CVPR-Cardiovascular+LOs+Unit+1

toc //Compiled by Sarah Nelson, CO 2013// =CVPR Overview/CV Anatomy= 1. Describe attendance and grading policies 2. Describe overall syllabus and schedule 3. Discuss expectations for small group participation


 * 4.** **Describe the basic anatomy of the heart, including the arrangement and names of the chambers, valves, and major vessels.**
 * The heart is a dual pump—two sides work in parallel, but there is no direct connection between them.
 * **Chambers:**
 * **Ventricles:** the main pumping chambers
 * Left ventricle: supplies higher pressure systemic circulation. Bigger and thicker. Does more work and uses more O2 than right ventricle.
 * Right ventricle
 * **Atria:** small “primer” chambers, supply the ventricles with blood. Thinner walls than ventricles.
 * Left atrium
 * Right atrium
 * **Valves:** in two sets. Tricuspid and mitral valves are between the atria and ventricles; they are attached to the papillary muscles inside ventricles by chordae tendonae. Valves are one-way and pressure-operated. Thin flaps of fibrous tissue covered by endothelium; mitral has two cusps, the rest have three. All of the valves are located on the same horizontal plane of the heart.
 * Tricuspid valve: between right atrium and the right ventricle
 * Pulmonic valve: between right ventricle and pulmonary artery
 * Mitral valve: between left atrium and left ventricle
 * Aortic valve: between left ventricle and aorta.
 * **Major vessels:**
 * Vena cava (superior and inferior): inlet vessels into right atrium.
 * Pulmonary artery: outlet vessel from right ventricle.
 * Aorta: outlet valve from left ventricle—main blood supply to body.
 * 5.** **Describe the blood flow pathway through the heart.**
 * **Deoxygenated blood returns from systemic circulation** via the superior and inferior vena cavae, passively enters the right atrium (no valve). Right atrium contracts, increased pressure pushes open the tricuspid valve, blood enters the right ventricle. The right ventricle contracts, pushes open the pulmonic valve, blood enters pulmonary circulation via pulmonary arteries.
 * **Oxygenated blood returning from the lungs** enters the left atrium via the pulmonary vein. The left atrium contracts, pushes open the mitral valve, and blood enters the left ventricle. The left ventricle contracts, pushing open the aortic valve, and blood enters systemic circulation via the aorta.
 * 6.** **Describe the major components of blood.**
 * **Red blood cells (~45%)** : large cells without nuclei that transport O2 and CO2 via hemoglobin (O­2) and carbonic anhydrase (CO2). Produced by stem cells in the bone marrow.
 * **White blood cells (<1%):** cells which mediate the immune response. Produced in the bone marrow.
 * **Platelets/thrombocytes (<1%):** small cells which provide blood clotting at wound sites. Adhere to vessel walls to plug rupture, release clotting factors. Thrombus—pathological clot; embolus—moving clot.
 * **Plasma (>55%):** clear liquid phase of blood. Contains proteins, salts and other substances.
 * 7.** **Describe the major types of blood vessels.**
 * **Types of vessels:**
 * Aorta: single outlet from heart; d=2.5 cm.
 * Arteries: thick walled, resist expansion, d=0.4 cm
 * Arterioles: relatively thicker walls (more vascular smooth muscle); d = 30 um.
 * Primary site of regulation of vascular resistance and blood flow.
 * Capillaries: smallest vessels—walls are just a single layer of epithelium thick, approximately the same size as RBCs, which travel through in a single-file; d = 6 um.
 * Venules/veins: thin walls relative to diameter compared to equivalent-sized arteries (but still some smooth muscle), not much elasticity; d = 20um—0.5cm
 * One-way valves compensate for lower pressure in venous system to ensure blood flow is only in one direction.
 * Vena cava (superior and inferior): input to heart; d=3 cm.
 * 8.** **Describe the arrangement of the microcirculation.**
 * **Microcirculation:** defined as vasculature from the first-order arterioles to the venules.
 * Capillaries are the site of gas, nutrient, and waste exchange. Blood flow through capillary beds is determined by the pressure gradient, and is highly regulated via constriction/dilation of arterioles and precapillary sphincters.
 * Movement of substances between capillaries and tissue is driven by concentration and pressure gradients.
 * 9.** **Describe the function of the lymphatic system.**
 * Pathway for fluid and large molecules to move from interstitial space to blood.

=Hemodynamics & Vasculature= See for a sheet of all the equations presented in this lecture.
 * 1.** **Understand the relationship between pressure, flow, and resistance in the circulatory system (Flow Equation), and describe how changes in vascular resistance determine the distribution of cardiac output among tissues.**
 * **Q =** **D** **P/R**
 * Q—flow, D P—pressure difference, R—resistance.
 * Analogous to Ohm’s law (V=IR).
 * Flow requires a pressure difference.
 * Flow is inversely proportional to resistance.
 * Changes in vascular resistance can increase flow (↓in resistance) or decrease (↑in resistance) flow through a particular vessel. Orchestrated changes in vascular resistance can change the distribution of cardiac output among different tissues.
 * 2.** **Know how vascular resistance, blood viscosity, vessel length, and vessel radius affect blood flow (Poiseuille's Law).**
 * **Poiseuille’s Law:**
 * Expanded version of the flow equation: F—flow, D P—pressure difference, r—radius, h --viscosity of blood, l—length.
 * The extra term is a more detailed description of resistance.
 * An increase in the radius decreases resistance and increases flow.
 * The radius of a vessel has a huge effect on flow (r4), so doubling the radius increases flow by 16-fold.
 * Vessel diameter is the major mechanism by which flow is controlled (vasoconstriction and vasodilation).
 * An increase in the length of the vessel results in increased resistance and decreased flow.
 * An increase in viscosity results in increased resistance and decreased flow.
 * 3.** **Explain how the pulsatile flow of blood produced by the heart is converted to steady flow in the capillary beds.**
 * **Pulsatile flow:** the heart pumps intermittently, creating a pulsatile flow in the aorta. Pulsatile flow requires more work (analogy: stop and go driving requires more gas).
 * **Steady flow:** once blood reaches the capillary beds, there is no pulse variation, pressure (and thus flow) is constant and continuous.
 * The conversion of pulsatile flow to steady flow is achieved via compliance (see below) in the main arteries.
 * 4.** **Define vascular compliance.**
 * **Vascular compliance:** the elastic properties of vessels (or chambers of the heart) by describing the change in volume ( D V) that results from a change in pressure ( D P)
 * **C=** **D** **V/** **D** **P**
 * The degree of compliance in main arteries contributes to transformation of pulsatile flow in microcirculation.
 * **Arteriosclerosis:** loss of compliance caused by thickening and hardening of arteries. Some arteriosclerosis is normal with age.
 * 5.** **Understand the relationship between vascular wall tension, transmural pressure, radius, and wall thickness (LaPlace's Law).**
 * **LaPlace’s Law:**
 * T—tensions/wall stress, D P—transmural pressure (pressure across the wall), r—radius, m --wall thickness.
 * Tension in the vessel wall increases as pressure and radius increase. Thus, hypertension increases stress on vessel walls.
 * **Aneurysm:** weakened vessel wall bulges outward, increasing the radius, thus increasing the tension that cells in the wall have to withstand to prevent the vessel from splitting open. Over time, cells become weaker, allowing the wall to bulge more so that tension increases further, until the aneurysm ruptures.
 * 6.** **Understand Fick's Principle and know how it can be used to determine transcapillary efflux.**
 * **Fick’s Principle:** **Xtc=[Xi] – [Xo]**
 * However much of substance X was used in the capillary (Xtc)—the transcapillary efflux—is the difference between the amount of substance X that went into the capillary and the amount of substance X that came out of the capillary.
 * X=Q[conc], where X is the transport rate (mass/time), Q is the flow (volume/time) and [conc] is the concentration (mass/volume).
 * 7.** **Understand how the balance between hydrostatic and oncotic pressure in a capillary bed determines the direction of transcapillary transport (Starling's Equation).**
 * **Hydrostatic pressure, P:** fluid pressure.
 * The net hydrostatic pressure in the capillary bed is the difference between capillary pressure and interstitial pressure. Solvents move from high pressure to low pressure.
 * Hydrostatic pressure promotes filtration (movement of fluid out of capillaries).
 * **Oncotic pressure,** **p** **:** osmotic force created by proteins in the blood and interstitial fluid.
 * Alpha-globulin and albumin are the major determinants of oncotic pressure.
 * Solutes move from high concentration to low concentration. Solvents→high concentrations of solutes.
 * Oncotic pressure promotes reabsorption (movement of fluid into capillaries).
 * p capillaries > p interstitial fluid.
 * **Starling’s Equation for transcapillary transport:**
 * **Flux = k [ ( Pc – Pi ) – (** **p** **c –** **p** **I ) ]**
 * Flux—net movement across capillary wall; k—constant; Pc—capillary hydrostatic pressure; Pi—interstitial hydrostatic pressure; p c—capillary oncotic pressure; p I—interstitial oncotic pressure.
 * **Pc – Pi:** net hydrostatic pressure; tends to be outwards→filtration.
 * ** p ** **c –** **p** **I:** net oncotic pressure; tends to be inwards→reabsorption.
 * Net movement of water in and out of a capillary is simply the outward force minus inward force, or the balance between filtration and reabsorption.
 * Factors that increase blood pressure (hypertension) or reduce oncotic pressure (liver disease) tend to promote filtration. Excess filtration causes edema (swelling) in tissues, such as pulmonary and peripheral edema in heart failure.
 * Net flux is not constant from arterial to venous end of capillaries.
 * Pc is higher on the arterial side and lower on the venous side.
 * p c is lower on the arterial side and higher on the venous side.
 * Thus, there is a tendency toward filtration on the arterial side and reabsorption on the venous side.
 * Net flux is different in different capillary beds.
 * Net flux is regulated primarily by control of capillary hydrostatic pressure.
 * Vasoconstriction and vasodilation of the arterioles.

=Cardiac Muscle Structure & Function= · **Interrelating cardiac muscle cell mechanics and ventricular function:**
 * 1.** **Understand the unique cellular properties of cardiac muscle.**
 * **Cardiac muscle:**
 * Composed of interconnected mono-nucleated cells imbedded in a weave of collagen.
 * Cells contain a large number of myofibrils.
 * Much of the cell volume is occupied by mitochondria.
 * Cells are coupled **both electrically and mechanically.**
 * Contractile proteins:
 * **Myosin:** two heavy chains and four light chains. Developmental and pathophysiological regulation of Isoform composition.
 * **Actin:** similar to skeletal muscle actin; binds tropomyosin and troponin.
 * Thin filament regulatory proteins:
 * **TN-C:** contains only one Ca2+- binding site.
 * **TN-I:** contains a unique N-terminal extension of 32 amino acids which is highly regulated by Phosphorylation.
 * **TN-T:** Isoforms are developmentally and pathologically regulated.
 * **TM:** only alpha Isoform (skeletal muscle has alpha and beta).
 * 2.** **Understand the cross-bridge cycle.**
 * **Molecular basis of the cross-bridge cycle:**
 * Cardiac contraction is a series of interactions between Ca2+, the regulatory proteins and the actomyosin system.
 * In resting muscle, at low intercellular Ca2+, the TN-TM complex inhibits the actin-myosin combination and with an increase in the myoplasmic Ca2+, TN releases its inhibition, moving TM out of the actin groove and allowing myosin to bind.
 * **Force-velocity relationship:**
 * The greater the afterload, the slower the velocity of shortening.
 * 3.** **Understand the mechanisms of altering cross-bridge cycling in cardiac muscle.**
 * **Regulation of calcium flow:**
 * Depolarization opens L-type calcium channels leading to calcium influx.
 * Calcium influx triggers more calcium release from the SR through the ryanodine receptors (CICR).
 * Calcium binding to TN-C triggers contraction.
 * Calcium is removed by the SR Ca2+-ATPase.
 * 4.** **Understand the length-tension relationship (Frank-Starling) in cardiac muscle**
 * **Length tension relationship:**
 * When cardiac muscle is stimulated to contract at low resting lengths (low preload), the amount of active tension developed is small.
 * If you increase the muscle length (increased preload), the active tension developed dramatically increases.
 * **Frank-Starling Law:**
 * **Molecular basis:**
 * Cardiac titin isoform is very stiff (low compliance).
 * Ca2+-sensitivity of the myofilaments increases as sarcomeres are stretched (for the same amount of calcium you get a greater force of contraction).
 * Closer lattice spacing—stretched sarcomeres have altered spacing between actin and myosin (which may result in more force generated per cross-bridge).
 * 5.** **Addendum:**
 * Certain geometric factors dictate how the length-tension relationships of cardiac muscle fibers in the ventricular wall determine the volume and pressure relationships of the ventricular chamber.
 * ^ ventricular volume ^ ventricular circumference ^ length of the individual cardiac muscle cells.
 * At any given ventricular volume, an increase in the tension of individual cardiac muscle cells in the wall causes an increase in intraventricular pressure.
 * ^ ventricular volume ^ the force required from each individual muscle cell to produce any given intraventricular pressure.

=Muscle Physics & Heart as Pump=
 * 1.** **To define cardiac output (CO) and to know that CO = heart rate x stroke volume.**
 * **Cardiac output (CO):** volume of blood pumped per minute by the left ventricle.
 * **At rest:** 4-6 L/min. Can be increased up to 8-fold during strenuous exercise.
 * **Stroke volume (SV):** volume of blood pumped per beat.
 * Determined by the strength of contraction of the heart and by venous return and vascular resistance (“preload” and “afterload”).
 * **CO = heart rate (HR) x stroke volume**
 * 2.** **To describe changes in pressure and volume through the cardiac cycle as a function of time, and to identify the four phases of the cardiac cycle.**
 * **Four phases of the cardiac cycle:**
 * **Filling phase:** At the end of diastole, the left atrium has filled with blood from the pulmonary vein. Contraction is triggered by an electrical signal that originates at the sinoatrial node.
 * As the atrium begins to contract, the atrial pressure increases.
 * **↑ atrial pressure**
 * **no change in volume**
 * This is seen as “the wave” in both the atrial pressure and the ventricular pressure because at this stage, the mitral valve between the left atrium and left ventricle is open, so blood flows freely into the ventricle as the atrium contracts.
 * **Isovolumetric contraction phase:**
 * As the wave of depolarization reaches the ventricle, it begins to contract and ventricular pressure increases.
 * **^ ventricular pressure**
 * This initial increase in pressure pushes the **mitral valve closed** because the ventricular pressure quickly exceeds that in the atrium.
 * However, the aortic pressure is initially greater than the ventricular pressure, so the aortic valve is also closed during the initial stage of ventricular contraction.
 * Thus, the ventricular pressure increases rapidly because the ventricle is contracting but the blood has no place to go.
 * **No change in volume**
 * **Ejection phase:** As the ventricle continues to contract, the ventricular pressure exceeds that in the aorta, thus the aortic valve is pushed open and blood begins to flow.
 * **↓ ventricular volume**
 * ** ­ ** **↑ and then** **↓ in ventricular pressure.**
 * **Isovolumetric relaxation phase:** As the ventricle begins to relax, the ventricular pressure falls. When the ventricular pressure drops below the aortic pressure, the aortic valve closes. The ventricle continues to relax with both valves closed, so the pressure falls rapidly.
 * **Ventricular pressure** **↓** **slowly at first and then rapidly.**
 * As the ventricle continues to relax, the pressure eventually falls below that in the atrium, allowing the mitral valve to open and bloow flow into the ventricle beginning a new cycle.
 * **Summary of Volume changes:**
 * First, the ventricle passively fills, with a slight hump toward the end of diastole when the atrium contracts.
 * Then, during the isovolumetric contraction phase, there is no change in volume, because the aortic and mitral valves are closed.
 * When the aortic valve opens and blood can leave the ventricle, the volume decreases.
 * **Summary of Pressure changes:**
 * After diastole and passive filling of the left atrium with blood, contraction of the atrium results in increased atrial pressure, followed by an increase in ventricular pressure (while the mitral valve is open).
 * Once the mitral valve is closed and ventricular contraction commences, ventricular pressure increases rapidly until the ventricular pressure exceeds that in the aorta and the aortic valve is pushed open.
 * This immediately results in a slow decrease in ventricular pressure followed by a much faster drop in ventricular pressure once the ventricular pressure drops below the aortic pressure and the aortic valve. The ventricle continues to relax with both valves closed, so the pressure falls rapidly.
 * 3.** **To understand systolic and diastolic pressure-volume relations and ventricular function curves.**
 * **Pressure and volume changes in the left ventricle are bounded by two curves, the systolic pressure-volume relation and the end diastolic pressure-volume relationship**
 * **End-diastolic pressure volume relationship (EDPVR):** pressure-volume relationship during filling of the heart BEFORE contraction : passive elastic properties of ventricle (compliance).
 * Slope of EDPVR is shallow in the normal physiologic range—there is not much change in pressure with an increase in volume - normal ventricle is compliant.
 * Some pathologies **↓** compliance, making EDPVR steeper, impairing the ventricle.
 * The slope of the EDPVR steepens at very high volumes where the heart is so full it is bounded by the epicardium.
 * The diastolic PVR represents the PRELOAD on the heart.
 * **Systolic pressure volume relationship (SPVR):** pressure-volume relationship at the peak of isometric contraction.
 * Much steeper than EDPVR—pressure increases even at low volume.
 * SPVR includes the passive properties of the heart.
 * **Active tension:** the difference in the force between the peak systolic pressure and the end diastolic pressure, that is, the tension developed by the contraction.
 * 4.** **To understand and be able to state the Frank-Starling Law of the Heart.**
 * **Frank-Starling Law of the Heart:**
 * **Intrinsic mechanism by which the heart adapts to changes in preload (in the normal physiologic range):**
 * Heart response to an **↑**EDV by **↑**force of contraction.
 * The heart always functions on the ascending limb of the ventricular function curve.
 * What goes in, must come out. Cardiac output must equal venous return (on average).
 * **Molecule basis:**
 * Cardiac titin Isoform is very stiff, resists stretch.
 * Ca2+ sensitivity of myofilaments increases as sarcomeres are stretched. So the same intracellular Ca2+ produces a greater force of contraction.
 * Closer lattice spacing—stretched sarcomeres have altered spacing between actin and myosin which results in more force generated per cross-bridge.
 * 5.** **To describe relative changes in pressure and volume through the cardiac cycle (PV loop diagram).**
 * **Filling Phase (A to C):** Start at beginning of diatole.
 * **Point A:** Volume = End systolic volume (ESV): not zero. There is always some blood left in the heart.
 * **Point A** **-** **Point B:** Ventricle relaxes and fills, ventricular pressure falls to…
 * **Point B:** Minimum ventricular pressure.
 * **Point B - ****Point C:** Ventricular volume increases as blood flows into the left ventricle from the left atrium. There is little change in pressure, except the “a wave” which corresponds with atrial contraction.
 * **Point C:** End-diastolic volume (EDV)
 * **Isovolumetric contraction phase (C to D):**
 * **Point C:** Ventricle begins to contract
 * **Point C - ****Point D:** Pressure in the ventricle exceeds that in the atrium and the mitral valve is pushed closed. Since both valves are closed, blood can neither enter nor leave the ventricle, and the volume is constant. Since the ventricle is contracting with both valves closed, the pressure increases dramatically.
 * **Point D:** end diastolic volume (EDV).
 * **Ejection phase (D to F):**
 * **Point D:** left ventricular pressure exceeds the aortic diastolic pressure, resulting in opening of the aortic valve.
 * **Point D - ****Point E:** As blood leaves the ventricle, the volume decreases. At first pressure continues to increase, as the blood cannot leave the aorta as fast as it is entering..
 * **Point E:** Peak systolic pressure
 * **Point E - ****Point F:** As myocytes in the ventricle stop contracting, the ventricular pressure begins to fall. Blood is still leaving the ventricle.
 * **Point F:** end-systolic volume (ESV).
 * **Isovolumetric relaxation phase (F to A):**
 * **Point F:** end-systolic volume (ESV).
 * **Point F - ****Point A:** When the ventricular pressure falls below the aortic pressure, the aortic valve closes. Again, both valves are closed, so the ventricular volume is constant. When the ventricular pressure falls below the atrial pressure, the mitral valve opens and filling begins again.
 * 6.** **To define stroke volume, ejection fraction, stroke work, and pulse pressure, and to identify them graphically on a pressure-volume loop diagram.**
 * **Stroke volume (SV):**
 * SV=EDV-ESV
 * **Ejection fraction (EF):** the fraction of the EDV ejected during systole.
 * EF=SV/EDV= (EDV-ESV)/EDV
 * **Stroke work:** energy per beat (Joules), corresponds to the area inside the PV loop diagram.
 * **NOT** the same for the left and right sides of the heart.
 * **Pulse pressure/Blood pressure:**
 * End diastolic pressure at point D
 * Peak systolic pressure at point E
 * Difference = pulse pressure.
 * 7.** **To define preload, afterload and contractility, and to describe how altering these variables changes ventricular function.**
 * **Preload:** the pressure stretching the ventricle of the heart prior to contraction.
 * **Increase in preload:** Results in an increase stroke volume for the next beat à Starling’s law! Same ESV is achieved, EF is increased. On subsequent beats, SV returns to normal since ESV and contractility are unchanged.
 * **EDV** can be changed by changes in filling pressure, filling time, and ventricular compliance.
 * **Afterload:** end-systolic pressure → pressure in the aorta following systole.
 * **Increase in afterload:** decrease in stroke volume. The ventricle has to work harder against the increased aortic pressure, so less blood is ejected. ­ Aortic pressure → aortic valve opens later in the cycle, reducing ejection time.
 * **EDV** unchanged, EF decreased, ESV increased.
 * Stroke volume recovers on subsequent beats because the ­ ESV with constant venous return means ­ EDV, which increases stroke volume.
 * **Contractility/inotropy:** reflects the strength of contraction at any given preload and afterload.
 * **Changes in inotropy:** describe new starling curves.
 * If you hold the preload and afterload constant, and increase inotropy: new starling curve that corresponds to greater systolic pressure development for any given volume.
 * Increased inotropy is associated with an increased risk of stroke.

=Introduction to Autonomic Nervous System=
 * 1.** **Describe the anatomical projections of the sympathetic and parasympathetic autonomic nervous system and the central control of the autonomic nervous system.**
 * **Sympathetic nervous system (SNS):**
 * Thoracolumbar outflow—preganglionic fibers originate in the intermediolateral columns of the spinal cord.
 * Preganglionic fibers are short and usually synapse well before the target organ either:
 * Vertebral (paravertebral) ganglia—22 pairs beside vertebral column.
 * Prevertebral ganglia (celiac, superior and inferior mesenteric)—abdomen.
 * Postganglionic neurons are long and innervate target organs
 * Postganglionic fibers from the vertebral ganglia innervate blood vessels, the eye, salivary glands, heart, bronchi, sweat glands and hair follicles.
 * Postganglionic fibers from prevertebral ganglia innervate the intestine, organs mediating metabolic functions, bladder, urinary and rectal sphincters and genital organs.
 * Adrenal medulla—embryologically and functionally a sympathetic ganglion; innervated by typical sympathetic preganglionic neurons.
 * Diffuse system; usually pre:post ganglionic ration = 1:20.
 * **Parasympathetic nervous system (PNS)**
 * Craniosacral outflow—preganglionic fibers originate in midbrain (3rd cranial nerve), medulla oblongata (7th, 9th and 10th cranial nerves) and 2nd-4th segments of the sacral spinal cord.
 * Preganglionic fibers are long and usually synapse in a ganglion on or within the target organ.
 * Postganglionic fibers are short and innervate target organs.
 * Cranial division
 * 3rd cranial (oculomotor) nerve→ciliary ganglion→sphinter muscle (iris) and ciliary muscle (ciliary body).
 * 7th cranial (facial) nerve→sphenopalatine ganglion→lacrimal gland
 * 7th cranial (facial) nerve→submaxillary ganglion→sublingual and submaxillary salivary glands.
 * 9th cranial (glossopharyngeal) nerve→otic ganglia→heart, larynx, trachea, lungs, liver, pancreas, spleen and GI tract.
 * 10th cranial (vagus) nerve→terminal ganglia→heart, larynx, trachea, lungs, liver, pancreas, spleen and GI tract.
 * Sacral division:
 * Pelvic nerves→terminal ganglia→rectum, kidney, bladder, and sex organs.
 * Discrete system; usually pre:post ganglionic ration 1:1.
 * **Central control of the autonomic nervous system:** afferent information is processed and integrated and efferent responses are initiated.
 * Within the autonomic nervous system there is overlap with somatic centers of integration.
 * Structures involved:
 * **Spinal cord:** reflex change sin blood pressure, sweat production and micturition (urine production).
 * **Brain stem (medulla oblongata):** centers for control of blood pressure and respiration.
 * **Hypothalamus:** principal locus of integration; controls body temperature, water balance, carbohydrate metabolism, sexual reflexes and autonomic emotional responses.
 * **Cerebral cortex:** volitional changes and conditioned autonomic responses.
 * 2.** **List the primary neurotransmitters and their receptors that mediate neurotransmission at the ganglia and end organs in the parasympathetic and sympathetic nervous systems.**
 * **Parasympathetic nervous system:**
 * **Acetylcholine (ACh)**
 * Preganglionic neurons release ACh
 * In the ganglia Ach interacts with **neuronal-type nicotinic cholinergic receptors** (NNRs or neuronal-type nAChRs).
 * Postganglionic neurons release ACh
 * In the end organs Ach interacts with **muscarinic cholinergic receptors** (MRs or mAChRs).
 * **Sympathetic nervous system:**
 * **Acetylcholine (ACh)**
 * Preganglionic neurons release ACh.
 * In the ganglia and adrenal medulla ACh interacts with **neuronal-type nicotinic cholinergic receptors** (NNRs).
 * **Norepinephrine (NE)**
 * Postganglionic neurons release the catecholamine NE.
 * Exceptions:
 * Adrenal medulla releases primarily **epinephrine** (EPI)
 * Postganglionic neurons innervating sweat glands release **ACh.**
 * Postganglionic neurons innervating renal vasculature release **dopamine** (DA).
 * In the end organs NE and EPI interact with ** a ** **-** and ** b ** **-adrenergic receptors.**
 * Exceptions:
 * In thermoregulatory sweat glands, ACh interacts with MRs to increase sweat production.
 * Anatomically→sympathetic
 * Chemically→cholinergic
 * In renal vasculature, DA interacts with DA1Rs to cause vasodilation.
 * **Autonomic nervous system:**
 * ANS neurons usually also contain peptides and ATP co-transmitters.
 * This is why maximal concentrations of MR or AChR antagonists do not abolish some ANS responses.
 * **Nonadrenergic, noncholinergic neurons (NANC):**
 * GI tract, airways, bladder.
 * Common transmitters include **purines** and/or **peptides**.
 * Also nitric oxide, peptides, purines and serotonin.
 * 3.** **Describe the relationship of the adrenal medulla to the sympathetic nervous system.**
 * The adrenal gland is only innervated by the sympathetic nervous system.
 * The adrenal gland is an exception in the SNS, in that the postganglionic neurons innervating it primarily release epinephrine.
 * The adrenal gland is the primary source of epinephrine within the body which drives the sympathetic response.
 * 4.** **List and describe the responses of end organs to activation of the “rest-and-digest” parasympathetic nervous system and the “flight-or-fight” sympathetic nervous system.**
 * The PNS and SNS often, but not always, have opposite actions on the same organ.
 * **Parasympathetic nervous system (“rest and digest”):** general goal—conserve and restore energy.
 * ↑salivary gland secretion; ↑lacrimal gland secretion (tears); ↑bronchial gland secretion
 * miosis (constriction of the pupil; iris circular muscle) and accommodation (focusing for near vision; ciliary muscles)
 * ↓heart rate (bradycardia)
 * ↓conduction at the S-A node indirectly ↓blood pressure.
 * Constriction of bronchioles
 * ↑GI absorption; ↑GI motility; relaxation of sphincters; ↑GI secretions.
 * ↑urinary tract motility; relaxation of sphincters; bladder contraction.
 * **Sympathetic nervous system (“fight or flight”):** generally discharges as a unit in response to an acute stress.
 * ↑Heart rate (tachycardia); ↑force of cardiac contractility
 * ↑total peripheral resistance (vasoconstriction) resulting in ↑blood pressure.
 * ↑blood glucose; ↑lipolysis
 * Mydriasis (dilation of the pupil; iris radial muscle)
 * Dilation of bronchioles.
 * The SNS is also responsible for control of tone in blood vessels (see below).
 * 5.** **Discuss the concept of autonomic nervous system “tone” and explain the consequences of the fact that parasympathetic tone predominates at cardiac muscle and most smooth muscles and organs. What is the important exception?**
 * Vascular smooth muscle within arteries and arterioles is innervated solely by the sympathetic
 * 6.** **Describe the general mechanisms by which most drugs alter activity in the autonomic nervous system.**
 * Most drugs act by one of the following:
 * Mimicking the neurotransmitter action
 * Blocking the neurotransmitter action
 * Changing the normal action of the neurotransmitter by altering
 * Synthesis of the neurotransmitter
 * Release of the neurotransmitter
 * Inactivation of the neurotransmitter following release

=Parasympathetic Nervous System=
 * 1.** **List the steps in the synthesis, storage, release and inactivation of acetylcholine (ACh), and drugs that interface with these processes.**
 * **Synthesis:**
 * The synthesis of ACh depends on the uptake of choline across the neuronal plasma membrane by a high affinity, sodium-dependent choline transporter (ChT).
 * This is the rate-limiting step of ACh synthesis.
 * ChT is blocked by **hemicholinium-3**
 * ACh synthesis is catalyzed by the enzyme **choline acetyltransferase (ChAT)**.
 * This enzyme catalyzes the formation of ACh from choline and the acetyl moiety of acetyl coenzyme A.
 * **Storage:**
 * ACh is then sequestered in vesicles by a specific vesicular ACh transporter, VAChT.
 * **Release:**
 * **Spontaneous release** can occur in the absence of nerve stimulation and results in small amounts of ACh release.
 * **Stimulated release** is calcium dependent.
 * Elevated calcium promotes fusion of the vesicular membrane with the cell membrane, and exocytosis of ACh occurs.
 * Stimulated release results in several hundred quanta (small packages) of ACh being released.
 * **Inactivation:**
 * Stimulated release is modulated by presynaptic receptors:
 * Autoreceptors: MRs and NNRs are activated by released ACh—>feedback loop.
 * Heteroreceptors: stimulated by other neurotransmitters and usually inhibit ACh release.
 * Acetylcholinesterase (AChE) hydrolyzes ACh and terminates its action—> critical for normal neurotransmission.
 * Hydrolysis: ACh→choline + acetate (catalyzed by AChE)
 * Inhibition of ACh hydrolysis potentiates ACh action.
 * Pseudocholinesterase in plasma also terminates ACh action.
 * **Drugs that interfere with these processes:**
 * **Bethanechol:** A synthetic analog of ACh that is resistant to hydrolysis by AChE (ACh is not used clinically due to its rapid hydrolysis).
 * MR agonist.
 * Activates MRs at the end organs in the parasympathetic nervous system producing effects similar to physiological stimulation of the PNS.
 * At high doses, can cause bradycardia, resulting in heart block.
 * Activates non-innervated MRs on endothelial cells of arterioles and veins resulting in ↑vasodilation and ↓peripheral resistance.
 * Increase thermoregulatory sweating via activation of MRs on sweat glands.
 * Sympathetic cholinergic response.
 * **Physostigmine:** AChE inhibitor.
 * **Functions:**
 * Blocks the hydrolysis of ACh and thereby prolongs the lifetime of ACh in the synaptic cleft.
 * Indirectly stimulates MRs, producing effects like the direct acting MR agonists (above).
 * Initially stimulates and causes a depolarization block of NNRs in autonomic ganglia and NMRs at the NMJ.
 * Physostigmine is a tertiary amine that **crosses the BBB** . T1/2=30 minutes.
 * **Atropine:** prototypic MR antagonist found in plants.
 * Competitive, reversible antagonist of ACh at MRs that exhibits a high degree of specificity for MRs (but, as with all drugs, its specificity is not absolute).
 * Tertiary amine, readily **crosses the BBB**.
 * **Actions:** largely the result of blockade of the parasympathetic nervous system.
 * **↓** Salivary and bronchial secretions.
 * Tachycardia
 * Mydriasis and paralysis of accommodation.
 * Bronchodilation
 * Urinary retention
 * ↓GI motility and secretions.
 * **Other effects:**
 * Impaired sweating
 * Vasodilation
 * **CNS effects:** increasing dose can causes stimulation of medullary centers and higher centers leading to restlessness, disorientation, delirium and hallucination. Eventual depression of vital centers is possible and potentially fatal.
 * 2.** **For cholinergic receptors: List the locations of and the differences between nicotinic and muscarinic cholinergic receptors (NRs/nAChRs and MRs/mAChRs, respectively), describe the signal transduction mechanisms activated by stimulation of nicotinic versus muscarinic cholinergic receptors, state the significance of presynaptic versus postsynaptic cholinergic receptors.**
 * **Nicotinic cholinergic receptors (NRs or nAChRs):** belongs to a superfamily of ligand-gated ion channels. Each NR is a pentomer composed of 5 subunits—receptor subtypes are designated based upon the specific subunit composition of the receptor.
 * **Location:** NNRs are found in postganglionic neurons as well as in the presynaptic neurons.
 * **Signal transduction mechanism:** ligand-gated sodium ion-channel.
 * **Brief stimulation:** ↑inward Na+ conductance, depolarization and excitation.
 * **Prolonged stimulation:** “depolarization blockade” and receptor desensitization.
 * **Muscarinic cholinergic receptors (MRs or mAChRs):** belongs to a superfamily of G protein-coupled receptors. Single polypeptide with 7 transmembrane spanning domains. Five MR subtypes (m1-m5).
 * **Location:** MRs are found in smooth muscle, glands and as presynaptic receptors; M3Rs are found in the vascular smooth muscle; M2Rs are found in cardiac muscle.
 * **Signal transduction mechanism:** G protein-coupled receptor.
 * **Stimulation of m1, m3 and m5 receptors:** activates phospholipase C-->↑intracellular [Ca2+] and [diacylglycerol].
 * ↑ intracellular [Ca2+]→stimulates Ca2+-dependent nitric oxide synthase → ↑NO → ↑cGMP → smooth muscle relaxation.
 * **Stimulation of m2 and m4 receptors:**
 * Inhibits adenylyl cyclase → ↓cAMP.
 * Activates voltage-gated K+ channels → hyperpolarization.
 * Inhibits voltage-gated Ca2+ channels.
 * **Significance of presynaptic versus postsynaptic cholinergic receptors:**
 * **Postsynaptic receptors:** generally propagate or enhance ACh action and stimulation of the end organ.
 * NNRs in postganglionic neurons: depolarization raises postsynaptic membrane potential to threshold creating an action potential.
 * M2Rs in cardiac muscle are responsible for creating hyperpolarization.
 * MRs in smooth muscle:
 * In smooth muscle tissue containing pacemaker cells, the time to threshold is shortened.
 * In other smooth muscles, Contraction or relaxation.
 * M3Rs increase ↑NO in the endothelial cells of vascular smooth muscle, initiating muscle relaxation.
 * **Presynaptic receptors:** modulate stimulation-evoked release.
 * M2/4Rs inhibit release of ACh.
 * NNRs stimulate release of ACh.
 * 3.** **For selective muscarinic cholinergic drugs: List the pharmacologic actions of direct acting muscarinic agonists, Describe the differential pharmacokinetic disposition of muscarinic agonists, List the pharmacologic actions of muscarinic antagonists.**
 * **Pharmacologic actions of direct acting muscarinic agonists:**
 * Activate MRs at the end organs in the parasympathetic nervous system producing effects similar to physiological stimulation of the PNS.
 * At high doses, can cause bradycardia, resulting in heart block.
 * Activate non-innervated MRs on endothelial cells of arterioles and veins resulting in ↑vasodilation and ↓peripheral resistance.
 * Increase thermoregulatory sweating via activation of MRs on sweat glands.
 * Sympathetic cholinergic response.
 * **Differential pharmacokinetic disposition of muscarinic agonists**
 * Relative potencies at MRs and NRs
 * Methyl substitutions increase selectivity for MRs
 * Quaternary ammonium compounds
 * DO NOT CROSS THE BBB.
 * **Pharmacologic actions of muscarinic antagonists**
 * Inhibit MR agonist-induced responses at parasympathetic end organs and sweat glands.
 * Atropine, a tertiary amine, readily crosses the BBB.
 * 4.** **For acetylcholinesterase inhibitors: Describe their pharmacologic actions and why they affect both muscarinic and nicotinic cholinergic neurotransmission. Explain the reason why some acetylcholinesterase inhibitors are useful clinically whereas others are toxic agents.**
 * **Acetylcholinesterase inhibitors:**
 * **Pharmacologic actions:** block the hydrolysis of ACh and thereby prolong the lifetime of ACh in the synaptic cleft.
 * Quaternary amines do not cross the BBB and have moderate direct NNR agonist actions.
 * **Affect both muscarinic and nicotinic cholinergic neurotransmission:**
 * AChE inhibitors indirectly stimulate MRs by increasing the pool of free ACh
 * AChE inhibitors initially stimulate and then cause depolarization block of NNRs in autonomic ganglia and NMRs at the NMJ→see description of NRs above.
 * **Clinical usefulness vs. toxicity:** while in controlled situations AChE inhibitors are of great clinical usefulness, irreversible AChE inhibitors are toxins.
 * Organophosphate insecticides
 * Nerve gases
 * Very lipid soluble and easily cross the BBB.

=Adrenergic Neurotransmission=
 * 1.** **Describe the elements of adrenergic neurotransmission (neurotransmitter synthesis / storage / release / inactivation and interaction with receptors) that represent targets for adrenergic and anti-adrenergic drug action.**
 * **Synthesis:**
 * Tyrosine (precursor) is taken up by active transport.
 * Tyrosine is converted to dihydroxyphenylalanine (**DOPA** ) by **tyrosine hydroxylase.**
 * RATE LIMITING step in catecholamine synthesis.
 * Inhibited by **metyrosine.**
 * DOPA is converted to **dopamine** by **L-aromatic amino acid decarboxylase** (l-AAD).
 * Inhibited by ** a ** **-methyl dopa**.
 * After being taken up into a storage vesicle, dopamine is converted to **norepinephrine** by **dopamine** **b** **-hydroxylase (D** **b** **H).**
 * Norepinephrine is converted to **epinephrine** by **phenylethanolamine N-methyl transferase**
 * This enzyme is at its highest level of concentration in the adrenal medulla (the main endogenous source of epinephrine).
 * **Storage and release:**
 * Storage vesicles found in adrenergic nerve endings (and the adrenal medulla) contain an active catecholamine uptake pump (**VMAT** ).
 * VMAT transports cytosolic norepinephrine into the vesicle.
 * VMAT is a different protein from the presynaptic membrane pump, NET, that removes release NE from the synapse.
 * Norepinephrine is stored in vesicles where it is packaged for release and protected from degradation by monoamine oxidase (MAO) on the mitochondria.
 * If:
 * VMAT is blocked by drugs (**reserpine** ), then NE is degraded by MAO→↓NE and loss of sympathetic effect.
 * MAO is inhibited by an MAO inhibitor (**phenelzine** ), ↑NE storage and release → enhanced sympathetic effect.
 * **Release** into synapse is Ca2+ dependent and occurs following nerve stimulation.
 * This can be blocked by **bretylium**.
 * **Inactivation:**
 * **__>__ 80% of release NE is taken back up** via the NE transporter, NET. Most is taken back up into secretory vesicles, some is metabolized by MAO.
 * Inhibitors of NET (**cocaine, tricyclic antidepressants** ) are associated with potentiation of synaptic action of released norepinephrine.
 * Some phenylethylamine drugs (**amphetamines, pseudoephedrine** ) act indirectly to release NE by reversing this transport process.
 * **Uptake 2:** some released NE is taken up into extraneuronal tissue and metabolized by catechol-O-methyltransferase (COMT) a/o MAO.
 * Plays a role in terminating action of exogenous or circulating catecholamines.
 * Metabolites (MOPEG, VMA and DOPEG) can be conjugated in the liver and renally excreted.
 * 2.** **Compare and contrast the modes of drug action with respect to selectivity of action and clinical utility.**
 * **Modes of drug action in the adrenergic neuron**
 * **Inhibition or stimulation of synthesis, storage, and release**
 * **Selectivity of action:** lack of selectivity, result in widespread physiologic effects.
 * **Clinical utility:** lesser clinical utility due to the lack of selectivity.
 * **Inhibition of metabolism (MAO and COMT)**
 * **Selectivity of action:** very little selectivity.
 * **Clinical utility:** some clinical utility, particularly in the CNS; can elicit greater adrenergic effects following nerve stimulation. Inhibition of COMT increases duration of exogenously administered catecholamines.
 * **Inhibition of reuptake (termination of transmitter action)**
 * **Selectivity of action:** can be selective. Inhibitors specific for various neurotransmitters are available.
 * **Clinical utility:** moderate clinical utility, particularly in the CNS. Blockade of reuptake prolonges neurotransmitter action in the synapse→↑adrenergic action.
 * **Receptor stimulation or blockade**
 * **Selectivity of action:** MAXIMUM SELECTIVITY. Specific agonists and antagonists for the various adrenergic receptor subtypes.
 * **Clinical utility:** GREATEST CLINICAL UTILITY!!!!
 * 3.** **For adrenergic agonists, distinguish the different mechanisms whereby direct-acting, indirect-acting, and mixed-acting agents work.**
 * **Direct-acting:** Drug binds directly to adrenergic receptors and elicits the same effects as the endogenous neurotransmitter→mode of action for most commonly used therapeutic agents.
 * Receptor subtype specificity→selectivity of action.
 * **Indirect-acting:** Drug exerts an effect on the processing of the neurotransmitter that results in increased amounts of the neurotransmitter at the receptor, thus indirectly increasing the neurotransmitter’s action.
 * Most commonly, these drugs increase storage and release of the neurotransmitter targeted.
 * Can also include effects to
 * Inhibit synaptic reuptake
 * Block metabolic degradation
 * Increase synthesis.
 * **Mixed-acting:** drugs which are both direct-acting and indirect-acting agents.
 * 4.** **For anti-adrenergic agents, describe the logic behind the various sympatholytic strategies.**
 * **Sympatholytic action:** interference with adrenergic function in the presynaptic neuron.
 * Lack of specificity limits clinical utility.
 * **Inhibitors of catecholamine synthetic enzymes:** block synthesis of catecholamines.
 * Tyrosine hydroxylase (rate-limiting)
 * **Metyrosine**
 * L-aromatic amino acid (DOPA) decarboxylase
 * ** a ** **-methyldopa**
 * Dopamine b -hydroxylase
 * **Disulfiram**
 * **Inhibitors of catecholamine storage:** deplete catecholamine stores.
 * **Reserpine**
 * **Inhibitors of catecholamine release:** deplete synaptic levels of catecholamines following increases in presynaptic interneuronal calcium levels.
 * **Bretylium**
 * **Guanethidine**
 * 5.** **List the gross distribution of adrenergic receptor subtypes on the following organ systems and describe the physiologic responses that result from activation or blockade of these receptors or of synaptic activity.**
 * **Heart:** primarily b 1 receptors (also some b 2 and a 1, but to a much lesser extent).
 * **Physiologic responses:**
 * **Activation:**
 * SA node: ↑heart rate (positive chronotropy)
 * AV node: ↑conduction velocity; ↓refractory period.
 * Atrial and ventricular cardiac muscle: ↑force of contraction (positive inotropy).
 * **Blockade:**
 * Negative inotropic and chronotropic effects with decreased AV conduction.
 * **Blood vessels:** a 1 and b 2 receptors.
 * **Physiologic responses:** The effect of any given drug depends on the relative adrenergic receptor subtype specificity, the density of that receptor in a particular vascular bed and the potency of the drug.
 * **Activation:**
 * **Cutaneous, mucous membranes, splanchnic vasculature:** primarily a 1 receptors.
 * Vasoconstriction→↑total peripheral resistance.
 * **Skeletal muscle:** a 1 and b 2 receptors
 * Vasoconstriction ( a 1)
 * Vasodilation ( b 2)→↑blood flow→↓peripheral resistance
 * **Renal vasculature:** a 1 receptors.
 * Relaxation via D1 dopamine receptors balanced by a 1-mediated vasoconstriction.
 * **Blockade:**
 * Arterial and venous dilation via block of a 1 receptors with reflex tachycardia; reflex tachycardia is enhanced if presynaptic a 2 receptors are also blocked (due to loss of negative feedback on NE release).
 * Opposes vasodilation via block of b 2 receptors (decreasing tissue perfusion).
 * **Lungs:** b 2 and a 1 receptors.
 * **Physiologic responses:**
 * **Activation:**
 * **Bronchial smooth muscle** : b 2­­ receptors
 * Relaxation and bronchodilation.
 * **Upper respiratory tract mucosal blood vessel:** a 1 receptors
 * Constriction.
 * **Blockade:**
 * Increases in airway resistance via block of b 2 receptors (may cause bronchospasm in asthmatics)
 * **Kidney:** b 1 receptors
 * **Physiologic responses:**
 * **Activation:**
 * **↑** Release of renin via b 1 receptors on juxtoglomerular cells→↑vasoconstriction (via angiotensin II) and ↑fluid retention (via aldosterone) and ↑blood pressure.
 * **Blockade:**
 * None listed in notes.
 * 6.** **Describe the baroreceptor reflex, its effect on heart rate, and its role in mediating indirect cardiovascular actions of adrenergic agonists and antagonists.**
 * **Postural baroreceptor reflex arc:** Most important acute compensatory response, involved in acute regulation of blood-pressure.
 * **Activation of the baroreceptor** in the carotid sinus (via elevated blood volume) inhibits sympathetic discharge from the medulla.
 * ↓blood pressure and ↓heart rate.
 * **Relaxation** as a result of ↓blood pressure disinhibits tonic sympathetic discharge results in SNS-mediated release of norepinephrine at the heart and blood vessels.
 * ↑blood pressure and ↑heart rate.
 * Adrenergic agonists and antagonists that elicit either vasodilation or vasoconstriction can mediate indirect effects on heart rate via the baro-receptor reflex arc.
 * **Drug induced vasodilation** ↓blood pressure and via the baroreceptor reflex arc ↑NE resulting in reflex tachycardia.
 * **Drug induced vasoconstriction** ↑blood pressure and via the baroreceptor reflex arc ↓NE resulting in reflex bradycardia.
 * 7.** **List subtype (alpha-1, alpha-2, beta-1, beta-2) specific receptor agonists and antagonists and CVPR therapeutic indications for the use of each (as per the bolded drugs from the drug lists on pages 28 and 29).**
 * ** a ** **1-receptor specific**
 * **Agonists**
 * **Phenylephrine:** Primarily a vasoconstrictor.
 * Systemically a vasopressor; topically a decongestant and mydriatic.
 * Formerly used in paroxysmal supraventricular tachycardia (PSVT) by reflex HR action.
 * **Antagonists:**
 * **Doxazosin:** vasodilator
 * Hypertension, vasospastic conditions and Raynaud’s Disease
 * ** a ** **2-receptor specific**
 * **Agonists**
 * **Clonidine:** clonidine is an a 2-receptor agonist, but counter intuitively reduces SNS activity.
 * Hypertension and treatment of opiate/alcohol withdrawal symptoms.
 * **Antagonists:**
 * **None**
 * ** b ** **1-receptor specific**
 * **Agonists:**
 * **None**
 * **Antagonists**
 * **Atenolol:** ↓ inotropy, ↓ chronotropy, ↓AV conduction rate, ↓renin release from kidneys, anti-remodelling effect in heart.
 * Hypertension.
 * **Metoprolol:** ↓inotropy, ↓chronotropy, ↓AV conduction rate, ↓renin release from kidneys, anti-remodelling effect in heart.
 * Hypertension
 * Angina Pectoris: reduces myocardial oxygen demand in chronic stable angina
 * Hyperthyroidism: blocks symptoms of thyroid storm due to excessive catecholamine action.
 * ** b ** **2-receptor specific**
 * **Agonists**
 * **Albuterol:** bronchodilator
 * Acute asthmatic bronchospasm.
 * **antagonists**
 * **None**
 * 8.** **Describe the relationship of adrenergic drug structure to their pharmacokinetics with regards to absorption, distribution, and duration of action.**
 * **Absorption:** The effectiveness after oral administration is largely determined by the drug’s resistance to first pass metabolism in the liver. Oral effectiveness is increased with:
 * **Drugs that are non-catechols** (they do not contain a 3,4-hydroxyl [OH] group on the phenyl ring) since they are not substrates for COMT in the liver.
 * **Drugs that possess a methyl group on the** **a** **-carbon** of the phenylethylamine structure are protected against degradation by MAO in the liver.
 * **Distribution:** The ability to enter the CNS is increased with drugs that have **no hydroxyl groups on the phenyl ring** since this increases the drug’s lipophilicity.
 * **Duration of action:** The half-life is increased by the same factors that protect the drug from MAO and COMT metabolism.
 * 9.** **Relate the physiologic responses produced by the receptor actions of adrenergic agonists and antagonists to their therapeutic uses and adverse affects and toxicities.**
 * ** a ** **1-receptor**
 * **Agonists**
 * **Physiologic response:** vasoconstriction
 * **Therapeutic uses:** vasopressor action (elevation of blood pressure), relief of nasal congestion (decongestion via vasoconstriction), and local vasoconstriction in local anesthetic solution.
 * **Adverse effects:** marked elevation in blood pressure can lead to cerebral and pulmonary hemorrhage.
 * **Antagonists**
 * **Physiologic Response:** vasodilation
 * **Therapeutic uses:** preoperative management of pheochromocytoma, local vasoconstrictor excess (following inadvertent infiltration of NE, prevents tissue necrosis), Hypertension/vasospastic conditions (Reynaud’s disease), and urinary obstruction (urinary symptoms of benign prostatic hyperplasia).
 * **Adverse effects:** syncope at onset of treatment and postural hypotension.
 * ** a ** **2-receptor:** clonidine is an a 2-receptor agonist, but counterintuitively reduces SNS activity
 * a 2-receptor activation
 * **Physiologic response:** reduced peripheral sympathetic nervous system activity and ↓NE release from sympathetic neurons.
 * **Therapeutic uses:** Hypertension, treatment of opiate/alcohol withdrawal symptoms
 * **Adverse effects:** dry mouth, drowsiness, sedation and fatigue.
 * ** b ** **1-receptor**
 * **Agonists**
 * **Physiologic response:** cardiac stimulation
 * **Therapeutic uses:** cardiogenic shock, acute heart failure, bradyarrhythmias, and ACLS protocol.
 * **Adverse effects:** increased cardiac work can lead to severe angina, myocardial infarction, tachycardia, palpitations and serious ventricular arrhythmias.
 * **Antagonists**
 * **Physiologic response:** ↓contractility, ↓heart rate, ↓AV conduction rate, ↓renin released from kidneys, and anti-remodeling effect in the heart.
 * **Therapeutic uses:** Hypertension, angina pectoris, arrhythmias, congestive heart failure and hyperthyroidism.
 * **Adverse effects:** Depression of myocardial contractility/excitability; can precipitate acute heart failure.
 * ** b ** **2-receptor**
 * **Agonists**
 * **Physiologic response:** smooth muscle relaxation
 * **Therapeutic uses:** anaphylaxis, asthma/COPD and relief of premature labor contractions.
 * **Adverse effects:** muscle tremors.
 * **Antagonists**
 * **Physiologic response:** block of excessive discharge of muscle spindles
 * **Therapeutic uses:** treatment of tremors
 * **Adverse effects:** worsening of pre-existing asthma which may precipitate bronchospasm ( b 2-receptor agonists are used to treat asthma), undesirable change in lipid profile (↑serum triglycerides and total cholesterol), and may compromise peripheral circulation.
 * ** b ** **1 and** **b** **2-receptor**
 * **Antagonists:**
 * **Physiologic response:** blocks the somatic manifestations of anxiety mediated via adrenal epinephrine.
 * **Therapeutic uses:** stage fright.
 * **Adverse effects:** Hypoglycemic episodes (masks the early signs of insulin reaction—mediated by epinephrine release→tachycardia, anxiety and tremor) and CNS effects (sedation, sleep disturbances and depression).
 * 10.** **For the bolded drugs on the drug list, describe their: Mechanism and site of action (receptors and effector organs involved); pharmacokinetic factors (when clinically relevant): central vs. peripheral activity, organ of elimination, duration of action (short vs. long); major clinical uses, most common and most severe side effects (treatment of overdose / toxicity) / Significant contraindications.**
 * **Norepinephrine:** direct-acting, targets a and b 1 receptors.
 * **PCK:** Action very brief due to rapid metabolism. Administered via IV infusion.
 * **Use:** Vasoconstrictor, used for vasopressor action to restore systolic blood pressure in hypotensive states.
 * **SE:** marked elevations in blood pressure (↑risk of hemorrhage) and increased cardiac work (severe angina, myocardial infarction, tachycardia, palpitations and serious ventricular arrhythmias)
 * **Isoproterenol:** direct-acting, targets b 1 and b 2 receptors.
 * **PCK:** Administered by inhalation in asthma; administered via IV for systemic treatment.
 * **Use:** bronchodilator in asthma, treatment of cardiogenic shock, acute heart failure, and some bradyarrhythmias. Largely replaced by other drugs.
 * **SE:** pronounced cardiac stimulation.
 * **Albuterol:** direct-acting, targets b 2 receptors
 * **PCK:** administration via inhalation.
 * **Use:** bronchodilation in asthma and COPD.
 * **SE:** tremor, b 1 cardiac stimulation possible at high doses.
 * **Phenylephrine:** direct-acting, targets a 1 receptors
 * **PCK:** Action very brief due to rapid metabolism. Administered via IV infusion.
 * **Use:** vasopressor action to restore systolic blood pressure in hypotensive states.
 * **SE:** marked elevations in blood pressure (↑risk of hemorrhage); CNS stimulation—anxiety, restlessness, insomnia.
 * **Epinephrine:** direct-acting, targets a, b 1 and b 2 receptors.
 * **PCK:** Action very brief due to rapid metabolism. Administered via IV infusion.
 * **Use:** vasopressor action to restore systolic blood pressure in hypotensive states, local vasoconstriction in local anesthetic solution; cardiac stimulation in cardiogenic shock, acute heart failure, and bradyarrhythmias; smooth muscle relaxation to treat anaphylaxis.
 * **SE:** marked elevations in blood pressure (↑risk of hemorrhage) and increased cardiac work (severe angina, myocardial infarction, tachycardia, palpitations and serious ventricular arrhythmias)
 * **Pseudoephedrine:** mixed-acting, targets a, b 1 and b 2 receptors
 * **PCK:** given orally; indirect effects at low doses via release of NE at a 1/ b 1 receptor and direct effects at high doses via b 2 receptor.
 * **Use:** as a vasoconstrictor for treatment and relief of nasal congestion.
 * **SE:** generally less potent at producing tachycardia, increased blood pressure and central stimulation than ephedrine.
 * **Dopamine:** mixed-acting, targets a and b 1 receptors (and dopamine D1)
 * **PCK:** Action very brief due to rapid metabolism. Administered via IV infusion. Acts via DA1 at low doses, b 1 at moderate doses, and a at high doses.
 * **Use:** Low doses improve blood flow to the kidney and abdominal organs, higher doses have a positive inotropic effect and produce vasoconstriction. Dopamine is also used as a cardiac stimulant in the management of cardiogenic shock, acute heart failure, and bradyarrhythmias.
 * **SE:** dose dependent; marked elevations in blood pressure (↑risk of hemorrhage) and increased cardiac work (severe angina, myocardial infarction, tachycardia, palpitations and serious ventricular arrhythmias).
 * **Clonidine:** direct-acting, targets a 2 receptors; agonist, but targeting of a 2 receptors depresses SNS response.
 * **PCK:** given orally or transdermally
 * **Use:** hypertension, treatment of opiate/alcohol withdrawal symptoms.
 * **SE:** dry mount, drowsiness, sedation and fatigue. Abrupt withdrawal may lead to sympathetic overactivity.
 * **Phentolamine:** reversible, targets a 1 and a 2 receptors.
 * **PCK:** given parenterally.
 * **Use:** given as a vasodilator to treat local vasoconstrictor excess (following inadvertent infiltration of NE, prevents tissue necrosis).
 * **SE:** postural hypotension and reflex tachycardia, nasal stuffiness, inhibition of ejaculation, sedation, weakness and sense of fatigue.
 * **Doxazosin:** reversible, targets a 1 receptors
 * **PCK:** given orally.
 * **Use:** as a vasodilator for the treatment of hypertension and vasospastic conditions including Raynaud’s disease.
 * **SE:** syncope at onset of treatment, postural hypotension.
 * **Propanolol:** reversible, targets b 1 and b 2 receptors.
 * **PCK:** given orally.
 * **Use:** treatment of certain tremors given its ability to block excessive discharge of muscle spindles.
 * **SE:** Hypoglycemic episodes—masks early signs of insulin reaction (mediated by epinephrine release→tachycardia, anxiety, tremor); CNS effects—sedation, sleep disturbances, and depression.
 * **Atenolol:** reversible, targets b 1 receptors
 * **PCK:** given orally.
 * **Use:** For the treatment of hypertension.
 * **SE:** depression of myocardial contractility/excitability; can precipitate acute heart failure.
 * **Metoprolol:** reversible, targets b 1 receptors
 * **PCK:** given orally.
 * **Use:** for the treatment of hypertension, angina pectoris and hyperthyroidism.
 * **SE:** depression of myocardial contractility/excitability; can precipitate acute heart failure.
 * **Carvedilol:** reversible, targets a 1, b 1 and b 2 receptors
 * **PCK:** given orally.
 * **Use:** management of congestive heart failure.
 * **SE:** syncope at onset of treatment, postural hypotension; Hypoglycemic episodes—masks early signs of insulin reaction (mediated by epinephrine release→tachycardia, anxiety, tremor); CNS effects—sedation, sleep disturbances, and depression.

=Sympathetic Nervous System= LOs not available

=Cardiac Ion Channels & Action Potentials=
 * 1.** **Sketch typical "fast" and "slow" cardiac action potentials, labeling both the voltage and time axes, and describe the cells in which each type of action potential is found.**
 * **Fast cardiac action potentials** are found in myocardial cells and cells of rapid conduction pathways.
 * **Slow cardiac action potentials** are found in pacemaker cells of the SA and AV nodes.


 * 2.** **Describe the properties of the ion channels that underlie "fast" and "slow" cardiac action potentials and describe ionic mechanisms that are likely to account for the ability of pacemaker cells to generate rhythmic firing without neural input.**
 * **Sodium ion channel (INa­):** Cardiac sodium channels (containing //NaV1.5// as the principle subunit) are similar to sodium channels in neurons and skeletal muscle. Depolarization causes them to activate rapidly and then inactivate.
 * **Calcium ion channels (ICa):** The properties of calcium channels are mainly determined by the principle (CaV) subunit, which has a structure like that of the NaV subunit of voltage-gated sodium channels.
 * **ICa-L:** contain CaV1.2 and are predominantly in ventricular and atrial myocardium and cells of the SA and AV nodes and conductive pathways. L-type channels activate quite rapidly in response to depolarization and exhibit both voltage- and calcium- dependent inactivation. L-type calcium currents are blocked by dihydropyridines (anti-hypertensive agents).
 * **ICa-T:** “LVA”—activated by weaker depolarization than those required for HVA channels. T-type calcium currents activate and then inactivate in response to depolarization and are expressed in the SA node and in the nervous system.
 * **Potassium and cation non-selective currents:** tetramers.
 * **Time-dependent potassium currents:**
 * **IKto:** Depolarization causes both activation and inactivation on a time scale only slightly slower than that of sodium current.
 * **IKr and IKs:** “rapid” delayed rectifier and “slow” delayed rectifier, respectively. Depolarization causes activation of these two currents on a time scale of 20-100 ms.
 * **Inward rectifier potassium currents:**
 * **IK1:** The “inward rectifier” channel—not gated in the traditional sense. Conductance is steeply voltage dependent as a consequence of block by cytoplasmic constituents. These channels display strong, instantaneous (<1 ms) rectification such that they readily conduct inward K+ current at potentials below EK­ and only weak pass outward K+ current at potentials slightly positive to EK.
 * Suited for holding cells near EK­ between action potentials without producing an outward current upon depolarization.
 * **IKACh:** GIRK tetramer; current is increased in response to ACh acting on muscarinic receptors (MRs)→important in the ability of the PNS to slow pacemaker activity of the SA node.
 * **Non-selective cation current:**
 * **If (or Ih­)—HCN tetramer:** “funny”—turned off by depolarized potentials and turned on at hyperpolarized potentials. Permeable to both Na+ and K+. “Activated” at both depolarized and hyperpolarized potentials.
 * Current flow depends upon hyperpolarization because the channel is inactivated at depolarized potentials; this inactivation is removed by hyperpolarization.
 * **Pacemaker cells:** Pacemaker cells do not require neuronal input to maintain regular rhythmic firing. Ionic mechanisms likely to account for this:
 * The balance between ICa and delayed rectifier current (IKr and IKs) is such that repolarization occurs shortly after the peak of the action potential.
 * The repolarization is followed by a slow depolarization (the **pacemaker potential** ) which brings the cell back to threshold for the generation of another action potential.
 * Funny current (If): induced by hyperpolarization. Induction of If allows cation fluxes which drive voltage potential towards the reversal potential of If (-30 mV).
 * 3.** **Describe the significance of the IK1 channels in myocardial cells that have “fast” action potentials and the If[or Ih] currents in cells having “slow” action potentials.**
 * **IK1 and the “fast” action potential:**
 * IK1 is the inward rectifier potassium channel. This channel does not gate in the traditional sense, although its conductance is steeply voltage dependent as a consequence of block by cytoplasmic constituents. IK1 has a strong, “instantaneous” rectification such that they readily conduct inward K+ current at potentials below EK and only weakly pass outward K+ current at potentials slightly positive to EK. Consequently these channels are ideally suited for holding cells near EK between action potentials without producing an outward current.
 * In the context of the “fast” action potential, the IK1 channel—the inward rectifier—being so ideally suited to maintain potentials slightly positive to EK, do exactly that—they hold the cell near EK in between action potentials.
 * **If/Ih and the “slow” action potential:**
 * If is responsible for generating the funny current—a current induced by hyperpolarization.
 * Induction of If in the context of the “slow” cardiac action potential allows cation fluxes which drive voltage towards the reversal potential of If and may play a role in generation of the pacemaker potential—which is critical to allowing pacemaker cells generate rhythmic firing in the absence of neuronal input.
 * 4.** **Define absolute refractory period, relative refractory period.**
 * **Absolute refractory period:** The period of time following a “fast” cardiac action potential a second action potential cannot be initiated until most of the inactivation of INa is removed (during the repolarizing phase).
 * **Relative refractory period:** The period of time following a “fast” cardiac action potential during which the threshold for a second action potential remains elevated until after repolarization is complete (complete removal and inactivation of INa and deactivation of IKr and IKs has occurred).
 * 5.** **Discuss the mechanism and significance of "overdrive suppression".**
 * Myocardial cells in the heart (other than the pacemaker cells in the SA node), including those of the AV node, are capable of spontaneous activity.
 * The frequency at which they would fire action potentials is lower than the frequency of discharge of cells in the SA node.
 * Under normal circumstances, these cells are driven by action potentials originating in the SA node; that is, an action potential will spread to them from the SA node before they reach threshold on their own.
 * **This is called overdrive suppression**.
 * Under abnormal circumstances these cells can take over initiation of the heartbeat→ectopic pacemakers.

=Cardiac Conduction System & ECG=
 * 1.** **Describe the relationship between the ventricular action potentials of individual cardiac myocytes and the surface electrocardiogram.**
 * The initial rapid upward deflection of the R wave corresponds to phase 0 of the action potential, which is due to the fast sodium current.
 * The isoelectric ST segment on the ECG which links the QRS to the T wave is isoelectric normally and corresponds to phase 2 of the action potential—in which there is a long plateau with little change in voltage (calcium influx and potassium efflux are balanced).
 * The T wave of the ECG (in which repolarization is occurring) corresponds to phase 3 of the action potential in which there is a rapid decrease in voltage as potassium efflux continues.
 * The isoelectric segment after the T wave corresponds to phase 4 of the action potential.
 * 2.** **Know the components of the cardiac electrical conduction system and the sequence of its activation.**
 * Electrical impulses are initiated by pacemaker cells in the SA node (which is high in the right atrium) and spread via cell to cell through gap junctions.
 * The wave of depolarization created then goes through the right and then the left atrium (generating a P wave).
 * The wave of depolarization then arrives at the AV node (located between the fibrous mitral and tricuspid valve rings).
 * At this site, (the “junction”) there is a delay before the depolarization wave enters the ventricles—ensures that contraction of the atria ends before depolarization of the ventricles occurs.
 * Depolarization wave then proceeds through the bundle of His into the left and right bundle branches. The bundles then divide into fibers made up of Purkinje cells. These Purkinje fibers radiate toward the contractile cardiac myocytes that induce contraction.
 * The right bundle is a single entity primarily supplying the right ventricle.
 * The left bundle divides into anterior and posterior branches or fascicles that supply corresponding regions of the left ventricle.
 * The bundle of His, left and right branches and Purkinje fibers all contain cells which conduct depolarization very rapidly (compared to the vast majority of cardiac cells).
 * 3.** **Describe the P wave, QRS complex, T wave, PR interval and the QT interval.**
 * **P wave:** small depolarization (reflecting the depolarization of the atria) prior to the larger depolarization of the ventricles (QRS complex).
 * **QRS complex:** a large wave reflecting the depolarization of the ventricles after the P wave (depolarization of the atria) and before the T wave (repolarization of the ventricles).
 * **T wave:** a small wave after the QRS complex that reflects the repolarization of the ventricles.
 * The T wave and the QRS complex should always be in the same direction.
 * **PR interval:** the plateau between the P wave and the initiation of the QRS complex, where depolarization pauses at the bundle of His after depolarization of the atria and before depolarization of the ventricles.
 * The PR interval is also the index of conduction time across the AV node.
 * **QT interval:** The plateau after the QRS complex and the T wave, reflecting the period of time between depolarization and repolarization of the ventricles.
 * The QT time: total duration of depolarization and repolarization.
 * 4.** **Know the three types of atrioventricular block.**
 * **First degree block:** conduction delayed but all P waves conduct to the ventricles.
 * **Second degree block:** some P waves conduct, others do not.
 * **Third degree block:** none of the P waves conduct and a ventricular pacemaker takes over.
 * 5.** **Know the three major mechanisms by which disturbances in cardiac conduction cause tachyarrhythmias.**
 * **Abnormal reentry pathways:** present in the atria, ventricles or the junctional tissue. Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway. After the slow reentry the previously depolarized tissue has recovered and reentry into it will occur.
 * **The most common mechanism of serious tachycardias.**
 * **Ectopic foci:** when a focus of myocardium outside the conduction system acquires automaticity and if the rate of depolarization exceeds that of the sinus node an abnormal rhythm occurs. These can be isolated ectopic beats or sustained tachyarrhythmias.
 * **Triggered activity:** abnormal “afterpolarizations” may be triggered by the preceding action potential. Here, an early afterpolarization before the action potential has fully repolarized triggers tachyarrhythmia. Delayed afterpolarizations appearing after an action potential is complete can also trigger arrhythmias.

=Molecular Mechanisms of Arrhythmias=
 * 1.** **Describe the gene defects and molecular basis of long-QT syndrome**
 * **Long-QT syndrome:** prolongation of the duration of the cardiac action potential that leads to ventricular arrhythmia and sudden death. Prolongation of the plateau phase of the fast response action potential in ventricular myocytes initiates a ventricular tachycardiac called **torsades de pointes**, with subsequent syncope and sudden cardiac death.
 * **Gene defects**
 * More than 200 mutations have been identified and associated with the autosomal dominant form of Long-QT syndrome (Romano-Ward syndrome), with the most prevalent ones found in the slow cardiac K+ channel IKs (LQT1), the rapid cardiac K+ channel IKr (LQT2)and the cardiac Na+ channel INa (LQT3).
 * In the autosomal recessive form of long QT syndrome, Jervell-Lange-Nielson syndrome (JLNS), homozygous carriers of mutations in IKs (LQT1) suffer in addition from congenital deafness, which heterozygous carriers are asymptomatic.
 * **Molecular basis**
 * The mutations in the cardiac K+ channel subunits generally reduce the number of K+ channels expressed n the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current that helps terminate the plateau phase of the fast response and return the membrane to resting potential during diastole.
 * Mutations in the myocyte Na+ channel (INa) prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response.
 * Depending upon the molecular basis of the syndrome, therapeutic treatment out to employ entirely different kinds of drugs.
 * 2.** **List the cardiac ion channels and the phases of the slow and fast responses that are targeted by the various antiarrhythmic drugs**
 * **Class I antiarrhythmic drugs:** Na+ channel blockers
 * **Ia:** Na+ channel blockers; slow the upstroke of the fast response (phase 0), prolong refractory period (phase 4) because depolarization (phase 2) is prolonged.
 * **Ib:** Na+ channel blockers; slow upstroke (phase 0) mildly, shorten depolarization (phase 2) and prolong refractory period (phase 4).
 * **Ic:** Na+ channel blockers; pronounced slowing of the upstroke of the fast response (phase 0), mildly prolong depolarization (phase 2).
 * **Class II antiarrhythmic drugs:** beta-adrenergic receptor blockers à ¯ Ih, LTCC, and K+ current; reduces the rate of diastolic phase 4 depolarization in pacing cells, reduces the upstroke rate and slows repolarization.
 * **Class III antiarrhythmic drugs:** K+ channel blockers; prolongation of fast response phase 2 and prominent prolongation of refractory period.
 * **Class IV antiarrhythmic drugs:** Ca2+ channel blockers; slow the Ca2+ -dependent upstroke in slow response tissue (slow rise of action potential), prolong the refractory period (prolonged repolarization).
 * 3.** **Describe the cellular mechanism of triggered (early and delayed) afterdepolarizations.**
 * **Afterdepolarizations**
 * During prolonged phase 2, excessive Ca2+ entry triggers further Ca2+ release from the sarcoplasmic reticulum (CDCR). The pathologically elevated level of intracellular Ca2+ requires increased Na/Ca exchange via NCX1 exchanger. This electrogenic exchanger (3 Na+ in for 1 Ca2+ out) adds one positive charge to the inside of the myocyte on each exchanger cycle, which depolarizes the myocyte and thereby initiates delayed or early afterdepolarizations.
 * 4.** **Describe how a re-entrant, or circus, arrhythmia originates**
 * **Re-entry arrhythmia**
 * Initiation requires two conditions:
 * Uni-directional conduction block in a functional circuit.
 * Conduction time around the circuit is longer than the refractory period.
 * Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway. After the slow reentry the previously depolarized tissue has recovered and reentry into it will occur.
 * 5.** **Describe the basis of use-dependent block of Na+ channels by class I antiarrhythmic drugs.**
 * **Use-dependence:** the block of Na+ channels by class I antiarrhythmic drugs is optimized such that Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than Na+ channels in normal, healthy myocytes.
 * Channels must open before they can be blocked.
 * The channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel
 * Mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+channels.
 * 6.** **Describe how class I antiarrhythmics increase Na+ channel refractory period, whether or not they prolong phase 2 of the fast response.**
 * These drugs also have a higher affinity for the inactivated state of the Na+ channel. This means that these use-dependent blockers stabilize the inactivated state. That is, they prolong the time the channel spends in its inactivated state.
 * This prolongation of channel inactivation is the fundamental mechanism of prolongation of cellular refractory period, whether with Na+ channels in non-pacemaker cells or with Ca2+ channels in SA nodal or AV nodal cells.
 * **Alternative mechanism:** some class I drugs prolong the refractory period by a second, entirely different mechanism. This effect is a class III action exerted by class I drugs, and probably owes to K+ channel block.
 * Prolonging phase 2 means that the myocyte membrane is depolarized for a longer period of time and therefore more Na+ channels become inactivated, making the refractory period longer.
 * 7.** **Describe how beta-adrenergic receptor blockers help suppress arrhythmias**
 * The action of beta-blockers is to reduce Ih current, L-type Ca2+ current, and K+ current. Reduction of Ih, ICa,L and IK reduces the rate of diastolic depolarization in pacing cells, reduces the upstroke rate and slow repolarization.
 * Thus, pacing rate is reduced ( ¯ automaticity), and in addition, refractory period is prolonged ( ¯ reentry) in the SA and AV nodal cells.
 * Beta-blockers are used to terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.
 * 8.** **Describe how class III drugs increase refractory period**
 * These drugs work by blocking cardiac K+ channels. The consequences of which are prolongation of fast response phase 2, and a prominent prolongation of refractory period ( ¯ reentry). Prolongation of refractory period occurs because the prolonged duration of phase 2 leads to an increased inactivation of Na+ channels.
 * This mechanism of increasing refractoriness is different from the use-dependent block mechanism of all class I drugs, but is similar to the secondary mechanism of increasing refractoriness exhibited by class Ia drugs.
 * 9.** **Describe how increasing refractory period may help suppress re-entrant arrhythmias**
 * **How antiarrhythmic drugs suppress reentrant arrhythmias:**
 * **Terminating re-entry by slowing conduction velocity** **à** ** ¯ ** **upstroke rate:** A drug-induced reduction in upstroke rate results in a slower conduction velocity. Slower conducting action potentials are more likely to fail to propagate through a depressed region.
 * Unidirectional block can be converted to bi-directional block via this mechanism.
 * **Terminating re-entry by prolonging refractory period:** Prolonged refractoriness can help suppress re-entrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential, and so the re-entrant wave of excitation is extinguished.
 * 10.** **Describe how some antiarrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity.**
 * Some arrhythmias are generated by rogue cardiomyocytes that generate their own action potential without getting “directions” from the action potential propagated by the pacemaker cells of the AV or SA nodes.
 * Decreasing cardiac automaticity, generally by decreasing the rate at which a cell fires, ensures that cells do not generate their own “pacemaking” activity à thereby suppressing these arrhythmias.
 * Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.
 * 11.** **Describe how adenosine can help suppress cardiac arrhythmias.**
 * Adenosine forms its own unclassified category of antiarrhythmic drugs.
 * The action of adenosine is to increase a K+ current, while also decreasing both L-type Ca2+ current and Ih in SA and AV nodes.
 * Similar to beta-blockers.
 * Adenosine is NOT a beta-blocker. However, adenosine does work via Gi-coupled receptor, which inhibits adenylyl cyclase and cAMP production (thereby ¯ cAMP).
 * Adenosine induced changes in membrane currents cause a reduction in SA node and AV node firing rate as well as a reduced conduction rate in the AV node.

=Anti-Arrhythmic Drugs= See "Molecular Mechanisms of Arrhythmias" Vocabulary pharmacokinetics supraventricular arrhythmias ventricular arrhythmias defibrillation cardioconversion cardiac glycosides

=EC Coupling & Calcium I= · **NCX sodium/calcium exchanger:** exchanges 3 Na+ for 1 Ca2+ and can run in either direction—calcium efflux in exchange for sodium influx or calcium influx in exchange for sodium efflux. The direction in which is turn depends on both membrane potential and the gradients for sodium and calcium.
 * 1.** **Know the sequence of major events between the initiation of an action potential in a cardiac muscle fiber, through contraction (action potential spreads into t system, Ca2+ channel in t-membrane opens and allows entry of extracellular Ca2+, which triggers the opening of RyR2 in the SR membrane, Ca2+ ions leave SR lumen and enter myoplasm, bind troponin, allowing actin-myosin cross-bridge cycling and contraction.**
 * The release of Ca2+ originates at junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the plasma membrane, or plasma membrane invaginations termed transverse tubules (t-tubules).
 * Near the plasma membrane side of these junctions, Ca2+ enters the myoplasm via the dihydropyridine receptor (DHPR)—an L-type Ca2+ channel—and activates and opens the ryanodine receptor (RyR2) causing a much larger flux of Ca2+ from the sarcoplasmic reticulum (SR) into the myoplasm.
 * Ca2+ activates contraction by binding to troponin on thin filaments and allowing actin-myosin cross-bridge cycling.
 * 2.** **Understand the processes that control relaxation of contraction by removing of Ca2+ from the myoplasm (SERCA2 pumps are the most important, taking the majority of Ca2+ ions from myoplasm back into SR lumen). Next important is the NCX Na+/Ca2+ exchanger in the t-tubules/plasma membrane.**
 * **Relaxation is achieved via:**
 * Removal of Ca2+ from the myoplasm by:
 * **SERCA2** **pump:** located in longitudinal SR (2 Ca2+ per cycle); Ca2+ diffuses within SR to terminal cisternae, where it binds to calsequestrin.
 * SERCA2 dominates since SR surrounds each myofibril; requires less energy since VSR=0.
 * **NCX Na+/Ca2+ exchanger:** in the junctional domains of plasma membranes and t-tubules. Brings in 3 Na+ for every Ca2+ pumped out.
 * The NCX Na+/Ca2+ exchanged is next in importance and can be arrhythmogenic.
 * In steady-state, Ca2+ released from the SR is recycled back into SR by SERCA2, and surface extrusion balances L-type Ca2+ current.
 * 3.** **Know basic differences between EC coupling in skeletal and cardiac muscle.**
 * **Skeletal muscle:**
 * ECC **does not require** entry of external Ca2+
 * CaV1.1( a 1s), b 1a, a 2 d 1, g 1
 * RyR1
 * **Cardiac muscle:**
 * ECC **requires** entry of external Ca2+.
 * CaV1.2( a 1C), b 2a, a 2 d 1
 * RyR2
 * 4.** **Understand how the exchange of 1 Ca2+ ion for 3 Na+ ions, together with membrane potential and the sodium and calcium gradients, governs the direction of Ca2+ and Na+ movements via NCX. Understand why the extrusion of Ca2+ from the cytoplasm via NCX can cause membrane depolarization.**
 * **Vr=-74 mV**
 * **What does this mean?**
 * If the cell membrane potential is -74 mV, Ca2+ will be extruded until the [Ca2+]i falls to 100 nm at which point net movement via NCX will be zero.
 * If the [Na+]i were to increase (causing a ↓ in ENa and a negative shift in Vr), then the steady state level of [Ca2+]I would increase.
 * If a cell is at a membrane potential of -74 mV, a sudden increase in [Ca2+]I would result in a **net inward current** —as a consequence of Ca2+ extrusion.
 * This inward current would cause the cell to **depolarize**.
 * Depolarization triggered by Ca2+ release from the sarcoplasmic reticulum has the capacity to trigger arrhythmias.

=EC Coupling & Calcium II=
 * 1.** **Understand basic elements of calcium homeostasis in the myocardium.**
 * Except for short term increases or decreases, it is important that SR calcium content be kept roughly constant.
 * **Mechanisms of Calcium homeostasis:**
 * **NCX calcium exchanger**.
 * **L-type Ca2+ channe** l: undergoes a form of inactivation that depends on the concentration of Ca2+ near the cytoplasmic side of the channel.
 * **Calcium dependent inactivation (CDI)**
 * If the amount of Ca2+ in the SR increases, greater CDI causes less Ca2+ to enter via the L-type channel.
 * If the amount of Ca2+ in the SR decreases, less CDI causes more Ca2+ to enter via the L-type channel.
 * 2.** **Know how stimulation of β-adrenergic receptors increases both contraction strength, and rate of relaxation, of cardiac muscle.**
 * **Stimulation of β-adrenergic receptors** leads to elevation of cAMP and activation of PKA.
 * **Target of PKA:**
 * **L-type Ca2+ channel:** Phosphorylation of the channel increases the amplitude of the L-type Ca2+ current and thus increases the size of the trigger to activation of RyR2. The increase Ca2+ entry also helps to increase the quantity of Ca2+ stored in the SR. This contributes to positive inotropy.
 * **RyR2:** phosphorylation of RyR2 causes it to be sensitized to activation by trigger Ca2+. This contributes to positive inotropy.
 * **Phospholamban (PLB):** The association of PLB with SERCA2 inhibits Ca2+ pumping activity. Phosphorylation causes PLB to dissociate from SERCA2, which relieves the inhibition and thus increases Ca2+ pumping into the SR. This speeds relaxation and increases the quantity of Ca2+ stored in the SR. This contributes to both positive inotropy and positive lusitropy.
 * 3.** **Understand why Timothy syndrome mutations of the L-type Ca2+ channel could result in a lengthened cardiac action potential and why Brugada syndrome mutations of the L-type Ca2+ channel could result in shortened action potentials.**
 * **Timothy Syndrome:** disorder characterized by syncope, cardiac arrhythmias and sudden death, in addition to intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism.
 * Associated with de novo mutations in CaV1.2 (the principle subunit of the L-type Ca2+ channel).
 * One variant (TS) arises from the mutation G406R in exon 8a and another variant TS2 arises from two mutations (G402S and G406R) of exon 8 (which encodes the same region as exon 8a.
 * TS2 mutations profoundly suppress voltage-dependent inactivation.
 * Both TS and TS2 patients display AV block, prolonged Q-T intervals and episodes of polymorphic ventricular tachycardia.
 * **Brugada syndrome (also known as sudden unexplained death syndrome):** associated with a number of ECG alterations, which in some instances are revealed by administration of class IC anti-arrhythmics (sodium channel blockers) including ajmaline.
 * Associated with mutations of the cardiac sodium channel, KChip2 a modulatory subunit associated with Kv4.3 to produce IKto and several other proteins including ankyrin.
 * A subset of Brugada syndrome patients either have mutations in the principle subunit or a mutation in the main accessory subunit of the L-type Ca2+ channel.
 * These mutations appear to cause a large reduction in the magnitude of L-type Ca2+ current which may be a consequence of impaired membrane trafficking.
 * These patients have significantly shortened Q-T intervals.
 * 4.** **Know the mechanism whereby CPVT mutations, in combination with activation of β-adrenergic receptors, causes ectopic depolarizations.**
 * **Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT):** patients with CPVT do not display ECG abnormalities at rest, but do display abnormalities upon exercise or infusion of catecholamines.
 * Associated with causative mutations in RyR2—with dominant inheritance—and in the lumenal Ca2+ buffer calsequestrin2 (CasQ2)—with recessive inheritance.
 * RyR2 mutations increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2+.
 * Some homozygous CasQ2 mutations result in dramatic loss of luminal Ca2+ buffering, some result in no effect. CasQ2 has also been thought that have a role in the regulation of RyR2 function—this regulation may be altered in CPVT associated with CasQ2 mutations.
 * CPVT mutations + increased SR Ca2+ (increased as a consequence of activation of β-adrenergic receptors) is presumed to result in releases of Ca2+ that are not directly triggered by the L-type Ca2+ current during the plateau of the action potential but instead occur either shortly or long after repolarization.
 * Extrusion of the Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias.

=Cardiac Signaling Pathways=
 * 1.** **Describe the mechanisms by which PKA-mediated phosphorylation of L-type Ca2+ channels, ryanodine receptors, phospholamban, and troponin I affect inotropy and lusitropy.**
 * **L-type Ca2+ channels**
 * L-type Ca2+ channels on the plasma membrane are activated by depolarization. Influx of Ca2+ through these channels triggers a larger Ca2+ release from the SR via RyRs (Ca2+-induced Ca2+ release—CICR).
 * Sympathetic stimulation results in ↑cAMP and ↑PKA. PKA-mediated phosphorylation of L-type Ca2+ channels results in slowed inactivation. Thereby increasing the magnitude of the L-type Ca2+ channel induced influx of Ca2+ which results increases inotropy.
 * **Ryanodine receptors (RyRs)**
 * Sympathetic stimulation also results in PKA-mediated phosphorylation of RyRs, increasing RyR sensisitivyt to Ca2+, so that less Ca2+ is needed to evoke Ca2+ release. This increases intropy.
 * **Phospholamban (PLB)**
 * PLB is an inhibitor of SERCA (which removes Ca2+ from cytosol following contraction and pumps it back into the SR).
 * PKA-mediated phosphorylation of PLB results in PLB dissociation from SERCA, alleviating inhibition and increasing Ca2+ reuptake.
 * Faster Ca2+ reuptake directly ↑luistropy (the ability of the heart to relax) and ↑inotropy by increasing SR Ca2+ load.
 * **Troponin I (TnI)**
 * TnI is the inhibitory unit of the troponin complex (TnC, TnI, TnT), which along with tropomyosin inhibits the actin-myosin interaction in the absence of Ca2+.
 * Phosphorylation of TnI (TnI is phosphorylated by multiple kinases, including PKA) ↓Ca2+ sensitivity of TnC, which ↓inotropy; BUT also ↑ dissociation of Ca2+ from TnC, which ↑lusitropy—which allows the heart to fill more quickly, which is particularly important at higher heart rates.
 * 2.** **Describe how HCN channels, L-type Ca2+ channels, and GIRK channels contribute to autonomic control of heart rate.**
 * **Autonomic control of heart rate:**
 * **Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs)**
 * HCNs produce the cardiac funny current (If), which is an inward (depolarizing current) at diastolic potentials.
 * **Sympathetic stimulation** of the SA-node cells causes an increase in cAMP. cAMP binds directly to HCNs, shifting the voltage dependence of activation, making the channels more likely to open, thereby providing more inward current to speed the rate of diastolic depolarization.
 * **Parasympathetic stimulation** via ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o. Activation of Gi/o releases two signals: the G a i/o subunit and the G bg subunit complex.
 * The G a i/o subunit inhibits adenylyl cyclase, ↓intracellular cAMP. This has the oppositve effect of sympathetic stimulation→↓cAMP binding to HCN and ↓ in inward current via HCN→slowing heart rate.
 * **L-type Ca2+ channels**
 * Action potentials in nodal cells are “slow” Ca2+ action potentials, thus changes in the magnitude and voltage-dependence of Ca2+ channels impacts the spontaneous firing rate.
 * b -adrenergic stimulation increases L-type Ca2+ current and this effect is thought to contribute the sympathetic increase in heart rate.
 * **Sympathetic stimulation** increases SR Ca2+ load via PKA-mediated phosphorylation of L-type Ca2+ channels and RyRs. ↑SR Ca2+ load in nodal cells→↑spontaneous release rate→contributes to the diastolic depolarization by activating inward current through the sodium-calcium exchanger (NCX)
 * **Parasympathetic stimulation** via ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o. Activation of Gi/o releases two signals: the G a i/o subunit and the G bg subunit complex.
 * The G a i/o subunit inhibits adenylyl cyclase, ↓intracellular cAMP. This has the opposite effect of sympathetic stimulation→↓PKA mediated phosphorylation of L-type Ca2+ channels→↓SR Ca2+ load in nodal cells→↓spontaneous release rate→slowing heart rate.
 * **G-protein coupled inwardly-rectifying K+ (GIRK) channels**
 * The G bg subunit complex binds directly to GIRK channels to activate the IKACh current. IKACh is a K+ current, thus it hyperpolarizes the cell, driving the membrane potential toward the K+ equilibrium potential (away from the AP threshold), and slowing the spontaneous firing frequency.
 * This is the **primary mechanism for parasympathetic regulation of heart rate.**
 * 3.** **Describe the differences between vascular smooth muscle cells and cardiac myocytes.**
 * **Vascular smooth muscle cells (VSMCs)**
 * Small, mononucleated cells, which are electrically coupled via gap junctions.
 * Not striated, myofilaments are not arranged in the sarcomere.
 * Ca2+ release from the SR is not essential for contraction in VSMCs.
 * Rate of contraction is slower and contractions are sustained and tonic in VSMCs.
 * Contraction in VSMCs can be initiated by mechanical, electrical or chemical stimuli.
 * VSMCs do not have troponin.
 * **Cardiac Myocytes (CMs)**
 * CMs are striated and arranged in sarcomeres.
 * Ca2+ release from the SR is essential for contraction in CMs.
 * Rate of contraction is faster and unsustained in CMs.
 * 4.** **Describe the molecular steps involved in Ca2+ regulation of vascular smooth muscle contraction.**
 * **Ca2+ regulation of VSM contraction**
 * Ca2+ enters the cytoplasm from the SR (mainly) and from voltage-gated Ca2+ channels on the surface membrane.
 * Ca2+ binds to calmodulin (CaM), a ubiquitous intracellular Ca2+ binding protein.
 * Ca2+-CAM binds to myosin light chain kinase (MLCK), activating it.
 * Activated MLCK phosphorylates the light chain of myosin (the myosin head), which permits cross bridge cycling to occur.
 * Contraction halted by dephosphorylation of myosin light chain by myosin light chain phosphatase (MLCP).
 * cAMP causes relaxation of vascular smooth muscle cells, in contrast to its effect in cardiac myocytes, via PKA-mediated phosphorylation/inhibition of MLCK which reduces VSMC contraction.
 * 5.** **Describe the mechanisms by which sympathetic stimulation (via α1 adrenergic receptors) alters vascular tone.**
 * a 1 adrenergic receptors are GPCRs, which are coupled to the Gq G-protein.
 * G a q activates phospholipase C (PLC)→DAG and IP3.
 * IP3 activates IP3Rs on SR of VSMCs.
 * IP3Rs are intracellular Ca2+ release channels. Activation of IP3Rs ↑Ca2+ release from the SR.
 * ↑Ca2+ →VSMC contraction and vasoconstriction.
 * PKC (a Ca2+ -dependent protein kinase) phosphorylates many targets in VSMCs, including L-type Ca2+ channels, which in turn activates additional intracellular Ca2+ release (CICR).
 * 6.** **Describe the arterial baroreceptor reflex arc.**
 * **Arterial baroreceptors:** pressure-sensitive neurons in the aortic arch and carotid sinus.
 * Mechanosensitive epithelial Na+ channels (eNaC) open in response to mechanical stimulation (stretching induced by high blood pressure) and the ensuing Na+ current depolarizes the baroreceptor neurons, causing them to fire action potentials.
 * Baroreceptor neurons project to a sensory area of the “cardiovascular control center” in the brainstem. Distinct output areas of the CV center control sympathetic and parasympathetic output to the heart and vasculature.
 * **Arterial baroreceptor reflex arc:** ↑blood pressure→↑baroreceptor firing rate→↓sympathetic output and ↑parasympathetic output from the cardiovascular center→↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)→↓blood pressure.
 * The baroreceptor reflex is an acute short-term effect. Baroreceptors can adapt to prolonged changes in blood pressure by resetting to the new level over a time course of minutes to hours.
 * Sensitivity of the baroreceptor reflex ↓ in hypertension and aging, so there is less feedback response to changes in blood pressure.
 * 7.** **Name four tissue metabolites that control local flow to a capillary bed.**
 * **Vasoactive metabolites:**
 * **↓ PO2**
 * **↑PCO2/pH**
 * **↑K+:** in active skeletal muscle, Na+ enters cell and K+ leaves during action potentials. With a high level of activity, the Na+/K+-ATPase can’t keep up, so K+ accumulates in interstitial space.
 * **↑Adenosine:** Adenosine is used by hydrolysis of ATP. In VSMCs, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs. Thus, adenosine ↑cAMP levels in VSMCs causing vasodilation by inhibition of MLCK.
 * 8.** **Describe the myogenic response.**
 * The myogenic response is a feedback mechanism designed to maintain constant flow despite changes in pressure.
 * Mechanism is intrinsic to VSMCs—occurs in denervated vessels and is independent of vascular endothelium.
 * Stretch causes VSMC contraction by opening stretch-activated ion channels, which depolarize the VSMC, thereby ↑intracellular Ca2+ via L-type Ca2+ channels.
 * 9.** **Describe how nitric oxide and endothelin regulate vascular smooth muscle tone.**
 * **Nitric oxide (NO) regulation of VSM tone**
 * Many humoral regulators (ie ACh) stimulate activity of nitric oxide synthase (NOS) in vascular endothelial cells. Nitric oxide readily diffuses across the endothelial and vascular smooth muscle cell membranes. In VSMCs, NO activates guanylate cyclase→↑cGMP. cGMP activates PKG→↓intracellular Ca2+ via activation of SERCA and inhibition of L-type Ca2+ channels. ↓Ca2+ concentration causes relaxation of the VSMC (vasodilation).
 * NOS is highly susceptible to cardiovascular disease risk factors (oxidative stress, cigarette smoke)
 * Basal release of NO helps set resting vascular tone (↓NO→↑BP)
 * NO is anti-atherosclerotic and inhibits many steps in the development of plaques and ↓NO is associated with greatly increased risk for atherosclerosis.
 * Hypertensive patients often have ↓NO, which worsens there condition.
 * **Endothelin regulation of VSM tone**
 * Endothelin is a potent vasoconstrictor produced by the vascular endothelium.
 * Endothelin binds to ET receptors, GPCRs primarily coupled to Gq. Endothelin response is similar to the a -adrenergic response, but the time course is different.
 * Endothelin has both transient effects and longer lasting effects.
 * 10.** **Describe the renin-angiotensin-aldosterone system and how it regulates blood pressure.**
 * **Renin-Angiotensin-aldosterone system:** critical system for regulation of blood volume, mediated by the kidney.
 * **Renin:** released into circulation by the juxtoglomerular cells when stimulated by (1) sympathetic stimulation of JG cells; (2) decreased blood pressure in the renal artery; and (3) decreased sodium reabsorption in the kidney.
 * Renin cleaves the circulating inactive protein angiotensinogen to angiotensin I (AI)—another inactive precursor.
 * AI is then cleaved by angiotensin converting enzyme (ACE) to form the active peptide, angiotensin II (AII).
 * ACE: important therapeutic target for treatment of hypertension and heart failure—ACE inhibitors.
 * **Direct effects of AII** : AII is a potent systemic vasoconstrictor which acts via binding to GPCRs on VSMCs.
 * **Indirect effects of AII:** (1) stimulates sympathetic activity→↑vasoconstriction; (2) ↑aldosterone release from adrenal cortex; (3) stimulates release of endothelin from vascular endothelium→↑vasoconstriction; and (4) stimulates release of ADH from the pituitary.
 * **Aldosterone:** promotes sodium and water reabsorption in the kidney→↑blood volume→↑blood pressure.
 * **Anti-Diuretic Hormone (ADH—arginine vasopressin):** formed in hypothalamus, released by pituitary. ↑water reabsorption in the kidney; ↑peripheral vasoconstriction during systemic shock.
 * 11.** **Describe the origin and effects of atrial natriuretic peptide on blood pressure.**
 * **Atrial natriuretic peptide (ANP)**
 * Vasodilator peptide release by atria following mechanical stretch→endocrine function of the heart.
 * Involved in long-term sodium regulation and water balance, blood volume, and arterial pressure.
 * ANP acts on ANPRs throughout the body. ANPRs are receptor guanylate cyclases (NOT GPCRs_ that produce cGMP, which activates SERCA to stimulate Ca2+ uptake.
 * Kidney: ↑glomerular filtration rate and ↑secretion of sodium and water.
 * Vasculature: ↑ vasodilation
 * Adrenal gland: inhibits release of aldosterone and renin release.

=Vascular Signaling Pathways= Please see learning objectives under "Cardiac Signaling Pathways" Vocabulary striated muscle vascular smooth muscle vascular endothelial cells nitric oxide nitric oxide synthase paracrine myogenic autoregulation recumbent

=Exercise & CV System Physiology= See for the equations
 * 1.** **Describe the Fick equation and how its components relate to the circulatory responses to dynamic exercise.**
 * **Fick equation:**
 * The Fick equation is the unifying concept between the respiratory and circulatory systems.
 * The total cardiac output is described by the total volume of oxygen that is taken in divided by the oxygen delivered to tissue (the difference between the arterial oxygen concentration and the venous oxygen concentration).
 * 2.** **Describe the phases of the cardiac cycle and the effect of heart rate on ventricular filling and contraction. What is stroke volume? Ejection fraction?**
 * **Systole:** contraction phase. At rest 2/3 of the ventricular volume is ejected in systole with 1/3 remaining in the ventricle.
 * **Diastole:** filling and relaxation of the ventricle. During exercise the increase in heart rate results in a decrease in diastolic filling time. The duration of systole is also affected but not as much as diastole.
 * **Stroke volume:** LVEDV-LVESV = stroke volume. The volume of blood ejected with each ventricular contraction.
 * **Ejection fraction:**
 * The proportion of the total volume of blood that can fill the left ventricle that is ejected with each contraction.
 * 3.** **Describe the heart rate response to exercise and the influence of the autonomic nervous system on heart rate during exercise.**
 * At rest, a typical heart rate in an untrained person is 60-80 bpm. In an endurance athlete the resting heart rate can be as low as 28-40 bpm.
 * **Anticipatory Response:** Just prior to the beginning of exercise the heart rate is often increased compared to a true resting heart rate. This is caused by sympathetic stimulation as a result of central command in the brain preparing the circulatory system for exercise.
 * **Heart rate during exercise:**
 * The increase in heart rate is directly related to exercise intensity.
 * There is a linear response of heart rate to workload up to near maximal exercise.
 * Maximal exercise heart rate is highly reproducible: 220-age. After 15 years, maximal heart rate decreases by 1 bpm annually.
 * During lower levels of exercise, the increase in heart rate up to 100 bpm is related to **parasympathetic withdrawal.** At rates above 100 bpm, during moderate to heavy exercise, the heart rate is controlled by **sympathetic activity.**
 * When heart rate increases with exercise, there is an increase in stroke volume caused by a combination of vasodilation, increase in venous return, and venoconstriction. All these factors lead to preservation of ventricular filling.
 * 4.** **Describe the factors responsible for changes in stroke volume during exercise. What is the Frank Starling relationship? What is ventricular compliance? How does the stroke volume response during exercise differ between untrained persons and elite athletes?**
 * **Stroke volume and exercise:** Defined as EDV-ESV. Stroke volume increases during exercise up to workloads 40-60% of maximal exercise and then stroke volume reaches a plateau with no further increases.
 * Factors that influence stroke volume:
 * **End-diastolic volume (EDV** )/cardiac preload. Both venous return and ventricular distensibility are important in maintaining cardiac preload.
 * **Strength of contraction** (contractile state).
 * **Aortic or pulmonary pressure**, depending on the ventricle of interest. This is cardiac afterload.
 * **Venoconstriction:** this is the result of reflex sympathetic control of vascular smooth muscle. The majority of blood at rest is in the venous return channels.
 * **Muscle pump:** component of venous return during dynamic exercise—however, not operative in isometric exercise where sustained muscle contraction leads to a reduction in venous return.
 * **Respiratory pump:** major factors for venous return in upright exercise. Negative thoracic pressure aids venous return to the heart.
 * **Frank Starling relationship (aka Starling’s Law of the Heart):** The force of contraction is proportional to the initial resting length. With an increase in EDV there is an increase in stroke volume on the steeper portion of the curve. If the curve is shifted to the left, then there will be a greater increase in stroke volume for any EDV value.
 * **Ventricular compliance:** Compliance is the relationship between the change in pressure and the change in volume. The steeper the curve, the greater the cardiac pressure in diastole at any level of EDV.
 * This limits performance due to the effects of the greater intracardiac filling pressures.
 * Mechanisms of enhanced ventricular contractility enhances the stroke volume response to exercise. There are two main factors responsible for the enhanced contractility:
 * ↑SNS activity: as a result of both direct innervation and elevation in circulating catecholamines.
 * Frank Starling Effect: ↑stretch of ventricular muscle fibers that lead to ↑contractility.
 * **Stroke volume in elite athletes vs. untrained persons:** In sedentary subjects the resting stroke volume (50-60 mL) doubles to values of 100-120 mL during exercise. In endurance athletes there is greater resting stroke volume (80-110 mL) with a doubling to values of 160-200 mL. In more elite athletes who either are genetically endowed or have trained for many years, stroke volume continues to increase throughout exercise. This change in stroke volume is responsible for the greater cardiac output responses in these subjects.
 * The mechanism for this response has been explained as an increase in EDV with enhanced Starling forces at lower levels of exercise and increased ventricular contractility at higher levels of exercise.
 * 5.** **Describe the cardiac output response to exercise in untrained and trained persons.**
 * The increase in cardiac output during incremental exercise is proportional to the metabolic rate and VO2 required to perform the exercise. There is a linear relationship between cardiac output and % VO2 max.
 * With upright exercise at workloads <50% VO2 max both increases in heart rate and stroke volume are responsible for the increase in cardiac output.
 * At workloads >50% VO2 max only increases in heart rate are responsible for the increase in cardiac output.
 * The exception is elite athletes who increase their stroke volume throughout exercise. At maximal exercise trained persons have the same maximal heart rate as untrained persons but they have a greater stroke volume.
 * 6.** **What is the relationship between blood flow, arterial pressure, and resistance? What is the equation for vascular resistance? What is Poiseuille's Law?**
 * Blood flow through the circulatory system depends on differences in pressure at two ends of the system. The rate of flow is proportional to the pressure difference. The largest pressure drop occurs across the arterioles.
 * **Blood flow = Change in pressure / resistance.** During exercise the increase in blood flow is accomplished by a decrease in vascular resistance and not an increase in blood pressure.
 * **Systemic vascular resistance = (MAP – RAP)/cardiac output**
 * **Resistance = (length x viscosity)/radius4**
 * **Poiseuille’s Law:** Flow = (pressure gradient x vessel radius4)/(vessel length x fluid viscosity)
 * The vessel diameter is under dynamic control with SNS controlling blood flow in both nonexercising and somewhat in exercising muscle beds. The main determining factor of regulating blood flow in exercising muscle beds is autoregulation. This is local blood flow regulation involving substances released locally at the time of exercise.
 * 7.** **Describe the response of blood pressure during exercise and its regulation.**
 * Mean Arterial Pressure (MAP) is the average blood pressure during a cardiac cycle. This is not an average of systolic and diastolic blood pressure as more time is spent in diastole.
 * MAP = diastolic BP + 0.33 (SBP – DBP); MAP determines the rate of blood flow through the systemic circuit.
 * Blood pressure is increased by elevations in one or several of the following factors:
 * ↑blood viscosity
 * ↑blood volume
 * ↑Heart rate
 * ↑stroke volume
 * ↑peripheral resistance.
 * Blood pressure is regulation by:
 * Acutely: SNS→major regulation mechanism during exercise.
 * Long-term: kidneys control of blood volume. Arterial baroreceptors in the carotid body and the aortic arch are activated by increases or decreases in blood pressure. The baroreceptors send nerve impulses to the cv control center in the medulla, and this center regulates sympathetic activity that relates to both heart rate and blood pressure.
 * During incremental exercise systolic blood pressure rises along with cardiac output and heart rate. There is little change in diastolic blood pressure. MAP increases due to the rise in systolic pressure.
 * 8.** **Explain how the redistribution of blood flow during exercise contributes to an increase in muscle blood flow. How does the coronary circulation differ from the systemic circulation?**
 * At rest, skeletal muscle blood flow is 15-20% of total cardiac output, while during exercise muscle blood flow increases to 80-85%.
 * This great increase in blood flow is accomplished by vasodilation in the exercising muscle bed and vasoconstriction of non-exercising vascular beds with redirection of blood flow to exercising muscle.
 * Splanchnic blood flow the liver, kidneys and intestines decreases in response to the increase in muscle blood flow as a function of % VO2 max.
 * The blood flow to the brain is maintained during exercise. The absolute blood flow increases slightly during exercise as compared to rest. However, the % of total cardiac output decreases. At rest, blood flow is 15% of the resting cardiac output (5L/min). During exercise brain blood flow is 3-4% of cardiac output.
 * **Coronary circulation vs. systemic circulation:** coronary blood flow increases during exercise in proportion to the increase in cardiac output. Myocardial oxygen consumption (MVO2) is also a reflection of increases cardiac work. There is a high level of oxygen extraction by the resting myocardium, this is countered with increased coronary blood flow.
 * **Only skeletal muscle and coronary blood flow increase during intense exercise.** All other inactive vascular beds have decreased blood flow. In hot, humid conditions, skin blood flow also increases as a means to regulate temperature.
 * 9.** **Describe the concept of oxygen delivery and factors that can enhance it during exercise?**
 * **Oxygen delivery during exercise is governed by the following relationships:**
 * O2 delivery = blood flow x arterial O2 content.
 * Blood flow = cardiac output x heart rate
 * Arterial O2 content = [Hgb] x 1.34 x O2 saturation (%)
 * Aspects of blood oxygen:
 * PaO2 (partial pressure, mmHg): driving force of tissue oxygenation. Gradient of oxygen from arteriole→capillary→tissue→vein.
 * CaO2 (content, ml/100mL): bulk quantity of deliverable.
 * SaO2 (content/capacity, %): relative quantity of oxygen.
 * **Approaches to increase oxygen delivery during exercise:**
 * Exercise training: increases in blood flow.
 * Blood doping: increases in the arterial concentration of oxygen.
 * Blood transfusion, EPO injections, high altitude exposure.
 * **Intrinsic mechanisms to increase oxygen delivery during exercise:**
 * Hemoconcentration during exercise: There is a 10-20% decrease in plasma volume during exercise.
 * Onset: ↓plasma volume with ↑fluid in interstitial space.
 * Elevated bp during exercise forces fluid into the interstitial space. Metabolic waste products during muscular contraction ↑intramuscular osmotic pressure→↑fluid accumulation.
 * Overall, 10-20% ↓plasma volume depending upon intensity and duration of exercise→↑RBC concentration→↑oxygen carrying capacity.
 * A rightward shift in the oxygen dissociation curve.
 * ↓PO2; ↓PaO2; ↓blood pH; ↑body temperature.
 * 10.** **What is the role of the arterial-venous O2 content difference at maximal exercise? How does the increase in a-v O2 difference compare to the increase in cardiac output during exercise?**
 * According to the Fick Equation, changes in the arteriovenous oxygen content difference can also affect oxygen consumption:
 * VO2=cardiac output x (a-v) VO2
 * At rest, the arterial oxygen content is 20 mL per 100 mL of blood while the venous oxygen content is 15-16 mL per 100 mL of blood.
 * The a-v O2 difference at rest is around 5 mL O2 per 100 mL of blood.
 * At high intensity exercise, the arterial oxygen content is unchanged as it does not usually change with exercise. However, the venous oxygen content can drop as low as 5 mL O2 per 100 mL of blood.
 * The a-v O2 content is 15 mL O2 which represents a three-fold increase over resting values.
 * Compared to cardiac output (which exhibits a 4-5 fold increase in cardiac output), the a-v O2 only undergoes a three-fold increase.
 * 11.** **Describe the regulation of circulatory adjustments to exercise. What is the exercise pressor reflex?**
 * **Regulation of circulatory adjustments to exercise:**
 * Initial sign—central command (higher cerebral center)
 * Cardiovascular control center—medulla
 * Exercise pressor reflex—peripheral feedback to cardiovascular control center from heart, vasculature, and skeletal muscle.
 * **Modulating “feedback” systems:** fine tuning
 * Heart mechanoreceptors: sensitive to intracardiac pressures.
 * Muscle chemoreceptors (K+, lactate)
 * Muscle mechanoreceptors (sense force and speed of muscle contraction)
 * Pressure-sensitive receptors (baroreceptors): in carotid body and aortic arch.

=Exercise Training and the CV System=
 * 1.** **Describe the contribution of the cardiovascular, respiratory, skeletal muscle, and autonomic nervous system to the physiology of exercise.**
 * **Cardiovascular system:** central cardiac adaptations include an increase in cardiac output related to increases in both heart rate and stroke volume.
 * **Respiratory system:** Both tidal volume and respiratory rate increase with progressive exercise.
 * Minute ventilation increases in proportion to workload up until the ventilatory threshold. After that time there is an increase in the ratio of ventilation to oxygen consumption while the ratio between ventilation and VCO2 (CO2 production) is unchanged. More ventilation is needed to eliminate CO2 from cellular processes.
 * **Skeletal muscle:**
 * The fiber type of skeletal muscle has a major influence on the development of fatigue, the use of energy substrates, and the need for blood flow and oxygen.
 * **TYPE 1:** “slow twitch” due to their response to neural stimulation. They are more fatigue resistant and are considered “aerobic fibers”. This fiber type is enhanced in its function by endurance. The soleus muscle is a type 1 fiber muscle.
 * **TYPE 2:** “fast twitch” and muscle with this fiber type are designed to respond to rapid, short-lived contractions and are considered “anaerobic” fibers. They are more susceptible to fatigue. They are usually larger than type 1 fibers and have fewer surrounding capillaries and fewer mitochondria. The triceps muscle is a type 2 fiber muscle. These fibers hypertrophy in response to resistance training.
 * Oxidative metabolism is more productive in the generation of ATP but requires oxygen and increases in blood flow. Glycolytic metabolism does not require oxygen and the muscle can function for a limited time with recruitment of the respiratory and cardiovascular systems.
 * **ANS:** During exercise there is predominantly sympathetic stimulation with parasympathetic withdrawal. Beta-adrenergic sympathetic stimulation has a major role in the increases in heart rate, contractility and afterload effects.
 * 2.** **Describe the importance of VO2 max in the determination of exercise performance and the factors that influence this measurement. What is the ventilatory (anaerobic) threshold and how does it relate to exercise performance?**
 * **Maximal oxygen consumption—VO2 max.**
 * VO2 increases with workload until a plateau is reached where further increases in workload do not result in an increase in VO2. This has been designated as VO2 max and is the ultimate descriptor of exercise capacity.
 * Many people, especially those with CVD, are unable to obtain a plateau during exercise, and therefore reach what is described as a “peak VO2­”
 * The cardiovascular system is obviously crucial in adapting to exercise and increasing the VO2. However, many other systems are involved in establishing and maintaining oxygen delivery.
 * Must be able to transfer atmospheric oxygen from the lungs to blood
 * Must be able to extract and utilize the provided oxygen at the site where it is needed—skeletal muscle.
 * **Ventilatory (anaerobic) threshold:** the workload at which there is unexcessive ventilation.
 * **Below the threshold:** steady-state exercise, less metabolic and ventilatory stress, less SNS activation.
 * **Above the threshold:** non stead-state exercise, progressive rise in VO2, HR and BP, progressive increase in metabolic and ventilatory stress, and an increase in SNS activation.
 * 3.** **Describe the Fick equation and its relevance to the cardiovascular and peripheral circulatory and skeletal muscle responses to exercise.**
 * **Fick equation:** the link between cardiovascular function and respiratory measurements:
 * VO2=cardiac output x (a-v) VO2
 * Cardiac output: blood flow
 * CaO2: [Hgb] x 1.34 x O2 saturation (%)
 * CvO2: [Hgb] x 1.34 x venous O2 saturation (%)
 * Cardiovascular response to exercise is described by the cardiac output (HR x SV)
 * Peripheral circulatory and skeletal muscle response to exercise is described by the difference between arterial and venous VO2 concentrations—as this is the amount of oxygen that is being used by the peripheral skeletal muscle.
 * 4.** **Describe how skeletal muscle contributes to exercise performance.**
 * **Skeletal muscle:**
 * The fiber type of skeletal muscle has a major influence on the development of fatigue, the use of energy substrates, and the need for blood flow and oxygen.
 * **TYPE 1:** “slow twitch” due to their response to neural stimulation. They are more fatigue resistant and are considered “aerobic fibers”. This fiber type is enhanced in its function by endurance. The soleus muscle is a type 1 fiber muscle.
 * **TYPE 2:** “fast twitch” and muscle with this fiber type are designed to respond to rapid, short-lived contractions and are considered “anaerobic” fibers. They are more susceptible to fatigue. They are usually larger than type 1 fibers and have fewer surrounding capillaries and fewer mitochondria. The triceps muscle is a type 2 fiber muscle. These fibers hypertrophy in response to resistance training.
 * Oxidative metabolism is more productive in the generation of ATP but requires oxygen and increases in blood flow. Glycolytic metabolism does not require oxygen and the muscle can function for a limited time with recruitment of the respiratory and cardiovascular systems.
 * 5.** **Describe the cardiovascular, respiratory, and skeletal muscle adaptations associated with aerobic exercise training.’**
 * **Cardiovascular adaptations:** in general, the VO2 is greater and at a higher workload; heart rate at maximal exercise is unchanged and O2 extraction is greater at maximal exercise due to greater vasodilation, improved vascularity and skeletal muscle adaptation. Stroke volume increases at rest, during submaximal and maximal exercise. Thereby cardiac output at maximal exercise increases due to increases stroke volume with no increase in heart rate. This increase in blood flow contributes to increase O2 delivery to exercising muscle.
 * **Rest:** ↓HR, ↓BP, ↑SV (LVEDV – LVESV), ↑LV diastolic volume, no to slight increase in CO, ↓systemic vascular resistance, ↑PSN tone, ↓SNS tone, ↓ to no change in CmvO2, no change in resting VO2.
 * **Submaximal exercise:** ↓HR, ↓BP, ↑SV (LVEDDD – LVESV), ↑LV diastolic volume, ↑CO, ↓systemic vascular resistance, ↑SNS activity, ↓ in CmvO2, no change in absolute VO2 at a given workload, ↓ in relative % of VO2 max.
 * **Maximal exercise:** ↑VO2 max, ↑CO, no increase to slight decrease in HR, ↑SV (↑LVEDV and ↓LVESV), ↓systemic vascular resistance, no change to ↓↑ in systemic BP, no change to ↑ in SNS activity, ↓ CmvO2
 * **Respiratory adaptations:**
 * ↓ in minute ventilation for any given VO2 (absolute and relative workloads) which is most pronounced at workloads above the ventilatory (lactate) threshold.
 * ↑ VO2 and % VO2 max at the ventilatory threshold.
 * ↑CO2 elimination by the lungs, related to an increase in tidal volume.
 * No change in oxygenation (SaO2).
 * **Skeletal muscle adapations:**
 * ↑mitochondrial biogenesis
 * favorable alterations in substrate metabolism:
 * ↑insulin sensitivity and glucose transport.
 * ↑substrate availability
 * ↑lactate kinetics.
 * ↑oxidative metabolism
 * ↑ production of oxidative enzymes
 * ↑PCr kinetics.
 * Fiber type transformation: type 2→type1
 * ↑vascularity
 * arteriogenesis (↑# and diameter of conduit vessels)
 * angiogenesis (↑# of capillaries).
 * 6.** **Describe the similarities and differences in adaptation with exercise training in normal subjects and patients with cardiovascular disease.**
 * **Adaptation to exercise in patients with CVD:**
 * Risk factor modification: ↓ BP, favorable effects of lipids, ↓weight, ↑glycemic control.
 * Direct cardiac adaptations: ↑cardiac function, ↑LVEF
 * Favorable effects on heart rate, catecholamines, and VO2
 * ↓SNS activity, ↑PSN activity
 * ↓in % VO2 during submaximal exercise.
 * ↑anginal threshold.
 * ↑myocardial perfusion.
 * 7.** **Describe the potential clinical benefits of exercise training in patients with cardiovascular disease.**
 * **Clinical benefits:**
 * Antiatherogenic effects
 * Reduction in adiposity (upper body and abdominal)→reduce obesity
 * Reduction in systemic blood pressure.
 * ↓triglycerides and LDL, ↑HDL
 * ↑insulin sensitivity, ↑glucose transport.
 * ↓ inflammation (lower CRP and cytokines)
 * ↑endothelial-dependent vasodilatory mechanisms.
 * Antithrombotic effects: enhanced fibrinolytic system.
 * ↑plasma volume
 * ↓blood viscosity
 * **↓** platelet aggregation
 * Enhanced endothelial function: enhanced vasodilatory capacity.
 * Favorable effects on ANS function: ↑PNS, ↓SNS
 * ↑heart rate variability
 * Anti-ischemic and antiarrhythmic effects: ↓myocardial O2 demand (HR and BP), ↓ SNS tone.

=Preserving Cardiac Output in Acute Stress= (No LOs for this lecture)
 * **Calcium handling processes in cardiocytes:**
 * Cardiocytes can regulate the availability and levels of cytosolic calcium over three orders of magnitude in milliseconds→amazing.
 * Calcium Calcium Calcium→drug targets, drug targets, drug targets
 * SERCA2: a SR pump responsible for storing Calcium in the SR.
 * Regulated by phospholamban
 * Calcium stored in the SR are bound by calsequestrin→creates a gradient that helps SERCA2 pump calcium across the SR membrane.
 * With each heart beat, calcium is released from the SR via RyRs via Calcium dependent calcium release (CDCR).
 * Calcium enters from external space through the LTCC, which is very close to the RyR. Increases Calcium causes RyR to allow a HUGE unleashing of calcium from the SR→this calcium can then associate with the myofilament such that contraction can take place.
 * Maintenance of calcium levels in the cardiocyte→regulated by LTCC and NCX.
 * Changes in sensitivity of these things are related to the pathophysiology of many disease processes of the heart.
 * **Cardiac sarcomeric proteins.**
 * **Myofilament:**
 * thick filament→myosin
 * thin filament→actin and associated regulatory proteins (TrC, TrI, TrT)
 * Calcium binds troponin C and causes a structural change which allows troponin I to swing down and lift up troponin T which then moves tropomyosin out of the way such that myosin is now able to bind actin.
 * ATP-hydrolysis mediated shortening of the myofilament can then occur.
 * ↓ calcium results in a removal of calcium from troponin c, resulting in a reversal of the conformational changes seen with increased calcium→inhibits binding of myosin to actin and myofilament contraction.
 * Too much calcium results in shortening with impaired relaxation.
 * Too little calcium results in no shortening.
 * **Cardiac muscle is uniquely calcium sensitive**
 * Increased calcium sensitivity results in an increased force that can be generated for the same amount of calcium.
 * Many factors can influence calcium sensitivity→pH, temperature, sarcomere length, contractile protein phosphorylation, caffeine, etc.
 * **Effects of phosphorylation on calcium sensitivity**
 * PKC→depresses force generation
 * PKA→changes the velocity of contraction and calcium sensitivity→alters the contractility of the myocardium
 * Take home message: signaling processes present within the heart can influence the maximal force generated by myofilament and can generate sensitivity of the myofilament to calcium.
 * **There are three mechanisms by which the heart can moderate its performance acutely:**
 * Length-dependent activation→Frank-Starling relationship
 * Respond to inotropes and change contractility
 * Change heart rate.
 * **The Frank-Starling Law of the Heart.**
 * ↑length→↑tension
 * The greater the volume of blood entering the heart during diastole (EDV), the greater the volume of blood ejected during systolic contraction (SV) and vice versa.
 * **Plausible cellular basis for the Frank-Starling Relationship**
 * How does this translate to the molecular level of the myocyte?
 * Hypothesis: ↑sarcomere length→↑Ca2+ sensitivity→↑force of contraction.
 * How? When the muscle length is short, interactions between actin and myosin are not as plentiful as when the muscle is longer.
 * Chinese finger trap analogy.
 * Actin/myosin interactions are the basis for contraction.
 * Another hypothesis: myocyte stretch ↑ Ca2+ efflux → ↑contractility.
 * **Impact of positive inotropes on cardiac muscle mechanics:**
 * Response of the heart to inotropes: ↑contractility and ↑ force of contraction at a given muscle length.
 * Beta-adrenergic agonists are the primary cardiac inotropes
 * BIG PICTURE: all of this eventually increases STROKE VOLUME.
 * **Beta-adrenergic signaling**
 * Stimulation of the beta-adrenergic receptors ↑cAMP → ↑PKA.
 * PKA phosphorylates:
 * LTCC: ↑calcium entry into the cell; increases on relative to off→↑CDCR.
 * PLB: inhibitory protein of SERCA; phosphorylation ↓ inhibition of SERCA→↑reuptake of calcium into the SR
 * Beta-adrenergic regulation enhances CYCLING→RyR pumping calcium OUT of the SR and SERCA pumping calcium IN to the SR→both of these processes are necessary for contraction and release.
 * **Major coordinate responses of heart muscle to beta adrenergic stimulation**
 * Allows heart to CONTRACT AND RELAX more vigorously.
 * Phosphorylation of Ca2+ channels (SAN cells)→↑HR→↑CO
 * Phosphorylation of LTCC (ventricular cells)→↑Ca2+ entry and ↑ force of contraction→ improves EF (+ inotropy).
 * Phosphorylation of NCX→↑Ca2+ efflux (via Na-Ca exchange)→ enhanced relaxation and diastolic filling.
 * Phosphorylation of PLB→disinhibition of SERCA2 and ↑SR calcium load→improved diastolic filling.
 * Phosphorylation of FKB→↑RyR receptor mediated calcium release→enhanced contractility.
 * Phosphorylation of troponin I→↓Calcium affinity for TnC→enhanced relaxation.
 * **Postural Accommodation:**
 * When you stand up, gravity naturally pulls blood to your feet.
 * Muscles in legs contract and create a venous pump to increase venous return such that you don’t pass out.
 * ↑EDV→↑Stroke volume.
 * **Isotonic exercise**
 * ↓ Peripheral vascular resistance→in anticipation of exercise
 * ↓ Afterload→↑cardiac output
 * Increase venous return→frank-starling→↑preload→↑SV
 * Increase heart rate (adrenergic tone)→↑Ca2+ in the SA node.
 * Increase inotropy (SR calcium ↑ and ↓)
 * EDV doesn’t change, ESV changes.
 * **Isometric exercise**
 * Increased peripheral vascular resistance (in order to maintain blood flow to exercising muscle group)→↑afterload.
 * ↑HR→makes up for ↓SV.
 * No ↑ or ↓ in CO.
 * Volumes don’t change, but point at which aortic valve opens ↑, because afterload ↑ and diastolic ↑, stroke volume↓

=Heart Failure and Hypertrophy= No LOs available

=Diagnostic Features of the EKG=
 * 1.** **Review the anatomy and function of the cardiac structures responsible for generation and spread of cardiac depolarization which produce the normal heart beat**
 * The sinoatrial (SA) node is the pacemaker of the heart. Electrical impulses initiated by the SA node proceed through the internodal tracts which activates a wave of depolarization in the atrium that converges on the atrioventricular (AV) node. Here, there is a brief delay, after which impulses are sent rapidly towards the Bundle of His and activate the ventricles through the right and left bundles (the left bundle also further splits into anterior and posterior segments). The impulses then diverge into Purkinje fibers which activate ventricular myocardial cell depolarization and contraction.
 * 2.** **List the clinically relevant components of the normal EKG. Understand their functional actions.**
 * **P wave:** atrial depolarization.
 * **PR interval (from the beginning of P to beginning of Q):** measure of AV node conduction time. Normal PR interval is 0.12 to 0.20 seconds.
 * **QRS complex:** ventricular depolarization. Duration is normally 0.06-0.10 seconds.
 * **Q:** negative
 * **R:** positive
 * **S:** late negative deflection
 * **QT interval (from beginning of Q to the end of T):** total duration of depolarization and repolarization.
 * **T wave:** ventricular repolarization
 * **U wave:** not constantly present.
 * **Other things to know:** Paper speed is 25 mm/second. Thin vertical lines are 0.04 seconds apart and thick vertical lines are 0.2 seconds apart.
 * **Heart Rate:** 300/# of heavy lines.
 * 3. Describe the EKG changes produced by:**
 * **Ventricular Hypertrophy:** both left and right ventricular hypertrophy result in greater muscle mass. Greater muscle mass results in a greater voltage associated with depolarization and repolarization of the myocardium. Therefore, on an ecg ventricular hypertrophy is seen as a R wave with greater amplitude.
 * **Left ventricular hypertrophy:** large positive deflections (R waves) in V5 and V6 and large negative deflections (S waves) in V1.
 * **Right ventricular hypertrophy:** high voltage in V1 and V2.
 * **Myocardial Ischemia:** Ischemia occurs when blood supply is insufficient to meet oxygen demand in the ventricles. Ischemic changes in the EKG alter ventricular repolarization and affect the ST segment and the T wave. Ischemia due to sudden high oxygen demand in the presence of a fixed coronary obstruction causes depression of the ST segment. Ischemia due to acute coronary artery obstruction during low oxygen demand can cause T wave inversion.
 * In some patients a resting ekg is normal, but ST depression is only visible during exercise due to transient ischemia.
 * Normally, T waves are in the same direction of the QRS complex.
 * Inversion of a T wave→myocardial ischemia
 * **Myocardiac Injury or Infarction:**
 * **ST elevation** is a sign of transmural injury in an acute coronary syndrome, usually with a clot due to platelet aggregation obstructing a coronary artery.
 * **Acute myocardial infarction**
 * **Sizeable (__>__0.04 s) Q waves** can be a sign of transmural necrosis. Infarcts usually involve only the left ventricle.
 * **Inferior leads (II, III, aVF):** inferior infarcts
 * **V1-V4:** anterior wall infarct
 * **I, aVL and V5, V6:** lateral wall infarcts.
 * A transmural acute myocardial infarct evolves over time:
 * Giant upright “hyperacute” T wave
 * T wave inverts and ST segment rises.
 * Sometimes, ST elevation precedes of occurs simultaneously with T inversion.
 * Q waves are usually the last to develop.
 * **Transmural vs. subendocardial**
 * Transmural—involves the entire thickness of the LV
 * Subendocardial—localized to the inner layer of the LV wall.
 * Subendocardial infarcts do not have Q waves or ST elevation. They do have persistent ST depression.
 * **Electrolyte Disorders:**
 * **Hypercalcemia:** shortened QT interval. Often associated with hyperparathyroidism.
 * **Hypocalcemia:** lengthened QT interval. May be associated with life threatening ventricular arrhythmias.
 * **Hypokalemia:** QT interval is generally prolonged, prominent U waves are frequent and T waves may be inverted.
 * **Hyperkalemia:** increased T wave voltages with a distinctive peaked, symmetrical appearance. At higher levels, the P waves may be flattened and the QRS and T waves widened. A broad S wave often appears. At very high levels, a sinusoidal pattern appears without P or R waves.

=Arrhythmias=
 * 1.** **Differentiate the EKG features of sinus, atrial, junctional (nodal) and ventricular rhythms.**
 * **Sinus rhythms:** a normal P wave (atrial depolarization), PR interval (resistance to conduction at the AV node), QRS complex (ventricular depolarization), and a T wave (ventricular repolarization).
 * Normal sinus rate in adults is 60-100 bpm.
 * Normal PR interval is 0.12-0.20 seconds.
 * Widening of the QRS, preceded by a normal P wave and a normal PR interval→rhythm is still sinus.
 * Rate and regularity of rhythm may vary slightly with respiration.
 * **Sinus tachycardia:** regular, fast heart rate (>100 bpm). Commonly occurs during exercise or emotional stress. No treatment is generally needed, but in patients with coronary artery disease the increased cardiac oxygen demand may precipitate angina. Sinus tachycardia is associated with hyperthyroidism. If treatment is needed, a **beta-blocker** is usually effective.
 * **Sinus bradycardia:** regular, slow heart rate (<60 bpm). Common in normal individuals, especially athletes and requires no treatment. Sinus bradycardia may produce syncope during intense vagal activation as in fainting for which **atropine** is effective. Often occurs with small inferior wall infarctions that increase vagal tone. Can cause syncope, lightheadedness or fatigue in elderly patients with age-related dysfunction→ **sick sinus syndrome** . Treatment may require placement of an electronic pacemaker.
 * **Atrial rhythms:** rhythms originating in the atria. See below for discussion of atrial fibrillation and atrial flutter.
 * **Junctional (nodal) rhythms:** Regular, narrow (normal) QRS complex with no antecedent P waves.
 * The region surrounding the AV node is often termed the “junction” and rhythms originating there are called junctional rhythms. They may be either slow or fast. They are a regular rhythm usually with narrow QRS complexes. P waves are often not seen because they are buried within the QRS complex or they may occur very shortly before or after the QRS. They are often inverted because they are conducted upward from the AV node rather than downward from the SA node.
 * **Ventricular rhythm:** rhythms originating in the ventricle. See below for discussion of ventricular tachycardia and ventricular fibrillation.
 * 2.** **Describe the EKG features of atrioventricular block and their clinical significance**
 * **Atrioventricular block**
 * **First degree A-V block:** PR interval prolonged, increased junctional delay.
 * **Causes:** drug-induced (beta-blockers, some calcium blockers, digitalis), conduction system disease.
 * **EKG features:** PR interval is greater than 0.2 seconds (one large block on the EKG).
 * This is a benign condition that can proceed to more serious types of block.
 * **Second degree A-V block:** Some P waves conduct and some do not.
 * **Causes:** conduction system disease, high vagal tone, excessive effects of drugs.
 * **EKG features:** Some P waves conduct normally to ventricles but others do not. Patterns vary.
 * If the rate is too slow to slow to support cardiac output adequately, syncope or confusion may occur requiring a pacemaker.
 * **Third degree A-V block:** Both Ps and QRSs show regular rhythm, but they are at different rates.
 * **Causes:** av node or junctional failure with aging, infarct or disruption during cardiac surgery—rarely caused by drugs.
 * **EKG features:** Both Ps and QRSs show regular rhythm, but they are at different rates. With P rate > QRS rate.
 * May cause syncope or sudden death. Usually requires a pacemaker.
 * 3.** **List the EKG features, causes, clinical manifestations and treatment of atrial fibrillation and atrial flutter.**
 * **Atrial fibrillation:**
 * **EKG features:** irregularly irregular ventricular rhythm. No p waves.
 * **Causes:** NI subjects, aging, post-operative, heart disease, hyperthyroidism
 * **Clinical manifestations:** rapid heart rate (syncope, ischemia, heart failure), loss of atrial kick (heart failure), atrial thrombi (embolic stroke).
 * **Treatment:** anticoagulation, rate control with drugs, cardioversion—electrical or drugs, ablation.
 * **Atrial flutter:**
 * **EKG features:** P waves (flutter waves) at rate of 240-320 bpm. Pulse may be regular or irregular. Ventricular rates vary widely—typically rapid if untreated.
 * **Complications:** atrial flutter has some risk of embolic stroke due to clot in the left atrium, and may result in rapid ventricular rates that are poorly tolerated.
 * **Treatment:** anticoagulation, rate control with drugs, cardioversion, ablation.
 * **Atrial tachycardia:**
 * **EKG features:** harrow QRS complex, P waves present, but abnormal. Heart rate may be as high as 180.
 * **Causes:** abnormal re-entry pathway.
 * **Clinical manifestations:** rapid heart rate, very uncomfortable and disturbing.
 * **Treatment:** Adenosine, ablation if recurrent problem.
 * **Premature atrial contraction**
 * **EKG features:** premature beat, preceded by abnormal P wave, narrow QRS complex.
 * **Clinical manifestations:** single-beat palpitation, most commonly noticed at rest, when low heart rates permit occurrence of premature ‘skipped beats’ and when distractions are reduced allowing awareness.
 * **Treatment:** none. Beta-blockers if really annoying.
 * 4.** **List the EKG features, causes, clinical manifestations and treatment of ventricular tachycardia and ventricular fibrillation.**
 * **Premature ventricular contraction (PVC)**
 * **EKG features:** wide-abnormal QRS, No P-wave.
 * **Causes:** random single, reentry arrhythmia—short path-length blocks re-entry.
 * **Clinical manifestations:** single-beat palpitation, most commonly noticed at rest, when low heart rates permit occurrence of premature ‘skipped beats’ and when distractions are reduced allowing awareness.
 * **Treatment:** none, beta-blockers if really annoying.
 * **Ventricular tachycardia**
 * **EKG features:** repetitive wide-abnormal QRS complexes, no p-wave,
 * **Causes:** fibrosis, infiltrate, dilation, long path length permitting reentry.
 * **Clinical manifestations:** very bad. Abnormal ventricular contraction
 * **Treatment:** emergency defibrillation.
 * **Ventricular fibrillation**
 * **EKG features:** abnormal, abnormal, abnormal—all noise, no p waves, no QRS complexes, no T waves.
 * **Causes:** can progress from ventricular tachycardia. Heart failure.
 * **Clinical manifestations:** very bad. No ventricular contraction.
 * **Treatment:** immediate emergency defibrillation.

=Heart Failure Part 1 - Pathophysiology=
 * 1.** **Appreciate the major significance of heart failure in the United States; it is a common chronic health care problem that affects survival, quality of life, and health care costs.**
 * **Heart failure in the United States:**
 * **Prevalence:** approx 5,000,000
 * **Annual incidence:** 550,000
 * **Mortality:** 250,000
 * **Cost:** $37.5 billion.
 * HF is a highly symptomatic and progressive disease. Consequently, decreased quality of life, hospitalizations, and death are common. For patients with HF, half will be dead within 5 years, making HF more deadly than most cancers.
 * Incidence and prevalence are increasing for a number of reasons:
 * Aging population
 * Increased survival of initial cardiac disease
 * Therapies generally stabilize HF, but do not often cure it.
 * 2.** **Define the syndrome of heart failure, and recognize that both a decrease in cardiac output and increase in filling pressures are fundamental to the pathophysiology.**
 * **Heart failure as a syndrome:**
 * Heart failure is the inability of the hear to pump blood forward at a sufficient rate to meet the metabolic demands of the body (forward failure), or the ability to do so only if the cardiac filling pressures are abnormally high (backward failure).
 * Components of the HF syndrome (a constellation of signs and symptoms caused by many possible abnormalities of heart function)
 * **Poor forward blood flow**
 * Low flow →↓CO
 * **Backward buildup of pressure**
 * Congestion→↑filling pressure
 * Typically a response to low flow.
 * **Decrease in cardiac output and an increase in filling pressure are fundamental to the pathophysiology of heart disease**
 * 3.** **Understand the difference between systolic and diastolic dysfunction.**
 * **Systolic dysfunction:** a problem with squeeze→↓contraction→↓inotropy.
 * **Hallmark:** decreased ejection fraction and entricular enlargement
 * **Decreased ejection fraction**
 * Heart failure with reduced ejection fraction=HFrEF
 * Left ventricular systolic dysfunction=LVSD
 * **Ventricular enlargement**
 * Dilated cardiomyopathy= DCM
 * Primary causes:
 * Direct destruction of heart muscle cells→**myocardial infarction**, viral myocarditic, peripartum cardiomyopathy, idiopathic dilated cardiomyopathy, alcohol.
 * Overstressed heart muscle→tachycardia-mediated HF, meth abuse, catecholamine mediated.
 * Volume overloaded heart muscle→mitral regurgitation, high cardiac output
 * **Diastolic dysfunction:** a problem with filling→↓lusitropy/decrease in relaxation.
 * **Hallmark:** normal ejection fraction and ventricular wall thickening.
 * **Normal ejection fraction:**
 * HF with preserved ejection fraction=HFpEF
 * Preserved systolic function=PSF
 * **Ventricular wall thickening:**
 * Left ventricular hypertrophy=LVH
 * Hypertrophic cardiomyopathy=HCM→genetic
 * Primary causes:
 * High afterload/pressure afterload→hypertension, aortic stenosis, dialysis (inadequate volume removal)
 * Myocardial thickening/fibrosis→HCM, primary restrictive cardiomyopathy
 * External compression (may not be HF since it doesn’t involve heart itself)→pericardial fibrosis/constrictive pericarditis, pericardial effusion.
 * 4.** **Describe compensatory responses to decreased cardiac output seen in heart failure, including neurohormonal activation of the adrenergic and renin-angiotensin-aldosterone systems, Frank-Starling increases in preload, and ventricular remodeling via hypertrophy and dilation.**
 * **Compensatory responses to decreased cardiac output**
 * **Neurohormonal activation**
 * ↓filling/↓SV→↓CO
 * Juxtaglomerular apparatus in kidney senses lower flow→renin-angiotensin-aldosterone (RAAS) activation
 * ↑Sodium retention
 * vasoconstriction
 * Carotid sinus/aortic baroreceptors sense lower pressure→autonomic nervous system/adrenergic activation
 * ↑HR
 * vasoconstriction
 * ↑sodium retention + vasoconstriction + ↑HR →↑volume→↑LV filling
 * **Frank-Starling increases in preload**
 * **↑** LV filling→↑SV
 * stroke volume is preserved by increasing the end diastolic filling/pressure.
 * **Ventricular remodelling via hypertrophy and dilation**
 * Long term increases in cardiac workload and increased metabolic demands promote adverse myocardial remodelling.
 * Ventricular hypertrophy
 * Ventricular dilation
 * Myocardial damage/apoptosis
 * Myocardial fibrosis
 * Overtime remodelling causes:
 * Decreased contractile force
 * Decreased dynamic function
 * Increased diastolic stiffness
 * 5.** **Addendum: Right-sided heart failure**
 * Under normal circumstances, the pulmonary vasculature is a low pressure system
 * Normal systemic bp/LV—120/80 mmHg; normal pulmonary bp/RV—22/10 mmHg
 * Most heart failure involves the left heart, because the left heart does the majority of the work under circumstances of normal pulmonary pressures.
 * Stresses to the RV can cause it to fail to adequately pump blood through the lungs:
 * ↓ Circulating blood flow (forward RV HF)
 * **↑** Venous pressures (backward RV HF)
 * **Major causes of right-sided HF:**
 * **Left heart failure**
 * Backward HF from LV dysfunction stresses the right side by increasing pulmonary venous pressures.
 * Lung disease/pulmonary HTN/RV pressure overload
 * “cor pulmonale”→primary lung disease causes HF
 * COPD, primary pulmonary hypertension, sleep apnea
 * RV volume overload
 * Shunt, tricuspid regurgitation
 * Damage to the RV myocardium
 * Isolated RV infarct (rare), myocarditis.

=Heart Failure Part 2 - Clinical manifestations, diagnosis and testing=
 * 1.** **Recognize the major symptoms associated with heart failure, particularly those related to decreased cardiac output (fatigue), increased pulmonary venous pressure (dyspnea), and increased central venous pressure (edema).**
 * **Major symptoms associated with heart failure**
 * **Decreased cardiac output**
 * **FATIGUE**
 * Symptoms of decreased organ perfusion
 * Muscle→fatigue, tiredness/sleepiness
 * Gut→anorexia, wasting (cachexia)
 * Kidney→↓urine output, renal dysfunction
 * Exercise intolerance→inability to augment cardiac output to meet increasing demands of stress/exercise.
 * **Increased pulmonary venous pressure**
 * **DYSPNEA** (breathlessness)
 * Dyspnea on exertion
 * Orthopnea→SOB when lying flat (blood pooling in legs now pulling in abdomen/thorax)
 * Paroxysmal nocturnal dyspnea (PND)→delayed SOB, waking patients from sleep→mobilization of edema from tissue through lymphatics back into blood stream.
 * Acute pulmonary edema: acute, intense shortness of breath; occurs once fluid retention/left atrial pressure overwhelms compensatory mechanisms→fluid spills from the pulmonary vasculature into the interstitial space and then into the alveoli→hypoxia
 * “fluffy” infiltrates on an CXR
 * **Increased central venous pressure**
 * Peripheral swelling/dependent **EDEMA**
 * Ascites
 * Hepatic congestion
 * Intestinal congestion (protein-losing enteropathy)
 * 2.** **Be acquainted with the functional classification schemes for heart failure (e.g. New York Heart Association [NYHA] functional class).**
 * **New York Heart Association Functional Class**
 * **I:** asymptomatic
 * **II:** symptomatic with moderate exertion
 * **III:** symptomatic with minimal exertion
 * **IV:** symptomatic at rest
 * **ACC/AHA HF Stage**
 * **A:** At high risk for heart failure but without structural heart disease or symptoms of heart failure
 * **B:** Structural heart disease but without symptoms of heart failure.
 * **C:** Structural heart disease with prior or current symptoms of heart failure.
 * **D:** refractory heart failure requiring specialized interventions.
 * 3.** **Be familiar with common precipitants of worsening heart failure symptoms, and the variable clinical course of heart failure.**
 * **Common precipitants of worsening heart failure**
 * Increased circulating volume (Preload)→**sodium load in diet**, renal failure
 * Increased pressure (afterload)→uncontrolled hypertension (LV), worsening aortic stenosis (LV), pulmonary embolism (RV)
 * Worsened contractility (inotropy)→myocardial ischemia, initiation of negative inotrope (beta-blocker or calcium channel blocker)
 * Arrhythmia (rate)→bradycardia, atrial fibrillation
 * Increased metabolic demands→fever, infection, anemia, hyperthyroidism, pregnancy
 * **NON-ADHERENCE WITH HF MEDICATIONS.**
 * **Variable clinical course of heart failure**
 * HF is marked by a non-linear course. It is typically marked by episodic exacerbations with significant symptoms (sometimes requiring hospitalization), with intervening periods of relative stability. Patients rarely stay at a singly NYHA class over time; they may move between functional classes depending on a number of factors that dictate cardiac function and symptomatology. However, the usual course is an average of progressive decline over time.
 * 4.** **Understand how to assess the key physical signs of heart failure, and how they relate to the underlying pathophysiology.**
 * **Physical signs of heart failure and their relation to underlying pathology**
 * **Signs of low flow:**
 * Cool extremities—peripheral vasoconstriction to redirect what existing blood flwo there is to vital organs.
 * Tachycardia—compensate for low stroke volume
 * Low pulse pressure—reflection of low output.
 * **Signs of elevated left-sided filling pressures**
 * rales (pulmonary crackles)—fluid in the lungs, wet alveoli opening.
 * Hypoxia
 * Tachypnea
 * Sitting bolt upright
 * Popping open of alveoli
 * **Signs of elevated right-sided pressures**
 * Edema—dependent=follows gravity
 * Hepatic congestion/hepatomegaly
 * Jugular venous distention (JVD) = ↑ central venous pressure
 * JVP = CVP = right atrial pressure
 * Normal < 5 cm H2O.
 * With a person lying flat or a person with JVD in HF, the jugular vein (internal and external) will fill with blood. Thus the neck veins will appear full on visual examination. More importantly, they will transmit pressure changes in the right atrium as waves, **visible fluctuations in the vein size and in the meniscus**.
 * **Gallops**
 * S3 gallop—rapid expansion of the ventricular walls in early diastole
 * HFrEF/dilated heart
 * Ken-tuc-ky (S1-S2-S3)
 * S4 gallop—atria contracting forcefully in an effort to overcome abnormally stiff or hypertrophic LV
 * Ten-ne-ssee (S4-S1-S2)
 * 5.** **Know the primary laboratory tests and imaging studies that are most helpful in making a diagnosis of heart failure, including natriuretic peptides, cardiac imaging studies (and how to assess left ventricular ejection fraction [LVEF]), and hemodynamics obtained from a pulmonary artery catheter.**
 * **Laboratory tests:**
 * **Natriuretic peptides**
 * B-type natriuretic (BNP) is secreted by the myocardium in response to
 * Primary: **ventricular stretch**
 * Secondary: hyperadrenergic state, RAAS activation, ischemia
 * BNP: cutoff for diagnosis is relative (100 pg/mL)
 * NT-proBNP: n-terminus breakdown product of BNP (sticks around longer and easier to measure)
 * **Use of BNP/NT-proBNP:** clinically used to rule out HF, very unlikely that you have HF if you have a low BNP. Hard to rule-in, lots of causes (even ones associated secondarily with HF) that can raise BNP.
 * **Imaging studies:**
 * **CXR:**
 * Enlarged cardiac silhouette in HFrEF
 * ↑upper lobe vascular markings with acute decompensation
 * fluffy infiltrates of pulmonary edema
 * pleural effusions
 * **Electrocardiogram (EKG)**
 * No direct diagnosis of HF
 * Infer possibility of HF from other findings
 * Q waves—prior MI
 * Increased voltage—LVH
 * Arrhythmia (AF, PVCs), non-sustained ventricular tachycardia (NSVT)
 * **Echocardiography**
 * Provides: LVEF, chamber size (dilation), LV wall thickness (hypertrophy), measures of relaxation (diastology), valvular anatomy and function, filling pressures, pulmonary pressures.
 * Advantages: real time, non-invasive, no radiation, inexpensive
 * **Right heart catheterization**
 * A plastic catheter is placed into a major vein and floated through the right heart and into the pulmonary artery. A balloon on the end helps blood flow carry it to the lungs.
 * Balloon allows a branch of the pulmonary artery to be occluded so that the downstream pressure can be measured = left atria pressure / left sided filling pressure.
 * Measure pressures—CVP/RA, RV, PA, PCWP
 * Measure flow/CO
 * Resistances can be calculated from pressures and flow.

=Drugs used in the treatment of CHF= Note: Contains the following lectures - Diuretics and Aldosterone Inhibitors in CHF, Adrenergic and Angiotensin Block in CHF, Inotropic Drugs - Limitations in HF
 * 1.** **Understand that both the progression and treatment of congestive heart failure occurs in stages. Understand that there is generally no cure, per se, for congestive heart failure. The main therapeutic goal is to slow to as great an extent possible the rate of progression of this highly prevalent disease.**
 * Congestive heart failure is a highly prevalent disease affecting approximately 1-2% of the non-institutionalized US population. This disease carries a poor prognosis, particularly for males over the age of 55 years. In spite of all the recent advances in medical treatment, the one-year mortality of patients with advanced heart failure is on the order of 40-50%.
 * Heart failure is a generally progressive disease and requires incremental treatment.
 * As symptoms of the disease increase, the therapy or combination of therapy used to treat the disease becomes more complex. First and foremost, elimination of contributing factors must be attempted. This includes:
 * Reduction of hypertension
 * Reduction of Na+ intake
 * Weight reduction
 * Cessation of smoking.
 * 2.** **Understand the principles of intracellular calcium handling in cardiomyocytes. In this context, understand how cardiac glycosides modulate increased myocardial contractility via blocking the Na+/K+/ATPase thereby effecting [Ca++]i. Understand that by completely different pathways, both β-AR and α-AR stimulation also increase [Ca++]i. In essence, understand the fundamental basis of inotropic activity.**
 * **Intracellular calcium handling in cardiomyocytes**
 * **L Type Ca2+ Channel:** responsible for calcium influx into the cell.
 * Phosphorylation by PKA—via beta adrenergic stimulation—increases the sensitivity of the LTCC to allow a greater influx of calcium into the cell.
 * **RyRs:** in close proximity to the LTCCs, undergo CDCR from the SR after influx through the LTCC.
 * **SERCA:** pumps calcium back into the SR. Inhibited by PLB. Disinhibition of SERCA is regulated by PKA mediated phosphorylation of PLB.
 * **IP3 mediated release of calcium** from the SR also takes place following alpha1 adrenergic stimulation.
 * **Na+/Ca2+ exchanger (NCX)** pumps out 3 sodium ions for every 1 calcium that is brought in—this exchanger can be reversed in direction dependent upon the reversal potential (Erev) which changes as a function of the action potential.
 * **Na+/K+/ATPase** pumps out 3 sodium and in 2 potassium ions with the help of ATP hydrolysis.
 * Calcium homeostasis within the cardiomyocytes is important, given that calcium is the ultimate regulator of muscle contraction—calcium binds to troponin C, which weakens the interaction of troponin I with actin so that tropomyosin can move laterally out of the way such that myosin can act as an ATPase in the presence of actin—thus creating muscle contraction.
 * **How do cardiac glycosides modulate increased myocardial contractility?**
 * Cardiac glycosides ultimately act by increasing effective intracellular calcium.
 * **Digitalis** binds selectively and saturably to the α-subunit of the heterodimeric Na+/K+/ATPase, decreasing the rate of extrusion of intracellular sodium.
 * The increase in intracellular sodium decreases the transsarcolemmal sodium gradient. This in turn is responsible for a decrease in the rate of efflux of intracellular calcium, as well as an increase in the rate of influx of extracellular calcium facilitated by the bidirectional NCX.
 * The increase in intracellular calcium levels produces a positive inotropic effect via enhancement of the interaction between actin and myosin.
 * **How does β-adrenergic stimulation increase intracellular calcium (and inotropy)?**
 * The β-adrenergic receptor is coupled to the G-protein Gs. Stimulation of Gs increases adenylyl cyclase mediated production of cAMP from ATP. ↑cAMP activates PKA; PKA phosphorylates phospholamban, releasing inhibition of SERCA2 and increasing calcium sequestration in the SR, and the LTCC, increasing its sensitivity to turn on calcium influx into the cell.
 * Overall, beta-adrenergic stimulation increases intracellular calcium and its cycling between the intracellular space and inside the SR—such that an increase in inotropy and contractility is observed.
 * **How does α-adrenergic stimulation increase intracellular calcium (and inotropy)?**
 * The α-adrenergic receptor is coupled to G-protein Gq. Stimulation of Gq increase PLC mediated conversion of PIP2 into IP3 and DAG.
 * IP3 directly stimulates release of calcium from the SR.
 * 3.** **Understand that the electrophysiological effects of cardiac glycosides are both the basis of their usefulness in treating supraventricular arrhythmias and are also the basis for their proarrhythmic effects (PVC’s, nodal block) .**
 * **Electrophysiological effects of cardiac glycosides**
 * In the **AV node**, there is a decrease in conduction velocity and an increase in effective refractory period (ERP). As with the SA node, these effects are modified by the SNS and the PNS. For the most part, vagal influence dominates. The increase in the effective refractory period (ERP) of the AV node is the rationale for the use of cardiac glycosides in the treatment of supraventricular tachycardia, atrial flutter and atrial fibrillation.
 * The excitability of the Purkinje fibers and specialized atrial conduction fibers is enhanced due to the increase rate of rise of phase-4 depolarization. The increase in automaticity can be proarrhythmic and at high doses, can cause PVCs, ventricular tachycardia and ventricular fibrillation. The enhanced conduction velocity in the accessory pathways, combined with the decrease in effective refractory period provide the main reasons why cardiac glycosides are contraindicated in Wolff-Parkinson-White Syndrome—where there is aberrant AV conduction bypassing the AV node.
 * In ventricular muscle, effective refractory period is, in general, decreased and automaticity is increased—this is especially true at toxic levels.
 * 4.** **Understand the role (limited) of non cardiac glycoside positive inotropic agents (PDE I’s, β- AR agonists) in the treatment of chronic CHF.**
 * **Non-cardiac glycosides are positive inotropic agents in the treatment of chronic CHF**
 * **Phosphodiesterase Inhibitors (PDEs):** prevent the breakdown of cAMP by phosphodiesterase, increase the affinity of troponin C for calcium, increase the reuptake of calcium by the SR and can completely competitively inhibit the adenosine receptor.
 * **PDE-III inhibitors** are composed of three classes. Milrinone is in the bipyridine class of PDE-III inhibitors.
 * **Milrinone** appears to have few advantages over the beta-agonists other than lack of tachyphylaxis.
 * **One advantage:** for comparable degrees of inotropic stimulation, the PDE inhibitors appear to shift the MVO2 in a direction opposite that of beta-agonists. That is, they appear to affect positively the balance between work and oxygen consumption.
 * **Side effects:** including excess mortality.
 * Not considered a first-line therapy in the treatment of mild, chronic CHF. But may play a role in the treatment of moderate to severe CHF—especially when used in conjunction with certain beta-blocking agents
 * **Beta-Adrenergic receptor agonists:** stimulation of the beta-adrenergic receptor by a beta-adrenergic agonist results in ↑cAMP production by adenylyl cyclase and subsequent PKA activation. PKA-mediated phosphorylation of L-type Ca2+ Channels (LTCCs) and phospholamban (SERCA inhibitor) contribute to increased intracellular calcium levels and increased inotropy.
 * **Epinephrine:** high affinity for both alpha- and beta- adrenergic receptors.
 * **Heart:** positive inotropy is modulated by both beta1- and beta2- adrenergic receptors; positive chronotropy is modulated by just the beta2-adrenergic receptor.
 * IV administration; main indication is during the post-cardiopulmonary bypass setting when difficulty in removing the patient from the bypass pump is encountered.
 * In patients with CHF, there is selective downregulation of the beta1-receptor, probably due to high levels of circulating catecholamines. Thus, in the failing heart, beta2-adrenergic receptors become increasingly important—important to exploit this reservoir of potential for stimulating this pathway.
 * **Norepinephrine:** differs from epinephrine in that it is much less potent at beta2-receptors than at beta1-receptors.
 * Although it is a strong inotrope, it does not cause the peripheral vasodilation characteristic of low dose epinephrine and isoproterenol.
 * Also a potent alpha1-adrenergic receptor agonist—making it a potent vasoconstrictor and mitogen.
 * **Dopamine:** a direct and indirect agonist (as it also causes the release of synaptic norepinephrine and blocks its reuptake). Modest beta1- and alpha-adrenergic receptor activity.
 * Stimulation of dopaminergic receptors markedly enhances splanchnic and renal circulation→↑diuresis.
 * At lower doses, vasodilatory; at higher doses, via the release of norepinephrine, it can be a potent vasoconstrictor causing a significant increase in afterload.
 * **Dobutamine:** potent beta-agonist. Mostly beta1-selective.
 * IV dobutamine is used in the treatment of severe CHF to reverse decompensated condition.
 * Dobutamine appears to cause less beta-receptor down-regulation that other beta-agonists of similar efficacy, leading to a lower tendency for tachyphylaxis.
 * 5.** **Understand the basis of the usefulness of vasodilators (including ACE inhibitors) in the treatment of CHF.**
 * **Vasodilators in the treatment of CHF**
 * Vasodilators decrease systemic vascular resistance (SVR), LV size, and MVO2.
 * Vasodilators may act preferentially at:
 * Arteries to reduce afterload—hydralazine, minoxidil and nifedipine (calcium channel blocker).
 * Veins to reduce preload—nitroglycerin and isosorbide dinitrate (ISDN)
 * Non-selectively at both arteries and veins—ACE inhibitors.
 * **ACE inhibitors:**
 * **Review of the RAAS:** angiotensinogen is converted to angiotensin I by renin (produced by juxtoglomerular cells in response to low blood volume). In turn, angiotensin I is converted to angiotensin II (a potent vasoconstrictor) by the angiotensin converting enzyme (ACE). ACE also causes the degradation of the potent vasodilator, bradykinin.
 * **ACE inhibitors** (including captopril, enalapril, and lisinopril) all inhibit ACE and decrease production of AngII and destruction of bradykinin—creating a net vasodilatory effect→↓BP.
 * The differences between ACE inhibitors are mainly pertaining to their PCKs and not to their efficacy or mode of action—there do not appear to be any major therapeutic differences amount the individual ACE inhibitors.
 * Enalapril: slower onset and longer duration of action (1-2 times a day dosing). Prodrug Converted enalaprilat (can be given directly IV) in the liver.
 * Catopril: faster onset and shorter duration of action.
 * Lisinopril: even longer duration of action (once daily dosing).
 * 6.** **Understand the basis of the usefulness of β-blockers in the treatment of CHF.**
 * **Beta-blockers in the treatment of CHF:**
 * Patients with CHF have ↑ adrenergic drive as manifested by high levels of circulating catecholamines.
 * Beta-blockers competitively block endogenous catecholamines from interacting with beta-adrenergic receptors and in doing so, reduce the metabolic demands associated with increased heart rate and myocardial contractility.
 * Prevents norepinephrine-induced beta-receptor down regulation and/or desensitization→ resensitizes the signal transduction pathway.
 * Until the 1990’s beta-blockers were contraindicated for use in CHF due to their negative inotropic effects on the heart. However, beta-blockers without these significant negative inotropic effects have been developed and have proven to be highly useful in the management of CHF.
 * **Metoprolol:** beta1-AR selective agent
 * **Carvedilol:** relatively nonselective inhibitor of both beta1- and beta2- ARs and also alpha1-ARs (may explain vasodilatory action).
 * Use of beta-blockers over time, ↑CO, ↑EF and ↑submaximal exercise tolerance; ↓PA and LV end-diastolic pressures.
 * Evidence for prolonged survival—but may not be tolerated in Class IV heart failure patients (due to preexisting limitations in cardiac function).
 * **Problems with beta-blockers:** CHF patients have a limited cardiac reserve and must be titrated up to the correct dose of beta-blockers. Patients may be uncomfortable and feel worse before they start feeling better (remodelling of the heart takes time—up to 3 – 12 months). And some patients may never reach the recommended dose.
 * Current treatment of CHF includes the use of diuretics, ACE inhibitors a/o ARB’s in addition to the newer generation of beta-blockers (and occasionally cardiac glycosides).

=Clinical Treatment of Heart Failure=
 * 1.** **Understand the major goals of therapy, including correction of any reversible causes, reduction of congestion, and optimization of cardiac function.**
 * **General goals of any therapy:**
 * ↑ Quantity of life (↑survival)
 * **↑** Quality of life (↓ symptoms)
 * **↓** financial/resource burden of disease.
 * **HF specific goals:**
 * **Correction of the underlying cause of HF**
 * Example: revascularization for ischemia
 * Not possible to reverse many causes.
 * Elimination of precipitating factors
 * **Reduction of congestion** (fluid optimization is a major part of HF therapy)
 * Improve flow (may be difficult to do medically)
 * Modulate neurohormonal action
 * Long-term stabilization, positive remodelling, increased survival.
 * **Optimization of cardiac function**
 * 2.** **Know the major classes of medications for heart failure, including diuretics, vasodilators, neurohormonal antagonists, and inotropes; appreciate how each class affects the deleterious cycle of heart failure.**
 * **Diuretics:** reverse the sodium and fluid retention of HF
 * Typically work at the far end of the frank-starling curve, such that significant decreases in pressure produce minimal changes in stroke volume (and thus CO). Thus, symptoms of congestion can be reduced without major effects on blood flow.
 * **Vasodilators:** arterial, venous, and pulmonary arterial vasodilation
 * **Arterial:** ↓ LV afterload, ↓ cardiac work, ↓ mitral regurgitation
 * **Venous:** ↓ preload
 * **Pulmonary:** ↓ RV afterload
 * **Neurohormonal antagonists**
 * **ACE inhibitors:** block conversion of ATI to ATII→direct vasodilation, decreased aldosterone activation.
 * **Side effects:** hypotension, worsening renal failure, hyperkalemia, cough (kinin production), angioedema
 * **Angiotensin receptor blockers:** block receptor of ATII→ equivalent to ACE Is, but without cough.
 * **Aldosterone receptor blockers:** block aldosterone action in kidney→↓sodium→diuretic.
 * **Beta-blockers:** antagonize effects of the SNS→↓chronotropy ↓inotropy (short term loss for long term gain)
 * **Side-effects:** bronchoconstriction
 * **Inotropes:** administered via IV agents short term in the ICU to reverse shock (long term—worsen remodelling ↑mortality)
 * **Digoxin** —K/Na exchanger
 * **Dobutamine** —beta agonist
 * **Milrinone** —PDEi
 * 3.** **Be familiar with other non-pharmacologic therapies for heart failure, including electrical therapies (defibrillators and resynchronization) and advanced therapies (transplantation, mechanical support devices, and hospice).**
 * **Electrical therapies**
 * **Defibrillators:** for patients with LVEF __<__ 35% or with prior dangerous rhythms. Implanted.
 * Abort sudden cardiac death from ventricular tachycardia/fibrillation.
 * **Resynchronization:**
 * Left ventricular lead placed from the RA through the coronary sinus over the epicardium of the LV (3 leads: RA, RV coronary sinus/LV)
 * For patients with QRS > 120 msec (bundle branch block)
 * Cause the lateral wall and septal wall to contract together, which produces
 * More efficient contraction→↑stroke volume
 * May also improve mitral valve function→↓regurgitation
 * **Advanced therapies**
 * **Transplantation:** shortage of organs.
 * **Mechanical support devices:** often used as a bridge to transplantation or as a destination therapy.
 * **Hospice:** palliative advanced therapy→paradigm shift from quantity to quality of life.
 * 4.** **Comprehend the non-linear clinical course of heart failure, and how different therapeutic approaches are used at different stages of the disease process.**
 * **Stage A:** at risk for HF but without structural disease or symptoms
 * **Therapy goals:** treat hypertension, smoking cessation, treat lipid disorders, regular exercise, discourage alcohol intake, drug use, control metabolic syndrome
 * **Drugs:** ACEi or ARB in appropriate patients.
 * **Stage B:** structural heart disease but without signs or symptoms of HF.
 * **Therapy goals:** see stage A
 * **Drugs:** ACEi, ARB, beta-blockers
 * **Devices:** implantable defibrillators
 * **Stage C:** structural heart disease with prior or current symptoms of HF.
 * **Therapy goals:** see stage A and B + dietary salt restriction.
 * **Routine drugs:** diuretics, ACEi, beta-blockers
 * **Drugs in selected patients:** aldosterone antagonist, ARBs, digitalis, hydralazine/nitrates
 * **Devices:** biventricular pacing, implantable defibrillators
 * **Stage D:** refractory HF requiring specialized interventions
 * **Therapy goals:** A, B, and C + end of life decisions regarding the appropriate level of care.
 * **Options:** compassionate end-of-life care/hospice; extraordinary measures: transplant, chronic inotropes, permanent mechanical support, experimental surgery/drugs.
 * 5.** **Understand that most specific heart failure therapies are indicated for patients with reduced ejection fraction (HFrEF); for the approximately 50% of patients with heart failure and relatively normal ejection fraction (HFnEF), treatment consists of diuretics and management of underlying causes.**
 * Most of the treatments mentioned above are designed and indicated for patients with reduced ejection fraction (HFrEF)
 * **What kinds of treatments are used for patients with heart failure and relatively normal ejection fraction (HFnEF)?**
 * Trials for neurohormonal antagonists have not been successful in improving outcomes for patients with HF and normal ejection fraction.
 * Similarly, ICD/CRT are not generally indicated in patients with LVEF > 35-40%
 * Therapy consists of treating the underlying disorder—hypertension, diabetes, kidney dysfunction, aortic stenosis.
 * Diuretics are used to keep volume normal (sodium retention is common)
 * Vasodilators are used to maintain normal blood pressure.
 * 6.** **Recognize the importance of prevention and list specific prevention goals.**
 * Most of the conditions that predicate the development of HF are preventable with changes in diet and lifestyle.
 * Hypertension
 * Diabetes
 * Hyperlipidemia
 * Physical inactivity
 * Excessive alcohol intake
 * Dietary sodium
 * Specific prevention goals

=Pathology of Valvular Heart Disease=
 * 1.** **Compare right-sided and left-sided heart failure - the pathophysiology and main pathologic findings.**
 * **Right-sided heart failure**
 * **Causes:** Left sided heart failure, mitral stenosis, interstitial lung disease, chronic obstructive airway disease, pulmonary emboli, congenital heart disease (left to right shunts), other (cardiomyopathy, left atrial myxoma).
 * **Pathophysiology, signs and symptoms:** Right sided heart failure leads to increased right atrial pressure and increased systemic venous pressure resulting in liver and spleen congestion, lower extremity edema and raised JVP.
 * **Liver:** hepatomegaly, tender liver, abnormal liver function tests; nutmeg liver—centrilobular congestion around central veins with paler hypoxic peripheral regions; chronic passive congestion can lead to “cardiac” cirrhosis.
 * **Left-sided heart failure**
 * **Causes:** myocardial ischemia, hypertension, valve disease (aortic stenosis/regurgitation, mitral regurgitation), primary myocardial disease
 * **Pathophysiology, signs and symptoms:** Increased pressures are transmitted backwards to the left atrium and to the pulmonary circulation resulting in passive pulmonary venous congestion with fluid exudation w/wo blood into alveolar spaces (pulmonary edema) and into pleural cavities (effusion).
 * Dyspnea on exertion, Orthopnea, paroxysmal nocturnal dyspnea, anxiety, cough, ↑HR and RR, lung basal crepitations, pleural effusions
 * Frothy pink sputum (alveolar hemorrhage)
 * Chronic left heart failure leads to hemosiderin laden macrophages in the alveoli (“heart failure cells”)
 * 2.** **Describe the pathogenesis and pathology of acute and chronic rheumatic fever including valves most commonly involved and clinical-pathologic findings in mitral stenosis.**
 * **Acute and chronic rheumatic fever:** Rheumatic fever is an acute
 * **Pathogenesis:** Rheumatic fever is an acute immune-mediated systemic inflammatory disease that follows an acute streptococcal infection; almost always pharyngitis caused by group A beta-hemolytic streptococcus (strep pyogenes). The pathogenesis remains unclear but it is thought to be due to anti-streptococcal antibodies cross-reacting with tissue glycoproteins in the heart, joints and other tissues.
 * **Pathology:** The valves leaflets, particularly the left sided valves which close under greater pressures become inflamed and edematous. This results in damage of the endocardium along the lines of closure with fibrin deposition. Healing of these lesions results in fibrous adhesions along the commissures in particular. There is also fibrosis of the leaflets resulting in thickening of the valve.
 * **Morbidity and mortality:** long term sequelae of the valve damage and fibrosis with resulting valve stenosis/incompetence.
 * **Pancarditis** with Aschoff bodies, consisting of fibrinoid necrosis, lymphocytes, macrophages and modified histiocytes. These foci typically result without permanent sequelae.
 * **Chronic rheumatic heart disease:**
 * Thickening, fibrosis, fusion and calcification of valve leaflets and cusps
 * Thickening, fibrosis, fusion and shortening of chordae tendineae
 * Mitral valve stenosis/regurgitation
 * Aortic valve stenosis/regurgitation
 * **Valves most commonly involved:** 65% involvement of mitral valve; 25% involvement of mitral and aortic valves—uncommon involvement of tricuspid and pulmonary valves.
 * **Mitral stenosis:** “Fish mouth stenosis” with left atrial dilatation and mural thrombi w/wo embolization and atrial fibrillation
 * Pulmonary vascular changes occur eventually leading to right ventricle hypertrophy.
 * 3.** **Know the clinical-pathologic findings of mitral valve prolapse.**
 * **Mitral valve prolapse**
 * **Clinical findings:** asymptomatic in majority of patients.
 * Clinical manifestations involving the cardiovascular system:
 * Mitral valve prolapse
 * Dilatation of the aortic ring
 * Dissecting aneurysm of the ascending aorta.
 * **Pathologic findings**
 * Significant mitral regurgitation and infective endocarditis (complication).
 * **Pathogenesis**
 * Uncertain
 * Characterized by a defect in the metabolism of extracellular matrix resulting in accumulation of myxomatous connective tissue in the valve leaflets causing them to become soft and enlarged with ballooning (esp. of posterior leaflet) into the left atrium during systole; also results in elongation of the chordae tendineae
 * Can occur in association with Marfan syndrome
 * 4.** **List the causes and clinical-pathologic features of calcific aortic stenosis (i.e. age related calcification, congenital bicuspid valve, chronic rheumatic heart disease).**
 * **Calcific aortic stenosis**
 * **Causes**
 * Develops in elderly patients as a degenerative process
 * Rheumatic heart disease
 * Congenital bicuspid aortic stenosis.
 * **Clinical-pathologic features:** results in obstruction to the left ventricular outflow leading to gradual narrowing of the valve orifice.
 * May occur in a congenital bicuspid valve, often with earlier clinical presentation.
 * Results in LVH
 * Clinical features:
 * Angina
 * Syncope
 * Left heart failure
 * 5.** **Know the clinical-pathologic findings of anorectic drug associated valve disease.**
 * **Valvular heart disease associated with anorectic drugs**
 * Valvular heart disease was identified in patients without a history of cardiac disease who were treated with appetite suppressing anorectic drugs (fen-phen).
 * **Right and left sided valves** were involved, with regurgitation.
 * Some had **multiple valve involvement** and some patients had pulmonary hypertension.
 * Histopathological findings included plaque like encasement of the leaflets and chordae with intact valve architecture and myofibroblastic proliferation.
 * Histopathologically resembles carcinoid valve disease that affect right sided valves only and is associated with neuroendocrine carcinoid tumors.
 * 6.** **Describe the complications of prosthetic valves.**
 * **Complications of prosthetic valves:**
 * Mechanical deterioration
 * Thromboemboli
 * Infective endocarditis
 * Paravalvular leaks
 * Hemolysis
 * 7.** **List the causes and associations of infective endocarditis. Compare and contrast subacute and acute infective endocarditis - including risk factors, pathologic features ("vegetation" and what this consists of) and complications of infective endocarditis (valve perforation, emboli).**
 * **Infective endocarditis:** colonization/infection of the cardiac valves or endocardium by microorganisms resulting in the formation of “vegetation” composed of fibrin, RBCs, inflammatory cells and organisms.
 * **Causes**
 * Virulent organisms can infect normal valves/less virulent organisms can infect damaged valves.
 * Organisms are implanted on the valve/endocardial surfaces during bacteremic episodes in association with:
 * Interventional/surgical procedures
 * Indwelling access lines
 * Intravenous drug use.
 * Risk of infective endocarditis is increased with:
 * Preexisting cardiac abnormalities and congenital abnormalities and prosthetic heart valves
 * Immunodeficiency, neutropenia, immunosuppressive therapy.
 * Causative organisms:
 * Alpha hemolytic strep (damaged valves)
 * Staph aureus (normal valves)
 * Enterococci
 * Staph epidermidis, gram-negative bacilli and fungi.
 * **Associations**
 * Organization of the inflammation ant rhombus leads to fibrosis, distortion of the valves and functional stenosis/incompetence.
 * Thrombus is a potential source of systemic thromboemboli/sceptic emboli.
 * **Infective endocarditis**
 * **Subacute endocarditis**
 * Low virulence organisms
 * Usually effects abnormal valves
 * Insidious clinical onset.
 * **Acute** **endocarditis**
 * Caused by highly virulent organisms, which can destroy valve leaflets resulting in perforation and incompetence with congestive heart failure.
 * Can affect normal as well as abnormal valves/endocardium
 * More acute onset with high mortality.
 * 8.** **Compare infective to non-infective endocarditis.**
 * **Infective endocarditis:** colonization/infection of the cardiac valves or endocardium by microorganisms resulting in the formation of vegetation composed of fibrin, red blood cells, inflammatory cells and organisms.
 * **Non-infective endocarditis:** sterile small vegetations composed of fibrin, loosely attached along lines of valve closure.
 * Often occur on normal valves and are often asymptomatic; larger vegetations may embolize with infarcts in organs or may become infected.
 * The cause is poorly understood.
 * Associations:
 * Endocardial trauma
 * Hypercoagulability states
 * Cachexia
 * End stage chronic debilitating diseases (renal failure, metastatic carcinoma)
 * Libman sacks endocarditis—associated with SLE.

=Anticoagulant, Antiplatelet, etc. Drugs=
 * 1.** **Describe the general mechanisms of platelet function, coagulation, and fibrinolysis, with special emphasis on the sites and targets for pharmacotherapeutic interventions in disorders of hemostasis.**
 * **Platelet function**
 * **Adhesion:** platelets adhere to damaged (thrombogenic) vascular surface through bridging of vWF between the subendothelial macromolecules and GpIb receptors on the platelet surface.
 * **Activation:** thrombin, thromboxane A2 (TXA2) and exposed collagen (binds GpIb receptors) cause release of arachidonic acid (AA) from the platelet membrane and further synthesis of TXA2 by the COX-1 pathway.
 * **TXA2** binds to TXA2 on the surface of other platelets and initiates “chain reaction” release of other aggregating agents (ADP, 5HT) via secretion of granule contents.
 * Aggregating agents (TXA2, ADP) act via GpIIb/IIIa receptors on platelet surface.
 * Fibrinogen binding to GpIIB/IIIa receptors results in linkage of adjacent platelets.
 * **Prostacyclin** is synthesized via COX2 pathway and released from healthy, intact vascular endothelium and binds to platelet receptors to increased intracellular levels of cAMP. cAMP then inhibits release of granules containing aggregating agents.
 * **Coagulation**
 * **Blood emerges:** escaping blood increases mechanical pressure on normal tissues collapsing surrounding venules and capillaries, thus limiting blood loss. Damage to vessel exposes collagen of subendothelium.
 * **Vessels constrict:** transient vasoconstriction (mediated by vasoactive substances released by platelets). Reduced lumen diameter ↓blood loss and facilitates obstruction by platelets.
 * **Platelets adhere to damaged endothelium and aggregate** : Biochemical reaction involving collagen of endothelial wall and vWF that upon adhesion with platletes causes release of aggregating substances which cause further release in other platelets. “Chain reaction” of platelet adhesion and aggregation eventually produces a thrombus plug that obstructs leak in damaged vessel (must be reinforced by fibrin for long-term effectiveness).
 * **Blood coagulates:** aggregated platelets produce surface for fibrin deposition and coagulation. Platelets the release additional factors to initiate and/or sustain coagulation process.
 * **Coagulation cascade:**
 * TF + Ca2+ + PLs + VIIa → activates Xa
 * Xa then catalyzes conversion of prothrombin (II) → thrombin (IIa)
 * Thrombin then catalyzes conversion of fibrinogen (I) → fibrin (Ia)
 * End result is fibrin reinforcement of aggregated platelet plug.
 * **Extrinsic pathway:** tissue factor→Xa; measured by PTT
 * **Intrinsic pathway:** involves factors in plasma XII-->XI--> etc; measured by aPTT.
 * **Fibrinolysis:** the central process of fibrinolysis is the conversion of inactive plasminogen to the active proteolytic enzyme plasmin. Proteolytic digestion of fibrin by plasmin then limits extension of thrombus. The regulation of fibrinolysis by plasmin is an important site for therapeutic intervention.
 * All fibrinolytic drugs produce rapid lysis of thrombi by increasing formation of plasmin from plasminogen resulting in generalized lytic state.
 * 2.** **For the following categories of drugs utilized in the treatment of disorders of hemostasis, describe their mechanism of action and pharmacokinetics, list their uses, adverse reactions (plus treatment of overdosage if applicable), and drug-drug interactions. Explain the relative advantages and disadvantages of drugs in each category with special emphasis on their use in the following cardiovascular conditions: venous thromboembolic disorders, acute myocardial infarction, atrial fibrillation, percutaneous coronary interventions (pre-, peri-, post-), secondary prevention of myocardial infarction, unstable angina/acute coronary syndrome**
 * **Anticoagulants:**
 * **Heparin/low MW heparins [enoxaparin, dalteparin]**
 * **MOA:**
 * Heparin: acts indirectly by binding to and accelerating activity of antithrombin III 1000-fold in inhibiting the activated clotting factor proteases.
 * Antithrombin III: inhibits action of activated factors IIa, IXa, Xa, Xia, XIIa, XIIIa→preventing conversion of prothrombin to thrombin and fibrinogen to fibrin.
 * LMWH: Binds to ATIII and inactivates factor Xa, but not IIa (thrombin)
 * **PCK:** no PO—all IV, SC or IM. Does not cross placenta. Short half life, continous infusion preferred for constant therapeutic effect.
 * **Use:** adjunct in treatment of coronary occlusion in unstable angina/acute MI; prophylaxis/treatment of DVT.
 * **Adverse reactions:** hemorrhage, hypersensitivity, thrombocytopenia, osteoporosis
 * **Overdose treatment:** protamine. Complexes with and neutralizes heparin.
 * **Drug-drug interactions:** increases bleeding tendencies with drugs that interfere with platelet aggregation (aspirin, indomethacin, ibuprofen, dextran).
 * **Warfarin**
 * **MOA:** Acts in liver to prevent synthesis of clotting factors (II, VII, IX, X). VitK analog prevents reactivation of vit K.
 * **PCK:** 100% oral absorption; cross placenta—contraindicated in pregnancy; metabolized by CYP2C9—source of ddi.
 * **Use:** Atrial fibrillation (prevention of thrombolytic complications); prophylaxis (patients with prosthetic heart valves)/treatment (of established disease) of venous thromboembolism patients with prosthetic heart valves)
 * **Adverse reactions:** hemorrhage, necrosis of fatty soft tissue, GI, osteoporosis, contraindicated in pregnancy.
 * **DDI:**
 * Increased effect (inhibition of metabolism): amiodarone, cimetidine, fluconazole, fluoxetine, metronidazole, rosuvastatin; interfere with platelet of vit k function—aspirin, oral antibiotics.
 * Decreased effect: PCK—barbiturates, carbamazepine, Phenytoin, rifampin, St JW, cholestyramine, colestipol. VITAMIN K.
 * **Thrombolytic agents**
 * **Streptokinase**
 * **MOA:** complexes with plasminogen, then converts uncomplexed plasminogen to active plasmin→systemic activation of plasmin.
 * **PCK:** infusion
 * **Use:** acute MI, multiple PE, DVT, arterial thromboembolism.
 * **AE:** hemorrhage, antibody formation.
 * **Tissue plasminogen activator (tPA)**
 * **MOA:** binds to fibrin and selectively activates bound plasminogen under physiological conditions→clot selective.
 * **PCK:** bolus followed by infusions; weight based dosing.
 * **Use:** acute MI, multiple PE, DVT, arterial thromboembolism.
 * **Antiplatelet agents:**
 * **Aspirin**
 * **MOA:** inhibits platelet aggregation; greater effect on circulating platelets COX1 (inhibits TXA1 synthesis) ↓ tendency for clotting
 * **PCK:** effective orally in low dose
 * **USE:** acute MI, unstable angina, percutaneous coronary interventions, secondary prevention of myocardial infarction, secondary prevention of ischemic stroke
 * **AR:** side effects generally rare with low dose; dyspepsia, nausea, vomiting, GI bleeding.
 * **Clopidogrel**
 * **MOA:** ADP receptor antagonist interferes with ADP-induced platelet aggregation.
 * **PCK:** orally 3-4 times a day before meals.
 * **USE:** acute MI, unstable angina, percutaneous coronary interventions
 * **AR:** better tolerated and preferred agent.
 * **Dipyridamole**
 * **MOA:** blocks PDE breakdown of cAMP, ↑cAMP and potentiating prostacyclin’s anti-aggregatory action.
 * **PCK:** once daily; slow onset, often given with loading dose.
 * **Use:** secondary prevention of ischemic stroke
 * **AR:** side effects are minimal and transient; some dizziness, GI distress.
 * **abciximab/epifibatide/tirofiban**
 * **MOA:** blocks IIb/IIIa receptors on platelet thus preventing integrin and fibrinogen binding that facilitates aggregation→blocks all pathways of platelet activation
 * **PCK:** continuous IV infusion.
 * **Use:** percutaneous coronary interventions
 * **AR:** bleeding.

=Intro to the 12-Lead ECG Interpretation= a. I, II, III, avF, aVL, aVR – Bipolar, (a indicates augmented) b. V1-V6 – unipolar c. V1&V2 – septal wall and right ventricle d. V3& V4 – anterior surface of the heart e. V5 & V6 – left ventricle (especially lateral) f. II, III, avF – inferior portion of the heart g. I, aVL – high lateral portion of the heart. a. Normal QRS axis – positive I and II, negative III b. L.A.D – negative II, positive I, negative III c. R.A.D – positive III, negative II, negative I, a. Left bundle branch block – Away from V1 and toward V6, widended QRS i. Anterior hemiblock – ii. Posterior hemiblock - b. Right bundle branch block – Towards V1 and Towards V6, widened QRS a. Hypertrophy – more conduction, thus more voltage on ekg. V5,6 have greater voltage in left ventricular hypertrophy. V1,2 greater voltage in right ventricular hypertrophy. a. Inverted t waves
 * 1.** **Learn the lead systems of the 12 lead ecg and the planes and regions monitored by the individual leads.**
 * 2.** **Learn how to determine the frontal plane QRS axis.**
 * 3.** **Learn the EKG findings in right and left bundle branch block**
 * 4.** **Learn to distinguish Right and left ventricular hypertrophy**
 * 5.** **Learn the ECG finding in actue coronary syndromes**

=Valvular Heart Disease=
 * 1.** **Describe the ventricular anatomic and hemodynamic responses to aortic valvular stenosis and regurgitation, i.e pressure and flow overloads**
 * **Aortic valve stenosis:**
 * **Ventricular anatomy:** aortic valve becomes fused, narrow and unable to open under normal pressures.
 * **Hemodynamic response:** ↑end diastolic pressure ↑systolic pressure, ↓aortic diastolic pressure.
 * **Aortic valve regurgitation (insufficiency)**
 * **Ventricular anatomy:** aortic valve can not close properly to allow the build up of pressure during diastole. Vegetation may be present and causing the destruction of the valve.
 * **Hemodynamic response:** ↑stroke volume, ↑pulse pressure,↓ aortic diastolic pressure (blood leaks back)
 * 2.** **Review the CAUSES, HEMODYNAMIC EFFECTS, SYMPTOMS AND SIGNS of: a) aortic stenosis and regurgitation; and b) mitral stenosis and regurgitation**
 * **Aortic stenosis**
 * **Causes:** bicuspid aortic valve (most common congenital heart disease), senile aortic stenosis, rheumatic heart disease
 * **Hemodynamic effects**
 * **Symptoms**
 * Dyspnea on exertion
 * Syncope
 * Angina (hypertrophy, ↑systolic pressure, ↓aortic diastolic pressure, ↑end diastolic pressure)
 * **Signs:**
 * Murmur:
 * Ejection __+__ thrill (diamond or crescendo-decrescendo)
 * Peaks later as stenosis becomes more severe.
 * Radiates to neck.
 * Heart sounds:
 * S2: becomes softer as valve becomes more immobile and if myocardium deteriorates.
 * Opening: sudden forceful valve opening or high pressure jet hitting aorta
 * S4: LVH
 * S3: if ventricle fails.
 * If LV fails: narrow pulse pressure, peripheral vasoconstriction, rales, S3
 * If RV fails too: ↑JVP, peripheral edema.
 * **Aortic regurgitation**
 * **Cause:**
 * **Aortic leaflet disease:** bicuspid valve disease, rheumatic heart disease, endocarditis.
 * **Aortic root disease:** aortic aneurysm/dissection, marfan’s syndrome, syphilis.
 * **Hemodynamic effects:** low aortic diastolic pressure, large stroke volume, high pulse pressure.
 * **Symptoms:** well tolerated, symptoms of heart failure only after years.
 * **Signs:** wide pulse pressure bounding (waterhammer) pulses, capillary pulses (quinke), diastolic decrescendo murmur (turbulence), displaced vigorous LV apex impulse.
 * **Mitral stenosis**
 * **Cause:** rheumatic heart disease (4:1 in females)
 * **Hemodynamic effects:** obstruction of flow from left atrium to left ventricle→↑LA pressure↑PA and RV pressure.
 * **Symptoms:**
 * ↑ Left atrial and pulmonary capillary pressures: dyspnea, cough, pulmonary edema
 * RV failure: ↑elevated jugular venous pressure, edema.
 * **Signs**
 * **Diastolic murmur:** heard best in left lateral decubitus, soft, accentuated when flow is greatest; loud S1; opening snap (as mitral valve gets more severe).
 * **CXR:** signs of ↑LA pressure→LA enlargement, Kerley B-lines and heart failure, pulmonary artery enlargement.
 * **Mitral regurgitation**
 * **Cause**
 * **Hemodynamic effects**
 * **Symptoms**
 * **Signs**
 * 3.** **Describe the use of diagnostic tools in the identification and quantification of these abnormalities**
 * **Chest X-ray (CXR):** used to identify symptoms related to each disorder
 * **Aortic stenosis:** post-stenotic dilation of aorta, enlarged LA and LV if failure occurs.
 * **Aortic insufficiency:** LV enlargement, dilated aorta.
 * **Mitral stenosis:** signs of elevated LA pressure—LA enlargement, Kerley B-lines and heart failure, pulmonary artery enlargement.
 * **ECG:**
 * **Aortic stenosis:** LVH, occasionally L or R Bundle Branch Block.
 * **Aortic insufficiency:** LVH
 * **Mitral stenosis:** left atrial enlargment, RVH
 * **ECHO:**
 * **Aortic stenosis:** abnormal valve structure, ventricular hypertrophy, dilated aorta, pressure gradient, aortic valve area.
 * **Aortic insufficiency:** valve or root pathology, ventricular enlargement, amount of aortic insuffiency.
 * **Mitral stenosis:** abnormal valve, pulmonary pressures, mitral valve area.
 * 4.** **Review the natural history (behavior over time) of each of these abnormalities and timing and nature of therapeutic intervention**
 * **Aortic stenosis:** can occur early in life due to a congenital malformation (bicuspid aortic valve) or late in life (senilar aortic stenosis, or somewhere in between (rheumatic heart disease). Good health and youth can mask the symptoms making younger people more at risk for sudden death. After the onset of symptoms however, there is a sharp decrease in survival, thus, treatment and therapeutic interventions should take place right away.
 * **Aortic insufficiency:** generally well tolerated until symptoms of heart failure appear (generally takes years). However, quick response to treat the ventricular hypertrophy associated with aortic insufficiency via replacement of the valve can result in the ventricle returning back to its near normal state.
 * **Mitral stenosis:** treat urgently can cause heart failure and atrial fibrillation.
 * 5.** **Describe the kinds of valve abnormalities produced by valve infection (endocarditis)**
 * **Aortic insufficiency** can be caused by endocarditis (aortic stenosis is rarely caused by endocarditis).