cardiology1 Flashcards

Question

Capillaries

Answer 1

smallest vessels – walls just single layer of epithelial cells, no smooth muscle; approx. same size as RBCs, which travel through single-file. diameter <10 μm; huge total surface area. primary site of gas & nutrient exchange with interstitial fluid

Answer 2

thin walls relative to diameter compared to equivalent-sized arteries (but still some smooth muscle), not much elasticity. diameter ~ 20 μm – 0.5 cm. Primary capacitance vessels of the body (most of blood volume). one-way valves compensate for lower pressure in venous system to ensure blood flows  only in the correct direction

Answer 3

superior & inferior. diameter ~ 25-30 mm

Answer 4

Arterial walls have three layers: tunica adventitia, tunica media, and tunica intima

Answer 5

outer laye. Mostly connective tissue, composed of collagen and elastin

Answer 6

middle layer. It is mostly innervated vascular smooth muscle. Controls diameter of vessels, particularly resistance arteries. Not present in capillaries

Answer 7

inner layer of vessel lined with vascular endothelium: single continuous layer of endothelial cells, very important in regulation of blood flow, and is the site of atherosclerotic plaque formation.

Answer 8

Defined as vasculature from the first-order arterioles to the venules. Capillaries are the site of gas, nutrient, and waste exchange. Blood flow through capillary beds is determined by the pressure gradient, and is highly regulated via constriction/dilation of arterioles & precapillary sphincters. Precapillary sphincters are smooth muscle bands at junction of arteriole and capillaries. Capillaries do not have a smooth muscle layer, only endothelial cells surrounded by basement membrane. Movement of substances between capillaries and tissue is driven by concentration and pressure gradients (more in hemodynamics lecture)

Answer 9

Lymph is excess interstitial fluid. Lymphatic capillaries are blind end capillaries. Less numerous than regular capillaries and much more porous (regular capillaries have tight junctions between cells, lymphatic capillaries do not). Lymph flows into lymphatic capillaries in response to increased interstitial pressure, contraction of smooth muscle in lymph vessels, and contraction of surrounding skeletal muscle. Lymph vessels have one- way valves (like veins) so that lymph flow is uni-directional. Lymph is filtered through lymph nodes (bacteria removed), and rejoins the circulatory system in the subclavian veins. Lymph flow ~ 2-4L per day (vs~7000 L blood flood per day). Edema occurs when interstitial fluid exceeds capacity of lymphatic system.

Answer 10

basic physics of blood flow. Movement of blood is driven by differences in pressure throughout the CV system. Basic physics of flow through a tube predicts many properties of CV system.

Answer 11

Pressure differences (∆P) drive blood flow through vessels. The difference between arterial and venous pressure drives blood flow through an organ. Transmural pressure is the difference in pressure between the in side and out side of a vessel (across the wall). Gravitational pressure also affects blood flow (positional changes). Pressure units = mmHg. Highest pressure in aorta; elastic walls of vessels dampen pulsatile pressure but little resistance to flow, so not much drop in blood pressure through arteries. Big fall in pressure in arterioles (AKA “resistance vessels”). Very low pressure in capillaries and venous system. Pressure in systemic circulation >> pulmonary circulation. Cardiac out put from left and right sides of heart are equal, but resistance and pressure are different — much lower in pulmonary circulation.

Answer 12

Total blood volume ~ 5L. Greatest blood volumein venous system (veins = “capacitance vessels”). Relative blood volume between arterial and venous sides varies a lot depending on blood volume and pressure

Answer 13

volume per unit time (ml/min). it is constant through the system– the cardio vascular system is a closed loop, so flow through the capillaries must be same as flow through the aorta (on average). Total flow in the cardio vascular system is the cardiac output (CO)

Answer 14

distance per unit time (cm/sec). v=Q/A. Velocity depends inversely on cross-sectional area(A): velocity is slowest through sections with biggest cross-sectional area (like a river). Total cross-sectional area is smallest in the aorta (fastest flow), and greatest in capillary beds and pulmonary circulation (slowest flow in these areas of exchange.

Answer 15

Q = ∆P/R. where Q = Flow (volume/time) (some books use F). ∆P = pressure difference. R = resistance. Cardiac output (CO)= (mean arterial pressure – venous pressure)/(total peripheral resistance (TPR)). Flow equation is analogous to Ohm’s law for electricity (V=IR,orI=V/R), where blood flow is like current, pressure is like voltage, and resistance is resistance. Flow requires a pressure difference. Flow in must equal flow out. Flow is directly proportional to pressure, inversely proportional to resistance. Assumptions of flow equation that are not really valid for cardiovascular system: constant pressure, constant resistance, straight rigid tube. Nonetheless, pressure and flow through the system as a whole can be approximated fairly well with the flow equation.

Answer 16

expanded version of flow equation. Q= ∆P *(πr4/8ηl). Q = flow, r = radius, l = length, ∆P = pressure difference, η = viscosity of blood. The term πr4/8ηl is the inverse of resistance in the flow equation. This can be understood intuitively: increase size of vessel (radius) = decrease resistance, increase flow. Radius of vessel has huge effect on flow (flow varies with 4th power), so doubling the radius increases flow by 16-fold (24). In CV system, vessel diameter is the major mechanism by which flow is controlled (vasoconstriction & vasodilation). increase length of vessel = increase resistance, decrease flow. increase viscosity = increase resistance, decrease flow . viscosity mostly depends on hematocrit (proportion of red blood cells; normally 38-46% in women, 42-54% in men). Assumptions that are not valid for cardiovascular system: constant pressure, constant resistance, constant radius, single length, constant viscosity, laminar flow

Answer 17

Poiseuille’s Law is only valid for single vessels. Parallel vessels, such as in most of the systemic circulation, decrease total vascular resistance. Reciprocal of total resistance of a parallel network is the sum of the reciprocals of the individual resistances. Therefore: Total resistance of a network of parallel vessels is lower than the resistance of single lowest resistance vessel in the system. Changing the resistance of a single vessel in a parallel system has little effect on the total resistance of the system. Note that pressure is the same in each parallel vessel, but the blood flow through each can be different. Example: capillaries are highest resistance of all vessels (smallest diameter), yetthe total resistance of capillary beds is quite low and is independent of individual capillaries because there are many parallel vessels. Resistances in series are additive Rt =R1 +R2 +R3. Total resistance of a series of vessels is higher than the resistance of any individual vessel. Largest proportion of total resistance is in arterioles. Blood flow through vessels in series is constant, but the pressure decreases through the series of vessels (e.g.,, pressure drops through the systemic circulation). Example: Resistance to blood flow to a particular organ system. Rt = Rartery + Rarteriole + Rcapillaries

Answer 18

smooth, streamlined, and most efficient. velocity slowest at edge of tube, fastest in center

Answer 19

irregular, with eddies & vortices. requires more pressure for same average velocity compared to laminar flow. factors that increase turbulent flow: large diameter, high velocity, low viscosity, abrupt changes in diameter, irregularities on tube walls. Turbulent flow produces shearing force – viscous drag of fluid flowing through tube, which exerts force on the walls. Shear forces can damage vascular endothelium, which promotes formation of thrombi and embolisms. Damage to the vascular endothelium is a first step in the development of atherosclerotic plaques.

Answer 20

Heart pumps intermittently, creating pulsatile flow in the aorta — arterial pressure is not constant. Systolic pressure = peak aortic (~arterial) pressure; Diastolic pressure = minimum aortic pressure. Systole = contraction phase of cardiac cycle; Diastole = relaxation phase. Normal systolic/ diastolic pressure <120/80mmHg (normal range for systolic pressure ~ 90 – 120 mmHg; diastolic ~ 60 – 80 mmHg). pulse pressure = systolic – diastolic = 120 – 80 = 40 mmHg. In capillary beds, no pulse variation, pressure (and thus flow) is continuous. Pulse pressure, mean pressure and velocity all decrease from aorta to capillaries. Important because pulsatile flow requires more work – basically acceleration of mass vs. maintaining constant velocity (example: stop & go driving at rush hour uses more gas). Mean arterial pressure (MAP) ~ diastolic pressure + 1/3(systolic – diastolic). MAP is not the arithmetic average of systolic and diastolic pressures because diastole is longer than systole (at resting heart rates). MAP depends on HR, this equation is approximately correct for resting heart rate. At higher heart rates, diastole is relatively shorter, so MAP approaches the average between systolic & diastolic pressures.

Answer 21

C= ∆V/∆P. Compliance (C, in ml/mmHg) equals change in volume (∆V, in ml) that results from a change in pressure (∆P, in mmHg), Compliance represents the elastic properties of vessels (or chambers of the heart). Veins are more compliant than arteries – more ∆V per ∆P. Degree of compliance in main arteries contributes to transformation of pulsatile flow from heart into continuous flow in microcirculation. More compliance in aorta = lower pulse pressure. Compliance is determined by relative proportion of elastin fibers versus smooth muscle and collagen in vessel walls. Arteriosclerosis (is not the same as atherosclerosis) is the general term for loss of compliance caused by thickening and hardening of arteries. Some arteriosclerosis is normal with age; pulse pressure 40 mmHg in young adults, ~60+ mmHg in elderly people.

Answer 22

describes the relationship between tension in a vessel wall and the transmural pressure. T=(∆P*r)/(μ). T is tension (or wall stress), ∆P is transmural pressure, r is radius, μ is wall thickness. Tension in the vessel wall increases as pressure and radius increase. Thus, hypertension increases stress on vessel (and chamber) walls. In ananeurysm, the weakened vessel wall bulges outward, increasing the radius, thus increasing the tension that cells in the wall have to withstand to prevent the vessel from splitting open. Over time cells become weaker, allowing the wall to bulge more so that tension increases further, until the aneurysm ruptures.

Answer 23

Two major processes: Bulk transport – cargo from point A to point B in whole CV system. Can be applied also to consumption of a substance. Transcapillary transport – movement of cargo between capillaries and tissue

Answer 24

Bulk transport describes the movement of substances through the CV system. Transport rate is flow time concentration: x=Q[x]. where x is the amount of substance x, Q is the flow, and [x] is the concentration of x. For instance, how much O2 is carried to a muscle in 1 minute? O2/min = Q.[O2] where O2/min = transport rate (ml O2/min), CO = cardiac output (ml blood/min), and [O2] = concentration of O2 (ml O2/ml blood)

Answer 25

Fick’s Principle is an expansion of the bulk transport idea to consider how much of a substance is used by a tissue. The basic idea is that the amount used is equal to the amount that enters the tissue minus the amount that leaves, and the amount can be determined as the flow times the concentration. xused =xi –xo = (Q ⋅ [x] )i − (Q ⋅ [x]o ) = Q([x]i − [x] o). where xused is the amount used xi is the initial amount, xo is the final amount, and Q is flow (constant through system).

Answer 26

Fick’s law was originally developed as a way to measure cardiac output mV02 = CO* ([O2]a - [O2]v). where mV02 is myocardial oxygen consumption (X in general Fick equation) CO is cardiac output (flow, Q) [O2]a and [O2]v are arterial and venous oxygen concentrations (xi and Xo). The equation can also be rearranged to solve for cardiac output. CO= mV02 / ([O2]a - [O2]v). Myocardial oxygen consumption is defined as the amount of oxygen consumed per minute (ml O2/min), and is often expressed as ml O2/min/100 g tissue. Typically the oxygen contentis ~ 0.2mlO2/ ml blood. mVO2 at rest is ~ 8 ml O2/min/100 g and can increase to ~70 ml O2/min/100g. Note that oxygen consumption for the whole body can be determined by looking at the difference between oxygen levels in the pulmonary vein minus the pulmonary artery, which is opposite from the usual expression (of arterial minus venous concentration) because blood in the pulmonary vein is oxygenated and blood in the pulmonary artery is deoxygenated. One can also determine the Fractional O2 Extraction (EO2) from blood. EO2 is the amount of oxygen used by a tissue expressed as a fraction of the original (arterial) oxygen concentration. EO2=[O2]a - [O2]v / [O2]a.

Answer 27

includes solvent and solute movement and diffusion.

Answer 28

Two opposing forces determine solvent movement – hydrostatic pressure and oncotic pressure.

Answer 29

Hydrostatic pressure is simply fluid pressure as we have been considering so far–blood pressure in this case. Net hydrostatic pressure in a capillary bed is the difference between capillary pressure and interstitial pressure. Solvents move from high pressure to low pressure. BP in capillaries ~ 25 mm Hg. P in interstitial space ~ 0 mm Hg (or very low anyway). Hydrostatic pressure promotes filtration (movement of fluid out of capillaries)

Answer 30

Oncotic pressure (colloid osmotic pressure) is the osmotic force created by proteins in the blood and interstitial fluid. α Globulin and albumin are major determinants of oncotic pressure. Solutes move from high concentration to low concentration. Solvents move toward high concentration of solutes. Oncotic pressure of blood in capillaries (πc) is higher than oncotic pressure of interstitial fluid (πi). Capillary oncotic pressure promotes reabsorption of fluid (movement of fluid into capillaries)

Answer 31

Flux = k[(Pc-Pi) – (πc – πi)]. Flux = net movement across capillary wall, k = constant, Pc = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, πc = capillary oncotic pressure, and πi = interstitial oncotic pressure. (Pc - Pi) = net hydrostatic pressure – tends to be outward (filtration) (πc – πi) = net oncotic pressure – tends to be inward (reabsorption). Net movement of water in and out of a capillary is simply the outward force minus inward force, or the balance between filtration and reabsorption. Factors that increase blood pressure (hypertension) or reduce oncotic pressure (liver disease) tend to promote filtration. Excess filtration causes edema (swelling) in tissues. Net flux is not constant from arterial to venous end of capillaries. Pc is higher on arterial side and lower on venous side. πc is lower on arterial side and higher on venous side. Thus, there is a tendency toward filtration on the arterial side and reabsorption on the venous side. Net flux is different in different capillary beds (eg: capillaries in kidney favor filtration, capillaries in gut favor reabsorption). Net flux is regulated primarily by control of capillary hydrostatic pressure (via vasoconstriction / vasodilation of arterioles).

Answer 32

Gases are lipid soluble and diffuse freely across cell membranes. (e.g.: O2, CO2, and Nitric Oxide (NO) – more in vascular regulation). For O2, the rate of diffusion from capillary to tissue depends on the distance between the capillary and the tissue, and on the amount of O2 carried in blood (free and bound to hemoglobin). Lipid soluble molecules also diffuse freely (e.g.: some vitamins). Small lipid-insoluble molecules (e.g.: water, salts, glucose) can diffuse through “inter- endothelial junctions” between capillary endothelial cells. Interendothelial junctions vary in size, density, and permeability in different tissues. Large molecules (e.g.: proteins such as albumin) cannot cross most capillary walls (except in some cases by endo- or exocytosis, or in lymphatic capillaries, in which the junctions are quite permeable).

Answer 33

the relative ability of the heart to eject a stroke volume (SV) at a given prevailing afterload (arterial pressure) and preload (end-diastolic volume; EDV). Various measures of contractility are related to the fraction as the SV/EDV or the ejection fraction, and the dynamics of ejection as determined from maximum pressure rise in the ventricles or arteries or from aortic flow velocities determined by echocardiography. At the cellular level, the ultimate determinant of contractility is the relative tension generation and shortening capability of the molecular motors (myosin cross-bridges) of the sarcomeres as determined by the rates and extent of Ca activation, the turnover kinetics of the cross-bridges, and the relative Ca responsiveness of the sarcomeres. Engagement of the regulatory signaling cascades controlling contractility occurs with occupancy and signal transduction by receptors for neurohumors of the autonomic nervous system as well as growth and stress signaling pathways. Contractility is also determined by the prevailing conditions of pH, temperature, and redox state. Short-term control of contractility is fully expressed during exercise. In long-term responses to stresses on the heart, contractility is modified by cellular remodeling and altered signaling that may compensate for a time but which ultimately may fail, leading to disorders.

Answer 34

It is critical to the matching of cardiac output to venous return during exercise with little change in end diastolic volume and with tuning of the dynamics of contraction and relaxation to heart rate.

Answer 35

CO = HR × SV. CO = HR × (EDV − ESV) where CO is cardiac output; HR is heart rate, SV is stroke volume, EDV is end diastolic volume, and ESV is end-systolic volume. During filling and ejection, there are length changes in the fibers of the chamber. Applying the mathematics in the above equation could provide a quick assessment of how one might alter CO, i.e., simply by a change in HR, EDV and/or ESV. However, the variables are not independent. For example, increases in HR beyond a certain level induce a depression in SV by limiting EDV, i.e., filling time. CO is essentially a linear function of the work load, and does not change with blockade of beta receptors. This result reflects the necessity and capability of the cardiovascular system to meet the demands of the tissues. A critical driving force is tissue oxygen needs. Oxygen extraction as blood flows through the tissues is about 20% of the arterial concentration, making oxygen among the most flow limited components of the blood together with carbon dioxide and heat. Other components of blood have extraction ratios much less than oxygen and are much less flow limited. Thus, meeting tissue oxygen demands automatically provides all of the needs of the cell for exchange of other nutrients and wastes. The coupling of tissue oxygen needs to CO involves neural, mechanical, and chemical control mechanisms.

Answer 36

The EDV is viewed as the pre-load, a term that arose from studies of isolated strips of heart muscle in which a load had to be added to stretch the fibers in a way mimicking the stretch occurring with filling of the ventricle to the EDV. Similarly afterload denotes the pressure against which the ventricle must develop pressure for ejection to occur.

Answer 37

The ESV is equated roughly to contractility and end-systolic sarcomere length, i.e., the extent of cellular shortening.

Answer 38

In the vast majority of cases, cardiac arrhythmias are acquired subsequent to myocardial infarction, ischemia, acidosis, alkalosis, electrolyte abnormalities, or excessive catecholamine exposure. Drug toxicity is another common cause of arrhythmic activity, with cardiac glycosides (digoxin), some antihistamines (e.g., astemizole, terfenadine) and antibiotics (e.g., sulfamethoxazole) among the many drugs that can trigger arrhythmias. The antiarrhythmic drugs themselves are among the most arrhythmogenic pharmaceuticals. The CAST (Cardiac Arrhythmia Suppression Trial) study of 1989 revealed, unexpectedly, that post myocardial infarction patients treated prophylactically with the antiarrhythmics flecainide or encainide had a 2-3x greater mortality rate as compared to patients on placebo. This result drastically changed the way antiarrhythmic drugs are used today: catheter ablation of ectopic foci and implantable cardioverter-debrillator devices (ICDs) are now commonly used in place of pharmacological therapy. However, antiarrhythmic drugs (1) remain very useful as first-line therapy in treating certain arrhythmias; (2) are frequently used in conjunction with ICDs to decrease the frequency of arrhythmic episodes and thereby both prolong battery life and reduce the number of painful shocks; and (3) may become more useful as research reveals new information about their mechanisms of action and their molecular targets. The primary targets of antiarrhythmic drugs are cardiac Na+ channels (INa), Ca2+ channels (ICa-L), K+ channels (IKs and IKr), and β-adrenergic receptors. Na+ channels, Ca2+ channels, K+ channels and β-adrenergic receptors are direct drug targets. Via the β-adrenergic receptor pathway, the pacemaker current, If, and ICa-L, and IKs are indirect targets of antiarrhythmic drug action. To date, only β-blockers have been demonstrated to reduce the incidence of sudden cardiac death.

Answer 39

People with sudden death due to increased sympathetic tone have familial long QT syndrome, a prolongation of the duration of the cardiac action potential (QT interval) that can lead to ventricular arrhythmia and sudden death. In this disease, prolongation of the plateau phase (phase 2) of the fast response action potential in ventricular myocytes initiates a polymorphic ventricular tachycardia called torsades de pointes, which can degenerate into ventricular fibrillation followed by syncope and sudden cardiac death. Torsades de pointes is typically triggered by an abrupt increase in sympathetic tone as occurs with emotional excitement, fright, or physical activity. For this reason, current clinical practice includes treating long QT patients with β-adrenergic receptor blockers (β-blockers). The heritable varieties of long QT syndrome have an estimated total incidence of 1 in 5,000. In the United States, the heritable syndrome is responsible for about 3,000 deaths annually, mostly in children and young adults.

Answer 40

To unravel the underlying causes of long QT syndrome, the extensive human pedigrees maintained by the LDS Church were screened for families with a history of sudden death early in life. Genetic linkage analysis of the identified pedigrees revealed a variety of different mutations, depending upon pedigree, but nearly all of the mutations were found in cardiac ion channels. Thus the autosomal dominant form of long QT syndrome, Romano-Ward syndrome (RWS), is genetically heterogeneous: more than 200 mutations have been identified, with the most prevalent ones found in the slow cardiac K+ channel IKs (LQT1), the rapid cardiac K+ channel IKr (LQT2), and the cardiac Na+ channel INa (LQT3). In an autosomal recessive form of long QT syndrome, Jervell-Lange-Nielson syndrome (JLNS), homozygous carriers of mutations in IKs (LQT1) suffer in addition from congenital deafness, while the heterozygous carriers are asymptomatic. Ion channels bearing long QT syndrome mutations have recently been cloned, the various long QT-linked mutations engineered into the channels via site-directed mutagenesis, and the electrophysiological characteristics of the mutant ion channels have been studied. Long QT mutations in cardiac K+ channel subunits generally reduce the number of K+ channels expressed in the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current (IKr + IKs) that helps terminate the plateau phase of the fast response and return the membrane to resting potential during diastole. Long QT mutations in the cardiac Na+ channel (INa) prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response. Hence QT interval is lengthened in distinctly different ways.

Answer 41

reduced IKs for LQT1 mutant channels. incomplete inactivation for LQT3 mutant cardiac sodium channels.

Answer 42

INa is the cardiac Na+ channel, ICa-L is the cardiac Ca2+ channel, INCX is the electrogenic Na:Ca exchanger, IKr is the rapidly activated cardiac delayed rectifier K+ channel, IKs is the slowly activated cardiac delayed rectifier K+ channel, IK1 is the hyperpolarization-activated K+ channel largely responsible for the resting potential in ventricular myocytes, and Ito is a very rapidly activated K+ channel that is responsible for phase 1 of the fast response.

Answer 43

The α subunit of the cardiac sodium channel is encoded by the SCN5A gene, the α subunit of the rapidly-activating potassium channel (IKr) is encoded by the KCNH2 gene, and the α subunit of the slowly-activating potassium channel (IKs) is encoded by the KCNQ1 gene. Long QT mutations have subsequently been identified in almost all of the major kinds of cardiac ion channels. Consequently, an important lesson is that antiarrhythmic drugs should be selected based on the specific molecular basis of long QT syndrome. For patients with the LQT3 mutations, drugs that block Na+ channels should be used, whereas for patients with LQT1 or LQT2 mutations, drugs that open K+ channels ought to be used, ideally (theoretically; no K+ channel opening drugs are currently approved for clinical use). For acquired arrhythmias, it similarly may be that incomplete knowledge regarding the basis of rhythm disturbance hinders proper pharmacological management of disease. Two other forms of congenital arrhythmia reveal the range of molecular errors that underlie arrhythmias. In patients with Brugada syndrome, ventricular fibrillation results in a survival rate of only 40% by 5 years of age. More than 30 different mutations in the cardiac Na channel have been linked to Brugada, with many of these reducing peak inward Na+ current that drives action potential upstroke in ventricular myocytes.In another congenital arrhythmia, β-adrenergic receptors are able to upregulate cardiac Ca2+ channel (ICa-L) activity, but not the activity of cardiac K+ channels (IKs). A protein called yotiao normally targets protein kinase A, the effector of β receptors, to both cardiac Ca2+ channels and K+ channels. Yotiao targets the kinase to the channels by binding directly to these channels. In this particular arrhythmia, however, the yotiao binding site on the K+ channel has a mutation that impairs yotiao binding, and hence diminishes β receptor upregulation of cardiac K+ channel activity. The result is that with increased sympathetic activity, for example during exercise or emotional response, there is not enough repolarizing K+ current to match the increased depolarizing Ca2+ current. Phase 2 is prolonged, Ca2+ levels rise in the cytosol, and this triggers after depolarizations and arrhythmia.

Answer 44

Fundamentally, there are two types of problems: (1) inappropriate impulse initiation in SA node or elsewhere (ectopic focus), and (2) disturbed impulse conduction in nodes, conduction cells (Purkinje cells) or myocytes.

Answer 45

Causes: a.) ectopic foci: because normal SA nodal pacemaker is abnormally slow, or ectopic focus is abnormally fast infarct - causes membrane to depolarize (decrease in [K+]i occurs as Na/K-ATPase fails). b.) triggered afterdepolarizations: triggered by action potential, mechanism poorly understood early afterdepolarizations (EADs): appear during late phase 2 and phase 3 largely dependent upon re-activation of Ca2+ channels in response to elevated [Ca2+]in prolongation of phase 2 (long QT) contributes to elevated [Ca2+]in delayed afterdepolarizations (DADs): during early phase 4 initiated by elevated [Ca2+]in and, consequently, elevated Na+/Ca2+ exchange the Na+/Ca2+ exchanger is electrogenic: 3 Na+ move in for 1 Ca2+ moved out net increase in positive charge inside myocytes corresponds to depolarization this exchanger is called NCX, and the current it generates is INCX

Answer 46

Prolonged phase 2 causes excess Ca2+ entry, which triggers excess Ca2+ release from SR. Elevated [Ca2+]in drives increased Na/Ca exchange via the NCX exchanger.

Answer 47

Causes: a.) conduction block (1°, 2°, 3°) 1°: long P-R interval 2°: some P waves not followed by QRS 3°: no relationship between timing of P and QRS (called “complete heart block”) use implantable pacemaker in this latter case. b.) re-entry: means loop current flowing – also called “circus rhythm” can occur in circuits made up of every type of cell in heart re-entrant circuit can be small, or very large, involving a combination of atria and ventricles re-entrant arrhythmias require two conditions: (i) uni-directional conduction block in a functional circuit (ii) conduction time around the circuit is longer than the refractory period. Re-entry underlies atrial flutter and fibrillation, torsades de pointes and ventricular fibrillation. In many cases, arrhythmia is triggered by afterdepolarizations, but is maintained by re-entry. For example, an EAD-induced extra systole is believed to be responsible for the premature beat that initiates torsades de pointes, but the maintenance of the arrhythmia is thought to be due to re-entry.

Answer 48

Unidirectional conduction block in the conduction pathway establishes a re- entrant circuit. Not illustrated is the fact that conduction time around the re-entrant circuit is longer than the refractory time, which is a required condition for re-entry.

Answer 49

The plateau of the fast response (phase 2 of the action potential) can be prolonged either by increased inward current during this time (e.g., incomplete Na+ channel inactivation in LQT3) or by decreased outward current (e.g., smaller K+ current in LQT1, LQT2). Ca2+ entry during the resulting prolonged QT interval can result in EADs (via Ca2+ channel reactivation) or DADs (via NCX-dependent depolarization). Increased sympathetic tone (startled, excited) increases the likelihood of triggered afterdepolarizations because Ca2+ influx is enhanced by β-adrenergic receptor activity. Alternatively, heart failure increases the frequency of occurrence of triggered afterdepolarizations (even without LQT mutations). An EAD or DAD may be able to initiate re-entry, resulting in torsades de pointes which can degenerate into ventricular fibrillation (disorganized contraction of ventricular muscle, poor ejection fraction) and sudden cardiac death. Re-entry can develop from many other insults, such as myocardial infarction, or drugs that block K+ channels.

Answer 50

the drug classification scheme presented here (Vaughan Williams) actually describes the effects of drugs, rather than truly classifying drugs themselves. Drugs can, and do, have more than one class of action. Nonetheless, we generally refer to the drugs according to their dominant mechanism of action, calling them “class I drugs” or “class III drugs”, but for example, a so- called class I drug can have in addition to its primary class I action a secondary class III action. All class I drugs act primarily by blocking voltage-gated Na+ channels. Thus their primary action is on fast- response cells, but they also affect slow response cells (this latter effect probably occurs because these drugs also block, less effectively, L-type Ca2+ channels). All Na+ channel blockers decrease conduction rate and nearly all increase refractory period; these effects underlie the clinical efficacy of the Na+ channel blockers.

Answer 51

Class I action results in slowed upstroke. Class Ib drugs exhibit pure class I action, slowing upstroke and also decreasing action potential duration: Na+ current block lessens depolarization, decreases phase 2 Ca2+ current, hastens phase 3 repolarization. In contrast, class Ia and class Ic drugs delay phase 3 onset by virtue of their block of K+ channels. This K+ channel blocking action of class Ia and Ic drugs is more effective in prolonging phase 2 than is their Na+ channel blocking action in shortening phase 2.

Answer 52

Drugs: quinidine, procainamide, disopyramide. All class Ia drugs slow the upstroke of the fast response, and they also delay the onset of repolarization slowed upstroke results from block of Na+ channels (class I action) delay of repolarization owes to K+ channel block (a class III effect). Class Ia drugs prolong refractory period, via two processes: (i) via classic, use-dependent mechanism, similar to local anesthetics in action (ii) because depolarization (phase 2 duration) is prolonged. Quinidine (the 1st drug used to treat arrhythmia) has important effects not related to Na+ channel block blocks K+ channels particularly well, thereby prolonging action potential duration it is a vagal inhibitor (anti-cholinergic) it is an α-adrenergic receptor antagonist these effects underscore the non-selectivity of action for antiarrhythmic drugs

Answer 53

Drugs: lidocaine, mexiletine, phenytoin. Like class Ia drugs, class Ib drugs are use-dependent blockers of voltage-gated Na+ channels. class Ib drugs slow upstroke (more mildly than class Ia or Ic), and prolong refractory period. In contrast to class Ia drugs, class Ib drugs do not prolong phase 2 of the action potential despite shortened duration of phase 2, refractory period is nonetheless increased these drugs show the purest form of class I action on the fast response. In treating arrhythmias, lidocaine is the most important of the Class Ib drugs.

Answer 54

Drugs: propafenone, flecainide, encainide. Here again, class Ic drugs are use-dependent blockers of Ina. Class Ic drugs produce the most pronounced slowing of upstroke rate, and mildly prolong phase 2 net effect is powerful prolongation of tissue refractory period. Encainide is no longer marketed: the 1989 CAST study showed increased mortality with encainide

Answer 55

The block of Na+ channels by class I antiarrhythmic drugs is optimized so that Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than are Na+ channels in normal, healthy myocytes. This is an important drug property not only in the treatment of cardiac arrhythmias, but also in treating other ion channel-based disorders such as epilepsies or stroke, and also in the alleviation of pain by local anesthetics. This kind of drug behavior to preferentially target (1) over-active cells or (2) cells that have abnormally depolarized resting potentials is obviously very useful, and it is called “use-dependent block”. The mechanism of use-dependent ion channel block is summarized as: (1) use-dependent channel block = channel must open (be used, or activated) before it can be blocked (2) the channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel (3) mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+ channels. Use-dependent blockers include both class I Na+ channel blockers and class IV Ca2+ channel blockers.

Answer 56

Charged, hydrophilic drug may enter and exit the channel when the channel is in the open state, and not when the channel is either closed or inactivated. Neutral, hydrophobic drug, at a much slower rate, can reach the local anesthetic site even when the channel is closed or inactivated.

Answer 57

How do use-dependent channel blockers prolong the refractory period? The main reason is that these drugs actually block initially by entering the open channel, but they in fact have a higher affinity for the inactivated state of the channel (whether Na channel blocker like lidocaine or Ca2+ channel blocker like verapamil). High affinity for the inactivated state of the channel means that these use-dependent blockers stabilize the inactivated state. That is, they prolong the time the channel spends in its inactivated state. This prolongation of channel inactivation is the fundamental mechanism of prolongation of cellular refractory period, whether with Na+ channels in non-pacemaker cells or with Ca2+ channels in SA nodal or AV nodal cells. It is a vital part of the mechanism by which re-entrant arrhythmias are suppressed by these drugs. Some class I drugs prolong refractory period by a second, entirely different mechanism. Class Ia drugs in particular prolong phase 2 and delay repolarization. This effect is a class III action exerted by class I drugs, and probably owes to K+ channel block. Prolonging phase 2 means that the myocyte membrane is depolarized for a longer period of time and therefore more Na+ channels become inactivated, making the refractory period longer. Compare this action of class Ia drugs to that of class Ib drugs (e.g., lidocaine), which prolong refractory period even though they actually shorten phase 2 duration and hasten the onset of repolarization (phase 3). Class Ib drug action is nearly pure class I effect. (Like the other class I drugs, class Ib drugs do affect slow response action potential, probably by blocking L-type Ca2+ channels).

Answer 58

with drug, there are fewer channels available to open. The exact percentage available to open depends upon the membrane potential, with depolarization reducing the percentage. Depolarization also reduces the percentage of channels available to open in control because of depolarization causes inactivation of these channels. drug-treated channels recover from inactivation more slowly than do control channels, that is, they have a longer time constant for recovery from inactivation. This means that the use-dependent channel blocking drug will prolong the refractory period.

Answer 59

Recall that the two conditions required to support re-entry are (1) unidirectional conduction block in any kind of functional circuit and (2) that conduction time around the circuit be longer than the refractory time. Re-entry could therefore be terminated by converting unidirectional block into bi-directional block and by prolonging the refractory time. Unidirectional block can be converted to bi-directional block (1) by slowing action potential conduction velocity or (2) by prolonging refractory period. Class I drugs generate both of these effects, and therefore these drugs may terminate re-entrant arrhythmias by either mechanism: terminating re-entry by slowing conduction velocity and terminating re-entry by prolonging refractory period.

Answer 60

The steeper the upstroke of the action potential, the faster the action potential will propagate. This is because the steeper upstroke corresponds to a steeper voltage gradient along the conduction pathway, which in turn makes a larger flow of action current. This larger action current pushes the adjacent, previously resting section of the conduction pathway, up to firing threshold more quickly than would a smaller action current. A drug-induced reduction in upstroke rate therefore results in slower conduction velocity. Slower conducting action potentials are more likely to fail to propagate through a depressed region, for the simple reason that the underlying action current density is smaller and therefore may fail to actively re-excite tissue beyond the depressed region. Unidirectional block can be converted to bi- directional block via this mechanism. Conduction velocity reports action current density. The focus on conduction velocity, as opposed to action current, is attributable to the simple fact that it is easier to measure conduction velocity than it is to measure the underlying action current. Thus slowed conduction velocity is an easy-to-measure reporter of drug-mediated block of some of the Na+ channels in the re-entrant circuit. Fundamentally, partial block of INa by drugs such as lidocaine means that, in a depressed region (Fig. 7), retrograde or circus conduction is more likely to fail, which is the intent with the use of these kinds of drugs

Answer 61

Prolonged refractoriness can help suppress re-entrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential, and so the re-entrant wave of excitation is extinguished.

Answer 62

As described above, one way to convert unidirectional block to bi- directional block is by slowing conduction velocity. Yet slowing conduction velocity makes it less likely that conduction time around the circuit will be shorter than the refractory period. Paradoxically, the two fundamental means of terminating re-entry, slowing conduction velocity and prolonging refraction, work via conflicting processes. All that matters clinically, however, is that by one process or the other, re-entry can be terminated. Of course, removing conduction block altogether (restoring normal anterograde conduction) would also eliminate re-entry, but there are no antiarrhythmic drugs capable of achieving this goal.

Answer 63

Drugs: propranolol, metoprolol, esmolol. The action of class II drugs — β-adrenergic receptor blockers, or more simply, β-blockers — is to reduce If current, L-type Ca2+ current, and K+ current. Reduction of If, ICa-L and IKs reduces the rate of diastolic depolarization in pacing cells, reduces the upstroke rate, and slows repolarization particularly in AV nodal myocytes. Thus pacing rate is reduced, and in addition, refractory period is prolonged in SA and AV nodal cells. β-blockers are thus used to terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.

Answer 64

beta receptor blockers decreased slope of phase 4 depolarization and prolonged repolarization at AV node. Decrease phase 4 slope leads to decrease rate of firing, which leads to decrease automaticity. Prolonged repolarization of AV node leads to increase effective refractory period, which leads to decrease re-entry.

Answer 65

Drugs: ibutilide, dofetilide, amiodarone, sotalol, bretylium. These drugs work by blocking cardiac K+ channels, with ibutilide and dofetilide specifically blocking IKr channels. The consequences of K+ channel block are prolongation of fast response phase 2, and a prominent prolongation of refractory period. Prolongation of refractory period occurs because the prolonged duration of phase 2 (e.g., duration of depolarization) leads to increased inactivation of Na+ channels. This mechanism of increasing refractoriness is different from the use-dependent block mechanism of all class I drugs, but is similar to the secondary mechanism of increasing refractoriness exhibited by class Ia drugs (see Fig. 8). The very pronounced increase in refractoriness produced by class III antiarrhythmics makes these drugs very potent antiarrhythmics, especially against re-entrant arrhythmias. Not all effects of class III antiarrhythmics can be ascribed to block of K+ channels. For example, amiodarone, but not ibutilide, dofetilide, bretylium, nor sotalol, markedly reduces conduction velocity and increases refractory period by blocking Na+ channels. Amiodarone also decreases the rate of diastolic depolarization (phase 4) in automatic cells, thus reducing firing rate. Sotalol not only blocks K+ channels, but it also acts as a β-blocker. This latter property is not at all surprising, as sotalol is structurally related to other β-blockers.

Answer 66

they markedly prolong repolarization. Effective refractory period leads to decrease in re-entry. Only amiodarone reduces conduction velocity, which leads to decrease re-entry and decrease rate of firing (decrease in phase 4 slope) leads to a decrease in automaticity.

Answer 67

Drugs: verapamil, diltiazem. These drugs are use-dependent blockers of L-type Ca2+ channels. Their principal effects are exerted via actions on Ca2+ channels in nodal cells, but these drugs also block Ca2+ channels in fast response myocytes. All Ca2+ channel blockers slow the Ca2+-dependent upstroke in slow response tissue (normal or abnormal), which in turn slows conduction velocity, particularly in the AV node. Just as in the case of class I blockers of Na+ channels, class IV Ca2+ channel blockers prolong refractory period and can thereby suppress re-entrant arrhythmias, particularly in the AV node.

Answer 68

The slowed upstroke and reduced action potential amplitude are the direct results of block of L-type Ca2+ channels. Slowed repolarization (phase 3) results indirectly from L channel block: the reduced amplitude of the action potential activates fewer K+ channels. Both the decrease in conduction velocity of AV node and the increase effective refractory period of AV node lead to a decrease in re-entry.

Answer 69

(via an A1 adenosine receptor) is to increase a K+ current, while also decreasing both L-type Ca2+ current (dihydropyridine-sensitive, slow inward current) and If in SA and AV nodes. These actions are actually similar in some ways to β-adrenergic receptor blockers, i.e., class II antiarrhythmic action. Adenosine is not a β-blocker however. The similarity of adenosine action to β-blocker action arises from the fact that adenosine, via a Gi-coupled receptor, inhibits adenylyl cyclase and thus cAMP production. The adenosine-induced changes in membrane currents cause a reduction in SA node and AV node firing rate as well as a reduced conduction rate in the AV node. The K+ channel activated by adenosine can also be activated by acetylcholine via muscarinic receptors. This current was designated as IK-ACh, but is designated as IK-Ado (Ado = adenosine).

Answer 70

The adenosine receptor is indicated as AdoR. Note that IK-Ado is the same potassium channel as IK-ACh: both adenosine A1 receptors and M2 muscarinic ACh receptors on nodal myocyte membranes can activate the inhibitory GTP-binding protein, Gi, which in turn binds to and increases IK-Ado (or IK-ACh).

Answer 71

Antiarrhythmic drugs are primary therapy for atrial fibrillation only. Ablation or ICD is currently thought to be equal or superior in the management of all other arrhythmias. Paroxysmal supraventricular tachycardia (PSVT) – pathophysiology arises from re-entry Acute: adenosine (short half-life is advantageous). Chronic: AV nodal blockers Class II (β-blockers) Class IV (Ca2+ channel blockers) Class III (amiodarone, sotalol) digoxin catheter ablation of ectopic focus. Atrial fibrillation – pathophysiology arises from re-entry. Acute: AV nodal blockers, electrical cardioversion. Chronic: AV nodal blockers combined with long-term anticoagulation (warfarin). Cardioversion (electrical, ibutilide), and maintenance of sinus rhythm with drug therapy Class III (amiodarone, sotalol, dofetilide) Class Ic (propafenone, flecainide). Ventricular tachycardias/fibrillation – pathophysiology arises from afterdepolarizations plus re-entry Acute: amiodarone, lidocaine, procainamide. Drug prevention of sudden cardiac death: Proven benefit: β-blockers, angiotensin converting enzyme (ACE) inhibitors, aspirin, statins. Perhaps of benefit: amiodarone, digoxin. Potentially harmful: Class I drugs (Na channel blockers), Class IV drugs (Ca channel blockers)

Answer 72

half life of 10 min (metabolized via red cell esterase)

Answer 73

half life of 13 to 100 days

Answer 74

half life of less than 10 seconds, given as IV bolus, which can be repeated if necessary.

Answer 75

Lupus syndrome (occurs in 1/3 of patients on long-term therapy).

Answer 76

Least cardiotoxic agent of Class I drugs. Side effects: paresthesia, tremors, seizures, agitation, confusion.

Answer 77

Highly pro-arrhythmic, particularly with ventricular tachycardia.

Answer 78

Hypotension, aggravation of heart failure, bronchospasm, impotence.

Answer 79

Cardiac problems include bradycardia and heart block. Dose-related effects include: thyroid dysfunction, corneal deposits, pulmonary fibrosis and skin discoloration. Problems with side effects are exacerbated by the very long half-life of amiodarone (13-100 days).

Answer 80

Structurally, this drug is a β-adrenergic receptor ligand. Principal side effects are similar to those of the other β-blockers.

Answer 81

The major adverse effect of these drugs is hypotension, via action on vascular smooth muscle. Negative cardiac inotropy occurs as well.

Answer 82

Flushing (20%), chest burning and shortness of breath (10%), brief AV block. Adenosine action on coronary circulation is responsible.

Answer 83

Contraction of cardiac muscle, as of skeletal muscle, is elicited by an increase in the myoplasmic calcium concentration: the binding of calcium to troponin on the thin filaments enables the force-producing interaction between the thin filaments and the myosin heads of the thick filaments. Another similarity is that an intracellular store, the sarcoplasmic reticulum (SR), serves as the chief source of the calcium that causes contraction. In both muscle types, the release of calcium originates at junctions between the terminal cisternae of the SR (junctional SR, jSR) and the plasma membrane, or plasma membrane invaginations termed transverse tubules (t-tubules). Located on the plasma membrane side of these junctions is a type of voltage-gated Ca2+ channel, also termed the dihydropyridine receptor or DHPR (dihydro- pyridines are used clinically as antihypertensive agents). The junctional SR contains a different category of Ca2+ channel, which binds the poisonous alkaloid ryanodine and is thus termed the ryanodine receptor (RyR).

Answer 84

ECC requires entry of external Ca. receptors include CaV1.2 (α1C), β2a or β2b, α2δ1, and RyR2

Answer 85

ECC does NOT require entry of external Ca. receptors include CaV1.1 (α1S), β1a, α2δ1, γ1, and RrR1

Answer 86

Ca2+ enters via DHPR (“L-type Ca2+ channel”) and activates RyR2 to cause a much larger flux of Ca2+ from SR into myoplasm. Ca2+ activates contraction by binding to troponin on thin filaments. Ca2+ is removed from the myoplasm by: (i) SERCA2 pump located in longitudinal SR (2 Ca per cycle); Ca diffuses within SR to terminal cisternae, where it binds to calsequestrin (low affinity, high capacity) (ii) NCX Na+/Ca2+ exchanger in junctional domains of plasma membrane and t-tubules. SERCA2 dominates since SR surrounds each myofibril; requires less energy since VSR≈0. NCX is next in importance and can be arrhythmogenic, as will be discussed later. In steady-state, Ca2+ released from SR is recycled back into SR by SERCA2, and surface extrusion balances L-type Ca2+ current.

Answer 87

exchanges 3 Na for 1 Ca and can run either direction: calcium efflux in exchange for sodium influx or calcium influx in exchange for sodium efflux. The direction in which it runs depends on both membrane potential and the gradients for sodium and calcium. The membrane potential (Vr) at which the transport reverses direction is set by energetics: 3(ENa-Vr)=2(ECa–Vr), which rearranges to: Vr= 3ENa-2ECa By way of illustration, suppose that in a cardiac cell at diastole, [Na]o= 150 mM, [Na]i=15 mM, [Ca]o=2 mM, [Ca]i=100 nm, then ENa=58 mV, ECa=124 mV, and Vr =-74 mV.

Answer 88

1. If the cell membrane potential is -74 mV, then Ca2+ will be extruded until [Ca]i falls to 100 nm at which point net movement via NCX would be zero. However, if [Na]i were to increase (causing a decrease in ENa and a negative shift in Vr), then the steady-state level of [Ca]i would increase. Indeed, this is the molecular mechanism that underlies the use of cardiac glycosides, which were formerly a standard treatment for cardiac failure (lack of sufficient pumping power by the heart). These agents work by blocking the Na/K pump, leading to an increase in intracellular sodium (dosage is obviously critical since too much inhibition would lead to cell depolarization or even cell death). As just described, raising intracellular sodium has a secondary consequence of raising cytoplasmic calcium and the amount of calcium stored in the SR. Currently in more common use are β-adrenergic blockers, angiotensin antagonists and diuretics. 2. A consequence of the reversible operation of the NCX is that depolarization (e.g., during the cardiac action potential) can cause it to reverse direction and produce Ca2+ influx at the expense of Na+ efflux. For example, depolarizing to 0 mV would cause Ca2+ entry until Vr moved to 0 mV. [Na]o= 150 mM, [Na]i=15 mM (ENa=58 mV) and [Ca]o=2 mM, this would require [Ca]i to increase to 2 μM (ECa=87 mV, Vr=0) Put another way, during depolarization, the NCX exchange becomes a significant source of Ca2+ entry. This is reflected as an outward current on the accompanying diagram since every Ca2+ ion that enters is accompanied by the extrusion of 3 Na ions. The NCX current reverses direction towards the end of the action potential because [Ca]i increases beyond 2 μM as a consequence of both the L-type current and release from RyRs. Repolarization further increases the extrusion of Ca2+ via NCX. In the steady-state Ca2+ extrusion via NCX precisely balances the entry of external Ca2+ (via the L-type current and the NCX exchanger itself). 3. Although the precise details do not matter, suppose a cell is at a membrane potential of -74 mV (with [Na]o= 150 mM, [Na]i=15 mM and [Ca]o=2 mM, [Ca]i=100 nm. A sudden increase in [Ca]i would result in net inward current (as a consequence of Ca2+ extrusion). This inward current would cause the cell to depolarize. Depolarization triggered by Ca2+ release from the SR has the capacity to trigger arrhythmias as will be discussed in more detail in the next lecture. However, SR Ca2+ release has also been postulated to play a role in the normal pacemaking of cells of the SA node. The notion is that that there is an oscillatory Ca2+ release from the SR of SA nodal cells which occurs independently of any events at the plasma membrane; this results in Ca2+ release during diastole and the activation of Na+ entry via NCX, which causes (or at least contributes to) the pacemaker depolarization.

Answer 89

In the long term, calcium entry into myocardial cells from the extracellular space must equal efflux of calcium into the extracellular space, since any continuing imbalance would cause the cells to continuously gain or lose calcium. In the short term, however, calcium influx can exceed efflux. Similarly, short term calcium efflux can exceed influx. The consequence of the first of these two is that the amount of calcium stored in the SR can be increased (whereas in the latter, SR calcium content would decrease). Except for these short term increases or decreases, however, it is important that SR calcium content be kept roughly constant. The NCX calcium exchanger, discussed in the last lecture, represents one mechanism for calcium homeostasis. However, another important mechanism is that the L-type Ca2+ channel undergoes a form of inactivation that depends on the concentration of Ca2+ near the cytoplasmic side of the channel. This process is termed calcium-dependent inactivation (CDI). CDI depends, in part, on Ca2+ entering through the channel but also, to a large extent, on Ca2+ released via RyR2. This means that if the amount of Ca2+ in the SR (and thus the amount released via RyR2) increases, greater CDI causes less Ca2+ to enter via the L-type channel. Conversely, if there is decreased content of Ca2+ in the SR and decreased Ca2+ release via RyR2, then there is less CDI and greater Ca2+ entry via the L-type channel. Thus, CDI helps to maintain a constant SR Ca2+ content.

Answer 90

The L-type Ca2+ channel, RyR2, Phospholamban (PLB), and Troponin. 1. Phosphorylation of the channel (i.e., the DHPR with Cav1.2 as its principal subunit) increases the amplitude of the L-type Ca2+ current, and thus increases the size of the trigger to activation of RyR2. The increased Ca2+ entry also helps to increase the quantity of Ca2+ stored in the SR. 2. Phosphorylation of RyR2 causes it to be sensitized to activation by trigger Ca. 3. The association of PLB with SERCA2 inhibits Ca2+ pumping activity. Phosphorylation causes PLB to dissociate from SERCA2, which relieves the inhibition and thus increases Ca2+ pumping into the SR. This speeds relaxation and increases the quantity of Ca2+ stored in the SR. 4. Phosphorylation of troponin speeds the rate of Ca. Actions (1 and 2) contribute to positive inotropy. Action (3) contributes to both positive inotropy and positive lusitropy. Action (4) contributes to positive lusitropy.

Answer 91

Not surprisingly, mutations of proteins important for cardiac EC coupling can seriously alter cardiac function. Examples are given below. In some instances, the cardiac abnormalities can be easily understood (or at least rationalized) on the basis of altered function of the mutated protein, but in other instances this connection is less clear. Difficulty in linking altered phenotype to altered genotype arises because studying the altered protein almost always requires a model system. For ion channels heterologous expression in fibroblastic cells (HEK293, CHO) or in Xenopus oocytes is typically used. The environment of the expressed channels in such systems would be expected to differ from that in vivo (e.g., splicing, associated proteins). Transgenic, knock-out or knock-in mice are often used to study protein function, but cardiac function of mice differs significantly from that of humans (mice have ~5-fold higher heart rates than humans). Disease manifestation in humans may take many years to occur, during which time substantial cardiac remodeling may have taken place.

Answer 92

a debilitating disorder resulting in syncope, cardiac arrhythmias and sudden death. In addition to congenital heart disease, patients display intermittent hypoglycemia, immune deficiency and cognitive abnormalities including autism. The disease has been linked to recurrent, de novo mutations in CaV1.2 (the principle subunit of the L-type Ca2+ channel), which is consistent with the multi-system nature of the syndrome given that CaV1.2 is expressed not only in the heart but in many other tissues as well. One variant (TS) arises from the mutation (G406R) in exon 8A, and another variant (TS2) from two mutations (G402S, G406R) of exon 8 which encodes the same region as exon 8A. Analyzed by heterologous expression, the TS2 mutations have been shown to profoundly suppress voltage-dependent inactivation (accompanying illustrations from Splawski et al., PNAS 102: 8089–8096, 2005). TS and TS2 patients display AV block, prolonged Q-T intervals (indicative of a prolonged ventricular action potential) and episodes of polymorphic ventricular tachycardia.

Answer 93

(also known as Sudden Unexplained Death Syndrome) is associated with a number of ECG alterations, which in some instances are revealed by administration of class IC anti-arrhythmics (sodium channel blockers) including ajmaline. Brugada syndrome has been linked to mutations of the cardiac sodium channel (NaV1.5), KChip2 a modulatory subunit association with Kv4.3 to produce IKto, and several other proteins including ankyrin (a protein that links NaV1.5 to the cytoskeleton). A subset of Brugada Syndrome patients either have mutations (A93V, G490R) in the principal subunit (CaV1.2) or a mutation (S481L) in the main accessory subunit (β2b) of the L-type Ca2+ channel. Analyzed by heterologous expression in CHO cells, these mutations appear to cause a large reduction in the magnitude of L-type Ca2+ current which for A93V and G490R may be a consequence of impaired membrane trafficking. These patients have a significantly shortened Q-T interval.

Answer 94

Patients with CPVT do not display ECG abnormalities at rest, but do display abnormalities upon exercise or infusion of catecholamines. A number of causative mutations have been found in RyR2, all of which have dominant inheritance. Causative mutations have also been found in the lumenal Ca2+ buffer calsequestrin2 (CasQ2), the isoform expressed in heart); these result in recessive inheritance. The RyR2 mutations are thought to increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2+. Some of the CasQ2 mutations would, in the homozygous condition, result in a dramatic loss of lumenal Ca2+ buffering, whereas others would not have such a pronounced effect. However, in addition to buffering lumenal Ca2+, calsequestrin has also been suggested to regulate the function of RyR2 and this regulation may be altered by the CPVT causing mutations. The presence of the CPVT mutations together with the increased SR Ca2+ content that is a consequence of activation of β-adrenergic receptors is presumed to result in releases of Ca that are not directly triggered by the L-type Ca2+ current during the plateau of the action potential but instead occur either shortly or long after repolarization. Extrusion of this Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias.

Answer 95

Heart failure (HF) is often the final and more severe manifestation of nearly all types of heart disease. This makes HF common and costly. HF is a highly symptomatic and progressive disease. Consequently, decreased quality of life, hospitalizations, and death are common. For patients with symptomatic HF, half will be dead within 5 years, making HF more deadly than most cancers. HF is primarily a disease of older individuals. The median age of patients with HF is 75 yrs. The incidence and prevalence of heart failure are increasing for a number of reasons: Aging population, People surviving initial cardiac disease (victim of our success): Revascularization for myocardial infarction and Surgery for congenital heart disease. Therapies generally stabilize HF but do not often cure it

Answer 96

the inability of the heart to pump blood forward at a sufficient rate to meet the metabolic demands of the body (forward failure), or the ability to do so only if the cardiac filling pressures are abnormally high (backward failure). HF is a syndrome (i.e. garbage term) describing a constellation of signs and symptoms caused by many possible abnormalities of heart function.

Answer 97

Poor forward blood flow is a key requirement of HF = low flow (decrease cardiac output). Backward buildup of pressure is almost always present as well = CONGESTION (↑ filling pressures) Typically a response to low flow Function determines dysfunction – key cardiac concepts to keep in mind: The heart is a displacement pump: Squeeze (contract) and Fill (relax). Failure of either function causes HF. 2x pumps (left and right) in series: Share a common septal wall and Left, right, or both can fail. Share an electrical system. Both R and L heart beat together. Too slow, too fast, asynchronous all decrease cardiac efficiency The heart’s primary function is to pump blood. Blood flow is measured in “cardiac output” in liters per minute.

Answer 98

Ventricular output increases in relation to greater filling. Frank-Starling curves. Left ventricular end-diastolic pressure (LVEDP) v. stroke volume The more the LV is filled, the more it will contract. Preload (left ventricular end diastolic pressure [LVEDP]) produces increased SV (and thus CO) for the same inotropic state

Answer 99

Inotropy = contractility. Same filling (preload) of LV produces a greater squeeze of contraction. Determinants: Catecholaminergic / adrenergic stimulation and Calcium. Increase in inotropy produces increased SV (and thus CO) for the same level of preload

Answer 100

systolic v. diastolic. left v. right. acute v. chronic. symptomatic v. asymptomatic v. at risk

Answer 101

A problem with squeeze: decrease contraction / decrease inotropy. Hallmark is: Decreased ejection fraction (“heart failure with reduced ejection fraction” = HFrEF and “left ventricular systolic dysfunction” = LVSD), Ventricular enlargement (“dilated cardiomyopathy”=DCM). Etiologies / primary causes of systolic heart failure: Direct destruction of heart muscle cells (Myocardial infarction, Viral myocarditis, Peripartum cardiomyopathy, Ideopathic dilated cardiomyopathy, Alcohol), Overstressed heart muscle (Tachycardia-mediated HF, Methamphetamine abuse, Catecholamine mediated (takotsubo cardiomyopathy), Volume overloaded heart muscle (Mitral regurgitation and High cardiac output-- Shunting of blood (holes in the heart, AVM) and Wet beriberi (thiamine B1 deficiency)).

Answer 102

Recall that the heart is a displacement pump. So it must both squeeze and relax to function normally. Problems with relaxation cause problems with filling. This produces diastolic (filling time) heart failure. A problem with filling: decrease lusitropy / decrease in relaxation. Hallmark is: Normal ejection fraction (“HF with preserved ejection fraction” = HFpEF and “preserved systolic function” = PSF) and Ventricular wall thickening (“left ventricular hypertrophy” = LVH (a general term) and “hypertrophic cardiomyopathy = HCM (a specific genetic disease)). Etiologies / primary causes of diastolic heart failure: High afterload / pressure overload (Hypertension (long-standing), Aortic stenosis, or Dialysis (inadequate volume removal)), Myocardial thickening / fibrosis (Hypertrophic cardiomyopathy and Primary restrictive cardiomyopathy), External compression (although a problem of filling, some people would not consider these diastolic heart failure because they do not involve the heart muscle itself) (Pericardial fibrosis / constrictive pericarditis or Pericardial effusion)

Answer 103

Recall the heart is really 2 pumps in series: Body / SVC+IVC -> RA ->RV ->Lungs ->LA ->LV ->Body in a loop and In the absence of a shunt / hole in the heart, the RV and LV pump the same amount of blood (RV cardiac output = LV cardiac output). The pulmonary vasculature is a low pressure system under normal circumstances: The afterload (pressure the heart has to pump against) is much higher in the systemic vascular bed than in the pulmonary vascular bed (Normal systemic BP 120/80 mmHg (LV) and Normal pulmonary BP 22/10 mmHg (RV)), Work is determined by the product of flow x resistance (RV work is much less, and thus a normal RV is a thin walled structure). Most heart failure involves the left heart, because the left heart does the majority of work under circumstances of normal pulmonary pressures. Example to emphasize this point: e.g. Fontan procedure in single ventricle physiology. In congenital heart disease where there is effectively only one ventricle, it is possible to hook the veins (SVC/IVC) directly to the pulmonary artery and in the setting of low pulmonary pressures, blood flow can be maintained. Increasing pulmonary pressures / resistance is problematic. Stresses to the RV can cause it to fail to adequately pump blood through the lungs: decrease circulating blood flow (forward RV HF) and increase venous pressures (backward RV HF). Etiologies / primary causes of right-sided heart failure: Left heart failure (Backward HF from LV dysfunction stresses the right side by increasing pulmonary venous pressures and “The most common cause of right heart failure is left heart failure”), Lung disease / pulmonary HTN / RV pressure overload (Called “cor pulmonale” when primary lung disease causes HF. COPD, primary pulmonary hypertension, sleep apnea), RV Volume overload (Shunt (interatrial septal defect) or Tricuspid regurgitation), Damage to the RV myocardium (Isolated RV infarct or Myocarditis)

Answer 104

Systolic dysfunction is typically accompanied by diastolic dysfunction and vice versa (Fibrosis (scar tissue can’t contract or relax) and Ischemia (relaxation is energy dependent)). LV failure often causes RV failure

Answer 105

the problem = Inusfficient blood flow (all HF pathophys starts here). the “solution” is a Compensatory responses: Neurohormal activation, Frank-Starling (increasing preload), and Ventricular hypertrophy and dilation. Low cardiac output results in fluid retention to maintain SV/CO, and thus the congestion in “Congestive Heart Failure”

Answer 106

Chronic neurohormonal activation begets worsening heart failure. Adrenergic activation leads to Vasocontriction, Tachycardia, and Inotropic augmentation. RAAS activation leads to Vascoconstriction and Salt/water retention. This long term increase in cardiac workload and increased metabolic demands promote adverse myocardial remodeling:Ventricular hypertrophy, Ventricular dilation, Myocardial damage / apoptosis, and Myocardial fibrosis

Answer 107

volume of blood pumped per minute by left ventricle. At rest, Cardiac Output = 4-6 L/min Depends on size of person, metabolism, exercise, etc. “Cardiac index” is the CO normalized to body size, measured as surface area in m. Normal range is 2.6 to 4.2 L/min/m2. CO increases by as much as 8 fold during strenuous exercise (max~25L/ min in untrained people, up to ~40 L/min in elite endurance athletes). CO = arterial pressure ÷ total peripheral resistance (flow equation/Ohm’s law again). The two mechanisms for heart to control cardiac output are heart rate and stroke volume. Cardiac output must equal venous return (on average). Venous return = volume of blood flowing into right atrium per minute, Cardiac out put must be the same for left and right sides of heart (on average). Edema (peripheral or pulmonary) results if volumes are not closely matched.

Answer 108

volume of blood pumped per beat

Answer 109

set by pace maker cells in sinoatrial node. Highly regulated by autonomic nervous system. Resting HR ~70bpm (in untrained people; a slow as ~35 bpm in elite endurance athletes). Max HR up to ~200 bpm. Maximum HR decreases with age. Can be estimated as 220 minus age, however that is highly variable, and active people tend to have less decrease in max HR as they age. HR can increase by a larger percentage than stroke volume can, so HR can produce larger changes in cardiac output. High HR alone allows less time for filling so would tend to decrease in stroke volume in absence of other regulation.

Answer 110

Determined by the strength of contraction of the heart, venous return (“preload”),and vascular resistance (“afterload”). Strength of contraction of the heart is controlled via two mechanisms: 1. Length-dependent intrinsic mechanism = Frank-Starling Law of the Heart (see below) 2. Length-independent mechanism = Inotropy (or “contractility”), most obviously regulated via sympathetic nervous system stimulation.

Answer 111

At the end of diastole, the left atrium has filled with oxygenated blood from the pulmonary vein. Contraction is triggered by an electrical signal that originates in the sinoatrial node. As the atrium begins to contract (atrial systole), the atrial pressure increases. This is seen as the “a wave” (the hump) in both the atrial and the ventricular pressure because at this stage, the mitral valve between the left atrium and left ventricle is open, so blood flows freely into the ventricle as the atrium contracts.

Answer 112

As the wave of depolarization reaches the ventricle, it begins to contract and ventricular pressure increases. The initial increase in pressure immediately pushes the mitral valve closed because the ventricular pressure quickly exceeds that in the atrium, which is now relaxing. However, the aortic pressure (~80 mmHg in the example) is initially greater than the ventricular pressure, so the aortic valve is also closed during the initial stage of ventricular contraction. Thus, the ventricular pressure increases dramatically because the ventricle is contracting but the blood has no place to go (both valves are closed). This is the isovolumetric contraction phase of the cardiac cycle (AKA isovolumic contraction phase).

Answer 113

As the ventricle continues to contract, the ventricular pressure exceeds that in the aorta, thus the aortic valve is pushed open and blood begins to flow. This is the ejection phase of the cardiac cycle. As the ventricle begins to relax, the ventricular pressure falls. Pressure decreases slowly at first, and ejection continues. However, when the ventricular pressure drops below the aortic pressure, the aortic valve closes.

Answer 114

The ventricle continues to relax with both valves closed, so the pressure falls rapidly. This is the isovolumetric relaxation phase of the cardiac cycle. As the ventricle continues to relax, the pressure eventually falls below that in the atrium, allowing the mitral valve to open and blood to flow into the ventricle, beginning a new cycle.

Answer 115

The ventricle fills passively at first, with a slight hump toward the end of diastole when the atrium contracts. Then, during the isovolumetric contraction phase, there is of course no change in volume, because the aortic and mitral valves are closed. When the aortic valve opens and blood can leave the ventricle, the volume decreases.

Answer 116

Pressure and volume changes in the left ventricle are bounded by two curves, the systolic pressure-volume relation and the end diastolic pressure-volume relation.

Answer 117

Pressure-volume relationship during filling of heart before contraction. Determined by passive elastic properties of ventricle (~compliance, but note compliance is ∆V/∆P, now we are plotting P as a function of V, so slope of EDPVR is inverse of compliance). Slope of EDPVR is shallow in normal physiological range– there is not much change in pressure w/ change in volume, normal ventricle is compliant. Some pathologies decrease compliance, making EDPVR steeper, which impairs filling of the ventricle. The slope of the EDPVR steepens at very high volumes. The end-diastolic PVR represents the preload on the heart. Analogy is a small weight hanging on muscle before it begins to contract. Preload is strictly defined as ventricular wall tension at the end of diastole (from Law of LaPlace)

Answer 118

The length to which a muscle is stretched before shortening. For left ventricle, preload ~ end diastolic volume.

Answer 119

The load against which a muscle contracts. For left ventricle, afterload ~ aortic pressure.

Answer 120

Pressure - volume relationship at the peak of isometric contraction. Maximum pressure that can be developed by the ventricle for a given set of circumstances. Much steeper than EDPVR – pressure increases a lot even at low volume (since the ventricle is contracting). Systolic PVR includes the passive properties of the heart (ie, includes the diastolic pressure- volume relationship)

Answer 121

Analogy is a small weight PLUS large weight lifted off table. Muscle contracts with force equal to both. For the ventricle, the pressure developed during a contraction (at the end systolic volume) depends on the afterload (approximately the aortic pressure, strictly defined as wall stress during contraction). Increased after load increases the pressure with which the ventricle must contract to eject blood (in the cartoon, this would correspond to the force required to lift a bigger weight off the table).

Answer 122

difference in force between peak systolic pressure and end diastolic pressure curves, i.e., tension developed by the contraction itself, independent of the preload. (Difference in curves)

Answer 123

or Ventricular function curve is a plot of cardiac performance(such as active tension or CO or SV) as a function of preload (such as length or EDV). Note ascending & descending limbs. Analogous to sarcomere length-tension curves. There is not a single Starling curve. Families of Starling curves describe different inotropic states of heart.

Answer 124

intrinsic mechanism by which the heart adapts to changes in preload (in the normal physiological range). Violation of Starling’s law corresponds to Heart Failure.

Answer 125

1) Heart responds to an increase in EDV by increasing the force of contraction. (i.e., ventricular output/active tension increases as the end diastolic volume increases). 2) Healthy heart always functions on the ascending limb of the ventricular function curve. 3) What goes in, must come out. Cardiac output must equal venous return and cardiac output from left and right ventricles MUST match (on average). Frank-Starling mechanism helps balance output between left and right ventricle. Example: Left ventricular stroke volume = 60.0 ml/beat, Right ventricular SV = 60.1 ml/beat. How much would pulmonary blood volume change over 1 hour if the heart rate is 60 beats/min? 0.1 ml/beat x 60 beat/min x 60 min/hr = 360 ml/hour increase Starlings mechanism would usually compensate for this by increasing left ventricular stroke volume in response to increased venous return from the pulmonary circulation.

Answer 126

Cardiac titin isoform is very stiff, resists stretch. Ca2+ sensitivity of myofilaments increases as sarcomeres are stretched. So the same intracellular Ca2+ produces a greater force of contraction. Closer lattice spacing – stretched sarcomeres have altered spacing between actin & myosin which results in more force generated per crossbridge.

Answer 127

Another way in which increased venous return causes increased cardiac output. Stretch sinus node→ increase in heart rate. Bain bridge reflex is mainly via increased sympathetic tone (via sensory afferents & brainstem, more in Regulation lecture), but there are also intrinsic mechanisms in the sinoatrial node.

Answer 128

PV loop diagrams are a graphical representation of the relationship between ventricular pressure & volume during the cardiac cycle. They are useful because they illustrate some measures of cardiac performance and because they demonstrate how changes in preload, afterload, and contractility affect cardiac performance.

Answer 129

includes filling phase, isovolumetric contraction phase, ejection phase, and isovolumetric relaxation phase.

Answer 130

Start at the beginning of diastole, when the mitral valve opens. The volume is the end systolic volume (ESV). Note that ESV is not zero. The heart does not pump out all the blood, there is always some left, about 50 ml in the example. As the ventricle relaxes and fills, the ventricular pressure falls to its minimum value. During diastole, the ventricular volume increases as blood flows into the left ventricle from the left atrium. There is little change in pressure, except the “a wave” (a slight hump near point C, sometimes referred to as “atrial kick”) that corresponds to atrial contraction. Note that the filling phase is also the end diastolic pressure-volume relationship (passive filling curve).

Answer 131

The ventricle begins to contract. Almost immediately, the pressure in the ventricle exceeds that in the atrium and the mitral valve is pushed closed. Since both valves are closed, blood can neither enter nor leave the ventricle, and the volume is constant; thus this is the isovolumetric (or isovolumic) contraction phase. The constant volume during this phase is the end diastolic volume (EDV), which is the maximum reached at the end of filling

Answer 132

When the left ventricular pressure exceeds the aortic diastolic pressure, the aortic valve is pushed open and the ejection phase begins. As blood leaves the ventricle, the volume decreases. At first the pressure continues to increase, as the blood cannot leave the aorta as fast as it is entering. As myocytes in the ventricle stop contracting, the ventricular pressure begins to fall.

Answer 133

When the ventricular pressure again falls below the aortic pressure, the aortic valve closes. Again, both valves are closed, so the ventricular volume is constant (at the end systolic volume, the minimum reached at the end of ejection); this is the isovolumetric relaxation phase. When the ventricular pressure falls below the atrial pressure, the mitral valve opens and filling begins again.

Answer 134

The fraction of the EDV ejected during systole. EF=SV/EDV=(EDV–ESV)/EDV. EF= 70/120= 58%. Normal ejection fraction ~50-70%, reduced in systolic heart failure

Answer 135

Stroke work= energy per beat (in Joules), corresponds to the area inside the PV loop diagram. NOT the same for left & right sides of heart, as systemic circulation has higher pressure, so left heart does more work

Answer 136

Blood volume (IV fluid, hemorrhage), filling pressure (venous blood pressure), filling time (reduced at high heart rates), resistance to filling (e.g., right atrial pressure, AV valve stenosis), resistance to emptying= afterload (e.g., hypertension, pulmonic or aortic stenosis, reduced inotropy

Answer 137

Compliance is defined as ∆V/∆P; on PV plots, compliance is the reciprocal of the slope of the EDPVR. Steeper EDPVR = less compliant (stiffer). Decreased compliance causes lower EDV at any given pressure. Decreased compliance can result from thicker walls in some types of hypertrophy or from impaired ventricular relaxation associated with diastolic heart failure. Dilated cardiomyopathy can increase ventricular compliance

Answer 138

The immediate effect is an increase in stroke volume via Starling’s law (i.e., the heart contracts with more force because sarcomere length is increased). The ventricle matches the stroke volume to compensate for an increase in venous pressure on a beat-to-beat basis. Thus, the same ESV is achieved and ejection fraction is increased. Note that stroke work is also increased (area inside curve). On subsequent beats, SV returns to normal since ESV and contractility are unchanged

Answer 139

Afterload is the load against which the heart must contract to eject blood.

Answer 140

Under normal circumstances, aortic pressure is the major determinant of afterload for the left ventricle and pulmonary artery pressure is the main source of afterload for the right ventricle. Wall thickness and ventricular radius also affect afterload. From Hemodynamics lecture, remember the Law of LaPlace, which shows that wall stress (T) increases as radius (r) increases and wall thickness (μ) decreases, for example in dilated cardiomyopathy. T= ∆P * r/ μ.

Answer 141

This causes a decrease in stroke volume on the next beat: 1) the ventricle has to generate more pressure before the aortic valve opens, allowing less time for ejection. 2) From the force-velocity relationship: shortening velocity is reduced when afterload is increased. Thus, in the relatively fixed time period of systole, the ventricle will develop less pressure, and the ejection velocity will be reduced. Overall, this means less blood is ejected (decreased stroke volume). Summary of immediate effects: EDV unchanged, EF decreased, ESV increased, SV decreased. Stroke volume recovers on subsequent beats because the increased ESV with constant venous return means increased EDV (preload), which increases stroke volume

Answer 142

Inotropy (contractility) reflects the strength of contraction at any given preload and afterload (i.e., independent of fiber length, and therefore independent of the Frank-Starling response). Changes in inotropy describe new Starling curves (systolic ventricular function curves). Inotropy is regulated by nervous and humoral agents, most notably by sympathetic stimulation. In some pathologies (e.g., systolic heart failure) inotropy can be reduced via changes in gene expression and loss of myocytes. Changes in inotropy are particularly important in exercise — help to maintain high stroke volume even at high heart rate.

Answer 143

This results in a new Starling curve which corresponds to greater systolic pressure development any given volume. Increased inotropy is associated with increases in stroke volume and ejection fraction and a decrease in end systolic volume. These effects persist as long as the inotropy remains high (do not recover on next beat).

Answer 144

Generates repetitive firing in specialized, “pacemaker” regions. Propagates within the myocardium and via specialized conductive pathways. Serves as a trigger for contraction of the myocardium

Answer 145

The cardiac action potential is the trigger for an increase in the intracellular concentration of calcium ions, which, in turn, causes contraction of the myocardium. Cardiac action potentials are initiated by pacemaker cells, which slowly depolarize to threshold in the absence of extrinsic input. The rate at which a normal heart beats is controlled by pacemaker cells in the sinoatrial node (SA node). The SA node is a cluster of small (7 μm diameter), round and spindle-shaped cells that contain few myofilaments. These cells are spontaneously active (automaticity) and will fire action potentials at a frequency of about 100/min (rhythmicity). The SA node is innervated by both sympathetic and parasympathetic axons. Ongoing activity in the parasympathetic axons (parasympathetic tone) typically slows the rate at which cells in the SA node fire to 60-80 action potentials/min. Cells in other regions of the heart, including those of the atrioventricular node (AV node), are also capable of spontaneous activity. However, the frequency at which they would fire action potentials is lower than the frequency of discharge of cells in the SA node. Consequently, under normal circumstances these cells are driven by action potentials originating in the SA node; that is, an action potential will spread to them from the SA node before they reach threshold on their own (overdrive suppression). Under abnormal circumstances these cells (or others, especially cells in damaged regions of the myocardium) can take over initiation of the heartbeat, becoming ectopic pacemakers.

Answer 146

Because heart rate is controlled by electrical activity of the SA node, the propagation of this activity to other regions of the heart has to occur such that the two atria contract and relax in a coordinated fashion, that two ventricles contract and relax in a coordinated fashion, and that ventricular contraction occurs during atrial relaxation (and vice versa). Gap junctions connecting individual myocytes provide for cell-to-cell propagation of action potentials within the atrial myocardium, as well as within the ventricular myocardium. Additionally, specialized conductive pathways, in which individual cells are also connected by gap junctions, conduct the action potential from the SA node to the left atrium, from the SA node to the atrioventricular node (AV node), which is a cluster of small cells located on the right side of the inter-atrial septum near the opening of the coronary sinus. In the normal heart the AV node is the only place where action potentials can spread from the atria to the ventricles. Elsewhere, myocardial cells in the atria are electrically insulated from those in the ventricles by an intervening layer of connective tissue. From the AV node, additional conducting pathways propagate the action potential to the left and right ventricles. Cells in these conducting pathways are relatively large in diameter (30-70 μm), so that the action potentials propagate more rapidly through them than through typical myocardial cells, which are about 15 μm in diameter. These conducting pathways are considered in more detail in the next lecture of the CVPR block.

Answer 147

In the myocardium, the action potential lasts a few hundred ms and triggers a sustained contraction of about the same duration. Action potentials in the SA and AV nodes are somewhat briefer, but still much longer than the action potential in skeletal muscle which lasts only about 1 ms.

Answer 148

Ionic currents (“Iion”) are categorized based on species of permeant ion(s), kinetics, dependence on voltage or other activators, and pharmacology. Depending on the tissue, there may be a relatively good correspondence with specific ion channel subunits, but such a correspondence is often difficult to achieve owing to alternate splicing, post-translational modification, and the heteromeric structure of many ion channels. While this may seem to be of only obscure academic interest, it turns out to be of fundamental importance in an era of “molecular medicine” for at least two reasons. First, the consequences of altered sequence in the gene encoding a particular ion channel subunit can vary dramatically from tissue to tissue (e.g., a mutation might affect the sequence of a splice isoform expressed only in some tissues). Second, the pharmacological profile of a particular ion channel subunit can be strongly influenced both by alternate splicing and by the identity of other subunits with which it associates. Major ionic currents underlying cardiac action potentials are summarized, along with the principle channel subunits that are thought to produce these currents.

Answer 149

Cardiac sodium channels (containing NaV1.5 as the principle subunit) are similar to sodium channels in neurons and skeletal muscle. Depolarization causes them to activate rapidly and then inactivate.

Answer 150

The properties of calcium channels are mainly determined by the principle (CaV) subunit, which has a structure like that of the NaV subunit of voltage-gated sodium channels.

Answer 151

L-type channels: CaV1.1, CaV1.2, CaV1.3, CaV1.4 Neuronal channels: CaV2.1, CaV2.2, CaV2.3

Answer 152

CaV3.1, CaV3.2, CaV3.3

Answer 153

are predominant in ventricular and atrial myocardium and cells of the SA and AV nodes and conductive pathways. SA nodal cells also express L-type channels containing CaV1.3. L-type channels activate quite rapidly in response to depolarization and subsequently inactivate in a manner dependent both on voltage (voltage-dependent inactivation, VDI) and cytoplasmic calcium (calcium-dependent inactivation, CDI). In addition to being expressed in the heart, L-type channels are expressed in smooth and skeletal muscle and in the nervous system. L-type calcium currents (ICa-L) are blocked by dihydropyridines (nifedipine, for example), which are used as anti-hypertensive agents.

Answer 154

are described as “LVA” because they are activated by weaker depolarizations than those required for activation of HVA channels. T-type calcium currents (ICa-T) activate and then inactivate in response to depolarization (with a time course similar to, but slower than, sodium currents). T-type channels are expressed in the SA node and in the nervous system.

Answer 155

Unlike sodium and calcium channels, the principle subunits of potassium channels assemble as tetramers. Multiple genes encode subunits of the tetrameric channels, and in some instances hetero-tetramerization may occur between these gene products. This complexity is omitted in the simplified summary given below.

Answer 156

IKto – (Kv4.3 tetramer + KChiP2) Depolarization causes both activation and inactivation on a time scale only slightly slower than that of sodium current. IKr (HERG tetramer + miRP1) and IKs (KvLQT1 tetramer + minK) are the so-called “rapid” delayed rectifier and “slow” delayed rectifier, respectively. Depolarization causes activation of these two currents on a time scale of 20-100 ms.

Answer 157

IK1 - The “inward rectifier” channel (Kir tetramer) does not gate in the conventional sense, although its conductance is steeply voltage dependent as a consequence of block by cytoplasmic constituents. As a result, these channels display a strong, “instantaneous” (< 1 ms) rectification such that they readily conduct inward K+ current at potentials below EK and only weakly pass outward K+ current at potentials slightly positive to EK. Consequently, these channels are ideally suited for holding cells near EK between action potentials without producing an outward current upon depolarization that would be energetically costly and make it more difficult to generate an action potential. IKACh – This current (GIRK tetramer) is increased in response to acetylcholine acting on muscarinic receptors (G-protein coupled receptors). This mechanism is important for the ability of the parasympathetic nervous system to slow pacemaker activity of the SA node.

Answer 158

If (or Ih) (HCN tetramer) – This current is considered “funny” (hence the “f“ in If) because it is turned off at depolarized potentials and turned on at hyperpolarized potentials (hence the “h” in Ih). The channel is permeable to both Na+ and K+ (Erev ≈ -30 mV). It is thought to be “activated” (in the Hodgkin-Huxley sense) at both depolarized and hyperpolarized potentials. However, current flow depends upon hyperpolarization because the channel is inactivated (also in the Hodgkin-Huxley sense) at depolarized potentials; this inactivation is removed by hyperpolarization. If has been postulated to play an important role in pacemaking by SA nodal cells.

Answer 159

The categorization of cardiac action potentials as fast or slow is based on whether the initial upstroke is rapid or slow. Myocardial cells and cells of the rapid conduction pathways display fast action potentials. The initial upstroke (phase 0) of a fast cardiac action potential consists of a rapid depolarization caused by the entry of sodium ions (INa) through voltage- activated sodium channels. The rapid upstroke of fast cardiac action potentials is an indicator of the much faster spatial propagation than occurs for slow action potentials. Following the rapid upstroke is a small, partial repolarization (phase 1), which is produced by a combination of inactivation of sodium current and activation of a transient potassium current IKto. This followed by a prolonged plateau (phase 2), during which voltage-activated, L-type calcium channels are open. The influx of calcium ions (ICa-L) is approximately balanced by an efflux of potassium ions (IKr and IKs) via delayed rectifier channels so that membrane potential remains at a roughly constant level (near 0 mV) during the plateau. The combination of inactivation of (ICa) and increasing activation of IKr and IKs causes termination of the plateau by a rapid repolarization (phase 3). As a result, IKr and IKs are de-activated, and inactivation of INa and ICa is removed; the cell is held near EK (phase 4) by the inward rectifier (IK1). Note that a second action potential cannot be initiated (absolute refractory period) until most of the inactivation of INa is removed (during the repolarizing phase), and the threshold for a second action potential remains elevated (relative refractory period) until after repolarization is complete (complete removal of inactivation of INa and deactivation of IKr and IKs has occurred).

Answer 160

The ionic currents in pacemaker cells of the SA and AV nodes differ in a number of important ways from those of cells of the myocardium and fast conducting pathways. Notably, pacemaker cells have reduced INa and little IK1; moreover, pacemaker cells express If and ICa-T which are essentially absent in myocardial cells. The complement of ionic currents expressed in pacemaker cells has the result that there is no stable resting potential, and these cells produce repetitive, “slow action potentials.” The upstroke (phase 0) is attributable to activation of ICa-T and ICa-L and is relatively slow owing to the absence of INa. Additionally, slow cardiac action potentials lack the partial repolarization (phase 1) and prolonged plateau (phase 2) characteristic of fast action potentials. Rather, the balance between ICa and delayed rectifier current (IKr and IKs) is such that repolarization (phase 3) occurs shortly after the peak of the action potential. Importantly, the repolarization is followed by a slow depolarization (the “pacemaker potential”) during phase 4, which brings the cell back to threshold for the generation of another action potential. It seems likely (to the author of these notes, certainly) that a number of processes contribute to the pacemaker potential. However, one contribution of likely importance is the funny current (If) which is induced by hyperpolarization. Induction of If allows cation fluxes (sodium and to a slightly lesser extent potassium) which drive voltage towards the reversal potential of If (-30 mV). The pacemaker depolarization during phase 4 of slow cardiac action potentials is also likely facilitated by the slow deactivation of IKr and IKs, and by activation of LVA Ca2+ current (ICa-T). Although the ion channels present in the plasma membrane of pacemaker cells provide a highly plausible mechanism for rhythmic firing, it has also been suggested that internal calcium release and the resultant movements of sodium and calcium via the NCX sodium/calcium exchanger play an important role in generating the pacemaker potential. This mechanism will be described during the lecture on EC coupling and calcium movements.

Answer 161

an important “anti-target” tested in preclinical evaluation of new drugs. Because IKr (tetramer of HERG) is important for repolarization of both fast and slow cardiac action potentials, altered HERG function can disrupt normal cardiac electrical activity, leading to arrhythmias. This is significant in regard to clinically administered drugs because HERG channels are blocked by a wide variety of structurally unrelated compounds. Thus, it has now become standard practice to that an early pre-clinical test of any investigational drug is to determine whether it blocks HERG channels.

Answer 162

Cells in the sinoatrial node and AV node are capable of spontaneous depolarization. Phase 4 the period of repolarization is not static as occurs in contractile myocytes. During phase 4 there is slow depolarizing due to a “funny current” or “pacemaker current” until it reaches a critical voltage where a more rapid Phase 0 occurs due entirely to a calcium current – no fast sodium current is present. These cells are very poor conductors of electrical current because of lack of a fast sodium current. The SA node is the usual cardiac pacemaker because it has the fastest spontaneous rate. The AV node has a slower spontaneous rate but it delays conduction at the junction between the atria and ventricles.

Answer 163

have a stable baseline during repolarization in stage 4 but exhibit a rapid, robust increase during phase 0 due to the fast sodium current and are fairly good at conducting from cell to cell enabling fairly rapid electrical excitation of the atria and ventricles.

Answer 164

have a similar shape to contractile myocytes with a slightly higher voltage during phase 0 and a longer total duration. Probably because of greater numbers of fast Na channels they conduct faster than contractile myocytes. They allow extremely rapid conduction from the AV node to the ventricles through the left and right bundles and their extensions into the myocardium.

Answer 165

Once an electrical impulse is initiated by a pacemaker it will spread rapidly through the gap junctions, cylindrical structures formed by connexins that allow ions to pass from cell to cell. The sinoatrial (SA) node has automaticity and normally is the pacemaker generating the electrical signal that starts a wave of depolarization through the heart. It is located high in the right atrium. The depolarization wave then goes through the right and then the left atrium generating the P wave. It then arrives at the atrioventricular (A-V) node located between the fibrous tricuspid and mitral valve rings that separate the atria from the ventricles. At this site, which is also called the “junction”, there is a delay before the depolarization wave enters the ventricles. This delay allows contraction of the atria to end before ventricular contraction begins.The depolarization wave then proceeds through the bundle of His into the left and right bundle branches. The bundles then divide into fibers made up of Purkinje cells. These Purkinje fibers radiate toward the contractile cardiac myocytes that induce contraction. The right bundle is a single entity primarily supplying the right ventricle. The left bundle divides into anterior and posterior branches or fascicles that supply corresponding regions of the left ventricle. The bundle of His, left and right bundles, and Purkinje fibers all contain specialized cells that conduct depolarization very rapidly. The vast majority of ventricular cardiac myocytes are primarily specialized to contract (“contractile myocytes”) and conduct depolarization waves much more slowly.

Answer 166

use compact solid electrodes. In the normal heart depolarization begins in the atria and then proceeds to the ventricles. On the right is a composite signal that is obtained during a single heart beat. Alphabetically in order there is a P wave due to depolarization of the atria, a QRS which is due to depolarization in the ventricles and a T wave that is due to repolarization of the ventricles. Repolarization of the atria is not seen because it normally occurs at the same time as ventricular depolarization and is buried in the much larger signal from the ventricles. Note that the T wave of repolarization in the ventricles is in the same direction in the normal electrocardiogram as the QRS or depolarization signal, whereas in individual myocytes depolarization and repolarization are in opposite directions.

Answer 167

The initial rapid upwards deflection of the R wave corresponds to phase 0 of the action potential, which is due to the fast sodium current. The isoelectric ST segment on the electrocardiogram which links the QRS to the T wave is isoelectric normally and corresponds to phase 2 of the action potential in which there is a long plateau with little change in voltage. That is the time in which calcium influx and potassium efflux are balanced. The T wave of the ECG in which repolarization is occurring corresponds to phase 3 of the action potential in which there is a rapid decrease in voltage as potassium efflux continues. The isoelectric segment after the T wave corresponds to phase 4 of the action potential. Note that during action potential repolarization in Phase 3 there is a decreasing or negativevoltage change in the opposite direction from depolarization in Phase 0 but the T wave in the ECG and the R wave are in the same direction for reasons we will explain.

Answer 168

In each cardiac myocyte, repolarization is in the same direction as depolarization but because of different polarity the two waves are in opposite directions (discordance). Then why are the QRS of depolarization and the T wave of repolarization both in the same direction (concordance) in the surface ECG? The endocardium depolarizes earlier than the epicardium. However, there is a transmural repolarization gradient and epicardial cells repolarize earlier than endocardial cells because they have shorter action potential duration. The key point is that normally there is concordance in direction between the QRS and the T in every ECG lead: If the QRS is positive the T wave should be positive! if the QRS is negative the T wave should be negative as well. Discordance between the QRS and T waves in any lead is pathological, reflecting abnormalities such as ischemia or ventricular hypertrophy.

Answer 169

atrial depolarization 

Answer 170

ventricular repolarization 

Answer 171

ventricular repolarization

Answer 172

index of conduction time across the AV node 

Answer 173

total duration of depolarization and repolarization

Answer 174

The sinus node depolarization initiates the beat but is too small to see on the ECG. The first signal seen is the P wave generated by depolarization of first the right and then the left atrium. The next deflection, the QRS, is ventricular depolarization.The Q is an initial negative deflection, the R is the upward deflection and the S is a terminal negative deflection. There are 12 separate leads in the ECG and the shape of the QRS depends on where the positive electrode is placed. The T wave is generated by repolarization of the ventricle. The P, QRS, and T in a given lead are all approximately in the same direction normally. The QRS voltage is much greater than the P voltage because ventricular mass exceeds atrial mass. The T wave is wider than the QRS because ventricular repolarization takes considerably longer than depolarization. Atrial depolarization is not seen because normally it s buried in the QRS which is a much larger signal.

Answer 175

If the activation wave is toward a sensing electrode a positive (upward) deflection will be recorded. The greater the muscle mass the greater the voltage recorded. The pattern of the deflection varies with the position of the recording electrodes. The SA node is high in the right atrium and the depolarization wave sweeps downward and leftward. Therefore, a lead with a positive electrode near the right arm normally has a predominantly negative QRS and a lead with a positive electrode near the left leg has a positive QRS.

Answer 176

1. The upper portion of the septum is depolarized from left to right. 2. There is then depolarization downward in the septum to the apex. 3. Depolarization is from endocardium to epicardium. 4. Depolarization moves upward from apex in the free walls of both ventricles. 5. Finally there is depolarization of the base of the ventricles.

Answer 177

These commonly cause “sick sinus syndrome” resulting in slow sinus rates or takeover by other pacemakers which may be either fast or slow.

Answer 178

First degree AV block: conduction delayed but all P waves conduct to the ventricles. 2nd degree block: some P waves conduct but others do not 3rd degree block: none of the P waves conduct & a ventricular pacemaker takes over

Answer 179

When the right bundle is blocked - QRS widening with delayed conduction to the right ventricle. When the left bundle is blocked –QRS widening with delayed conduction to the left ventricle. When left bundle fascicles (anterior and posterior fascicles) are blocked there are shifts in direction of depolarization but no QRS widening.

Answer 180

abnormal reentry pathways, ectopic foci, and triggered activity

Answer 181

can be present in the atria, ventricles, or the junctional tissue. Reentry occurs when there is a unidirectional block and slowed conduction through the reentry pathway. After the slow reentry the previously depolarized tissue has recovered and reentry into it will occur. This is probably the most common mechanism of serious tachycardias.

Answer 182

occur when a focus of myocardium outside the conduction system acquires automaticity and if the rate of depolarization exceeds that of the sinus node an abnormal rhythm occurs. These can be isolated “ectopic beats” or sustained tachyarrhythmias.

Answer 183

abnormal “afterpolarizations” may be triggered by the preceding action potential. Here an early afterpolarization when the action potential has only partially repolarized triggers a tachyarrhythmia. Delayed afterpolarizations appearing after an action potential Is complete can also trigger arrhythmias. Arrhythmias due to this mechanism are usually associated with a delay in repolarization seen in the ECG as a “long QT interval”.

Answer 184

In the vast majority of cases, cardiac arrhythmias are acquired subsequent to myocardial infarction, ischemia, acidosis, alkalosis, electrolyte abnormalities, or excessive catecholamine exposure. Drug toxicity is another common cause of arrhythmic activity, with cardiac glycosides (digoxin), some antihistamines (e.g., astemizole, terfenadine) and antibiotics (e.g., sulfamethoxazole) among the many drugs that can trigger arrhythmias.

Answer 185

themselves are among the most arrhythmogenic pharmaceuticals. The CAST (Cardiac Arrhythmia Suppression Trial) study of 1989 revealed, unexpectedly, that post myocardial infarction patients treated prophylactically with the antiarrhythmics flecainide or encainide had a 2-3x greater mortality rate as compared to patients on placebo. This result drastically changed the way antiarrhythmic drugs are used today: catheter ablation of ectopic foci and implantable cardioverter-debrillator devices (ICDs) are now commonly used in place of pharmacological therapy. However, antiarrhythmic drugs (1) remain very useful as first-line therapy in treating certain arrhythmias; (2) are frequently used in conjunction with ICDs to decrease the frequency of arrhythmic episodes and thereby both prolong battery life and reduce the number of painful shocks; and (3) may become more useful as research reveals new information about their mechanisms of action and their molecular targets. The primary targets of antiarrhythmic drugs are cardiac Na+ channels (INa), Ca2+ channels (ICa-L), K+ channels (IKs and IKr), and β-adrenergic receptors. Na+ channels, Ca2+ channels, K+ channels and β-adrenergic receptors are direct drug targets. Via the β-adrenergic receptor pathway, the pacemaker current, If, and ICa-L, and IKs are indirect targets of antiarrhythmic drug action. To date, only β-blockers have been demonstrated to reduce the incidence of sudden cardiac death.

Answer 186

SA node gets slower.

Answer 187

The role of the autonomic nervous system is to maintain homeostasis in the internal environment. It regulates the physiological systems over which we have only minimal conscious control, such as the cardiovascular, GI, and respiratory systems. Changes in autonomic control of these systems are responsible for eliciting the responses we associate with stressful stimuli and other emotions. In contrast to the somatic (motor) nervous system that controls skeletal muscle contraction, the autonomic nervous system is characterized by a two-neuron link between the central nervous system (CNS) and the peripheral target organ. Preganglionic neurons located in the brainstem or spinal cord connect to postganglionic neurons located in autonomic ganglia outside the CNS. The postganglionic neurons project to the target organ where they innervate smooth muscle, cardiac muscle, or glands. Transmission over the preganglionic fibers is relatively fast, because they are composed of myelinated fibers. The postganglionic fibers are unmyelinated. The autonomic nervous system consists of the sympathetic nervous system and the parasympathetic nervous system. These in turn innervate the enteric nervous system of the gastrointestinal system.

Answer 188

The sympathetic nervous system initiates responses to emergency or stressful situations. It is classically associated with "fight and flight" responses. The preganglionic neurons of the sympathetic nervous system are located in the intermediolateral column of the thoracic and upper lumbar segments of the spinal cord. The axons from these neurons exit the spinal cord in the ventral roots of the corresponding spinal nerves. After passing through the white ramus communicans (myelinated) and entering the sympathetic trunk, they branch to innervate postganglionic neurons in multiple levels of the spinal trunk. In addition, the splanchnic nerves contain preganglionic axons arising from the lower 7 thoracic spinal levels. These axons pass through the spinal trunk to innervate postganglionic sympathetic neurons located in the celiac and mesenteric ganglia. Acetylcholine is the neurotransmitter released by preganglionic sympathetic neurons. Vasodilation and vasoconstriction are controlled primarily by the sympathetic nervous system. Increased sympathetic output causes vasoconstriction, while decreased sympathetic output causes vasodilation. Note that, at rest, sympathetic output maintains the vasculature in an intermediate state between constriction and dilation. Increased sympathetic output also results in increased heart rate and force of contraction.

Answer 189

release norepinephrine as their neurotransmitter. They are located in the ganglia of the sympathetic trunk (paravertebral chain ganglia). The axons from these postganglionic neurons exit the spinal trunk through the gray rami communicans (unmyelinated) and travel in the spinal nerves to reach the sweat glands, peripheral blood vessels, hair follicles, etc. The postganglionic sympathetic neurons involved in regulation of the GI tract are located in the celiac and mesenteric ganglia. Their axons form the perivascular plexuses innervating the abdominal viscera.

Answer 190

a specialized component of the sympathetic nervous system. It functions as a neuroendocrine gland, because the postganglionic cells contained in the adrenal medulla secrete epinephrine (80-90%) and norepinephrine (10-20%), both of which bind to adrenergic receptors (see below), into the blood stream. Thus, rather than acting as neurotransmitters, these agents become hormones that regulate the activity of distant target tissues. These specialized postganglionic cells in the adrenal medulla are innervated by preganglionic sympathetic neurons located in thoracic levels 6-9 of the spinal cord.

Answer 191

The parasympathetic nervous system is involved in conservation and replenishing of resources. It is classically associated with "rest and digest" responses. The actions of the parasympathetic system generally oppose those of the sympathetic nervous system. The preganglionic neurons of the parasympathetic nervous system are located in brainstem nuclei and in the sacral spinal cord. The parasympathetic, preganglionic fibers exit the brainstem in cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus). They are characterized by long axons, use acetylcholine as a neurotransmitter, and innervate postganglionic neurons located in ganglia near or in the effector organ. The parasympathetic, postganglionic neurons also use acetylcholine as a neurotransmitter. Due to their location in or near the effector organ, they are characterized by short axons. The axons from the preganglionic neurons in the sacral portion of the parasympathetic system travel in the splanchnic nerves to innervate ganglia associated with the colon, rectum, urinary bladder, and genital organs. This portion of the system functions to control "emptying", e.g. urination, defecation, and erection. Increased parasympathetic output results in decreased heart rate and force of contraction. While parasympathetic output may result in some small amount of vasodilation, most vasodilation is controlled by decreased sympathetic output.

Answer 192

In most cases, the neurotransmitter released by the preganglionic neurons of the sympathetic and parasympathetic system is acetylcholine (ACh). ACh acts on the nicotinic cholinergic receptors on postganglionic neurons and causes depolarization and firing of the postganglionic neuron. The action potentials that arrive at the nerve terminal of the postganglionic neuron then cause release of synaptic vesicles containing norepinephrine or ACh by the process of exocytosis. The neurotransmitter released by the sympathetic postganglionic neuron is norepinephrine (NE) whereas the neurotransmitter released by the parasympathetic postganglionic neuron is ACh. Co-localized agents (e.g. ATP, peptides) also participate.

Answer 193

There are two types of cholinergic receptors to which ACh binds and elicits a cholinergic response. They are nicotinic (stimulated by nicotine) and muscarinic (stimulated by muscarine) receptors. Mainly nicotinic receptors are present in the cell body of postganglionic neurons of the autonomic ganglia whereas muscarinic receptors are present on the effector cells of cardiac muscle, smooth muscle, and glands. The cellular mechanisms by which ACh produces its effects are also very different for nicotinic and muscarinic receptors.

Answer 194

itself is a ligand-gated, non-selective cation channel. When ACh binds to the receptor, the ion channel that is part of the receptor protein opens and allows rapid movement of Na+ and K+ across the membrane, leading to depolarization and excitation.

Answer 195

in the cell membrane are linked to a GTP-binding (G) protein. When ACh binds to the extracellular site of the muscarinic receptor protein, a conformational change occurs within the receptor molecule causing "activation" of the G protein coupled to the receptor. The G protein then either stimulates or inhibits other intracellular effectors such as enzymes or ion channels, producing a physiological response. There are five subtypes of muscarinic receptors (M1-M5). Different muscarinic receptors are coupled to different effectors within a cell. Thus, a simple molecule like ACh has the potential to produce a variety of physiological responses in different cell types, depending on which muscarinic receptor subtype is activated. For example, in atrial cells, ACh released from the vagus nerve binds to the muscarinic receptor, and the activated G protein then opens K channels, causing hyperpolarization and slowing down of the heart rate. In contrast, in other cells activation of muscarinic receptors causes a different type of K+ channel to close thus resulting in a sustained depolarization of the neuron.

Answer 196

Analogous to cholinergic receptors, there are multiple receptor subtypes for NE, the neurotransmitter for the adrenergic system. Adrenergic receptors consist of alpha (α) and beta (β) receptors. Adrenergic receptors are subdivided into α1, α2, β1, and β2. NE only activates α1, α2, and β1 receptors. Epinephrine, released from the adrenal medulla into the bloodstream, activates all 4 subtypes.

Answer 197

Drugs are available that selectively activate or inhibit the subtypes of adrenergic receptors. For example, to counteract the bronchoconstriction that occurs in asthma or severe anaphylactic reactions, epinephrine or a more selective β2 agonist is administered to initiate bronchodilation. Beta-blockers such as propranolol are used to treat hypertension (high blood pressure) and coronary artery disease. The table below shows the downstream effects on the cardiovascular system resulting from activating each adrenergic receptor subtype. Note that the example agonists and antagonists shown are used in a variety of clinical contexts, not only to treat cardiovascular symptoms. Drugs that result in sympathetic activation are considered sympathomimetic, while drugs that result in parasympathetic activation are considered parasympathomimetic. Note that agonists and antagonists of cholinergic receptors would also be considered parasympathomimetic and sympathomimetic, respectively.

Answer 198

cv-related action of agonist include vasoconstriction in skin. Example agonist (sympathomimetic) is phenylephrine. Example antagonist (parasympathomimetic) is doxazosin.

Answer 199

cv-related action of agonist include presynaptic inhibition of NE release; some vasoconstriction. Example agonist (sympathomimetic) is clonidine. Example antagonist (parasympathomimetic) is trazodone.

Answer 200

cv-related action of agonist include increased heart rate. Example agonist (sympathomimetic) is dobutamine. Example antagonist (parasympathomimetic) is atenolol.

Answer 201

cv-related action of agonist include increased heart rate and vasodilation in skeletal muscle. Example agonist (sympathomimetic) is albuterol. Example antagonist (parasympathomimetic) is butaxamine.

Answer 202

The activity of the autonomic nervous system is regulated by information coming from visceral afferents and from higher CNS centers. Visceral sensory information is conveyed via the nucleus of the solitary tract, in the medulla. This nucleus provides the feedback information to preganglionic ANS neurons that initiates autonomic reflexes. The afferent fibers from these neurons travel in the cranial and spinal nerves that also contain the efferent fibers of the autonomic nervous system. Autonomic reflexes are organized in the spinal cord and brainstem. For example, the baroreflex is organized in the medulla with afferent information transmitted in the glossopharyngeal nerve (cranial nerve IX) from the carotid sinus to the dorsal vagal complex of the medulla that in turn contains neurons projecting to regions of the medulla that regulate sympathetic and parasympathetic activity. The respiratory reflexes are organized in the pons, and the pupillary reflexes are organized in the midbrain. Higher CNS centers also project to the areas in the brainstem that regulate autonomic outflow. The hypothalamus is considered the "head ganglion" of the autonomic nervous system, because it integrates information from several brain regions in order to convey the needs of the organism to the preganglionic autonomic centers in the brainstem and spinal cord. The hypothalamus also coordinates the humoral (i.e., hormonal) response via the pituitary and somatic motor response, in addition to the visceromotor response via the ANS, in order to maintain homeostasis. For example, the hypothalamus stimulates the release of vasopressin from the posterior pituitary into the bloodstream, resulting in vasoconstriction

Answer 203

GPCRs are 7-transmembrane-spanning (7TM) integral membrane proteins that transduce ligand binding to intracellular signaling. A few (of the many) cardiovascular GPCRs include: α & β adrenergic receptors, acetylcholine receptors, endothelin receptors, adenosine receptors, angiotensin II receptors. Review of GPCR activation scheme: agonist binds receptor, GTP replaces GDP on α subunit of heterotrimeric G protein causing dissociation of α and βγ G protein subunits. Both α and βγ can be active signals. GPCR deactivation: auto dephosphorylation of GTP to GDP by α subunit permits reassociation with βγ. Rebinding of G protein to receptor causes inactivation. Families of G proteins involved in cardiovascular function: Gs, Gi/o, Gq. Gs and Gi/o are stimulatory & inhibitory, respectively, for cAMP production by adenylate cyclase. Gq activation increases intracellular Ca via activation of phospholipase C (PLC) and Protein Kinase C (PKC).

Answer 204

α1-Adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC), which causes an increase in IP3 and calcium. This triggers further effects, primarily through the activation of an enzyme Protein Kinase C. This enzyme, as a kinase, functions by phosphorylation of other enzymes causing their activation, or by phosphorylation of certain channels leading to the increase or decrease of electrolyte transfer in or out of the cell. In smooth muscle cells of blood vessels the principal effect of activation of these receptors is vasoconstriction.

Answer 205

Gs renders adenylate cyclase activated, resulting in increase of cAMP. Heart: increase chronotropy, inotropy, lusitropy, dromotropy vascular beds in skeletal muscle: vasodilation

Answer 206

M2 and M4 receptors are coupled with Gi/o proteins. Gi/o mainly inhibits the cAMP dependent pathway by inhibiting adenylate cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Therefore, the ultimate effect of Gi is the opposite of cAMP-dependent protein kinase. Resulting in decreased chronotropy.

Answer 207

includes cAMP signaling and molecular targets for sympathetic regulation of inotropy and lusitropy (PLB, LTCCs, RyRs, Tn1)

Answer 208

Sympathetic neurons innervate the heart, release norepinephrine, which binds to β adrenergic receptors to increase cAMP. Phosphodiesterases–counter part to adenylate cyclase– break down cAMP (and cGMP)– help to establish intracellular signaling microdomains and specificity of signaling. PKA = cAMP-dependent protein kinase. Major effector for cAMP signaling in heart. Phosphorylates target proteins (counterpart = phosphatases that dephosphorylate targets). Phosphorylation changes protein function by changing conformation and charge.

Answer 209

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Hormones such as glucagon and epinephrine begin the activation cascade (that triggers protein kinase) A by binding to a G protein-coupled receptor (GPCR) on the target cell. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP and is released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP) -- increasing cAMP levels. Four cAMP molecules are required to activate a single PKA enzyme. This is done by two cAMP molecules binding to each of the two regulatory subunits on a PKA enzyme causing the subunits to detach exposing the two (now activated) catalytic subunits. Next the catalytic subunits can go on to phosphorylate other proteins.

Answer 210

This protein is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase (PKA) in cardiac muscle. The protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca++-ATPase (SERCA) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca++ pump leads to shorter intervals between contractions, thereby contributing to the lusitropic response elicited in heart by beta-agonists. The protein is a key regulator of cardiac diastolic function . Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure.

Answer 211

its ability to inhibit the sarcoplasmic reticulum calcium pump (SERCA) is lost. Thus, activators of PKA, such as the beta-adrenergic agonist epinephrine (released by sympathetic stimulation), may enhance the rate of cardiac myocyte relaxation. In addition, since SERCA is more active, the next action potential will cause an increased release of calcium, resulting in increased contraction (positive inotropic effect). When phospholamban is not phosphorylated, such as when PKA is inactive, it can interact with and inhibit SERCA. The overall effect of phospholamban is to decrease contractility and the rate of muscle relaxation , thereby decreasing stroke volume and heart rate, respectively.

Answer 212

removes Ca from cytosol following contraction (pumps it back into the sarcoplasmic reticulum (SR)). PLB is an inhibitor of SERCA. Phosphorylation of PLB by PKA causes it to dissociate from SERCA, thereby relieving the inhibition and increasing Ca2+ reuptake rate. Faster Ca2+ reuptake has two effects on cardiac performance: 1) directly increases “lusitropy” – the ability of the heart to relax, and 2) increases inotropy by increasing SR Ca2+ load.

Answer 213

L-type Ca channels on the plasma membrane are activated by depolarization. The influx of Ca2+ through L-type Ca2+ channels triggers a larger Ca2+ release from the SR via ryanodine receptors, a process termed Ca2+-induced Ca2+ release (CICR). Phosphorylation of L-type Ca2+ channels by PKA slows inactivation, thereby increasing the magnitude of the L-type Ca2+ current. This increase in “trigger Ca2+” elicits a larger release of Ca2+ from the SR, thereby increasing inotropy.

Answer 214

PKA also phosphorylates ryanodine receptors, making them more sensitive to Ca2+, so that less trigger Ca2+ is needed to evoke Ca2+ release. This also increases inotropy.

Answer 215

troponin I is the inhibitory unit of the troponin complex (which consists of TnC, TnI, TnT). Along with tropomyosin, TnI inhibits the interaction between actin and myosin in the absence of Ca2+. TnI is phosphorylated by multiple kinases, including PKA. Phosphorylation of TnI decreases the Ca sensitivity of TnC. This decreased sensitivity would be expected to decrease inotropy – counter to the sympathetic effect. However, the decreased sensitivity also results in faster dissociation of Ca2+ from TnC, thereby increasing lusitropy, which allows the heart to fill more quickly. This is particularly important at higher heart rates.

Answer 216

Parasympathetic innervation of the ventricle is sparse, thus there is little parasympathetic control of inotropy.

Answer 217

mechanisms for autonomic regulation of chronotropy includes basal autonomic tone and intrinsic heart rate and molecular targets for both sympathetic stimulation of chronotropy and parasympathetic inhibition of chronotropy

Answer 218

Resting heart rate in humans is normally between 60 and 80 bpm. However, both divisions of the autonomic nervous system have basal activity that influences the resting heart rate. Block of M2 muscarinic acetylcholine receptors with atropine increases heart rate by inhibiting tonic parasympathetic activity. Block of β adrenergic receptors with propanolol decreases heart rate by inhibiting tonic sympathetic activity. Normally the parasympathetic tone at rest is greater than the sympathetic tone. Intrinsic heart rate is revealed by block of both sympathetic and parasympathetic tone.

Answer 219

such targets include Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs), L-type Ca2+ channels and ryanodine receptors, and Ryanodine receptors and Sodium-Calcium exchanger.

Answer 220

HCN channels produce the cardiac funny current (If), which is an inward (depolarizing) current at diastolic potentials. Sympathetic stimulation of sinoatrial cells causes an increase in cAMP. cAMP can bind directly to HCN channels to shift the voltage dependence of activation, making the channels more likely to open, thereby providing more inward current to speed the rate of diastolic depolarization and stimulating chronotropy.

Answer 221

Action potentials in nodal cells are “slow” Ca2+ action potentials, thus changes in the magnitude and voltage-dependence of Ca2+ channels impacts the spontaneous firing rate. β adrenergic stimulation increases L-type Ca2+ current and this effect is thought to contribute to the sympathetic increase in heart rate.

Answer 222

Sympathetic stimulation increases SR Ca2+ load via PKA phosphorylation of L-type Ca2+ channels, ryanodine receptors, and phospholamban (see above). The increased SR Ca2+ load in nodal cells increases the spontaneous Ca2+ release rate, and contributes to the diastolic depolarization by activating inward current through the sodium-calcium exchanger (NCX).

Answer 223

Parasympathetic regulation of pacemaking is mediated by release of acetylcholine (ACh) from vagal nerve endings in the sinoatrial node. ACh activates M2 muscarinic ACh receptors, which are coupled to the Gi/o heterotrimeric G protein. Activation of Gi/o releases two signals: the Gαi/o subunit and the Gβγ subunit complex. With GIRKs, the Gβγ subunit complex binds directly to GIRK channels (G-protein coupled inwardly-rectifying K+) to activate the IKACh current. IKACh stabilizes the membrane potential near the K+ equilibrium potential, thereby dampening excitation and slowing the spontaneous firing frequency. This appears to be the primary mechanism for parasympathetic slowing of heart rate. With HCNs, L-type Ca2+ channels, and ryanodine receptors, the Gαi/o subunit inhibits adenylate cyclase, thus reducing intracellular cAMP levels. This has the opposite effect to sympathetic stimulation of pacemaking: reduction in inward current via HCN channels, L-type Ca2+ channels, and RyR-NCX. These mechanisms appear to play a secondary role in parasympathetic regulation of heart rate.

Answer 224

vascular resistance can be regulated by affecting vascular smooth muscle contraction, neural control of vasculature, local (intrinsic control of vasculature, and humoral control of the vasculature.

Answer 225

Vascular smooth muscle cells (VSMCs) are small mononucleate cells, which are electrically coupled via gap junctions. Smooth, not striated because myofilaments not arranged in sarcomeres in smooth muscle. Ca2+ release from the SR not essential for contraction in VSMCs. However, Ca2+ reuptake mechanisms are similar (SERCA and PLB are present). Rate of contraction slower in VSMCs, and contraction is sustained and tonic (vs. short duration in cardiac muscle).

Answer 226

Contraction in VSMCs is different from striated muscle. Contractile proteins in striated muscle are arranged in sarcomeres. The major contractile proteins are the actin thin filaments and myosin thick filaments. At rest, troponin I is bound to actin. Troponin T recruits tropomyosin, which blocks myosin binding site on actin. An action potential triggers Ca2+ release from the SR via excitation-contraction coupling. Ca2+ binds to troponin C, causes rearrangement of troponin complex and tropomyosin that uncovers the myosin binding site on actin, and permits cross bridge cycling to occur. Contraction is halted by removal of Ca .

Answer 227

Smooth muscle contraction can be initiated by mechanical, electrical, or chemical stimuli. Different from striated muscle. Mechanical stretching can cause contraction via the myogenic response. Electrical depolarization can elicit contraction via activation of L-type Ca2+ channels. Different from striated muscle in that action potentials are not required; graded potentials are sufficient, and strength of contraction is proportional to stimulus intensity. Chemical stimulation by a number of neural and hormonal regulators (eg: norepinephrine, angiotensin II, vasopressin, endothelin, and thromboxane A2) can directly activate contraction. Contraction of VSMCs depends on phosphorylation of myosin head. Ca2+ does not directly activate VSMC contraction, instead phosphorylation of myosin is the essential step (although this is indirectly Ca2+ dependent). Thus Ca2+ regulation of smooth muscle contraction is via myosin thick filaments, whereas Ca2+ regulation of striated muscle contraction is via actin thin filaments. (smooth muscle does not have the Ca2+- sensitive troponin complex or tropomyosin). cAMP causes relaxation of vascular smooth muscle cells. In contrast to effect of cAMP in cardiac myocytes, where it promotes contraction via PKA, PKA phosphorylates myosin light chain kinase to inhibit its activity, and thus reduce VSMC contraction.

Answer 228

1. Ca2+ enters cytoplasm – from SR mainly, but also via voltage-gated Ca2+ channels on surface membrane. 2. Ca2+ binds to Calmodulin (CaM), a ubiquitous intracellular Ca2+ binding protein. 3. Ca2+-CaM binds to Myosin Light Chain Kinase (MLCK) to activate it. 4. Activated MLCK phosphorylates the light chain of myosin (myosin head), which permits cross bridge cycling to occur. 5. Contraction halted by dephosphorylation of myosin light chain by Myosin Light Chain Phosphatase (MLCP).

Answer 229

such regulation includes autonomic regulation of the vasculature, arterial baroreceptor reflex and CNS cardiovascular center, low pressure barorecptors, and peripheral and central chemoreceptors.

Answer 230

Primarily sympathetic innervation of the vasculature (relatively little parasympathetic innervation). Sympathetic stimulation generally causes vasoconstriction. Sympathetic stimulation causes contraction of VSMCs, independent of membrane depolarization. α1 adrenergic receptors are GPCRs, which are coupled to the Gq heterotrimeric G protein. Gαq activates phospholipase C (PLC), an enzyme that produces diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 activates IP3 receptors on the sarcoplasmic reticulum of VSMCs. IP3Rs are intracellular Ca2+ release channels, which are similar to ryanodine receptors. Activation by IP3 opens IP3Rs causing Ca2+ release from the SR into the cytoplasm. This increase in intracellular Ca2+ causes VSMC contraction and thus vasoconstriction. Protein kinase C (Ca2+-dependent protein kinase, PKC) phosphorylates many targets in VSMCs, including L-type Ca2+ channels (LTCC), which are activated. Inward current through LTCCs in turn activates additional intracellular Ca2+ release (Ca2+-induced Ca2+ release). Sympathetic innervation is not equal in all vascular beds. Abundant in skin and kidneys (so that sympathetic stimulation decreases blood flow). Sparse in cerebral and coronary circulation; thus sympathetic activation reduces blood flow to skin without compromising blood flow to the brain and heart. α1 adrenergic receptors are the predominant subtype in most vascular beds, however striated muscle arteries express both α1 and β2 adrenergic receptors. Norepinephrine released from sympathetic neurons acts on α1 receptors to cause vasoconstriction in all vascular beds. However, circulating epinephrine causes a partially compensating vasodilation in striated muscle (so that flow in striated muscle may be somewhat higher than in other tissues). This is a relatively minor point, however, because vasodilation of striated muscle in response to activity is mediated primarily by local tissue metabolites. α2 receptors on sympathetic fibers exert feedback inhibition of NE (also minor point)

Answer 231

Fast (minute-to-minute) neural mechanism for control of blood pressure. The baroreceptor reflex is an acute, short term effect that plays little role in long term regulation of blood pressure (long term regulation of blood pressure is achieved primarily via renal regulation of blood volume). Baroreceptors adapt to prolonged changes in blood pressure by simply resetting to the new level over a time course of minutes to hours. This is useful because the feedback mechanism is preserved even in hypertension. However, sensitivity of the baroreceptor reflex decreases in hypertension and aging, so there is less feedback response to changes in blood pressure. Arterial baroreceptors are pressure-sensitive neurons in the aortic arch and carotid sinus. Baroreceptors respond to stretch of arterial walls by increasing their firing rate. This stretch sensitivity is conferred by epithelial Na+ channels (eNaC), which are mechanosensitive ion channels (NOT voltage-gated channels). eNaCs open in response to mechanical stimulation and the ensuing Na+ current depolarizes the baroreceptor neurons, causing them to fire action potentials. Baroreceptor neurons project to the sensory area of the “cardiovascular control center” in the brainstem. The CV control center integrates signals from baroreceptors as well as from other brain regions (eg: hypothalamus – CV response to emotion). Output areas of the CV center project sympathetic and parasympathetic fibers to the heart and sympathetic fibers to the vasculature.

Answer 232

An increase in blood pressure increases firing rate of baroreceptors, which decreases sympathetic and increases parasympathetic output from cardiovascular center. The result is a decrease in heart rate, a decrease in inotropy, and a decrease in vascular tone, all of which counter the increased blood pressure (negative feedback). Set point for baroreceptor reflex is ~100 mmHg mean arterial pressure. Lower pressure than that increases sympathetic tone and decreases parasympathetic tone to increase heart rate, contractility, stroke volume, and vasoconstriction. Mean arterial pressure greater than ~ 100 mmHg does the opposite.

Answer 233

In atria and vena cavae (NOT arteries). Respond to changes in venous pressure by changing firing rate, but the pressure sensitivity range is much lower for the venous system. Afferents project via the vagus nerve, efferents primarily innervate the sinoatrial node to control heart rate. Low pressure baroreceptors mediate the “Bain bridge reflex” whereby stretch of the atria causes an increase in heart rate.

Answer 234

Peripheral (arterial) chemo receptors are found in aortic and carotid bodies, which are near the aortic arch and carotid sinus baroreceptors. Peripheral chemoreceptors respond to changes in arterial PO2 and PCO2. They are primarily involved in control of respiration, but they also project to cardiovascular control center to regulate the heart and vasculature, such that low PO2/high PCO2 results in increased sympathetic output (thus sparing O2 delivery to heart and brain). Other chemoreceptors in the heart respond to ischemia to transmit the sensation of angina. Central chemoreceptors are found in the medulla, and increase cerebral blood flow in response to ischemia.

Answer 235

such regulation includes control by vasoactive metoblites, myogenic response (autoregulation), and endothelial- mediated regulation

Answer 236

This is the primary mechanism by which flow in a capillary bed is matched to the metabolic demand of the tissue it perfuses. Vasoactive substances are produced by increased oxygen consumption, for example during skeletal muscle contraction. This is a direct, local response, which is independent of blood pressure. It can have profound effects on blood flow (up to 50- fold increase in flow in active skeletal muscle).

Answer 237

decreased PO2, increased PCO2/ decreased pH (partly due to lactic acid), increased K+ (In active skeletal muscle, Na+ enters cell and K+ leaves during action potentials. With a high level of activity, the Na+/K+-ATPase can’t keep up to pump K+ back in, so it accumulates in the interstitial space.), increased adenosine 

Answer 238

produced by hydrolysis of ATP. In vascular smooth muscle cells, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs (the stimulatory G protein that activates adenylate cyclase). Thus, adenosine increases cAMP levels in VSMCs causing vasodilation by inhibition of myosin light chain kinase. Other purinergic receptor subtypes (A1 and A3) are coupled to Gi (the inhibitory G protein), and thus adenosine reduces cAMP in cells expressing these receptor subtypes. Adenosine is used for emergency treatment of some re-entrant supraventricular tachycardias because it acts on A1 receptors to inhibit cAMP production in the AV node, thereby causing a transient conduction block.

Answer 239

Feed back mechanism to maintain constant flow despite changes in pressure (independent of metabolic demand). Example: postural change– standup, blood pressure increases in legs (assume minimal change in metabolic demand). The initial effect is an increase in blood flow due to the increased pressure (according to flow equation, Q = P/R). This is shown by the solid symbols in the figure. The myogenic response is shown by the open symbols, which illustrate the steady state flow, after adaptation. The flow tends to return to the initial level, and note that flow is relatively constant across the range of pressures. Mechanism is intrinsic to VSMCs (occurs in denervated vessels, and is independent of vascular endothelium). Stretch causes VMSC contraction by opening stretch-activated ion channels of the Trp family. Inward Ca2+ current through Trp channels directly causes vasoconstriction, also depolarizes the VSMC, thereby further increasing intracellular Ca2+ via L-type Ca2+ channels.

Answer 240

Many regulators of blood flow act via mechanisms involving the vascular endothelium. Two major mechanisms by which the endothelium controls vascular tone include nitric oxide, which is a vasodilator, and endothelin, which is a vasoconstrictor.

Answer 241

Nitricoxide (a gas) is a potent vasodilator produced invascular endothelium by the enzyme nitric oxide synthase. NO = free radical, highly reactive & labile, 1⁄2 life 10-60 s. Readily oxidized. Oxidizing agents reduce NO lifetime, so reduce potency of vasodilatory response. Short half life means local response. Basal release of NO helps set resting vascular tone (decrease NO=increase BP). Agonist-stimulated release= MAJOR physiological mechanism for vasodilation. NO= anti-atherosclerotic–inhibits many steps in development of plaques, and decreased. NO is associated with greatly increased risk for atherosclerosis. NO is decreased in hypertensive patients– not an immediate cause of hypertension, but makes condition worse. (Also one mechanistic link for how hypertension is a risk factor for atherosclerosis). Nitricoxide synthase–highly susceptible to CV disease risk factors (eg: oxidative stress, compounds in cigarette smoke). Some treatment strategies for CV disease use NO system, such as L-arginine supplements (precursor to NO) and NO donors such as nitroglycerin. NO PATHWAY= story of two cells–vascular endothelial cells (produce NO) and vascular smooth muscle cells (site of NO action). This is an example of “paracrine” signaling. Many humoral regulators (eg:ACh) stimulate activity of Nitric Oxide Synthase, in vascular endothelial cells. Nitric oxide readily diffuses across the endothelial and vascular smooth muscle cell membranes. In the vascular smooth muscle cells, NO activates the enzyme guanylate cyclase, which produces cGMP. cGMP activates Protein Kinase G (PKG), which reduces intracellular Ca2+ via activation of SERCA and inhibition of L-type Ca2+ channels (among other targets). The decreased [Ca2+]I causes relaxation of the VSMC (vasodilation).

Answer 242

Endothelin is a potent vasoconstrictor produced by vascular endothelium. 21 amino acid peptide, synthesized from precursors with Endothelin Converting Enzyme (ECE) being the rate-limiting step. ECE inhibitors are under investigation as potential pharmacological agents for treatment of hypertension. Endothelin binds to ET receptors, which are GPCRs on VSMCs. ET receptors that are primarily coupled to Gq and so increase intracellular Ca2+ levels, which results in vasoconstriction. Endothelin pathway and response is similar to α adrenergic response, but the time course is different – endothelin has both a transient (minutes) effect like α adrenergic system and a longer lasting (hours) effect. Natural counter part to NitricOxide

Answer 243

includes renin-angiotensin-aldosterone system and atrial natriuretic peptide (ANP)

Answer 244

Critical system for regulation of blood volume and long-term control of blood pressure (vs short term control by barorecptor reflex). Mediated by kidney, and will be covered in more detail in renal sub-block.

Answer 245

a proteolytic enzyme that is released into the circulation by the juxtaglomerular(JG) cells (adjacent to renal glomerulus). Release is stimulated by: 1) sympathetic stimulation of JG cells, 2) decreased blood pressure in the renal artery, and 3) decreased Na+ reabsorption in the kidney.

Answer 246

Renin cleaves the circulating inactive protein precursor angiotensinogen to angiotensinI (AI), which is another inactive precursor. Angiotensin I is then cleaved by Angiotensin Converting Enzyme (ACE) to form the active peptide, Angiotensin II (AII), which is a potent vasoconstrictor. ACE is an important therapeutic target for treatment of hypertension and heart failure, via ACE inhibitors. Angiotensin II receptor blockers are another class of drug used to block the renin-angiotensin-aldosterone system. Direct effect of AII: systemic vasoconstriction via binding to GPCRs on VSMCs. Indirect effects of AII:1) stimulates sympathetic activity (thus more vasoconstriction), 2) stimulates Aldosterone release from adrenal cortex (see below), 3) stimulates release of endothelin from vascular endothelium (= more vasoconstriction), and 4) stimulates release of ADH from the pituitary.

Answer 247

a steroid hormone produced by the adrenal cortex. It acts on receptors in the kidney collecting ducts to promote reabsorption of Na+ and water. This increases blood volume, and thus increases blood pressure.

Answer 248

Peptide hormone formed in hypothalamus, released by pituitary in response to hypovolemia, hypotension, high osomolarity, Angiotensin II, and sympathetic stimulation. Major role: Binds to receptors in kidney and increases water reabsorption. Minor role: can also bind to receptors in vasculature to cause vasoconstriction.

Answer 249

Vasodilator peptide released by atria (more right than left) = endocrine function of heart. One of a family of natriuretic peptides. Natriuretic= sodium excretion. Involved in long- term regulation of Na and water balance, blood volume, and arterial pressure. Secretion stimulated by mechanical stretch of atria. ANP acts on Natriuretic Peptide Receptors found throughout the body. NPRs are receptor guanylate cyclases (not GPCRs) that produce cGMP, which activates SERCA to stimulate Ca2+ uptake, thereby reducing cytoplasmic Ca2+ levels. In kidney, ANP increases glomerular filtration rate and increases secretion of Na and water. In vasculature, ANP is a vasodilator, mechanism similar to NO, but longer lasting. In adrenal gland, ANP inhibits release of aldosterone and renin.

Answer 250

When a person stands up: Blood pools in veins of legs (“venous pooling”), which increases capillary hydrostatic pressure (Pc from the Starling Law of the Capillary, Hemodynamics lecture) leading to net capillary filtration and an increase in interstitial fluid. Venous return consequently decreases, which causes by the Frank-Starling mechanism a decrease in stroke volume and cardiac output. (Can be plotted on PV loop diagrams, as in Heart as a Pump lecture). Cardiac output tends to fall by ~20%. Arterial pressure decreases as a consequence of the reduced cardiac output. Compensatory reaction due to baroreceptor reflex. Decreased firing of baroreceptors increases sympathetic and decreases parasympathetic tone from the medullary cardiovascular centers. This increases heart rate and inotropy to increase cardiac output, and increases vasoconstriction to increase venous return. Myogenic response. Increased pressure in vasculature in lower body results in vasoconstriction, which promotes venous return.

Answer 251

fainting or light headedness upon standing can occur in patients with a compromised baroreceptor reflex, or those whose blood pressure is already low. This effect is more pronounced in warm weather, due to vasodilation in the skin.

Answer 252

Anticipation of exercise increases sympathetic and decreases parasympathetic activity to increase heart rate and inotropy, thereby increasing cardiac output. (“Central Command” mechanism). Increased sympathetic activity increases arterial resistance in non-exercising tissues, including skin, kidneys and inactive muscles. Activity of skeletal muscles increases venous return, which increases stroke volume via the Frank-Starling mechanism. In the exercising muscles, vasoactive metabolites dilate arterioles to increase blood flow (remember Pouiseulle’s Law, r4). Vasodilation in exercising muscle over comes the vasoconstriction in other tissues to cause a net decrease in TPR, which corresponds to an increase in CO (from Flow Equation, CO = Pa/TPR).

Answer 253

Acute blood loss decreases mean arterial pressure (remember MAP ~ Pd + 1/3(Ps-Pd). This decreases cardiac output (dramatically decreased venous return is more important than decreased afterload). Baroreceptor reflex, as in postural change: decreased firing of baroreceptors increases sympathetic and decreases parasympathetic tone, which increases heart rate and inotropy. Vasoconstriction increases venous return. The renin-angiotensin system is activated by decreased renal blood pressure. Angiotensin II increases vascular tone and promotes release of ADH, which increases blood volume. Decreased capillary hydrostatic pressure, Pc, promotes reabsorption from the interstitial fluid, which increases blood volume.

Answer 254

are a direct reflection of the pathophysiology and fall into three categories: reduced cardiac output (symptoms of decreased organ perfusion), increased pulmonary venous pressure (breathlessness), and increased central venous pressure (edema).

Answer 255

low flow. Decreased muscle perfusion (fatigue and tiredness/sleepiness), decreased gut perfusion (anorexia and wasting (cachexia)), decreased kidney perfusion (reduced urine output and progressive renal dysfunction/ cardiorenal syndrome), exercise intolerance (inability to augment cardiac output to meet increasing demands of stress/ exercise).

Answer 256

causes increased pulmonary venous pressure. Results in breathlessness (dyspnea) and dyspnea on exertion). Upon exertion, a small increase in stroke colume at the cost of large rise in end-diastolic pressure.

Answer 257

immediate shortness of breath when lying flat. Relates to lost venous pooling of blood in the legs.

Answer 258

delayed SOB, waking patients from sleep. Classically patient gets out of bed and ambulates to relieve symptoms.

Answer 259

acute intense shortness of breath. Occurs once fluid retention/ left atrial pressure overwhelms compensatory mechanisms (e.g. lymphatic fluid return). Fluid spills from the pulmonary vasculature into the interstitial space and then into the alveoli, producing hypoxia. Increase vascular prominence on CXR first, followed by fluffy infiltrates.

Answer 260

peripheral swelling/ dependent edema, ascites, hepatic congestion, intestinal congestion (protein losing enteropathy).

Answer 261

increased circulating volume (preload), through increase of sodium in diet or renal failure. Increased pressure (afterload) through uncontrolled hypertension (LV), worsening aortic stenosis (LV), or pulmonary embolism (RV). Worsened contractility (inotropy) due to myocardial ischemia or initiation of negative inotrope (beta-blocker or calcium channel blocker). Arrhythmia (rate) such as breadycardia or atrial fibrillation. Increased metabolic demands due to fever, infection, anemia, hyperthyroidism, or pregnancy. Non-adherence with HF medications.

Answer 262

symptoms are important in heart failure for a number of reasons: symptoms decrease quality of life and are highly relevant to patients. Symptoms define the severity of the disease. Disease severity is one of the strongest predictors of death in heart failure. Symptoms are often used to determine therapy (e.g. more aggressive therapies are indicated for more advanced disease) There are 2 classification systems for heart failure which are largely based on symptoms (these classifications are frequently used to describe patients with HF): ACC/AHA HF stage and NYGA functional class.

Answer 263

A= high risk for heart failure but without structural heart disease or symptoms of heart failure (e.g. patients with hypertension or coronary artery disease). B= structural heart disease but without symptoms of heart failure. C= structural heart disease with prior or current symptoms of heart failure. D= refractory heart failure requiring specialized interventions.

Answer 264

I= asymptomatic, II= symptomatic with moderate exertion, III= symptomatic with minimal exertion, and IV= symptomatic at rest.

Answer 265

HF is marked by a non-linear course. It is typically marked by episodic exacerbations with significant symptoms (sometimes requiring hospitalization), with intervening periods of relative stability. Patients rarely stay at a single NYHA class over time; they may move between functional classes depending on a number of factors that dictate cardiac function and symptomatology. However, the usual course is an average of progressive decline over time.

Answer 266

cool extremities (peripheral vasoconstriction to redirect what existing blood flow there is to vital organs), tachycardia (compensate for low stroke volume), and low pulse pressure (difference between systolic and diastolic pressure, reflection of low output).

Answer 267

rales (pulmonary crackles, sounds like Velcro pulling apart on inspiration, due to wet alveoli opening), hypoxia, tachypnea, sitting bolt upright, popping open of alveolie.

Answer 268

edema (dependent on gravity, in legs, sacrum, and scrotum), hepatic congestion./ hepatomegaly, jugular venous distention (JVD) due to increase of central venous pressure (CVP). JVD=CVP= right atrial pressure. Assumes no blockage or valve in between RA and neck. Normal is < 5 cm H2O, so jugular vein is typically collapsed – with a person standing up, only the carotid pulsation should be visible (brisk upstroke during systole only). With a person lying flat or with JVD in HF, the jugular vein (internal and external) fill with blood. Thus the neck veins will appear full on visual examination. More importantly, they will transmit pressure changes in the right atrium as waves, visible as fluctuations in the vein size and in the meniscus (location of the highest point in filling). Unlike the single systolic pulsation of the carotid, the jugular veins will have multiple fluctuations during a cardiac cycle (triphasic). These waves are: A wave=atrial contraction, C wave= closing of the tricuspid valve early early in systole, and V wave= movement of the RV annulus and tricuspid valve backward at the very end of systole (before the valve opens). One of the only ways to noninvasively assess vascular filling pressures.

Answer 269

[S1 is mitral (tricuspid) valve closure; S2 is aortic (pulmonary valve closure)]. S3 gallop is thought to be caused by rapid expansion of the ventricular walls in early diastole. Can be present in normal young people; abnormal after age 40. Typical of HFrEF / dilated heart. Cadence of “Ken-tuc-ky” (S1-S2-S3). S4 gallop is caused by atria contracting forcefully in an effort to overcome an abnormally stiff or hypertrophic LV. Usually abnormal. Cadence of “Ten-ne-ssee” (S4-S1-S2). By definition, absent in atrial fibrillation

Answer 270

Because HF is a syndrome, diagnosis can be difficult, particularly in patients with preserved ejection fraction with shortness of breath. Diagnosis comes from a combinations of the following: Constellation of symptoms consistent with HF, Medical history / presence of conditions which lead to HF (Coronary disease, hypertension, valvular disease, Diabetes, kidney disease, Rule out non-HF cause of shortness of breath), Testing

Answer 271

Pulmonary disease (COPD, asthma, pneumonia, pulmonary embolus, primary pulmonary hypertension). Sleep apnea. Obesity. Deconditioning. Anemia. Renal failure. Hepatic failure. Venous stasis / lymphedema. Depression

Answer 272

Enlarged cardiac silhouette in HFrEF. Increased upper lobe vascular markings with acute decompensation. Fluffy infiltrates of pulmonary edema (not on this image). Pleural effusions

Answer 273

B-type natriuretic (BNP) is secreted by the myocardium in response to Primary: ventricular stretch (measure of preload) and Secondary: hyperadrenergic state, RAAS activation, ischemia. Two assays: BNP (Cutoff for diagnosis is relative (100 pg/mL often used)) and NT-proBNP (N-terminus breakdown product of BNP, Inactive, Half life ~120 minutes (BNP 20 minutes), ~6 times the BNP). Both increase with age. NT-proBNP especially increased with renal failure. Practical use of BNP / NT-proBNP. Elevations are most often due to HF. Other reasons include increased BNP include sepsis, pulmonary embolism (PE). Clinically BNP = “rule out symptomatic HF”. In patients with chronic HF, an elevated BNP is less useful to determine if new dyspnea is from acute HF decompensation or from some other process (e.g. COPD exacerbation). Thus the negative predictive value of BNP is more useful (a low BNP makes HF unlikely as the cause of symptoms)

Answer 274

No direct diagnosis of HF. Infer possibility of HF from other findings. Prior myocardial infarction (e.g. Q waves). LVH (increased voltage). Diffuse conduction disease from fibrosis or myocardial damage (e.g. LBBB). Arrhythmia (atrial fibrillation [AF], paroxysmal ventricular contractions [PVCs], non-sustained ventricular tachycardia [NSVT] are more common in HF) CARDIAC IMAGING (Echo, CT, MR, nuclear MUGA/SPECT). Gross measure of systolic function: left ventricular ejection fraction (LVEF): EF= end-diastolic-end systolic volume/ end-diastolic volume%. Examples: Normal = (100 ml – 40 ml) / 100 ml = 60%. HFrEF = (200 ml – 150 ml) / 200 ml = 25% (Dilated AND reduced stroke volume)

Answer 275

Provides: LVEF (systolic function), Chamber size (dilation), LV wall thickness (hypertrophy), Measures of relaxation (diastology), Valvular anatomy and function, Estimated filling pressures (LA, CVP), Estimated pulmonary pressures (pulmonary hypertension). Advantages: Real time, Non-invasive, No radiation, Relatively “inexpensive”

Answer 276

Also called a Pulmonary Artery (PA) Catheter, or a Swan-Ganz catheter (or “Swan”) after the physicians who invented it. A plastic catheter introduced into one of the major veins and then “floated” through the right heart into the pulmonary artery. Has a balloon on the end of it to help blood flow carry it into the lungs. The balloon also allows a branch of the pulmonary artery to be occluded so that the downstream pressure (post-capillary wedge pressure [PCWP]) can be measured, which is equivalent to the left atrial pressure / left-sided filling pressure. Gives 2 major types of measurements: Pressures (CVP/RA, RV, PA, PCWP) and Flow = cardiac output (Fick CO (oxygen consumption measure) and Thermodilution CO (timed flow measure)). Resistances can be calculated from pressures and flow. Ohm’s law: V=IR. Hemodynamic equivalent: ΔP = CO x R. Across a body capillary bed: ΔP = mean arterial BP – central venous pressure. Systemic vascular resistance = ΔP / cardiac output (in woods units)

Answer 277

General goals of any therapy 1. Increase quantity of life (improve survival) 2. Increase quality of life (reduce symptoms) 3. Decrease financial / resource burden of disease. HF-specific goals: Correction of the underlying cause of HF (e.g. revascularization for ischemia, not possible to reverse many causes (e.g. infarcted tissue)). Elimination of precipitating factors (e.g. infection, anemia). Reduction of congestion (fluid optimization is a major part of HF therapy). Improve flow (may be difficult to do medically; mechanical devices/txplt). Modulate neurohormal activation. Long-term stabilization, positive remodeling, increased survival.

Answer 278

Studies should be tailored to a patient’s risk of having the secondary causes or precipitants. Vitals BP / HR (hypertension), EKG (tachyarrhythmia, AFib, PVCs), CMP, CBC (renal failure, liver dysfunction, anemia, infxn, DM, ...), CXR (coexistant lung disease, for future comparison), BNP / NT-proBNP, troponin (prognosis), Echo (dilation, LV function, wall motion, PHTN, prognosis) Coronary angiogram v. CTA, stress testing, MRI (ischemia, scar), Thyroid function tests, Iron studies (hemochromatosis, iron deficiency). The rest of these tests can be done in unique circumstances: Toxicology studies (stimulants / cocaine, alcohol), HIV, and other microbiology (Chagas, Lyme, ...), ANA (dermatomyositis, other rheumatologic disease), Thiamine, selenium, L-carnitine, phosphate, calcium, Urine cortisol, metanephrines (Cushing’s, pheochromocytoma), IGF-1 (growth hormone excess), Genetic testing (HCM, channelopathy, Duchenne’s, ...), and Sleep study (not routinely due to CAN-PAP)

Answer 279

transthoracic echocardiography is recommended to evaluate cardiac structure and function, including diastolic function and to measure LVEF to make the diagnosis of HF, assist in planning and monitoring of treatment and to obtain prognostic information. A 12-lead ECG is recommended to determine heart rhythm, heart rate, QRS morphology, and QRS duration, and to detect other relevant abnormalities. This information also assists in planning treatment and is of prognostic importance. A completely normal ECG makes systolic HF unlikely. Measurement of blood chemistry (including sodium, potassium, calcium, urea/ blood urea nitrogen, creatinine/ estimated glomerular filtration rat, liver ezymes and bilirubin, ferritin/ TIBC) and thyroid function is recommended to : evaluate patient suitability for diuretic, renin-angiotensin- aldosterone antagonist, and anticoagulant therapy (and monitor treatment); detect reversible/ treatable causes of HF (e.g. hypocalcaemia, thyroid dysfunction) and co-morbidities (e.g. iron deficiency); obtain prognostic information. A complete blood count is recommended to detect anemia, which may be an alternative cause of the patient’s symptoms and sign and may cause worsening of HF and to obtain prognostic information. Measurement of natriuretic peptide (BNP, NT-proBNP, or MR-proANP) should be considered to exclude alternative causes of dyspnea (if the level is below the exclusion cut-point HF is very unlikely) and to obtain prognostic information. A chest radiograph should be considered to detect/ exclude certain types of lung disease, e.g. cancer (does not exclude asthma. COPD). It may also identify pulmonary congestion/ edema and is more useful in patients with suspect HF in the acute setting. CMR imaging is recommended to evaluate cardiac structure and function, to measure LVEF, and to characterize cardiac tissue, especially in subjects with inadequate echocardiographic images or where the echocardiographic findings are inconclusive or incomplete (but taking account of cautions/ contraindications to CMR). Coronary angiography is recommended in patients with angina pectoris, who are considered suitable for coronary revascularization, to evaluate the coronary anatomy. Myocardial perfusion/ ischemia imaging and viable myocardium. Left and right heart catheterization is recommended in patients being evaluated of heart transplantation or mechanical circulatory support, to evaluate right and left heart function and pulmonary arterial resistance. Exercise testing should be considered: to detect reversible myocardial ischaemia; as part of the evaluation of patients for heart transplantation and mechanical circulatory support; to aid in the prescription of exercise training; and to obtain prognostic information.

Answer 280

Reverses the sodium and fluid retention of HF. Classes include loop diuretics are preferred due to potency. These can be augmented with a thiazide diuretic. The most common HF therapy: 90% of HF hospitalizations, 70% only Rx Δ. Can be used chronically and acutely. Typically PO dose at baseline, adjust to patient need. Often used IV in the hospital. Congested intestine may not absorb PO as well. With worsening renal function, also need higher dose. Typically work at the far end of the Frank-Starling curve, such that significant decreases in pressure produce minimal changes in stroke volume (and thus cardiac output). Thus, symptoms of congestion can be reduced without major effects on blood flow. No survival data; increase doses signify worse disease

Answer 281

...prils (lisinopril, enalapril, benazepril). Block conversion of ATI to ATII. Effects: Direct vasodilation, Decreased aldosterone activation, and Other effects beyond ATII? Side effects: Hypotension, Worsening renal function (afferent vasocontraction), Hyperkalemia,Cough (kinin potentiation), and Angioedema

Answer 282

...sartans (e.g. valsartan, candesartan, losartan). Effect: Block the receptor of angiotensin II. Clinical use: In studies have been equivalent to ACEI. Controversial whether use in combination (ARB + ACEI) provides added benefit. Generally used when patients develop cough to ACEI. Side effects: ARBs do not produce kinin potentiation (no cough); Otherwise side effects are similar

Answer 283

Spironolactone and eplerenone. Effect: Block effect of aldosterone on the kidney. ACEI/ARB aldosterone block is incomplete. Produces additional sodium loss (diuretic). Other effects. Antifibrotic. Side effects: Hyperkalemia (requires close monitoring)

Answer 284

...olols (metoprolol, carvedilol, bisoprolol). Effect: Antagonize effect of sypathetic system (epinephrine/norepinephrine). β1 blockade: Negative chronotrope (slow heart rate, less arrhythmia) and Negative inotrope (decreased metabolic demand). [α1 blockade: vasodilation]. Side effects: Negative inotrope: short-term loss for long-term gain; Fluid retention; Hypotension; Decreased cardiac output, even cardiogenic shock; and Bronchoconstriction

Answer 285

an ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF is equal to or less than 40% to reduce the risk of HF hospitalization and the risk of premature death. A beta-blocker is recommended, in addition to an ACE inhibitor not tolerated), for all patients with an EF is equal to or less than 40% to reduce the risk of HF hospitalization and the risk of premature death. An MRA is recommended for all patients with persisting symptoms (NYHA class II-IV) and an EF less than or equal to 35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a beta-blocker, to reduce the risk of HF hospitalization and the risk of premature death.

Answer 286

includes Angiotensin II Receptor Blockers. (ARBs), digoxin, and hydralazine/isosorbide dinitrate (H-ISDN)

Answer 287

recommended to reduce the risk of HF hospitalization and the risk of premature death in patients with an EF is less than or equal to 40% and unable to tolerate an ACE inhibitor because of cough (patients should also receive a beta-blocker and a magnetic resonance angiogram (MRA). Recommended to reduce the risk of HF hospitalization in patients with an EF less than or equal to 40% and persisting symptoms (NYHA class II-IV) despite treatment with an ACE inhibitor and a beta-blocker who are unable to tolerate and MRA.

Answer 288

may be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF is less than or equal to 45% who are unable to tolerate a beta-blocker (ivabradine is an alternative in patients with a heart rate greater than or equal to 70bpm). Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). May considered to reduce the risk of HF hospitalization in patients with an EF less than or equal to 45% and persisting symptoms (NYHA class II-IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and a MRA (or ARB).

Answer 289

may be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature death in patients with an EF less than or equal to 45% and dilated LV (or EF less than or equal to 35%) and persisting symptoms despite treatment with a beta blocker, ACE inhibitor (or ARB), and a MRA (or ARB).

Answer 290

Arterial vasodilation (antihypertensives): Decrease in LV afterload, Reduced cardiac work, and Less mitral regurgitation. Venous vasodilation: Decrease in preload. Pulmonary arterial vasodilation: Decrease in RV afterload

Answer 291

Implanted Cardioverter Defibrillators: Patients with LVEF 120 msec (bundle brank block); Cause the LV lateral wall and septal wall to contract together, which produces (a more efficient contraction / increase stroke volume and may also improve mitral valve function / decrease regurgitation); and Usually placed with ICD

Answer 292

Hospitalized patients with an acute decompensation of HF (fluid retention, shortness of breath, etc), generally require a change in therapeutic approach: IV diuretics; IV vasodilators (nitrates, if BP allows); IV inotropes for shock; Positive pressure ventilation (CPAP/BiPAP, intubation) for hypoxia (May also reduce preload); and May need to cut back on beta-blockers (only in severe cases)

Answer 293

Digoxin (PO) - K/Na exchanger, Dobutamine (IV) – β agonist (opposite of beta blocker), Milrinone (IV) – phosphodiesterase inhibitor (effect is similar to dobutamine)

Answer 294

IV agents used short term in the ICU to reverse shock. Long-term they worsen remodeling, increase mortality. Digoxin has no effect on mortality but may reduce symptoms and hospitalization (also some decrease in heart rate in AFib). In high doses causes dig toxicity (mostly arrhythmias). Completely renally cleared, so needs dose adjustment with renal dysfunction

Answer 295

HF is generally a progressive disease. Median survival for patients with symptomatic disease is about 5 years. Many patients are older (approximately half will be >75 years of age). Consequently, even with optimal medical and electrical therapy, HF will progress in most patients. Once standard therapies begin to fail, advanced therapies should be considered: Aggressive advanced therapy (typically requires up front risk, and cost; used only in patients with HFrEF): Cardiac transplantation (<2500 organs available per year) and Mechanical circulatory support (ventricular assist devices [LVAD]) (As a “bridge to transplantation”, to stabilize patients while waiting and As “destination therapy” – the final therapy. Palliative advanced therapy (paradigm shift from quantity to quality of life): Hospice and Continuous infusion of inotropic therapy

Answer 296

improve symptoms: Diuretics (furosemide), Inotropes (for HFrEF - digitalis PO [acute HF w/ shock: dobutamine, milronone). Prolong survival (for HFrEF) – reduce remodeling, so help symptoms too, ACE Inhibitors (prils – e.g. lisinopril), Angiotensin Receptor Blockers (sartans – e.g. valsartan) Beta Blockers (olols – e.g. carvedilol, metoprolol), Aldosterone Antagonists (spironolactone, eplerenone), Vasodilators (nitrates, hydralazine, …) Cardiac Resynchronization Therapy (biventricular pacing) Implantable Cardioverter Defibrillator (ICD) [does not improve symptoms]

Answer 297

Trials of neurohormonal antagonists (e.g. ACEI, ARB) have not been successful in improving outcomes for patients with HF and normal ejection fraction (HFnEF); spironolactone did not increase exercise tolerance in a HFnEF study. Similarly, ICD / CRT are not generally indicated in patients with LVEF >35-40%. Therapy consists of treating the underlying disorder (hypertension, diabetes, kidney dysfunction, aortic stenosis). Diuretics are used to keep volume normal (sodium retention is common). Vasodilators are used to maintain normal blood pressure

Answer 298

Compared to prazosin and placebo, hydralazine-ISDN improved LV function and lowered mortality. Compared to ACE-inhibitors, hydralazine-ISDN equally improved EF, but ACE-inhibitor had a greater reduction in mortality. The fixed dose of hydralazine-ISDN reduced mortality in AA receiving beta blocker, ACE-inhibitor and a aldosterone antagonist.

Answer 299

the combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for African American patients with NYHA class III-IV HErEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated. A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated. In African americans, there is an increase in TGFB and TGFB mRNA, which increases the amount of type 1 and 2 collagen in the myocardium leading to increased fibrosis. There is also increased levels of endothelin-1, which is a very potent vasoconstrictor. There is also a decreased role of RRA and may be a decrease in NO synthatase leading to NO deficiency (NO is potent vasodilator).

Answer 300

bradykininogen is released by the liver and is transformed into bradykinin by kallikrenin. Bradykinin is converted into inactive fragments by kinase II (ACE). Bradykinin is a very potent pulmonary irritant leading to cough, also has large impact on remodeling of LV, and is a potent vasodilator effecting afterload. ACE inhibitors cause an increase in bradykinin

Answer 301

captopril is dosed 6.25mg three times a day. Enalapril 2.5 mg twice a day. Lisinopril is dosed at 2.5-5mg once a day.

Answer 302

angiotensin II targets: vascular smooth muscle to increase arteriolar constriction, increasing arterial blood pressure, central and peripheral nercous system to facilitate sympathetic activity increasing arteriolar constriction and cardiac output leading to increased arterial blood pressure, adrenal cortex causing an increased of aldosterone secretion leading to increased sodium reabsorption leading to increased arterial blood pressure, the tubules of the kidney causing an increase in sodium reabsorption, the arterioles of the kidney causing an increase in filtration fraction (leading to an increase in sodium reabsorption) and changes in the glomular filtration rate (leading to increase in sodium and water retention), the brain causing an increase in antidiuretic hormone (increasing water absorption) and an increase in thirst (leading to more water ingestion). All of this leads to an increase in arterial blood pressure.

Answer 303

cough, hyperkalemia, angioedema, renal dysfunction, neutropenia, and hypotension.

Answer 304

lithium, NSAIDs, salt substitute, loop diuretics, K sparing diuretics

Answer 305

pregnancy, bilateral artery stenosis, angioedema, hyperkalemia, and renal failure? Be careful with elderly patients

Answer 306

in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality.

Answer 307

captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril

Answer 308

candesartan, losartan, valsartan

Answer 309

are a class of G protein-coupled receptors with angiotensin II as their ligands. They are important in the renin-angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II.

Answer 310

there are non renin enzymes (t-P factor, cathepsin G, and tonin) that convert angiotensinogen to angiotensin II. There are also non-ACE enzymes (chymase, CAGE, and cathepsin G) the convert angiotensin I to angiotensin II. There are also tissue ACE that may be able to escape ACE inhibitors. Therefore ACE inhibitors do not block all production of angiotensin II

Answer 311

is an angiotensin receptor. It has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system. Angiotensin II receptor antagonists are drugs indicated for hypertension, diabetic nephropathy and congestive heart failure. The angiotensin receptor is activated by the vasoconstricting peptide angiotensin II. The activated receptor in turn couples to Gq/11 and thus activates phospholipase C and increases the cytosolic Ca2+ concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C. Activated receptor also inhibits adenylate cyclase and activates various tyrosine kinases. The AT1 receptor mediates the major cardiovascular effects of angiotensin II. Effects include vasoconstriction, aldosterone synthesis and secretion, increased vasopressin secretion, cardiac hypertrophy, augmentation of peripheral noradrenergic activity, vascular smooth muscle cells proliferation, decreased renal blood flow, renal renin inhibition, renal tubular sodium reuptake, modulation of central sympathetic nervous system activity, cardiac contractility, central osmocontrol and extracellular matrix formation. Actions include aldosterone secretion, vascular constriction, dyspogenic response, renal/inotropic response, growth promoting (fibroblast, endothelial cells), and angiotensinogen gene expression.

Answer 312

are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. These substances are AT1-receptor antagonists; that is, they block the activation of angiotensin II AT1 receptors. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.

Answer 313

reduce the activity of the renin-angiotensin-aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease. ACE inhibitors block the conversion of angiotensin I (AI) to angiotensin II (AII).[4] They thereby lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of AI to AII. AI increases for the same reason; AII and aldosterone decrease. Bradykinin increases because of less inactivation by ACE. With ACE inhibitor use, the production of AII is decreased, leading to decreased blood pressure.

Answer 314

Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by AII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli. It contributes to ventricular remodeling and ventricular hypertrophy of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death). Stimulation by AII of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure. Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients. A decrease renal protein kinase C

Answer 315

well tolerate—less angioedema, no cough. Hyperkalemia, uricosuric effects

Answer 316

over-producers of uric acid, pregnancy, volume depletion, renal arterial stenosis, hyperkalemia

Answer 317

are recommended in patients with HFrEF with current or prio symptoms who are ACE inhibitor intolerant, unless contraindicated, to reduce morbidity and mortality. ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as first-line therapy for patients with HFrEF, especially for patients already taking ARBs for other indications, unless contraindicated. Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACE inhibitor and a beta blocker in whom as aldosterone antagonist is not indicated or tolerated.

Answer 318

The β -adrenoceptors were initially divided into β1 and β2-adrenoceptors defined in terms of agonist potencies, β1-adrenoceptors demonstrated equal affinity for adrenaline and nor- adrenaline while β2-adrenoceptors displayed a higher selectivity for nor-adrenaline than for adrenaline. The discovery of these receptor subtypes led to the development of selective agonists and antagonists for each subtype. The story does not end there, further experimentation using β-antagonists exposed another receptor subtype which appeared to be insensitive to typical β-adrenoceptor antagonists this was classified as β3-adrenoceptor. More recent pharmacological evidence is now emerging in support of a further receptor subtype β4-adrenoceptor, although as yet there are no selective compounds for this particular subtype.

Answer 319

For all β-adrenoceptors transduction is via G-proteins coupled to the intracellular second messenger adenylate cyclase. All β-receptors are positively coupled to adenylate cyclase via activation of Gs G-protein, however activation of the β2 and β3-adrenoceptors results in stimulation or stimulation and inhibition of adenylate cyclase. Activation of the β1 and β4 receptor results in an increase in the formation of cAMP and the subsequent stimulation of cAMP-dependent protein kinase. cAMP also activates PK-A causing Ca release from SR and outside of the cardiac myocyte leading to contraction.

Answer 320

Adrenergic drugs are used in the treatment of a wide range of medical conditions. Including the use of β2-receptor selective agonists in the treatment of asthma and other related bronchospastic conditions examples of these drugs include salbutamol and salmeterol. Beta-blocker drugs are commonly used in the treatment of angina pectoris, cardiac arrhythmia and for the long-term treatment of patients who survive myocardial infarction. β-receptor antagonists have also been used as anti-hypertensive for a number of years. Beta -blockers have also proven useful in the treatment of conditions such as migraine, anxiety disorders, hyperthyroidism, alcohol withdrawal and when applied topically are useful in the treatment of glaucoma and ocular hypertension.

Answer 321

beta 1 and 2, alpha 1

Answer 322

beta 1 and 2, and alpha 1 (minimal)

Answer 323

beta 1 and 3

Answer 324

beta 1 and 2

Answer 325

prevents apoptosis/oxidative stress (cell death), arrhythmia potential, hypertrophy/fibrosis, and down regulation of beta 1 receptors

Answer 326

first generation are nonselective for beta 1 and 2 blockade, no ancillary properties (ie, intrinsic sympathomimetic activity (ISA), beta 1-selectivity, membrane stabilizing activity, and lipophilicity) (e.g. propranolol and timolol). Second generation are selective for beta 1 or 2, no ancillary properties (metoprolol, atenolol, and bisoprolol). Third generation are selective or nonselective, has potentially important ancillary property (carvedilol, bucinodolol, nebivolol). Fourth generation are nonselective; several designer efficacy enhancing or adverse event-lowering ancillary properties.

Answer 327

Mild to severe symptoms of heart failure. Systolic dysfunction of the left ventricle (EF<40%). Receiving treatment with an ACE inhibitor and a diuretic. Any age and either sex. CAD or nonischemic dilated cardiomyopathy. Diabetic and nondiabetic. COPD without reactive airway disease.

Answer 328

Tx with a diuretic so that patient has minimal evidence of fluid retention. Tx with an ACE inhibitor for at least 2 weeks. No recent use of IV vasodialators or positive inotropic agents. Systolic blood pressure > 90 mmHg. Heart rate > 60 beats/min (unless tx with a pacemaker). Absence of end-organ failure

Answer 329

The NP system comprises three structurally similar peptides with cardiorenal protective properties: atrial NP (ANP), B-type NP (BNP) and C-type NP (CNP). ANP and BNP are primarily expressed in the heart and released by cardiomyocytes in response to mechanical stretch. CNP is derived mainly from endothelial and renal cells and secreted in response to endothelium-dependent agonists and pro-inflammatory cytokines. As filling pressures rise in HF, increased cardiac stretch causes the secretion of precursor NPs, which are cleaved by specific proteases to produce biologically active NPs which then act on NP receptors (NP receptor-A [NPR-A], NPR-B and NPR-C). Binding of NPs to NPR-A and NPR-B activates particulate guanylate cyclase resulting in increases in the second messenger, cyclic guanosine monophosphate (cGMP), which mediates many of the cardiovascular and renal effects of the NPs. NPs are cleared from the circulation by two mechanisms – binding to NPR-C and inactivation (hydrolytic cleavage) by neprilysin. Neprilysin has a high affinity for both ANP and CNP, and a lower affinity for BNP, which is more resistant to hydrolysis. Since neprilysin does not hydrolyze N-terminal pro-BNP (NT-proBNP), it remains a useful cardiac biomarker to assess therapeutic effect and prognosis in patients treated with neprilysin inhibitors. The cardiovascular and renal effects of the NP system oppose those of the RAAS, providing the scientific and therapeutic basis for neprilysin inhibition in the setting of HF. One of the major effects of NPs is vasodilation, which results from cGMP-mediated relaxation of smooth muscle cells as well as indirect effects of NPs to inhibit the RAAS and decrease endothelin-1 (ET-1) production. NPs have been shown to cause significant reductions in systemic vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure and right arterial pressure in patients with severe HF. NPs promote sodium and water excretion by inhibiting sodium reabsorption in the proximal and distal nephron, while preventing decreases in glomerular filtration rate by regulating tubuloglomerular feedback. These effects of NPs have been observed in patients with severe HF, resulting in improvement in hemodynamics and renal function. In addition to the direct effects of NPs on the kidney, their inhibitory actions on the RAAS and sympathetic nervous system also contribute to their natriuretic, diuretic and hemodynamic effects. The NPs have potent cardiac antihypertrophic and antifibrotic properties. ANP and CNP inhibit cardiac hypertrophy induced by angiotensin II (Ang II) or ET-1. Furthermore, in cardiac fibroblasts, ANP and BNP inhibit the fibrotic effects of transforming growth factor beta (TGF-ß), while Ang II-induced interstitial fibrosis was inhibited by CNP. ANP has been shown to stimulate lipolysis in human adipocytes by activating the NPR-A receptor and increasing intracellular cGMP. ANP-induced lipolysis could contribute to cardiac energy utilization by providing substrate in the form of free fatty acids and promoting lipid oxidation through increased mitochondrial biogenesis. On the other hand, an imbalance between fatty acid uptake and utilization for adenosine triphosphate (ATP) generation could result in mitochondrial oxidative stress and lead to excessive cardiomyocyte accumulation of neutral lipids, contractile dysfunction and lipotoxicity.

Answer 330

While it was initially thought that the NP system was upregulated in HF due to high circulating levels of total immunoreactive ANP and BNP, recent studies indicate that mature BNP (BNP1–32) levels are reduced and levels of less biologically active BNP fragments are increased. This is due to altered processing of proBNP to biologically active BNP1–32 and partly explains the blunting of the physiological response to high levels of total immunoreactive BNP observed in patients with HF. Thus, advanced HF may represent a state of NP deficiency. Furthermore, the expression and activation of neprilysin are increased in patients with HF, which enhances the rate of degradation of NPs and contributes to reduced levels of biologically active NPs. As HF progresses, relative resistance or hyporesponsiveness to NPs develops, which is particularly evident in the kidney and vasculature. This hyporesponsiveness is an important feature of HF that adversely affects prognosis by worsening sodium retention and volume overload and increasing peripheral vascular resistance. The mechanisms for NP resistance are multifactorial and include: downregulation of NP receptors, dysregulated NP signal transduction, increased cGMP degradation and activation of the RAAS. In addition to hydrolyzing the NPs, neprilysin also hydrolyzes other vasoactive peptides, including substance P, bradykinin, ET-1, angiotensin I (Ang I) and Ang II. Since there are multiple neprilysin substrates with differing and, in some instances, opposing biologic actions, the pharmacologic profile of neprilysin inhibitors is complex and will depend on the net effect on all biologically relevant substrates. While inhibition of neprilysin is expected to result in beneficial cardiovascular and renal effects in HF by increasing NP levels, corresponding increases in Ang II and ET-1, both of which have vasoconstrictor, pro-fibrotic and pro-hypertrophic properties, would be expected to oppose the beneficial effects of the NPs. In the case of angiotensin, neprilysin hydrolyzes and inactivates Ang II; therefore, neprilysin inhibition alone will not only increase NP levels but can also result in accumulation of Ang II, which could attenuate or negate any beneficial NP effects in the setting of HF. The increase in Ang II observed with neprilysin inhibition provides a rationale for concomitant RAAS blockade. However, neprilysin also converts Ang I to Ang 1–7, which has vasodilating, antiproliferative and natriuretic actions mediated through activation of the Mas receptor. In the case of ET-1, neprilysin not only hydrolyzes ET-1, but also its precursor peptide big ET-1. Thus, the effect of a neprilysin inhibitor on ET-1 levels will depend on the net effect of hydrolysis of both big-ET1 and ET-1. It should also be noted that both substance P and bradykinin, which are both inactivated by neprilysin, have vasodilatory properties, increase vascular permeability and, when combined with an angiotensin-converting-enzyme inhibitor (ACEI), are implicated in the pathogenesis of angioedema, a potential side effect of neprilysin inhibitors.

Answer 331

which consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan, was designed to minimize the risk of serious angioedema. In small trials involving patients who had hypertension or heart failure with a preserved ejection fraction, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone. In conclusion, angiotensin receptor–neprilysin inhibition with LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for heart failure. The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on cardiovascular mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo. This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin–angiotensin system alone in patients with chronic heart failure.

Answer 332

Today, the most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response, though beta blockers and/or calcium channel blockers are a better first choice. High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling. The use of digoxin in heart problems during sinus rhythm was once standard, but is now controversial. In theory, the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable, and other effective treatments are now available. Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment. Digitalis/digoxin has recently fallen out of favor because it did not demonstrate a mortality benefit in patients with congestive heart failure; however, it did demonstrate a reduction in hospitalizations for this condition. Because other therapies have shown a mortality benefit in congestive heart failure, maximizing other therapies (e.g., beta blockers) first is recommended before using digoxin.

Answer 333

heart failure with reduced systolic function: In patients in sinus rhythm or atrial fibrillation, regardless of age and gender, who continue to have signs and symptoms of heart failure despite standard therapies with ACE inhibiters or ARBs, beta blockers and diuretics. In all patients with severe symptoms (NYHA class III or IV), cardiomegaly on chest x-ray (cardiothoracic ratio greater than 0.55), or LVEF less than 25%. In patients with persistent heart failure symptoms despite the addition of aldosterone antagonists or ARB to an ACE inhibitor or CRT. Heart failure with preserved systolic function: in patients with symptoms not responding to other available therapies.

Answer 334

no loading dose (except in atrial fibrillation with rapid ventricular response). Low dose (0.0625-0.25 mg/d) individualized on the basis of lean body weight, age, renal function, and concomitant medications. Therapeutic serum concentration of 0.5-1 ng/ml).

Answer 335

cardiac amyloidosis, active myocardial ischemia, electrolyte imbalance (especially hypokalemia), acid-base imbalance, concomitant drug administration (eg catecholamines), hypothyroidism, hypoxemia (especially in setting of acute respiratory failure), and altered autonomic tone (eg vagotonic states).

Answer 336

hypokalemia results in increased digoxin binding increasing its therapeutic and toxic effects. Digoxin enhances Ca absorption into cardiac myocytes, which is one of the ways it increases inotrophy. This can also lead to Ca overload and increased sysceptibility to digitalis- induced arrhythmias. Hypomagnesemia can sensitize the heart to digitalis-induced arrhythmias (includes any arrhythmia except supraventricular tachydysrhythmias).

Answer 337

nausea, vomiting, abdominal pain, weakness, confusion, hyperkalemia (>5.5 mEq/L is a poor prognostic sign), bradycardia, heart block, several types of arrhythmias, sensitivity to light, yellow halos around lights, blurred vision.

Answer 338

severe ventricular arrhythmias, progressive bradycardia, second or third degree heart block unresponsive to atropine, serum potassium levels greater than 5.5 mEq/L (adults) or 6 mEq/L (children) with rapidly progressive signs and symptoms of digoxin toxicity.

Answer 339

can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalization for HF.

Answer 340

diuretics to reduce fluid volume (eg bumetanide, furosemide, and torsemide). Inotropes augment contractility (eg dobutamine and milrinone). Vasodilators decrease preload and afterload (eg nitroglycerin, nitroprusside, and nesirtide). Relief of congestion and volume overload generally accomplished with sodium and fluid restriction and the use of diuretics. Intravenous vasodilators may be added (i.e., nitroglycerin, nitroprusside, nesiritide). The use of inotropes should be severely limited. Discharge evaluation and planning for follow-up are important factors in reducing readmission

Answer 341

is used to treat acute but potentially reversible heart failure, such as which occurs during cardiac surgery or in cases of septic or cardiogenic shock, on the basis of its positive inotropic action.

Answer 342

can be used in cases of congestive heart failure to increase cardiac output. It is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of patients with cardiac decompensation due to depressed contractility, which could be the result of either organic heart disease or cardiac surgical procedures. It is not useful in ischemic heart disease because it increases heart rate and thus increases myocardial oxygen demand. The drug is also commonly used in the hospital setting as a pharmacologic stress testing agent to identify coronary artery disease. Primary side effects include those commonly seen for β1 active sympathomimetics, such as hypertension, angina, arrhythmia, and tachycardia. Used with caution in atrial fibrillation as it has the effect of increasing the atrioventricular (AV) conduction. The most dangerous side effect of dobutamine is increased risk of arrhythmia, including fatal arrhythmias. Dobutamine is a direct-acting agent whose primary activity results from stimulation of the β1-adrenoceptors of the heart, increasing contractility and cardiac output. Since it does not act on dopamine receptors to induce the release of norepinephrine (another α1 agonist), dobutamine is less prone to induce hypertension than is dopamine. Dobutamine is predominantly a β1-adrenergic agonist, with weak β2 activity, and α1 selective activity, although it is used clinically in cases of cardiogenic shock for its β1 inotropic effect in increasing heart contractility and cardiac output. Dobutamine is administered as a racemic mixture consisting of both (+) and (−) isomers; the (+) isomer is a potent β1 agonist and α1 antagonist, while the (−) isomer is an α1 agonist. The administration of the racemate results in the overall β1 agonism responsible for its activity. (+)-Dobutamine also has mild β2 agonist activity, which makes it useful as a vasodilator.

Answer 343

commonly known and marketed under the brand name Primacor, is a medication used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, recent studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically. Overall, milrinone supports ventricular functioning of the heart by decreasing the degradation of cAMP and thus increasing phosphorylation levels of many components in the heart that contribute to contractility and heart rate. Milrinone use following cardiac surgery has been under some debate because of the potential increase risk of postoperative atrial arrhythmias. However, in the short term milrinone has been deemed beneficial to those experiencing heart failure and an effective therapy to maintain heart function following cardiac surgeries. There is no evidence of any long term beneficial effects on survival.

Answer 344

People experiencing heart failure have a significant decrease in the contractile ability of heart cells (cardiomyocytes). This impaired contractility occurs through a number of mechanisms. Some of the main problems associated with decreased contractility in those with heart failure are issues arising from imbalances in the concentration of calcium. Calcium permits myosin and actin to interact which allows initiation of contraction within the cardiomyocytes. In those with heart failure there may be a decreased amount of calcium within the cardiomyocytes reducing the available calcium to initiate contraction. When contractility is decreased the amount of blood being pumped out of the heart into circulation is decreased as well. This reduction in cardiac output causes many systemic implications such as fatigue, syncope and other issues associated with decreased blood flow to peripheral tissues.

Answer 345

There are receptors on cardiomyocytes called β-adrenergic receptors. These receptors are stimulated by molecules such as norepinephrine and epinephrine. Stimulation of these receptors causes a cascade of events ultimately leading to increase cyclic adenosine monophosphate (cAMP) within the cell. Cyclic adenosine monophosphate causes increase activation of protein kinase A (PKA). PKA is a protein that phosphorylates many components within the cardiomyocytes and either activates or inhibits their action. Phosphodiesterases are enzymes responsible for the breakdown of cAMP. Therefore, when phosphodiesterases break down cAMP the amount of PKA within the cell decreases as well.

Answer 346

a phosphodiesterase-3 inhibitor. This drug inhibits the action of phosphodiesterase-3 and thus prevents degradation of cAMP. With increase cAMP levels there is an increase activation of PKA. This PKA will phosphorylate many components of the cardiomyocyte such as calcium channels and components of the myofilaments. Phosphorylation of calcium channels permits an increase in calcium influx into the cell. This increase in calcium influx permits increased contractility. PKA also phosphorylates potassium channels promoting their action. Potassium channels are responsible for repolarization of the cardiomyocytes therefore increasing the rate at which cells can depolarize and generate contraction. PKA also phosphorylates components on myofilaments allowing actin and myosin to interact more easily and thus increasing contractility and the inotropic state of the heart. Milrinone allows stimulation of cardiac function independently of β-adrenergic receptors which appear to be down-regulated in those with heart failure.

Answer 347

angina, tachyarrhythmia, cardiac dysrhythmia

Answer 348

hypotension, thrombocytopenia, tachycardia, arrhythmias, fever, increased LFTs.

Answer 349

Intravenous inotropes (milrinone or dobutamine) may be considered in patients with advanced HF and low output syndrome (LV dilation, reduced, decrease end-organ dysfunction): To relieve symptoms and improve end-organ function. Patients with marginal systolic blood pressure (<90 mm Hg). Patients with symptomatic hypotension despite adequate filling pressure. Unresponsive to, or intolerant of, intravenous vasodilators (Strength of Evidence = C)

Answer 350

endogenous precursor of norepinephrine exerts its effects by directly stimulating adrenergic receptors, as well as, release norepinephrine from nerve terminals. Administration: dose-dependent effects; continuous infusion via infusion pump.

Answer 351

Under the trade names Intropin, Dopastat, Revimine, or other names, dopamine can be used as a drug in injectable form. It is most commonly used in the treatment of severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest, especially in newborn infants. Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate, and an increase in blood pressure. At a "cardiac/beta dose" of 5 to 10 μg/kg/min, dopamine acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure. At a "pressor/alpha dose" of 10 to 20 μg/kg/min, dopamine also causes vasoconstriction that further increases blood pressure, but can produce negative side effects such as an impairment of kidney function and cardiac arrhythmias. Multiple types of dopamine receptors are present in cells of the kidneys. Dopamine is also synthesized there, by tubule cells, and discharged into the tubular fluid. Its actions include increasing the blood supply to the kidneys, increasing filtration by the glomeruli, and increasing excretion of sodium in the urine. Defects in renal dopamine function can be produced by high blood pressure or by genetic problems, and can lead to reduced sodium excretion as well as hypertension.

Answer 352

arterial vasodilation (decrease in afterload) dose 75mg po. Side effects include drug incuduced SLE and headache

Answer 353

venous vasodilation (decrease in pre load). Dose is 10-40 mg po. Side effects include hypotension, headache, and dizziness