Cardiac Muscle, L32, Flashcards

Cardiac Muscle: Structure and Function

Learning Objectives

• Describe the structural organization of the heart and the roles of its regions.
• Explain the initiation and regulation of the heartbeat at the SA node.
• Compare the calcium cycle in cardiac cells to that of skeletal muscle.
• Explain the modulation of contraction force by length, frequency, and neurotransmitters.

Cardiac Muscle Overview

• Striated muscle with electrically connected cells (unlike skeletal muscle).
• Contraction force is modulated differently than in skeletal muscle (no recruitment).

Structure of the Heart

• Hollow, multi-chambered organ with two atria and two ventricles.
• Volume changes during contraction to pump blood.

Atrial Cells

• Approximately 100 µm long and 10 µm in diameter.
• Central nucleus.
• Lack t-tubules.
• Contract relatively weakly.
• Joined by gap junctions for electrical activity spread.

Ventricular Cells

• Larger (approximately 100 µm long and 30 µm in diameter).
• Branched with numerous gap junctions forming 'sheets' around ventricles.
• Well-developed t-tubular system for excitation into the cell interior.
• Numerous mitochondria and large amounts of myoglobin, indicating oxidative metabolism and giving a deep red color.
• One to three nuclei per cell.
• Growth mainly through hypertrophy with little cell division after birth.
• Sarcomeres are similar to skeletal muscle, but t-tubules occur at Z-disks, and the sarcoplasmic reticulum (SR) is less developed.
• Myofilament organization is similar to skeletal muscle.

Initiation of Contraction

• Cardiac muscle is myogenic, initiating contractions without nervous input.
• Action potentials start in the sino-atrial (SA) node in the right atria.
• Action potential spreads through the atria and via Purkinje fibers to the ventricles.
• Cardiac action potential lasts longer (100-200 ms) than nerve and skeletal muscle action potentials.

Ionic Currents

• Large sustained inward I_{Ca} (calcium current) causes significant calcium influx.
• Calcium influx triggers calcium release from the SR via calcium-induced calcium release (CICR).
• Large calcium extrusion capacity via the Na^+/Ca^{2+} exchange mechanism.
• The Na^+/Ca^{2+} exchange produces a depolarizing current, prolonging the action potential as it brings three Na^+ ions into the cell for each Ca^{2+} ion extruded.
• K^+ currents contribute to repolarization.

Refractory Period

• Long refractory period due to membrane depolarization, preventing re-excitation and summation of responses.
• Tetanization of cardiac muscle is not normally possible.

Calcium and Contraction

• Calcium entering via I_{Ca} and SR calcium release activates troponin/tropomyosin.
• Troponin has one calcium-specific site (unlike skeletal muscle with two).
• The calcium transient is of lower amplitude than in skeletal muscle, so troponin is not fully saturated with calcium under normal conditions.

Calcium Removal and Relaxation

• Calcium is pumped back into the SR by a Ca-ATPase and extruded by the Na^+/Ca^{2+} exchanger during repolarization.
• A weak Ca-ATPase mechanism in the sarcolemma contributes about 10% of total calcium extrusion.

Determinants of Contraction Rate (Heart Rate)

• Ventricular muscle cells have a limited contraction rate due to the long refractory period.
• Maximum action potential rate in cardiac muscle is much slower than skeletal muscle. (Humans: max rate = 4 Hz, or 240 beats per minute, which is not sustainable).
• The sino-atrial (SA) node in the right atria determines the normal contraction rate.
• SA node cells have an unstable resting membrane potential.

Regulation of Contractile Force

• Cardiac muscle fibers are all activated, so contractile force is not regulated by recruitment.
• Alternatives for regulating contractile force:
  • Increase the rate of firing (automaticity).
  • Increase the dimensions of the ventricle (stretch).
  • Use neurotransmitters to alter rate and calcium handling (direct and rate effects).

Modulation by Stimulation Frequency (Automaticity)

• The force of contraction can be modulated by changing the amplitude of the calcium transient because troponin is not fully saturated.
• Incomplete troponin saturation modulates the availability of actin binding sites for myosin.
• Increased stimulation frequency leads to residual calcium accumulation, increasing cytoplasmic calcium levels.
• Elevated cytoplasmic calcium increases calcium levels in the SR and consequently increases the amount released during CICR.
• Calcium level rises until extrusion mechanisms reach a steady state where the amount entering equals the amount extruded.

Modulation by Muscle Length

• Resting cardiac muscle cells have a sarcomere length of about 1.8 µm.
• Maximum active force is developed when stretched to about 2.1 µm.
• Force is modulated by ventricular dimensions (volume).
• The force-sarcomere length relation for cardiac muscle does not have a descending limb because passive force rises rapidly after about 2.0 µm.
• Cells cannot be stretched beyond 2.4 µm without damage, due to the cardiac connective tissue matrix.
• The ascending limb of the cardiac length-tension curve is steeper than skeletal muscle because the amplitude of the calcium transient increases with length.
• Increased length causes an immediate force increase due to actin-myosin interaction, followed by a slower increase in calcium transient amplitude over several beats.
• Increased calcium then increases troponin saturation.

Starling's Law of the Heart

• As resting ventricular volume increases, the force of contraction increases.
• Allows the heart to match ejected blood volume to the amount received, preventing venous pooling.

Modulation by Neurotransmitters

• The heart is innervated by the sympathetic and parasympathetic nervous systems.

Sympathetic Nervous System (Noradrenaline)

• Noradrenaline (NA) increases the frequency of SA node cell discharge, increasing action potential frequency (from about 70 to 180 beats per minute).
• NA increases I_{Ca}, leading to more calcium entering the cell and increasing contraction strength.
• NA stimulates the SR calcium pump, increasing calcium uptake during diastole and allowing more SR calcium release during subsequent CICR.
• NA decreases the sensitivity of contractile proteins to calcium, which is masked by the increase in calcium transient amplitude.
• Decreased calcium sensitivity allows faster relaxation as the calcium transient subsides, leading to a briefer but more intense contraction.
• With increased rate, this shortened contraction allows more time for the ventricle to refill between contractions.

Parasympathetic Nervous System (Acetylcholine)

• Acetylcholine (ACh) slows the rate of discharge of SA cells, reducing heart rate.
• Decreased heart rate decreases the force of contraction.

Key Structural and Functional Differences

Cardiac Output (CO)

• CO = SV eq HR
  • SV = Stroke Volume
  • HR = Heart Rate
• Heart Rate (HR) is set by the pacemaker cells in the sinoatrial node.
• Stroke volume (SV) reflects the tension developed by the cardiac muscle fibres in one contraction.
• Can be increased by:
  • increased rate of firing (heart rate/HR)
  • increased stretch of ventricles (length)
  • certain neurotransmitters (e.g. Noradrenaline)

Pacemaker Cells

• Unstable resting membrane potential!
• Depolarization due to relatively slow Ca^{2+} current (not fast Na^+)

Pacemaker Potential

• This slow depolarization is Due to If current (mostly Na^+ driven).

Depolarization

• At threshold, Ca^{2+} channels open. Explosive Ca^{2+} influx (I{CaT}) produces the rising phase of the action potential, sustained by opening of slow Ca^{2+} channels (I{CaL}).

Repolarization

• Repolarization is due to Ca^{2+} channels inactivating and K^+ channels opening.

Neural Control of Heart Rate

• Via alteration of pacemaker potential

Vagal Nerves (Parasympathetic)

• Release acetylcholine (ACh):
  • Decrease rate of spontaneous depolarization and hyperpolarizes the resting membrane potential = decrease heart rate

Sympathetic Nerves

• Release noradrenaline (NA):
  • Increases rate of spontaneous depolarization = increase heart rate

Length-Tension Relationship

• Increased stretch (filling=preload) results in more force developed (stroke volume)
• Starling's law of the heart: “as the resting ventricular volume is increased the force of the contraction is increased”
• Entirely intrinsic!

Neural Control of Stroke Volume

• Noradrenaline (NE = NA) acting on β receptors and via second messengers acts on:

  • L-Type channels resulting in more calcium entering the cell.
  • Ca^{2+} pump in SR so SR increases its Ca^{2+} stores

• Net result = bigger/shorter contraction

• Noradrenaline released by sympathetic nerves leads to increased cytosol calcium due to increased HR shortening time for extrusion

• And via second messengers :

  • by increasing Ca^{++} influx (via Ca^{++} channels) during the action potential (primarily during phase 2),
  • by increasing the release of Ca^{++} by the sacroplasmic reticulum (due to greater SR uptake)

• Increased sympathetic stimulation results in increased output at any filling pressure due to increase in inotropy and heart rate