Heart Muscle & Signal Transduction

Heart Muscle & Signal Transduction

• Cardiac myocytes are a type of striated muscle, microscopically exhibiting crossbands.
• These myocytes share structural and functional similarities with skeletal muscle, with significant differences.
• Cardiac myocytes form a branching network, functioning as a syncytium, formed by cell fusion.
• Individual myocytes connect via specialized cell membranes, called intercalated discs.
• Intercalated discs contain gap junctions for low-resistance electrical transmission between cells
• Gap junctions facilitate electrical (ionic) currents between cells.
• Stimulation of one cardiac myocyte transmits the impulse to all interconnected myocytes.

Regulation of Contraction (Inotropy)

• Calcium entry occurs through L-type calcium channels.
• Calcium is released from the sarcoplasmic reticulum.
• Calcium binds to TN-C.
• Myosin undergoes phosphorylation.
• SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase) activity is involved.
• Calcium efflux occurs across the sarcolemma

Calcium Entry into Myocytes

• Calcium entry during depolarization is controlled mainly by L-type calcium channel phosphorylation.
• Cyclic adenosine monophosphate (cAMP), related to β-adrenergic receptors, is essential in this regulation.
• Norepinephrine and epinephrine (from sympathetic nerves or adrenal glands) bind primarily to β1-adrenergic receptors on the sarcolemma.

G-Protein regulation

• Gs protein activates adenylyl cyclase, which hydrolyzes ATP creating cAMP.
• cAMP activates protein kinase A (PKA), phosphorylating various sites within the cell.

Regulation of Calcium Efflux

• Key mechanisms include the Na+/Ca++ exchange pump and ATP-dependent calcium pump.
• These pumps move calcium out of the cell, preventing overloading.
• Inhibition of calcium extrusion increases intracellular calcium, and thus, inotropy.

Cardiomyocyte Metabolism

• Cardiac myocytes have a very high metabolic rate, due to their continuous, repetitive contraction.
• Unlike intermittent, short contractions of skeletal muscle, heart muscle contracts one to three times per second throughout life.
• ATP production for contraction is entirely aerobic.
• Accordingly, cardiac myocytes have a large number of mitochondria.
• In oxygen deprivation, contraction is possible for only about a minute.
• Unlike some skeletal muscle fibers, cardiac myocytes have limited anaerobic capacity for ATP.
• They utilize various substrates to produce ATP:
  • Primarily fatty acids (approx. 60%) and carbohydrates (approx. 40%) in the overnight fasted state.
  • Glucose during high-carbohydrate meals.
  • Lactate, especially during exercise, in place of glucose.
  • Amino acids and ketones (e.g. acetoacetate) instead of fatty acids.

Myocardial Action Potential

• Cardiac muscle has fast sodium channels, slow sodium-calcium channels, and potassium channels.
• Fast sodium channel opening initiates the rapid upstroke of the action potential.
• The plateau period is primarily due to the opening of slow sodium-calcium channels, lasting around 0.3 seconds.
• Potassium channel opening causes large amounts of positive potassium ions to diffuse outward, returning membrane potential to resting levels.

Self-Excitation of Sinus Nodal Fibers

• The high sodium ion concentration outside sinus nodal fibers, existing sodium channels that tend to leak this positive ion to the inside, allow a slow rise in the resting membrane potential. -Sodium influx happens between heartbeats leading to positive potential shift.
• During the action potential, sodium-calcium channels become inactivated and potassium channels open.
• Influx of positive ions ceases; and significant potassium diffusion outwards occurs, returning the membrane potential to the resting level, which is called hyperpolarization.

Conduction System of the Heart

• The heart generates rhythmic electrical impulses to cause rhythmic contraction of the heart muscle.

• Conduction of these impulses is rapid through the heart, enabling simultaneous contraction in most of the ventricular muscle.

• The sinus (SA node) is the heart's primary pacemaker. -It produces impulses faster than other parts of the heart, leading to coordinated heart contractions.

• The atrial conductive system is organized so that the cardiac impulse does not travel too rapidly from the atria into the ventricles, creating a delay that allows the atria to empty their contents into the ventricles before ventricular contraction starts.

• The conduction velocity in the atria is about 0.3 m/sec, while in the atrial fibers, it is considerably faster, at roughly 1 m/sec.

• The anterior interatrial band acts as a conducting pathway from the atria to the left atrium. Additional pathways also help in efficient atrial impulse conduction.

• The AV node delays the impulse transmission to the ventricles, roughly 0.13 seconds after the propagation through internodal pathways.

• The delay is mainly because there are fewer gap junctions between the successive cells, causing resistance during conduction.

• Following the A–V node, the impulse is transmitted through the penetrating bundle, which is composed of small fascicles.

• Specialized Purkinje fibers transmit the action potential quickly throughout the ventricles, creating almost instantaneous transmission throughout the ventricular muscle.

Extrinsic Control of Heart

• The heart rhythm is controlled by both intrinsic and extrinsic factors. Intrinsic factors are natural inherent components of the heart's conduction system, generating electrical signals for heartbeats.
• Extrinsic factors typically originate outside the heart, such as nerve impulses, hormones, or drugs, impacting rhythm.

Clinical Relevance

• Digitalis and similar glycosides inhibit Na+/K+-ATPase, increasing intracellular sodium.
• This subsequently increases intracellular calcium, leading to enhanced inotropy.