Typical Human Cell Three structural features of human cells identify them as eukaryotic cells. They are 1. a distinct membrane surrounding a central nucleus, 2. several membrane-lined intracellular structures and organelles, 3. a number of well-defined subcellular domains in which different microenvironments are maintained so that several chemical reactions can occur simultaneously and optimally
Cardiac Surgical Physiology Electrical & membrane properties of cardiac cells Contraction of cardiac muscle The pump Coronary blood flow Heart failure
Heart Function The human heart consists of a few billion myocytes, cells that are capable of creating mechanical force from chemical energy. The process is named excitation– activation–contraction coupling. Heart function differs from skeletal muscle function in that every cardiac myocyte contracts with each heart beat. As a result, the strength of cardiac contraction is not modulated by altering the number of contracting cells but is modulated by changes in the intrinsic contractile properties of myocytes.
Cardiac Muscles Differences from skeletal muscle Cardiac muscle is striated muscle. Its contractile proteins are actin and myosin, and its regulatory proteins are tropomyosin and troponin-T, -C, and -I. Its microanatomy differs from that of skeletal muscle in that it has (1) only one or two centrally located nuclei as opposed to the several nuclei of skeletal muscle cells; (2) extensive cross connections between adjacent fibers ; (3) gap junctions between adjacent cells ; and (4) fewer but larger T-tubules (one per z-line).
Cardiac Muscles Microanatomy A mature cardiac muscle cell is up to 100 μm long and 25 μm in diameter. It contains numerous myofibrils, which are chains of sarcomeres, the fundamental contractile unit. Many have two nuclei. The sarcomere length typically ranges between 1.5 and 2.2 μm, contraction to relaxation. Myocytes are coupled to one another by a net-like collagen matrix.
Cardiac Cells Electrical & membrane properties Cell membrane or sarcolemma T-tubules & sarcoplasmic reticulum Electrical activation of heart Regulation of cellular function by sarcoplasmic receptors
Cardiac Cell Membrane The cardiac cell is surrounded by a membrane (plasmalemma or sarcolemma) with unique properties These properties allow the origination and then the conduction of an electrical signal through the heart, leading to near-synchronous depolarization of atrial myocyte and, with appropriate delay, synchronous depolarization of ventricular myocytes The sarcolemma further possesses properties leading to initiation of excitation-contraction coupling process. The sarcolemma allows regulation of excitation, contraction, and intracellular metabolism in response to neuronal and chemical stimulation
F unctional Syncytium Myofibrils are formed by chains of sarcomeres and bundles of myofibrils form fibers. Extensive cross-connections between neighboring cardiac muscle fibers are the basis of the functional syncytium
Sarcoplasmic Reticulum SR is an intracellular network of membrane-lined tubules that forms a mesh around each myofibril. SR abuts the T-tubules and sarcolemma and forms functionally important junctions at these sites. It has at least three electronmicroscopically different regions: 1. Network SR courses over the myofibrils and forms the connection among other SR parts and has a high content of Ca++ -ATPase (adenosinetriphosphatase) and phospholamban. 2. Corbular SR is the bulges that are found in the region of the I-band (light region adjacent to the Z-line). It has a high Ca++ content. 3. Junctional SR is found near the T-tubules, in the region of the triads. It does not make intimate contact with the T-tubules but appears to be “connected” to them by electron-dense foot processes. These are the large cytosolic domain of the SR Ca++ release channel (ryanodine receptor).
Composition of Sarcolemma The phospholipid bilayer provides a fluid barriers, like a film of oil on the surface of water, that is particularly impermeable to diffusion of ions. Small lipid-soluble molecules such as oxygen and carbon dioxide diffuse easily through the membrane. The water molecule, although insoluble in the membrane, is small enough that it diffuses easily through membrane Other larger molecules( sodium, chroride, potassium, calcium ) cannot easily diffuse through lipid bilayer & require specialized mechanisms (channels) for transport Specialized ion transport systems within the sarcolemma consists of membrane-spanning proteins that float in and penetrate through the lipid bilayer
Membrane-spanning Proteins Membrane-spanning proteins are associated with three different types of ion transport Diffusion through transmembrane channels that can be opened or closed (gated) in response to electrical or chemical (ligand) stimuli Exchange (antiport) of one ion for another with binding of these ions to portions of the transmembrane protein for exchange in response to an electrochemical gradient Active (energy-dependent) transport of ions against electrochemical gradient In addition, other proteins are located in sarcolemma that serve as receptors for neuronal or chemical control of cellular processes
Basic Composition of Sarcolemma Interior of membrane Outside of membrane
Sarcolemmal Channels Voltage-gated sodium channels Fast channel Most in electrically excitable muscle & nerve cells Voltage-gated calcium channels T(transient)-calcium channels L(long-lasting)-channels Potassium channels Cardiac cells contain a variety of potassium channels, both voltage-regulated and ligand-gated Three of these voltage-regulated potassium channels are important in the repolarization of the cell membrane
Ion Pumps & Ion Exchange Sodium-potassium ATP-dependent pump Utilizes the energy obtained from the hydrolysis of ATP to move three sodium ions out of the cell & two potassium ions into the cell ATP-dependent calcium pump By hydrolyzing the ATP, & utilizing the consequent energy to transport calcium out of cell, but magnitude of current is small Sodium-calcium exchange The energy used for this exchange comes from the electrochemical gradient favoring the influx of sodium ions into the cell and it is the primary mechanism for removal of excess cytosolic calcium Sodium-hydrogen exchange This pump extrudes one intracellular hydrogen ion in exchange for one extracellular sodium ion from the electrochemical gradient favoring sodium influx. This mechanism has been implicated in the maintenance of neutral intracellular pH.
Scheme of Sodium Ion Channel Shaded region within narrow portion of the pore is selectivity filter A : the activation gate, I : the inactivation gate As the transmembrane potential rises from -80 to -60 mV, the activation gate opens, leading to the open state that allows the passage of sodium ions through the channel.
Sarcolemmal Channels of Myocytes Action Potential & Ion Currents Inward (depolarizing) currents ; positive, outward (repolarizing) currents ; negative. The horizontal filled bars show the state of the gate of the ion channel (white = open, black = closed, shaded = partially open) In case of the sodium channel, both activation and inactivation gates are shown I = current, Na = sodium, Ca = calcium, K = potassium
T-tubules & Sarcoplasmic Reticulum T-tubules A system of transverse tubules( t-tubules ) extends the sarcolemma into the interior of the cardiac cell to bring very close to the contractile proteins. These tubules are generally perpendicular to the sarcomere at the level of the z-lines. Sarcoplasmic reticulum The bulk of sarcoplasmic reticulum in the cardiac cell contains only small amount of RNA and is not concerned with protein synthesis. Its primary function is excitation-contraction coupling by sudden release & then rapid removal of calcium to allow relaxation Subsarcolemmal cisternae; excitation-contraction coupling by sudden release of calcium Sarcotubular network; uptake of calcium from the cytosol
Resting Membrane Potential The cardiac cell, in its polarized (diastolic) state, has a negative resting electrical transmembrane potential across the sarcolemma determined primarily by the concentration gradient of potassium across membrane. Since the sarcolemma prevents the diffusion of large anions (e.g., proteins and organic phosphorous) and is relatively permeable at rest to potassium ions because of the open state of most potassium channels but less permeable to sodium, potassium ions flow across the membrane in response to the concentration gradient. With approximate potassium concentrations inside and outside the cell of 100mM and 4mM, respectively, the resting transmembrane potential of cardiac cell is predicted to be -86mV
Depolarization of Sarcolemma Phase 0 ; This inward movement of sodium ions causes the rapid spike of the action potential Phase 1 ; A transient potassium current causes a very early repolarization of action potential, but this fast channel closes quickly Phase 2 ; The plateau of action potential is sustained at a neutral or slightly positive by an inward flowing calcium current Phase 3 ; With time, long-lasting calcium current begin to close and repolarizing potassium current (delayed rectifier current) leads to initiation of phase 4, leading to repolarization Phase 4 ; As repolarization progresses, stronger first potassium current predominates, leading to full repolarization.
Action Potential of Myocytes The action potential is the result of exquisitely tuned ion currents that are activated and deactivated at different intervals Upstroke (phase 0) Early rapid repolarization (phase 1) The plateau (phase 2) Late rapid repolarization (phase 3) Diastole (phase 4)
Pacemaker Activity The action potential of the slow fibers of the nodal tissue (siniatrial node and atrioventricular node) differs from that in the fast fibers of the ventricular myocytes Rapid upstroke & overshoot of phase 0 are less prominent or even absent due to lack of fast sodium channel The plateau channel is abbreviated because of lack of sustained active sodium and calcium ion inward current The repolarization phase leads to a resting phase that begins to depolarize again The slowly depolarizing phase 4 resting potential is called diastolic depolarization current or pacemaker potential
Pacemaker Cells Pacemaker cells differ from other myocytes in that they do not have a stable membrane potential in diastole. After they have repolarized to the maximum diastolic potential, their membrane potential gradually depolarizes, and an action potential is generated when Ca++ influx increases explosively. The instability of diastolic potential arises mostly from (1) the absence of the inwardly rectifying K+ channel, IK1, the major diastolic stabilizing current; and (2) the presence of a mixed Na+/K+ pacemaker channel, If. The slope of the diastolic potential in pacemaker cells is determined by the imbalance between If and IK(Ach), the acetylcholine-sensitive K+ channel.
Propagation of Action Potential Each myocyte is electrically connected to next myocyte by an intercalated disc at the end of the cell. These discs contain gap junctions that allow free permeability of charged molecules from one cell to next. These pores in the intercalated discs are composed of a protein, connexin. Permeability through cardiac gap junction is increased by both ATP- & cyclic AMP-dependent kinases. This allow the gap junctions to close if ATP levels fall, thereby reducing electrical and presumably mechanical activity, which is essential in limiting cell death when one region of the heart is damaged
Membrane Potential Inward (depolarizing) currents ; positive, Outward (repolarizing) currents ; negative I = current, Na = sodium, Ca = calcium, K = potassium Potential of a cell of SA node, & ion currents
Reentry or Circus Pathway Normally, as the action potential travels through the atrium or ventricle, all the muscle is depolarized sufficiently that the action potential encounters no more nonrefractory muscle and stops (A). If there is slowed conduction speed or a long pathway (B), the action potential may find repolarized (nonrefractory) muscle and continue in a circular path. Similarly, a shortened refractory period (C) may lead to rapid repolarization and predispose to a reentry continuation of action potential.
Generation of Electrocardiogram Whenever a sufficiently large number of cardiac cells undergo synchronized depolarization & repolarization, the resulting electrical activity can be detected as potential differences between any two points on the body surface ( bipolar lead electrocardiograms), but with reference to a point that is derived electronically by the recording apparatus ( unipolar lead ECGs). The wave P corresponds to atrial depolarization, Q to very early septal depolarization, R to ventricular depolarization, and S to late ventricular depolarization. T is inscribed by ventricular repolarization.
Regulation of Cell Function Regulation by sarcoplasmic receptors Parasympathetic regulation Adrenergic stimulation & blockade Adenosine Cardiac glycosides Calcium channel blockers
Regulation of Cellular Function Function by sarcolemmal receptors Parasympathetic regulation Adrenergic stimulation and blockade Adenosine Cardiac glycosides Calcium channel blockers
Arrhythmias Aberrant pacemaker foci Reentry arrhythmias, unidirectional block Afterpotentials or parasystole Antiarrhythmic agents, proarrhythmic agents Class 1 ; sodium channel blockers (A,B,C) Class II ; beta-adrenergic blockade Class III ; prolong cardiac action potential Class IV ; calcium channel blocker
Beta-receptor Stimulation Increased tendency for calcium channel to open Accelerated discharge rate of the SA node and other spontaneously depolarizing areas of the heart (positive chronotropic) There is accelerated conduction (conduction velocity) through AV node and area dependent upon calcium channels (positive dromotropic) The increased cytosolic levels of calcium lead to a positive inotropic effect Increased activity of sarcoplasmic reticulum calcium pump leads to a rapid removal of calcium, thereby leading to more rapid relaxation of the cell (lusitropic)
Adrenergic Stimulation Adrenergic stimulation via the action of beta agonists on beta receptors in myocyte. Note that an increase in cyclic adenosine monophosphate causes the activation of two inhibitory pathways, retarding excessively sustained adrenergic stimulation ( Gs= stimulatory G-protein, GTP= guanosine triphosphate, SR= sarcoplasmic reticulum )
Adenosine Adenosine is useful in treating rapid supraventricular tachycardias and as an arresting agents in cardioplegia based on hyperpolarizing effects The vast majority of physiologic effects are exerted by interactions with sarcoplasmic receptors There are 4 types of adenosine receptors, and A1 receptors are located on cardiomyocytes, & inhibit adenyl cyclase activity via an inhibitory G-protein. Activation of adenosine A1 receptors leads to inhibition of slow calcium channel and opening of an adenosine- activated ATP-sensitive potassium channel. This leads to hyperpolarization in the pacemaker cells, slowing spontaneous depolarization and decreased depolarization in nodal cells, leading to delayed conduction
Cardiac Glycosides Cardiac gycosides (oubain, digitoxin, digoxin ) act, not through a separate receptor protein, but by binding to and inhibiting ATP-dependent sodium-potassium pump. Inhibition of the pump leads to a slightly increased intracellular sodium concentration. When considering the sodium-calcium exchange system, the driving force for calcium removal from the cell is decreased & increased intracellular sodium leads to less calcium binding to the intracellular portion of sodium- calcium exchange protein These two effects decrease the excrusion of calcium from the cell, which, in turn, leads to an increased strength of myocardial contraction
Calcium Channel Blockers Calcium channel blockers bind to the membrane- spanning protein of the L-type calcium channel. There are three chief categories of these drugs, represented by nifedifine, verapamil and diltiazem. Each category appears bind in a different site on the calcium channel protein, leading to, different effects upon these voltage-gated and time-dependent channels Diltiazem and verapamil are particularly useful in slowing AV conduction, thereby decreasing the ventricular response to atrial tachycardia, because AV nodal depolarization is primarily dependent upon a calcium current in the general absence of functional sodium channel
Contractile Element, Sarcomere The myocyte is made up of a number of myofibrils. Each myofibril is made up of a number of sarcomeres connected end-to-end by dense attachments between sarcomeres at the z-band Sarcomere is made up of several proteins important in generating, or regulating cardiac contraction. The major contractile proteins are myosin in thick filament and actin found in thin filament. Among other regulatory proteins that modulate activity of actin and myosin, tropomysin is a filamentous protein composed two tightly coiled helical peptide chain & bind another complex regulatory protein, called troponin.
Regulation of Contraction Both contraction (systole) phase & relaxation (diastole) phase are ATP-requiring steps and the transduction of electrical depolarization into a mechanical contraction requires the presence of calcium. The strength of myocardial contraction is mediated primarily by the degree of uncovering of the actin active sites as tropomyosin is pulled away from the active sites after calcium has bound to troponin. The magnitude of initial calcium ion influx through the sarcolemmal calcium channels is altered by cyclic AMP levels, by stimulatory G-proteins from beta-adrenergic receptors, and by inhibitory G-proteins from the adenosine and acetylcholine receptors. In addition to cytosolic calcium levels, the rate at which binding of ATP reenergizes the myosin heads can alter the speed and strength of the contraction.
Actin & Myosin Filaments The interaction of actin and myosin filaments converts chemical energy into mechanical movement
Mechanics of Cardiac Pump The Frank-Starling relationship Preload & diastolic distensibility and compliance Afterload & aortic impedance Pressure volume loops Other clinical indices of contractility Myocardial wall tension
Principles of Pump Mechanics Within the physiologic limit, the heart will function as a sump pump. That is, the greater the heart is filled during diastole, the greater the quantity of blood that will be pumped out of the heart during systole. The preload of LV describes the intracavitary pressure and volume immediately prior to contraction. Afterload of an isolated muscle is the tension against which it contracts. The basis for the ventricular-volume relationship is the force-length relationship between sarcomere length and peak developed force in cardiac muscle To assess the contractility ; diastolic pressure-volume relationship, ejection fraction, end-systolic pressure- volume relation & preload recruitable stroke work
Starling Curves for Left Ventricle Influence of 4 different states of neurohumoral stimulation on global ventricular performance
LV Pressure-Volume Curves The bold curved line at the bottom of each loop series represents the diastolic pressure-volume relationship. The straight line located on the upper left side of each loop series is the end-systolic pressure-volume relationship.
LV Pressure Loops Loops were generated in normal left ventricles (Normal) and after 30 minutes of global normothermic ischemia and subsequent reperfusion (dashed line). The end-systolic pressure-volume points from each series are connected to a line generated by linear regression. The end-diastolic pressure-volume relationship indicating chamber stiffness (inverse of compliance) is generated by fitting the end-diastolic point from each loop to an exponential curve.
Energetics of Pump With sufficient oxygen, these fuels (carbohydrates and nonesterified free fatty acids) are broken down to acetyl coenzyme A, which enters the tricarboxylic acid cycle (Krebs cycle) in the mitochondria to form ATP. In the fasting state when free fatty acid levels are high, lipid may account for 70% of fuel utilized by the heart During acute exercise, elevated lactate inhibit the uptake of free fatty acids, carbohydrate can then account for up to 70% of cardiac fuel use. The primary determinant of oxygen demands in the heart is the development of wall tension or wall stress with each cardiac cycle
Coronary Blood Flow Normal coronary blood flow Control of coronary blood flow Autoregulation Coronary artery stenosis Endothelial dysfunction Sequelae of myocardial hypoperfusion Infarction Myocardial stunning Myocardial hibernation
Normal Coronary blood flow Resting coronary blood flow is slightly less than 1ml per gram of heart muscle per minute. Cardiac muscle requires 1.3mL of oxygen per 100g of muscle for cellular survival, in comparision with 8 mL of oxygen per 100g per minute in normally contracting LV. Reduction of local coronary blood flow less than 20% of resting level acutely, a portion of myocardium in the affected region will die. As oxygen delivery is reduced, contraction decreases dramatically within 8-19 heart beats. Bulk of resistance to coronary flow is in penetrating arterioles (20-120um in size)
Normal Coronary blood flow There is a greater capillary density (one capillary to one myocyte) in subendocardial myocardium Increased blood flow is accomplished by vasodilation, & by recruitment of additional capillaries. Blood flow of left ventricle is phasic in nature, with greater occurring in diastole than in systole due to extravascular compression of arteries and intramyocardial microvessels ( greatest in the subendocardial tissue) Blood flow in right coronary artery is relatively constant during the cardiac cycle
Normal Coronary blood flow Greater blood flow during diastole Greater capillary density in the subendocardium facilitates the distribution to inner layer of endocardium The myocardial blood flow is normally greater in the subendocardium than in the subepicardial tissue Selective perfusion of the subendocardial myocardium The higher metabolic demands of the subendocardial myocardium Continued perfusion (during both systole & diastole) of the epicardial tissue
Control of Coronary Blood Flow The local coronary blood flow is controlled by a balance of vasodilatory and vasoconstrictor mechanisms. Mechanical factors, such as extravascular compressive forces or myogenic responses play little part in adjusting blood flow to meet demands under normal circumstances Coronary artery flow is also determined by perfusion pressure, but the autoregulatory plateau (constant flow by adjusting resistance ) occurs between around 60-120 mmHg of perfusion pressure The three components of this delicate system are (1) the metabolic vasodilatory system, (2) the neurogenic control system, and (3) the vascular endothelium
Control of Coronary Blood Flow Metabolic vasodilatory system Adenosine; primary mediator Carbon dioxide, lactic acids, histamine, hydrogen ions Neurogenic control system Alpha receptors (vasoconstriction) Beta receptors (vasodilation) Vascular endothelium Vasodilators ( EDRF such as NO, endothelially released adenosine, acetylcholine ) Vasoconstrictors (peptide endothelin)
Factors of Coronary Blood Flow 1. Hydrostatic pressures 2. Anatomic factors 3. Metabolic control 4. Autoregulation * Correlates with myocardial oxygen consumption a) Myocardial tension development b) External work c) Heart rate d) Contractility
Coronary Artery Stenosis Poiseuille’s law ; Resistance is inversely proportional to the fourth power of the radius & directly proportional to the length of the narrowing As proximal resistance with stenosis increases between 60-90%, coronary reserve progressively decreases as the capacity of distal resistance vessels to dilate is exhausted. In human, coronary vessels are end vessels with little collateral flow between major branches. With sudden occlusion, there is very modest collateral flow through very small vessels (20-299micron) and insufficient to maintain cellular viability. Collateral flow begins to increase over next 8-24 hours, doubling by about 3 rd day after total occlusion
Coronary Artery Stenosis The subendocardium of heart is particularly susceptible to reductions in the perfusion caused by proximal stenosis or total occlusion Greater systolic compressive forces Smaller flow reserve in the subendocardial vascular bed Greater degree of wall tension and segmental shortening Flow to the subendocardium, however, is effectively autoregulated only down to a mean distal coronary artery pressure of 60-70mmHg. Below this level, local coronary flow reserve in the subendocardium is exhausted, & local blood flow decreases linearly with decreases in distal coronary artery pressure
Endothelial Dysfunction EDRF is diffusible free radical gas nitric oxide which is synthesized from l-arginine by nitric oxide synthase Besides endothelium-derived NO, vasoconstrictors are produced by endothelium, endothelin-1, angiotensin II, ad superoxide free radicals NO is released by the coronary vascular endothelium by both soluble factors and mechanical signals. Ischemia-reperfusion, hypertension, diabetes, and hypercholesterolemia reduces the tonic generation and release of NO The vascular endothelium repels the interaction of neutrophils and platelets with the endothelium by tonically releasing adenosine and NO, both of which have potent antineutrophil and platelet inhibitory effects.
Endothelial Dysfunction Damage to endothelium causes notably the heart, including increasing vascular permeability, creating blood flow defect ( no-reflow phenomenon), and promoting the pathogenesis of necrosis and apoptosis. Triggers of these inflammatory reactions in the heart include cytokines (IL-1, IL-6, IL-8 ), complement fragments (C3a, C5a, membrane attack complex), oxygen radicals, and thrombin, which upregulate adhesion molecules expressed on both inflammatory cells (CD11a/CD18) and endothelin (P-selectin, E- selectin, and ICAM-1). Both adenosine and NO reduce the inflammatory responses to cardiopulmonary bypass, and to reduce ischemic-reperfusion injury.
Myocardial Hypoperfusion The contractility decreases to the point that is sustainable by the oxygen availability, and this condition can lead to a chronic hypocontractile state known as hibernation. With reperfusion, hibernating myocardium can very quickly resume normal and effective contraction. With sustained reduction, loss of adenosine nucleotides, elevation of intracellular & intramitochondrial calcium may lead to cellular death and subsequent necrosis In the myocyte is reperfused prior to irreversible damage to subcellular organelles, the myocyte may slowly recover, and this gradual recovering myocardium is called stunned myocardium.
Reperfusion Injury Reperfusion of ischemic myocardium may lead to cellular damage & necrosis rather than to immediate recovery This reperfusion injury is multifactorial Damaged endothelium can cause adhesion & activation of leucocyte & platelet Oxygen free radical can be released, and further damage to subcellular organelles Membrane leakage leads to elevation of intracellular calcium levels with uptake of calcium into mitochondria Derangement of ATP-dependent sodium-potassium pump can lead to loss of cell volume regulation.
Modification of Reperfusion Injury Leucocyte depletion or inactivation Prevention of endothelial activation Free radical scavenging Reperfusion with solutions with low calcium content Reperfusion with hyperosmolar solution Adaptive mechanisms called ischemic preconditioning
Heart Failure Heart failure is a progressive and chronic disorder that occurs when the ability of the heart to fill and/or pump is impaired such that the heart is unable, with acceptable filling (venous) pressure, to deliver adequate blood to the tissues to meet metabolic needs. Heart failure may be primarily systolic failure such that an impairment of contractility leads to low cardiac output and excessive filling pressure. Diastolic failure may occur without an impairment of systolic contractility if myocardium becomes fibrotic or hypertrophic (increased myocardial stiffness), or if there is an external constraint on filling such as with pericardial tamponade.
Pathophysiology of Heart Failure Heart failure from stimulus to acute adaptive & chronic maladaptive response. (+) positive stimulation; (-) negative stimulation of heart failure