Heart Development

Overview Primitive system is developed(ing) by week 4 First system to function Primitive heart tube is formed from the lateral folding and fusion of the endocardial heart tubes EMBRYONIC STRUCTURE ADULT STRUCTURE

Sinus venosus

Smooth part of RA (sinus venosus), coronary sinus, crista terminalis

Auricles (trabeculated atria) Trabeculated part of ventricles Smooth part of ventricles Aorta, pulmonary trunk

Primitive atrium Primitive ventricle Bulbus cordis Truncus arteriosus

Vascular Development Two ways: 1. Vasculogenesis Blood vessels arise from hemangioblasts/blood islands SV:sinus venosus, PA:primitive atrium, Forms major vessels PV:primitive ventricle, BC:bulbus cordis, FGF initiates hemangioblast formation TA:truncus arteriosus VEGF begins vasculogenesis 2. Angiogenesis Vessel formation via branching of Partitioning of AV Canals existing vessels After folding, atria and ventricles are seperated by narrow AV Initiated through VEGF regulation canal Dorsal and ventral blocks of tissue grow together Forming ECC in the middle of the heart (critical first step) Divide single AV canal into right & left AV canals Provides anchor for septum, valves & walls Formation of ventricular septum Interventricular septum grows up towards ECC and stops (muscular portion) Forms the interventricular foramen Filled in by membranous portion (migrating neural crest cells) Obliterates the interventricular foramen Complications result in ventral septal defects (VSDs) Formation of atrial septum Septum primum grows down towards and fuses with ECC Tissue regression forms a hole near the top (foramen ovale) Septum secundum drops down covering opening, creating one way valve Fossa ovalis (viewed from RA) or valve of foramen ovale (viewed from LA) Foramen ovale allows blood to be shunted from the RA to LA during fetal life After birth, the increased pressure in the LA (due to lung expansion) closes the foramen ovale Limbus is the rim around the fossa ovalis in the RA Formed by septum secundum

Great Vessel Partitioning Neural crest cells invade ridges that form BC and TA Seperates the truncus arteriosis Vessels form via a spiral method Derivations of Aortic Arches Arches I - III Head & neck circulation Arch IV Arch of the aorta Arch V Disappears Arch VI Forms the left & right pulmonary arteries and the ductus arteriosus

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Fetal Hematopoeisis & Circulation

Embryonic Hematopoiesis Three phases: 1. Primordial Cells arise from yolk sac and aorta-gonadmesonephros (AGM) region These also colonize the liver Yolk-sac derived blood cells express gene Runx1 2. Hepatosplenothymic Weeks 4-8 Highest hematopoietic activity 3. Medullolymphatic Week 9+ By 5th month, bone marrow is major site Shifts are regulated by cortisol

Embryonic Hematopoiesis

Vitelline & Umbilica Shunts Vitelline Vitelline circulation supplies & drains the yolk sac Vitelline veins become incorporated into the liver, the IVC & some GI veins Liver develops in the septum transversum (diaphragm area) Umbilica Umbilica vein loses direct connection with the heart Joins large venous shunt around the liver (ductus venosus) connecting to IVC
Umbilical Circulation High pressure in the RV & lungs (due to closed circulation in the uninflated lungs) keeps the tricuspid valve "closed", shunts the majority of the blood through the foramen ovale and through the ductus arteriosus

Changes Post-Parturition Clamping of umbilical arteries & veins increases fetal TPR Ductus venosus closes Lungs expand and pulmonary resistance falls LV& LA generate much greater pressures to overcome increased TPR Greater than RV & RA which is now pumping against a low resistance This reversal of pressure gradients closes the foramen ovale Flow reverses through the ductus arteriosis From aorta to pulmonary artery (Left-to-right shunt) Increased PO2 & hormonal changes (decreased prostaglandins) closes the ductus arteriosis Two major factors that cause blood flow pattern changes following birth: Increased systemic vascular resistance Decreased pulmonary resistance

Fetal-Postnatal Derivatives Umbilical vein Ligamentum teres hepatis Umbilical arteries Medial umbilical ligaments Ductus venosus Ligamentum venosum Ductus arteriosus Ligamentum arteriosus

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Congenital Heart Disease I

Overview VSD is the most common, followed by ASD Pathogenesis Genetic mutations DiGeorge syndrome 4th brachial arch and the 3rd & 4th pharyngeal pouches develop abnormally Abnormal formation fo the thymus, parathyroids & heart Turner syndrome (monosomy X), and trisomies 13, 18 & 21 Most common genetic cause of congenital heart disease is Down syndrome 40% of patients of 1+ heart defects (usually the atrioventricular septae & valves) Maternal factors Maternal metabolic disorders DM Maternal teratogen exposure Alcohol - septal defects Dilantin - AS, PS, CoA Maternal rubella - PDA, PPS, septal defects Three categories Right-to-left shunts Left-to-right shunts Obstructions Screening for CHD 30-60% of congenital heart disease can be detected by careful prenatal U/S (ultrasound) at 20 weeks Every newborn should have: Pulse-ox on right foot Screens for PDA 4 extremity BPs Good initial ausculatory exam Heart is completely formed by 7 weeks

Left-to-Right Shunt (acyanotic, late cyanosis) Pulmonary flow is increased but it is not associated with cyanosis Can lead to RVH & atherosclerosis of the pulmonary vasculature Prolonged pulmonary vasoconstriction (as a result of increased pulmonary pressure) can lead to vascular wall proliferation (irreversible) Pulmonary vascular resistance reaches systemic levels inducing a new right-to-left shunt (Eisenmenger syndrome) Types ASD VSD Patent ductus arteriosis AVSD

Right-to-Left Shunt (cyanotic, early) Causes hypoxemia and cyanosis ("blue baby") Poorly oxygenated venous blood mixes with the systemic arterial blood Tetralogy of Fallot Transposition of the great vessels Patent foramen ovale Patent truncus arteriosis Failure of the separation of the embryological truncus arteriosis into the aorta and pulmonary artery Tricuspid atresia Total anomalous pulmonary venous connection (TAPVC) Pulmonary veins fail to join the LA Emboli arising in peripheral veins can directly enter systemic circulation Stroke Long standing cyanosis can lead to clubbing & polycythemia

Obstructions Abnormal narrowing of chambers, valves, or blood vessels Coarctation of the aorta Aortic valvular stenosis Pulmonary valvular stenosis Complete obstruction (atresia)

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Congenital Heart Disease II

Tetralogy of Fallot Four cardinal features are all caused by the anterosuperior displacement of the infundibular septum VSD Obstruction of the right ventricular outflow tract (subpulmonary stenosis) Aorta overrides the VSD RVH Morphology Heart is enlarged and "boot shaped" The aortic valve forms the superior border of the VSD Overrides both chambers Narrow infundibulum and pulmonary valve stenosis Sometimes blood flow through a patent ductus arteriosis is necessary for survival ASD may also be present Clinical features Right-to-left shunting can develop (classic TOF) Cyanosis Subpulmonary stenosis protects the pulmonary vasculature RV failure is rare because the RV shunts its blood into the LV and aorta (preventing hypertrophy) "tet attacks" Cyanotic episodes that are relieved when the patient squats Repair Closure of VSD Resection of infundibulum Widening of pulmonary valve Transposition of the Great Vessels Aorta arises from the RV and the pulmonary artery from the LV Defect stems from abnormal formation of the aortopulmonary septum Only patients with a shunt (PDA) will survive as the pulmonary and systemic circulations are completely separated

Patent Foramen Ovale Results in a right-to-left shunt Foramen ovale is a one-way valve Closes permanently in 80% of people Lutembacher's syndrome Mitral stenosis after RF causes marked LA dilation & stretch This re-opens the foramen ovale Huge left-to-right shunt

ASD Abnormal, fixed opening in the atrial septum Not a patent foramen ovale Morphology Three types: Secundum (90%) Deficient or fenestrated fossa ovale Exam will reveal the loss of physiologic splitting of S2 Primum (5%) Occur adjacent to AV valves, often in Down's kids Senus venosus (5%) Located near the entrance to the SVC Clinical features Left-to-right shunt Pulmonary over-circulation Low pressure, high volume Does NOT lead to cor pulmonale in children Cor pulmonale is caused by high pressure

Tricuspid Atresia Survival is only possible if there is an ASD and a patent ductus Only a single useful ventricle (LV) No tricuspid valve Will NOT be repairable Can be palliated Fontan circulation Reroute the circulation LV -> systemic -> lungs -> LV Steps to Fontan physiology 1. Blalock-Taussig shunt Birth Shunt between R. innominate artery & R. pulmonary artery Allows for growth and physiologic drop in pulmonary vascular resistance (necessary for next step) 2. Bidirectional Glenn shunt 6-12 months SVC is disconnected from the heart directly to the right pulmonary artery 3. Fontan completion 18-36 months IVC is disconnected from the heart and reconnected to the pulmonary artery

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Congenital Heart Disease III

VSD Morphology 90% involve the membranous interventricular septum There is a higher proportion of muscular VSDs, but they close spontaneously Clinical features Left-to-right shunt RVH & pulmonary hypertension Overtime there will be irreversible pulmonary vascular disease, shunt reversal, cyanosis & death Patent Ductus Arteriosis (PDA) The ductus arteriosis remains open after birth Produces a "machine like" continuous murmur The shunt is originally left-to-right but there will be eventual shunt reversal PDA can accompany other defects (such as aortic valve atresia) in which the ductus arteriosis is vital for survival In this case it can be kept open with prostaglandin E until a repair can be made Closure can be spontaneous Indomethacin can close the defect (primarily in premature infants) Coil embolization is the preferred method of closure in older children

Atrioventricular Septal Defect (AVSD) Result of embryologic failure of the superior & inferior ECC fusion Incomplete closure of the AV septum & malformation of the tricuspid and mitral valves 1/3 of all patients have Down syndrome

Coarctation of the Aorta Narrowing of the aorta Frequently seen in Turner syndrome Two forms Infantile (preductal) R-to-L shunt Tubular hypoplasia proximal to a patent ductus arteriosis Surgical intervention is required Adult (postductal) No shunt, acyanotic Infolding of the aorta disal to the ligamentum arteriosum Often there is hypertension in the upper extremities & weak pulse in the lower extremities Development of colateral circulation through enlarged intercostal and internal mammary arteries Significant coarctations can produce cardiomegaly due to LVH

Aortic Stenosis & Atresia Can occur: Valvular Subvalvular Supravalvular Valvular The cusps may be hypoplastic, dysplastic or abnormal in number ("fibrous diaphragm") Hypoplasia of the LV & ascending aorta Usually fatal Subvalvular (subaortic) Can be caused by a thickened ring of dense endocardial tissue below the cusps Associated with a crescendo-decrescendo systolic murmur and a thrill Supravalvular Inherited form of aortic dysplasia Ascending aortic wall is greatly thickened Hypercalcemia & facial anomalies (Williams-Beuren syndrome)

Pulmonary Stenosis & Atresia RVH often develops Blood reaches the lungs through a PDA

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Congenital Heart Disease IV

CHD by Disorder Down's ECC defects VSD & ASD Turner's Coarctation of the aorta Immotile cilia (Kartagener's) Mirror-image hearts Fetal alcohol syndrome VSD Diabetic mother Transposition of the great vessels 22q11 deletions Patent truncus arteriosus & TOF Maternal Rubella PDA, septal defects Malpositions of the Heart Acardius Birth defect where there is no heart If to term, it is because the child shares circulation with a twin Dextrocardia Heart is on the right side Kartagener's syndrome can lead to dextrocardia Situs inversus totalis Everything is backwards

Hypoplastic Left Heart Underdevelopment of the aortic & mitral valves, LV and proximal aorta Usually lethal & the family is not required to treat this condition (palliative care)

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Superficial Heart I
Layers of the Heart (Inside -> Out) Endocardium Innermost layer that contacts the blood Simple squamous Myocardium Composed of myocytes Pericardium Double layered sac: Outer fibrous covering Double-walled serous layer Parietal layer next to fibrous covering Visceral layer (epicardium) next to heart Transverse sinus Transverse space between the artrial and venous mesocardia Behind aorta & pulmonary trunk but in front of superior vena cava Oblique sinus Space behind the entire heart (posterior) Blood supply Pericardiocophrenic artery and vein Azygous vein Innervation Vagus n. Sympathetic trunks Vasomotor Phrenic Sensory/pain Heart Organization Pulmonary trunk is anterior Aorta is posterior Mitral valve is left ventricle (L w/ L) Tricuspid is right ventricle Semilunar valves separate ventricles from arteries Mitral & tricuspid separate atria from ventricles

Anterior = top; posterior = bottom. P = pulmonary, A = Aorta, M = mitral, T = tricuspid.

Projection of Pericardium & Heart on Body Wall Pericardium 2nd rib - 5th intercostal space 2cm to left and right of sternum Heart 3rd rib - 5th rib Pericardiocentesis Upper left of xiphochondral junction Just to left of xiphoid process Angle needle in posterosuperior direction

Other Heart Surface Landmarks Sulcus terminalis Shallow, vertical depression (groove) on the surface of the RA Seperates RA and SVC SA node resides here Coronary sulcus Seperation of atria & ventricles Interventricular sulci Anterior and posterior grooves indicating the interventricular septum

Surfaces and Borders of the Heart Sternocostal/anterior RV (pressed during CPR) Diaphragmatic Inferior LV & RV Pulmonary Left LV & LA Right RA Base Top of the heart LA & RA, great vessels Apex Bottom left (tip of left ventricle)

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Superficial Heart II
Coronary Arteries/Veins Branches of the right coronary artery Right marginal Supplies: Lateral wall of RV Posterior descending Supplies: Posterior wall of LV (80%) Posterior 1/3 of interventricular septum (80%) SA nodal Supplies: SA node AV nodal Supplies: AV node Branches of the left coronary artery Left anterior descending (LAD) Supplies: Apex Anterior wall of LV Anterior 2/3 of interventricular septum Circumflex Supplies: Lateral wall of LV Posterior wall of LV (20%) Posterior 1/3 of interventricular septum (20%) Main cardiac veins Coronary sinus Anterior cardiac veins

Cardiac Landmarks. 1.SVC 2.RA 3.Aortic arch 4.Main pulmonary artery 5.Left atrial appendage 6.Left ventricle

Cardiac Size Should be 50% of less of entire chest diameter

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Heart Interior
Papillary Muscles Three in the right ventricle (attach to tricuspid valve) Anterior attaches to anterior and posterior cusp Posterior attaches to posterior and septal cusp Septal attaches to septal and anterior cusp Attached through chordae tendineae Two papillary muscles in the left ventricle (anterior & posterior) attach to both cusps of the mitral valve (anterior & posterior) Ventricles Covered by trabeculae carnae Left 2-3x thicker than the right ventricle Aortic sinuses house the openings to the right & left coronary arteries respectively Right Septomarginal trabeculae Contains part of right conducting bundle Partially gives rise to the anterior papillary muscle

Semilunar Valves Each cusp has a: Central nodule Lunula Curved border moving away from nodule Conduction System SA node is located at the junction of the SVC and the RA, above the terminal crest AV node depolarizes the Bundle of His Transfers AP from atria to ventricles Bundle of Kent Bypasses th AV node if conduction through AV node/Bundle of His isn't operating properly Wolff-Parkinson-White See a delta wave on EKG

Cardiac Plexus SA node is innervated by the right half of the cardiac plexus AV node is innervated by the left half

Cardiac Skeleton Roles: Keeps valves patent Attachments for leaflets and cusps of valves Attachment for myocardium Electrical "insulator" seperating atrial and ventricular conduction Parts: Annuli fibrosae 4 rings that surround valve openings Trigona fibrosae 2 triangular masses connected to the annuli fibrosae Septum membranaceum Dense fibrous plate that forms parts of interatrial and interventricular septa

Annuli fibrosae (circles); Trigonal fibrosae (triangles); Septum membranaceum (SM & dotted line)

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Cardiac Action Potential I

Key Facts [K+]I >> [K+]e [Na+]e >> [Na+]I Inward current Depolarization -> positive charge enters cell Resting membrane potential becomes less negative Outward current Hyperpolarization -> positive charge leaves cell Resting membrane potential becomes more negative 1. 2. 3. 4. 5. 6. Action Potential (AP) Review Membrane potential crosses threshold Na+ open, Na+ enters cell Rapid depolarization Na+ gates close K+ gates open, K+ leaves cell Cell repolarizes

Fast Action Potential Caused by changes in permeability (conductance) of K+ , Na+ , and Ca+ + Changes are the result of voltage dependent gates Phase 4 Resting High K+ , low Na+ & Ca+ permeability Phase 0 High Na+ permeability Na+ flows in Phase 1 Decreasing Na+ permeability, increasing K + permeability K+ flows out Phase 2 High Ca+ permeability, low K + permeability Ca+ gates open, K+ gates close Ca+ flows in, offsetting repolarization by K + Phase 3 High K+ permeability (causative change), low Na+ and Ca+ permeability Timed K+ gates open, K+ flows out, repolarizing cell Duration of K+ gate timer determines length of AP/contraction force Different gates are in different areas of the heart Depolarization in Phase 0 caused the Ca + gates to open, the opening of the K + gates closes them

Cardiac AP Self generating and propagates from myocyte to myocyte All or none Phases of cardiac AP Systole Heart is contracting Depolarization of ventricular myocytes Diastole Heart is relaxed Follows myoctye repolarization Sequence SA node Atria AV node Purkinje system Ventricles Types of cardiac APs Fast Atria, ventricles and purkinje system 5 phases 4. Resting potential 0. Rapid depolarization 1. Initial, incomplete repolarization 2. Plateau 3. Repolarization Slow SA and AV nodes Automatically depolarizes during rest phase

Slow AP No fast Na+ gates Depolarization proceeds slowly Resting potential is closer to -60mV (vs. -80mV in fast) The amplitude of the depolarization is smaller Slow AP tissues will spontaneously depolarize slowly during Phase 4 to reach threshold without outside influence

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Cardiac Action Potential II

AP Points of Interest Usually, concentration gradients are maintained, even after several APs Changing the plasma concentration of ions usually doesn't change the net charge either because the change is usually accompanied by a equal and opposite change in the other ion species The more beats/min, the shorter the duration of depolarization (Phase 1/2) Conduction Velocity of AP The greater the AP amplitude, the faster the depolarization in Phase 0, and the larger the cell diameter,the faster the conduction velocity Slow vs. Fast Tissue (Cells) Fast contractile Myocytes have a larger diameter High amplitude and rapid onset AP's Fast non-contractile (purkinje fibers) Very large diameter with rapid upstroke Slow (AV & SA nodes) Small diameter Low amplitude AP's Slow depolarization

K+ and Ca+ + have an inverse relationship

Action Potential Proliferation APs spread throughout heart as if it was one, giant cell Due to intercalated disks & gap junctions Termination of AP's When AP's spread throughout the tissue, they eventually meet Once they meet, they cannot proceed further as the tissue in front of them is in a refractory period Re-entry When AP's never meet AP "chases it's tail" around and around the heart Results in heart "twitching" Fatal

Automaticity Slow cardiac tissue will gradually depolarize during phase 4 SA node (120-100/min) Normal pacemaker Sinus rhythm AV node (60-40/min) Purkinje fibers (40-30/min) Slow depolarization in phase 4 is due to special Na+ channels Begin opening during phase 3 Continue to open during phase 4 Cause membrane potential to gradually depolarize Ectopic focus/pacemaker AP's originating anywhere else besides the SA node AV node & purkinje fibers Overdrive suppression The fastest functioning slow tissue will set the HR

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Cardiac Action Potential III

Electromechanical Coupling AP travels along surface of myocytes AP penetrates cells via T-tubules Ca++ enters the cell from the surface and T-tubules during AP plateau The elevated intracellular Ca++ triggers more Ca++ release from the SR Slightly different from skeletal muscle Ca++ binds to troponin & contraction proceeds Autonomic Influences Sympathetic stimulation increases the depolarization rate Positive chronotropic effect 1 receptors Norepi Increases Ca++ permeability Parasympathetic stimulation decreases depolarization rate Negative chronotropic effect Muscarinic receptors Ach Increased K+ permeability Force of Contraction PRELOAD Frank-Starling law of the heart The more actin/myosin fibers are stretched, the stronger the force of contraction Preload is defined as the tension on the ventricular or atrial walls as contraction begins

Sympathetic & Parasympathetic Stimulation Sympathetic Increased force of contraction & conduction speed (HR) Via activation of 1 receptors Increases intracellular Ca++ Norepi & cardiac glycosides (Digoxin) have same effect by inhibiting Na+/K+ pump Also increases rate of Ca++ reuptake Shortens phase 2 (systole) Vasculature effects Constriction via 1 receptors Relaxation via 2 receptors Parasympathetic Weak effect on contractile myocytes Decreased HR via Ach receptor In atria only

Top is contractive force, bottom is tension force. K+/Ca++ Changes Hypokalemia Causes hyperpolarization Influences Na+/K+ pump Low K+ leads to membrane depolarization because loss of ability to pump Na+ out Needs K+ for ion exchange Hyperkalemia Partial membrane depolarization Causes a slowed AP & alters phase 3 Reduced amplitue of the AP Hypocalcemia Decreased contractility Hypercalcemia Increased contractility

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Cardiac Output
Cardiac Output (CO) CO = BP/TPR TPR (total peripheral resistance) BP = MAP (Mean Arterial Pressure) CO = SV x HR HR (heart rate) SV (stroke volume) SV = EDV - ESV EDV (end diastolic volume) ESV (end systolic volume) EF (Ejection fraction) % of blood pumped out with each beat EF = SV/EDV x 100% MAP = diastolic x (1/3)pulse pressure Pulse pressure = systolic - diastolic Inotropy Contractility (inotropy) is controlled by two mechanisms: 1. Intrinsic Frank-Starling Law of the heart 2. Extrinsic Mediated by autonomic system Cardiac Function 2 ways to alter cardiac function: 1. Change the HR Chronotropy 2. Change the force of contraction Inotropy Increasing contractility and SV Sympathetic regulation SA & AV nodes Secrete NE which acts on 1 receptors Increased activity of Ca+ pump in SR Increased intracellular Ca+ Decreased extracellular Na+ Digitalis Inhibit Na+/K+ ATPase resulting in increased intracellular Na+ (and thus increased intracellular Ca+) Decreasing contractility and SV Parasympathetic regulation Vagus N. goes to both SA & AV nodes Secrete Ach which acts on muscarinic receptors 1 blockers Heart failure Acidosis Hypoxia/hypercapnia

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Regulation of MAP
General Detected by baroreceptors or decreased ECV in the kidney

Low Pressure Baroreceptors Located in low pressure areas such as the atria & pulmonary vasculature Reflexes: Increases atrial volume causing increased HR Vasodilation & fluid excretion in response to increased BP Can act as "brakes" when BP may become to high Chemoreceptors that are stimulated to increase ventilation simultaneously increase the HR

Kidney Regulation of MAP Decreased renal blood flow activates the RAAS Results in increased TPR and blood volume Increases MAP Long-term regulation of BP

High Pressure Baroreceptors & Vasomotor Center High pressure baroreceptors are located in the carotid sinus & the aortic arch Sense changes in systemic arterial BP Serve to increase BP Mean firing rate is proportional to BP Decreased firing means BP is low Carotid massage can artificially increase the firing rate and thus lower BP Acts on vasomotor center in the medulla Vasomotor center Increases ANS sympathetic activity Increased NE release Heart (1) Increased HR (Increased CO) Increased contractility (Increased CO & SV) Vasculature () Increased venous tone (increased venous return) Increased TPR Results in increased MAP

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Local Vasculature Hemodynamics

Peripheral Circulatory Control Meant to control flow, not BP Local control of flow is mediated by altering the resistance/vessel radius by: Myogenic reflex Mechanical force on the vessel wall change tone Increased pressure causes vasoconstriction Reduces pressure Sheer stress Increased sheer stress causes vasodilation Metabolic products Myogenic reflex Increase in BP stretches walls of arterioles Stretch causes smooth muscle contraction Vasoconstriction increases resistance of the tissue Purpose is to maintain tissue flow, not alter TPR (although there would be a small increase) Net effect is that if central BP changes, tissue flow remains the same Sheer stress Downstream resistance decreases due to increased metabolism, flow increases Upstream this causes a drag on endothelial walls NO is secreted causing vasodilation This upstream change compliments downstream changes Metabolic regulation CO2, H+, K+, or O2 reduction causes vasodilation Reduction in resistance increases flow Reactive Hyperemia (Repurfusion Injury) Vascular inflow to an area is interrupted or obstructed Causes an extreme vasodilation due to accumulation of vasodilator substances When flow is returned, the area is flooded with a great than normal flow (hyperemia) possibly causing damage

Special Circulations Heart ignores sympathetic stimulation of the vasculature of the heart and only responds to local control Brain also ignores sympathetic stimulation Pulmonary circulation lacks sympathetic stimulation but instead vasoconstricts in response to alveolar hypoxia Directs blood to areas that have O2

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Jugular Venous Pressure

Jugular Venous Pressure S1 1st heart sound Mitral, tricuspid closure S2 2nd heart sound Aortic, pulmonic closure Systole S1 - S2 Diastole Beginning of S2 A wave Atrial contraction Giant A waves seen in: Obsruction between RA & RV Increased pressure in RV Pulmonary HTN A-V dissociation Atria contracts against a closed valve Complete heart block "Cannon A waves" C wave Backward push by the closure of the tricuspid valve X wave Passive atrial filling Steep X descent indicates constrictive pericarditis Tricuspid valve is still closed V wave Atria is filling as pressure increases Tricuspid valve is still closed Y Slope Open tricuspid valve Rapid RV filling

Kussmauls Sign Venous column rises during inspiration, rather than falls Seen in R heart failure

Measuring JVP Place patient in supine position to allow veins to engorge, then raise patient to 30-45 Measure from sternal notch up to level of waveform in jugular vein Add 5cm (due to RA 5cm below sternal notch) Normal is 0-9cm Most common cause of elevated JVP is elevated RV diastolic pressure Also: SVC obstruction HF Constrictive pericarditits Hepatojugular reflex (HJR) Positive indicatesproblems

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EKG Basics I
EKG Characteristics Measures electrical extracellular POTENTIAL Not contraction At rest, the extracellular potential in the heart is +90mV Different from intercellular potential EKGs are measured from the outside of the cell (and body) thus the potential readings are opposite of intercellular potential changes An EKG change is only seen when: Part of the cardiac tissue is at a different potential than the rest of the heart AND current can flow between those two regions No change when atria and ventricles are different potential because they are electrically isolated P wave AP spreading through atria QRS AP spreading through the ventricles T wave Repolarization of the ventricles Atrial repolarization is hidden in the QRS complex Repolarization in the ventricles is mirror-like The last cell to depolarize is the first to repolarize EKG Leads Standard limb leads Placement RA - Right arm LA - left arm LL - left leg Lead 1 Connects LA to RA Looks right to left through heart Lead 2 Connects RA to LL Looks from upper right to lower left Lead 3 LA to LL Upper left to lower left Lead 1, 2 & 3 form Einthoven's triangle Augmented leads aVR Between RA and combo of LA & LL Lower left to upper right aVL Between LA and combo of RA & LL Lower right to upper left aVF Between LL and combo of RA & LA Looks directly down Cardiac Depolarization Path SA node Depolarizes atria P wave AV node Delays signal PR interval Bundle of His Purkinje fibers Ventricles depolarize Generally from right to left Apex to base QRS complex Prolonged QRS could indicate ventricular damage Action potential phase 2 delays repolarization QT interval Ventricles repolarize T wave From left to right and base to apex Last cell to depolarize is first to repolarize (due to K+ channels) Atrial repolarization is buried in the QRS complex

STANDARD LEADS

AUGMENTED LEADS

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EKG Basics II
Axis of Depolarization Calculation Normal axis is lower right quadrant Use QRS complex of any two leads Lead I and AVF work best Determine if vector is positive or negative for each lead by summing the negative value (mm in Q & S waves) with positive value (R wave) Plot both vectors and determine quadrant of vector By simply determining direction (positive or negative) of AVF and lead I, the quadrant can be determined LAD (Left Axis Deviation) Upper right quadrant Often due to LVH RAD (Right Axis Deviation) Lower left quadrant Often due to RVH

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Normal EKG
Wave P Wave Atrial depolarization Upright in 1, 2, V 4-V 6, AVF Inverted in AVR If not inverted on the AVR lead, the depolarization is NOT coming from the SA node P-R Interval From beginning of P wave to beginning of QRS complex Travels through AV & purkinje fibers Typical interval is 0.12-0.20 seconds If less: Pre-excitation, tachyrythmia If longer: AV block QRS complex Ventricular depolartization 0.5-0.1 secs ST segment End of QRS complex to beginning of T wave Observe: Level Shouldn't be elevated more than 1mm in standard leads and 2mm in chest leads Should never be depressed more than 1/2mm relative to baseline Shape Should be isoelectric T Wave Ventricular repolarization Upright in 1, 2, V 3-V 6 Inverted in AVR Should not be greater than 5mm in standard leads Massive T waves can indicate MI QT Duration Length of ventricular systole From beginning of QRS complex to end of T wave Should be less than 1/2 the time interval from R wave to R wave Notes Everything is inverted in AVR Prominent T waves are found in African Americans Abnormal P Waves Notched (Leads 1 & 3) P-mitrale Left atrial enlargement Flat in lead 1; tall in 2 & 3 P-pulmonale Right atrial enlargement Inverted in 2 & 3 AV nodal rhythm

Normal EKG

Left: P-mitrale. Middle: P-pulmonale. Right: AV nodal rhythm.

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Diagnostic Testing
EKG Depressed ST segment Indicates subendocardial injury Elevated ST segment Indicates subepicardial injury Pharmacologic Stress Test Useful in patients who can't exercise Adenosine Contraindications Asthmatics COPD Smokers Dobutamine
Positron Emission Tomography (PET) Assessment of myocardial viability Assesses glucose utilization in hypoperfused myocardium

Stress Testing Used for screening patients for CAD A negative result does not exclude CAD Need a 12-lead EKG before, during & after the test Monitor BP Target HR for patient is 85% max HR Max HR = 220 - age False positives can be due to Digitalis Quinidine Adverse prognosis/positive test ST changes at low workload Low peak HR Greater than 2mm ST depression in any stage ST depression in multiple leads Prolonged ST depression after exercise ST elevation w/o pathologic Q waves Dropped BP Ventricular ectopy (multifocal PVC)

Echocardiography Used in acute MI, aneurysms, pericardial effusions, LV thrombus Not good for coronary arteries Transthoracic echo Useful for assessing chamber sizes, wall motion, valves, pericardium, EF, SV & muscle mass Transesophageal echo Good for posterior heart structures LA, MV, aorta Useful for aortic dissection, patent foramen ovale, vegetations & mitral prosthesis
Positive Stress Test. Top is normal EKG, bottom shows significant ST segment depression with exercise

Cardiac Catherization-Contrast Angiography Gold standard Visualized with X-rays Dye has to be renally cleared Use caution with renal failure Contraindications Uncontrolled ventriculat irritability, hypokalemic, digitalis toxicity, hypertension Fever Decompensated CHF Anticoagulated state Renal insufficiency

Electron Beam Computed Tomography (EBCT) 3D images Measures Ca++ content of coronaries

Radionuclide Imaging Isotopes are taken up by myocytes according to blood flow 2 techniques Labeling RBCs with isotope to assess endocardial motion Tracers to assess differences between resting/stress blood flow Establishes presence or absence of CAD Indications False positive on stress test

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Cardiopulmonary Adaptations to Exercise (Aerobic)

Aerobic Exercise Training methods Interval High intensity w/periods of rest Continuous Steady paced Fartlek Alternate between fast and slow Borg scale Rate of perceived exertion Rate number is associated with a specific heart rate and percieved exertion Reversibility Exercise benefits are transient & reversible There are significant losses after 2 weeks of apathy Cardiac Adaptations Increased stroke volume/ejection fraction Left ventricle Internal dimensions increase Increased ventricular filling Hypertrophy Increased contractility Frank-Starling law Overall result is increased stroke volume Increased EDV and decreased ESV Increased blood volume Increased plasma volume due to: ADH Aldosterone Plasma proteins Total RBC count stays the same Results in dilutional anemia Decreased blood viscosity Pulmonary Adaptations Improves circulation & O2 delivery Diffusion Decreased BP (systolic & diastolic) Increased pulmonary diffusion Reduced adrenergic receptor responsiveness Increased circulation & ventilation Lowered resistance to the flow of blood out of More alveoli involved during maximal exercise LV Respiratory volumes Decreased HR Decreased respiratory rate & pulmonary ventilation Reduced sympathetic tone Increased tidal volume Improved cardiac vagal tone (parasympathetic) Heart expends less energy by contracting more Cellular Respiration Adaptations forcefully Decreased oxygen consumption Increased CO (Q) Better metabolic & mechanical efficiency Increases due to the increase in maximal SV Greater O2 extraction by the tissues More efficient conversion of O 2 to ATP VO2 max increases

Physiologic/Body Composition Adaptations Increased lean body mass & muscle density Decreased body weight and stored fat

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AV Blocks I
1st Degree Block Lengthens the delay between atrial and ventricular depolarization Retards AV node conduction Characteristics P wave precedes QRS complex Prolongs the PR interval >0.2sec Etiology Drugs Digitalis Inflammatory Ischemic

1st Degree AV Block 2nd Degree AV Block Mobitz I (Wenchebach) Progressive PR interval prolongation w/ultimate dropped QRS "Grouped beats" Etiology Results from earlier arrival in relative refractory period of AV conduction Similar etiology to 1st degree Mobitz II PR interval is uniform Random dropped QRS Block occurs below the bundle of His Progressive/irreversible More serious than Wenckebach, can lead to 3rd degree block Etiology Ischemia Degeneration of conduction system

Mobitz I

Mobitz II

3rd Degree Heart Block P waves are unrelated to QRS complexes AV dissociation Can occur above or below the AV node Above (Junctional rhythm) Narrow QRS (rate 40-55) Below (Ventricular rhythm) Wide QRS (rate 20-40) Etiology Ischemic Treatment Pacemaker

3rd Degree Block. Junctional Rhythm

3rd Degree Block. Ventricular Rhythm

Pathology Page 22

AV Blocks II
Fasicular Blocks (Hemiblocks) Term for blockage of one of two main divisions of left bundle branch Types: Left anterior hemiblock (LAH) Left posterior hemiblock (LPH) No significant widening of QRS complex Denotes disease in conduction system LAH Characteristics LAD Small Q wave in Lead I Small R wave in Lead II & AVF Deep S wave in Lead III

II

LAH. Small Q in I, Small R in II and AVF, Deep S in III III AVR

AVL

AVF

LPH Criteria RAD Small R in Lead I & AVL Small Q in Lead II & AVF Less common than LAH I

LPH. RAD, Small R in I and AVL, Small Q in II and AVF II III AVR AVL

AVF

Pathology Page 23

Bundle Branch Blocks (BBB) I

Ventricular Conduction As impulse travels toward the electrode, a + deflection occurs (R) And vice versa (S) Common Features of BBB Wide QRS complex >.12 sec T waves in ST segment slope off in opposite direction of QRS

RBBB Right side is blocked Left side of septum is activated first and moves to the right Followed by left ventricle Then right ventricle Criteria R + R' in V 1 & V 2 Deep S wave in Lead I, AVL & V 6

Sequence of Depolarization in RBBB

RBBB. R + R' in V1 , Deep S wave in I, AVL, & V 6

RBBB

RBBB

RBBB

Pathology Page 24

Bundle Branch Blocks (BBB) II

LBBB Left side is blocked Right side of the septum is activated first and moves to the left Followed by right ventricle Then left ventricle Criteria Deep QS complex in V1 & V 2 Monophasic R waveand no Q wave in Lead I, AVL & V6 Sequence of Depolarization in LBBB

LBBB

LBBB

LBBB

Pathology Page 25

Superventricular Arryhthmias
Supraventricular Tachycardias (SVT) Normal width QRS Etiology Sometimes SVT is normal Drugs Valvular disease (mitral) Ischemic disease (CAD, MI) Increased BP Thyrotoxicosis Classification Ectopic Re-entrant Reciprocating Paroxysmal Starting/stopping abruptly Majority of SVT are reciprocating reentry tach (RT) due to a circulating wave Atrial Tachycardias Sinus tach Atrial fib Atrial flutter Atrial tach Multifocal atrial tach (MAT) When in doubt, call it SVT! Bradycardia Causes: Vagal stimulation Inflammation of SA node Factors released by myocardium following MI Sinus bradycardia AV block Medical conditions assoc. w/bradycardia Acute, inferior MI Ischemia Decreased pO2 Hypercapnia (increased pCO2 ) Acidosis Increased BP SSS (sick sinus syndrome) Drugs Digitalis, quinidine, clonidine & -blockers Treatment of Sinus bradycardia Treat the cause If hemodynamically compromised, symptoms: Decreased BP, CO, SV, renal perfusion (oligiurea), cerebral profusions (confusion), and SOB Treat w/ Atropine or Epi

Atrial Fibrillation Total irregularity of pulse Irregular rate, irregular EKG Features Absence of P wave Normal QRS complexes, irreg in time Combo of A. fib + right axis deviation think mitral stenosis

A. Fibrillation. No discernable P waves.

Atrial Flutter AP "chases its tail" Features Saw tooth pattern Leads II, III & AVF Sharp P-like wave in V 1 Flutter waves are usually 250-350/min 2:1 or 4:1 AV conduction is common 3:1 is less common

A. Flutter. Regular repeating waves, but not always associated w/QRS. Ratio is 4:1

MAT 3 or more different P waves P-R interval varies Irregular rhythm Associated w/ lung disease

MAT. Different P waves

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Ventricular Arrhythmias
Ventricular Premature Beats (VPB)/Premature Ventricular Contraction (PVC) PVC originates from an ectopic focus within the ventricle Can be induced by: Drugs Digitalis toxicity Normal stress Hypoxia Bigemmy Every other beat is a PVC Trigemmy Every third beat is a PVC Quad Every fouth beat is a PVC Morphology of PVC In V 1 Left ventricle ectopics Peak early Upstroke is steep Down stroke is slurred Other leads Distorted QRS complex QRS interval is prolonged ST segment slope is away in the opposite direction of the QRS complex There is a long pause following the PVC before the next sinus beat Deep QS or RS in V6 Fusion beats

PVC
Accelerated Idioventricular Rhythm (AIVR) Seen after administration of thrombolytics Resembles sustained PVC rhythm

PVC. Bigemmy

Monomorphic VT

Polymorphic VT

Torsade de Pointes

Ventricular Fibrillation

Ventricular Tachycardia At least 3 consecutive bizarre QRS complexes Usually irregular P wave often lost Types: Monomorphic Bizarre QRS complexes but, all QRS complexes appear the same Spaced evenly Origin is constant Polymorphic QRS complexes are different shapes Multiple origins Different time intervals Ventricular fibrillation No regular pattern of rate to the rhythm Coarse, irregular pattern Torsade de Pointes Twisting of the QRS complex Associated with prolonged QT interval Treatment If hemodynamically stable Amiodarone, lidocaine or procainamide If hemodynamically unstable Shock

Pathology Page 27

Hypertension (HTN)
General Definition/diagnosis Sustained systolic > 140 mmHg or: Diastolic > 90 mmHg Must be confirmed on three separate occasions Epidemiology & risk factors Black Obesity DM Age Oral contraceptives Familial (genetics) EtOH Smoking Diagnosis Elevated on 2+ occasions Primary HTN Diagnosis of exclusion HTN is the disease, not a symptom Treatment Lifestyle/diet Pharmacological Diuretics Thiazides are 1st line therapy -antagonists ACE inhibitors Good for DM ARBs CCBs -antagonists Secondary HTN Increased peripheral vascular resistance Renal artery stenosis Clinical Sudden onset HTN Abdominal bruit Neurofibromatosis Renal parenchymal disease Treat with ACEIs Pheochromocytoma Adrenal tumors Hyperthyroidism Hyperparathyroidism Acromegaly Hyperaldosteronism Cushing's syndrome Coarctation of the aorta Treatment Treat underlying disease Similar to primary HTN HTN Disease Complications Cardiovascular Atherosclerosis Stroke Left ventricular hypertrophy Heart failure Aortic dissection IHD End-organ damage Retinopathy DM Kidney disease Brain HTN encephalopathy HA/V Visual disturbances Paralysis Convulsions, stupor & coma

Pathology Page 28

Arterosclerosis I
Arteriosclerosis "Hardening of the arteries" Characteristics Arterial wall thickening Loss of elasticity Three general patterns: Arteriolosclerosis Affects intima of small arteries & arterioles Two subtypes: Hyaline arteriolosclerosis Associated with diabetics Hyperplastic arteriolosclerosis Seen in malignant HTN "Onion skinning" Especially renally Monckeberg arteriosclerosis Benign medial calcification of muscular (medium) arteries Lesions do not encroach on vessel lumen and are usually not clinically significant Atherosclerosis Lipid deposition leads to fatty streaks and plaques in the intima Soft, yellow core of lipid with a white fibrous cap Affects medium and large arteries Aorta, coronaries, carotids, cerebral, and popliteal Risk factors: Major Hyperlipidemia, HTN, smoking, diabetes and obesity Minor Male, oral contraceptives, age, sedentary lifestyle, stress, genetics (familial) Epidemiology Risk factors have a multiplicative effect Constitutional risk factors: Age Gender More common in men & post-menopausal women Genetics Tangier disease Patients have near-zero levels of HDL, low LDL & extensive deposition of cholesterol Modifiable risk factors: Hyperlipidemia (hypercholesterolemia) High LDL LDL is the form of cholesterol delivered to peripheral tissues Low HDL HDL is the form of cholesterol delivered from tissue to the liver for excretion Exercise and moderate consumption of alcohol raise HDL Obesity & smoking lower it Hypertension Damges the intima Smoking Smoke oxidizes LDL Diabetes Induces hypercholesterolemia Lack of exercise Additional risk factors: Inflammation Present during all stages of atherogenesis Intimately linked to plaque formation & rupture Hyperhomocystinemia Can be caused by low folate and B12 Metabolic syndrome Characterized by a number of abnormalities associated with insulin resistance Glucose intolerance Hypertension Central obesity Systemic pro-inflammatory state Low HDL Elevated fasting TG Lipoprotein (a) Altered form of LDL Increased Lipoprotein (a) = increased risk Factors affecting hemostasis Increased clotting factors

Pathology Page 29

Arterosclerosis II
Pathogenesis Arteriosclerosis is a chronic inflammatory and healing response of the arterial wall to endothelial injury Pathogenic events: 1. Endothelial injury Causes increased vascular permeability, leukocyte adhesion & thrombosis 2. Accumulation and oxidization of LDL in the vessel wall 3. Monocyte adhesion to the endothelium Transformation into macrophages & foam cells 4. Platelet adhesion 5. Cytokine/factor release Inducing smooth muscle hyperplasia and cell migration 6. Smooth muscle proliferation & ECM production i. Fibrous cap formation, calcification, and ulceration Causes of Endothelial Injury Hemodynamic disturbances (turbulent flow) Occur at branch points & along the posterior wall of the abdominal aorta Laminar flow products protect against arterosclerosis HTN Hyperlipidemia Increased LDL & lipoprotein (a) Decreased HDL Mechanism: Chronic hyperlipidemia can directly impair endothelial functiona via increasing O2 free radical production Lipids are oxidizied by free radicals forming oxidized LDL that is ingested by macrophages (foam cells) Oxidized LDL stimulates growth factor release, cytokines & chemokines Oxidized LDL is also cytotoxic to endothelial cells and smooth muscle Smoking Homocysteine Chlamydia & CMV Cause inflammation and release of inflammatory cytokines Inflammatory cytokines NO, IL-1, TNF &TGF- Dysfunctional endothelial cells express adhesion molecules (VCAM-1) Macrophages adhere and avidly engulf lipoproteins & oxidized LDL T-lymphocytes can generate a chronic inflammatory state

Complications MI, stroke, aortic aneurysms & peripheral vascular disease Atherosclerotic stenosis Critical occlusion is 70% Patients will develop angina (stable) on exertion Acute plaque change/rupture Plaque erosion or rupture is typically followed by partial or complete occlusion (resulting in infarction) Three categories of plaque changes: Rupture Erosion/ulceration Hemorrhage into the atheroma Thrombosis Thrombus superimposed on a disrupted but previously only partially stenotic plaque converts it to a total occlusion Vasoconstriction (leading to MI, angina, etc.) Stimulated by: Adrenergic agonists Locally released platelet contents Impaired secretion of NO Mediators released by inflammatory cells

Smooth Muscle Proliferation Converts a fatty streak into a mature artheroma Growth factors PDGF, FGF & TGF- Smooth muscle cells also synthesize collagen Activated inflammatory cells can cause intimal smooth muscle cell apoptosis & increase ECM catabolism Result: a plaque formerly stabilized by collagen and muscle becomes unstable and susceptible to rupture

Pathology Page 30

Lipoproteins & Hypercholesterolemia I

Lipoproteins Dietary Cholesterol & Chylomicrons Transport lipids/cholesterol Chylomicrons Structure Deliver dietary lipids to fat, muscle & liver Apoptrotein Via lymphatics Target recognition Formed in enterocytes in the small intestine Cellular receptor recognizes apoprotein Aquire ApoC-II & ApoE from plasma HDL Classes of lipoproteins Fatty acids are removed by lipoprotein lipase (LPL) Chylomicron ApoC-II is a co-factor for LPL Main component is TG Fatty acids are absorbed by tissue Apoprotein B48 Chylomicron remnant is broken down by the liver VLDL Chylomicron remnant is composed of cholesterol, Main component is TG ApoE & ApoB-48 Apoprotein B100 IDL LDL/HDL Main component is TG, cholesterol Deliver endogenous cholesterol from the liver Apoprotein B100 1. VLDLs are synthesized in the liver LDL 2. VLDLs are converted to LDLs in the plasma by LPL Main component is cholesterol 3. LDLs are primary plasma carriers of cholesterol delivery Apoprotein B100 to the tissues HDL LDL Main component is protein Long half life Apoprotein AI, AII 75% of LDL uptake is at the liver HDL Facilitates removal of cholesterol from cells Classification of Lipoprotein Disorders Transports cholesterol to liver for bile acid synthesis Type IIA LDL elevated High cholesterol Type IIB LDL & VLDL elevated High cholesterol & triglycerides

Consequences of LDL-R Mutations Class 1 Null alleles Failure to produce protein Class 2 Transport-defective alleles Protein blocked between ER & golgi Class 3 Binding defect alleles Protein fails to bind LDL Class 4 Internalization-defect alleles Protein unable to cluster in clathrincoated pits

Pathways of Lipoprotein Metabolism. LPL: lipoprotein lipase

Pathology Page 31

Lipoproteins & Hypercholesterolemia II

Hyperlipidemias Total cholesterol has the highest heritability for all blood lipid characteristics Familial hypercholesterolemia (FH) Dominant inheritance Defective LDLR on cells leads to increased circulating LDL Can also be a problem w/ApoB-100 (LDL binding protein) but this is rare In the liver Insulin & T3 increase the binding of LDL to receptors Glucocorticoids decreases binding In diabetes & hypothyroidism there is an increase in hypercholesterolemia Symptoms Xanthoma Benign fat deposits beneath the skin Corneal Arcus Common in older patients but rare in young people Xanthelasma Xanthomas on skin of eyelid Compound heterozygotes possible Two different mutations inherited two different mutations from seemingly normal parents The combination of two heterozygote defects in different areas (LDLR, endocytosis failure, etc.) involving LDL intake mimics a homozygous FH patient Apo E Genotypes (Type III) ApoE plays a key role in metabolism of lipoprotein remnants Recognized by the LDL-R Slows down the uptake of remnants resulting in familial dyslipidemia Important for lipid metabolism in the nervous system Three alleles: Residues 112 & 158 ApoE e2 Reduce LDL-R binding Cys & Cys ApoE e3 Normal form Cys & Arg ApoE e4 Arg & Arg Risk factor for Alzheimer's Atherosclerosis risk factor ApoE e2 & e4

Corneal Arcus

LPL/Apo CII Defect (Type I) LPL present on vascular endothelial cells of extra-hepatic tissue Essential for breakdown of TG in chylomicrons LPL deficiency is an autosomal disorder Absence of LPL activity Massive accumulation of chylomicrons/TG Apoprotein CII is a necessary cofactor for LPL Autosomal recessive APO CII is absent Chylomicrons/TG accumulae LDL Receptor (LDL-R) Defect (Type II) LDL-R is key receptor for apoproteins LDL-R uses clathrin-coated pits and is recycled back to the membrane after receptor-mediated endocytosis of chylomicron Domain structure of LDL-R Found on chromosome 19 Ligand binding domain Exon 2-6 EGF precursor homology Exons 7-14 O-linked sugars Exon 15 Membrane spanning domain Exons 16-17 Cytoplasmic domain Exons 17-18 Most mutations are point mutations in the ligand binding and EGF precursor homology domains Familial hypercholesterolemia (FH) Autosomal dominant Defects in LDL-R Symptoms: Coronary atherosclerosis Tendon xanthomas Increased LDL & cholesterol

Pathology Page 32

Myocarditis
Myocarditis Inflammation of the heart muscle secondary to other etiologies Viral Most common etiology CMV (most common) Coxsackie B Rubella Bacterial Staphylococcus aureus Corynebacterium diphtheriae Haemophilus influenzae Chlamydia HIV Coinfection: Trypanosoma cruzi (Chagas) ECG RBBB LAH Complete AV block Lyme disease Borrelia burgdorferi Kaposi's sarcoma Giant cell Results from: Direct damage to the myoctyes by the agent Damage by a toxin produced by an infectious agent Damage due to immunologic injury Treatment Supportive bed rest No vigorous physical activity Steroids worsen myocyte damage Treat arrhythmias with amiodarone Clinical Manifestations of Myocarditis Non-specific ST-segment changes in EKG New EKG/echo findings following a viral illness Chest pain similar to MI Arrhythmias, SVT, PVCs and VT Tachycardia out of proportion with infectious illness CHF during or following acute viral illness Physical exam Usually normal Can demonstrate pericardial friction rub

Giant Cell Myocarditis Multi-nucleated giant cells in myocardium Associated with SLE, thyrotoxicosis, thymoma Typically affects young, middle aged patients Clinical features Cardiac enlargement Ventricular thrombi Myocardial necrosis Often fatal CHF

Pathology Page 33

Pericarditis I
General Pericardium Pericarditis Normal function of pericardium Most common pathologic process that involves the Restricts anatomical movement of the heart pericardium Minimizes friction Clinical classification Retards spread of infection from to the heart Acute Layers <6 weeks Visceral pericardium Subacute Attached/adjacent to the heart 6 weeks - 6 months Parietal pericardium Chronic Fibrous sac superficial to visceral layer >6 months Negative intrapericardial pressure during ejection Etiological classification Infectious facilitates atrial filling during ventricular systole Viral, bacterial, mycotic, TB, parasites Noninfectious MI, uremic, neoplasms, myxedema Autoimmunity SLE, RA, RF Drugs INH, procainamide, hydralazine, minoxidil, chromylin Post-cardiac injury Post-MI (Dresslers syndrome) Cardiac surgery Pericardotomy Signs/symptoms Pain Usually present in infectious & autoimmune type Often severe Pleuritic character Hurts to breathe, cough etc. Sharp, aggravated by inspiration Often relieved by sitting forward CPK-MB & troponin-I levels don't rise (unless associated with a MI) Pericardial Effusion Pericardial friction rub Complication of pericarditis To & fro leathery sound Enlarged cardiac silhouette Heard best during expiration, leaning forward or in Ewart's sign left lateral decubitus position Large pericardial effusion EKG changes Dullness & tubular breath sounds at left Wide spread ST segment elevation WITH UPWARD scapula CONCAVITY Echo Later, ST segment returns to normal Used for diagnosis and to guide needle for Can look similar to a NSTEMI pericardiocentesis Treatment Large effusions NSAIDs & ASA Heart may swing freely in the sac resulting in electrical alternans Chronic pericardial effusion TB is most common cause

Pathology Page 34

Pericarditis II
Cardiac Tamponade Accumulation of fluid in pericardial sac in sufficient amounts to cause obstruction of filling/return Etiology Neoplasm CHF Hemorrhage TB Dissecting aortic aneurysm Clinical features Increased JVD Patient is anxious Decreased BP, heart tone & CO Paradoxical pulses Inspiratory fall in SBP > 10mmHg SOB Electrical alternans 3 classic signs of pericardial tamponade (Beck's triad) 1. Decreased BP 2. Increased JVP 3. Muffled heart sounds

Electrical Alternans. QRS alternates

Chronic Constrictive Pericarditis Results when healing of acute pericarditis is followed by obliteration of pericardial cavity with granulation or scar formation Encases heart and interferes with ventricular filling Decreased stroke volume Clinical features Constiutional Weak, fatigue, weight loss Peripheral edema Dyspnea & orthopnea Kussmaul's sign Distended neck veins that fail to decline on inspiration Ascites & splenomegaly Calcification seen in 50%

Pathology Page 35

Endocarditis
General Endocarditis is inflammation of the lining of the heart and valves Valves are avascular, therefore WBCs can't be recruited to the area Produces vegetations on the endocardium or on a heart valve Associated w/congenital heart disease or valvular disease Types of endocarditis: Infective Libman-Sacks Autoantibody damage due to SLE Sterile vegetations form on both sides of the heart valves Prosthetic valve endocarditis Aorti c valve is more effected than mitral Arising within 2 months post surgery Coag. (-) staph & Staph aureus Arising 2-12 months post surgery Coag. (-) staph Arising 12 months post surgery Strep viridans Always fatal if untreated Physical Exam New or changing murmur Especially diastolic Hepatosplenomegaly Mucocutaneous petechiae Roth spots Flamed shaped hemorrhagic lesions w/pale centers in the retina Osler's nodes Tender, painful, erythematous lesions on the palms & soles Janeway lesions Non-tender, non-painful , erythematous, papular lesions Splinter hemorrhages Linear streaks under the fingernails & toenails Positive cultures Classification Acute Usually involves normal heart valves Usually caused by S. aureas Associated with IV drug abuse Rapidly destructive, produces metastatic foci of bugs Pulmonary emboli Septic pneumonia Fatal in 6 weeks Subacute Involves previously damaged valves Caused by Strep viridans Does not produce metastatic foci Prolonged course (1 year)

Etiology and Presenting Factor Prosthetic device Staph epidermidis (<6 months) >6 months Staph aureus Strep viridans Dental procedure Strep viridans Alcoholics/homeless Bartonella henselae Fastidious/culture negative HACEK group Haemophilus Actinobacillus Cardiobacterium Eikenella Kingellla IV drug abuse S. aureus Pseudomonas aeruginosa Candida

Endocarditis Treatment Prophylaxis only used for HIGH risk patients Porsthetic heart valves Prior bacterial endocarditis Surgical shunts Congenital heart disease Dental, oral or upper respiratory surgery

1. 2. 3. 4. 5. 6.

General Clinical Symptoms Fever Weakness/fatigue Night sweats Arthralgias Embolic manifestations HF Fever, Murmur & Anemia! Echocardiogram Visible vegetations

Pathology Page 36

Cardiomyopathies I
General Cardiomyopathy is a disease that involves the myocardium with cardiac dysfunction Types Dilated Hypertrophic Restrictive Dilated Cardiomyopathy Impaired systolic function Dilated left ventricle Right or left heart failure Associated with CHF, arrythmias and emboli Etiology Idiopathic Familial/genetic Mutations in dystrophin Duchenne and Becker muscular dystrophies Friedreich's ataxia EtOH Beri-beri disease Thiamine (B1) deficiency Coxsackievirus B Drugs Cocaine, doxorubicin, cyclophosphamide & TCAs Chagas' disease Peripartum Last trimester of pregnancy and up to 6 months after birth Clinical manifestations Reduced EF & CO Decreased JVP Faitgue Cardiomegaly Dyspnea Edema Physical exam JVD, S3, S4, MR (mitral regurg.) & TR (tricuspid regurg) Papillary muscles are so far away that valves can't close Narrow pulse pressure Tachycardia Displaced PMI Crackles, peripheral edema & hepatomegaly CXR Enlarged cardiac sillhouette Pulmonary congestion Echo LV dilation & decreased EF Treatment Treat like CHF Non-pharmacologic No alcohol Monitor weight Exercise Na+ & fluid restriction ACE inhibitors ARBs -blockers Defibrillator for malignant arrhythmias Cardiac transplant

Hypertrophic Cardiomyopathy Hypertrophy of IVS (interventricular septum) Etiology Autosomal dominant (genetic) Mutations in genes encoding sarcomeric proteins Clinical manifestations Syncope/sudden death Most common cause of sudden, unexplained death in young athletes Probably from ventricular arrhythmias related to exertion Angina Dyspnea S4 Physical exam S2 paradoxically split Loud systolic murmur Indicates LV outflow tract obstruction Echo Asymmetric IVS hypertrophy Treatment Limit strenuous activity Drugs to increase contractility and decrease left ventricular outflow tract obstruction blockers CCBs Surgical reduction of the septum

Pathology Page 37

Cardiomyopathies II
Restrictive Cardiomyopathy Least common Diseases infiltrate the myocardium, resulting in rigid walls that impede diastolic filling Etiology Amyloidosis Sarcoidosis Hemochromotosis Loeffler's endomyocarditis Eosinophilic endomyocardial disease Other diseases associated with fibrosis Clinical Edema Dyspnea Ascites JVD Treatment Treat underlying etiology Carcinoid syndrome Results in endocardial fibrosis with stenosis/regurg of tricuspid/pulmonic valves

Pathology Page 38

General Cardiac Hypertrophy

Cardiac Hypertrophy Heart weighs more and myocytes show increased mitochondria and enlarged nuclei Increased ploidy Increase in myocyte size is not accompanied by an increase in capillaries The supply of O2 and nutrients per myocyte is reduced, but demand is increased due to the elevated work load The hypertrophied heart is vulnerable to decompensation & death Etiology HTN (pressure overload) Valvular disease (pressure & volume overload) MI All three lead to: Increased cardiac work, wall & cell stretch, and hypertrophy and/or dilation Characteristics Increased heart size, mass, protein synthesis Fibrosis Inadequate vasculature Leads to cardiac dysfunction HF Arrhythmias Neurohumoral stimulation Types Pressure-overload hypertrophy (concentric hypertrophy) Concentric increase in wall thickness, but heart empties fine New sarcomeres are assembled in parallel to the long axis of the cells, expanding their cross-sectional area Volume-overload hypertrophy (eccentic hypertrophy) Ventricular dilation, heart doesn't empty fine New sarcomeres are assembled in series with existing sarcomeres Wall thickness may be increased, normal or decreased Aerobic exercise (physiological hypertrophy, Athlete's heart) Leads to volume-load hypertrophy WITH an increase in capillary density/collateral circulation More and "better" mitochondria Decreased HR & BP Apex beat can be felt far lateral to the mid-clavicular line Large QRS complexes Static exercise (weight lifting) is associated w/pressure hypertrophy & deleterious effects Hypertrophic cardiomyopathy Uneven fiber enlargement with bumps on the heart around the outflow tract

Pathology Page 39

EKG Hypertrophy I
P Wave Abnormalities Inversion Ectopic atrial or A-V junctional rhythm Increased amplitude (> 3mm) Atrial hypertrophy or dilation Found in hypertension, cor pulmonale & congenital heart disease Increased width (>.11 sec) Left atrial enlargement (LAE) Notching LAE P-mitrale Peaking (tall, pointed P-waves) R atrial overload P-pulmonale ST Segment Should be isoelectric Exception: young, healthy black males Displacement is a sign of myocardial ischemia/injury

QRS Complex Features to inspect: Duration Normal is .05-.10 >.12 is indicative of hypertrophy or bundle branch block (BBB) Amplitude Shouldn't be less than: 5mm in standard limb leads, V1, & V6 7mm in V2 & V5 9mm in V3 & V4 Presence of Q waves Shouldn't be greater than 2mm and longer than .03 sec Axis

A. P-mitral B. Ppulmonale T Wave Upright in 1, 2, V3-V6 Observe: Shape Sharp point suggests MI Height shouldn't exceed 5mm in standard and 10mm in precordial leads Tall waves suggest MI of hyperkalemia

Left Ventricular Hypertrophy (LVH) Most common cause is hypertension Romhilt-Este's Scoring System Score of 5 indicates LVH, 4 is probable LVH Look at Lead I, II, V5 & V 6 Check for "strain" pattern Downsloaping ST segment Massive R peaks Left Axis Deviation (LAD)

Pathology Page 40

EKG Hypertrophy II

LVH. Notice massive R waves and "strain"

More LVH Right Ventricular Hypertrophy (RVH) Causes: COPD Mitral stenosis Tricuspid regurg. Look for Right Axis Deviation (RAD) Look at leads I, V 1 & V 6 Prominent S waves in I & V 6 Prominent R waves in V 1 R/S ratio is greater than 1 in V 1 P-pulmonale

RVH

Right Atrial Enlargement (RAE) Leads II & V 1 Giant, wide P waves; IE. "P-pulmonale"

Left Atrial Enlargement Leads II & V 1 Broad, notched, P waves IE. "P-mitrale"

RAE. Large, prominent P waves (P Pulmonale); LAE. Notched P waves (P Mitrale)

Pathology Page 41

Congestive Heart Failure (CHF) I

Overview CHF occurs when the heart is unable to pump blood at a rate sufficient to meet metabolic demands of the tissues CHF is a syndrome or diagnosis, NOT a specific disease Types Left-sided HF Right-sided HF Several physiological mechanisms attempt to maintain arterial pressure when cardiac function is impaired: Frank-Starling mechanism Increased filling (stretching) leads to increased contractility Hypertrophy Adaptive early but can culminate in impaired cardiac function Activation of SNS Increased NE Vasoconstriction Increases HR & contractility Activation of RAAS Vasopression system ADH Stimulation of thirst leads to increase in total body water and hyponatremia (dilutional) Increased preload Release of atrial natriuretic peptide (ANP) Adaptive mechanisms are ultimately overwhelmed, leading to CHF General clinical symptoms Decreased CO & tissue perfusion (forward failure) Pooling of blood in the venous system (backward failure) Pulmonary & tissue edema Weakness/fatigue Respiratory problems Dyspnea on exertion (DOE) Shortness of breath (SOB) Paroxysmal nocturnal dyspnea (PND) Since the cardiovascular system is a closed circuit, failure of one system often results in strain/failure on the other (global failure) Left-Sided Heart Failure Treatment Treatment O2 Diuretics Nitrates Morphine blockers ACE inhibitors ARBs Left-Sided Heart Failure Systolic dysfunction Impaired contractility Etiology MI Myocardial disease Ischemic heart disease Volume overload Mitral regurg Aortic regurg Increased afterload Etiology HTN Aortic stenosis Hypertrophic cardiomyopathy Clinical Dyspnea Orthopnea Fatigue Palpitations Ascites S3 Diastolic dysfunction Impaired ventricular relaxation/compliance Etiology Ventricular hypertrophy Cardiomyopathy Ischemic heart disease Impaired ventricular filling Etiology Mitral stenosis Tamponade Pericardial constriction Clinical Filling defect w/increased or normal EF S4 Edema Hepatomegaly Morphology Heart Left ventricle is hypertrophied & dilated Fibrosis Myocyte hypertrophy LA dilation Lungs Edema (Kerley B lines) Edematous widening of alveolar spaces Heart failure cells/hemosiderin-laden macrophages

Pathology Page 42

Congestive Heart Failure (CHF) II

Right-Sided Heart Failure Etiology Left-sided heart failure (most common) Pulmonary HTN PE Emphysema & cystic fibrosis Cor pulmonale Pure right-sided failure Clinical JVD Edema Can cause portal hypertension Morphology Hypertrophy & dilation of the right ventricle Liver & portal system Congestive hepatomegaly due to passive congestion "nutmeg liver" Portal hypertension produces congestive splenomegaly Treatment ACE inhibitors -blockers Diuretics NYHA Functional Classification of HF Class I No limitation of activity Class II Slight limitation of activity Ordinary activity causes symptoms Class III Marked limitation of activity Less than ordinary activity causes symptoms Class IV Inability to carry out physical activity Symptoms at rest
General Pharmacologic Treatment of HF ABCs A. ACE inhibitors, ARBs, Aldactone B. blockers US Carvedilol HF Trial Reduced mortality by 65% & hospitalization by 29% Coreg C. CCBs D. Diuretics, digitoxin E. Eplerenone (aldosterone antagonist) F. Fluid restriction I. Inotropes (Dobutamine, dopamine) N. Nitrates, Na+ restriction H. Hydralazine OMM Lymphatic treatments for optimal fluid drainage

Pathology Page 43

Aneurysms I
Overview Abnormal dilation of a blood vessel due to compromise of the connective tissue within the vessel wall True aneurysm Aneurysm involves an intact arterial wall or thinned ventricular wall of the heart Atherosclerotic, syphilitic, congenital & ventricular aneurysms that follow MI False aneurysm Defect of the vascular wall leading to an extravascular hematoma that communicates with the intravascular space "pulsating hematoma" Dissection Blood enters the arterial wall itself Saccular aneurysm Spherical outpouchings (asymetrical) Fusiform aneurysm Circumferential dilation (symmetrical) Pathogenesis Intrinsic connective tissue is weak Marfan syndrome Loeys-Dietz syndrome Ehlers-Danlos Scurvy Inflammation Arteriosclerosis Common cause of aneurysms in the abdominal aorta HTN Common cause of aneurysms in the ascending/thoracic aorta Smooth muscle loss in the vascular wall Marfan Scurvy Other conditions that lead to aneurysms Trauma Vasculitis Infections Syphilis Mycotic aneurysms (Salmonella) Abdominal Aortic Aneurysm (AAA) Common in men & smokers Morphology Usually positioned below the renal arteries AAAs are accompanied by smaller aneurysms of the iliac arteries Inflammatory AAAs Dense periaortic fibrosis Abundant lymphocytic infiltration Giant cells Mycotic AAAs Lesions that have become infected by circulating microorganisms Salmonella Clinical features/consequences: Rupture Shock and death Risk of rupture is directly related to the size of the aneurysm Obstruction of a branch vessel Ischemia downstream Embolism Impingement of an adjacent structure Back/flank pain Treatment Surgery

Thoracic Aortic Aneurysms Usually associated with hypertension Other causes are Marfan and Loeys-Dietz Symptoms Encroachment on mediastinal structures Respiratory difficulties Difficulty swallowing Persistent coughing Recurrent laryngeal nerve compression Pain Myocardial ischemia Rupture

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Aneurysms II
Aortic Dissection Occurs predominantly in: Men with hypertension Younger patients with connective tissue abnormalities Pathogenesis Hypertension is the major risk factor Initiates with an intimal tear (ascending aorta) Dissection can extend distally or retrograde Morphology Lack of inflammation "Double-barreled" aorta Hematoma re-enters the lumen Clinical features Two types: Type A Involves the ascending aorta (Type I DeBakey) Involves the ascending & descending aorta (Type II DeBakey) Type B Does not involve the ascending aorta (Type III DeBakey) Symptoms Sudden onset of pain (similar to MI) Manifestations Cardiac tamponade, aortic insufficiency & MI

Pathology Page 45

Rheumatic Fever (RF)

General Elicited by GABHS Strep pyogenes Antigens elicit antibody production that cross-reacts with cardiac antigens 1-4 weeks following a pharyngeal infection Types of RF Acute Chronic Jones criteria for diagnosis (symptoms of RF) Major: Polyarthritis Carditis (murmur) Nodules (subcutaneous) Erythema marginatum Pink rash on the trunk Sydenham's chorea Minor: Arthralgia Fever Elevated ESR/CRP/WBC count PR interval elongation Anemia Treatment Symptomatic Penicillin Acute Rheumatic Fever Divided into: Pericarditis Myocarditis Ascoff's bodies Focal interstitial myocardial inflammation with deposits of collagen and fibrinoid material surrounded by Anitschkow's cells and Aschoff's cells Anitschkow's cells Macrophages surrounding myocardial inflammation and collagen deposits Aschoff's cells Multi-nucleated giant cells formed from Anitschkow's cells Endocarditis Chronic Rheumatic Fever Mitral and aortic valvular fibrosis Leads to mitral stenosis, mitral regurg, aortic regurg & CHF Predisposes to infectious endocarditis

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Heart Murmurs I
Murmur Grades Barely audible Easily audible Loud (no thrill) Loud (with thrill) Loud - audible with stethoscope barely touching skin 6. Audible with stethoscope off the chest
1. 2. 3. 4. 5.

Heart Sound Listening Points/Valves Heart Sounds S2 is the sound of the aortic and pulmonary valve closing The pulmonary valve closes after the aortic valve Wide S2 S2 can be further split by increased RV ejection time Lesions causing an RV volume load (delays P2 further) ASD, pulmonary insufficiency Early closure of the aortic valve Severe systematic hypertension Coarctation of the aorta Narrow S2 Lesions causing late closure of the aortic valve AS Early closure of the pulmonary valve Pulmonary hypertension More prominent P2 S2 may be single with severe pulmonary hypertension Respiration and S2 During exhalation, P2 occurs later During inspiration, P2 occurs earlier VSD Blood forced through the defect during systole Murmur is HOLOSYSTOLIC With a large defect Increased flow through the pulmonary valve, lungs & mitral valve creates a diastolic mitral inflow rumble Innocent Murmurs A beating heart will always create noises of blood flowing (Basal) ejection murmur Location Upper left sternal border Common in all ages up through adolescence Still's murmur Early systolic murmur Location Lower left sternal border Aortic root Vibratory "twanging" murmur Common up to 4 years Carotid Bruit Ejection murmur Location Neck

ASD RV is volume loaded, not pressure loaded There will be more FLOW RV ejection will be prolonged Flow through the tricuspid valve will be INCREASED S2 will be split and will no "close" No respiratory split Pulmonary flow murmur Tricuspid inflow rumble

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Heart Murmurs II
Pulmonary Stenosis Click present at left mid & upper sternal borders Click may be more accentuated with expiration Softer (or absent) with inspiration Crescendo-descrescendo contour The more severe the PS, the louder the murmur TOF Mild TOF sounds similar to extreme PS Extreme TOF has a quiet murmur The more severe the TOF, the quieter the murmur Regurgitation vs. Stenosis Systole Mitral & tricuspid regurg Pansystolic murmur Aortic & pulmonary stenosis Crescendo-decrescendo pattern (ejection murmur) Click present (but not as crisp as PS click) Diastole Mitral & tricuspid stenosis Diastolic rumble Aortic & pulmonary regurg Decrescendo murmur Mitral valve prolapse Mid-systolic click Best heard at the apex Aortic Stenosis (AS) Etiology Valve calcification & thickening Age RF Symptoms Dyspnea, angina, syncope Crescendo-decrescendo systolic murmur Base of the heart and radiates to carotids Treatment HF treatments Surgery Valve replacement Balloon valvuloplasty

Mitral Regurgitation (MR) Etiology Chronic Mitral valve prolapse (MVP) RF Cardiomyopathy Dilated Hypertrophic Endocarditis Acute Papillary muscle rupture Ruptured chordae tendineae Endocarditis Symptoms RHF/LHF Pulmonary edema S3 Holosystolic murmur Prominent at apex, radiating into left axilla Echo P. mitrale EKG LV hypertrophy LA enlargement Treatment Afterload reduction Diuretics ACE inhibitor Useful for chronic MR Surgery

Tricuspid Regurgitation (TR) History Prominent "V" waves in JVP Hepatomegaly Ascites Auscultation Blowing holosystolic murmur Severe TR Decreased CO Treatment If pulmonary HT is present Surgery for repair/ replacement

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Heart Murmurs III

Mitral Stenosis (MS) Etiology RF Valve calcification (age) Edocarditis Symptoms Dyspnea, fatigue and orthopnea Narrow "fish mouth" valve Hemoptysis Hoarseness Left atria enlargement compresses left recurrent laryngeal nerve Physical exam Malar flush (plum colored cheeks) Opening snap after S2 followed by a rumbling, decrescendo, diastolic murmur EKG Shows P. mitrale signs Echo "hockey stick" deformity in mitral valve Treatment Diuretics Na+ restriction Warfarin Mitral valve replacement -blocker Tricuspid Stenosis (TS) Etiology RF Symptoms Prominent "A" wave Pulmonary congestion Fatigue due to low CO Ascites, edema Auscultation Diastolic murmur Treatment Na+ restriction Diuretics Surgery

MVP Etiology Genetic Marfan's, Ehlers-Danlos, OI Clinical features Can be asymptomatic Palpations, dizziness, syncope & angina Auscultation Systolic click after S1 Due to tensing of slack chordae tendinae Systolic murmur EKG Non-specific T wave changes Treatment blockers

Aortic Regurgitation (AR) Etiology RF Endocarditis HTN Syphilis Marfan's syndrome Pathophysiology AR leads to volume over load condition which increases LVED volume Leads to LVH Myocardial ischemia develops due to increased muscle oxygen requirements Symptoms DOE Angina Fatigue Physical exam De Musset sign Bobbing of head w/systole Corrigan's Pulse Rapid rising 'water hammer pulse' which collapses as pressure falls Quincke's Pulse Capillary pulsation w/flushing at root of nail Auscultation Decrescendo diastolic murmur Treatment Medical LV failure treatments, ACE inhibitors Surgical

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Cardiac Failure/Shock I
Hemorrhage Changes Decreased preload & blood volume Decreases BP Stimulates short & long term reflexes Short term: Baroreceptors (neural) Long term: Hormonally (kidney) Fluid retention changes are slow, but progressive TPR changes are fast Kidney filtration Decreased BP causes decreased perfussion pressure of glomeruli Decreased urine production Fluid retention Interstitial fluid Reduced BP decreases capillary pressure Net movement into vascular space Decreased hematocrit Shock Inadequate O2 delivery to the tissues 3 states of shock: Compensated Natural compensatory mechanisms will bring BP back up to a reasonable level Decompensated Compensatory mechanisms are inadequate & tissue death will ensure w/o clinical intervention Irreversible Nothing can be done to save the system/patient

Kidney Changes During Shock Decreased blood flow due to reflex & decreased BP Nephrotic necrosis Accumulation of cellular debris Inflammatory response Cardiac Failure Preload immediately increases partially offsetting the decreased contractility 2 types: 1. Compensated 2. Decompensated Compensated Reflex mechanisms gradually increase BP until an equilibrium is reached No further increase in fluid retention Preload stabilizes at a higher level Natriuretic factor Produced by atria in response to large preload stretch Causes natriuresis (water & Na+ loss) Limits effect of renin/AG & volume overload Cardiac reserve is decreased Less ability to increase CO during strenuous activity Decompensated Enough preload CANNOT be generated to adequately increase CO & BP Heart becomes TOO dilated/stretched Too much stretch actually reduces the effeciency of the heart Positive feedback loop results in complete failure

Causes of Shock 1. Hypovolemic Decreased blood volume Hemorrhage Vomiting/diarrhea Dehydration 2. Cardiogenic Inability to deliver O 2 to the tissue MI etc. 3. Distributive Inflammatory cause Sepsis & anaphylaxis Massive vasodilation and tissue leakage 4. Obstructive Extracardiac compression 5. Neurogenic Spinal trauma etc. Loss of pressor output

Cerebral Ischemia Stimulates pressor region & inhibits depressor region If cerebral tissue becomes to ischemic, sympathetic stimulation will fail Vascular collapse

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Cardiac Failure/Shock II
Hormonal Response - TPR BP drops Renin production (kidney) increases Renin increases Angiotensin I (AG I) production (liver) AG I is converted to AG II (lungs) by Angiotensin Converting Enzyme (ACE) 5. AG II causes vasoconstriction a. AG II causes ADH (Anti-diuretic Hormone, Vasopressin) release (posterior pituitary) b. ADH causes vasoconstriction 6. TPR increases 7. BP increases
1. 2. 3. 4.

Hormonal Response - CO 1. BP drops 2. Renin production increases (kidney) a. Increases H2O retention b. Increases salt retention 3. AG I production increases (liver) 4. AG I is converted to AG II by ACE (lung) 5. AG II a. Vasoconstriction (vasculature) i. Increases preload 1) Increases CO b. Increases salt retention (kidney) i. Increases blood volume 1) Increases CO c. Increases ADH release (posterior pituitary) i. Increases H2O retention (kidney) 1) Increases blood volume a) Increases CO d. Increases Aldosterone production (adrenal cortex) i. Increased salt retention (kidney) 1) Increases blood volume a) Increases CO

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Ischemic Heart Disease (IHD)

Overview Leading cause of death for men & women IHD symptoms ultimately stem from myocardial ischemia Imbalance between the O2 supply & demand of the heart IHD usually presents as: MI Angina Chronic IHD with heart failure Progressive heart disease as a consequence of ischemic myocardial damage Morphology Heart is enlarged and heavy LV hypertrophy & dilation Sudden cardiac death Etiology 90% of cases of IHD are caused by obstructive atherosclerotic lesions in the coronaries IHD = coronary artery disease (CAD or CHD) Risk factors are the same as for arteriosclerosis IHD can also be caused by shock (lowered SBP) EKG (not always present) T wave inversion or prominent & upright ST depression or elevation VT/VF Angina Treatment Catheterization PCI (Percutaneous Coronary Intervention) Stent insertion w/angioplasty Can't perform on left main coronary (surgery) Pharmacologic Platelet GP inhibitors ASA Nitrates MONA (for ACS) Morphine DOC for refractory chest pain Oxygen Nitro ASA -blockers (decrease sympathetic tone) Ca++ channel blockers Surgery CABG Excellent prognosis 95% survival, 95% resolution of symptoms, freedom of MI 99% Best graft is the bypass using the internal mammary artery Sudden Cardiac Death (SCD) Usually the consequence of a fatal arryhthmia due to rupture or an untable plaque Acute myocardial ischemia is the most common trigger for fatal arrhythmias Predisposed risk factors include: Long QT syndrome Brugada syndrome Na+ channelopathy ST segments up & late T wave inversion in V 1-V 3 Short QT syndrome WPW SSS Cocaine heart Coronary malformations Angina Transient myocardial ischemia that falls short of producing necrosis Clinical presentation Retrosternal chest pain or pressure that can radiate to the head, neck or left arm Crescendo/decrescendo pain pattern Heart burn, indigestion Levine's sign Substernal pain w/clenched fist Three patterns of angina: Stable (typical) Prinzmetal variant Unstable Cardiac syndrome X Stable An imbalance in coronary perfusion and myocardial demand Produced by: Physical activity Emotional excitement Not associated with plaque disruption Relieved by rest & nitro Prinzmetal Caused by coronary artery spasm (vasoconstriction) Relieved by nitro and Ca++ channel blockers Unstable Caused by plaque disruption Acute MI is imminent Increasingly frequent pain, abnormal Cardiac syndrome X "microvascular angina" Clinical angina with wide open coronaries

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MI I
Cardiac Perfusion Coronary flow is dependent on 3 things: Metabolic demand Increased contractility increases metabolic demand Pressure generated Pressure generated by the contrac ting heart reduces coronary blood flow Pressures are greatest in systole, the LV & the endocardium Coronary perfusion in the LCA peaks at the beginning of diastole Coronary perfusion in the RCA peaks during systole Aortic hydrostatic BP (elevated) Increases cardiac work load and metabolic demand Increases mechanical "pinching" of the coronaries during systole Accelerates atherosclerosis Increases likelihood of thrombus formation Ischemia Changes Ion changes Increased Na+ , Ca++ & decreased K+ intracellularly Ca++ conductance is increased in Phase 4 Within 10 mins, the membrane potential begins to depolarize Cells are predisposed towards arrhythmias Lack of ATP Cross bridge interaction is inhibited Decreased contractility Lower amplitude AP & decreased slope of Phase 0 Decreased conduction speed Favors arrhythmias & re-entry Decreased CO & BP

MI Overview Most occur between 6:00AM - 12:00PM Cause of death is often 'electrical' arrythymias Risk factors Gender Men & post-menopausal women have a greater risk Age Hypercoaguable states Vasculitis Athersclerotic risk factor Pathogenesis Coronary artery occlusion (90% of cases) 1. Intraplaque hemorrhage, erosion, ulceration, or rupture 2. Subendothelial collagen is exposed Platelets adhere, become activated & aggregate 3. Vasospasm is stimulated by platelet mediators 4. Coagulation pathway is activated 5. Thrombus evolves/grows 6. Lumen is completely occluded Other (w/o coronary occlusion) Vasospasm Cocaine Emboli or endocarditis Ischemia without thrombi Sickle cell, amyloid deposition, shock Types of MI STEMI NSTEMI

MI Clinical Symptoms Clinical Rapid, weak pulse Profuse sweating Dyspnea & edema EKG changes Labs Elevated troponin-T & I CK-MB Lactate dehydrogenase

Myocardial MI Response Outcome depends on severity & duration of flow deprivation Biochemical Cessation of aerobic metabolism Inadequate production of ATP Lactic acid accumulation Loss of contractility within 60 secs Ischemia lasting longer than 20-30 mins leads to irreversible damage (necrosis) Marked by leakage of cardiac enzymes Cells adjacent to theoriginal ischemic area can become ischemic due to increased mechanical work load & demand Results in a "wavefront of death" that moves through the myocardium

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MI II
Necrosis and Associated Arteries LAD Apex, anterior wall of the LV, anterior 2/3 of the ventricular septum Left circumflex Lateral wall of the LV RCA Entire RV free wall, posterior 1/3 of the ventricular septum NSTEMI (Non-ST-segment Elevation MI) Non-transmural Partial or transient occlusion EKG Non-Q wave MI ST segment downsloaping and/or inverted T waves Clinically may be indistinuishable from unstable angina Presence of cardiac enzymes identify MI STEMI (ST-segment Elevation MI) Transmural Complete thrombotic occlusion Location Anterior High probability of CHF, arryhthmias, free wall rupture, mural thrombi & aneurysm Posterior Complicated with conduction blocks & RV involvement EKG ST elevation > 1 mm in 2+ limb leads or >2 mm in precordial leads Lead and associated MI locations Inferior wall Leads II, III & AVF Lateral Leads I & AVL Anteriolateral Leads V 1 - V 5 , & AVL Heart Gross and Microscopic Changes Following MI 0-30 mins Wavy fibers at the edges of the infarct Due to forceful contraction of adjacent viable myocytes Loss of glycogen from cytoplasm 1-2 hours Contraction bands Found in irreversibly damaged myocytes Intensely eosinophilic, intracellular stripes composed of closely packed sarcomeres 4-8 hours Neutrophils appear 8-24 hours First gross changes Soft, pallor 24-72 hours Numerous neutrophils Necrotic fibers Infarct is soft, pale and yellow 3-7 days Macrophages replace neutrophils Granulation tissue starts forming at the rim of the infarct 10 days Nice granulation tissue Continued phagocytosis 2-6 weeks Scar begins to form 7 weeks Nice scar

Cocaine and the Heart Blocks reuptake of NE from sympathetic nerve endings Increased stimulation of -receptors Tachycardia Increased inotropy, work & BP Increased stimulation of -receptors Overpowers local reflexes Coronary vascular smooth muscle contraction Decreased myocardial perfusion Facilitates atherosclerosis (due to elevated BP) Specific myocardial effects Cardia ischemia Chest pain EKG changes Can lead to MI Long term use can cause LVH

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MI III (Complications of MI)

Complications of MI Three categories: Electrical Mechanical Structural Electrical Complications Rhythm disturbances VT & VF PVC's Sustained VT Treatment (unstable) Shock 'em Treatment (stable) Lidocaine Amiodarone Procainamide AIVR Bradycardia Seen w/inferior wall MI Due to stimulation of vagal receptors & SA node dysfunction Treatment is atropine if unstable AV blocks Associated w/inferior wall MI Supraventricular tachycardias 1/3 of patients with an anterior MI Specific Mechanical & Structural Complications Dressler's Syndrome Presents similar to another MI 1-2 months after previous MI Due to an inflammatory reaction Treatment ASA Pericarditis Associated with a STEMI Begins 2-4 days after MI LV failure LV aneurysm Occurs weeks/months after a STEMI Expansile, paradoxical wall motion Can cause HF, arryhythmias & arterial clots Treatment Anticoagulant if mural thrombus present Papillary muscle/chordal rupture Associated with inferior MI (3-5 days later) Sudden onset of new holosytolic murmur (MR) Pulmonary edema HF & hypotension Treatment MV surgery VSR (ventricular septal rupture) 3-5 days following an anterior MI Sudden onset of a new murmur (loud & with a thrill) Treatment Surgery Venricular free wall rupture 3-5 days following an anterior MI Sudden loss of pulse, BP & consciousness EKG Pulseless electrical activity Cardiac tamponade Treatment Pericardiocentesis Surgery RVF Associated with RV infarction (inferior wall MI) Diagnosis STEMI in right chest leads Clinical exam Hypotensive & clear lungs Treatment Volume expansion to maintain RV preload

General Mechanical & Structural Complications General ventricular dysfunction Remodeling LV changes shape, size, thickness & dilates Treatment -> ACE Can lead to cardiogenic shock General HF Crackles, S3, S4, increased LVEDP, increased PAP (pulmonary arterial pressure) & pulmonary congestion General hemodynamic changes Decreased CO, SBP & coronary perfusion Hypoxia

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MI IV (EKG)
Zones of Infarction Ischemia Deficient blood supply Impaired repolarization T wave changes Injury Deficient blood supply Inability to fully polarize ST segment shifts Infarction Dead tissue Lacks depolarization Q waves MI/Ischemia Localization Anterior wall Artery LAD Leads V1 - V6 Inferior wall (RV infarction) Artery RCA Leads II, III & AVF V 3R- V 6R(Right side of the heart) Lateral wall Artery Circumflex Leads I, AVL & V 5 - V 6 Posterior wall Artery Posterior descending artery Leads V 1 - V 3 (reciprocal changes)
1. Stage I: Ischemia causes inversion/peak of the T wave 2. Stage II: Muscle injury causes ST segment elevation 3. Stage III: Death of muscle causes Q waves due to absence of depolarization current from dead tissue 4. Stage IV: Recovery returns the ST segment to normal, followed by T wave return to upright. Q waves will remain permanently, even after healing

STEMI: elevation shows localization!

Evolutionary Changes in STEMI

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MI V (STEMI EKG)

Inferior STEMI. ST elevation in II, III & AVF. Reciprocal changes in I and AVL.

Lateral STEMI. Leads I & AVL show ST elevation. Reciprocal changes in II, III & AVF.

Inferior STEMI. ST elevation in leads II, III & AVF. Reciprocal changes in I & AVL.

Anterior STEMI. ST elevation in V1-V 4

Anterior STEMI. ST elevation in V 1-V 4

Inferior STEMI. ST elevation in II, III & AVF

Anterior STEMI. ST elevation in V1-V 4

Anteriolateral STEMI. Q waves in I, AVL, V5 & V 6 (lateral) with ST elevation in V1 - V 4

Anteriolateral STEMI. ST elevation in V1-V 5

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MI VI (NSTEMI EKG)

Posterior NSTEMI. Lead V 1 shows an unusually large R wave (reciprocal of posterior Q wave)

Inferior Wall NSTEMI. Q and T wave inversions in leads II, III & AVF. Lateral damage is also seen in leads V 5 & V 6

NSTEMI. No ST elevation but T wave inversion

NSTEMI. Inverted T waves in I, AVL & V 1-V 6

NSTEMI. Inverted T waves in I, II, AVL & V 3-V 6

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MI VII (MI Treatment)

Treatment Admit/invasive monitoring MONA -blocker Lowers HR & BP Decrease myocardial workload and energy demand Contraindications 2nd or 3rd AV block HF Hypotension Severe sinus bradycardia Cocaine induced MI ACE inhibitor Indicated for patients w/HTN, DM & HF Prevents cardiac changes due to MI Contraindications Pregnancy, renal failure & hypotension ARBs Similar treatment pattern as ACEIs Heparin/LMWH GP inhibitors Reperfusion therapy Thrombolytic therapy (TLT) "Door to EKG" - <10 min "Door to Needle" - <30 min Most beneficial if given <6 hours, specifically for STEMI or LBBB No benefit with NSTEMI Absolute contraindications Bleeding Malignant intracranial neoplasm Cerebrovascular anomaly Suspected aortic dissection Stroke within 3 months Prior history of intracranial hemorrhage Significant closed head or facial trauma within 3 months PCI (percutaneous coronary intervention) Alternative to thrombolytics "Door to Cath" - <90 min Only applies for STEMI Vasopressors for hypotension Norepi, Dopamine, Dobutamine Reperfusion Injury Reperfusion can trigger arrhythmias, hemorrhage & injury Injury due to: Inflammatory process Macrophage/cytokine invasion Mechanical damage when ATP is returned Reactive hyperemia can potentiate the harmful effects of sudden reperfusion

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Miscellaneous Vascular Disease

Thrombophilia Hypercoaguable Factor V Leiden deficiency HIT Heparin induced thrombophilia Critical Limb Ischemia Persistent, recurring ischemic rest pain Requires opiate analgesia for at least 2 weeks Can cause ulceration or gangrene of the foot or toes Ankle systolic pressure <55mmHg & toe pressure <30mmHg Mortality rate at 5 years is 70% Worse if: DM Smoking Claudication Bad, often clots Intermittent claudication Lower extremity muscular pain in the calves induced by exercise Relieved by short periods of rest Pathogenesis Arterial obstruction proximal to affected muscle beds Clinical presentation Severe pain Cramps Fatigue on exertion May be associated with ED Physical exam Absent or decreased pulses Dependent rubor Management Encourage supervised walking exercise program

EVAR Endovascular Aneurysm Repair Alternative to open surgery

EVAR

Acute Limb Ischemia Sudden decrease or worsening in perfusion resulting in threatened limb viability Patients present with the "5 P's" Pain Paralysis Paresthesias Poikilothermia Pulselessness Immediately threatened Limb is salvageable if promptly treated (immediate revascularization/surgery) Findings Minimal sensory loss Rest pain Mild to moderate muscle weakness Doppler signals show inaudible arterial pulse Venous is audible

Pathology Page 60

Cell Wall Synthesis Inhibitors I

-Lactams Spectrum Narrow is effective only against one (or one group of) species Extended has an intermediate range of activity Broad has a spectrum against a wide range of bugs MOA Inhibits cell wall synthesis by binding to Penicillin binding proteins (PBPs) MOR -lactamase degradation PBP alteration (MRSA, pen-resistant S pneumoniae (PRSP)) Decreased penetration Bacteriocidal Except against Enterococcus Time-dependent -lactamase inhibitors (anti--lactamases) Used in combo with -lactams to overcome resistance due to degradation Clavulanate Sulbactam Tazobactam Combos include: Amox/clav Amp/Sulb Pip/Sulb Ticar/Clav Some preparations of IV penicillins contain a large amount of sodium Important for patients with renal failure Cilastatin Combined with imipenem to prevent degradation of imipenem by dehydropeptidase (dehydropeptidase inhibitor) Glycopeptides & Others Vancomycin MOA Binds firmly to D-alanine-D-alanine portion of cell wall precursors Inhibits addition of peptidoglycan units to growing polymer chain Bacteriocidal (except Enterococcus) Some Enterococcus sp. show resistance (VRE) MOR Terminal D-ala replaced with D-lactate Given IV (except for C. difficile) Not absorbed via the gut Good for treating C. difficile orally because it will not be absorbed and thus stay in the gut and kill C. difficile Adverse effects Red-Man syndrome Flushing, rash etc. on face and torso Telavancin MOA D-ala-D-ala (like Vanco) but also depolarizes cell membrane Concentration dependent Adverse effects Metallic taste Foamy urine BLACK-BOX warning Abnormal fetal development, do NOT take while pregnant Daptomycin Cyclic lipopeptide MOA Causes rapid depolarization of cell membrane Concentration dependent IV only DO NOT use to treat pneumona Death, serious complications Reserved for serious infx caused by resistant bacteria Adverse effects Myopathy and CPK elevation Bacitracin Inhibits incorporation of AAs and nucleotides into cell wall Bacteriostatic Causes nephrotoxicity when used systemically (topically only)

Pharmacology Page 61

Cell Wall Synthesis Inhibitors II

CLASS Penicillins Penicillins FAMILY Natural penicillins Penicillinaseresistant penicillins PRE/ SUFFIX -cillin -cillin NAME(S) Penicillin G, Penicillin VK Nafcillin, Dicloxacillin, Oxacillin, Methicillin
Ampicillin, Amoxicillin Ticarcillin, Piperacillin

SPECIAL/DOC Syphillis, Neisseria meningitidis, pen-susceptible S. pneumoniae Anti-Staphylococcal (MSSA), especially skin & soft tissue; can cause renal failure (methicillin & nafcillin)

Penicillins Penicillins

Aminopenicillin -cillin AntiPseudomonal penicillins -cillin

Greater action against gram (-) aerobes; Enterococcal infections Pseudomonas aeruginosa, Bacteroides, Clostridium (not difficile)

Cephalosporins 1st Gen.

Cef-

Cefazolin, Cephalexin, Cefadroxil Cefuroxime, Cefoxitin, Cefotetan, Cefprozil

Cefdinir,Cefixime, Cefotaxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone Cefepime

Best against gram (+) aerobes; do not penetrate the CNS; surgical prophylaxis Better than 1st Gen. against gram (-) aerobes; some anaerobes

Cephalosporins 2nd Gen.

Cef-

Cephalosporins 3rd Gen.

Cef-

Greater against gram (-) aerobes; SOME are best for gram (+) aerobes including PRSP (Ceftriaxone & cefotaxime); P. aeruginosa (ceftazidime); can cross BBB

Cephalosporins 4th Gen. Carbapenems

Cef-enem

Extended spectrum gram (+) & (-); P. aeruginosa & Enterobacter sp.; cross BBB

Imipenem/cilastin, Most broad spectrum of activity of all antimicrobials; Ertapenem, hospital-aquired infx, polymicrobial infx & empiric Meropenem therapy; NOT covered include MRSA, VRE, coag (-) staph., C. difficile, S maltophilia, Nocardia; cross BBB; Imipenem can cause seizures

Monobactams

Aztreonam

Gram (-), including P. aeruginosa; Penicillin-allergic patients who need gram (-) coverage; cross BBB

-LACTAMS

CLASS

NAME(S)

SPECIAL/DOC MRSA, gram (+) bacteria (especially those with allergies to -lactams

Glycopeptides Vancomycin

Glycopeptides Telavancin/Vibativ MRSA, gram (+)

Other Other

Daptomycin Bacitracin

Gram (+), MRSA, VRE, Enterococcus faecalis Gram (+) & (-); Used topically

GLYCOPEPTIDES & OTHER

Pharmacology Page 62

Protein Synthesis Inhibitors I

Selection of Antimicrobial Drugs Host factors Pregnancy Tetracycline produces tooth discoloration and enamel hypoplasia Age Older people have lower clearance rates Can't give tetracycline to kids under 8 (teeth) Antimicrobial activity Pharmacokinetic properties Sites not easily penetrated by drugs CNS Drugs that do penetrate include: Chloramphenicol Tetracyclines TMP-SMZ Bone Prostrate Ocular tissue Adverse effects Cost Aminoglycosides MOA Inhibition of protein synthesis Binds to 30S subunit Bacteriocidal Concentration dependent MOR Decreased penetration Aminoglycoside-modifying enzymes Alteration in binding site Adverse effects Ototoxicity Vertigo, hearing loss etc. Nephrotoxicity Acute tubular necrosis Neuromuscular blockade Hypersensitivity reactions Streptogramins MOA Combo agent that acts on 50S subunit Protein synthesis inhibitor Bacteriostatic MOR Alterations in binding sites Enzymatic inactivation Tetracyclines MOA Inhibit bacterial protein synthesis by binding to 30S subunit Bacteriostatic MOR Efflux of tetracycline Decreased permeability Enzymatic inactivation Distribution Good tissue penetration Minimal CSF penetration Adverse effects Photosensitivity Discoloration of teeth in children Glycylcyclines Tigecycline is only drug MOA Similar to other tetracyclines Binds 30S subunit (5x higher than other tetracyclines)

Macrolides/Ketolides Inhibit protein synthesis by binding to 50S subunit Bacteriostatic Time-dependent MOR S. pneumoniae Active efflux Mef gene encodes for efflux pump Altered target sites Erm gene alters binding site Distribution Minimal CSF penetration Adverse effects (Macrolides) GI effects Elongation of QT interval Adverse effects (Ketolides) CNS Dizziness, headache Hepatotoxicity Severe liver injury Blurred vision Contraindicted for patients w/myasthenia gravis Worsening symptoms Elongation of QT interval

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Protein Synthesis Inhibitors II

Clindamycin MOA Binds 50S subunit Bacteriostatic MOR Altered target sites Erm gene Active efflux Mef gene encodes for effllux pump Adverse effects GI C. difficile colitis Oxazolidinones Only Linezolid MOA Binds 50S subunit Bacteriostatic Time-dependent Moderate CSF penetration Chloramphenicol MOA Binds to 50S subunit Penetrates CNS Limited usee due to adverse effects Adverse effects Hematologic Bone marrow suppression Anemia, leukopenia etc. Aplastic anemia (fatal) Hemolytic anemia Gray baby syndrome Newborns have a decreased ability to conjugate drug High serum concentrations CNS Optic neuritis Headache, depression & confusion

CLASS

NAME(S)

PRE/ SUFFIX

SPECIAL/DOC

Tetracyclines

Demeclocycline, Doxycycline, Minocycline, Tetracycline

Tigecycline

-cycline

Community-aquired pneumonia (doxycycline); Rickettsial Infx (RMSF); Chlamydia; Anthrax; Lyme disease (DOC for Borrelia burgdorferi)
Gram (+) & (-) aerobes, MRSA & VRE; Doesn't cover P. aeruginosa; Both types of pneumonia; intraabdominal infections

Glycylcyclines

NA

Macrolides/ Ketolides

Azithromycin, -thromycin Gram (+) & (-) aerobes; Intracellular organs Clarithromycin, (STDs); Mycobacterium; Telithromycin covers Erythromycin, all macrolides PLUS multi-drug resistant Telithromycin (Ketolide) Streptococcus pneumoniae -mycin/ -micin Gram (+) & (-) aerobes, not streptomycin; Mycobacteria (tuberculosis)

Aminoglycosides Amikacin, Gentamicin, Neomycin, Streptomycin, Tobramycin

Streptogramins
Oxazolidinones Clindamycin

Quinopristin/ NA Dalfopristin (Synercid)

Linezolid Clindamycin NA NA NA

VRE, MRSA, MSSA or Streptococcus pyogenes; not active against E. faecalis

MRSA, VRE & E. faecalis; Gram (+) & (-) Anaerobes outside of the CNS Gram (+) & (-) aerobes & anaerobes; spirochetes; Rickettsia; chlamydia,

Chloramphenicol Chloramphenicol

Pharmacology Page 64

Nucleic Acid Synthesis & Metabolic Inhibitors I

Flouroquinolones MOA Inhibit topoisomerases Concentration-dependent Bacteriocidal MOR Altered target sites Altered cell wall permeability Active efflux Adverse effects GI CNS Headache, hallucinations, insomnia Cardiac Extended QT interval Articular damage Tendonitis Anti-pseudomonal Antibiotics Penicillins Ticarcillin Piperacillin Carbapenems Aztreonam Cipro Cephalosporins Ceftazidime Cefepime Aminoglycosides Gentamicin Tobramycin Amikacin Metronidazole MOA Inhibits DNA synthesis Given as a prodrug Concentration-dependent bacteriocidal Adverse effects GI CNS Avoid during pregnancy Sulfonamides Metabolic inhibitor MOA Inhibits dihydrofolate reductase (DHFR) TMP-SMX Individually are bacteriostatic, together are bacteriocidal MOR Point mutations in DHFR Adverse effects GI Hematologic Skin disorders

Anti-MSSA Antibiotics Penicillins Nafcillin/Oxacillin Dicloxacillin Amox/Clavulanate Ticar/Clav Pip/Tazo Carbapenems Imi, dori, erta, mero

DOCs Penicillin Syphilis Neisseria meningitidis Tetracycline Lyme disease Borrelia burgdorferi Macrolides & Flouroquinolones Legionella pneumophila Vanco MRSA hospital aquired Metronidazole Pseudomembranous colitis due to C. difficile TMP-SMX Pneumocystis jirovecii pneumonia

Agents for C. difficile Glycopeptides Vanco Teicoplanin Telavancin Metronidazole DOC for C. diff colitis Carbapenems Doripenem Ertapenem Imipenem Meropenem

Anti-MRSA Antibiotics Vanco DOC for hospital aquired MRSA Teicoplanin Dapto Linezolid TMP-SMX Clindamycin Tigecycline

Pharmacology Page 65

Nucleic Acid Synthesis & Metabolic Inhibitors II

CLASS FAMILY NAME(S) PRE/ SPECIAL/DOC SUFFIX NA -xacin Gram (+) & (-); atypicals; DOC for Legionella pneumophilia; RTIs; UTIs; STDs "

Flouroquinolones 1st Gen. Nalidixic acid Flouroquinolones 2nd Gen. Ciprofloxacin, Norfloxacin, Ofloxacin

Flouroquinolones 3rd Gen. Levofloxacin Flouroquinolones 4th Gen. Moxifloxacin, Gatifloxacin Metronidazole NA Metronidazole

-xacin -xacin NA

" " Protozoa; anaerobes (including CNS); DOC for pseudomembranous colitis due to C. difficile RTIs; DOC for Pneumocystis jirovecii pneumonia; traveler's diarrhea (Salmonella & Shigella)

Sulfonamides

NA

Trimethoprim/ Sulfamethoxazole (TMP-SMX)

NA

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ACE Inhibitors
ACE Inhibitors ACEIs (cont.) Angiotensin Converting Enzyme Inhibitor Clinical considerations Drugs All ACE inhibitors have similar uses and AE Suffix -> -pril No reason to favor one over the other MOA Differ in potency, pharmacokinetic 1. Decreased formation of AG II properties & active entity Reduced vasoconstriction -> vasodilation Captopril is the only active drug, all 2. Decreased formation of AG II others are prodrugs Decreased aldosterone release Adverse effects Decreased fluid volume Dry, hacking cough 3. Reduced bradykinin breakdown Angioedema & anaphylaxis Vasodilation Hyperkalemia Clinical uses Drug interactions w/K+ sparing Hypertension diuretics Do NOT have reflex sympathetic action Contraindicated in pregnancy & renal artery 1st choice for patients w/diabetes, chronic kidney stenosis disease, & LVH NSAIDs may blunt antihypertensive action HF Prevent or delay progression of heart failure Decreases incidence of death, MI & hospitalizations In patients with high risk of developing HF, Renin Inhibitor structural abnormalities and/or those with a Drug previous MI Aliskiren Diabetic nephropathy Blocks renin conversion of Angiotensinogen Prevent or delay kidney disease in type 1 & 2 to AG I diabetes Approved for treatment of hypertension Improved renal hemodynamics Proteinuria Stroke prophylaxis Post MI ACE inhibitors have NO significant effect on cholesterol levels

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ARBs
ARBs Angiotensin Receptor Blockers Drugs Suffix -> -sartan Clinical uses Same as ACE inhibitors Do NOT differ significantly from ACE inhibitors for all causes of mortality & hospitalization due to heart failure ACE inhibitors are first line due to more data FDA approved HF ARBs Candesartan Losartan Valsartan Adverse effects Angioedema is less likely with ARBs than with ACE inhibitors Cross reactivity is possible Cough is much less likely than with ACE inhibitors Contraindications are same as ACE inhibitors Beware of increased risk of yperkalemia due to drug-drug interactions with ACE inhibitors and K+ sparing diuretics

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Vasopressors
Responses Elicited by Stimulation 1 Heart Increases rate & force of contraction Kidney Increases renin secretion 2 Lungs Bronchodilation Vascular smooth muscle Relaxation Responses Elicited by Stimulation 1 Vascular smooth muscle Contraction 2 Mixed responses 2 agonist (Clonidine) inhibits release of neurotransmitter of nerve terminal Reduces sympathetic output If drug effects both 2 and 1 , 1 will dominate response

Vasopressors All catecholamines are rapidly inactivated by monoamine oxidase (MAO) and catechol-Omethyltransferase (COMT) MAO and COMT are found in the gut and liver All catecholamines are given parenterally Also catecholamines have low bioavailability & short plasma half-lives

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Vasopressor Chart
NAME GROUP RECEPTOR TARGETS PHARM. ACTIONS THERAPEUTIC USES

Epinephrine

Direct-acting and ; dominates (low nonselective doses) catecholamines

Bronchial smooth muscle relaxation; increase HR, BP, contractility & CO

Increase BP, vasoconstriction, vascular resistance, HR & contraction; barorecepter reflex can decrease HR at lower doses Intense stimulation of HR & contraction force (increase CO); dilates arterioles of skeletal muscle (decreased vascular resistance) ( 2 action); Bronchodilation (2 action)

Severe allergic rxns (anaphylaxis); cardiac arrest

Acute hypotension; shock (cardiogenic or septic); Caution-> decreases renal blood flow Decreased CO

Norepinephrine Direct-acting Powerful agonist nonselective catecholamines

Isoproterenol

Direct-acting nonselective catecholamines

Dopamine

Dopamine receptors > 1 > 1

Dose dependent: low Increase GFR & natriuresis; dose-> dopamine receptors increase HR, contractility & (vasodilation), medium systolic BP dose-> dopamine receptors + 1 (increases CO), high dose-> 1 (increases BP) 1 Increases CO & contractility

Treatment of decreased CO, hypotension (septic & cardiogenic shock) Severe HF (symptomatic benefits only) Alternative to epinephrine; supportive treatment of severe hypotension in shock

Dobutamine

Selective 1

Vasopressin

Non-adrenergic Vasopressin receptors (non(smooth muscle & renal catecholamine) tubules) peripheral vasoconstrictor

Contraction in capillaries, arterioles & venules

Catecholamines & Vasopressin

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Beta Blockers
Responses Elicited by Stimulation 1 Heart Increases rate & force of contraction Kidney Increases renin secretion 2 Lungs Bronchodilation Vascular smooth muscle Relaxation Blocker Properties Differentiate between drugs by: Cardioselectivity Lipophilicity Hydrophilic drugs tend to have fewer CNS adverse effects Partial agonist activity (intrinsic sympathomimetic activity; ISA)

Blockers MOA Antagonize the effects of catecholamines at the receptor through competition 1 receptors: Cardiac myocytes & conduction cells SA & AV nodes, Purkinje fibers 2 receptor: Bronchial and peripheral vascular smooth muscle Some blockers are partial agonists and can cause partial receptor activation if endogenous catecholamine levels are low

Blocker Drugs Suffix -> -olol Except Carvedilol 1 & nonselective antagonist 1 selectivity Acebutolol Atenolol Bisoprolol Betaxolol Metoprolol ISA Pindolol

Blocker Effects Cardiovascular effects Decrease contractility, CO, renin release & AV nodal conduction (HR) Blunts sympathetic reflex w/exercise Adverse effects Respiratory tract Increase airway resistance Patients w/ashtma Cholesterol Lowers HDL & raises VLDL Blood glucose May inhibit recovery from hypoglycemia (caution in diabetic patients) Bradycardia, hypotension, heart block Sexual dysfunction Fatigue, depression & insomnia

Blocker Clinical Correlations Clinical uses Hypertension MI prevention Arrythmias HF Lessens symptoms Reversal of cardiac remodeling, hypertrophy & cell death Used in all patients with a history of MI, symptoms of HF and/or reduced LVEF Use on the 3 agents: 1. Bisoprolol 2. Carvedilol 3. Metoprolol Stable angina Migraine headaches "stagefright" Clinical considerations Use 1 selective for patients with: Asthma Peripheral vascular disease Always start w/low dose and increase slowly Taper when drug is discontinued

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Ca++ Channel Blockers

Calcium Channel Blockers (CCBs) Intracellular Ca+: Triggers contraction Required for pacemaker activity Bind to specific Ca+ channels in the myocardium & vascular smooth muscle Agents Nondihydropyridines Verapamil Diltiazem Dihydropyridines Suffix -> -pine Properties Based on different binding sites Dihydropyridines Vascular (Nifedipine -> prototypical) Nondihydropyridines Diltiazem In-between, some vascular but mostly myocardial Verapamil Myocardial Clinical uses Hypertension Angina (including variant) Arrythmias Migraine prophylaxis CCB Effects General Cardiac Reduced contractility Slowed conduction through AV & SA nodes Decreased HR Vascular Vasodilation Cardiac effects Strength of drug (for cardiac effects) Verapamil > Diltiazem > Nifedipine Reduces angina through reduced cardiac workload (result of decreased contractility and HR) Can cause serious cardiac depression and A-V block Vascular effects Nifedipine > Diltiazem > Verapamil Nifedipine reduces angina through coronary dilation Can cause tachycardia Adverse effects Nondihydropyridines AV block, sinus bradycardia Flushing, headache & hypotension Constipation (Verapamil) Dihydropyridines Vasodilation related Peripheral edema Flushing, headache, syncope, hypotension Dizziness Potential for lots of drug interactions!

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Antiarrhythmics I
CLASS NAMES TYPE MOA EFFECT (Pacemakers) Moderate Phase 0 slope depression and Phase 2 extension EKG AEs INDICATIONS

Class IA Quinidine, Na+ channel Procainamide, blocker Disopyramide (moderate binding). K+ channel blocker

Prolongs Increases Torsade de SVA & VA repolarization QRS pointes. and increases interval Quinidine: cinchonism APD (headache, dizzy, tinnitus), Procainamide: Lupus-like syndrome Disopyramide: Anticholinergic effects Shortens repolarization and decreases APD Increases Generally well QRS tolerated interval (only at very fast HR) Lidocaine: DOC for V.tach & prevention of V. fib after MI Mexilitine: VA Flecainide: maintaining sinus rhythm in patients W/O heart disease Propafenone : lifethreatening VA

Class IB Lidocaine, Mexiletine, Tocainide, Phenytoin

Na+ channel blocker (weak binding)

Mild Phase 0 slope depression and Phase 2 compression

Class IC Flecainide, Na+ channel Marked Phase No effect on Propafenone, blocker (strong 0 slope APD or Moricizine binding) depression repolarization, slows conduction velocity

Increases QRS interval, prolongs PR interval

Don't use in post MI patients (death) Propafenone: taste disturbances

Class II

Propanolol, -blocker Metoprolol, Acebutolol, Sotalol, Esmolol (-olol) K+ channel blocker. Also blocks Na+ & Ca+ channels and and adrenergic receptors K+ channel blocker. Also Class II

Phase 4 slope Decreases Slows HR Hypotension, AV SVA & VA; depression sympathetic block, impotence DOC for rate activity (rate & control contractility) Marked Phase Increases APD Prolongs Lots of AE!! V.fib, V.tach, Interactions: 2/3 extension and refractory QT maintaining period. Sinus interval (warfarin, dig) sinus rhythm must 1/2 the bradycardia dose of digitoxin when starting dose Marked Phase Increases APD Prolongs Fatigue, 2/3 extension and refractory QT bradycardia, period. interval dyspnea, torsade Decreases de pointes sympathetic activity Lifethreatening VA, A.fib and A.flutter

Class III Amiodarone

Class III Sotalol (cont.)

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Antiarrhythmics II
Class III Dofetilide (cont.) Class III Ibutilide (cont.) K+ channel blocker K+ channel blocker. Enhances slow inward Na+ current Marked Phase Increases APD Prolongs Torsade de 2/3 extension and refractory QT pointes period interval Marked Phase Increases APD Prolongs Torsade de 2/3 extension and refractory QT pointes period, interval prolongs repolarization Raises threshold & depresses slope of Phase 0 depolarization A.fib and A.flutter A.fib and A.flutter

Class IV Verapamil, Ca+ channel Diltiazem blockers (Nondihydropyridines)

Decreases HR, Increases AV block. Drug- DOC for A.fib contractility & PR & drug interactions and A.flutter SA/AV nodal slows HR (increases serum conduction digoxin concentrations). Constipation (Verapamil) SOB, bronchospasm (caution w/ asthmatics) DOC for AVNRT, AVRT & SVT

NA

Adenosine

Activates K+ channels in AV/SA node

Phase 4 slope Hyperpolarize Increases depression s atrial tissue, PR & decreases slows HR duration of atrial action potential & refractory period
See below Decreases SA node automaticity (HR) and AV node conduction, increases contractility

NA

Digoxin

Stimulates parasympathetic system & inhibits Na+/K+ ATPase

Slows HR Narrow Heart failure therapeutic & A.fib window. Lots of Drug-drug interactions. Hypokalemia, GI, CNS (blurred or yellow-greenish vision), arrhythmias. Treatment: K+ , Digibind (Anti-dig Abs)

NA

Mg++

Unknown

Unknown

Unknown

NA

NA

Arrhythmias and torsade de pointes

APD: action potential duration, SVA: supraventricular arrhythmias, VA: ventricular arrhythmias, SVT: supraventricular tachycardia Digoxin MOA Digoxin inhibits Na+ /K+ ATPase which decreases the extrusion of Na+ Leads to increased intracellular Na+ which slows the Na+ /Ca++ exchangers Ca+ + increases intracellularly More intracellular Ca+ + leads to increased contractility + decreases toxic effects K Digoxin binds only to phosphorylated form of Na+ /K+ ATPase Increased extracellular K + promotes dephosphorylation and thus decreases affinity of enzyme for digoxin

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Anti-hyperlipidemics
CLASS HMG-CoA Reductase Inhibitors (statins) NAME(S) MOA EFFECT Broad effect (potent LDL reducer) Dose & effect are NOT linearly related Reduces LDL AE Muscle & liver problems Atorvastatin, Inhibits HMG-Reductase (rate Fluvastatin, Pravastatin, limiting step in cholesterol Rosuvastatin, production), up-regulates LDL Pitavastatin, Lovastatin receptors and lipid metabolism (pro-drug), Simvastatin (pro-drug) Binds bile acids in intestinal lumen, upregulates LDL receptors

Bile Acid Cholestyramine, Sequestrants Colestipol, Colesevelam

Muscle, GI & Liver. EXTENSIVE drug-drug interactions (fat soluble vitamins, i.e. K) Flushing. Muscle & liver

Niacin (Nicotinic Acid) PPAR- Activators Cholesterol Absorption Inhibitors

Fish Oil

Niacin (Nicotinic Acid)

Reduction in synthesis of TG, VLDL & LDL, increased LDL receptors, decreases HDL catabolism Increases catabolism of VLDL via lipoprotein lipase Inhibits cholesterol & phytosterol absorption at the brush border of the small intestine
Decreases VLDL, TG & TC. Increases HDL

Broad effect (potent HDL raiser)

Gemfibrozil, Fenofibrate Ezetimibe

Decreases TG (potent) Reduces LDL

Muscle & liver/kidney GI, muscle & liver

Fish Oil

See MOA

Fishy burps

ANTI-HYPERLIPIDEMICS. TG: TRIGLYCERIDES, TC: TOTAL CHOLESTEROL

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Nitrates
Nitrates MOA Releases NO Activates guanylyl cyclase Increases cGMP Relaxes smooth muscles Effects Inhibits platelet aggregation Relaxes smooth muscle Large veins are dilated by small doses Decreases preload Large arteries dilate at higher doses Dilation of epicardial arteries Mild arteriolar dilation Decreases afterload Tolerance Need 8-12 nitrate free hours/day Adverse effects Throbbing headache Hypotension Rash Tachycardia Reflex sympathetic activation Methemoglobinemia Drug-drug interactions PDE5 inhibitors (used for ED; Viagra etc.) Dramatic increase in cGMP Leads to profound hypotension Drugs & O2 Balance Drugs that decrease O2 demand -blockers Decrease HR and contractility CCBs Decreases HR and contractility Nitrates Decrease preload and afterload Drugs that increase O2 supply Nitrates, CCBs and other vasodilators Increase coronary blood flow Increase regional myocardial blood flow

Types of Nitrates ISDN (Isosorbide Dinitrate) Used in combo w/hydralazine for CHF Nitroprusside Potent vasodilator IV only Exact NO release mechanism is unknown No tolerance develops Clinical uses Hypertensive emergencies Degrades rapidly (upon exposure to light etc.) Metabolized to cyanide Use caution in renal/hepatic impairment

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Alpha Blockers
Receptor Effector Organ Response Cardiovascular Effect

1
2

Vascular smooth muscle, bladder/sphincter, Prostate

Contraction

Vasodilation, decreased BP
Increase sympathetic stimulation & BP

Blood vessels, skeletal muscle Vasoconstriction Responses Elicited By Stimulation

Class

Name

MOA

Effect

AE

Indication

Non- Phenoxybenzamine selective

Inhibits reuptake of NE (irreversible binding)

Competitive

Reduces BP (when sympathetic tone is high). Vasodilation, increases cutaneous blood flow
Similar effects to Phenoxybenzamine Decreased preload (PVR & venous return), positive serum lipid effects

Reflex tach., postural hypotension, ejaculation inhibition

Hypotension, reflex tach., GI Postural hypotension & syncope, dizziness, sexual dysfunction

Pheochromocytoma (tumor of adrenals). Raynaud's, frostbite, acrocyanosis

Short term control of pheochromocytoma Hypertension, BPH

Nonselective

Phentolamine

1 Prazosin, Terazosin, Competitive selective Doxazosin

1A & D selective

Tamsulosin, Alfuzosin (distributionaly uroselective) Yohimbine

Competitive, Increase urinary flow, Impaired only targets decreases symptoms ejaculation, prostate & of BPH. Little effect on orthostasis, IFIS bladder BP Competitive Potentiate release of NE, increase sympathetic outflow (increase BP) Increase BP

BPH. Take alfuzosin w/food

2 selective

ED

Adrenergic Antagonists. NE: norepinephrine, PVR: peripheral vascular resistance, BPH: benign prostate hypertrophy, ED: erectile dysfunction.

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