Cardiac Cycle The wall of the right ventricle is thinner than the wall of the left ventricle, since

the pulmonary circulation pressure is lower than the systemic circulation pressure. This is because gas exchange occurs optimally at lower pressures in the pulmonary circulation. Aortic valve opens a little earlier than the pulmonic valve Aortic pressure on Wiggers diagram is similar to the arterial pressure During period of rapid ejection, the left ventricle and aorta have almost the same exact pressure, the reason being that the aortic valve has almost no resistance, so there is no pressure drop in aortic pressure, and the aortic pressure is the same as the left ventricular pressure After the aortic valve has closed, and the left ventricular pressure has decreased below the aortic pressure, the aortic pressure is independent of the left ventricular pressure since the two locations are isolated, and there is a recoil in the aorta which causes a slight increase in the aortic pressure called the incisura. The v wave of the left atrial pressure rises slowly during systole as the left atrium fills with blood, but as soon as the mitral valve opens when the left ventricular pressure decreases below atrial pressure, the left atrial pressure drops because the blood flows into the left ventricle which has even lower pressure. This is the rapid filling phase, and then there is a slower filling phase during the second two thirds, and the last third, there is a slight rise in left ventricular volume as the a wave of the left atrial pressure occurs as the left atrium contracts and pushes some blood into the left ventricle. However, most of the volume of blood that flows into the left ventricles is due to the rapid filling phase, which occurs passively without any contraction. The contraction of the left atrium only pushes about 25% of the blood into the left ventricle75% simply flow passively in the rapid and slow filling phase. The c wave of the left atrial pressure is due to the bulging of the mitral valve into the left atrium and increasing pressure somewhat Systole starts only when the aortic valve opensnot when the AV valves close; therefore, it starts after isovolumic contraction. However, systole starts after the AV valves have opened, not after the aortic valve has closedthat is after isovolumic relaxation has occurred. Therefore the isovolumic contraction/relaxation or after it is the start of systole/diastole respectively. Stroke volume is the difference between the end diastolic volume (after the filling phase of the ventricles), and the end systolic volume (after the ejection phase of the ventricles)therefore, it is the amount of blood that has left the heart after one cycle. That there is end systolic volume that does not equal to zero shows that the heart does not eject all of the blood in it and there is residual volume. The ejection fraction is the stroke volume/end diastolic volume, and this shows what percentage of the total blood in the heart is ejected. Normal values for ejection fraction are around 70%, but in heart problems, it can be as low as 10%. Cardiac output is the stroke volume times the heart rate, and it tells the amount of blood ejected in a minute. Stroke work is pressure times volume which is really the same thing as the force times distance. The heart sounds: S1 is AV valves, and S2 is aortic/pulmonic valves. MTAP The Wigger diagram for the right atrium, ventricle, and pulmonary artery is the same, but the maximum pressure in the right ventricle and the pulmonary artery is 30 mm Hg instead of 120 mm Hg. Order of valve opening and closing: mitral valve closes and then tricuspid closes at beginning of isovolumic contraction. Then the pulmonary valve and then the aortic valve opens (not heard) at end of the isovolumic contraction. Then at the beginning of the isovolumic relaxation, the aortic valve opens and then the pulmonary valve. At the end of isovolumic relaxation, then tricuspid opens, and then mitral valve opens. Isovolumic contraction and relaxation begins earlier and lasts longer on the right side of the heart. Preload and afterload influence stroke volume. The preload determines the length of the muscle, or the ventricular diastolic volume, and therefore determines the amount of force that will be

generated. Afterload determines the velocity of contraction. In cardiac contraction, the preload is the end diastolic pressure and the afterload is the arterial pressiure in the artery leading from the ventricle during ejection (i.e. the pulmonary artery or aorta). Left ventricular end diastolic pressure is the preload. End diastolic aortic bp can be the initial afterload. Gdds

Hemodynamics A. Physical properties of arteries and veins: always a single layer of endothelium including caps a. Veins are thinner and floppier. b. Arteries i. Aorta has a lot of elastic tissue, which allows stretching to double their resting length, and less fibrous tissue which is mainly collagen which stretches only 3% its resting length, and it limits stretching. The collagen fibers in the blood vessels are all slacked, but as the vessel gets stretched out, they become their full length and then the force or pressure of stretching will suddenly shoot up. There is less smooth muscle in aorta as well, which allows for changing the diameter, but the aorta does not need to contract a lot to get the blood moving ii. Arteries have more smooth muscle iii. Terminal arterioles have the most smooth muscle, and they increase resistance a lot c. Capillaries: only a single layer of endothelium, and are only a single layer thick, so there is not a large barrier. The greatest total resistance does not lie in the caps, but in the arterioles and terminal arterioles because they are small in diameter compared to the large arteries, but have not branched as much as the caps (decreasing parallel resistance) and their length is greater. d. Veins i. Large veins: wall thickness less than aorta, and does not have as much elastic tissue, since it does not need to absorb the pressure of the blood as much. It does have SM, but for a different reason than in arteries, which change diameter to change resistance. The vein does not change resistance, but it does change the volume of the blood in the veins through altering the diameter, and this increases or decreases the end diastolic volume, which can change the force of contraction and the CO therefore. The SM of the veins are controlled by the symp system. ii. Venules: have endothelial layer, and fibrous tissue, but no elastic and SM B. Law of Laplace: wall tension within a vesselthe capillaries can withstand such high pressures without the extensive SM because of the law of Laplace: T=Pr, where T is the wall tension, P is the pressure, and r is the radius. So capillaries have less tension in their walls because their radius is so small even though their pressure is high. In heart failure, the left ventricle dilates, and the radius of the sphere-shaped ventricle becomes larger, and the tension therefore increases even at the same pressure. The myocytes need to spend more energy to maintain the wall tension, and they are already damaged. Wall tension in the left ventricle is an important determinant of its oxygen requirements. C. Pattern of blood pressure throughout the systemic circulation: the mean pressure, the pressure waveform, and the velocity of blood flow change throughout the vascular system. This is a consequence of the dimensions (radius and length) and compliance of the different blood vessels and of the branching and rejoining of the blood vessels. a. The MAP decreases from the aorta to the large arteries, but the pulse pressure increases. WHY???? The systolic pressure in the large arteries actually increases. In addition, a pressure wave travels from the aorta in the walls of the blood vessels, 6 m/s in the aorta, and 10 m/s in the large arteries which is faster than the 1 m/s of blood flow. This is why

D.

E.

F. G.

pulse in the wrist which is a pressure wave can be felt at 0.1 s after the beat of the heart, even though the blood has not reached from the heart to the wrist, though the pressure wave has. b. Effect of gravity on blood pressures: while standing, the pressure in the arteries lower than the heart have the hydraulic pressure due to gravity (P=pgh) added, and are higher pressure. The MAP at the arteries of the feet are 183 mm Hg. So the question is that how can blood flow from an area of low pressure (left ventricle MAP of 93 mm Hg) to an area of high pressure? The answer is that the right heart acts as a feedback regulator or pressure and keeps its MAP at 0-2 mm Hg always, whether standing or recumbent. The pressure flow depends on the ENTIRE systemic circuit, which is from the left heart to the right heart, and can therefore go from 93 -2 mm Hg. Distribution of blood throughout the systemic circulationconsequence of larger compliance of veins than arteries: veins are 18 times more compliant than arteries. Arteries have greater content of elastic tissues, thicker wallas and more collagen. A certain volume of blood will cause the artery greater pressure than the vein. If you look at the P-V curve for veins, the pressure increases very slowly for each amount of volume added, but then it suddenly rises. This is because veins are usually floppy, and therefore once they are filled completely, their compliance increases, whereas arteries are always filled. Sympathetic stimulation or inhibition pushes the P-V curve, so that it changes the volume of blood that the vein can hold. With symp stimulation, the vein holds less blood. It does not change the slope, or compliance of the blood vessels. Note that the artery curve is also shifted, but bc the arteries do not hold as much blood at rest as the veins, symp has little effect on them. Arterial system as a hydraulic filter: consequences for cardiac work a. Bc of the elastic nature of the arteries, their compliance stores some of the stroke volume and their elastic recoil provides more continuous capillary flow throughout diastole b. The consequence of this is that the rate of the blood pressure change is slower???? c. Compliant arteries reduce the cardiac workinfinetly compliant which takes no increase of pressure for a change in volume vs completely rigid where the flow becomes pulsatile. In infinitely compliant, the work is less than the rigid tube, and this happens in real life where more oxygen is used when a rigid aorta is used Aging on arterial compliance: arteries become more rigid, and more work is required Determinants of pulse pressure: a larger stroke volume increases the pulse pressure and the MAP. Decreased arterial compliance increases pulse pressure but the MAP stays the same. This is because low compliance accentuates the waveform

Cardiac Electrophysiology Excitable structures of the heart include the SA, AV nodes, and the atria and ventricles, and the Purkinje fibers. AP are of two types: 1. Fast response which occur in the ventricular and atrial myocytes and Purkinje fibers. They have: a. More negative resting potentials b. Faster upstrokes c. Larger amplitudes in the rapid upstroke 2. Slow responses occur in the SA and AV nodes: a. More positive resting potentials because of leaky Na channels b. Increasing resting potential that is not really resting: pacemaker depolarization; this is because of an inward flow of Na through the IF channels which is continusouly depolarizing. Once it reaches threshold, the Ca channels open and slow depolarization occurs. c. Slow upstroke

d. Slower deactivationpostrepolarization refractoriness which means that there is recfractoriness even after complete repolarization. The rapid depolarization of a myocyte precedes the force generated in a twitchwhen the repolarization has been completed, that is when the force is at its maximum. The duration of the contraction lasts just as long as the APjust shifted later in time. IF is a channel that is permeable to Na, Ca, and K, and the resting potential is -37 mV. At rest, the K EK is closest and plays the largest role. The specific K channel through which K passes during rest is a voltage regulated channel called iK1 which is an inwardly rectifying K channel. These channels are not open during the depolarization phase. To test which ion is controlling the Vm the closest, alter the ions concentration and calculate the Ex of that ion, and if it is close to the Vm at most [x], except when [x] is small, then that ion is largely controlling the Vm. With this, we can see that EK is controlling the Vm at rest and ENa is controlling the peak potential but not at rest. Chord conductance: another way of calculating Vm: take the ratio of the conductance of each ion gX and divide it with the sum of the conductances of all the ions and multiply with the Ex and add all these up.

Currents that shape the ventricular AP 1. Depolarizing a. INa: found only in the atria, ventricles, and Purkinje fibersNOT found in SA, AV b. ICa,L c. IF: found only in the SA and AV, and PurkinjeNOT in atria or ventricles; important in pacemaker depolarizations and Purkinje fibers 2. Repolarizing a. IK1: the inward rectifying K channel that activates when almost completely repolarized or at rest. It activates during the resting phase, but the current is low bc at rest, the Vm is close to Ek; it remains open during phase 1 and 2, and it maintains the plateau, even with the Ca channels open. At such a depolarized state, the K current would be high, but the gK1 is low at high volatages, so this prevents excessive loss of K during the prolonged plateau. If the Ca channels are blocked by diltiazem, then the plateau phase and the amplitude of depolarization is smaller. b. Ito,1 and Ito,2: both activate quickly right after the rapid upstroke, and cause the small notch of repolarization before the Ca channels open and cause the plateau; TO= transient outward current c. IKr and IKs: activate more slowly during the plateau: delayed rectifier K currents; hERG channel belongs to this type; these and the I to currents are stronger in atrial cells, so the atrial AP curve has a faster repolarizing and less steady plateau than the V AP. Reducing the INa by blocking the Na channels by TTX reduces the rapid upstroke, and the AP is no longer fast, bc only Ca is acting, which is slow. Blocking the Ca channels with diltiazem reduces the plateau phase of the cardiac AP, and because the Ca is needed for the Ca induced Ca release and for the contraction as well, it also reduces the isometric contraction force. Blocking the IKr makes the AP longer in duration. If the myocyte is stimulated too fast during the relative refractory period, then the AP upstroke will be slower, since not all of the Na channels will have deactivated. Pacemaker activity of the heart: 1. Primary pacemaker: SA node60 beats/min 2. Secondary pacemakers: AV node40 beats/min, and Purkinje fibers: 20 beats/min

AP propagation is slower when there is less inward current. This can happen when (1) there are fewer Na channels activated (V or A muscle) through channel blocking, or (2) there are fewer Ca channels activated, or (3) the threshold for the regenerative AP is more positive. Inactivating the Na channels can be done by sustained depolarization (not at threshold) through elevation of [K]e, and that makes the upstroke slower, and the amplitude of the AP reduced, and the conduction velocity reduced, since it is proportional to change in voltage. Fastest AP conduction velocity is in Purkinje fibers, bc they have the most Na and Ca channels. V and A muscle is fast too, but not as fast. SA and AV nodes are the slowest since they have not Na channels, and only slow Ca channels. NE and Epi act on beta adrenergic receptors to increase the strength of contraction in A and contractility in V. Cholinergic agonists like ACh have no effect on A and V muscle. The way that catecholamines such as NE and synthetic isoproterenol increase strength of contraction and contractility is by interacting with the beta-adrenergic receptors and activating adenylyl cyclase to cAMP to PKA which Ps the L-type Ca channels to make a larger Ca transient current. It does not affect T-type Ca channels as much. Cycle length: if the duration between APs is decreased, the duration of the AP itself will also decrease a little, and this is because the IK channels will not inactivate as much, and cause repolarization faster. Electrocardiogram The SA node is not represented on the surface tracing, since the depolarization amplitude is too small to register on the surface. In addition, there is a U wave which may the repolarization of the Purkinje fibers. The first half of the P wave is right atrial depolarization, and the second half is the left atrial depolarization Normally, the AV node is the only connection between the atria and the ventricles, and if there is more than one connection, then Wolff Parkinson syndrome (how to tell on an ECG??) and bypass tract exists The His Purkinje system fans out and spreads into two fascicles and it is the electrical highway of the heart, since it allows for very fast conduction velocities. It allows the heart to start contracting from the apex and bottom of the heart towards the pulmonary artery and aorta, so that blood can be pushed out. If the His Purkinje system is messed up, the QRS wave will be fat QRS complex: first positive deflection is the R wave; the first negative deflection is the Q wave; the first negative deflection after the R wave is the S wave Delta wave where the QRS complex does not take off at a 90 degree angle, and there is a hump at the base which is a delta wave Normal HR: 60-100; lower than 60 is bradychardia; higher than 100 is tachychardia The PR interval is the time from the beginning of atrial depolarization to the beginning of ventricular depolarization; normal values are from 120-200 ms QRS interval is the time from the beginning of ventricular depolarization to the end of ventricular depolarization; should be between 80-120 ms QT interval is the time from the beginning of ventricular depolarization to the end of ventricular repolarization; it varies a lot with heart rate, and so QTc is the QT/sqrt(RR interval), and normally should be around 450 ms. QRS axis should be in adults between -30 and 90. In adolescents, up to 100 is normal. If axis is less than -30, left axis deviation; if more than 90, right axis deviation. If between 180 and -90, there is a right superior axisbizarre

Many, many more P waves that QRS waves (not just 2:1 like second degree block, or something like that) is atrial flutter Atrial fibrillation: P waves are just noise, and not regular and consistent Ventricular tachychardia: more Vs than As

Cardiac Arrhythmias: 1. Regulation of pacemaking: change heart rate by increased symp activity (epi and NE) which makes a faster pacemaker by activating B-adrenergic receptor which (1) increases Ca current and (2) increases IF which leads to depolarization in SA and AV nodal cells (recall that the Beta adrenergic affect on A and V cells is to increase contractility force, so it acts on both SA, AV, A and V). Such an increased inward current produces (1) a more rapid depolarization, and (2) a more negative threshold for regenerative AP. The epi and NE bind to the B-adrenergic receptors which is bound to Gs proteins whose alpha subunit binds to andenylyl cyclase which makes cAMP which binds directly to If or the PKA which Ps ICa. The ACh binds to the muscarinic receptor which stimulates Gs and uses the beta subunit to bind to IK ACh and allow K to pass out to repolarize. The muscarinic receptor can also bind to Gi which inhibits adenylyl cyclase. Cholinergic agonists thus reduce the conduction velocity and spontaneous rate of the SA and AV nodes, but HAVE LITTLE effect on the A and V cells. Increased parasymp activity results in a slower pacemaker through activation of muscarinic receptors which decreases the Ca current and decreases IF which leads to a less rapid depolarization through hyperpolarization of SA and AV nodal cells and requires also a more positive threshold for regenerative AP. ACh also activates a hyperpolarizing K current, the ACh activated K current, which causes hyperpolarization 2. Cellular mechanisms of arrhythmia: reentry. An arrhythmia is any cardiac rhythm other than a normal sinus rhythm. Two types: a. Conduction abnormalities: AV block i. First degree heart block: abnormal prolongation of the P to R interval >200 ms. Normal 120-200 ms. ii. Second degree heart block: inconsistent conduction of atrial impulse to ventricles, so there are 2 atrial APs to 1 ventricular APtwo P waves to every QRS complex iii. Third degree heart block: complete dissociation between the P waves and the QRS complex, and there is no regular relationship like 1:1 or 1:2 of P waves to QRS complexes, and that means that there is complete absence of AV conduction; usually fatal, and a distal pacemaker emerges???? The mechanism of an arrhythmia is a unidirectional entry. There can be other types of blocks, such as a complete block, or a bidirectional block, which dont cause any problem, but a unidirectional block has a AP blocked through one way, but not through the other, and this means that they cannot cancel each other out as in a normal loop, but neither is there a complete block (dead cells, or inactivation during refractory period), so that the effective refractory period of the reentered region must be less than the propagation time around the loop, other wise it will just be a bidirectional block. The loop can keep going around, and twitching without any concerted manner. One mechanism for unidirectional block is that there is adequate current to discharge the membrane capacitance during one way of traveling, but inadequate ionic current to discharge the membrane capacitance through the other direction because the cells are dead or some other problem. Another problem that can happen is the Wolfe-Parkinson White Syndrome where there is a bypass tract in either the atria or ventricles or both, where the SA node can conduct, bypassing the AV node. This results in a delta wave on the ECG, and this is not necessarily deadly, but the loop can keep going around and cause disconcerted twitching. b. Altered automaticity: problems in the SA node or AV node

i. Elongated P-P interval is tachycardia which means a fast beat, and slow P-P interval is bradychardia ii. Premature depolarizations: premature atrial depolarization has the 2nd P wave early, and premature ventricular depolarization has the second QRS complex early iii. Triggered activity 1. Early Afterdepolarizations (EADs): occur when the HR is slow, and the AP is prolonged; the afterdepolarization occurs just at the end of the plateau just before repolarization, or halfway during repolarization, and it occurs because the Ca channels reactivate during the elongated plateau which occurs because the K channels did not activate on time and another depolarization can occur because the reactivation. This leads to a run of spontaneous beats since the Na channels are inactivated bc of the depolarization (K channels did not open) 2. Delayed Afterdepolarization (DAD): occur when the HR is high, and are associated with elevated [Ca]i from elevated [Ca]e so that the [Ca]i can start CaICR and start another depolarization 3. Ion channel mutations in arrhythmias 4. Drug induced acquired arrhythmias Regulation of the Heartbeat Cardiac output= (HR)(SV), and heart rate is controlled by the nervous system (sympathetic and para) and hormonal (epi from the adrenal medulla), and the stroke volume is controlled by myocardial contractility and preload which increase stroke volume, and afterload which decreases stroke volume. A change in heart rate is a major method of regulating CO. SV can usually increase only by fifty percent, but HR can increase by 3-fold. Thus CO can increase 4-5 fold. So HR is the major mechanism of control of CO Sympathetic and parasympathetic efferent activity that controls the heart is controlled in the medulla. Afferent inputs also go to the medulla and include high and low pressure receptors in the carotid sinus and aortic arch and the medulla also receives afferent fibers from venoatrial stretch receptors. Effects of Beta adrenergic receptor stimulation on EC coupling: NE and epi activate the badrenergic receptor, activate adenylyl cyclase, then cAMP is produced, which activates PKA and phosphorylates the Ca channels to allow Ca into the myocyte and increase the Ca transient, Ps phospholamban which inhibits SERCA, so it can no longer inhibit and SERCA can pump more Ca into the SR, and Ps troponin so that it prevents binding of Ca to troponin Ccounterintuitive, but this allows troponin C to detach from Ca faster so that the heart can relax faster and beat fasterHR goes up this way and there is faster contractility, and even though there is a reduction in affinity of troponin C fo Ca, the increased Ca transient increases [Ca] so much that there is more Ca binding despite the decreased affinity, and the relaxation is faster too. Cardiac plexus contains both symp and parasympathetic efferent fibers to the heart. when we are not active, the vagal and parasymp controls the heart mainly. Propranolol which is a beta receptor blocker and blocks sympathetic activity, and atropine which is a muscarinic blocker and inhibits parasympathetic activity is given to a basal heart rate one after another. The atropine has a stronger effect, and increases the heart rate significantly in the basal state, and without continuous ACh release from vagal nerve endings on the SA node, the heart rate will be much higher. The propranolol does not have such a strong action

parasympathetic effects on HR are rapid and short lived. If parasymp stimulation occurs, it immediately causes a decrease in HR, and when the stimulation is stopped, the heart rate goes back up immediately, and controls HR rapidly. Sympathetic stimulation causes a slow and longer lasting effect when stimulated, and when let go, the heart rate does not decrease immediately. The reason for this is that sympathetic activity depends on intracellular production of cAMP in the SA node, which is a slow process. Parasymp involves direct activation of muscarinic receptors that respond to ACh and are direcly coupled to K channels by a G protein. This direct coupling allows a prompt response. Also, the postganglionic nerve ending of the vagus releases a lot of ACh to arrest the heartbeat, but the symp innervation releases very little NE. In addition, the SA and AV nodes are rich in cholinesterase so it rapidly hydrolyzes the ACh. vagal predominance is mediated by suppressing NE releaseso this shows that when para and symp stimulation is going on at the same time, vagal dominates, since it suppresses the NE release. G alpha beta gamma proteins, and IK channels??? The vagal dominates in another way: both sympathetic and parasymp nerves innervate each other, but the parasymp innervates the symp at the presynaptic terminal and prevents release of the NE. Carotid sinus baroreceptors: sensory components of cardiovascular reflexes that control HR: carotid sinus nerve firing inhibits sympathetic outflow from CNS. When pressure is at low, there is no carotid sinus firing except when the aortic pressure is about to increase, but when the pressure becomes high, the carotid sinus nerves fire more frequently, inhibiting sympathetic activity. HR is regulated via the baroreceptor reflex: as the MAP increases, the HR decreased. This happened bc at higher MAPs, the sympathetic activity was decreased bc the vagal activity was increased. The Bainbridge reflex increases HR as a result of increased right atrial pressure which is sensed by distention of venoatrial stretc receptors that send impulses to the SA node and increase the heart rate. The atrial tissue also responds to stretch by secreting atrial natriuretic peptide (ANP) which is a diuretic and promotes water and sodium excretion and dilates the capacitance vessels (i.e. veins) both of which decrease the atrial pressure. This increased pressure can come as a result of intravenous infusion. However, IV fusion which increases the right atrial pressure can also increase the CO or stroke volume since it is a large preload (Frank Starling), which increases arterial pressure (graphs on page 99 of concepts), and activates the baroreceptor reflex which decreases the HR, and so the effect of the IV fusion is not necessarily clear. The effect of blood transfusion and bleeding on CO is confusing bc the effect on SV and HR is not obvious: when there is volume depletion, the SV decreases, obiously since there is no blood to pump. When blood is loaded, there is an increase of SV to an extent, then it stays steady, since the SV of the heart can only reach a certain maximum. When there is blood depletion, there is a decrease in pressure, to which the BARORECEPTOR reflex responds more strongly, and it stops firing, which allows the symp activity to resume and increase the HR. when blood loading occurs, the BAINBRIDGE reflex dominates, and increases HR as wellso a decrease or increase in blood both lead to an increase in HR. Since CO=(HR)(SV), and the SV decreases more than the HR increases when there is blood loss, there is a net CO decrease during blood loss. During blood increase, SV rises a little, but HR increases a lot, so there is net increase in CO. Respiratory sinus dysrhythmia: HR increases during inspiration, and decreases during expiration. Activity during contraction of diaphragm and inspiration increases sympathetic nerve activity. The vagus nerve is active only when the phrenic nerve of the diaphragm is not firing, so during relaxation or exhalation of the diaphragm. This is controlled by the stretch receptors in the lungs, the Bainbridge reflex, and the baroreceptors in the carotid sinus and aortic arch 4 factors control CO: HR, already discussed, and preload and myocardial contractility, which increases SV and therefore CO, and afterload which decreases SV and CO.

Preload: classical experiment by Frank Starling: in an isolated heart, increasing the right atrial pressure (preload) causes an increase in SV. This demonstrates the length dependence of cardiac contraction. The cellular mechanism of the Franks-Starling length dependence are three: one like skeletal muscle, where cardiac muscle length increases, the active tension increases because of more actin-myosin overlap. But unique to cardiac muscle: 1) Ca transient increases as muscle is lengthened, and 2) the affinity of troponin C for Ca increases as you go up the length tension curve. The length tension active curve increases with increased contractility (comes from NE, Epi, digitalis), decreases with decreased contractility (Ca channel blockers or myocardial damage); the passive curve does not change. The slope of the curve of the ascending part of the curve increases with the increased contractilitythat is the end systolic pressure volume relation (ESPVR) or the contractility index which means that at a higher contractility, the muscle will generate a higher force for a given length. The P-V loop occurs within the limits of the length tension curve. Cardiac function curve: shows relationship between preload, afterload, and contractility with SV or CO: increased preload affects end diastolic volume, which increases SV; does not affect afterload, or contractility, and demonstrates Frank-Starling dependence. However, as the preload goes up, the SV starts increasing less until there is no increase. NE increases the SV at all preloads. The function curves are different for the preload of the left ventricle and the RV: the RV curve is higher than the LV, and this means it is stronger and can have a larger cardiac output (generate more force) at a given atrial pressure. However, because the right and left ventricles are in series and a loop, the output of the right ventricle must be the venous return to the LV, and bc the right side is stronger, and equivalent SV would mean an increased left atrial pressure than the right atrial pressure, and this is what we see. Cardiac function curve: afterload: an increased afterload at a given preload decreases SV, since the ejection rate is slower, and therefore, it cannot squeeze as strongly, and therefore wont squeeze as much blood out. The afterload is larger, so the muscle has to go to a higher pressure to pump the blood out, and it has less force left for the pumping. Contractility: performance of the heart at a given preload or afterloadincreases with NE and other drugs, increasing the slope of dP/dt. Increase in contractility (positive iontropic effect) produces an increase in force and velocity, and a hypodynamic heart has less contractility and increased end diastolic pressure, whereas a hyperdynamic heart has reduced end diastolic pressure. An increase in contractility increases SV since the cardiac function curve will go to the higher slope and can generate more force for a given length or volume, and the end systolic volume will be lower. Decreased ventricular compliance can also decrease CO An increase in HR also affects the contractility of the heart as well (contractility increases SV as well for double effect) because of (1) at each contraction there is a depolarization, and with a more frequent AP, there is an increase in the amount of Ca transient, and (2) each depolarization makes the next Ca current stronger and slower to inactivate which also increases the amount of Ca. When a premature systole occurls (extrasystole), the next beat after the subsequent pause is very strong, since the inadequate ventricular filling before the extrasystole will be followed by more filling with the Frank-Starling effect; also, the premature beat occurs early, so there was not enough time for SERCA to refill the Ca back to very high levels, and not enough Ca can be released from the SR. in the postextrasystolic contraction, there has been enough time for the SR to be filled, so the mechanism is not just Frank-Starling

Heart failure

Classical symptoms of heart failure: shortness of breath (pulmonary congestion) from bad doctors, exercise intolerance, peripheral edema, and weak pulse (tachycardia) Contractility (inotropy) is increased by increased B adrenergic receptor stimulation: it starts by firing of the cardiac sympathetic nerves, resulting in more NE release, which binds to the B receptors on the cardiomyocytes, and through a Gs protein, increases cAMP, which icreases the Ca transient (rate and total amount), which results in a greater force and velocity of contraction of the LV. Clinically, contractility is increased with a Beta adrenergic agonist such as dobutamine or a phosphodiesterase inhibitor that decreases cAMP breakdown such as sildenafil Inhibition of tonic B-adrenergic stimulation can be caused by Beta adrenergic antagonists or Beta blockers, or congenital adrenergic dysfunction (neuropathies or defects in NE synthesis) though these are rare. Clinically contractility is decreased by inhibiting the Ca transient using Ca channel blockers such as diltiazem The ejection fraction is not affected that much by preload changes, since the increased or decreased SV will also come with a concomitant change in EDV. However, contractility changes will alter the ejection fraction a lot. Four things affect the afterload: arterial compliance (if they are very compliant, they will take in the SV blood with ease and little pressure, and the afterload pressure will not be much), SV (if there is a lot of blood being ejected into the arteries, that will increase the afterload), contractililty (if the LV is strong, it will pump a lot of blood, and the SV will be high, which will increase the afterload), and peripheral resistance (less important) If the afterload is high, the LV will have to spend more of its force meeting the afterload force, and less on ejection, so ejection will be slow, and the SV will be less Old geezers and people with heart failure have low SV. Why? Analyze the four things that affect SV: their preload is normal or a little high (their LV has become enlarged bc of pumping so hard, but the increase in preload is little compared to other problems), their afterload is probably the same (assuming no occlusion of aorta), their contractility is normal or weak (even though they have a lot of symp stimulation as we will see), but their LV compliance is VERY low, and that is the major problem. So their SV is very low. Therefore, these people have high HR to compensate for their low SV to maintain their CO which is usually normal or a little low (if even the high HR cannot compensate enough). HR is high because of a lot of symp stimulation. There are two types of heart failure: one in which the ejection fraction decreases a lot. This is because the EDV is so high because the LV has swollen up (cardiac hypertrophy) so high, not because there is a high preload, but over time it has become large. The SV is a little less or normal, but bc the ejection fraction= SV/EDV, it is very low, since EDV is so high, even if SV is normal. They are also characterized by decreased LV contractility (systolic dysfunction) which is why the SV might be less, decreased LV compliance (diastole dysfunction) as well. The low SV is compensated by HR. The other type of heart failure is with relatively normal ejection fraction, and this is bc the EDV is usually around the same as normal. The difference is that they have decreased compliance (diastole dysfunction), though usually they have normal or slightly decreased contractility (so normal or slightly decreased SV), but no increase in EDV, so normal ejection fraction (or a little low). Inevitably in heart failure, the CO will drop somewhat. Therefore, to keep the MAP normal, the body increases the TPR (CVP is the same or increased). This is called the Pressor response so that when MAP changes, it is sensed by arterial baroreceptors, and symp activation and RAS happens, which triggers an increase in TPR and HR as well. The SM of the vasculature is affected immediately, but the RAS happens slowly in hours.

Treatment of heart failure: digoxin (not used much anymore), diuretics (to remove fluid from system and lower bp), inotropic drugs (beta adrenergic agonists)can only be used in acute cases since with chronic use the patient dies, angiotensin converting enzyme inhibitors (blocks the RAS to decrease fluid uptake), beta blockers, and heart transplantation.

Short term blood pressure Control Only systolic bp rises significantly with age. Diastolic stays the same (usually with exercise too, since the CO needs to increase to provide enough O2, so the HR increases a lot, but so does the SV, and therefore, when SV increases, the pulse pressure and MAP both increase, so the diastolic stays the same, but systolic increases) Risk of stroke increases significantly for geezers even with normal bps Decline in bp occurs through standing up, blood loss, dehydration, vascular collapse, and left ventricular heart failure Gain: change in bp after homeostatic system is activated/bp before system was activated

Three most powerful systems in short term BP control: A. Baroreceptors: can also be externally activated by increasing carotid sinus pressure which slows the heart (vagal stimulation) and dilation of peripheral vasculature B. Chemoreceptors: carotid bodies that sense pH, pO2, pCO2. Made up of glomus cells which release ACh, ATP, and dopamine which activate synapsed neurons leading to the respiratory center. Activate respiration during hypoxia C. CNS ischemic responseonly one to influcne BP significantly in the long term; a sudden fall of blood to the brain activates the vasomotor center which increases sympathetic response so that the peripheral arteries are occluded somewhat and totally in some extreme cases. Cushings reflex is a variant of the CNS ischemic response where an increases in intracerbroventricular pressure causes compression of cerebral arteries which reduces blood to the brain, so that this reflex is activated which increases arterial pressure unitl it exceeds the intracranial pressure so that blood flow to the brain is restored. Pressure sensors are in carotid sinus and aortic arch and are actually stretch sensorchanges in bo cause changes in transmural diameter and the sensors generate electrical sensors that are converyed to the CNS. A. Arterial baroreceptors a. Carotid sinus receptors: located at bifurcation of carotid arteries. Maximal sensitivity correxponds to normal bp in an individual. Lasts only short term, and if there is a maintained change in bp that occurs for more than a few days, the carotid sinus baropreceptors preogressively reset the set point of maximal sensitivy to the new prevailing bp b. Aortic arch baroreceptors: located in the aortic arch, and exert their maximal effect at 2030 mm Hg above normal physiological level; important only in high bp c. Cardiac mechanoreceptors: measure the stretch of the venoatrial tissue which reflects the CVP, and activation of these atrial stretch receptors inhibits secretion of renin by kidney. Atrial receptors also influence HR (Bainbridge reflex) esp in heart failure B. Integration of sensory information a. Electrical information from baroreceptors travels to nucleus tractus solitarius (NTS) in the medulla of the brain. The NTS has axon projections that control three parts: i. Cardioinhibitor with vagal response

ii. Vasoconstrictor that connects to sympathetic chain system and postganglionics go to the vasculature and heart iii. Vasodilator which is not as important in humans for CVS, but important for urogenital b. Low bp causes fewer sensory impulses from the carotid sinus baroreceptors to the NTS, so that the NTS is freed to pursue its sympathetic ambitions. It decreases vagal impulses to the heart, and increases its symp to the heart, increasing contractility and HR, and sends symp to the vasculature causing increased TPR (which increases MAP), and decreasing ventricular compliance so that more blood can be sent to the right atrium, increasing preload, and therefore SV, which increases CO, which increases MAP. The change in myocardial cells is almost immeadiate (beat to beat), but the change in vasculature takes a few seconds C. Venous circulation can be affected by the abdominal reflex where ab tone contracts the venous beds in the abdomen increasing venous return. Exercising skeletal muscle does the same compression D. Respiration and arterial pressure: physical process of inspiration increases negative intrathoracic pressure which causes expansion of venous vessels in the chest cavity and reduces pulmonary capillary pressure and diminishes venour return ot the left atrium and lpwers cardiac output. This process is reversed during exhalation The renin angiotensin system affects (1) thirst, (2) brain to produce vasopressin, (3) adrenal cortex to produce aldosterone, (4) blood vessels to constrict. RAS does not have infinite gain. Renin secretion is inversely related to salt intake, and secretion increases when bp falls below normal. ANP system causes (1) vasodilation, (2) adrenal cortex to stop making aldosterone, (3) kidneys to get rid water and Naall when bp increases. Long term pressure and volume control The long term control of bp is through the kidneys and has infinite gain. It is orientateds maintenance of normal volume at the expense of blood pressure. The renal-body fluid system shows that if there is a high bp and the more output there will be. At this point, the output curve will be higher than the input curve, so there will be net excretionthis will continue until they are equal, and equilibrium is reached. The only way of changing the equilibrium bp level is to alter the salt input curve or to alter the output curve (alter the character of the kidneys themselves). In reality, increasing salt intake does not change bp as much bc of the RAS. This alteration of the physical characteristics of the kidney are done by renin, which shifts the output curve to the right, to higher pressures. An increase in body fluid causes an increase in blood volume, which primarily affects the capacitance vessels (i.e. the veins), so the CVP increases, which increases the preload on the heart, and the CO increases. The increase in CO causes a direct increase in MAP, but mainly through an indirect method called autoregulation, where each tissue starts constricting its vessels to decrease the amount of blood flow since there is increased CO. If volume is added over a lot of time to a body, that will increase the blood volume, ECF, and therefore the CO and therefore the MAP immediately. The TPR will actually decrease initially due to the baroreceptor reflex. By this time, the increased MAP will have reduced so much of the cap pressure that there will be absorption in the caps, and ECF will decrease. In addition the excess bp pushes the excess fluid out of the body. However, by this time, the increased CO is increasing TPR through autoregulation. Therefore, even though the CO starts going down as blood volume and ECF goes down, the TPR goes up, and maintains the new arterial pressure. The TPR will not reset since the baroreceptors have reset this as the new point. It is important to note that the increased bp is not a result of

the increase in TPR, since the high bp was a result of the CO autoregulation, though the TPR maintains it later on once the CO declines. The renal body-fluid curve does not always work perfectly because excretion of salt is not as easy, so the body cannot return to the equilibrium point as easily. Therefore, the excess salt content in the body causes accumulation of extracellular fluid as well to keep the oslolality of the body fluid constant (high osmolality triggers the thirst center and triggers the release of ADH from the posterior pituitary since it infers that high osmolality means a low ECF in the body). Two types of essential hypertension: salt sensitive and non-salt sensitive. Check by altering the [salt]. The RAS system works primarily by (1) constricting the arterioles around the body, increasing TPR, and (2) causing the kidneys to uptake more water and salt. This second method is done by direct action on the tubules of the kidney (constricting the tubules allows less fluid to go through for excretion, and reduces the pressure there causing less excretion), and through the effect on the zona glomerulosa of the adrenal cortex secreting aldosterone. The second method is more well-known, but the direct method on the kidneys seems to be more important. The main importance of the RAS is that the salt intake of the modern man can be high without causing extreme changes in the bp through shifts of the renal-body fluid curve depending on the amount of renin in the body. The goldblatt hypertension where the renal artery is occluded causes an initial increase in renin, increasing the peripheral bp until the renal artery pressure is normal. Microcirculation Shunts provide a direct path from the artery side to the venous side, esp in skin to control temp, so they are controlled by nerves. If there is a bee sting, the oncotic pressure of the capillary will go down, and the oncotic pressure of the interstitial fluid will go up since bees make the membrane permeable to proteins and other substances. Therefore, there will be more filtration, and edema Renal failure will cause increased capillary pressure since there will be fluid accumulation in the body, for increased filtration as well Liver disease will cause decreased capillary oncotic pressure, and therefore, more filtration In lung failure, there will also be increased capillary hydraulic pressure like in renal failure for increased filtration Kidneys normally have high rates of filtration, and that is normal

Integration Cardiovascualar Vascular function curve in exercise: the mean circulatory pressure increases, and the TPR decreases during exercise; the increase in venous tone happens because of venous constriction and the skeletal muscle pump are the two main reasons. The reason that there is increased venous tone is increases symp activity. The increased sympathetic response is coming from the baroreceptor response which is decreasing its inhibition of symp and allowing it due to decrease in TPR and therefore MAP, to push it back up. The changed slope is a decrease in TPR because of arteriolar dilation trhough metabolic vasodilation of the skeletal arteries. Cardiac function curve in exercise: increased CO at a given filling pressure, and that is through increased HR and contractility. Increased contractility causes increased SV, and this causes decreased ESV, not larger EDV. This is good energetically for the heart because of the Law of Laplace because if the EDV

increased a lot, the wall tension would increase. The cellular mechanisms of increased contractility is 1) beta adrenergic receptors through NE which increased Cu current, 2) phosphorylate phospholamban which inhibits the SERCA pump in its unphosphorylated state which causes faster Ca pumping, and 3) causing decreased affinity of troponin C to Ca MISSED SOMETHING. The mechanisms for the Frank Starling is different: 1) INCREASE in affinity of troponin Cwhich means the contraction of Frank Starling will be much larger, but not faster and briefer like contractility increase, 2) increase in Ca transient, and 3) actin myosin overlap. The intersection of the two curves is called the operating point and balances ithe two curves. Any other point does not satisfy both the cardiac function curve and the vascular function curve. Perturbation of the curve can be caused by change in volume, for example. Cannot tell whether the MAP has increased in this particular case, since there is an increase in CO but a decrease in TPR (if there was an increase in both, there would definitely be an increase in MAP), but usually for a person, the MAP does indeed increase with exercise. When volume is added for a prolonged period, there is an increase in MAP, and the baroreceptor reflex kicks in to decreae TPR, but after the persistent MAP increase, the baroreceptor reflex shuts off, and the TPR increasesnow because of autoregulation due to increased CO. Dry patients are not salt sensitive and wet patients are salt sensitive. With Pressor response, unlike exercise, there is an increase in TPR Blocking Ca channel will inhibit the myogenic response, and that means that the pressure causes some sort of Ca channel activation. Cholinergic causes vasodilation or does it increase in sweat gland Flight and fight on B1 on the heart to increase HR and contractility (circulating epi or agonist such as isoproteronal) and B2 on the vasculature.

Integrated GI No extrinsinc or vagus or symp in MMC; motilin starts, ends at ileum. At this time, the colon is absorbing water through Na channels, and electroyltes. Water is following passively. Mixing contractions are happening in the ascending, and the transverse colon has mixed and hastration migrations. Feeding interrupts MMC by vagal input. Ghrelin triggers hunger. Cephalic phase tells through vagovagal efferents, and salivary secretion increases. As rate increases, the osmolarity starts increasing, but it never reaches the osmolarity of the plasma. The thought of eating also triggers a little acid release, but a little. The fundus of the stomach relaxes via the vagus, and the antrum releases gastrin through vagal which also increases acid. Gastrin and ACh also causes some bicarbonate secretion. Sphincter of Oddi via liver???? Missed something. Once we eat, gastric phase starts, and gastrin starts going crazy. The food starts entering and the vagal allows distention without increase in pressure, but eventually the vagus starts to contract the upper stomach. We talk of the vagus controlling stuff, but it is doing it through the ENS; note that vagus is relaxing first the fundus, and then contracting it that is slow and sustained into the antrum. Here there are D and G cells. Pancreas releases bicarb through Cl- exchange, and if CFTR is damagedpancreatitis through cystic fibrosis.

Bile salt production, recycling, and bile acid dependent/bile acid independent????? Vagus knows where the meal is, so is involved in the ileal brake. Beginning of cephalic phase the vagus warns the colon that food is about to come. So at that point, the mixed contractions become haustration contractions. Role of sympathetics: allow blood flow through shutting off so that blood can go to the abdomenso they are quiet during the meal. They are involved in inflammation, pain, and pathophysiology, but also salivary salivation, which is mainly para, but some symp though it is transient, viscous, and small volume. Incretins are being released in the upper portion of the SI and the lower portion. They also increase beta cell proliferation, synthesis. Longitudinal muscle also has phasic contractions, but it does not have the same coupling as the circular muscle.

Electrocardiogram The SA node is not represented on the surface tracing, since the depolarization amplitude is too small to register on the surface. In addition, there is a U wave which may the repolarization of the Purkinje fibers. The first half of the P wave is right atrial depolarization, and the second half is the left atrial depolarization Normally, the AV node is the only connection between the atria and the ventricles, and if there is more than one connection, then Wolff Parkinson syndrome (how to tell on an ECG??) and bypass tract exists The His Purkinje system fans out and spreads into two fascicles and it is the electrical highway of the heart, since it allows for very fast conduction velocities. It allows the heart to start contracting from the apex and bottom of the heart towards the pulmonary artery and aorta, so that blood can be pushed out. If the His Purkinje system is messed up, the QRS wave will be fat QRS complex: first positive deflection is the R wave; the first negative deflection is the Q wave; the first negative deflection after the R wave is the S wave Delta wave where the QRS complex does not take off at a 90 degree angle, and there is a hump at the base which is a delta wave Normal HR: 60-100; lower than 60 is bradychardia; higher than 100 is tachychardia The PR interval is the time from the beginning of atrial depolarization to the beginning of ventricular depolarization; normal values are from 120-200 ms QRS interval is the time from the beginning of ventricular depolarization to the end of ventricular depolarization; should be between 80-120 ms QT interval is the time from the beginning of ventricular depolarization to the end of ventricular repolarization; it varies a lot with heart rate, and so QTc is the QT/sqrt(RR interval), and normally should be around 450 ms. QRS axis should be in adults between -30 and 90. In adolescents, up to 100 is normal. If axis is less than -30, left axis deviation; if more than 90, right axis deviation. If between 180 and -90, there is a right superior axisbizarre Many, many more P waves that QRS waves (not just 2:1 like second degree block, or something like that) is atrial flutter Atrial fibrillation: P waves are just noise, and not regular and consistent Ventricular tachychardia: more Vs than As