membrane Ca ATPase, or PMCA), which may function at even low levels of [Ca 2+ ] i .

Question 11

Waar draagt PMCA vooral bij?

Answer 11

PMCA draagt slechts in bescheiden mate bij aan relaxatie. Omdat PMCA geconcentreerd is in caveolae, die receptoren bevatten voor verschillende liganden, zou de rol van PMCA het moduleren van signaaltransductie kunnen zijn.

Question 12

Wat gebeurd er met Ca2+ tijdens de plateau?

Answer 12

Even during the plateau of the action potential, some of the Ca 2+ accumulating in the cytoplasm is sequestered into the SR by the cardiac subtype of the sarcoplasmic and endoplasmic reticulum Ca pump SERCA2a.

Question 13

Wat is Phospholamban (PLN),wat doet het als het ongefosfoliseerd is en als het wel gefosfoliseerd is?

Answer 13

Phospholamban (PLN), an integral SR membrane protein with a single transmembrane segment, is an important regulator of SERCA2a. In SR membranes of cardiac, smooth, and slow-twitch skeletal muscle, unphosphorylated PLN can exist as a homopentamer that may function in the SR as an ion channel or as a regulator of Cl − channels. The dissociation of the pentamer allows the hydrophilic cytoplasmic domain of PLN monomers to inhibit SERCA2a. However, phosphorylation of PLN by any of several kinases relieves PLN’s inhibition of SERCA2a, allowing Ca 2+ resequestration to accelerate. The net effect of phosphorylation is an increase in the rate of cardiac muscle relaxation. PLN-knockout mice have uninhibited SERCA2a Ca pumps and thus an increased velocity of muscle relaxation.

Question 14

Why does β 1 -adrenergic agonists (e.g., epinephrine), which act through the PKA pathway, speed up the relaxation of cardiac muscle?

Answer 14

Phosphorylation of PLN by protein kinase A (PKA). Phosphoprotein phosphatase 1 (PP1) dephosphorylates PLN, thereby terminating Ca 2+ reuptake.

Question 15

Leg de uptake van Ca2+ in mitochondria uit.

Answer 15

The mitochondria take up a minor fraction of the Ca 2+ accumulating in the cytoplasm. The inner mitochondrial membrane contains large-conductance, highly selective Ca 2+ channels (MiCas) that are inwardly rectifying. At potentials of –160 mV, which are typical for energized mitochondria, the MiCa channels carry a substantial Ca 2+ current. Unlike many other Ca 2+ channels, MiCa does not inactivate as intramitochondrial [Ca 2+ ] rises to micromolar concentrations.

Question 16

Wat zorgt voor de dissociation of Ca 2+ from Troponin C?

Answer 16

As [Ca 2+ ] i falls, Ca 2+ dissociates from troponin C, blocking actin-myosin interactions and causing relaxation. β 1 -adrenergic agonists accelerate relaxation by promoting phosphorylation of troponin I, which in turn enhances the dissociation of Ca 2+ from troponin C.

Question 17

Hoe verkrijg je een passive length-tension diagram?

Answer 17

We obtain a passive length-tension diagram by holding a piece of resting skeletal or cardiac muscle at several predefined lengths and measuring the tension at each length.

Question 18

Hoe verkrijg je een active length-tension diagram?

Answer 18

We obtain the active length-tension diagram by stimulating the muscle at each predefined length (i.e., isometric conditions) and measuring the increment in tension from its resting or passive value.

Question 19

Wat is het verschil tussen een skeletal muscle passive length-tension diagram en cardiac muscle passive length-tension diagram?

Answer 19

The passive tension of a skeletal muscle is practically nil until the length of the sarcomere exceeds 2.6 µm. Beyond this length, passive tension rises slowly. On the other hand, the passive tension of cardiac muscle begins to rise at much lower sarcomere lengths and rises much more steeply. As a result, cardiac muscle will break if it is stretched beyond a sarcomere length of 2.6 µm, whereas it is possible to stretch skeletal muscle to a sarcomere length of 3.6 µm.

Question 20

Wat is de reden voor the higher passive tension?

Answer 20

The reason for the higher passive tension is that the noncontractile (i.e., elastic) components of cardiac muscle are less distensible. The most important elastic component is the giant protein titin, which acts as a spring that provides the opposing force during stretch and the restoring force during shortening

Question 21

Wat is het verschil tussen de skeletal en cardiac muscle active length-tension diagrams?

Answer 21

De actieve spanning van skeletspieren is hoog en varieert slechts bescheiden tussen sarcomeerlengtes van 1,8 en 2,6 µm. In hartspieren heeft de actieve spanning een relatief scherpe piek wanneer de spier wordt voorgerekt tot een initiële sarcomeerlengte van ~2,4 µm. Naarmate de voorgerekte sarcomeerlengte toeneemt van 1,8 tot 2,4 µm, stijgt de actieve spanning sterk. We kunnen deze stijging niet verklaren door een toename in de overlap van dikke en dunne filamenten, omdat de afmetingen van de filamenten van hart- en skeletspieren vergelijkbaar zijn.

Question 22

Wat zijn de twee oorzaken van spanningsstijging bij langere sarcomeerlengten in hartspieren?

Answer 22

(1) Raising the sarcomere length above 1.8 µm increases the Ca 2+ sensitivity of the myofilaments. One mechanism controlling the Ca 2+ sensitivity may be interfilament spacing between thick and thin filaments, because fiber diameter varies inversely with fiber length. As we stretch the muscle to greater sarcomere lengths, the lateral filament lattice spacing is less than in an unstretched fiber so that the probability of cross-bridge interaction increases. Increased cross-bridge formation in turn increases the Ca 2+ affinity of TNNC1, thereby recruiting more cross-bridges and therefore producing greater force. Another mechanism could be that, as the muscle elongates, increased strain on titin either alters lattice spacing or alters the packing of myosin molecules within the thick filament.

(2) Raising the sarcomere length above 1.8 µm increases tension on stretch-activated Ca 2+ channels, thereby increasing Ca 2+ entry from the ECF and thus enhancing Ca 2+ -induced Ca 2+ release.

Question 23

Wat zorgt voor de fall off van active tension in cardiac muscle?

Answer 23

As cardiac sarcomere length increases above 2.4 µm, active tension declines precipitously, compared with the gradual fall in skeletal muscle. Once again, this fall-off does not reflect a problem in the overlap of thin and thick filaments. Instead, titin increases the passive stiffness of cardiac muscle and may also impede development of active tension at high sarcomere lengths.

Question 24

Leg Starling’s law uit.

Answer 24

• Ernest Starling in 1914 anticipated the results of Figure 22-12 A using an isolated heart-lung preparation.
• It states that “the mechanical energy set free on passage from the resting to the contracted state depends on the area of ‘chemically active surfaces,’ i.e., on the length of the fibres.” Therefore, the initial length of myocardial fibers determines the work done during the cardiac cycle.
• Starling assumed that the initial length of the myocardial fibers is proportional to the end-diastolic volume. Further, he assumed that tension in the myocardial fibers is proportional to the systolic pressure. Therefore, starting from a volume-pressure diagram, Starling was able to reconstruct an equivalent length-tension diagram

Question 25

Waaraan zijn Starlings diagram voor diastole en systole equivalent aan?

Answer 25

His diagram for diastole, which shows a rising pressure (tension) with increased EDV (fiber length), is very similar to the early part of the passive length-tension diagram for cardiac muscle. His diagram for systole is more or less equivalent to the ascending phase of the active length-tension diagram for cardiac muscle. Therefore, Starling’s systole curve shows that the heart is able to generate more pressure (i.e., deliver more blood) when more is presented to it.

Question 26

Wat laat een ventricular performance curve zien?

Answer 26

A ventricular performance curve is another representation of Starling’s length-tension diagram, but it is one a clinician can obtain for a patient. A ventricular performance curve shows stroke work ( P · Δ V ), which includes Starling’s systolic pressure (itself an estimate of muscle tension) on the y-axis, plotted against left atrial pressure, which corresponds to Starling’s end-diastolic volume (itself an estimate of muscle length), on the x-axis. What we learn from performance curves obtained for living subjects is that Starling’s law is not a fixed relationship. For instance, the norepinephrine released during sympathetic stimulation—which increases myocardial contractility (as we will see below in this chapter)—steepens the performance curve and shifts it upward and to the left. Similar shifts occur with other positive ino­tropic agents.

• Note also that ventricular performance curves show no descending component because sarcomere length does not increase beyond 2.2 to 2.4 µm in healthy hearts.

Question 27

Wat is een positive inotropic agent?

Answer 27

That is drugs that increase myocardial contractility.

Question 28

Op welke factoren depends the functional properties of cardiac muscle—how much tension it can develop, how rapidly it can contract?

Answer 28

1. Initial sarcomere length. For the beating heart, a con­venient index of initial sarcomere length is EDV. Both initial sarcomere length and EDV are measures of the preload imposed on the cardiac muscle just before it ejects blood from the ventricle during systole. Starling’s law, in which the independent variable is EDV, focuses on preload.
2. Force that the contracting myocytes must overcome. In the beating heart, a convenient index of opposing force is the arterial pressure that opposes the outflow of blood from the ventricle. Both opposing force and arterial pressure are measures of the afterload the ventricular muscle must overcome as it ejects blood during systole. Experiments on isotonic contractions focus on the afterload, factors that the ventricle can sense only after the contraction has begun.

Question 29

Hoe meet je de velocity of shortening in a way that is relevant for a cardiac muscle facing both a preload and an afterload?

Answer 29

• The muscle starts off at rest, stretched between a fixed support (bottom of the muscle) and the left end of a lever (top of the muscle). A weight attached to the other end of the lever, but resting on a table, applies stretch to the muscle to the extent allowed by the screw, which adjusts the “stop” of the lever’s left end. Thus, the combination of the weight and the screw determines initial sarcomere length (i.e., preload). At this time, the muscle cannot sense the full extent of the weight. The more we stretch the muscle by retracting the screw, the greater the preload. When we begin to stimulate the muscle, it develops a gradually increasing tension, but the length between the fixed point and the left end of the lever remains constant. That is, the muscle cannot shorten. Therefore, in the first phase of the experiment, the muscle exerts increasing isometric tension.
• When the muscle has built up enough tension, it can now begin lifting the weight off the table. This phase of the contraction is termed afterloaded shortening. The tension now remains at a fixed afterload value but the muscle gradually shortens (rising portion of upper blue curve). Therefore, in the second phase of the experiment, the muscle exerts isotonic contraction. From the slope of the upper curve in Figure 22-13 C , we can compute the velocity of shortening at a particular afterload.

Question 30

Wat bootst dit experiment na?

Answer 30

This experiment roughly mimics the actions of ventricular muscle during systole.

Question 31

Waar is de preload gelijk aan?

Answer 31

Initially, during its iso metric contraction, our hypothetical muscle increases its tension at constant length, as during the iso volumetric contraction of the cardiac cycle shown in segment CD. The initial length corresponds to EDV, the preload.

Question 32

Waar is de afterload gelijk aan?

Answer 32

Later, the muscle shortens while overcoming a constant force (i.e., generating a constant tension), as during the ejection phase of the cardiac cycle shown in segment DEF. The tension corresponds to arterial pressure, the afterload.

Question 33

Wat gebeurd er als je de weights varieert van de afterload?

Answer 33

As we already observed in our discussion of skeletal muscle, it is easier to lift a feather than a barbell. Thus, with a heavier weight, the muscle develops a lot of tension, but shortens slowly. Conversely, with a lighter weight, the muscle develops only a little bit of tension, but shortens rapidly (purple curves).

Question 34

Wat gebeurd er als je de velocities of shortening in Figure 22-13 D as a function of the three different afterloads plot?

Answer 34

If we plot the velocities of shortening in Figure 22-13 D as a function of the three different afterloads being lifted, we obtain the purple, blue, and red points on the load-velocity curve in Figure 22-13 E . The velocity of muscle shortening corresponds to the outflow velocity of the ventricle (see Fig. 22-8 D, E ). Thus, at higher opposing arterial pressures the outflow velocity should decrease. The black curve in Figure 22-13 E applies to a muscle that we stretched only slightly in the preload phase (i.e., low preload in Fig. 22-13 A ). The red curve in Figure 22-13 E shows a similar load-velocity relationship for a muscle that we stretched greatly in the preload phase (i.e., high preload). In both cases, the velocity of shortening increases as the tension (i.e., afterload) falls.

Question 35

Wat is isometric tension?

Answer 35

When the afterload is so large that no shortening ever occurs, that afterload is the isometric tension, shown as the point of zero velocity on the x-axis. As expected from Starling’s law, the greater the initial stretch (i.e., preload), the greater the isometric tension. In fact, at any velocity, the tension is greater in the muscle that was stretched more in the preload phase (red curve)—a restatement of Starling’s law.

Question 36

Wat voor conclusion kunnen we trekken uit de experiment met preload en afterload?

Answer 36

At a given preload, the velocity of shortening for cardiac muscle becomes greater with lower afterloads (i.e., opposing pressure). Conversely, at a given afterload—that is, comparing the black and red curves for any common x value —the velocity of shortening for cardiac muscle becomes greater with a greater preload (i.e., sarcomere length).

Question 37

Wat allows een positive inotropic agent?

Answer 37

A positive inotropic agent allows the heart to achieve a given velocity against a greater load, or to push a given load with a greater velocity.

Question 38

Wat een andere way of representing how velocity of shortening depends on the initial muscle length?

Answer 38

Another way of representing how velocity of shortening depends on the initial muscle length (i.e., preload) is to monitor velocity of shortening during a single isotonic contraction. If we first apply a large preload to stretch a piece of muscle to an initial length of 9.0 mm and then stimulate it, the velocity instantly rises to a peak value of ~8.5 mm/s; it then gradually falls to zero as the muscle shortens to 7.5 mm. If we start by applying a smaller preload, thereby stretching the muscle to an initial length of 8.5 or 8.0 mm, the peak velocity falls. Thus, initial length determines not only the tension that cardiac muscle can generate, but also the speed with which the muscle can shorten.

Question 39

Wat is de positieve staircase phenomenon?

Answer 39

The progressive rise of tension after an increase in rate—the positive staircase phenomenon —was first observed by Henry Bowditch in 1871. Underlying the staircase phenomenon is an increase in SR Ca 2+ content and release.

Question 40

Wat zijn de causes van an increase in SR Ca 2+?

Answer 40

First, during each action potential plateau, more Ca 2+ enters the cell through Cav1.2 L-type Ca 2+ channels, and the larger number of action potentials per minute provides a longer aggregate period of Ca 2+ entry through these channels.

Second, the depolarization during the plateau of an action potential causes the Na-Ca exchanger NCX1 to operate in the reverse mode, allowing Ca 2+ to enter the cell. At higher heart rates, these depolarizations occur more frequently and are accompanied by an increase in [Na + ] i , which accentuates the reversal of NCX1, both of which enhance Ca 2+ uptake.

Third, the increased heart rate stimulates SERCA2a, thereby sequestering in the SR the Ca 2+ that entered the cell because of the first two mechanisms. The mechanism of this stimulation is that the rising [Ca 2+ ] i , through calmodulin (CaM), activates CaM kinase II, which leads to phosphorylation of PLN; phosphorylation of PLN in turn enhances SERCA2a.

Question 41

Wat is contractility?

Answer 41

• A measure of the heart’s intrinsic contractile performance, independent of these extrinsic factors.
• Contractility is a somewhat vague but clinically useful term that distinguishes a better-performing heart from a poorly performing one.

Question 42

Waarom is ejection fraction niet helemaal een goeie measure voor contractility?

Answer 42

According to Starling’s law, ejection depends on EDV (i.e., preload), which is external to the heart.

Question 43

Wat zijn twee betere manieren voor contractility?

Answer 43

Two somewhat better gauges of contractility are the rate of pressure development during ejection (Δ P /Δ t ) and the velocity of ejection. Both correlate well with the velocity of shortening in Figure 22-13 E and F , and they are very sensitive guides to the effect of inotropic interventions.

Question 44

Waarom is het niet praktisch om cardiac performance in a patient assessen by using the approaches outlined in Figures 22-12 and 22-13?

Answer 44

First, with patients, we do not deal with isolated muscles in vitro.

Second, the aforementioned figures require that we study the muscle under the artificial conditions of only isometric (i.e., preloaded) or only isotonic (i.e., afterloaded) contractions. During a full cardiac cycle, of course, these conditions alternate.

Question 45

Wat is de third assessment of contractility focuses?

Answer 45

• A third assessment of contractility focuses on the physiological relationship between pressure and volume during the cardiac cycle.
• We return to the ventricular pressure-volume loop that we introduced in Figure 22-9 and redraw it as the purple loop in Figure 22-14 A . In this example, the EDV is 120 mL. Point D′ on the loop represents the relationship between pressure and volume at the end of the isovolumetric contraction, when the aortic valve opens. If we had prevented the aortic valve from opening, ventricular pressure would have continued to rise until the ventricle could generate no additional tension. In this case, the pressure would rise to point G′, the theoretical maximum isovolumetric pressure. We could repeat the measurement at very different EDVs by decreasing or increasing the venous return. Point G represents the maximum isovolumetric pressure for an EDV below 120 mL (orange loop), and point G″ represents this pressure for an EDV above 120 mL (green loop). The gold dashed line through points G, G′, and G″ in Figure 22-14 A would describe the relationship between pressure and EDV under isometric conditions (i.e., aortic valve closed)—the equivalent of an isometric Starling curve (e.g., brown curve in Fig. 22-12 A ). The steeper this line, the greater the contractility.

Question 46

Waarom is het moeilijk om maximum isovolumetric pressures te meten en hoe kan je er toch achterkomen?

Answer 46

It is impossible to measure maximum isovolumetric pressures in a patient because it is hardly advisable to prevent the aortic valve from opening. However, we can use the end-systolic pressure at point F′ on the normal pressure-volume loop with an EDV of 120 mL . For an EDV below 120 mL, the corner point would slide down and to the left. Conversely, for an EDV above 120 mL (green loop), the corner point would slide upward and to the right (point F″). The corner points of many such pressure-volume loops fall along a line— the end-systolic pressure-volume relation (ESPVR) —that is very similar to that generated by the points G, G′, and G″.

Question 47

Wat zijn de effecten van changes in contractility?

Answer 47

The ESPVR is a clinically useful measure of contractility. Enhancing the con­tractility increases the slope of the ESPVR line, just as it increases the steepness of the ventricular performance curves. For example, imagine that—with the same EDV and aortic pressure as in the control situation —we increase contractility. We represent increased contractility by steepening the ESPVR line. The result is that ejection continues from point D′ to a new point F until the left ventricular volume reaches a much lower value than normal. In other words, enhanced contractility increases stroke volume. Decreasing contractility would flatten the slope of the ESPVR and decrease stroke volume.

Question 48

Wat zijn de effect of changes in preload (i.e., Initial Sarcomere Length)?

Answer 48

A pressure-volume loop nicely illustrates the effect of increasing preload (i.e., increasing filling or EDV) without changing contractility. Starting from the control situation, increase of the EDV shifts the isovolumetric segment to the right (segment CD on the red loop). Because the volume change along segment DEF is larger than for the control situation, stroke volume increases—as predicted by Starling’s law.

Question 49

Wat zijn de effect of changes in afterload?

Answer 49

A pressure-volume loop also illustrates the effect of an increased afterload (i.e., increase in aortic pressure). Starting from the control situation, an increase of aortic pressure shifts the upper right corner of the loop from point D′ (purple loop) to D (red loop) because the ventricle cannot open the aortic valve until ventricular pressure reaches the higher aortic pressure. During the ejection phase—assuming that contractility (i.e., slope of the ESPVR) does not change—the ventricle necessarily ejects less blood until segment DEF intersects the ESPVR line. Therefore, an increase in afterload (at constant contractility) causes the loop to be taller and narrower, so that stroke volume and ejection fraction both decrease. However, if we were to increase contractility (i.e., increase the slope of the ESPVR), we could return the stroke volume to normal.

Question 50

Wat kan the dynamics of cardiac muscle contraction independent of preload or afterload veranderen?

Answer 50

• Modifiers of contractility
• When these factors increase myocardial contractility, they are called positive inotropic agents. When they decrease myocardial contractility, they are called negative inotropic agents

Question 51

Wat is een volume overload?

Answer 51

A volume overload is an excessive EDV (i.e., preload). For example, a large AV shunt would volume overload both the left and right hearts. The increased EDV leads to an increase in stroke volume, which elevates cardiac output. Systemic arterial pressure usually remains normal.

Question 52

Wat is een pressure overload?

Answer 52

A pressure overload is an excessive pressure in the ventricle’s outflow tract (i.e., afterload). For the left heart, the problem would be an increase in systemic arterial pressure (i.e., hypertension). The increased aortic pressure leads to a decrease in stroke volume (see Fig. 22-14 D ). However, because of a compensatory increase in heart rate, cardiac output usually remains normal. When, over time, the adaptive process of hypertrophy becomes inadequate to cope with demand, the result is mechanical dysfunction and, ultimately, heart failure.

Question 53

Waarom kan de stimuli that might be mitogenic in other cells niet elicit cell division in the heart doen?

Answer 53

Because cells of the adult heart are terminally differentiated, stimuli that might be mitogenic in other cells cannot elicit cell division in the heart, but rather cause the cardiac myocytes to hypertrophy and increase muscle mass.

Question 54

Wat is physiological hypertrophy en bij wie komt het voor?

Answer 54

• the cardiac cells increase proportionally both in length and in width
• elite athletes

Question 55

Waar leidt volume overload en pressure overload naar toe?

Answer 55

• Volume overload leads to eccentric hypertrophy characterized by increases in myocyte length out of proportion to width.
• Pressure overload causes concentric hypertrophy with a relatively greater increase in myocyte width.

Question 56

Wat zijn een paar agents implicated in cardiac hypertrophy?

Answer 56

the cardiac cytosolic protein myotrophin (Myo/V1) and the cytokine cardiotrophin 1 (CT-1), as well as catecholamines, angiotensin II (ANG II), endothelin 1, insulin-like growth factor 2, transforming growth factor-β, and interleukin-1.

Question 57

Wat activeren Catecholamines and ANG II?

Answer 57

Catecholamines and ANG II both activate the mitogen-activated protein kinase (MAPK) cascade.

Question 58

Farther downstream in the signal-transduction pathway, welke includes de transcriptional response to hypertrophic stimuli?

Answer 58

Farther downstream in the signal-transduction pathway, the transcriptional response to hypertrophic stimuli includes the zinc-finger transcription factor, GATA-4 (see pp. 80–81 ), and perhaps also the transcription factors SRF and Sp1, as well as the TEF-1 family.

Question 59

Waar zorgt elevated [Ca 2+ ] i voor, wanneer eleveert het en wat activeert het?

Answer 59

• Elevated [Ca 2+ ] i may be both a trigger for hypertrophy and part of signal-transduction pathways that lead to hypertrophy.
• [Ca 2+ ] i in heart cells is probably elevated initially during chronic volume or pressure overloads, just as [Ca 2+ ] i would be elevated in a normal heart that is working hard.
• Elevated [Ca 2+ ] i may activate calcineurin, a Ca 2+ -dependent phosphatase. After being dephosphorylated by calcineurin, the transcription factor NFAT3 can enter the nucleus and bind to GATA4 (see above), which transcriptionally activates genes responsible for hypertrophy. Mice that express constitutively activated forms of calcineurin develop cardiac hypertrophy and heart failure.

Question 60

Waar zorgt mechanical stretch voor?

Answer 60

• Mechanical stretch induces the expression of specific genes.
• Stretch activates a phosphorylation cascade of protein kinases: Raf-1 kinase, extracellular signal–regulated kinase (ERK), and a separate subfamily of the MAPKs called SAPKs (for s tretch- a ctivated p rotein k inases). These various kinases regulate gene expression by activating the transcription factor AP-1.
• The pathways we have just discussed lead to several changes in gene expression within cardiac myocytes during hypertrophy.

Question 61

Wat kan een mechanical sensor zijn that triggers cardiac hypertrophy?

Answer 61

The mechanical sensor that triggers cardiac hypertrophy may be MLP (muscle LIM protein), part of the myocardial cytoskeleton.

Question 62

“Some of the most striking changes include reduced levels of the mRNA encoding three critical proteins in the membrane of the SR” welke zijn dat?

Answer 62

(1) the Ca 2+ -release channel

(2) PLN

(3) SERCA2

• In addition, cardiac hypertrophy is associated with increased levels of mRNA for the skeletal α-actin, which is normally expressed in fetal heart, but not in adult heart. Hypertrophic hearts also have increased expression of the angiogenic factor vascular endothelial growth factor.

Question 63

Why should hypertrophied cardiac muscle not be as good as normal muscle?

Answer 63

Possibilities include alterations in the transient increases in [Ca 2+ ] i during the cardiac action potential and alterations in the expression of the contractile filaments, particularly the myosin isoenzymes.

Question 64

Wat gebeurd er in de hearts van people whose hearts cannot sustain?

Answer 64

People whose hearts cannot sustain an adequate cardiac output become breathless (because blood backs up from the left heart into the lungs) and have swollen feet and ankles (because blood backs up from the right heart and promotes net filtration in systemic capillaries). On the cellular level, decreased contractility in heart failure could be a result of cardiac hypertrophy, reflecting alterations in the transient increases of [Ca 2+ ] i , the expression of the contractile filaments, or both.

Question 65

Wat kan changes in [Ca 2+ ] i physiology refelecteren?

Answer 65

Changes in [Ca 2+ ] i physiology could reflect altered properties of the Cav1.2 L-type Ca 2+ channel in the plasma membrane or the Ca 2+ -release channel RYR2 in the SR membrane.

Question 66

Hoe leidt hypertension-induced cardiac hypertrophy to heart failure?

Answer 66

In an animal model of hypertension-induced cardiac hypertrophy that leads to heart failure, the Cav1.2 channels exhibit an impaired ability to activate RYR2 through Ca 2+ -induced Ca 2+ release. A distortion of the microarchitecture in hypertrophic cells, and thus a dis­tortion of the spacing between Cav1.2 channels and RYR2, could be responsible for impaired coupling. Each of the four RYR2 molecules in the Ca 2+ -release channel associates with a molecule of calstabin 2 (also known as the FK506-binding protein, FKBP12.6) that, together with other proteins, forms a macromolecular complex regulating the Ca 2+ -release channel. Depletion of calstabin 2 in heart failure results in leaky RYR2 channels that continually release Ca 2+ into the cytosol. High [Ca 2+ ] i makes the heart prone to delayed afterdepolarizations, ventricular arrhythmias, and sudden death.

Question 67

Waar zorgt changes in the expression of contractile proteins voor?

Answer 67

Changes in the expression of contractile proteins can reduce contractility.

Question 68

Wat zijn twee isoforms van myosin?

Answer 68

Two isoforms of myosin heavy chain, αMHC and βMHC, are present in the heart.

Question 69

Waar zorgt αMHC voor?

Answer 69

The speed of muscle shortening increases with the relative expression of αMHC. In human heart failure, the amount of αMHC mRNA, relative to total MHC mRNA, falls from ~35% to ~2%.

Question 70

Wat is te zien in een MLP-deficient (the muscle LIM protein) mice?

Answer 70

MLP-deficient mice have the same disrupted cytoskeletal architecture seen in failing hearts. In addition, these mice have a dilated cardiomyopathy. Although humans with failing hearts are generally not deficient in MLP, the evidence from these knockout mice suggests that the MLP system could play a role in certain forms of cardiomyopathy.

Question 71

Benoem de positive inotropic agents.

Answer 71

Factors that increase myocardial contractility increase [Ca 2+ ] i , either by opening Ca 2+ channels, inhibiting Na-Ca exchange, or inhibiting the Ca pump—all at the plasma membrane.

1. Adrenergic agonists. Catecholamines (e.g., epinephrine, norepinephrine) act on β 1 adrenoceptors to activate the α subunit of G s -type heterotrimeric G proteins. The activated α s subunits produce effects by two pathways. First, α s raises intracellular levels of cAMP and stimulates PKA (see p. 57 ), which can then act by the mechanisms summarized in Table 23-2 to increase contractility and speed relaxation. Second, α s can directly open L-type Ca 2+ channels in the plasma membrane, which leads to an increased Ca 2+ influx during action potentials, increased [Ca 2+ ] i , and enhanced contractility.
2. Cardiac glycosides. Digitalis derivatives inhibit the Na-K pump on the plasma membrane (see p. 117 ) and therefore raise [Na + ] i . We would expect the increased [Na + ] i to slow down the Na-Ca exchanger NCX1, to raise steady-state [Ca 2+ ] i , and to enhance contractility. Recent evidence suggests that cardiac glycosides may also increase [Ca 2+ ] i by a novel pathway—increasing the Ca 2+ permeability of Na + channels in the plasma membrane.
3. High extracellular [Ca 2 + ]. Acting in two ways, elevated [Ca 2+ ] o increases [Ca 2+ ] i and thereby enhances contrac­tility. First, it decreases the exchange of external Na + for internal Ca 2+ . Second, more Ca 2+ enters the myocardial cell through L-type Ca 2+ channels during the action potential.
4. Low extracellular [Na + ]. Reducing the Na + gradient decreases Ca 2+ extrusion through NCX1, raising [Ca 2+ ] i and enhancing contractility.
5. Increased heart rate. As we noted in introducing the staircase phenomenon (see p. 528 ), an increased heart rate increases SR stores of Ca 2+ and also increases Ca 2+ influx during the action potential.

Question 72

Benoem de negative inotropic agents.

Answer 72

Factors that decrease myocardial contractility all decrease [Ca 2+ ] i .

1. Ca 2 + -channel blockers. Inhibitors of L-type Ca 2+ channels —such as verapamil, diltiazem, and nifedipine—reduce Ca 2+ entry during the plateau of the cardiac action potential. By reducing [Ca 2+ ] i , they decrease contractility.
2. Low extracellular [Ca 2 + ]. Depressed [Ca 2+ ] o lowers [Ca 2+ ] i , both by increasing Ca 2+ extrusion through NCX1 and by reducing Ca 2+ entry through L-type Ca 2+ channels during the plateau of the cardiac action potential.

3 High extracellular [Na + ]. Elevated [Na + ] o increases Ca 2+ extrusion through NCX1, thereby decreasing [Ca 2+ ] i .