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Describe the structure and functional significance of the excitatory, conductive and contractile elements of the heart

(Structure see next question)

Functional significance of excitatory & conductive elements:

Functional significance of contractile elements:

describe the anatomy of the heart and pericardium

Size.—The heart, in the adult, measures about 12 cm. in length, 8 to 9 cm. in breadth at the broadest part, and 6 cm. in thickness. Its weight, in the male, varies from 280 to 340 grams; in the female, from 230 to 280 grams. The heart continues to increase in weight and size up to an advanced period of life; this increase is more marked in men than in women.

Cardiac Chambers

Right atrium

The SVC & IVC open into the posterior wall. The coronary sinus drains coronary venous blood into the anteroinferior portion. The thebesian valve is located at the orifice of the coronary sinus. On the medial wall, the limbus of the fossa ovalis circumscribes the septum primum of the fossa ovalis anteriorly, posteriorly, and superiorly. The right auricle is separated from the right atrium internally, by a vertical crest ie, the crista terminalis. The crista terminalis separates the right atrium into trabeculated and nontrabeculated portions. The right atrium is larger than the left, but its walls are somewhat thinner, measuring about 2 mm.; its cavity is capable of containing about 57 c.c.

Left atrium

The 4 pulmonary veins drain into the left atrium. The flap valve of the fossa ovalis is located on the septal surface. The appendage of the left atrium is consistently narrow and long & is the only trabeculated structure in the left atrium.

Right ventricle

Tricuspid valve is located in the large anterolateral portion (sinus) of the right ventricle. Pulmonic (semilunar) valve is located in the outflow tract (infundibulum). Internally, both the sinus area and infundibulum contain coarse trabeculations. The septal portion of the right ventricle has 3 components: (1) the inflow tract, which supports the tricuspid valve; (2) the trabecular wall, which typifies the internal appearance of the right ventricle; and (3) the outflow tract. The tricuspid valve is supported by a large anterior papillary muscle, which arises from the anterior free wall and the moderator band, and by several small posterior papillary muscles. The wall of the right ventricle is thinner than that of the left, the proportion between them being as 1 to 3; it is thickest at the base, and gradually becomes thinner toward the apex. The cavity equals in size that of the left ventricle, and is capable of containing about 85 c.c.

Left ventricle

The left ventricle can be divided into 2 primary portions, namely, the large sinus portion containing the mitral valve and the small outflow tract that supports the aortic (semilunar) valve. The free wall and apical half of the septum contain fine internal trabeculations. The septal surface is divided into a trabeculated portion (sinus) and a smooth portion (outflow). The outflow tract is located anterior to the anterior mitral leaflet and is part of the atrioventricular (AV) septum. The mitral valve is supported by 2 large papillary muscles (ie, anterolateral, posteromedial) attached to the free wall. The anterior papillary muscle is attached to the anterior portion of the left ventricular wall, and the posterior papillary muscle arises more posteriorly from the ventricle's inferior wall.1

Septi

Ventricular septum

The ventricular septum is divided into a muscular section (inferior) and a membranous section (superior). The muscular portion comprises the left and right ventricular walls. The membranous septum, also termed the pars membranacea, is a fibrous structure partially separating the left ventricular outflow tract from the right atrium and ventricle.

Atrioventricular septum

The atrioventricular (AV) septum, located behind the right atrium and left ventricle, is divided into 2 portions: a superior portion (membranous) and an inferior portion (muscular). Inside the left ventricle, the muscular component comprises part of the outlet septum. The AV node lies in the atrial septum, juxtaposed to the membranous and muscular portions of the AV septum.

Conduction System

The conduction system is composed for the most part of modified cardiac muscle that has fewer striations and indistinct boundaries. The SA node and, to a lesser extent, the AV node, also contain small round cells with few organelles, which are connected by gap junctions. These are probably the actual pacemaker cells, and therefore they are called P cells.

Sinus node

The sinoatrial (SA) node occupies a 1-cm2 area on the lateral surface of the junction of the superior vena cava and right atrium near the crista terminalis.

Internodal pathways

The spread of electrical activation from the sinus node extends toward the atrioventricular (AV) node via Purkinje like pale cells in atrial muscle bundles. There are three bundles: the anterior internodal tract of Bachman, the middle internodal tract of Wenckebach, and the posterior internodal tract of Thorel. Conduction also occurs through atrial myocytes, but it is more rapid in these bundles.

Atrioventricular node

The AV node is situated directly on the right atrial side of the central fibrous body in the muscular portion of the AV septum, just superior and anterior to the ostium of the coronary sinus. Measuring approximately 0.1 cm X 0.3 cm X 0.6 cm.

His bundle and bundle branches

The AV node continues onto the His bundle which follows a course along the inferior border of the membranous septum and, near the aortic valve, gives off fibers that form the left bundle branch. The left bundle branch divides into an anterior fascicle and a posterior fascicle. The branches and fascicles run subendocardially down either side of the septum and come into contact with the Purkinje system, whose fibers spread to all parts of the ventricular myocardium.

Cardiac Valves

Mitral valve

bicuspid AV valve of the left ventricle. The AV valve has a large anterior leaflet (septal or aortic) and a smaller posterior leaflet (mural or ventricular). The anterior leaflet is triangular with a smooth texture. The posterior leaflet has a scalloped appearance. The chordae tendineae to the mitral valve originate from the 2 large papillary muscles of the left ventricle and insert primarily on the leaflet's free edge.

Tricuspid valve

The AV valve of the right ventricle has anterior, posterior, and septal leaflets. The orifice is larger than the mitral orifice and is triangular. The tricuspid valve leaflets and chordae are more fragile than those of the mitral valve. The anterior leaflet, largest of the 3 leaflets, often has notches. The posterior leaflet, smallest of the 3 leaflets, is usually scalloped. The septal leaflet usually attaches to the membranous and muscular portions of the ventricular septum. The right atrioventricular orifice is the large oval aperture of communication between the right atrium and ventricle. Situated at the base of the ventricle, it measures about 4 cm. in diameter and is surrounded by a fibrous ring.

Aortic valve

The aortic valve has 3 leaflets composed of fragile cusps and the sinuses of Valsalva. Thus, the valve apparatus is composed of 3 cuplike structures that are in continuity with the membranous septum and the mitral anterior leaflet. The aortic sinuses of Valsalva are 3 dilations of the aortic root that arise from the 3 closing cusps of the aortic valve. The right and left sinuses give rise to the right and left coronary arteries; the noncoronary sinus has no coronary artery. The sinus of Valsalva walls are much thinner than the aortic wall, which is a factor of surgical significance; therefore, aortotomies are typically performed away from this region.

Pulmonary valve

As with the aortic valve, the pulmonary valve has 3 cusps, with a midpoint nodule at the free end and lunulae on either side; a sinus is located behind each cusp. 

Coronary Arteries

4 main arteries: the left main, the left anterior descending, and the left circumflex (LCX) arteries (which are all branches of the left coronary artery) and the right coronary artery (RCA). The RCA and LCXs form a circle around the atrioventricular (AV) sulci. The left anterior descending and posterior descending arteries form a loop at right angles to this circle; these arteries feed the ventricular septum. The LCX gives off several parallel, obtuse, marginal arteries that supply the posterior left ventricle. The diagonal branches of the left anterior descending artery supply the anterior portion of the left ventricle.

The term dominance is used to refer to the origin of the posterior descending artery (PDA). When the PDA is formed from the terminal branch of the RCA (>85% of patients), it is termed a right-dominant heart. A left-dominant heart receives its PDA blood supply from a left coronary branch, usually the LCX. This is often referred to as a left posterolateral branch (LPL).

Left main coronary artery

Typically is 1-2 cm in length. When it reaches the left AV groove, the LCA bifurcates into the left anterior descending (LAD) and the LCX branches. The LCA supplies most of the left atrium, left ventricle, interventricular septum, and AV bundles.

Left anterior descending artery

runs along the anterior interventricular sulcus and supplies the apical portion of both ventricles. Gives rise to 4-6 perpendicular septal branches which supply the interventricular septum. toward the apex, it turns sharply to anastomose with the posterior interventricular branch of the RCA. As the LAD artery courses anteriorly along the ventricular septum, it sends off diagonal branches to the lateral wall of the left ventricle.

Left circumflex artery

The LCX artery courses in the coronary groove around the left border of the heart to the posterior surface of the heart to anastomose to the end of the RCA. The atrial circumflex artery, the first branch off the LCX artery, supplies the left atrium. The LCX artery gives off an obtuse marginal (OM) branch at the left border of the heart near the base of the left atrial appendage to supply the posterolateral surface of the left ventricle. In fewer than 40% of patients, the sinus node artery may originate from the LCX artery.

Right coronary artery

The RCA is a single large artery that courses along the right AV groove. The RCA supplies the right atrium, right ventricle, interventricular septum, and the SA and AV nodes. In 60% of patients, the first branch of the RCA is the sinus node artery. As the RCA passes toward the inferior border of the heart, it gives off a right marginal branch that supplies the apex of the heart. After this branching, the RCA turns left to enter the posterior interventricular groove to give off the PDA, which supplies both ventricles.

The AV node artery arises from the "U-turn" of the RCA at the crux (ie, the junction of the AV septum with the AV groove). Terminal branches of the RCA supply the posteromedial papillary muscle of the left ventricle. (The LAD artery supplies the anterolateral papillary muscle of the right ventricle.)

Cardiac innervations:

The SA node develops from structures on the right side of the embryo and the AV node from structures on the left. This is why in the adult the right vagus is distributed mainly to the SA node and the left vagus mainly to the AV node. Similarly, the sympathetic innervation on the right side is distributed primarily to the SA node and the sympathetic innervation on the left side primarily to the AV node. On each side, most sympathetic fibers come from the stellate ganglion. Noradrenergic fibers are epicardial, whereas the vagal fibers are endocardial. However, connections exist for reciprocal inhibitory effects of the sympathetic and parasympathetic innervation of the heart on each other. Thus, acetylcholine acts presynaptically to reduce norepinephrine release from the sympathetic nerves, and conversely, neuropeptide Y released from noradrenergic endings may inhibit the release of acetylcholine. The parasympathetic system acts via M2 receptors & decreases cAMP while sympathetic system acts via β1 receptors & increases cAMP. The parasympathetic nerves are distributed mainly to nodes, to a lesser extent to atria and very little directly to the ventricles. The sympathetic nerves are distributed to all parts of the heart.

Pericardium

The heart is separated from the rest of the thoracic viscera by the pericardium. The myocardium itself is covered by the fibrous epicardium. The pericardial sac normally contains 5-30 mL of clear fluid, which lubricates the heart and permits it to contract with minimal friction. The pericardium is a conical fibro-serous sac, in which the heart and the roots of the great vessels are contained. It is placed behind the sternum and the cartilages of the third, fourth, fifth, sixth, and seventh ribs of the left side, in the mediastinal cavity.

In front, it is separated from the anterior wall of the thorax, in the greater part of its extent, by the lungs and pleuræ; but a small area, somewhat variable in size, and usually corresponding with the left half of the lower portion of the body of the sternum and the medial ends of the cartilages of the fourth and fifth ribs of the left side, comes into direct relationship with the chest wall. The lower extremity of the thymus, in the child, is in contact with the front of the upper part of the pericardium. Behind, it rests upon the bronchi, the esophagus, the descending thoracic aorta, and the posterior part of the mediastinal surface of each lung. Laterally, it is covered by the pleuræ, and is in relation with the mediastinal surfaces of the lungs; the phrenic nerve, with its accompanying vessels, descends between the pericardium and pleura on either side.

Although the pericardium is usually described as a single sac, an examination of its structure shows that it consists essentially of two sacs intimately connected with one another, but totally different in structure. The outer sac, known as the fibrous pericardium, consists of fibrous tissue. The inner sac, or serous pericardium, is a delicate membrane which lies within the fibrous sac and lines its walls; it is composed of a single layer of flattened cells resting on loose connective tissue. The heart invaginates the wall of the serous sac from above and behind, and practically obliterates its cavity, the space being merely a potential one.

The fibrous pericardium forms a flask-shaped bag, the neck of which is closed by its fusion with the external coats of the great vessels, while its base is attached to the central tendon and to the muscular fibers of the left side of the diaphragm.

Above, the fibrous pericardium not only blends with the external coats of the great vessels, but is continuous with the pretracheal layer of the deep cervical fascia. By means of these upper and lower connections it is securely anchored within the thoracic cavity. It is also attached to the posterior surface of the sternum by the superior and inferior sternopericardiac ligaments; the upper passing to the manubrium, and the lower to the xiphoid process.

The serous pericardium is, as already stated, a closed sac which lines the fibrous pericardium and is invaginated by the heart; it therefore consists of a visceral and a parietal portion. The visceral portion, or epicardium, covers the heart and the great vessels, and from the latter is continuous with the parietal layer which lines the fibrous pericardium. The portion which covers the vessels is arranged in the form of two tubes. The aorta and pulmonary artery are enclosed in one tube, the arterial mesocardium. The superior and inferior venæ cavæ and the four pulmonary veins are enclosed in a second tube, the venous mesocardium, the attachment of which to the parietal layer presents the shape of an inverted U. The cul-de-sac enclosed between the limbs of the U lies behind the left atrium and is known as the oblique sinus, while the passage between the venous and arterial mesocardia—i.e., between the aorta and pulmonary artery in front and the atria behind—is termed the transverse sinus.

describe the normal pressure and flow patterns (including velocity profiles) of the cardiac cycle

The figure shows electrical and mechanical events of cardiac cycle:

[pic]

The cardiac events that occur from the beginning of one heartbeat to the beginning of the next are called the cardiac cycle. Duration of one cardiac cycle is usually 0.8 sec, & consist systole & diastole which are further divided as follows:

Phases of systole:

1. Isovolumetric contraction (0.05 sec) – lasts from mitral valve closure until opening of aortic valve. Immediately after ventricular contraction begins, the ventricular pressure rises abruptly, causing the A-V valves to close. Then an additional 0.02 to 0.03 second is required for the ventricle to build up sufficient pressure to push the semilunar (aortic and pulmonary) valves open against the pressures in the aorta and pulmonary artery. Therefore, during this period, contraction is occurring in the ventricles, but there is no emptying.

1. Isotonic contraction (0.18 sec) – separated into phase of rapid ejection (0.1) & phase of reduced ejection (0.08 sec). When the left ventricular pressure rises slightly above 80 mm Hg (and the right ventricular pressure slightly above 8 mm Hg), the ventricular pressures push the semilunar valves open. Immediately, blood begins to pour out of the ventricles, with about 70 per cent of the blood emptying occurring during the first third of the period of ejection and the remaining 30 per cent emptying during the next two thirds. Therefore, the first third is called the period of rapid ejection, and the last two thirds, the period of slow ejection.

2. Protodiastole (0.04 sec) – ejection has finished & pressure starts to fall until aortic valve closes

Phases of diastole:

1. Isovolumetric relaxation (0.03-0.06): lasts from closure of the aortic valve until the mitral valve opens

2. Rapid filling phase: blood flows rapidly into the ventricles. The period of rapid filling lasts for about the first third of diastole.

3. Distasis (reduced filling): During the middle third of diastole, only a small amount of blood normally flows into the ventricles; this is blood that continues to empty into the atria from the veins and passes through the atria directly into the ventricles.

4. Atrial systole: During the last third of diastole, the atria contract and give an additional thrust to the inflow of blood into the ventricles; this accounts for about 20 per cent of the filling of the ventricles during each heart cycle.

Pressure Changes in the Atria:

The a wave: caused by atrial contraction. Ordinarily, the right atrial pressure increases 4 to 6 mm Hg during atrial contraction, and the left atrial pressure increases about 7 to 8 mm Hg.

The c wave: occurs when the ventricles begin to contract; it is caused partly by slight backflow of blood into the atria at the onset of ventricular contraction but mainly by bulging of the A-V valves backward toward the atria because of increasing pressure in the ventricles. Pressure drop after c wave is x descent.

The v wave: results from slow flow of blood into the atria from the veins while the A-V valves are closed during ventricular contraction. Then, when ventricular contraction is over, the A-V valves open, allowing this stored atrial blood to flow rapidly into the ventricles and causing the v wave to disappear. Pressure drop after c wave is y descent.

Pressure Changes in the Aorta:

Opening of semilunar valves allows blood to immediately flow out of the ventricle hence the pressure in the ventricle rises much less rapidly. The entry of blood into the arteries causes the walls of these arteries to stretch and the pressure to increase to about 120 mm Hg. Next, at the end of systole, after the left ventricle stops ejecting blood and the aortic valve closes, the elastic walls of the arteries maintain a high pressure in the arteries, even during diastole. A so-called incisura occurs in the aortic pressure curve when the aortic valve closes. This is caused by a short period of backward flow of blood immediately before closure of the valve, followed by sudden cessation of the backflow. After the aortic valve has closed, the pressure in the aorta decreases slowly throughout diastole because the blood stored in the distended elastic arteries flows continually through the peripheral vessels back to the veins. Before the ventricle contracts again, the aortic pressure usually has fallen to about 80 mm Hg (diastolic pressure). The pressure curves in the right ventricle and pulmonary artery are similar to those in the aorta, except that the pressures are only about one sixth as great.

Relationship of the Electrocardiogram to the Cardiac Cycle

• The P wave is caused by spread of depolarization through the atria, and this is followed by atrial contraction, which causes a slight rise in the atrial pressure curve immediately after the electrocardiographic P wave.

• About 0.16 second after the onset of the P wave, the QRS waves appear as a result of electrical depolarization of the ventricles, which initiates contraction of the ventricles and causes the ventricular pressure to begin rising, as also shown in the figure. Therefore, the QRS complex begins slightly before the onset of ventricular systole.

• ventricular T wave: This represents the stage of repolarization of the ventricles when the ventricular muscle fibers begin to relax. Therefore, the T wave occurs slightly before the end of ventricular contraction.

Explain the ionic basis of spontaneous electrical activity of cardiac muscle cells (automaticity)

Cardiac action potential (normal duration 250 ms): Figure shows the cardiac action potential with 4 phases & ionic currents:

PHASE 0: Resting membrane has potential is close to -90mv. Depolarization to threshold voltage results in opening of the activation gates of the sodium channels. These are now active. Na diffuses in rapidly across electrochemical gradient and membrane rapidly reaches the sodium equilibrium potential Ena (about +70 MV). The sodium current is brief as the opening of activation gate is followed by the closure of the inactivation gate. Inactivation gate (h) have voltage dependent function. They begin to close between -70 to - 55 mv and begin to recover from -55 to -70 mv.

PHASE 1 & 2: The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolarizing potassium current. Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel (the "L" type), the transitions occur more slowly and at more positive potentials.

PHASE 3: (repolarization phase) results from completion of sodium and calcium channel inactivation and the growth of potassium permeability, so that the membrane potential once again approaches the potassium equilibrium potential close to -90mv. The major potassium currents involved in phase 3 repolarization include a rapidly activating potassium current (IKr) and a slowly activating potassium current (IKs). These two potassium currents are sometimes discussed together as "IK.”

PHASE 4: is the resting membrane potential. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with diastole of the chamber of the heart. In addition to stimulus from adjacent cells, certain cells of the heart have the ability to undergo spontaneous depolarization, in which an action potential is generated without any influence from nearby cells

There are two types of action potential seen in heart: (Also see comparison table in Kerry pg 88)

|Fast response fibres ( cardiac muscle & HIS purkinje system) |Slow response fibres (SA & AV nodes) |

|[pic] |[pic] |

SA node and AV node have resting membrane potential in the range of – 50 to -70 mv hence all na channels are inactivated. Such depolarized cells exhibit “slow responses” – slow upstroke velocity and slow conduction – which depends on calcium inward current. Other relatively depolarized cells exhibiting slow depolarization & conduction include cells exposed to hyperkalemia, sodium pump blockade, or ischemic cells.

Pacemaker Potentials: Rhythmically discharging cells (eg SA & AV nodes)have a membrane potential that, after each impulse, declines to the firing level. Thus, this prepotential or pacemaker potential triggers the next impulse. At the peak of each impulse, IK begins and brings about repolarization. IK then declines, and as K+ efflux decreases, the membrane begins to depolarize, forming the first part of the prepotential. Ca2+ channels then open. These are of two types in the heart, the T (for transient) channels and the L (for long-lasting) channels. The calcium current (ICa) due to opening of T channels completes the prepotential, and ICa due to opening of L channels produces the impulse.

Describe the normal and abnormal processes of cardiac excitation

Normal process of cardiac excitation:

SA node is the normal pacemaker of heart. It has the steepest phase 4 pacemaker current & hence depolarizes first. Depolarization initiated in the SA node spreads radially through the atria, then converges on the AV node. Atrial depolarization is complete in about 0.1 s. Because conduction in the AV node is slow, there is a delay of about 0.1 s (AV nodal delay) before excitation spreads to the ventricles. This delay is shortened by stimulation of the sympathetic nerves to the heart and lengthened by stimulation of the vagi. From the top of the septum, the wave of depolarization spreads in the rapidly conducting Purkinje fibers to all parts of the ventricles in the 0.08-0.1 s. In humans, depolarization of the ventricular muscle starts at the left side of the interventricular septum and moves first to the right across the midportion of the septum. The wave of depolarization then spreads down the septum to the apex of the heart. It returns along the ventricular walls to the AV groove, proceeding from the endocardial to the epicardial surface. The last parts of the heart to be depolarized are the posterobasal portion of the left ventricle, the pulmonary conus, and the uppermost portion of the septum. The velocity of conduction of the excitatory action potential signal along both atrial and ventricular muscle fibers is about 0.3 to 0.5 m/sec. The velocity of conduction in the Purkinje fibers—is as great as 4 m/sec. The conduction velocity across SA & AV node is 0.05m/sec. The normal refractory period of the ventricle is 0.25 to 0.30 second, which is about the duration of the prolonged plateau action potential. There is an additional relative refractory period of about 0.05 second during which the muscle is more difficult than normal to excite but nevertheless can be excited by a very strong excitatory signal.

Abnormal process of cardiac excitation: (Arrythmias)

[pic]

Abnormal automaticity:

• Non-pacemaker cells begin to spontaneously and abnormally initiate an impulse, believed to be the result of reduced (more positive) RMP bringing it closer to the threshold potential. Eg. Ischemia and electrolyte imbalances

• Acceleration of pacemaker discharge, brought about by increased phase 4 depolarization slope. Eg. hypokalemia, β stimulation, positive chronotropic drugs, fibre stretch, acidosis and partial depolarization by currents of injury.

After depolarization (or triggered activity): Spontaneous depolarizations requiring a preceding impulse (a triggering beat)

• Early after depolarizations (EAD): After depolarizations originating during phase 2 or 3 of the AP. Seen with prolonged action potential eg. Prolongation of QT interval (repolarization) by inhibition of delayed rectifier potassium current (sotalol, quinidine, dofetilide and procainamide). Torsade de pointe (TdP), a potentially lethal polymorphic ventricular arrhythmia, is an example of EAD, precipitated by K+channel blockers

[pic]

• Delayed afterdepolarization (DAD): After depolarizations originating during phase 4 of AP. Ventricular arrhythmias secondary to digoxin toxicity is an example of delayed afterdepolarization. Digoxin mediated increased intracellular Ca++ is believed to be the mechanism of this type of arrhythmia.

[pic]

Disorders of impulse conduction: Most common mechanism of arrhythmias.

• conduction block: 1st , 2nd & 3rd degree heart block

• reentry:

o Impulse recirculates in the heart and cause repititive activation

o Pre-requisites:

▪ Propagating impulse encounters electrophysiologically inhomogeneous tissue with unidirectional block allowing retrograde conduction

▪ retrograde conducting impulse encounters excitable tissue

o Examples of reentrant arrhythmias: AV nodal reentrant tachycardia (AVNRT), Atrioventricular reentrant tachycardia (AVRT), Atrial flutter, Atrial fibrillation, Ventricular tachycardia.

To explain the physiological basis of the electrocardiograph in normal and common pathological states

Normal electrocardiograph:

[pic]

|Feature |Description |Duration |

|P wave |During normal atrial depolarization, the main electrical vector is directed from the SA node towards the AV|80ms |

| |node, and spreads from the right atrium to the left atrium. This turns into the P wave on the ECG. | |

|PR segment |The PR segment connects the P wave and the QRS complex. |150 to 200ms |

|QRS complex |The QRS complex is a recording of a single heartbeat on the ECG that corresponds to the depolarization of |70 to 110ms |

| |the right and left ventricles. | |

|ST segment |The ST segment connects the QRS complex and the T wave. Is iso-electric. Represents period when ventricles |80 to 120ms |

| |are depolarized. | |

|T wave |The T wave represents the repolarization (or recovery) of the ventricles. The interval from the beginning |160ms |

| |of the QRS complex to the apex of the T wave is referred to as the absolute refractory period. The last | |

| |half of the T wave is referred to as the relative refractory period (or vulnerable period). | |

|PR interval |The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. |120 to 200ms |

| |Represents AV nodal conduction delay. | |

|ST interval |The ST interval is measured from the J point to the end of the T wave. |320ms |

|QT interval |The QT interval is measured from the beginning of the QRS complex to the end of the T wave. Represents the |300 to 440ms |

| |entire period of depolarization & repolarization of the ventricles. | |

|U wave |The U wave is not always seen. It is typically small, and, by definition, follows the T wave. | |

ECG in common pathological states

|Pathological state |ECG finding |Mechanism |

|Abnormal potential |

|Pericardial effusion |Low voltage complexes |Fluid decreases conduction |

|Tamponade | | |

|Old infarcts | |Less myocardial mass |

|Emphysema | |Parenchymal Air decreases conduction |

|Axis Deviation |

|Left ventricle hypertrophy |Left axis deviation |Larger myocardium( increased action potential|

|LBBB | |Greater time to depolarize |

|Right ventricle hypertrophy |Right axis deviation | |

|RBBB | | |

|Abnormal P wave |

|Left atrial hypertrophy |P mitrale (biphasic p wave) |Mechanisms similar to ventricular hypertrophy|

|Right atrial hypertrophy |P pulmonale (tall p wave) | |

|Abnormal PR interval |

| | | |

|Abnormal QRS complex |

|Hypertrophic/dilated heart |Broad QRS |Increased mass/increased path of |

|Purkinje block syndromes | |depolarization |

|Ventricular ectopics |Broad, bizarre QRS |Normal pattern of depolarization lost |

|Abnormal QT |

| | | |

|Abnormal T wave |

|Chronic progressive ischemia |Inverted t waves |Slow conduction, abnormal repolarization |

|Hyperkalemia | | |

|Digitalis overdose |Earliest sign: biphasic t waves | |

|Current of injury |

|Mechanical trauma |ST changes |Damaged myocardium remains partially or |

|Infectious process | |totally depolarized, resulting in flow of |

|Ischemia | |current (current of injury) to adjacent |

| | |myocardium when it begins repolarizing. |

| | | |

| | | |

|NSTEMI |ST depression | |

|STEMI |ST elevation | |

|Anterior wall MI |V1-V4 ST changes | |

|Lateral wall MI |I, aVL, V5, V6 ST changes | |

|Inferior wall MI |II, III, aVF ST changes | |

|Electrolyte disorder |ECG changes |

|Hyperkalemia |Tall peaked T waves |

| |Flattening p-waves. In extreme hyperkalemia p-waves may disappear altogether. |

| |Prolonged depolarization leading to QRS widening (nonspecific intraventricular conduction |

| |defect) sometimes > 0.20 seconds |

| |At concentrations > 7.5 mmol/L atrial and ventricular fibrillation can occur |

|Hypokalemia |ST depression and flattening of the T wave |

| |Negative T waves |

| |A U-wave may be visible |

|Hypercalcemia |mild: broad based tall peaking T waves |

| |severe: extremely wide QRS, low R wave, disappearance of p waves, tall peaking T waves. |

|Hypocalcemia |narrowing of the QRS complex |

| |reduced PR interval |

| |T wave flattening and inversion |

| |prolongation of the QT-interval |

| |prominent U-wave |

| |prolonged ST and ST-depression |

|drugs |ecg |

|Quinidine, phenothiazines and |Low voltage T waves (or T wave inversion) |

|tricyclic antidepressants |ST segment depression |

| |Prolonged Q-T interval |

| |Increased height of U wave |

| |Widening and notching of P waves |

| |Toxic doses of quinidine may cause widened QRS complexes, heart block, VT and VF. |

|Lidocaine |No effects at therapeutic doses. Toxic doses may cause sinus tachycardia, sinus arrest and AV block. |

|Diphenylhydantoin (Phenytoin) |No noticeable changes occur at normal doses. Occasionally, an increase in PR interval may be seen. |

| |With pre-existing severe myocardial disease, the drug has been associated with bradycardia, A-V |

| |block, asystole or VF. |

|Amiodarone |Prolongation of the Q-T interval and increase in the height of the U waves occurs. This correlates |

| |with its effect of prolongation of the action potential. |

|Verapamil |slowing of the sinus rate and AV conduction (hence, a prolonged PR interval). The effects of |

| |verapamil on the SA and AV nodes are additive with beta-blocking drugs. The use of these two together|

| |can give rise to catastrophic bradycardias. |

|Digoxin |Digoxin can induce direct and indirect changes on the heart. The direct changes are due to inhibition|

| |of the normal active process of sodium ion transport (and also potassium ion transport) across the |

| |membranes of myocardial and pacemaker cells. Digoxin induces indirect changes by increasing the vagal|

| |tone. |

| | |

| |Therapeutic doses produce ECG changes in a patient taking digitalis. These changes are referred to as|

| |the "digoxin effect". These changes are: |

| | |

| |1) Decreased T wave amplitude |

| |2) ST segment depression |

| |3) Increase in U wave amplitude |

| |4) Shortening of the Q-T interval |

| | |

| |One of the earliest and commonest changes is reduction in T wave voltage. Occasionally, biphasic or |

| |inverted T waves may be seen. |

| | |

| |ST segment changes are seen as a downward sloping ST segment depression, which is often associated |

| |with T wave flattening. This is called the "reversed tick" phenomenon (resembles the tick made by a |

| |left-handed person). |

| | |

| |Digoxin toxicity: |

| |The following arrhythmias are seen commonly: |

| | |

| |1) Ventricular premature beats (including coupled and multifocal VPCs) |

| |2) Junctional tachycardia |

| |3) Sinus bradycardia |

| |4) Atrial tachycardia with A-V block |

| |5) Heart blocks (1st degree, 2nd degree Mobitz Type I and 3rd degree) |

| |6) Multifocal atrial premature beats |

| |7) Atrial fibrillation and flutter |

| |8) SA block and sinus arrest |

| |9) VF and VT |

Drugs causing prolonged QT:

|Antibiotics |Anaesthetics |Antipsychotics |

|azithromycin |halothane |risperidone |

|clarithromycin | |fluphenazine |

|erythromycin |Antiarrhythmics |haloperidol |

|roxithromycin |disopyramide |clozapine |

|metronidazole |procainamide |thioridiazine |

|(with alcohol) |quinidine |ziprasidone |

|Some fluroquinolone |amiodarone |pimozide |

| |sotalol |droperidol |

|Antifungals | | |

|fluconazole |Antidepressants  |Antihistamines |

|(in cirrhosis) |amitriptyline |terfenadine* |

|ketoconazole |clomipramine |astemizole* |

| |imipramine | |

|Antivirals |dothiepin |Other |

|nelfinavir  |doxepin |probucol |

| | |cisapride |

|Antimalarials | | |

|chloroquine | | |

|mefloquine | | |

Describe the factors that may influence cardiac electrical activity

Factors affecting electrical activity:

1. Nervous system

2. Electrolytes

3. Drugs

4. Temperature

5. Anatomical alterations:

a. Myocardial ischemia/infarction

b. Aberrant pathway

c. Bundle branch blocks

Nervous system:

(Also read the nerve supply under anatomy question)

Nodal tissue especially SA node is heavily innervated by both PANS (acetylcholine) & SANS (norepinephrine) fibres activating M2 & b1 receptors respectively

Phase 4 slope is increased by an increase in cAMP resulting from b1 receptor activation and slowed by a decrease in cAMP resulting from M2 receptor activation

Increase in cAMP will:

- Increase upstroke velocity in pacemaker by increase of iCa

- Shorten AP duration by increase of IK

- Increase HR by increase of Ina, thus increasing slope of phase 4

Decrease in cAMP will:

- Does the opposite plus produces a K+ current (IKIACh), which produces hyperpolarization and slows the rate of diastolic depolarization and thus decreases HR by both SA & AV nodal depression. Strong vagal stimulation can cause complete heart block with ventricular escape.

- Beta blockers prevent cAMP formation, with primary effects on SA & AV nodal tissues.

|Electrolyte disorder |Effect on cardiac electrical activity |

|Hyperkalemia |The faster repolarization of the cardiac action potential causes the tenting of the T waves, and |

| |the inactivation of sodium channels causes a sluggish conduction of the electrical wave around |

| |the heart, which leads to smaller P waves and widening of the QRS complex. Bradycardia can occur.|

|Hypokalemia |In the heart, it causes myocytes to become hyperexcitable. Lower membrane potentials in the |

| |atrium may cause arrhythmias because of more complete recovery from sodium-channel inactivation, |

| |making the triggering of an action potential more likely. In addition, the reduced extracellular |

| |potassium (paradoxically) inhibits the activity of the IKr potassium current and delays |

| |ventricular repolarization. This delayed repolarization may promote reentrant arrythmias. |

|Hypocalcemia |prolongs phase 2 of the action potential.  See ecg changes in previous question |

|Hypercalcemia |See ecg changes in previous question |

|Drugs |Effect on action potential |Effect on ECG |

|Class I A (Quinidine, procainamide, |Slow phase 0 depolarization, prolong APD |Supress AV conduction, prolong PR, QRS, QT |

|disopyramide) | | |

|Class I B (lidocaine, tocainide, |Shorten phase 3 repolarization & decrease APD|Usually no ECG changes |

|mexiletine) | | |

|Class IC (Flecainide, propafenone) |Markedly slow phase 0 depolarization. |Markedly delays conduction, prolong PR, broaden QRS |

| |variable effect on APD | |

|B blockers |Slow phase 4 depolarization |Prolong PR, decreased HR |

|Class III (sotalol, amiodarone) |Prolong phase 3 repolarization |Prolonged QT |

|CCB – verapamil & diltiazem |Slow phase 4 spontaneous depolarization |Prolonged PR |

Effect of temperature:

Increased body temperature, causes a greatly increased heart rate, sometimes to as fast as double normal. Decreased temperature causes a greatly decreased heart rate. These effects presumably result from the fact that heat increases the permeability of the cardiac muscle membrane to ions that control heart rate, resulting in acceleration of the self-excitation process.

Anatomical alterations:

a. Myocardial ischemia/infarction: results in current of injury. Reperfusion injury produces increased automaticity and ectopics. Re-entry arrhythmias. Scarred myocardium can delay in conduction or can lead to re-entry circuits.

b. Aberrant pathway: eg VPW syndrome can cause AV reentrant tachycardias

c. Bundle branch blocks: primarily result in delayed conduction.

Explain the Frank-Starling mechanism and its relationship to excitation-contraction coupling

Frank-Starling law: "energy of contraction is proportional to the initial length of the cardiac muscle fiber."

For the heart, the length of the muscle fibers (ie, the extent of the preload) is proportionate to the end- diastolic volume.

Increased venous return increases the end-diastolic volume and therefore preload, which is the initial stretching of the cardiac myocytes prior to contraction. Myocyte stretching increases the sarcomere length, which causes an increase in force generation. Increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber. The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation.

This ability of the heart to change its force of contraction and therefore stroke volume in response to changes in venous return is called the Frank-Starling mechanism. The mechanism is very important for:

1. Rapidly responding to acute changes in venous return

2. Keeping the right and left ventricle outputs exactly equal

The relation between ventricular stroke volume and end-diastolic volume is called the Frank-Starling curve.

Frank-Starling curves however, does not show how changes in venous return affect end-diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular function in terms of pressure-volume diagrams. The increased stroke volume is manifested by an increase in the width of the pressure-volume loop.

[pic]

Steps in excitation contraction coupling:

1. Action potential spreads from the cell membrane into the T tubules

2. Inward calcium current: During the plateau of action potential, Ca2+ conductance is increased and calcium enters the cell from the extracellular fluid

3. Ca2+ induced Ca2+ release: the Ca2+ entry triggers release of even more Ca2+ from the sarcoplasmic reticulum. The amount of calcium released from SR depends upon the amount of calcium stored and on the size of inward current during the plateau phase

4. Net intracellular calcium increases

5. Ca2+ binds to troponin C: & tropomyosin is moved out of the way, removing the inhibition of actin and myosin binding.

6. Actin and myosin bind: Thick and thin filament slide past each other and myocardial cell contracts. The magnitude of tension is proportional to intracellular calcium

7. Relaxation occurs when Ca2+ is re-accumulated by the SR by an active Ca2+ - ATPase pump

Define preload, afterload and myocardial contractility

Preload: is the load on myocardial cell just before the onset of contraction. The pre-load is said to be initial fiber length.

After load: is the impedance to the ejection of blood from the heart into the arterial circulation.

Myocardial contractility: is the intrinsic ability of the cardiac muscle to develop force at a given muscle length independent of changes in HR or After-load.

Describe the factors that determine preload, afterload and myocardial contractility

Factors determining preload:

|Factors that normally increase or decrease the length of ventricular cardiac muscle fibers. |

|Increase Preload (increased venous return) |

|Stronger atrial contractions : Atrial contractions aid ventricular filling |

|Increased total blood volume : An increase in total blood volume increases venous return. |

|Increased venous tone : Constriction of the veins reduces the size of the venous reservoirs, decreasing venous pooling and thus |

|increasing venous return |

|Increased pumping action of skeletal muscle : muscular activity increases it as a result of the pumping action of skeletal muscle. |

|Increased negative intrathoracic pressure : An increase in the normal negative intrathoracic pressure increases the pressure gradient|

|along which blood flows to the heart, whereas a decrease impedes venous return |

|Decrease Preload (decreased venous return) |

|Standing : Standing decreases venous return |

|Increased intrapericardial pressure |

|Decreased ventricular compliance : An increase in ventricular stiffness produced by myocardial infarction, infiltrative disease, and |

|other abnormalities |

Factors determining Afterload:

Afterload is related to ventricular wall stress (σ), where

[pic]

(P, ventricular pressure; r, ventricular radius; h, wall thickness).

This relationship is similar to the Law of LaPlace, which states that wall tension (T) is proportionate to the pressure (P) times radius (r) for thin-walled spheres or cylinders. Therefore, wall stress is wall tension divided by wall thickness.

Determinants of after load:

• Systemic vascular resistance

• Aortic root impedance

• Transmural pressure across ventricular wall: Myocardium has to contract against a negative intrathoracic pressure which constantly produces outward pull on myocardium.

• Ventricular wall thickness: A hypertrophied ventricle (thickened wall) reduces wall stress and afterload. The thicker the wall, the less tension experienced by each sarcomere unit.

• Ventricular radius: At a given pressure, wall stress and therefore afterload are increased by an increase in ventricular inside radius (ventricular dilation).

Factors determining myocardial contractility:

Factors that increase contractility:

1. Increased heart rate: Increased HR( increased frequency of action potential( more Ca2+ enters cell(more Ca2+ released from SR and greater tension is produced. Examples:

a. Positive staircase or bowditch staircase. Increased HR increases the force of contraction in a stepwise fashion as the intracellular Ca2+ increases cumulatively over several beats

b. Post extrasystolic potentiation: beat after extrasystole has increased force of contraction because extra Ca2+ enters during extrasystole.

2. Sympathetic stimulation via b1 receptors increases contractility by two mechanisms:

a. Increases inward Ca2+ current during the plateau of each action potential

b. Increases the activity of Ca2+ pump of SR by phosphorylation of phasopholamban resulting in more accumulation and subsequent release of Ca2+

3. Cardiac glycosides: inhibits Na K ATPase(intracellular Na+ increases(diminished Na+ gradient(inhibits Na-Ca exchange that extrudes Ca2+ out of cell and depends on Na gradient.

4. Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are positively inotropic. Glucagon, which increases the formation of cAMP, is positively inotropic.

Factors that decrease contractility:

1. Parasympathetic stimulation: via M2 receptor decreases the force of contraction in the atria by decreasing the inward Ca2+ current during the plateau phase of the action potential.

2. Hypercapnia, hypoxia, acidosis

3. Drugs such as quinidine, procainamide, and barbiturates

4. The contractility of the myocardium is also reduced in heart failure (intrinsic depression). The cause of this depression is not known.

Describe myocardial oxygen demand and supply, and the conditions that may alter each

[pic]

MYOCARDIAL OXYGEN DEMAND

• The basal myocardial O2 consumption in asystole: 2 mL/100 g/min.

• O2 consumption by the beating heart is about 9 mL/100 g/min at rest.

• Cardiac venous O2 tension is low i.e PO2 of 20mmhg , and little additional O2 can be extracted from the blood in the coronaries, so increases in O2 consumption require increases in coronary blood flow.

• Tension time index: Area under the systolic part of LV pressure time curve. Correlates well with the myocardial oxygen consumption

• Determinants of myocardial oxygen consumption:

o Major determinants:

▪ Myocardial wall tension: law of Laplace states that the tension developed in the wall of a hollow viscus is proportionate to the radius of the viscus, and the radius of a dilated heart is increased. Hence increased pre-load also leads to increased O2 consumption.

▪ Contractility

▪ Heart rate- O2 consumption per unit time increases when the heart rate is increased by sympathetic stimulation because of the increased number of beats and the increased velocity and strength of each contraction.

o Minor determinants:

▪ Basal energy metabolism (25% of total O2 consumption)

▪ External work performed: Work is measured as a product of pressure and volume. The oxygen cost of myocardial work depends on the way the work is performed eg ‘pressure work’ like AS requires higher myocardial oxygen consumption that ‘volume work’ like AR for the same cardiac output.

▪ Energy for electrical activation (1% of total O2 consumption)

MYOCARDIAL OXYGEN SUPPLY

Oxygen delivery = coronary blood flow * oxygen content

= Coronary blood flow * 1.34*Hb*SO2

Coronary blood flow:

• Coronary blood flow is 200-250mls/min. This is 5% of CO

• Coronary perfusion pressure: is the driving force for the coronary blood flow and is calculated as the aortic diastolic pressure – the larger of either LV diastolic pressure or the RA pressure (representing the coronary sinus pressure). Usually the perfusion pressure in circulations is just the difference between the arterial and venous pressure, however the circulations like heart, lung and brain are examples of starling resistors where another pressure needs to be considered eg LV pressure when calculating the perfusion pressure.

• Coronary blood flow variation with the cardiac cycle:

o LV: flow predominantly during diastole. Subendocardial flow ceases during systole.

o RV: flow during both systole and diastole, as RV pressures are low during both systole and diastole.

• Most important factors regulating coronary blood flow is vasodilatation produced by the local metabolic factors: hypoxia and adenosine. Sympathetic nerves play a minor role.

Describe and explain cardiac output curves, vascular function curves and their correlation

Cardiac and vascular curves are simultaneous plots of cardiac output and venous return as a function of the right atrial pressure or end diastolic volume

1. The cardiac output or the cardiac function curve

a. Depicts the frank starling relationship for the ventricle

b. Shows that cardiac output increases as a function of end diastolic volume(primary mechanism)

2. The venous return or vascular function curve

a. Depicts the relationship between blood flow through the vascular system and right atrial pressure

b. Mean systemic pressure:

i. Point at which vascular function curve intersects the X axis

ii. Equals the right atrial pressure when there is no flow in the cardiovascular system

iii. Increased by increase in blood volume or by decrease in venous compliance and is reflected by a shift of the vascular function curve to the right

iv. Decreased by decrease in blood volume or by increase in the venous compliance and is reflected by a shift of the vascular function curve to the left

c. Slope of the venous return curve: determined by the resistance of the arterioles

i. Clockwise rotation of venous return curve indicates a decrease in total peripheral resistance (TPR). Decrease in TPR increases the venous return

ii. Anticlockwise rotation of venous return curve indicates a increase in TPR. Increase in TPR decreases the venous return.

3. Combining cardiac output & venous return curves

a. The point at which the two curves intersect is the equilibrium or the steady state point ( Here the cardiac output equals venous return

b. Cardiac output can be changed by altering the cardiac output curve, the venous return curve or both the curves simultaneously. The superimposed curves can be used to predict the direction or magnitude of changes in cardiac output. Eg of such changes are as follows:

i. Inotropic agents change the cardiac output curve

1. Positive inotropic agents produce increased cardiac output. The equilibrium point shifts to a higher CO and a correspondingly lower RA pressure. RA pressure decreases because more blood is ejected from the heart on each beat

2. Negative inotropic agents produce decreased contractility and decreased CO

ii. Changes in blood volume or venous compliance

1. Increases in blood volume or decreases in venous compliance increases mean systemic pressure, shifting the venous return curve to the right in parallel fashion. A new equilibrium point is established at which both cardiac output and RAP are increased

2. Decreases in blood volume or increases in venous compliance decrease mean systemic pressure and shift the venous return curve to left in parallel fashion. A new equilibrium point is established at which both cardiac output and RAP are decreased.

iii. Changes in TPR change both the cardiac output & venous return curve

1. Increases in TPR causes a decrease in both cardiac output and venous return. There is counterclock wise rotation of venous return curve and there is a downward shift of the cardiac output curve. A new equilibrium point is reached at which both CO & venous return are decreased but right atrial pressure is unchanged.

2. Decreasing TPR causes an increase in both CO and venous return. There is clockwise rotation of venous return curve and upward shift of the cardiac output curve. A new equilibrium point is established at which both cardiac output and venous return are increased.

Describe the pressure-volume relationships of the ventricles and their clinical applications

In the above figure ‘10’ also represents end systolic elastance

Best index of preload ( LVEDV

Best index of afterload( slope of the line joining the LVEDV on x axis to the end systolic point. (line no. 12 in the above figure) also known as effective arterial elastance line(Ea)

The pressure volume graph can be used to predict the changes in pressurve volume relationship of heart produced by changes in preload, afterload or contractility

Increased Preload

• Referes to increase in end diastolic volume and is the result of increased venous return

• Causes an increase in the stoke volume based on frank starling mechanism and is reflected by the increased width of the loop.

• In the figure showing increased preload the afterload lines of the 2 loops are parallel so they have same afterload. Both end systolic points are on the same contractility line so they have same contractility

Increased afterload

• Refers to increased aortic pressure

• Results in the decreased stroke volume – reflected by decreased width of the pressurve volume loop

• Decrease in the stroke volume results in increased end systolic volume

• In the figure the preload is same in two loops because the EDV is same and contractility is also same as the end systolic point of the two loops are on the same contractility line

Increased contractility

• The ventricle develop greater than uisual tension during systole causing an increase in the stroke volume represented by the increased width of the PV loop

• The increase in the stroke vol. decrease the end systolic volume

• In the figure the slope of the end systolic pressure volume line is increased in for the loop 2 representing the increased contractility. The end systolic point of the two loops are on the same afterload line hence after load is same for the loops. Preload i.e. EDV is same for the two loops

Increased Preload

Increased afterload

Increased contractility

Describe the factors that determine cardiac output

[pic][pic]

Interactions between the components that regulate cardiac output and arterial pressure. Solid lines indicate increases, and the dashed line indicates a decrease.

|Effect of various conditions on cardiac output. |

|  |Condition or Factor1 |

|No change |Sleep |

| |Moderate changes in environmental temperature |

|Increase |Anxiety and excitement (50-100%) |

| |Eating (30%) |

| |Exercise (up to 700%) |

| |High environmental temperature |

| |Pregnancy |

| |Epinephrine |

|Decrease |Sitting or standing from lying position (20-30%) |

| |Rapid arrhythmias |

| |Heart disease |

|1 Approximate percent changes are shown in parentheses. |

|  |

Variations in cardiac output can be produced by changes in cardiac rate or stroke volume. The cardiac rate is controlled primarily by the cardiac innervation, sympathetic stimulation increasing the rate and parasympathetic stimulation decreasing it. The stroke volume is also determined in part by neural input, sympathetic stimuli making the myocardial muscle fibers contract with greater strength at any given length and parasympathetic stimuli having the opposite effect.

The force of contraction of cardiac muscle is dependent upon its preloading and its afterloading.

Preload: is the load on myocardial cell just before the onset of contraction. The pre-load is said to be initial fiber length.

After load: is the impedance to the ejection of blood from the heart into the arterial circulation.

Relation of Tension to Length in Cardiac Muscle

Frank starling law: "energy of contraction is proportional to the initial length of the cardiac muscle fiber." For the heart, the length of the muscle fibers (ie, the extent of the preload) is proportionate to the end- diastolic volume.

Regulation of cardiac output as a result of changes in cardiac muscle fiber length is sometimes called heterometric regulation, whereas regulation due to changes in contractility independent of length is sometimes called homometric regulation.

| |

|Increase Preload (increased venous return) |

|Stronger atrial contractions : Atrial contractions aid ventricular filling |

|Increased total blood volume : An increase in total blood volume increases venous return. |

|Increased venous tone : Constriction of the veins reduces the size of the venous reservoirs, decreasing venous pooling and thus |

|increasing venous return |

|Increased pumping action of skeletal muscle : muscular activity increases it as a result of the pumping action of skeletal muscle. |

|Increased negative intrathoracic pressure : An increase in the normal negative intrathoracic pressure increases the pressure gradient|

|along which blood flows to the heart, whereas a decrease impedes venous return |

|Decrease Preload (decreased venous return) |

|Standing : Standing decreases venous return |

|Increased intrapericardial pressure |

|Decreased ventricular compliance : An increase in ventricular stiffness produced by myocardial infarction, infiltrative disease, and |

|other abnormalities |

Factors determining Afterload:

Afterload is related to ventricular wall stress (σ), where

[pic]

(P, ventricular pressure; r, ventricular radius; h, wall thickness).

This relationship is similar to the Law of LaPlace, which states that wall tension (T) is proportionate to the pressure (P) times radius (r) for thin-walled spheres or cylinders. Therefore, wall stress is wall tension divided by wall thickness.

Determinants of after load:

• Systemic vascular resistance

• Aortic root impedance

• Transmural pressure across ventricular wall: Myocardium has to contract against a negative intrathoracic pressure which constantly produces outward pull on myocardium.

• Ventricular wall thickness: A hypertrophied ventricle (thickened wall) reduces wall stress and afterload. The thicker the wall, the less tension experienced by each sarcomere unit.

• Ventricular radius: At a given pressure, wall stress and therefore afterload are increased by an increase in ventricular inside radius (ventricular dilation).

Myocardial Contractility

The contractility of the myocardium exerts a major influence on stroke volume.

Factors that increase contractility:

5. Increased heart rate: Increased HR( increased frequency of action potential( more Ca2+ enters cell(more Ca2+ released from SR and greater tension is produced. Examples:

a. Positive staircase or bowditch staircase. Increased HR increases the force of contraction in a stepwise fashion as the intracellular Ca2+ increases cumulatively over several beats

b. Post extrasystolic potentiation: beat after extrasystole has increased force of contraction because extra Ca2+ enters during extrasystole.

6. Sympathetic stimulation via b1 receptors increases contractility by two mechanisms:

a. Increases inward Ca2+ current during the plateau of each action potential

b. Increases the activity of Ca2+ pump of SR by phosphorylation of phasopholamban resulting in more accumulation and subsequent release of Ca2+

7. Cardiac glycosides: inhibits Na K ATPase(intracellular Na+ increases(diminished Na+ gradient(inhibits Na-Ca exchange that extrudes Ca2+ out of cell and depends on Na gradient.

8. Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are positively inotropic. Glucagon, which increases the formation of cAMP, is positively inotropic.

Factors that decrease contractility:

5. Parasympathetic stimulation: via M2 receptor decreases the force of contraction in the atria by decreasing the inward Ca2+ current during the plateau phase of the action potential.

6. Hypercapnia, hypoxia, acidosis

7. Drugs such as quinidine, procainamide, and barbiturates

8. The contractility of the myocardium is also reduced in heart failure (intrinsic depression). The cause of this depression is not known.

Describe the distribution of blood volume and flow in the various regional circulations and to explain the factors that may result in redistribution of blood

[pic]

|Circulation |Local metabolic control |Vasoactive metabolites |Sympathetic control |Mechanical effects |

|(% of resting CO) | | | | |

|Coronary (5%) |Most important mechanism|Hypoxia |Least important mechanism |Mechanical compression |

| | |Adenosine | |during systole |

|Cerebral (15%) |Most important mechanism|CO2 |Least important mechanism |Increases in intracranial|

| | |H+ | |pressure decrease |

| | | | |cerebral blood flow |

|Muscle (20%) |Most important mechanism|Lactate |Most important mechanism at rest |Muscular activity causes |

| |during exercise |K+ |(α(vasoconstriction, β( |temporary decrease in |

| | |Adenosine |vasodilatation) |blood flow |

|Skin (5%) |Least important | |Most important mechanism is | |

| |mechanism | |temperature regulation | |

|Pulmonary (100%) |Most important mechanism|Hypoxia vasoconstricts |Least important mechanism |Lung inflation |

|Renal (25%) | | | | |

| | | | | |

Mechanisms of Blood Flow Control

Local blood flow control can be divided into two phases:

1) acute control : achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters,

2) long-term control : increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.

Acute Blood Flow Regulation

Local (intrinsic) control of blood flow:

1. Autoregulation:

a. Blood flow to the organ remains constant over wide range of perfusion pressure

b. Organs with auto regulation: heart, brain, kidney

2. Active hyperemia:

a. Blood flow to the organ is proportional to its metabolic demand

3. Reactive hyperemia:

a. Increase in blood flow to an organ that occurs after a period of occlusion of flow

b. The longer the period of occlusion the greater the increase in blood flow above preocclusion levels

Mechanisms that explain local control of blood flow

1. Myogenic hypothesis:

a. explains autoregulation but not active or reactive hyperemia

b. based on observation that vascular smooth muscle contracts when it is stretched

c. increased perfusion pressure causes stretch of the vascular smooth muscle which contracts & produces vasoconstriction to maintain constant flow.

2. Metabolic hypothesis

a. Based on observation that tissue supply of oxygen is matched to tissue oxygen demand

b. Vasodilator metabolites are produced as a result of metabolic activity in tissue. These vasodilators are CO2, H+, K+, lactate and adenosine.

3. Tissue pressure theory

a. Applicabale in encapsulated organs (evidence lacking)

b. As the perfusion pressure increases(increased extravasation of fluids(increased tissue hydrostataic pressure(small vessels compressed

4. Mechanism for dilating upstream arteries when microvascular blood flow increases— the endothelium-derived relaxing factor (nitric oxide): increase in blood flow( increase endothelial stress(release of EDRF (i.e. NO t1/2 of 6 sec) ( dilatation of arterioles( decrease flow

Humoral (extrinsic) control of blood flow:

1. Sympathetic innervations of vascular smooth muscle

a. Increased sympathetic tone causes vasoconstriction

b. Decreased sympathetic tone causes vasodilatation

c. Density of innervations varies: skin has the greatest innervations, while coronary, pulmonary, and cerebral vessels have little innervations

2. Local vasoactive hormones

a. Histamine

i. Causes arteriolar dilatation and venous constriction(increased capillary hydrostatic pressure(edema

ii. Released in reponse to trauma

b. Bradykinin:

i. Causes arteriolar dilatation and venous constriction(increased capillary hydrostatic pressure(edema

c. Serotonin

i. Arteriolar constriction

ii. Released in reponse to blood vessel trauma

iii. Implicated in vascular spasms of migrane

d. Prostaglandins:

i. Prostacyclin: vasodilator in several vascular beds

ii. E series prostaglandins: vasodilators

iii. F series prostaglandins: vasoconstrictors

iv. Thromboxane A2: vasoconstrictor

e. Endothelin:

i. A Powerful Vasoconstrictor in Damaged Blood Vessels as large as 5 millimeters.

ii. Present in the endothelial cells of all or most blood vessels, released by damage to the endothelium

3. Systemic vasoactive hormones

a. Angiotensin II

i. powerful potent vasoconstrictor of the small arterioles.

ii. Normally acts on many of the arterioles of the body at the same time to increase the total peripheral resistance, thereby increasing the arterial pressure.

b. Vasopressin

i. Most potent vasoconstrictor

ii. Formed in hypothalamus transported to the posterior pituitary gland, where it is finally secreted into the blood.

iii. Concentration of circulating blood vasopressin after severe hemorrhage can rise high enough to increase the arterial pressure as much as 60 mm Hg.

Long-Term Blood Flow Regulation:

Over a period of hours, days, and weeks, a long-term type of local blood flow regulation develops

in addition to the acute regulation and gives far more complete regulation.

• Mechanism of long-term local blood flow regulation is principally to change the amount of vascularity of the tissues. If metabolic demand increases vascularization increase and vice-versa.

• Rapidity & extent of change decreases with age

• Vascularity Is Determined by Maximum Blood Flow Need

• Factors promoting vascularization:

o O2: Oxygen is important not only for acute control of local blood flow but also for long-term control. Classic eg retrolental fibroplasia of neonate developing after removal of exposure to high O2

o Angiogenic factors: Important ones( vascular endothelial growth factor (VEGF), fibroblast growth factor, and angiogenin released by the lack of O2

Explain the factors that determine systemic blood pressure and its regulation

Blood pressure = CO * total peripheral resistance

The most important mechanisms for regulating arterial pressure are the fast, neutrally mediated baroreceptor mechanism and the slower hormonally regulated renin agiotensin aldosterone mechanism.

Major mechanisms:

1. Baroreceptor reflex (Acute control)

2. Renin-angiotensin-aldosterone system (long term control)

3. Other mechanisms:

a. Cerebral ischemia

b. Chemoreceptor in carotid and aortic bodies

c. Vasopressin

d. ANP

Baroreceptor reflex

1. Includes fast neural mechanisms

2. Responsible for minute to minute regulation of arterial blood pressure

3. Produces vbasoconstrictor activity tonically which accounts for vasomotor tone

4. Baroreceptors are stretch receptors located within the wall of carotid sinus near the bifurcation of common carotid arteries

5. STEPS:

a. Decrease in the arterial pressure decreases the stretch on the wall of carotid sinus. Baroreceptors are more sensitive to the ‘change’ in pressure rather than the actual pressure. Additional baro-receptors in the aortic arch respond to increases but not to decreases in pressure

b. Decreased stretch decreases the firing of the Hering’s nerve (cranial nerve IX) which carries signal to vasomotor centre in medulla.

c. The set point for the mean arterial pressure in the vasomotor centre is about 100mmHg. Therefore if mean arterial pressure is less than 100mmHg a series of autonomic responses is co-ordinated by the vasomotor centre to correct the pressure

d. The vasomotor centre responds to low pressure by decreasing parasympathetic outflow to the heart and increasing the sympathetic outflow to the heart and blood vessel. The results are as follows:

i. ↑ HR

ii. ↑ contractility: resulting from the increased sympathetic tone to the heart. Increased contractility + increased HR ( increased CO(increased pressure

iii. ↑ TPR due to vasoconstriction secondary to ↑ sympathetic outflow

iv. ↑ venoconstriction secondary to ↑ sympathetic activity ( shifts vascular function to right ( ↑ venous return (↑SV(↑CO

e. Baroreceptor mechanism is a negative feedback system. As the blood pressure picks up there will be increased stretch on the carotid sinus baroreceptors which will decrease the signals to vasomotor centre

6. Example of baroreceptor reflex mechanism: response to acute blood loss

Renin-Angiotensin-aldosterone system

1. Slow hormonal mechanism used in long term pressure regulation by adjusting the blood volume

2. Steps:

a. Decrease in the renal perfusion pressure causes the juxtaglomerular cells of the afferent arteriole to secrete rennin.

b. Renin catalyzes the conversion of angiotensinogen to angiotensin I in plasma

c. ACE converts angiotensin I to physiologically active angiotensin II in lungs

d. Angiotensin II has two effects:

i. Stimulates the synthesis and secretion of aldosterone from adrenal cortex. Aldosterone increases NaCl reabsorption by the renal distal tubule thereby increasing blood volume and arterial pressure

ii. Causes the vasoconstriction of the arterioles thereby increasing TPR and mean arterial pressure

Other mechanisms of arterial pressure regulation:

Cerebral ischemia

1. When the brain is ischemic the conc. Of CO2 and hydrogen ion in the brain tissue increases

2. Chemoreceptors in the vasomotor centre respond by increasing both sympathetic and parasympathetic outflow:

a. Ventricular contractility and TPR are increased but HR is decreased because of overriding parasympathetic influence

b. Peripheral vasoconstriction reduces blood flow to other organs to preserve blood flow to brain

3. Cushing’s reflex is an example of the response to cerebral ischemia. ↑ICP compresses blood vessels and ↓ blood flow & cerebral ischemia

Chemoreceptors in carotid and aortic bodies:

1. Located near the bifurcation of common carotid arteries and along the aortic arch

2. Have very high rates of O2 consumption and therefore are very sensitive to hypoxia.

3. A decrease in arterial pressure decreases O2 delivery to the chemoreceptors. In turn, information is sent vasomotor centre to increase BP

Vasopressin

1. Involved in regulation of blood pressure in response to hemorrhage but not in minute to minute regulation of normal blood pressure

2. Atrial receptors respond to decreased blood pressure and cause the release of vasopressin from posterior pituitary

3. Vasopressin has two affects:

a. Potent vasoconstrictor that increases TPR by V1 receptors in the arterioles

b. Increases water reabsorption by the renal distal tubules and collecting ducts via V2 receptors

ANP

1. Released from atria in response to increase atrial pressure

2. Causes relaxation of vascular smooth muscle cells, dilatation of arterioles and decreased TPR

3. Causes increased excretion of salt and water by the kidney, which reduces blood volume and attempts to bring arterial pressure down to normal

4. Inhibits renin secretion

Describe total peripheral vascular resistance and factors that affect it

Vascular resistance is a term used to define the resistance to flow that must be overcome to push blood through the circulatory system. The resistance offered by the peripheral circulation is known as the systemic vascular resistance (SVR) or total peripheral resistance.

Units for measuring vascular resistance are dyn·s·cm-5 or pascal seconds per cubic metre (Pa·s/m³). Pediatric cardiologists use hybrid reference units (HRU), also known as Wood units

Measurement Reference Range

Systemic vascular resistance 900–1200 dyn·s/cm5

Pulmonary vascular resistance 100–200 dyn·s/cm5

Factors affecting peripheral resistance:

As per Ohm’s law:

Resistance = ΔP/Flow……………………………(1)

As per poiseuille’s law:

Flow = ΔPπr4/8ηL ………………………….(2)

Combining equation (1) and (2)

Resistance = 8 ηL/ πr4

Hence Resistance ηL/r4

Where,

η represents viscosity

L represents length of vessel

r represents radius

In other words, resistance is directly proportional to both the fluid viscosity and the structure’s length, and inversely proportional to the fourth power of the structure’s radius. Blood viscosity is not fixed but increases as hematocrit increases, and changes in hematocrit, therefore, can have significant effects on the resistance to flow in certain situations. Under most physiological conditions, however, the hematocrit and, hence, viscosity of blood is relatively constant and does not play a role in the control of resistance.

Similarly, since the lengths of the blood vessels remain constant in the body, length is also not a factor in the control of resistance along these vessels. In contrast, the radii of the blood vessels do not remain constant, and so vessel radius is the most important determinant of changes in resistance along the blood vessels. Decreasing the radius of a tube twofold increases its resistance sixteenfold. Sympathetic nervous system would cause generalized vasoconstriction and hence would increase TPR.

There is a parallel arrangement of organs and their circulation. This is beneficial as parallel arrangement decreases total vascular resistance. This is because in parallel circuit,

R=1 / [(1/R1) + (1/R2) + (1/R3)]

Small arteries and arterioles are primary site of resistance.

Describe the essential features of the micro-circulation including fluid exchange (Starling forces) and control mechanisms present in the pre- and post-capillary sphincters

Microcirculation is the term used to refer to the smallest blood vessels and include : smallest arterioles, metarterioles, the pre-capillary sphincters, the capillaries and the small venules.

Structural aspects:

• Metarterioles branch into capillary beds. At the junction of the arterioles and capillaries is a smooth muscle band called the pre-capillary sphincter

• True capillaries do not have smooth muscle and consist only of a single layer of endothelial cell surrounded by basement membrane

• Systemic capillaries contain only about 5% of blood volume

• Clefts (pores) between the endothelial cells allow passage of water solube substances. Cleft represents very small fraction fraction of surface area ( ................
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