4: Cardiac Excitation-Contraction Coupling

Cardiac Excitation-Contraction Coupling and Muscle Mechanics

• Learning Objectives:
  • Define myofibrils, myofilaments, sarcomere, thick and thin filaments
  • Describe cellular components, excitation-contraction coupling sequence in cardiac muscle, and sites for regulating contraction
  • Compare and contrast excitation-contraction coupling in cardiac and skeletal muscle
  • Define preload, afterload, and inotropy
  • Contrast isometric and isotonic contractions, considering preload, afterload, and inotropy (tension-length changes, length-tension relationships, and force-velocity relationships)
  • Summarize how autonomic nerves, hormones, heart rate, and hypoxia alter inotropy

Cardiac Cell Structure

• Cardiac myocytes are relatively short (~100µm), branching cells connected by intercalated discs
• Myocytes are composed of myofibrils, containing bundles of myofilaments
• Sarcomeres are contractile units containing contractile and regulatory proteins
• Sarcomere length is 1.6-2.2 µm

Excitation-Contraction Coupling

• Action potentials travel across the sarcolemma and into T-tubules
• Membrane depolarization activates DHP receptors (L-type Ca++ channels), triggering Ca++ entry into the cell
• Ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) open, releasing Ca++ into the cytoplasm
• Ca++ levels increase from ~10^-7 to 10^-5 M
• Ca++ binds to troponin C (TN-C), causing a conformational change in the troponin complex. Tropomyosin shifts, exposing myosin binding sites on actin.
• Myosin heads bind to actin, forming cross-bridges and initiating contraction
• Ca++ is resequestered by the SR via SERCA pumps
• Ca++ unbinds from TN-C, myosin releases from actin (requires ATP), and the sarcomere returns to its relaxed length

Contractile Proteins: Thin Filaments

• Actin: Globular proteins arranged in repeating helical strands, with myosin-binding sites
• Tropomyosin: Rod-shaped protein associated with seven actin molecules, blocking myosin-binding sites in the relaxed state

Contractile Proteins: Thick Filaments (Myosin)

• Myosin: Comprised of a long tail region and two heads; each head contains myosin ATPase and an actin-binding site

Regulatory Proteins (Troponin)

• Troponin (TN): Inhibits actin-myosin interactions in the absence of Ca++; includes TN-T (binds to tropomyosin), TN-C (binds to Ca++), and TN-I (inhibits myosin binding to actin)

Distinguishing Characteristics of EC-Coupling in Cardiac Muscle Compared to Skeletal Muscle

• Cardiac muscle depolarization is cell-to-cell through gap junctions; skeletal muscle does not depend on these
• Cardiac muscle contraction can be graded, unlike skeletal muscle, which is all-or-none
• Autonomic nerves and hormones modulate contractile force and relaxation in cardiac muscle; there is no nerve activation of skeletal muscle contraction
• Ca++ release and reuptake in cardiac muscle are regulated by autonomic nerves; this is not true of skeletal muscles

Sliding Filament Theory of Contraction

• Ca++ release and binding to troponin C (TN-C) allows cross-bridge formation
• Cycles of cross-bridge attachment and detachment shorten sarcomeres, reducing the muscle length
• Reuptake of Ca++ by the SR causes relaxation and cross-bridge detachment.

Time-course of Cardiac EC-Coupling

• Action potentials (AP) and Ca⁺⁺ transients have slightly longer durations
• Active tension is slightly delayed compared to the Ca++ transient
• Active tension and Ca++ transients eventually return to baseline after the AP has subsided

Mechanical Properties of Cardiac Muscle

• Preload: Resting cardiac fiber length (initial sarcomere length) before contraction.
• Length-Tension Relationship: Relationship between sarcomere length and active tension generation within an isometric contraction; increase in sarcomere length leads to increase in active tension.

How Does Preload Affect Sarcomere Length?

• Increasing muscle preload length at a constant afterload increases the magnitude of shortening
• Increases the velocity of shortening for a given preload and afterload

Afterload

• The force that a muscle fiber (sarcomere) must generate to shorten against a load.
• An increased afterload leads to an increase in isometric force production before shortening occurs; it also lengthens the duration of isometric contractions, reduces shortening velocity, and reduces the magnitude of shortening

Force-Velocity Relationship

• Increased afterload reduces shortening velocity; shortening velocity is zero when the load cannot be moved (isometric contraction)
• Shortening velocity is maximal at zero afterload

Effects of Preload on the Force-Velocity Relationship

• Increasing preload shifts the force-velocity curve to the right
• This increases the maximum force without change in maximum velocity

Summary: Increased Preload

• Increases force of contraction
• Increases velocity of shortening
• Increases the magnitude of shortening

Summary: Increased Afterload

• Decreases magnitude and velocity of shortening
• Effects of increased afterload can be offset by increased preload

Inotropy

• Inotropy represents changes in the ability of cardiac muscle to alter its force and speed of contraction
• These changes occur through cellular mechanisms that regulate the interactions between actin and myosin and are independent of sarcomere length (preload)

Effects of Inotropy on the Length-Tension Relationship

• Increased inotropy increases the slope of the length-tension curve, thereby increasing isometric force generation at a given preload
• Decreased inotropy decreases the slope of the length-tension curve, thereby decreasing force development at a given preload

How Does Inotropy Affect Muscle Shortening (Isotonic Contractions)?

• Increasing inotropy increases shortening velocity and magnitude at a constant preload
• Decreases end-systolic length

Effects of Inotropy on the Force-Velocity Relationship

• Increasing inotropy shifts the force-velocity curve upwards, increasing V_max and F_max
• Allows the muscle to maintain the same shortening velocity at higher afterloads

Summary: Increased Inotropy

• Increases V_max in the force-velocity relationship and shifts the curve to the right
• Increases rate of isometric force development and maximal force
• Increases velocity of fiber shortening
• Increases the magnitude of shortening (decreases end-systolic length)
• Effects of increased afterload can be offset by increased inotropy

Regulation of Inotropy

• Autonomic Nerves: Sympathetic nerve activation (primarily β₁) increases inotropy in atria and ventricles; parasympathetic nerve (vagal) activation (primarily muscarinic type 2) decreases inotropy in atria
• Hormones: Circulating catecholamines stimulate inotropy via beta-adrenoceptors
• Increased Heart Rate: Increased heart rate (Bowditch effect) increases inotropy
• Cellular Hypoxia: Cellular hypoxia depresses inotropy

Test your understanding of the excitation-contraction coupling process in cardiac muscle. This quiz covers key concepts such as myofibrils, sarcomeres, and the differences between cardiac and skeletal muscle contraction mechanisms. Explore the role of preload, afterload, and inotropy in muscle mechanics.