HBAP EXAM 4

10 pp and 12.1-12.4 (prep11a)

Blood: What are the 3 components of the circulatory (cardiovascular) system, and why is the system needed?

Components: (1) pump = the heart; (2) set of interconnected tubes = blood vessels (vascular system); (3) blood = fluid connective tissue containing water, solutes, and cells that fills the tubes. Needed because diffusion is too slow beyond a few cell diameters, so large multicellular bodies need rapid transport of molecules over long distances between cells, tissues, and organs.

Blood: What is blood composed of, and what does each blood cell type do?

Formed elements (cells and cell fragments) suspended in a liquid called plasma. Erythrocytes (red blood cells; >99% of blood cells) carry O2 to the tissues and CO2 from the tissues. Leukocytes (white blood cells) protect against infection and cancer. Platelets (cell fragments) function in blood clotting. Constant motion of the blood keeps the cells dispersed throughout the plasma.

Blood: What is the hematocrit, how is it measured, and what are the normal values?

Percentage of blood volume that is erythrocytes. Measured by centrifugation: erythrocytes are forced to the bottom, plasma stays on top, and leukocytes + platelets form a very thin layer between them called the buffy coat. Normal: about 45% in men and 42% in women (plasma about 55%, slightly less because of the buffy coat).

Blood: In a 70 kg person, what are the blood volume, erythrocyte volume, and plasma volume?

Blood volume about 5.5 L. Erythrocyte volume = 0.45 x 5.5 L = 2.5 L. Plasma volume = blood volume - erythrocyte volume = 5.5 L - 2.5 L = 3.0 L (volume of leukocytes and platelets is usually negligible).

Plasma: What is plasma made of, and what are the 3 groups of plasma proteins?

Organic and inorganic substances dissolved in water (>90% water): proteins, nutrients, metabolic waste products, hormones, and mineral electrolytes (Na+, K+, Cl-, and others). Plasma proteins make up most of the plasma solutes by weight and exert an osmotic pressure that favors absorption of extracellular fluid into capillaries. 3 groups: albumins (most abundant; synthesized by the liver), globulins, and fibrinogen (functions in clotting). Albumins and globulins have many overlapping functions.

Plasma: What is serum?

Plasma with fibrinogen and other proteins involved in clotting removed from it.

Blood cells: Where do all blood cells come from, and how does differentiation start?

All descend from multipotent hematopoietic stem cells (undifferentiated cells that can give rise to precursors/progenitors of any blood cell). When one divides, the first branching yields either bone marrow lymphocyte precursor cells (give rise to lymphocytes) or 'committed' stem cells (progenitors of all other varieties). A committed stem cell differentiates along only one path (e.g., into red blood cells).

Erythrocytes: What is their major function, what does hemoglobin do, and what are the normal hemoglobin concentrations?

Major function: gas transport; carry O2 taken in by the lungs and CO2 produced by the cells. They contain large amounts of hemoglobin, to which O2 and CO2 reversibly combine. O2 binds to iron atoms (Fe2+) in hemoglobin. Average hemoglobin: 14 g/100 mL blood in women and 15.5 g/100 mL in men.

Erythrocytes: How do their structure and lack of nuclei relate to function, and what is their life span and fate?

Biconcave disk (thicker at the edges than the middle) and small size (7 um) give a high surface-area-to-volume ratio, so O2 and CO2 diffuse rapidly to and from the cell interior (structure determines function). They lack nuclei and most organelles, so they can neither reproduce nor maintain their structure for long. Life span about 120 days: almost 1% destroyed and replaced every day (250 billion cells/day). Destruction normally occurs in the spleen and liver. Major breakdown product of hemoglobin = bilirubin, which returns to the circulation and gives plasma its yellowish color. Most of the iron is conserved.

Erythrocytes: Where are they produced, and what are reticulocytes?

Produced in red bone marrow (soft interior of certain bones). Precursors produce hemoglobin, then lose their nuclei and organelles (machinery for protein synthesis). Reticulocyte = young erythrocyte that still has a few ribosomes, giving a weblike (reticular) appearance with special stains. Ribosomes are lost about a day after leaving the bone marrow, so reticulocytes are only about 1% of circulating erythrocytes. With unusually rapid erythrocyte production, many more are found in the blood, which can be clinically useful.

Erythrocyte production - iron: What happens to iron balance (losses, sources, disorders, and control)?

O2 binds to iron on hemoglobin. Iron is lost via urine, feces, sweat, and sloughed skin cells; women lose extra via menstrual blood. Loss must be replaced by ingested iron (rich sources: meat, liver, shellfish, egg yolk, beans, nuts, cereals). Iron deficiency = inadequate hemoglobin production; excess iron (hemochromatosis) = abnormal iron deposits and damage to liver, heart, anterior pituitary gland, pancreas, and joints. Homeostatic control is in the intestinal epithelium, which actively absorbs iron; normally only a small fraction is absorbed, and by negative feedback the more iron in the body, the less ingested iron is absorbed.

Erythrocyte production - iron: Where is iron stored and how is it recycled?

Stored mainly in the liver bound to ferritin (a buffer against iron deficiency). Distribution: about 50% of body iron in hemoglobin, 25% in other heme-containing proteins (mainly cytochromes), 25% in liver ferritin. Recycling is very efficient: iron from old erythrocytes destroyed in the spleen (and liver) is released into plasma and bound to transferrin (iron-transport plasma protein), which delivers almost all of it to the bone marrow for new erythrocytes. Recycling involves 20 times more iron per day than the body absorbs and excretes.

Erythrocyte production - vitamins: What roles do folic acid, vitamin B12, and intrinsic factor play?

Folic acid (found in leafy plants, yeast, liver): required for synthesis of the nucleotide base thymine, so essential for DNA formation and normal cell division; deficiency impairs cell division throughout the body, most strikingly in rapidly proliferating cells such as erythrocyte precursors, so fewer erythrocytes are produced. Vitamin B12 (cobalamin; cobalt-containing; needed in tiny amounts): required for the action of folic acid; found only in animal products, so strictly vegetarian diets can be deficient. Absorption of B12 from the GI tract requires intrinsic factor (secreted by the stomach). Lack of intrinsic factor causes B12 deficiency and erythrocyte deficiency = pernicious anemia.

Erythropoietin: What is it, where is it made, what does it do, and what increases its secretion?

Hormone that directly controls erythropoiesis (iron, folic acid, and B12 are necessary but are not the regulating signal). Secreted into the blood mainly by hormone-secreting connective tissue cells in the kidneys. Acts on bone marrow to stimulate proliferation of erythrocyte progenitor cells and their differentiation into mature erythrocytes. Secreted in small amounts normally (replaces usual loss); increased markedly when O2 delivery to the kidneys decreases (insufficient pumping by the heart, lung disease, anemia, prolonged exercise, high altitude). Testosterone also stimulates its release (part of why men have a higher hematocrit).

Erythropoietin: What is the negative feedback loop (Figure 12.4)?

Decreased O2 delivery to kidneys -> increased erythropoietin secretion by kidneys -> increased plasma erythropoietin -> bone marrow: increased production of erythrocytes -> increased blood Hb concentration -> increased blood O2-carrying capacity -> restoration of O2 delivery.

Anemia: What is it, what are its causes (Table 12.1), and what is sickle-cell disease?

Anemia = decrease in the ability of blood to carry O2 due to: fewer erythrocytes (each with normal hemoglobin), less hemoglobin per erythrocyte, or both. Causes: dietary deficiency of iron (iron-deficiency anemia), vitamin B12, or folic acid; bone marrow failure (toxic drugs, cancer); blood loss (hemorrhage); inadequate erythropoietin in kidney disease; excessive destruction of erythrocytes (e.g., sickle-cell disease). Sickle-cell disease (sickle-cell anemia): genetic mutation altering one amino acid in the hemoglobin chain. At low O2 levels (e.g., in capillaries) the abnormal hemoglobin forms fiberlike polymers that distort the erythrocyte membrane into sickle shapes -> blockage of capillaries (tissue damage and pain) and destruction of deformed erythrocytes (anemia).

Sickle-cell disease vs sickle-cell trait: Who gets which, and why does the mutation persist?

Disease is fully manifested only in people homozygous for the mutated gene (two copies, one from each parent). Heterozygotes (one mutated, one normal gene) have sickle-cell trait: erythrocytes contain both types of hemoglobin, and symptoms appear only when O2 is unusually low (e.g., high altitude). The mutation persists because heterozygotes are more resistant to malaria (blood infection by a protozoan parasite spread by mosquitoes in tropical regions).

Polycythemia: What is it, and what is the downside of a higher hematocrit?

More erythrocytes than normal. Example: high-altitude dwellers, where the increase is an adaptive response because it increases the O2-carrying capacity of blood. But a higher hematocrit increases blood viscosity, which makes blood flow through vessels more difficult and strains the heart. Abuse of synthetic erythropoietin (polycythemia) has killed competitive bicyclists, one reason 'blood doping' is banned.

Leukocytes: What is the function of each type (neutrophils, eosinophils, monocytes, macrophages, basophils, lymphocytes)?

Neutrophils: most abundant leukocytes; phagocytes; leave capillaries and enter tissues during inflammation; bacteria destroyed in endocytotic vacuoles by proteases, oxidizing compounds, and defensins; production/release from bone marrow greatly stimulated during infection. Eosinophils: in blood and mucosal surfaces of GI, respiratory, and urinary tracts; fight eukaryotic parasites (release toxic chemicals or phagocytose). Monocytes: phagocytes circulating briefly, then migrate into tissues/organs and develop into macrophages. Macrophages: large phagocytes (engulf viruses and bacteria) located where invaders are met (skin, linings of respiratory and digestive tracts). Basophils: secrete heparin (anticlotting factor; helps circulation flush out the infected site) and histamine (attracts infection-fighting cells and proteins). Lymphocytes: T and B; protect against specific pathogens (viruses, bacteria, toxins, cancer cells); some kill pathogens directly, others secrete antibodies that bind foreign molecules and begin their destruction.

Platelets: What are they and how are they produced?

Colorless, nonnucleated cell fragments with numerous granules, much smaller than erythrocytes; function in blood clotting. Produced when cytoplasmic portions of large bone marrow cells called megakaryocytes pinch off and enter the circulation.

Blood cell production: Which bones make blood cells, and what are hematopoietic growth factors (HGFs)?

Children: marrow of most bones. Adults: only bones of the chest, base of skull, spinal vertebrae, pelvis, and ends of the limb bones. Adult marrow weighs almost as much as the liver and produces cells at an enormous rate. HGFs = protein hormones and paracrine agents that stimulate proliferation and differentiation of progenitor cells at multiple points (belong to the larger family of cytokines). Physiology is complex: many types; one HGF is often produced by various cell types; HGFs often have other actions too; several HGFs cooperate (erythropoietin is the major stimulator of erythropoiesis, but at least 10 other HGFs cooperate); they can also inhibit apoptosis of progenitor cells.

HGFs (Table 12.2): Which progenitor cells does each HGF stimulate, and what are the clinical uses?

Erythropoietin -> erythrocytes. Colony-stimulating factors (CSFs; e.g., granulocyte CSF) -> granulocytes and monocytes. Interleukins (e.g., interleukin 3) -> various leukocytes. Thrombopoietin -> platelets (from megakaryocytes). Stem cell factor -> many types of blood cells. Clinical uses: erythropoietin in people with kidney disease (hormone deficiency); G-CSF to stimulate granulocyte production when bone marrow is damaged by anticancer drugs.

Blood flow: What is bulk flow, and what fraction of blood is in the capillaries?

Rapid flow of blood produced by pressures created by the pumping of the heart; all constituents of the blood move together. Extensive branching puts almost all cells within a few cells of a capillary. Nutrients and metabolic end products move between capillary blood and interstitial fluid by diffusion. Only about 5% of total circulating blood is in the capillaries at any moment, but this 5% performs the ultimate functions of the system (supply nutrients, O2, hormonal signals; remove metabolic end products); all other components serve to get adequate blood flow through the capillaries.

Circulation: How is the circulatory system organized (two circuits), and what are arteries and veins?

Closed loop; two circuits, both starting and ending in the heart, which is divided longitudinally into two functional halves. Each half has an upper atrium and a lower ventricle; the atrium empties into the ventricle on its side; there is usually no direct blood flow between the two atria or the two ventricles in a healthy adult. Arteries carry blood away from the heart; veins carry blood from organs and tissues back toward the heart (in both circuits).

Circulation: What is the path of the pulmonary circulation vs the systemic circulation?

Pulmonary: right ventricle -> pulmonary trunk -> two pulmonary arteries (one per lung) -> arterioles -> lung capillaries -> venules -> four pulmonary veins -> left atrium. Systemic: left ventricle -> aorta -> arteries -> arterioles -> capillaries (about 10 billion) -> venules -> veins -> inferior vena cava (blood from below the heart) and superior vena cava (blood from above the heart) -> right atrium. Arterioles, capillaries, and venules together = microcirculation (where exchange of gases, substrates, and waste occurs between blood and extracellular fluid).

Circulation: What is the oxygen content of blood in different vessels, and why must blood pass through the lungs?

Pulmonary veins, left side of the heart, and systemic arteries: high O2 content (blood picks up O2 in lung capillaries). Systemic venous and pulmonary arterial blood: lower O2 content (some O2 diffuses out in peripheral tissues). Blood can pass from systemic veins to systemic arteries only by first being pumped through the lungs, so blood returning from the body is oxygenated before being pumped back to the tissues.

Circulation: Why are the systemic organs arranged in parallel, and what is a portal system?

Lungs receive all the blood pumped by the right heart, but systemic arteries branch in a parallel pattern so each organ receives a fraction of the left ventricle's output. This guarantees that all systemic tissues receive freshly oxygenated blood and allows independent regulation of blood flow through different tissues as their metabolic activity changes. Exceptions (liver, anterior pituitary gland): blood passes from one capillary bed to veins, to a second capillary bed, then to the veins that return blood to the heart = portal system.

Blood flow at rest (Figure 12.6): How is the 5000 mL/min distributed over the organs?

Abdominal organs 1200 mL/min (24%); skeletal muscle 1030 (20%); kidneys 950 (20%); brain 650 (13%); other 525 (10%); skin 430 (9%); heart 215 (4%). Total 5000 mL/min (100%).

Hemodynamics: What does flow depend on (F = ΔP/R), in which direction does blood flow, and what are the units?

Hemodynamics = relationship among blood pressure, blood flow, and resistance. Flow is always from higher to lower pressure. F = ΔP/R: flow is directly proportional to the pressure difference between two points and inversely proportional to resistance (applies to any system with bulk flow of liquid or air, e.g., urinary and respiratory systems). It is the pressure DIFFERENCE between two points, not the absolute pressure, that determines flow. Units: flow = volume per unit time (L/min); pressure difference = mmHg. Pressure (hydrostatic pressure) = force exerted by blood, generated by contraction of the heart. Resistance = friction that impedes flow; cannot be measured directly but is calculated from F and ΔP (e.g., 90 mmHg / 10 mL/min = 9 mmHg/mL/min).

Resistance: What are the 3 determinants (equation 12-2), and which one is varied physiologically?

R = 8Lη / πr^4. Resistance is directly proportional to fluid viscosity (η; friction between molecules of a flowing fluid) and tube length (L), and inversely proportional to the 4th power of the inside radius (r). Vessel radius is the most important determinant of changes in resistance (length stays constant; viscosity, which rises with hematocrit, normally doesn't vary much and isn't involved in control of vascular resistance). Halving the radius increases resistance 16-fold; with constant ΔP, flow decreases 16-fold.

Viscosity: How does hematocrit affect blood viscosity and resistance?

Viscosity increases as hematocrit increases. Extreme dehydration: less body water -> relative increase in hematocrit -> higher viscosity. Anemia (decreased hematocrit): viscosity can decrease. Under most physiological conditions hematocrit/viscosity does not vary much. The same pressure-flow-resistance equation also applies to flow through heart valves (valve opening resistance determines flow at a given pressure difference).

Circulatory system components (Table 12.3): What is the function of the heart chambers and each type of vessel?

Atria: chambers through which blood flows from veins to ventricles; atrial contraction adds to ventricular filling but is not essential. Ventricles: contractions produce the pressures that drive blood through pulmonary and systemic vascular systems and back to the heart. Arteries: low-resistance tubes conducting blood to organs with little pressure loss; pressure reservoirs that maintain flow during ventricular relaxation. Arterioles: major sites of resistance; regulate the pattern of blood-flow distribution to organs; participate in regulation of arterial blood pressure. Capillaries: major sites of nutrient, gas, metabolic end product, and fluid exchange between blood and tissues. Venules: capacitance vessels; sites of leukocyte migration from blood into tissues during inflammation and infection. Veins: low-resistance, high-capacitance vessels carrying blood back to the heart; capacity adjusted to facilitate this flow. Plasma: liquid portion; composition equilibrates with interstitial fluid at the capillaries. Cells: erythrocytes (gas transport), leukocytes (immune defense), platelets (clotting). Ultimate function of the system = adequate blood flow through capillaries of various organs.

Heart anatomy (Vander): What are the layers and linings of the heart, and what separates the chambers?

Pericardium = protective fibrous sac enclosing the heart. Epicardium = fibrous layer closely affixed to the heart; the extremely narrow space between pericardium and epicardium is filled with a watery lubricating fluid. Myocardium = wall of the heart, mainly cardiac muscle cells. Endothelium = thin layer of endothelial cells lining the inner surface of the cardiac chambers (and the inner wall of all blood vessels). Heart has right and left halves, each with an atrium and a ventricle; the two ventricles are separated by a muscular wall, the interventricular septum.

AV valves: Where are they, what do they do, how do they open/close, and what keeps them from prolapsing?

Located between atrium and ventricle in each half; one-way: allow flow from atrium to ventricle but not backward. Right AV valve = tricuspid (3 cusps/flaps); left AV valve = bicuspid (2 flaps) = mitral valve (resembles a bishop's headgear, a 'mitre'). Opening/closing is passive, caused by pressure differences: atrial pressure > ventricular pressure -> valve opens; contracting ventricle pressure > atrial pressure -> valve forced closed (so blood goes into the pulmonary trunk from the right ventricle and the aorta from the left). To prevent the valves from being pushed up into the atria during ventricular contraction (prolapse), they are fastened by chordae tendineae (fibrous strands) to papillary muscles (muscular projections of the ventricular walls). Papillary muscles do not open or close the valves; they only limit valve movement and prevent backflow. Injury/disease of these tendons or muscles can lead to valve prolapse.

Semilunar valves: What are they, where are they, and how do they work?

Pulmonary valve (right ventricle -> pulmonary trunk) and aortic valve (left ventricle -> aorta); called semilunar because of the half-moon shape of the cusps. Allow blood to flow into the arteries during ventricular contraction but prevent it from moving back during ventricular relaxation. Like AV valves, passive: open or closed depending on pressure differences across them.

Heart valves: What is their resistance, and what happens in disease? Where are there no valves?

Open valves offer very little resistance, so very small pressure differences produce large flows. In disease a valve can be narrowed or not open fully, giving high resistance even when open; the contracting chamber must then produce an unusually high pressure. No valves at the entrances of the superior and inferior venae cavae into the right atrium or of the pulmonary veins into the left atrium; still, atrial contraction pumps very little blood back into the veins because it constricts their sites of entry, greatly increasing resistance to backflow (a little blood is ejected back, causing the venous pulse seen in the neck veins during atrial contraction).

Path of blood flow (Figure 12.11): What is the complete path through the heart and circulation?

Right atrium -> right AV valve -> right ventricle -> pulmonary valve -> pulmonary trunk -> pulmonary arteries -> pulmonary arterioles -> capillaries of lungs -> pulmonary venules -> pulmonary veins -> left atrium -> left AV valve -> left ventricle -> aortic valve -> aorta -> arteries -> arterioles -> capillaries -> venules -> veins -> venae cavae -> right atrium. (A systemic portal vessel would add a second capillary bed between two sets of veins.)

Cardiac muscle: What are its special features?

Cells arranged in layers, tightly bound together, completely encircling the blood-filled chambers (squeezes like a fist around a fluid-filled balloon). Every heart cell contracts with every beat (unlike skeletal muscle); beats about once per second, so about 3 billion contractions in an average life span without resting. Limited ability to replace muscle cells (only about 1% replaced per year). Like skeletal and smooth muscle: electrically excitable, converts ATP chemical energy to force, action potentials propagate along membranes, Ca2+ enters the cytosol, cross-bridge cycling is activated. Cardiac muscle cells are joined by gap junctions. About 1% of cardiac cells do not contract but form the conducting system (in electrical contact with muscle cells via gap junctions), which initiates the heartbeat and spreads the action potential rapidly.

Heart innervation (Vander): Which nerves supply the heart, and what do they release and act on?

Sympathetic postganglionic fibers innervate the entire heart and release norepinephrine on mainly beta-adrenergic receptors. Parasympathetic fibers (in the vagus nerves) terminate mainly on special cells in the atria and release primarily acetylcholine on muscarinic receptors. Epinephrine from the adrenal medulla binds the same receptors as norepinephrine and has the same actions on the heart.

Heart blood supply: How does the myocardium receive blood?

Blood in the chambers does not exchange nutrients/waste with myocardial cells. Myocardium is supplied by the coronary arteries (blood flow = coronary blood flow), which exit from behind the aortic valve cusps in the very first part of the aorta and branch into small arteries, arterioles, capillaries, venules, and veins. Most cardiac veins drain into a single large vein, the coronary sinus, which empties into the right atrium.

Heartbeat coordination: What is the sequence of excitation through the heart?

SA node (small group of conducting-system cells in the right atrium near the entrance of the superior vena cava) -> internodal pathways -> atria (right and left contract at essentially the same time) -> AV node (base of the right atrium) -> bundle of His (AV bundle) -> right and left bundle branches (separate at the apex) -> Purkinje fibers -> ventricular muscle cells. Atria and ventricles are otherwise separated by nonconducting connective tissue, so the AV node and bundle of His are the only electrical connection between them.

SA node: What is its role, and what does it determine?

Normally the pacemaker for the entire heart; its depolarization generates the action potential that depolarizes all other cardiac muscle cells. Its discharge rate determines the heart rate (number of contractions per minute), because electrical excitation is coupled to contraction.

AV node, bundle of His, and Purkinje fibers: What are their properties?

AV node: modified cardiac cells that have lost contractile capability but conduct with low electrical resistance; conduction through it is relatively slow (about 0.1 sec), which allows atrial contraction to be completed before ventricular excitation. Bundle of His divides in the interventricular septum into right and left bundle branches. Purkinje fibers: large-diameter, rapidly conducting cells connected by low-resistance gap junctions; the branching network conducts the action potential rapidly to ventricular myocytes, so right and left ventricular cells depolarize nearly simultaneously (single coordinated contraction). Depolarization and contraction begin slightly earlier at the apex and spread upward, like squeezing a toothpaste tube from the bottom, moving blood toward the exit valves.

Ventricular myocyte action potential: What are the phases and ion movements?

Resting membrane: much more permeable to K+ than Na+, so resting potential is close to the K+ equilibrium potential (-90 mV; Na+ is +60 mV). Depolarization: opening of voltage-gated Na+ channels (Na+ enters; positive feedback); Na+ channels inactivate quickly. Partial repolarization from a special class of transiently open K+ channels, then a plateau at about 0 mV for a prolonged period: K+ permeability declines below the resting value (resting K+ channels close) and permeability to Ca2+ increases greatly. Depolarization opens voltage-gated L-type Ca2+ channels (L = long lasting; also called dihydropyridine/DHP channels); they open more slowly than Na+ channels and stay open, so Ca2+ flows in and just balances K+ flowing out, keeping the membrane at the plateau. Repolarization: eventual inactivation of L-type Ca2+ channels and opening of another subtype of K+ channels (open in response to depolarization after a delay; close once the membrane is repolarized). Atrial muscle action potentials are similar, but the plateau is shorter.

Nodal cell (SA node) action potential: What is the pacemaker potential, and which 3 channel mechanisms produce it?

SA node cells have no steady resting potential; a slow depolarization (pacemaker potential) brings the membrane to threshold, where an action potential occurs. Mechanisms: (1) progressive reduction in K+ permeability (K+ channels from the previous repolarization gradually close); (2) F-type ('funny') channels = HCN channels (hyperpolarization-activated cyclic nucleotide-gated): open at negative potentials, nonspecific cation channels conducting mainly an inward depolarizing Na+ current; (3) T-type Ca2+ channels (T = transient): open briefly, add inward Ca2+ current and a final depolarizing boost.

Nodal cell action potential: What causes its depolarization and repolarization, and why is conduction through the AV node slow?

Depolarization is caused by Ca2+ influx through L-type Ca2+ channels (not Na+). Ca2+ currents depolarize more slowly than Na+ channels, so action potentials propagate more slowly along nodal-cell membranes, explaining the slow transmission through the AV node. L-type Ca2+ channels prolong the action potential; eventually they close, K+ channels open (a specific K+ channel subtype controls PK+ in nodal cells), and the membrane repolarizes; the return to negative potentials re-activates the pacemaker mechanisms and the cycle repeats. SA and AV node action potentials are basically similar in shape, but SA node pacemaker currents reach threshold more rapidly, which is why the SA node initiates action potentials and sets the pace.

Automaticity and pacemakers: What is automaticity, what is the inherent SA node rate, and what are ectopic pacemakers?

Automaticity = capacity for spontaneous, rhythmic self-excitation (from the pacemaker potential). The slope of the pacemaker potential determines how quickly threshold is reached. Inherent SA node rate (without neural/hormonal input) about 100 depolarizations/min. Other conducting-system cells have slower inherent rates, so they are normally driven by the SA node; when they set their own rhythm they are called ectopic pacemakers.

AV conduction disorder: What is it, what happens to the ventricles, and what is the treatment?

Drug- or disease-induced malfunction of the AV node reduces or eliminates transmission of action potentials from atria to ventricles (excitation reaches the ventricles only through the AV node). Autorhythmic cells in the bundle of His and Purkinje network then become the ventricular pacemaker at their own slow rate, generally 25 to 40 beats/min. Ventricles contract out of synchrony with the atria (which continue at the SA node rate); atria are less effective, but atrial pumping is relatively unimportant except during strenuous exercise. Treatment for severe cases (and many other abnormal rhythms): permanent surgical implantation of an artificial pacemaker that electrically stimulates the ventricular cells at a normal rate.

Electrocardiogram (ECG/EKG): What is it, and what do the P wave, QRS complex, and T wave represent?

Tool for evaluating electrical events in the heart: currents from simultaneous action potentials in many contractile myocardial cells are conducted through body fluids and detected by electrodes on the skin; it is NOT a direct record of the membrane potential of single cells. P wave = atrial depolarization. QRS complex = ventricular depolarization (about 0.15 sec after the P wave; complex because the depolarization path through the thick ventricular walls changes from instant to instant; still called QRS even if Q and/or S are absent). T wave = ventricular repolarization. Atrial repolarization is usually not seen because it occurs at the same time as the QRS complex. ECG only gives information about electrical activity (limited diagnostic value if a mechanical defect does not alter electrical activity).

ECG leads (Table 12.4): What are the standard limb leads, augmented limb leads, and precordial leads?

Standard limb leads (reference (-) / recording (+)): Lead I right arm / left arm; Lead II right arm / left leg; Lead III left arm / left leg (right leg = ground). Augmented limb leads: aVR left arm + left leg / right arm; aVL right arm + left leg / left arm; aVF right arm + left arm / left leg. Precordial (chest) leads V1-V6 (reference = combined limb leads): V1 4th intercostal space, right of sternum; V2 4th intercostal space, left of sternum; V3 5th intercostal space, left of sternum; V4 5th intercostal space, centered on clavicle; V5 5th intercostal space, left of V4; V6 5th intercostal space, under left arm. Each of the 12 leads views the heart from a different angle; P, QRS, and T shapes/sizes vary with electrode location.

AV block on the ECG (Figure 12.19): What do partial and complete AV block look like?

Normal ECG: each P wave followed by QRS and T. Partial AV block: damage to the AV node allows only every other atrial impulse to reach the ventricles (every second P wave is not followed by QRS and T). Complete AV block: no synchrony between atrial and ventricular electrical activity; ventricles driven by a very slow pacemaker cell in the bundle of His.

Excitation-contraction coupling in cardiac muscle: What is the sequence, and how is contraction strength determined?

Small amount of extracellular Ca2+ enters through L-type Ca2+ channels during the plateau -> triggers release of a larger quantity of Ca2+ from the sarcoplasmic reticulum (SR) through ryanodine receptor channels (Ca2+-induced Ca2+ release) -> Ca2+ activates thin filaments (troponin) and cross-bridge cycling -> force. Contraction ends when Ca2+ is returned to the SR and extracellular fluid by Ca2+-ATPase pumps and Na+/Ca2+ countertransporters. The rise in cytosolic Ca2+ is a major determinant of contraction strength: unlike skeletal muscle (where one action potential saturates troponin sites), Ca2+ released during a resting heartbeat does not saturate all troponin sites, so the number of active cross-bridges (and strength) can increase if more Ca2+ is released (e.g., during exercise).

Refractory period of the heart: Why can't cardiac muscle have tetanic contractions, and why is that important?

Cardiac muscle cannot sum contractions. Tetanus would stop the heart from working as a pump because the ventricles fill with blood only while relaxed. Reason: the long absolute refractory period (period during and after an action potential when the membrane cannot be re-excited); main mechanism = inactivation of Na+ channels. Because of the prolonged depolarized plateau, the absolute refractory period of cardiac muscle (about 250 msec) lasts almost as long as the contraction, so the muscle cannot be re-excited during an ongoing contraction. In skeletal muscle the refractory period (2 to 4 msec) is much shorter than the contraction (20 to 100 msec), so a second action potential can occur during contraction.

Heart facts (lecture): What are the key facts about the heart?

Hollow muscle through which blood is pumped; never rests; as big as your fist; beats about 100,000 times a day (70/min); pumps about 8,000 liters of blood a day.

Heart position: Where is the heart located, and where are its base and apex?

In the thoracic cavity. Base: at the back of the sternum, at the level of the third costal cartilage. Apex: 5th intercostal space, midclavicular, on the left.

Mediastinum: What is it, what does it contain, and what are its divisions?

Space between the left and right pleural cavity, from the thoracic inlet to the diaphragm and from sternum to vertebrae. Contains all organs of the thorax except the lungs. Divisions: superior mediastinum (yellow); inferior mediastinum, which is split into anterior (green), middle (blue), and posterior (pink) mediastinum.

Pericardium (lecture): What are its layers and spaces?

Serous pericardium: parietal pericardium and visceral pericardium (= epicardium), with the pericardial cavity between them. Fibrous pericardium: very firm connective tissue = the pericardial sac. Order from inside to outside: endocardium - myocardium - epicardium - pericardium.

Pericardial cavity: What are the sinuses, and how does the pericardium move with respiration?

Transition from visceral to parietal pericardium forms the transverse sinus and the oblique sinus; in the sinuses the heart can expand, for example with exercise. Respiration: the heart is lowest with inspiration; the pericardial sac is connected to the diaphragm.

Superficial anatomy of the heart (lecture): What should you remember?

Auricles ('ears') provide additional space for blood (right auricle, left auricle). Sulci: coronary sulcus, anterior interventricular sulcus (anterior view), posterior interventricular sulcus (diaphragmatic surface). Structures seen: ascending aorta, aortic arch, ligamentum arteriosum, pulmonary trunk, left/right pulmonary arteries, venae cavae, pulmonary veins, coronary sinus, cardiac apex. Watch out: red and blue in drawings are not always the same (artery/vein vs oxygenation).

Right side of the heart (lecture): What are the features of the right atrium and right ventricle?

Atrium: inferior vena cava, superior vena cava, coronary sinus; interatrial septum with the oval fossa (closed when born, open in the embryo); right auricle. Ventricle: tricuspid valve (3 cusps) with chordae tendineae and papillary muscles; pulmonary (semilunar) valve leading into the pulmonary trunk.

Left side of the heart (lecture): What are the features of the left atrium and left ventricle?

Atrium: 4 pulmonary veins; left auricle. Ventricle: bicuspid (mitral) valve (2 cusps) with chordae tendineae and papillary muscles; aortic (semilunar) valve leading into the ascending aorta.

Atria vs ventricles (lecture): What is the function of the atria and ventricles?

Atria: collect blood returning to the heart and direct it to the ventricles; no structural differences between left and right. Ventricles: left and right have different demands but pump equal amounts of blood (left pumps to the body, right to the lungs).

Heart chambers and valves (lecture): What do the AV valves and semilunar valves do, and what are diastole and systole?

4 chambers divided by septa and valves; two circulations (systemic and pulmonary). AV valves: prevent being forced upward during contraction of the ventricles. Semilunar valves: aortic and pulmonary valve (outflow tracts). Valves ensure the right direction of blood flow during the cardiac cycle. Diastole = relaxation (inflow); systole = contraction (outflow).

Auscultation (lecture): Where are the valves listened to, and where are murmurs best heard?

Aortic valve and pulmonary valve: 2nd; tricuspid valve: 4th-5th; bicuspid valve: 5th. Impaired blood flow (murmurs) is better heard at downstream auscultation sites than at the projection of the valve on the chest wall.

Conduction system and innervation (lecture): What is the conduction system, and how does the autonomic nervous system affect the heartbeat?

Conduction system = network of nodes (groups of cells that can be nerve or muscle tissue), specialized cells, and electrical signals that keep the heart beating: sinoatrial node, internodal bundles, atrioventricular node, atrioventricular bundle (bundle of His), right and left bundle branches, Purkinje fibers. Innervation: vagus nerve (nX, cardiac branches) and sympathetic trunk. (Ortho)sympathetic: heartbeat increases. Parasympathetic: heartbeat decreases.

Coronary vessels (lecture): Which arteries and veins supply and drain the heart?

Arteries: arise from the ascending aorta: right coronary artery and left coronary artery (gives the anterior interventricular artery); posterior interventricular artery (sometimes a branch from the left). Veins: great cardiac vein (with anterior interventricular artery), middle cardiac vein (with posterior interventricular artery), small cardiac vein; most cardiac veins drain into the coronary sinus, which empties into the right atrium.

Microcirculation (lecture): Which structures are in the capillary network?

Arteriole -> capillaries -> venule, with an arteriovenous anastomosis (direct connection between arteriole and venule).

Arteries of the thorax (lecture): Which arteries should you know?

Ascending aorta; aortic arch; thoracic aorta; brachiocephalic trunk; right common carotid artery; left common carotid artery; left subclavian artery; right subclavian artery; vertebral artery; internal thoracic artery; intercostal arteries; bronchial arteries.

Arteries of the abdomen (lecture): Which arteries should you know?

Abdominal aorta; celiac trunk (-> common hepatic artery, splenic artery, left gastric artery); superior mesenteric artery; renal arteries; testicular/ovarian arteries; inferior mesenteric arteries; common iliac arteries; external iliac artery; internal iliac artery.

Arteries of the upper leg (lecture): Which arteries should you know?

Right common iliac artery -> right external iliac artery and right internal iliac artery; femoral artery; deep femoral artery; lateral and medial circumflex (femoral) artery. An artery is usually accompanied by a vein.

Veins (lecture): What are the exceptions to 'an artery is usually accompanied by a vein', and which veins drain the abdomen?

Exception 1: the brain has venous sinuses. Exception 2: abdomen - the intestine drains to the liver via the portal system: inferior mesenteric vein, splenic vein, superior mesenteric vein, left gastric vein -> portal vein -> liver -> hepatic vein -> inferior vena cava.

Veins in the extremities (lecture): What is special about them, and what are varices?

Veins in the extremities have valves (direct flow toward the heart). Varices (varicose veins): deformed valves, abnormal blood flow, dilated veins with a thin wall that bulge under the skin, compared with the normal vein with working valves and normal blood flow.

Heart development (lecture): What is the timeline of early heart development?

Day 19: cranial lateral plate mesoderm initiates vasculogenesis to form lateral endocardial tubes; myocardiogenesis begins. Day 20: lateral body folding brings endocardial tubes and cardiogenic mesoderm together in the thoracic region. Day 21: endocardial tubes surrounded by myocardium fuse to form the primitive heart tube, divided into incipient chambers by sulci. Day 22: heart begins to beat. Day 23: heart begins to loop. Day 28: heart looping is complete; epicardium forms; septum primum and muscular ventricular septum begin to form. Later: cushion tissues and conotruncal swellings form; atrioventricular endocardial cushions fuse to form the atrioventricular septum; foramen secundum and foramen ovale form; coronary sinus forms; aortic and pulmonary outflow tracts become separated by fusion of the conotruncal swellings; semilunar and atrioventricular valves are complete by about day 63.

Fetal circulation (lecture): What are the 3 fetal adaptations, and what do they bypass?

Ductus venosus: vessel between the umbilical vein and the inferior vena cava; partly bypasses the liver. Foramen ovale: opening in the interatrial septum; partly bypasses the pulmonary circulation. Ductus arteriosus: connection between the pulmonary trunk and the aorta; partly bypasses the pulmonary circulation. After birth: ligamentum arteriosum (obliterated ductus arteriosus), closed foramen ovale (oval fossa), ligamentum venosum (obliterated ductus venosus), round ligament of the liver (obliterated umbilical vein), medial umbilical ligaments (obliterated umbilical arteries).

Congenital heart defects (lecture): How common are they, and what are the frequencies?

20% of all malformations at birth are heart defects; frequency in NL 5-8 per 1000 live births. VSD (ventricular septal defect; 25% of all heart defects) 12/10,000; ASD (atrial septal defect) 6/10,000; patent ductus arteriosus 1/10,000; transposition of the great vessels 5/10,000; Tetralogy of Fallot 10/10,000 (pulmonary stenosis, narrowing below the valve, aorta lying over a ventricular septal defect, right ventricular hypertrophy).