Cardio Chapter One PDF

# Cardiac Properties ## Circulations In humans, the right and left pumps are involved in two different circulations: 1. **Systemic (Major, High pressure) circulation:** * Carries oxygenated blood from the left ventricle to all body organs through the aorta → arteries → arterioles→ systemic...

# Cardiac Properties ## Circulations In humans, the right and left pumps are involved in two different circulations: 1. **Systemic (Major, High pressure) circulation:** * Carries oxygenated blood from the left ventricle to all body organs through the aorta → arteries → arterioles→ systemic capillaries (exchange with ISF) → venules → veins → superior and inferior venae cavae → right atrium. 2. **Pulmonary (Lesser, Low pressure) circulation:** * Carries deoxygenated blood from the right ventricle to the lungs through the pulmonary artery → arterioles → pulmonary capillaries (gas exchange with alveoli) → four pulmonary veins → left atrium. ## Cardiac Valves There are four valves that allow a unidirectional flow of blood, i.e., prevent the back flow of blood. **I) Atrio-Ventricular (A-V) valves:** two A-V valves 1. **Tricuspid** (has 3 cusps) between the right atrium and right ventricle. 2. **Mitral** "bicuspid" (has 2 cusps) between the left atrium and left ventricle. * **Function:** they allow the unidirectional flow of blood from the atria to the ventricles during the diastole. * **The papillary muscles:** They are attached to the cusps of the A-V valves by the cordae tendineae. **II) Semilunar valves:** two semilunar valves, i.e., aortic and pulmonary valves. * **Function:** they allow the unidirectional flow of blood from the ventricles into the systemic and pulmonary circulations, respectively, during the systole. ## Functional Histology of the Cardiac Muscle The Heart is Composed of: 1. **Contractile tissue (98-99%):** cells full of contractile muscle proteins, as the atrial and ventricular muscles. * The atrial muscle is separated from the ventricles by a fibrous ring (insulator). 2. **Excitatory-conductive system (1-2%):** cells that initiate and propagate the electric impulse throughout the whole cardiac muscle. They contain few contractile proteins, and this system is composed of: SAN, AVN, AV bundle "bundle of Hiss", right and left bundle branches, and Purkinje fibers. ### The Types of Cardiac Muscle Proteins: The cardiac muscle fiber (myocyte) contains actin, myosin, tropomyosin, and troponin, as in the skeletal muscles. In addition, myocytes contain titin and dystrophin. * **Titin:** * It is a very large, elastic, elongated protein. * It binds myosin to the Z line, and it extends from the Z to M lines. * It acts as a bidirectional spring that develops: * Passive force in stretched sarcomere. * Restoring force in shortened sarcomere. * The elastic energy stored in titin maintains myosin in the center of the sarcomere. * **Dystrophin:** * A large protein connects the actin with the extracellular matrix (ECM). * It provides structural support to the myocyte. * Congenital defects in dystrophin cause cardiac muscle weakness. ### The Characters of Myocyte: * It is similar to the skeletal muscle fiber in being striated in morphology. * It is similar to the smooth muscle fiber in that it is involuntary and acts as syncytium. * There are two functional syncytia: the two atria act as one syncytium, and the two ventricles act as another syncytium. * Cardiac muscle is formed of many separated muscle fibers arranged into a branched network. ### Intercalated discs: * Desmosomes provide intracellular connections between the cytoskeletons of adjacent cells. * They form a network of adhesive bonds connecting the end of one myocyte to the next at Z lines. ### Functions: * Provide strong mechanical strength to the myocytes, so the pull of one contractile unit can be transmitted to the next one to act as one unit. * Contain gap junction - electrical continuity between the myocytes. ### Gap junctions: * Low-resistance intercellular junctions composed of multiple channels permeable to ions → direct flow of ionic current between 2 adjacent cells. * It allows the spread of A.P. from one fiber to another to allow cardiac muscle to function as a syncytium. * Gap junctions are numerous in Purkinje fibers and ventricular muscle fibers → rapid conduction. * Gap junctions are few in the AV node → slow conduction. ## Cardiac Properties 1. **Excitability.** 2. **Automaticity (Rhythmicity).** 3. **Conductivity.** 4. **Contractility.** ### 1. Excitability #### Definition: It is the ability of the myocytes (atrial and ventricular muscle fibers) to respond to an adequate stimulus by generating a propagating action potential followed by contraction. #### A. Resting Membrane Potential (RMP) = “Polarized State” of the cardiac muscle ##### Definition: It is the electrical potential (voltage) difference between the inside and the outside membrane surfaces during rest. * The inside is negative relative to the outside of the membrane by about 90 mV (i.e., - 90 mV). ##### Ionic basis (Causes) of RMP: It is due to the unequal distribution of charged ions on both sides of the membrane, with more cations (+ve charges) outside and more anions (-ve charges) inside. This unequal distribution is caused by: 1. **Selective permeability of the membrane “Passive”:** - 86 mV 2. **Na+/K+ pump “Active”:** - 4 mV * 3 Na+ are actively transported to the outside of the cell, and 2 K+ are actively transported to the inside through a carrier protein with ATPase activity (using energy from ATP breakdown). * So, more (+ve) charges are pumped to the outside (electrogenic). #### B. Action Potential (A.P.) ##### Definition: The changes that occur in the membrane potential of atrial and ventricular muscle fibers in response to an excitatory impulse (pace-maker potential) that depolarizes the membrane beyond the threshold value (- 65 mV). ##### The Phases of the Ventricular A.P: (200 to 300 msec) **Phase 0: Rapid depolarization and overshoot** * It forms the rapid upstroke of the action potential. * It is caused by the opening of the rapid voltage-gated_Na channels → Na+ influx (entry) → depolarization of the membrane → opening of more voltage-gated Na+ channels in a positive feedback manner → until reaching the firing level (-65 mV) at which all voltage-gated Na+ channels become open → overshoot up to +20 mV. * The voltage-gated Na+ channels have two gates: the outer (activation) gate that opens to depolarize the membrane, and the inner (inactivation) gate that closes at +20 mV and prevents further Na+ influx until the A.P. is about to be over, causing an absolute refractory period (A.R.P). **Phase I: Initial rapid repolarization (from +20 to +10 mV)** * It is caused by: * Rapid closure of voltage-gated Na+ channels. * Transient Cl influx. * K⁺ efflux. **Phase II: Plateau phase (around 0 mV)** * It is unique to the cardiac muscle. * Repolarization slows down, forming a plateau during which the membrane potential is between +10 and 0 mV. * It is caused by the fine_balance_between Ca++ influx and K+ efflux. * Ca++ influx occurs through the long-lasting (L-type) voltage-gated Ca++ channels. * Opening of the voltage-gated L-type Ca++ channels is slow but prolonged. * Ca++ influx during the plateau induces the release of Ca++ from the sarcoplasmic reticulum (SR). This is an example of Ca++- induced Ca++ release (CICR). * Plateau prolongs the period of depolarization of action potential. **Phase III: Late rapid repolarization** * It is caused by the closure of L-type_Ca++_channels and the continuation of K⁺ efflux via voltage-gated K⁺ channels. * Therefore, the K+ efflux is not compensated, and the inside of the membrane becomes progressively more negative until repolarization is complete and the RMP is restored. **Phase IV: Resting membrane potential** The shape and duration of the A.P. are different according to the type of myocyte, for example: * Plateau is less prominent, and its duration is about 50-150 msec. in atrial muscle fibers. * Plateau is more prolonged, with a duration of about 300 msec. in ventricular muscle fibers. ### 2. Automaticity (Rhythmicity) #### Definition: The ability of the cardiac muscle to initiate its own action potentials regularly and spontaneously, independent of any nerve supply * It is due to the presence of _specialized_ self-excitable _fibers_ that have an unstable membrane potential because they are naturally leaky to Na+ and can auto-generate cardiac impulses. * This property is most developed in the sinoatrial node (SAN), and it can discharge its own action potentials most rapidly (90-110 impulse/min.). Hence, SAN is called the "Pace-maker" of the heart. While the discharge rate of AVN is 40-60 impulse/min., and of Purkinje fibers is 15-40 impulse/min. * Action potentials then pass directly to the atria, then to the ventricles through the conductive system to depolarize them. * The normal heart rate is 60-90 beat/min. due to the dominance of the vagal tone during rest. #### The Ionic Basis of the Sinoatrial Node (Nodal) A.P. SAN action potential has three main phases: 1. **Phase 4 (Prepotential):** it is the unstable RMP or the spontaneous slow diastolic depolarization. 2. **Phase 0 (Slow depolarization).** 3. **Phase 3 (Repolarization).** ##### Phase 4: (Prepotential) * The unstable RMP has a maximum negativity between -55 : -60 mV, then membrane potential decreases to the firing level (-40 mV). * This is called the prepotential (pace-maker potential), which triggers the next A.P. **The ionic basis of the prepotential (Spontaneous slow self-depolarization):** 1. **Background inward current:** (pace-maker current) * Spontaneous inward leakage of Na+ along its concentration gradient. * This is the most important current that remains, even though all other currents are blocked. 2. **Funny current:** * Influx of both Na⁺ and K+ through specific "f" channels. * It is called funny due to the unusual activation of these channels. 3. **Ca++ influx through T-type (transient type) Ca⁺⁺ channels:** * These channels are activated at about - 50 mV, causing a Ca++ influx → completing the prepotential to the firing level. * The presence of these multiple depolarizing currents provides a safety factor in the SAN. Blocking any current leaves the others to perform the vital prepotential. * The prepotential is more prominent in SAN and AVN only. While the other parts of the excitatory-conductive system are considered "Latent pace-makers" which can initiate A.P. when the SAN and AVN are inhibited or blocked. * Contractile tissues (atria and ventricles) do not have prepotential, and they may discharge spontaneously only if they are injured or have an abnormality. ##### Phase 0: (Slow depolarization) * At the firing level (- 40 mV): L-type (long-acting type) Ca++ channels open → slow inward calcium current (Ica) → A.P. ##### Phase 3: (Repolarization) * At the peak of depolarization (about + 10 mV): Ca++ channels close and K channels are activated → K+ efflux (delayed rectifying K⁺ current) → repolarization till reaching about 60 mV, where a new prepotential starts. ## Comparison Between The Ventricular and SAN A.P. | | Ventricular A.P. | SAN A.P. | |---------------|------------------------|----------------------------| | RMP | Stable at - 90 mV | Unstable between -55 : -60 mV | | Prepotential | Absent | Present due to 3 currents | | Firing level | At - 65 mV | At - 40 mV | | Depolarization upstroke | Slow upstroke due to gradual Ca++ influx | Sharp upstroke due to rapid Na+ influx | | Peak of depolarization (Apex of A.P.) | At + 20 mV | At + 10 mV | | Plateau | Present | Absent | | Time | Starts just before systole | Occurs during diastole | ### 3. Conductivity #### Definition: The ability of the cardiac muscle to conduct the cardiac impulse through the contractile tissues (atria and ventricles). * The atrial and ventricular functional syncytia are completely separated by an insulator _fibrous_ tissue, and the only connection between them is through the conductive system. The excitatory-conductive system is composed of: 1. **Sinoatrial node (SAN):** * **Site:** In the posterior wall of the right atrium, near the opening of the SVC. * **Rate:** It has the _most rapid slope of the prepotential_, and the highest rate of discharge (90-110 beat/min.). So, it is the normal pace-maker of the heart. * **Its fibers radiate within the atrial fibers, so the initiated A.P. is immediately conducted into the atrial muscle.** * **Innervation:** Right vagus nerve and sympathetic nervous system. 2. **Atrioventricular node (AVN):** * **Site:** On the right side of the interatrial septum, near the junction between the atria and ventricles. * **Rate:** It has a slow slope of prepotential and its discharge rate is 40-60 impulse/min. * **Function:** It is the only conductive pathway from the atria to the ventricles. * **Innervation:** Left vagus nerve and sympathetic nervous system. 3. **The internodal tracts:** Three bundles of specialized atrial fibers between the SAN and AVN; the anterior, middle, and posterior. 4. **AV bundle (bundle of His):** * **Site:** It is the continuation of AVN. It is located on the top of the right side of the interventricular septum. * **It continues as a right bundle branch (RBB) and gives off a left bundle branch (LBB).** 5. **RBB and LBB:** Each one runs on the respective side of the interventricular septum till reaching the apex, then they are reflected upwards in the ventricular wall towards the base of the heart. 6. **Purkinje fibers:** _Slowest discharge - fastest conducting point_ * They are many branches that arise from the RBB and LBB to penetrate the whole ventricular muscle bulk. * Its rate of discharge is ~15-40 impulse/min. ### The Velocity of Conduction of Cardiac Impulse in Different Tissues | Tissue | Conduction rate (meter/second) | |----------------|--------------------------------| | SAN | 0.05 | | Atrial muscle | 1 | | AVN | 0.05 | | Bundle of His | 1 | | Purkinje fibers | 4 | | Ventricular muscle | 1 | ### Initiation and Propagation of a Cardiac Impulse * The excitation wave is initiated in the SAN. Then, it spreads through the atrial fibers and the 3 internodal tracts to converge on the AVN. * Atrial depolarization is completed in about 0.1 second. * AV node delay (0.1 second): The conduction in the AVN is very slow as it contains a few number of gap junctions and intercalated discs. So the impulse is delayed for 0.1 second before it being conducted to the ventricles. * This delay is important to give a sufficient time for the atria to contract and empty their blood into the ventricles before the ventricular systole. * The depolarization wave then travels rapidly down the AV bundle, bundle branches, and the Purkinje fibers (have many gap junctions) to all parts of the ventricles; this ensures a single coordinated contraction of the both ventricles (syncitum). * Ventricular depolarization is completed in about 0.08-0.1 second. ### 4. Contractility #### Excitation-Contraction Coupling: ##### Definition: It is the ability of the myocytes to convert the electrical impulse (A.P.) into a mechanical response. ##### The mechanical response can be divided into: **A. Cardiac muscle contraction:** “Active process” * Sarcoplasmic reticulum (SR) does not store enough Ca++ to induce full muscle contraction. Hence, muscle contraction depends mainly on the Ca++ of the ECF rather than the Ca++ of SR. * During the plateau phase of the A.P., a large quantity of Ca++ diffuses from the ECF to the sarcoplasm of myocytes via the transverse (T) tubules. Ca++ influx causes the release of Ca++ from the SR; this is called calcium-induced calcium release (CICR). * Ca++ starts activation of contractile proteins by binding to troponin-C, which displaces the tropomyosin → exposure of the active sites of actin → myosin head binds actin - cross bridges cycling → sliding of actin over myosin → shortening of the sarcomere (muscle contraction). * The strength of cardiac muscle contraction depends on the concentration of Ca++ in the ECF, as the ends of the T-tubules open directly into the ECF. **B. Cardiac muscle _relaxation_:** “Active process” * At the end of the plateau of A.P., Ca++ suddenly decreases and is removed from the sarcoplasm as a result of: * Closure of L-type Ca++ channels → sudden stop of Ca++ influx. * Ca++ is pumped into the SR and out to the ECF via the T-tubules via Ca++ pump (Ca++ ATPase). * Ca++ removal from the cell via Na⁺-Ca++ exchanger. * Ca++ binds to intracellular buffering protein (calmodulin). * These mechanisms lead to the termination of the contraction and the start of the relaxation process. * Relaxation occurs by breaking the cross-bridges between actin and myosin. #### Types of Cardiac Muscle Contraction: 1. **Isotonic contraction** * A contraction in which shortening of muscle fiber occurs, and the force of contraction can be measured by: * Degree of shortening (A L). * Velocity of shortening (A L/A t). 2. **Isometric contraction** * A contraction in which the fiber cannot shorten, and the force of contraction can be measured by the developed tension. #### Factors affecting the _performance_ of the cardiac muscle 1. **Preload** (the initial resting muscle length). 2. **Afterload** (the degree of resistance faced by the contracting muscle). 3. **The inotropic (contractility) state of the muscle.** 4. **The frequency of contraction.** ##### 1) The Effect of Preload **Length-tension relationship:** "Starling's law" * Starling's law states that "the more the initial length of the muscle fiber, the greater the force of its contraction (developed active tension), within physiological limits". * When a relaxed muscle is stretched, a passive tension develops. However, when the muscle is stimulated, an active tension develops, which is proportional to the initial length of the fiber within limits. * The developed active tension in the contracting cardiac muscle is proportional to the number of cross-bridges between actin and myosin, which is proportional to the length of the sarcomere within limits. * **Active tension a Number of cross-bridges a Length of the sarcomere** * At the sarcomere length of 2.2 microns, the number of cross-bridges between the actin and myosin is maximal. * Over stretch of the sarcomere (more than 2.2 μ), the developed active tension starts to decrease due to disruption of the sarcomere (↓ number of cross bridges between actin and myosin). * In the whole intact heart, the initial muscle length is proportionate to the end diastolic volume (EDV), which is determined by the venous return (VR). * While the diastolic pressure in the ventricle can be considered as the preload. * i.e., ↑ VR → ↑ EDV → ↑ diastolic pressure in the ventricle (preload) → ↑ initial muscle length → ↑ force of contraction within limits. **N.B:** Passive tension is directly proportional to the muscle length until the cutting of the muscle fiber. ##### 2) The Degree of Afterload i.e., the resistance faced by the muscle when it starts to contract. ##### Load-velocity relationship: * Basically, the velocity of shortening is inversely proportional to the load on the muscle. * At the same initial length of the muscle (preload), as the afterload is progressively increased, the velocity of muscle shortening is progressively decreased until reaching (P0) at which the muscle is unable to lift the weight, reaching the peak of developed tension with zero velocity. * Vmax (determined by extrapolation): is the maximal velocity of shortening, which can be obtained only at zero load, which can never occur, as the muscle cannot shorten without being previously stretched at least by the preload. * At any level of afterload, the muscle is faster and can shorten more with a higher preload. * In the whole intact heart, the aortic pressure can be considered the afterload, which is faced by the left ventricle when it starts to contract. ##### 3) The Inotropic (Contractility) State * Normally, the activation of the cardiac muscle by Ca++ is submaximal. Contractility can be increased (by positive inotropics) or decreased (by negative inotropics) by changing the intracellular Ca++ concentration. * The inotropic state _does not depend_ on changes in the preload or afterload. * Positive inotropics shift the Starling's curve up and to the left, and the Load-velocity curve to the right. * While negative inotropics shift the Staling's curve down and to the right, and the _Load-velocity_ curve to the left. #### Factors affecting contractility: ##### Positive inotropics: * **Intracellular cAMP:** activates protein kinase A → phosphorylation of the voltage-gated Ca++ channels → more time in the open state → Ca++ influx. In addition, cAMP stimulates the active reuptake of Ca++ by the SR→ accelerating relaxation and decreasing the period of systole. * **Sympathetic supply (catecholamines):** act on B₁ receptors → activation of adenylcyclase enzyme → ↑ cAMP. * **Xanthines (e.g., caffeine):** inhibit the breakdown of cAMP→↑ CAMP. * **Glucagon:** ↑ the formation of cAMP. * **Digitalis:** inhibits the Na+-K+ pump in the myocardium → ↑ Na+ concentration inside the fiber → ↓ Na+ influx and Ca++ efflux through the Na+-Ca+ exchanger → accumulation of intracellular Ca++ →↑ the strength of myocardial contraction. * **Increased frequency of contraction:** has a positive inotropic effect and vice versa. * **Increased Ca⁺⁺ concentration in the ECF:** improves the inotropic state of the cardiac muscle, and at very high Ca++ concentration, the heart stops in systole (calcium rigor). ##### Negative inotropics: * **Parasympathetic supply (acetylcholine):** acts on M2 receptors. It has a negative inotropic effect on the atrial muscle and, to a small extent, on the ventricular muscle. * **Calcium antagonists, antiarrhythmic drugs, ether, barbiturates, and anesthetic agents:** have a negative inotropic effect. * **Ischemia:** produces a negative inotropic effect due to Oxygen Lake and the associated acidosis. * **Chronic myocardial failure:** has a negative inotropic effect. * **Removal of Ca++ from the ECF:** leads to decreased force of contraction and finally cardiac arrest in diastole. ##### 4) The frequency of contraction * The increased heart rate (frequency of A.P.) has a positive inotropic effect through causing changes in Ca++ release and/or reuptake. This response is known as "stair case or treppe phenomenon". * Slowing of the heart rate has the opposite effect (negative inotropic).