Cardiac Muscle Physiology

Heart Organization and Anatomy

• Location and Protection     - The heart is situated within the thoracic cavity.     - It resides in the mediastinum, which is the central compartment of the cavity.     - It is protected by the ribs, located approximately from the third to the sixth intercostal spaces.

• Chambers of the Heart     - The mammalian heart consists of four distinct chambers:         - Right atrium         - Right ventricle         - Left atrium         - Left ventricle

• Layers of the Heart Wall     - The thick wall of the heart is composed of three primary layers and is surrounded by a protective sac:         - Endocardium: The innermost layer that covers the inner surfaces of the heart. It consists of endothelium and areolar tissue.         - Myocardium: The central muscular wall of the heart. It consists primarily of cardiac muscle cells.         - Epicardium (Visceral Pericardium): The outer surface covering of the heart. It consists of mesothelium and areolar tissue.     - Pericardial Sac and Cavity:         - The parietal pericardium forms the outer wall of the pericardial cavity. It is composed of a dense fibrous layer, areolar tissue, and mesothelium.         - The pericardial cavity is the space between the parietal and visceral layers and contains serous fluid.

Cardiac Cell Types

• There are three specialized types of cells in the heart:     - Working Myocardial Cells (Myocardium): These include atrial and ventricular muscle cells. They are striated muscle cells specialized for contraction and impulse conduction.     - Pacemaker Cells: These cells exhibit automatic rhythmical electrical discharge in the form of action potentials.     - Conduction Cells: These cells conduct action potentials throughout the heart, providing an excitatory system to control the rhythmical beating.

Cardiac Muscle Comparison

• Similarities to Skeletal Muscle     - Fibers are striated.     - The organization of the sarcomere is similar.     - Myofibrils are composed of actin and myosin filaments (specifically cardiac isoforms).     - Contains Sarcoplasmic Reticulum (SR) and T-tubules.

• Differences from Skeletal Muscle     - Contraction is involuntary.     - Fibers are shorter and branched.     - Generally uninucleate (possessing a single nucleus).     - Cells are interconnected by specialized structures called intercalated disks.

• Concept of Functional Syncytium     - The word "Syncytium" is derived from Greek: Syn (together) and Kytos (cell).     - Unlike skeletal muscle, which forms a morphological syncytium (fusing into a single multinucleated fiber during development), cardiac muscle forms a functional syncytium.     - Cardiac myocytes branch or bifurcate during development and bind to other myocytes.     - While the fibers remain separate distinct cells with their own sarcolemmata, they are electrically connected to one another through intercalated disks.

Intercalated Disks and Cell-Cell Junctions

• An intercalated disk is a dark, dense cross-band found at the end of each myocardial cell.
• Functions of the intercalated disk:     - It is continuous with the sarcolemma.     - Gap Junctions: These allow for the rapid diffusion of ions, enabling action potentials to travel quickly from one cell to the next.     - Desmosomes: These provide necessary mechanical strength to the tissue.

Pacemaker Action Potential and Initiation

• Action potentials are generated by the sinoatrial (SA) node, located in the right atrium. It acts as the normal pacemaker and initiates the impulse conducted through the heart.

• Autonomic Nervous System Regulation:     - The heart is innervated by sympathetic and parasympathetic systems (autonomic motor neurons).     - Control is involuntary.     - Norepinephrine or Acetylcholine are released to bind to specific receptors, increasing or decreasing heart rate and contractility.

• Pacemaker vs. Myocardial Action Potentials:     - Myocardial cells have longer action potentials.     - Pacemaker cells have a slow depolarization phase (less steep) compared to myocardial cells.

• The Pacemaker Potential:     - This is the initial depolarization that brings the membrane potential from resting to the threshold level. It is caused by specific ion channels:         1. Pacemaker Sodium Channels (Funny Sodium Channels or $I_f$ channels): These open spontaneously.         2. Fast Calcium Channels (T-type calcium channels): "T" stands for transient, as they stay open for a very short duration.     - Sequence of Events:         1. Spontaneous opening of funny channels causes a progressive increase in sodium permeability.         2. Sodium enters from the extracellular fluid (ECF), pushing the membrane potential toward the threshold.         3. Fast (T-type) calcium channels open near the threshold to speed up the final approach.         4. Once the threshold is reached, the action potential begins and funny channels close.         5. Funny channels begin to open spontaneously again once the action potential finishes.

• Depolarization and Repolarization in Pacemaker Cells:     - Ion responsible for depolarization: Calcium ($Ca^{2+}$).     - When the threshold is reached, Slow Calcium channels (L-type) open. "L" stands for long-lasting.     - Repolarization occurs when L-type $Ca^{2+}$ channels close and Potassium ($K^+$) channels open.

Myocardial Action Potential Phases

• Phase 0: Depolarization     - Triggered by the influx of positive ions from adjacent cells via gap junctions.     - When threshold is reached, fast Sodium ($Na^+$) voltage-gated channels open, permitting a rapid influx of sodium.

• Phase 1: Initial Repolarization     - Fast $Na^+$ channels close.     - Fast (transient) Potassium ($K^+$) channels open briefly, allowing ions to leave; the cell begins to repolarize toward $0\,mV$.

• Phase 2: Plateau     - Fast $K^+$ channels close.     - Slow Potassium channels (delayed rectifier) open.     - Slow Calcium channels (L-type) open and remain open for several tenths of a second.     - Action potential plateaus due to balanced $Ca^{2+}$ influx and $K^+$ efflux.     - $Ca^{2+}$ entering during this phase activates the contractile process.

• Phase 3: Rapid Repolarization     - Slow $Ca^{2+}$ channels close.     - More slow $K^+$ channels open, creating an efflux that returns the potential to resting levels.

• Phase 4: Resting Membrane Potential     - Averages approximately $-90\,mV$.

Refractory Period and Regional Differences

• Refractory Period:     - The plateau phase constitutes most of the absolute refractory period, during which the cell is unexcitable to new stimuli.     - The duration of the action potential matches the duration of the mechanical response (contraction).     - Functional purpose: Ensures sufficient time for ventricles to empty and refill; prevents tetanization of the cardiac muscle.

• Atrial vs. Ventricular Myocardial Cells:     - Atrial cells have shorter action potentials than ventricular cells.     - Atrial slow calcium channels stay open for a shorter duration.     - Atrial potassium channels stay closed for a shorter duration.     - Timing markers:         - Atrial excitation is complete at approximately $0.1\,sec$.         - Impulse reached the beginning of the AV node at $0.17\,sec$.         - Ventricular excitation is complete at approximately $0.22\,sec$.

Excitation-Contraction (EC) Coupling

• Calcium Sources:     - Extracellular Fluid (ECF): Provides 20-30% of required $Ca^{2+}$. T-tubules allow direct inflow of ECF $Ca^{2+}$ to the fiber interior.     - Sarcoplasmic Reticulum (SR): Provides 70-80% of required $Ca^{2+}_2$.

• Sequence of Excitation-Contraction:     1. The Action Potential (AP) spreads to the interior along T-tubule membranes.     2. Voltage-gated $Ca^{2+}$ channels in the T-tubules open, allowing ECF calcium influx.     3. This influx triggers Ryanodine receptor channels on the SR membrane (a process known as calcium-induced calcium release).     4. A massive efflux of $Ca^{2+}$ from the SR causes a "calcium spark" (localized, transient increase).     5. Summed sparks create a calcium signal sufficient to trigger contraction.     6. $Ca^{2+}$ binds to troponin, leading to cross-bridge formation.

• Relaxation Mechanism:     1. $Ca^{2+}$ unbinds from troponin.     2. Calcium is pumped back into the SR for storage.     3. Calcium is exchanged for Sodium ($Na^+$) at the sarcolemma via a $Ca^{2+}/Na^+$ antiporter.     4. The Sodium gradient is maintained by the $Na^+/K^+\text{-ATPase}$ pump.

Questions & Discussion

• Question: Are there questions regarding the material?
• Closing Thought: "We don't have to be perfect, we just have to be less dumb than we used to be."