Muscle Physiology: Cardiac Muscle

Heart Organization and Anatomical Layers

• Location and Protection     * The heart is positioned within the thoracic cavity.     * It is located specifically inside the mediastinum, which is the central compartment of the thoracic cavity.     * It is physically protected by the ribs.     * Anatomically, it extends from approximately the $3\text{rd}$ to the $6\text{th}$ intercostal spaces.

• Chambers of the Mammalian Heart     * The heart consists of four distinct chambers:         * Right atrium.         * Right ventricle.         * Left atrium.         * Left ventricle.

• Layers of the Heart Wall     * The thick heart wall is composed of three primary layers:         * Endocardium: This is the innermost layer that covers the inner surfaces of the heart. It consists of endothelium and areolar tissue.         * Myocardium: This is the muscular middle wall of the heart. It consists primarily of cardiac muscle cells and is responsible for the pumping action.         * Epicardium: This is the outer surface of the heart, also known as the visceral pericardium. It is composed of mesothelium and areolar tissue.

• The Pericardial Sac and Cavity     * The heart is surrounded by a sac consisting of the following components:         * Parietal Pericardium: The serous membrane forming the outer wall of the pericardial cavity. It includes a dense fibrous layer and areolar tissue.         * Pericardial Cavity: A space between the parietal and visceral (epicardium) layers containing serous fluid to reduce friction.

Types of Cardiac Cells

• Working Myocardial Cells (Myocardium)     * These include the atrial and ventricular muscle cells.     * They are classified as striated muscle specialized for contraction and impulse conduction.

• Pacemaker Cells     * These cells exhibit automatic, rhythmical electrical discharge.     * Their primary function is to generate action potentials (APs) spontaneously to initiate the heartbeat.

• Conduction Cells     * These cells are specialized for conducting action potentials throughout the heart.     * They provide an excitatory system that controls the rhythmical beating of the organ.

Comparison of Cardiac and Skeletal Muscle

• Structural Similarities     * Both types of muscle fibers are striated.     * They share a similar organization of the sarcomere.     * Myofibrils in both are composed of actin and myosin filaments.     * Both contain Sarcoplasmic Reticulum (SR) and T-tubules.

• Key Differences     * Cardiac muscle exhibits involuntary contraction, whereas skeletal muscle is voluntary.     * Cardiac muscle fibers are shorter and characterized by branching or bifurcation.     * Cardiac cells are typically uninucleate (having one nucleus), while skeletal muscle is multinucleated.     * Cardiac myocytes are interconnected by specialized structures called intercalated disks.     * Cardiac muscle uses specific cardiac isoforms of actin and myosin.

• Concept of Functional Syncytium     * Cardiac muscle acts as a functional syncytium (from Greek: $syn = \text{together}$ and $kytos = \text{cell}$).     * Unlike skeletal muscle, which forms a morphological syncytium by fusing into a single multinucleated fiber during development, cardiac muscle fibers remain separated as distinct cells with their own sarcolemma.     * Because they are electrically connected via intercalated disks, the cells function together as a single unit.

The Intercalated Disk

• Description and Location     * The intercalated disk is a dark, dense cross-band found at the end of each myocardial cell.     * It is continuous with the sarcolemma.

• Cell-to-Cell Junctions     * Gap Junctions: These allow for the rapid diffusion of ions between cells. This ensures that action potentials travel quickly from one cell to the next, enabling synchronized contraction.     * Desmosomes: These provide mechanical strength to the tissue by holding the cells together during the high-stress activity of contraction.

Pacemaker Action Potential and Initiation

• The Sinoatrial (SA) Node     * The SA node is the normal pacemaker of the heart.     * It is located in the right atrium.     * It initiates the action potential that is subsequently conducted throughout the entire heart.

• Autonomic Regulation     * The heart is innervated by the autonomic nervous system via sympathetic and parasympathetic motor neurons.     * This provides involuntary control over heart activity.     * Norepinephrine or acetylcholine are released to bind to specific receptors, which can increase or decrease contractility and heart rate.

• Comparing Action Potentials     * Pacemaker cells have a different AP profile compared to atrial or ventricular myocardial cells.     * Myocardial cells have significantly longer action potentials.     * Pacemaker cells feature a slow depolarization phase (pacemaker potential) that is less steep than the rapid depolarization seen in myocardial cells.

Sequence of Events in Pacemaker Action Potential

• Pacemaker Potential (Slow Depolarization)     * This is the initial depolarization that brings the membrane potential from resting to the threshold.     * Funny Sodium Channels ($I_f$ or f-channels): These open spontaneously, causing a progressive increase in sodium ($Na^+$) permeability. Sodium enters from the extracellular fluid (ECF), pushing the membrane potential toward the threshold.     * T-type Calcium Channels (Transient): Near the threshold, these channels open briefly. They allow calcium ($Ca^{2+}$) to enter the cell, speeding up the final approach to the threshold.

• Depolarization Phase     * Once the threshold is reached, the action potential officially starts.     * The funny channels close during the actual action potential.     * L-type Calcium Channels (Long-lasting): These are the primary channels responsible for the depolarization phase in pacemaker cells. They open at the threshold and stay open longer than T-type channels, allowing an influx of extracellular calcium to depolarize the membrane.

• Repolarization Phase     * This occurs after the closing of L-type calcium channels and the opening of potassium ($K^+$) channels.     * Potassium efflux causes the membrane potential to return toward the resting level.     * Once the resting potential is reached, funny channels open spontaneously again to restart the cycle.

Myocardial Action Potential Phases

• Phase 0: Depolarization     * Started by the influx of positive ions from adjacent cells through gap junctions.     * Once the threshold is reached, fast voltage-gated sodium channels open, allowing a rapid influx of sodium ($Na^+$).

• Phase 1: Initial Repolarization     * Fast sodium channels close.     * Fast (transient) potassium channels open for a short period.     * Potassium ions leave the cell, bringing the potential back toward $0\text{ mV}$.

• Phase 2: Plateau Phase     * Fast potassium channels close.     * Slow potassium channels (delayed rectifier) open.     * Slow L-type calcium channels open and remain open for several tenths of a second.     * The action potential plateaus because the influx of calcium is balanced by the efflux of potassium.     * The calcium that enters during this phase activates the muscle contractile process.     * Significance: This phase constitutes most of the absolute refractory period (when the cell is unexcitable). It ensures the duration of the action potential matches the duration of the mechanical contraction, allowing the ventricles time to empty and refill and preventing tetanization.

• Phase 3: Rapid Repolarization     * Slow calcium channels close.     * Additional slow potassium channels open.     * The increased efflux of potassium returns the membrane potential to the resting level.

• Phase 4: Resting Membrane Potential     * The potential averages approximately $-90\text{ mV}$.

• Atrial vs. Ventricular Action Potentials     * Atrial myocardial cells have a shorter action potential duration than ventricular cells.     * In atrial cells, slow calcium channels stay open for a shorter time.     * In atrial cells, potassium channels stay closed for a shorter time.     * Approximate durations: Atrial excitation is complete by roughly $0.1\text{ sec}$, while ventricular excitation is complete by roughly $0.22\text{ sec}$.

Excitation-Contraction Coupling

• Calcium Sources for Contraction     * Extracellular Fluid (ECF): Provides $20\text{-}30\%$ of the calcium. T-tubules allow direct inflow of calcium from the ECF into the fiber interior.     * Sarcoplasmic Reticulum (SR): Provides $70\text{-}80\%$ of the calcium.

• Mechanism Steps     1. The action potential spreads along the membranes of the T-tubules to the interior of the fiber.     2. Voltage-gated calcium channels in the T-tubule membrane open, allowing extracellular calcium influx.     3. This calcium influx triggers Ryanodine receptor channels on the SR membrane, a process called calcium-induced calcium release.     4. A massive efflux of calcium from the SR occurs, known as a calcium spark (localized, transient increase).     5. Summed sparks create a calcium signal, which is a significant enough increase in intracellular calcium to trigger contraction.     6. Calcium binds to troponin, leading to cross-bridge formation between actin and myosin, causing contraction.

• Relaxation and Recovery     7. Relaxation begins when calcium unbinds from troponin.     8. Calcium is pumped back into the SR for storage via active transport.     9. Calcium is also removed from the cell through the sarcolemma by a $Ca^{2+}/Na^+$ antiporter (exchanger).     10. The sodium gradient required for this exchange is maintained by the $Na^+/K^+\text{-ATPase}$ pump.

Questions & Discussion

• Question: Are there any questions?
• Narrative Note: The speaker concludes with a quote from Nick Sell: "We don't have to be perfect, we just have to be less dumb than we used to be."