cardiology1 Flashcards
function of CV system
distributes dissolved gases and nutrients, removes metabolic waste, contributes to systemic homeostasis by controlling temp, O2 supply, pH, ionic composition, nutrient supply, and quickly adpts to changes in conditions and metabolic demands.
pulmonary circulation
low pressure. Single pathway between heart and lungs
systemic circulation
higher pressure. Multiple pathways from heart to different systemic vascular beds. Systemic circulation is primarily arranged in parallel. This is important because oxygenated blood visits only one organ system before returning to pulmonary ciruclation. changes in metabolic demand or blood flow in one organ do not significantly affect other organs. blood flow to different organs can be individually varied to match demand. At rest, most blood directed to brain (~14%), skeletal muscle (~15%), GI system (~21%), and kidney (~22%). During exercise up to 80% to exercising muscle. majorexception=hepaticcirculation—largefractionofhepaticblood
supply is via intestinal circulation
three major layers of the heart
epicardium is the outer membrane, mostly composed of connective tissue and fat. Myocardium is the thick muscle layer, endocardium is the inner membrane and is composed of endothelial cells, as in vessels.
pericardium
encloses entire heart. It is a fluid filled membranous sac and is not conncected to walls of the heart. It is stiff and non-compliant and resists sudden distension of chambers. Pericarditis can restrict the filling of the heart.
Tricuspid valve
between right atrium & right ventricle
Pulmonic valve
between right ventricle & pulmonary artery
Mitral valve
between left atrium & left ventricle
Aortic valve
between left ventricle & aorta
Atrioventricular
Tricuspid & mitral valves. Lies between atria & ventricles and is attached to papillary muscles in ventricles by chordae tendonae, which is tendon-like attachments that prevent valves from prolapsing into atria during ventricular contraction.
Semilunar valves
Pulmonic & aortic valves. Lies between ventricles and great arteries.
Valves
thin flaps (“cusps”) of fibrous tissue covered by endothelium. Mitral has two cusps (bicuspid), others have three. One-way, pressure-operated (passive) in order to direct forward blood flow, prevent backward blood flow. All located in the same horizontal plane in heart. Heart sounds generated by opening and closing of valves. Defective valves make unusual sounds, which are murmurs. Regurgitation is minor leakage. Prolapse is a major failure, where valve gets pushed backward.
Sinoatrial (SA) node
in wall of right atrium. It spontaneously depolarizes to initiate the heart beat. Intrinsic activity is about 100bpm. It is highly regulated by autonomic nervous system and many humoral factors. Impulse spreads through atria via gap junctions, it is not clear whether there is preferential conduction pathway through atria
Atrioventricular (AV) node
between atria and ventricles, slows conduction to allow atrial contraction to precede ventricular contraction
His-Purkinje system
specialized cells that rapidly
conduct depolarization to trigger coordinated ventricular contraction.
Coronary blood flow
Most coronary blood flow occurs during diastole because of compression of microvasculature during systole. Flow thus depends on heart rate — less time for perfusion at higher heart rates. Heart has high oxygen consumption. Supply must closely match demand or hypoxia results (angina).
Right & left coronary arteries
arise from root of aorta. Major coronary arteries course along epicardial surface of heart. Smaller branches enter myocardium. There is some variation in anatomy between individuals. Left main coronary artery (short ~ 1 cm)
bifurcates to left anterior descending (LAD) artery and circumflex artery and is the primary blood supply to left atrium and left ventricle. Right coronary artery is in groove between right atrium and right ventricle and is the primary blood supply to right atrium and right ventricle, as well as posterior part of left ventricle
Coronary capillaries
very dense, each myocyte is associated with several capillaries
Coronary veins
located adjacent to corresponding coronary arteries. It drains into coronary sinus, which opens into right atrium near inferior vena cava
Blood flow pathway
Deoxygenated blood returns from systemic circulation via superior & inferior venae cavae, passively enters right atrium (no valve). Right atrium contracts, increased pressure pushes open tricuspid valve, blood enters right ventricle. Right ventricle contracts, pushes open pulmonic valve, blood enters pulmonary circulation via pulmonary arteries. Oyxgenated blood returning from lungs enters left atrium via pulmonary veins. Left atrium contracts, pushes open mitral valve, blood enters left ventricle. Left ventricle contracts, pushes open aortic valve, blood enters systemic circulation via aorta.
Vascular system
has three parts: Arterial system distributes of oxygenated blood and nutrients. Microcirculation and lymphatic system is a diffusion and filtration system. Venous system is collection of deoxygenated blood and wastes
Aorta`single outlet from left side of heart.
diameter ~25 mm (garden hose). dampens pulsatile pressure
Arteries
thick walled, resist expansion. diameter ~ 0.2-6.0 mm, distribute blood to different organs
Arterioles
relatively thicker walls (more vascular smooth muscle). diameter ~ 10-70 μm. highly innervated by autonomic nerves, circulating hormones, and local metabolites. primary site of regulation of vascular resistance, via changes in diameter
Capillaries
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
Venules, veins
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
Vena cavae
superior & inferior. diameter ~ 25-30 mm
Anatomy of resistance vessels
Arterial walls have three layers: tunica adventitia, tunica media, and tunica intima
Tunica adventitia
outer laye. Mostly connective tissue, composed of collagen and elastin
Tunica media
middle layer. It is mostly innervated vascular smooth muscle. Controls diameter of vessels, particularly resistance arteries. Not present in capillaries
Tunica intima
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.
Microcirculation
Defined as vasculature from the first-order arterioles to the venules. Capillaries are the site of gas, nutrient, and waste exchange. Blood flow through capillary beds is determined by the pressure gradient, and is highly regulated via constriction/dilation of arterioles & 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)
Lymphatic system
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.
Hemodynamics
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.
Pressure changes across the vascular system
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»_space; 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.
Volume changes across the vascular system
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
Flow (Q)
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)
Velocity (v)
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.
Flow equation
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.
Poiseuille’s Equation
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
Resistances in parallel versus resistances in series
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
Laminar flow
smooth, streamlined, and most efficient. velocity slowest at edge of tube, fastest in center
Turbulent flow
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.
Pulsatile Flow
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.
Compliance
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.
LaPlace’s Law
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.
Cardiovascular transport
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
Bulk transport
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)
Fick’s Principle and myocardial oxygen consumption
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).
Common example of Fick’s law
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.
Transcapillary Transport
includes solvent and solute movement and diffusion.
Solvent & solute movement
Two opposing forces determine solvent movement – hydrostatic pressure and oncotic pressure.
Hydrostatic Pressure, P
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)
Oncotic Pressure, π
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)
Starling Equation for transcapillary transport (AKA Starling’s law of the capillary)
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).
Diffusion
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).
Contractility
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.
Control of cardiac contractility
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.
Cardiac output
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.
EDV
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.
ESV
The ESV is equated roughly to contractility and end-systolic sarcomere length, i.e., the extent of cellular shortening.
Overview of Arrhythmias
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.
Congenital Long-QT Syndrome
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.
Cause of long QT syndrome
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.
Effects of long QT mutations on currents carried by cardiac sodium and potassium channels
reduced IKs for LQT1 mutant channels. incomplete inactivation for LQT3 mutant cardiac sodium channels.
Ionic currents that contribute to the ventricular action potential (fast response)
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.
Some of the mutations in cardiac sodium channels and potassium channels that prolong QT interval
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.
Cellular and Molecular Mechanisms of Arrhythmia Generation
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.
Inappropriate impulse initiation - identified by abnormally depolarized diastolic membrane potential
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
Triggered afterdepolarizations
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.
Disturbed impulse conduction
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.
Re-entry
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.
Recapitulation of ion channels to sudden cardiac death
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.
Important note on the semantics of class I antiarryhmic (Na channel blockers) drug classification
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.
Overview of class I drug effects
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.
Class Ia Na+ channel blockers
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
Class Ib Na+ channel blockers
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.
Class Ic Na+ channel blockers
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
Use-Dependence of sodium channel blockers
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.
Mechanism of local anesthetic block of Na+ channels
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.
Prolongation of refractory period
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).
Use-dependence: a general mechanism of sodium channel blocker drug action
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.
How class I antiarrhythmic drugs suppress re-entrant arrhythmias.
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.
Terminating re-entry by slowing conduction velocity: reducing upstroke rate
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
Terminating re-entry by prolonging refractory period
Prolonged refractoriness can help suppress re-entrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential, and so the re-entrant wave of excitation is extinguished.
A paradox in combating re-entry
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.
Class II Antiarrhythmic Drugs: β-blockers
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.
Effects of beta-adrenergic receptor blockers on slow response (pacemaker) action potentials
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.
Class III Antiarrhythmic Drugs: Prolongation of Phase 2
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.
Effects of class III antiarrhythmics on cardiac action potentials
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.
Class IV Antiarrhythmic Drugs: Ca2+ Channel Blockers
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.
The effect of Ca2+ channel blockers on AV node action potentials
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.
An Unclassified Antiarrhythmic Drug
Adenosine
The action of adenosine
(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).
Mechanisms of action of adenosine on SA or AV nodal cells
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).
Some specific therapeutic uses of the antiarrhythmic drugs
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)
Pharmacokinetics of esmolol
half life of 10 min (metabolized via red cell esterase)
Pharmacokinetics of amiodare
half life of 13 to 100 days
Pharmacokinetics of adenosine
half life of less than 10 seconds, given as IV bolus, which can be repeated if necessary.
Major side effects of procainamide
Lupus syndrome (occurs in 1/3 of patients on long-term therapy).
Major side effects of lidocaine
Least cardiotoxic agent of Class I drugs. Side effects: paresthesia, tremors, seizures, agitation, confusion.
Major side effects of flecainide and propafenone
Highly pro-arrhythmic, particularly with ventricular tachycardia.
Major side effects of beta blockers
Hypotension, aggravation of heart failure, bronchospasm, impotence.
Major side effects of amiodarone
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).
Major side effects of sotalol
Structurally, this drug is a β-adrenergic receptor ligand. Principal side effects are similar to those of the other β-blockers.
Major side effects of verapamil
The major adverse effect of these drugs is hypotension, via action on vascular smooth muscle. Negative cardiac inotropy occurs as well.
Major side effects of adenosine
Flushing (20%), chest burning and shortness of breath (10%), brief AV block. Adenosine action on coronary circulation is responsible.
Calcium movements underlying myocardial contraction and relaxation.
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).
Cardiac muscle contraction
ECC requires entry of external Ca. receptors include CaV1.2 (α1C), β2a or β2b, α2δ1, and RyR2
Skeletal muscle contraction
ECC does NOT require entry of external Ca. receptors include CaV1.1 (α1S), β1a, α2δ1, γ1, and RrR1
The sequence of events during excitation, contraction and relaxation of cardiac muscle cells is
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.
The NCX sodium/calcium exchanger
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.
Three consequences of NCX sodium/ calcium exchanger
- 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.
Calcium Homeostasis
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.
Four important targets for PKA in myocardium
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.
Genetic Cardiac Disorders of Cardiac EC Coupling Proteins
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.
Timothy Syndrome
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.
Brugada Syndrome
(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.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT
Patients with CPVT do not display ECG abnormalities at rest, but do display abnormalities upon exercise or infusion of catecholamines. 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.
Epidemiology of heart failure
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
Heart failure
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.
Components of the HF Syndrome
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.
Preload and the force-tension relationship
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
inotropy
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
Major divisions of the heart failure syndrome
systolic v. diastolic. left v. right. acute v. chronic. symptomatic v. asymptomatic v. at risk
Systolic heart failure
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)).
Diastolic heart failure
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)
Right-sided heart failure
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)
Various forms of hf almost always co-exist
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
Pathophysiology / compensatory responses
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”
The cycle of heart failure / ventricular remodeling
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
Cardiac output
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.
Stroke Volume
volume of blood pumped per beat
Heart rate
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.
Stroke volume
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.
Diastole
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.
Isovolumetric contraction phase
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).
Ejection Phase
As the ventricle continues to contract, the ventricular pressure exceeds that in the aorta, thus the aortic valve is pushed open and blood begins to flow. 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.
Isovolumetric relaxation phase
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.
Volume changes during the cardiac cycle
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.
Systolic & diastolic PV relations
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.
End diastolic pressure-volume relationship (EDPVR)
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)
Preload
The length to which a muscle is stretched before shortening. For left ventricle, preload ~ end diastolic volume.
Afterload
The load against which a muscle contracts. For left ventricle, afterload ~ aortic pressure.
Systolic pressure-volume relationship (SPVR)
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)
Afterload
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).
Active tension
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)
Starling curve
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.
Frank-starling law of the heart
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.
Three ways to state Starling’s Law
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.
Molecular basis for Starling’s law
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.
