BMS 204 Cardiac Properties Part 2 PDF

BMS 204 : Cardiac Properties part 2 Dr Noha Lasheen Associate Professor of Physiology F A C U L T Y O F M E D I C I N E F a l l 2 0 2 4 By the end of this lecture, you should be able...

BMS 204 : Cardiac Properties part 2 Dr Noha Lasheen Associate Professor of Physiology F A C U L T Y O F M E D I C I N E F a l l 2 0 2 4 By the end of this lecture, you should be able to: ▪ Describe the spread of excitation wave and its significance ▪ Mention characteristics of AV node ▪ Describe excitation-contraction coupling ▪ Mention factors affecting Inotropic state of cardiac muscles 3) Conductivity All the cardiac muscle cells are conductive but at different rates. In general, conduction rate is decreased by vagal stimulation and increased by sympathetic stimulation. 1. SAN conduction: Very slow conduction (= 0.05 m/sec.). So, preventing any ectopic focus to depolarize it. ➔a protective mechanism to keep or restore the normal pacemaker. 2. Atrial conduction of excitation wave (EW): EW spreads rapidly through atria converging on AVN. This is completed in 0.1 sec. A) Specialized atrial pathways: are freeways with rapid conduction rate (1 m/ sec) and are composed of: - Interatrial pathway: from RA near the SAN to LA near the AVN. - Internodal pathways: anterior, middle & posterior bundles from RA near the SAN to AVN. B) Atrial muscle conduction: cell-to-cell conduction at a slow rate (0.3 m / sec). 3. AVN Conduction: It has the slowest conduction rate in the heart (0.02 – 0.05 m / sec). It has 3 functional divisions: *A-N zone: with maximal delay because of very long path length. * N zone: which has the slowest conduction velocity. *N-H zone. Characteristic functions of AVN: 1. A-V nodal delay (100 - 150 msec) between atria and ventricles. 2. A-V Nodal block (Refractoriness): the refractory period protects ventricles against high atrial rhythm. The refractory period does not allow except 180 - 200 bpm to pass from atria to ventricles in case of high atrial rhythms. 3. Decreased chance for retrograde direction in conduction. This protects the SAN from a ventricular ectopic focus. 4. Ventricular Conduction (A-V bundle, bundle branches & Purkinje fibers): through the conducting pathway His bundle which divides into right and left bundle branches (conduction rate of main bundle & branches is 1-2 m/sec). Each bundle ends by small fibers, Purkinje fibers which have the maximum conduction velocity (4-5 m/sec) to ensure synchronous activation of both ventricles. The final ramifications of Purkinje fibers go rather perpendicular from the endocardial surface to reach to about 2/3 of the thickness of ventricular muscle. 5. Ventricular myocardial Conduction: The rest of ventricular muscle thickness is activated by the slow cell-to-cell conduction ( 0.3 m/sec). Conduction through left wall is slower than right wall due to more thickness of its wall. First part of the ventricle to be excited is the mid portion of ventricular septum on the left side. Last part is the epicardial surface at the base of left ventricle. 4th Cardiac property is Contractility Def.: the ability of the heart to contract & generate force in response to its stimulation; Now, contractility is the intrinsic ability of the cardiac muscle to generate force at a constant length. The ability of the cardiac muscle to convert chemical energy into mechanical energy (work, tension and pressure) Sources of Ca++ needed for contraction: 1) ECF Ca++ = Depolarizing Ca++ : enters during the plateau phase. 2) SR Ca++ : released by the depolarizing Ca++. Mechanism of muscle contraction Mechanism of Cardiac Muscle Contraction Excitation-Contraction Coupling 1. Spread of excitation wave all over the membrane of the cardiac muscle fiber. 2. Inward spread of the action potential along the T tubules. 3. Arrival of the depolarization wave to the T tubules activates the DHP receptors ➔Ca++ influx via these voltage-gated Ca++ channels from the ECF into the sarcoplasm of the muscle. 4. Entry of the ECF Ca++ triggers the release of Ca++ ions from ryanodine receptors (ligand-gated calcium) (Ca++ release channel) of the cisterns of the SR (= Ca++ induced Ca++ release, CICR). 5. The amount of Ca++ released from the SR depends on the inward Ca++ current and also, on the amount of Ca++ that are previously stored in the SR ➔ ↑↑ intracellular Ca++ concentration. Mechanism of Cardiac Muscle Contraction Excitation-Contraction Coupling 6. Ca++ binds to troponin C subunit ➔ conformational changes in the troponin- tropomyosin complex & the tropomyosin moves laterally ➔exposing the myosin binding sites on the actin molecules ➔ allowing the formation of the cross linkages between actin and myosin. The actin myosin cross bridge cycles (binding, bending, and detachment) occur in cardiac muscle identical to that in skeletal muscles with sliding of actin over myosin producing the cardiac muscle contraction (systole). N.B. The skeletal muscles have sufficient stores Ca++ that are released upon excitation from the sarcoplasmic reticulum without dependence on ECF Ca++. Cardiac Muscle Contraction The strength of contraction depends on & is directly proportionate to the intracellular Ca++ concentration. Normally, not all the troponin sites are saturated with Ca++➔ the saturation degree of troponin sites with Ca++, and the strength of contraction is determined by Intracellular (IC) concentration of Ca++ ➔all factors raising the IC concentration of Ca++ can provide more sites for cross-bridge formation with a stronger contraction. Mechanism of Cardiac Muscle Relaxation an active process. Ca++ is pumped back into the longitudinal portions of the SR by Ca++ pump: sarcoplasmic reticulum Ca++ pump (SERCA). Also, Ca++ is extruded to outside the cell through: 1. membrane Ca++ pump 2. Na+-Ca++ exchanger. ➔ Return (reduction) of intra-sarcoplasmic Ca++ concentration to the resting level ➔Release of Ca++ ions from troponin C ➔Tropomyosin moves back to cover the active sites on actin ➔ Cessation of the interaction between actin and myosin ➔ Muscle relaxation (diastole). 3] The duration of contraction is dependent on & directly proportionate to the intracellular Ca++ concentration ↑intracellular Ca++ concentration➔ prolong the duration of contraction because more time is needed by the Ca++ pump to remove Ca++ from the sarcoplasm to induce relaxation & end of contraction. So, all factors raising intracellular Ca ++ concentration can provide a more prolonged contraction & vise versa. Regulation of Relaxation 4] The most important physiological factor that enhances relaxation is sympathetic stimulation, through a beta - adrenergic action mediated by c-AMP. The rate of relaxation is accelerated due to an increase in the activity of SR Ca++ - ATPase pump ➔faster and more Ca++ re-uptake by SR. very important especially when the heart rate increases as in exercise, because the increased rate of relaxation compensates for the decreased time of ventricular filling during the shortened diastole. 5] The most important pathological factor that impairs relaxation is heart disease, particularly ischemic heart disease. By interfering with the metabolic processes responsible for energy (ATP) production, the activity of SR Ca++ - ATPase pump & the Ca++ reuptake by SR are decreased resulting in a depressed rate of relaxation (diastolic dysfunction). Time Relations &Characteristics Of The Contractile Response 1- Contraction starts 20 msec. after the onset of action potential via excitation - contraction coupling independently of the CNS & requires the entry of Ca++ from ECF. 2- Contraction reaches its peak tension during the last 1/3 of the plateau of the action potential, (when sarcoplasmic Ca++ reaches its highest concentration). 3- The cardiac muscle cannot be tetanized completely why? because of the long ARP which may extend to about the middle of the diastole i.e. almost 50% of ventricular relaxation is obligatory before it can respond to a second stimulus & this guarantees satisfactory filling. 4- The contractile response is all-or-none there is no gradation of response with gradation of the stimulus. The muscle fiber contracts fully if it responds at all. Actually each of the atrial muscle sheet and ventricular muscle sheet behaves like one big muscle unit because it is a functional syncytium. Factors Affecting Myocardial Force Of Contraction: A) Intrinsic factors (=Determinants): 1) Initial Length (Preload). 2) Afterload. 3) Frequency Of Stimulation. 4) Contractility. B) Extrinsic factors (=Inotropic factors): 1) Nervous. 2) Neurohormonal. 3) ECF ions. 4) Drugs. EC coupling as target of contractility regulation Parasympathetic NS Sympathetic NS (-)Heart rate (+) Contractile force(+)  I) Extrinsic factors Affecting Myocardial Contraction Force (Inotropic Factors): All extrinsic factors that affect the contraction force are inotropic factors acting by changing the contractility: 1) Nervous Factors: a) Sympathetic stimulation: ↑strength of contraction (positive inotropic factor) through its Ca ++ raising effect by 3 ways: 1. ↑ Ca++ entry from ECF through activation of calcium slow channels (L-type) during the plateau of each cardiac action potential. 2. ↑ Ca++ entry from the ECF because of the increased number of action potential per unit time (force - frequency relationship). 3. ↑ Ca++ release from the SR: by ↑ Ca++ entry by the first and second effects (increased triggering Ca++) & also due to the increased SR Ca++ stores owing to potent Ca++-ATPase pump stimulated by sympathetic to accelerate relaxation. b) Parasympathetic stimulation has a negative inotropic effect due to its intracellular Ca++ lowering action (opposite to sympathetic). 2) Neurohormones: a. Epinephrine & norepinephrine: are positive inotropic factors (similar to sympathetic). b. Acetyl choline: is negative inotropic factor (similar to parasympathetic). 3) ECF ions: Effects of variations in Ca++ and K+ ions: a. Ca++ infusion (intravenous) may stop the heart during systole (Ca++ rigor). On the other hand, insufficient extracellular Ca++ has a negative inotropic effect. b. Effects of hyperkalaemia: depresses cardiac contractility and may stop the heart during diastole ➔ ↑ K+ ions have a negative inotropic effect. 4) Drugs: a. Drugs that hinder Ca++ entry into the cells (Ca++ entry blockers ) Nifadipin (adalat) are negative inotropic agents. b. Drugs that ↑ intracellular Ca++ conc are positive inotropic agents. Digitalis used in the treatment of heart failure is the most important of all; it acts through inhibition of Na+ K+ ATPase ➔Na+ ions accumulate inside the cells ➔ stimulate Na+ Ca++ exchanger (between intracellular Na+ & extracellular Ca++), ➔ ↑ the intracellular Ca++ concentration. Intrinsic Factors Affecting Myocardial Contraction Force: 1) Initial Length (Preload): *major determinant of the force of contraction *In the intact heart, the end diastolic volume (EDV) is used instead of length of muscle fiber. *The preload is determined by the EDV. *preload →the degree of passive stretch exerted by blood volume in the ventricle just before its contraction Starling forces of the heart The Length-Tension Relationship (Starling Law = Frank-Starling Relationship Or Law): Within physiological limits, the force of myocardial contraction is directly proportional to the initial length (resting length) of myocardial fibers. ↑ the initial length (preload) up to certain limit →the muscle developed tension is increased. Further increase muscle length beyond this limit depresses the muscle developed tension and this is not seen in the normal heart but only in heart failure 2) Afterload: Similar to the skeletal muscle, when the cardiac muscle lifts a load after starting contraction (after load), it contracts first isometric and then isotonic. isometric: shortening of Contractile Element is compensated by equal lengthening of SE which increases the muscle tension➔no net shortening of the whole muscle fiber with no lifting of the load. ➔the force generated in case of isometric contraction is in the form of increased tension alone.  isotonic: when the muscle tension developed is enough to carry the load, further shortening of the CE is allowed to shorten the whole muscle fiber, and thus the load is lifted. So the force generated in case of isotonic contraction is in the form of increased tension & then shortening. In the intact heart, the afterload is increased when beating against higher arterial blood pressure or a stenosed valve. Force-Velocity relationship =Afterload Increase blood pressure in aorta and pulmonary artery causes: decrease in the velocity of shortening of the cardiac muscle. The relation between afterload & Velocity (Force–Velocity relationship): Heavier loads are lifted at lesser velocities till the load is too heavy to be lifted (isometric contraction). On the contrary, lighter loads are lifted at higher velocities, till reaching to the maximum velocity at zero load. Vmax (maximum Velocity): is the maximum velocity of contraction, produced at zero load. A muscle with greater preload can overcome a larger afterload (the load not lifted before is now lifted when the muscle is preloaded); but the Vmax is the same because it is independent and not affected by preload. Being independent of the preload, the Vmax represents an important measure (index) for myocardial contractility. So, Vmax is increased by the factors that increase contractility (+ve inotropic factors) such as sympathetic stimulation & vice versa. 3] Frequency of stimulation: Cardiac muscle responds to high rates of stimulation by progressively greater forces of contraction & vise versa. This effect of heart rate on contractility is known as frequency -force relationship, and can be explained by the changes occurring in the sarcoplasmic Ca++ concentration.  Examples & Explanations: 1] In all conditions of physiological acceleration of the heart, the contractility is increased & when the heart is paced by an artificial pacemaker. ↑ the heart rate, more Ca++ ions enter into the myocardial cell & more Ca ++ trigger release from SR. Vice versa ex: the effect of vagus nerve on the contractility of the ventricle. Stimulation of the vagus nerve, which does not supply the ventricles, decreases their strength of contraction; explained by its effect on the SA node decreasing the heart rate ➔↓ the contractility of the ventricular muscle. 2] Stair-case phenomenon (= Treppe = Bodwitch effect): With ↑ rate of stimulation & ↓interval between each 2 stimuli, the strength of each contraction is increased stepwise as a stair till reach to a plateau. When a second stimulus comes early it induces Ca++ entry & this triggers Ca++ release by SR, before the active Ca++ uptake by SR had lowered the intracellular Ca++ concentration to its original low value after the previous beat. Summary of Cardiac Muscle Contraction: Ca handling, 12K ▪ During rest: the inhibitory troponin-tropomyosin complex prevents the actin-myosin interaction. ▪ Upon arrival of excitation wave rise in intracellular Ca++ concentration ➔combine with troponin C ➔ a conformational change of troponin, transferred to the tropomyosin molecule. ▪ Tropomyosin moves laterally and uncovers actin-binding sites for the myosin head on the actin filaments, allowing formation of cross-linkages between actin and myosin. ▪ Binding between actin & myosin, the myosin head rotates and draws the thin filaments into the center of A band and reduces the length of the sarcomere. ▪ Detachment in the presence of ATP, and the process is repeated. Sources of Ca+2 To Sum up: Myocardial Contractility (=Inotropic State): the intrinsic ability of the cardiac muscle to generate force at a constant length (ino=force). the inotropic state of the myocardium is dependent on the integrity of the muscle elements, and it is badly affected by a myocardial infarction. In this condition the contractility should be evaluated in order to decide whether or not to submit the subject to a major coronary bypass operation Contractility change is induced by changes in sarcoplasmic Ca++ concentration. All factors that raise intracellular Ca++ conc are positive inotropic factors & all factors that decrease intracellular Ca++ conc are negative inotropic factors. To Sum Up References: Ganong’s Review of Medical Physiology. Kim E. Barrett (editor), 26th edition, 2019. Lange Basic Science Guyton and Hall Textbook of Medical Physiology (Guyton Physiology) 14th Edition, ELSEVIER, USA Fox, Stuart Ira. Human physiology / Stuart Ira Fox. — 12th ed. THANK YOU