Chapter 1: Cardiovascular Physiology

 

 

1.1    Anatomy of the Heart

1.2    Circulatory Organization

1.3    Microcirculation

1.4    Transcapillary Fluid Exchange

1.5    The Lymphatic System

1.6    Electrical Conduction

1.7    The Cardiac Cycle

1.8    Hemopoiesis and Blood Components

1.9    Pathophysiology

1.10        Study Questions

1.11        Case Histories

1.12        Definitions

 

 

1.1 Anatomy of the Heart:

The heart serves as the central pump for the cardiovascular system and is responsible for moving the blood to the tissues of the body. About the size of a person’s fist, and composed of four separate chambers, the unique size and structure of the heart (Fig. 1.1) is truly remarkable, providing an excellent adaptation of mechanics. The chambers are broken down into the left and right atria, which are small chambers in the upper heart, and the left and right ventricles, the strong powerful chambers in the lower heart. The muscular wall of the heart, or the myocardium, is subdivided into four distinct muscle layers overlapping and wrapping around the heart to produce a wringing motion that is responsible for the pumping action. The myocardium is primarily composed of cardiac muscle fibers that resemble skeletal muscle due to striations or stripes across the fiber. The myocardium is lined with an inner layer of endocardium and covered with an outer layer called the epicardium. The entire package is situated in a fibrous sac, the pericardium, containing a small quantity of pericardial fluid that helps reduce friction between the heart and other organs.

Figure 1.1

Several other structures of the heart are important in the establishment of the blood flow direction through the heart. The intra-atrial septum divides the left and right atria and the intraventricular septum divide the ventricles, creating a double pump system within the same organ. Thus, it is sometimes convenient to refer to the left and right heart as if they were separate units although both sides of the heart act simultaneously in a heartbeat. The atrioventricular (AV) valves are sheets of connective tissue employed to separate the atria from the ventricles. The right AV valve is made up of three cusps or leaflets called the tricuspid valve. The left AV valve has two leaflets, thus called the bicuspid valve, and also known as the mitral valve. These AV valves allow ventricular filling of blood, while simultaneously preventing the back-flow of blood back into the atria during ventricular contractions. Two other valves (semilunar valves), situated at the beginning of the pulmonary artery and aorta, avert back-flow of the blood to the heart from the pulmonary and systemic circulation.

The right atrium receives venous blood from the caval veins, and the left atrium receives oxygenated blood from the pulmonary veins. The two atria function as thin walled reservoirs and conduit organs for the blood. On average, atrial systole contributes only about 15 % of the total ventricular filling, but in cardiac insufficiency the atrial contribution may increase importantly. The left and right ventricles provide most of the energy needed to transport the blood through the circulation. The left ventricle accelerates the blood into the systemic or peripheral high-pressure system, and its walls are thick in contrast to the thin, weak right ventricle, which pump blood into the low-pressure pulmonary system.

The left ventricle consists of cardiac muscle fibers originating from the fibrous rings at the base of the heart and the fibers are twitching towards the apex. The orifice between the left atrium and the left ventricle carries two valve cusps, the bicuspid or mitral valve. Three cusps form the tricuspid valve closing the orifice between the right atrium and ventricle during systole. Strong filaments (chordae tendineae) arise from the papillary muscles of the ventricles. These chordae are attached to the free edges of the atrioventricular valves and normally prevent the valves from bulging into the atria during ventricular systole. The two atrio-ventricular valve systems prevent the leakage of blood backward from the ventricles into the atria. Two other valve systems are interposed between the left ventricle and the aorta (the aortic valves) and between the pulmonary artery and the right ventricle (the pulmonary valves).

 

1.2    Circulatory Organization:

 

General arrangement 

The cardiovascular system consists of two pumps arranged in series (Fig. 1.2). They are the right ventricle that pumps blood into the pulmonary circulation, and the left ventricle, which pumps blood into the systemic circulation. Each of these pumps delivers blood through an efferent tube system (the arteries) and each pump receives blood through an afferent tube system (the veins). In the pulmonary system, blood is pumped from the right ventricle through the lung capillaries and is temporary collected in the left atrium. The coronary arteries are the first arterial branches that arise from aorta just above the aortic valve. Aorta and the elastic arteries are conductance vessels; the muscular arteries are distribution vessels; the arterioles are resistance vessels; the capillaries are exchange vessels; venules and veins are capacitance vessels. The arterio-venous anastomoses in fingers and toes are shunt vessels.

 

Figure 1.2

 

The principal function of the blood flow in the cardiovascular system is to provide oxygen (O2) and nutrients to the tissues of the body and to remove carbon dioxide (CO2) and waste products. The flow of blood through the cardiovascular system follows physical laws known from fluid mechanics (see Hemodynamics).

Strictly speaking, Poiseuille’s law has validity in a circulatory system, only when the fluid flow is laminar and non-pulsating in horizontally situated cylindrical vessels of constant dimensions. The resistance for laminar flow of a Newtonian fluid is only dependent on the dimensions of the vessel and the viscosity of the fluid. Resistance varies inversely as the fourth power of the radius of the vessel.

For resistances in parallel, the total resistance is less than that of any individual resistance (Fig. 1.2). Although the total cross sectional area of all arterioles is much larger than that of all arteries, their resistance to blood flow is much greater than that of the arteries. The number of daughter vessels is not high enough to balance the decrease in vessel diameter. The resistance is highest in the capillaries and it diminishes as the vessels increase in radius.

For resistances in series, the total resistance equals the sum of the individual resistances.

In contrast to Poiseuille’s conditions, the blood flow in the human circulation is pulsating and sometimes turbulent, and its blood vessels are not horizontally located, cylindrical or inflexible. Neither is the blood viscosity constant nor independent of vessel diameter and flow.

At rest the mean red cell velocity in the capillaries is observed to be approximately 1 mm in one s; this provides ample time for gas exchange. Since the circulating blood moves continuously, the cardiac output must pass a cross section of all open capillaries. At rest a cardiac output of 5000 ml per min is a reasonable estimate; when changed into volume rate per s, the cardiac output is equal to 10-4 m3 s-1. Hence, it is possible to calculate the large cross sectional area of all open capillaries in a resting person.  The total blood volume is approximately 5 l in a healthy adult.

 

Distribution of blood and flow 

The total blood volume (5 l) is distributed with 60-75% in veins and venules, 20% in arteries and arterioles, and only 5% in capillaries at rest. Of the total blood volume only 12% are found in the pulmonary low-pressure system. 

The distribution of the cardiac output to the main organ systems of the body in a healthy person at rest and during maximal exercise is given in Box 1-1.

Box 1-1: Distribution of flow in % of the cardiac output, arteriovenous oxygen content difference, oxygen uptake and absolute blood flow at rest. The same variables are given for maximal exercise (in brackets).

Organ system

Distribution

A-v difference

O2 uptake

Bloodflow

 

Flow%

ml STPD* l-1

ml STPD*min-1 

ml*min-1 

Splanchnic

27 (2)

40 (80)

60 (40)

1500 (500) 

Kidneys (300 g)

22 (2)

12-14 (28) 

16 (17) 

1200 (600)

CNS

14 (1)

60 (120)

45 (36)

750 (300) 

Myocardium (250 g)

4.5 (6.7)

140 (190)

35 (380)

250 (2000)

Muscle (35 kg)

19 (88)

50 (160)

53 (4200)

1050 (26 250)

Other organs

14 (1-2)

50 (100)

38 (35)

750 (350)

Total body

100 (100) 

50 (150) 

250 (4500) 

5500 (30 000)

A top athlete can show a 6-fold increase in cardiac output from 5 to 30 l of blood each min, when going from rest to maximal dynamic exercise. The heart rate increases from 60 to 180-200 beats per min. The muscle blood flow can rise from 3 to 75 ml per min per 100 g of muscle tissue (FU) or factor 25 in a total muscle mass of 35 kg. The muscular arterio-venous-O2 content difference can rise from the resting level (200 - 150) = 50 ml STPD per l of blood to (200 - 40) = 160 ml STPD per l.

At rest the athlete typically has an oxygen uptake of 250 ml STPD per min. The total muscle blood flow at rest is (35 000/100) * 3 = 1050 ml of blood per min. The total muscular oxygen uptake at rest is (1050 * 50/1000) = 53 ml per min (Box 1-1).

During maximal dynamic activity the total muscle blood flow is: (35 000/100) * 75 = 26 250 ml/min or 26.25 l per min. The total muscular oxygen uptake is increased to (160 * 26.25 l per min) = 4200 ml STPD per min (Box 1-1). 

Accordingly, the total muscular oxygen uptake rises by a factor of (4200/53) almost 80 from rest to exercise.

At the start of exercise, signals from the brain and from the working muscles bombard the cardiopulmonary control centers in the brainstem. Both cardiac output and ventilation increase, the a-adrenergic tone of the muscular arterioles falls abruptly, whereas the vascular resistance increases in inactive tissues. The systolic blood pressure increases, whereas the MAP only rises minimally during dynamic exercise. The total peripheral vascular resistance (TPVR) falls during exercise towards 30% of the level at rest, because of the massive vasodilatation in the muscular arterioles of almost 35 kg muscle mass. This is why the major portion of the cardiac output passes through the skeletal muscles (Fig. 1.3) and why the diastolic pressure often decreases during exercise. At moderate exercise the skin blood flow and heat dissipation is increased. The coronary blood flow increases from rest to exercise (Fig. 1.4 A to B).

 

Figure 1.3: Distribution of cardiac output during exercise

 

Figure 1.4: Blood flow through the left coronary artery at rest and during exercise

 

 

1.3     Microcirculation

 

The microcirculation is responsible for the transport of nutrients and oxygen to the tissues, and for removal of cellular waste products and CO2. The arterioles control the flow of blood to each tissue unit, and the metabolic conditions of the tissue cells determine the diameters of the vessels. Hereby, the tissue unit often controls its own blood flow by local mechanisms.

A microcirculatory unit is a collection of vessels that originate from an arteriole, which is characterized by well-developed smooth musculature in its wall (Fig. 1.5). Arterioles of the face, fingers and toes often branches into an arteriovenous anastomose, which functions as a shunt vessel, but which also can be closed completely. In certain tissues the arteriole branches into metarterioles (with so-called precapillary sphincters of smooth muscle fibers without nervous supply), which continue into large capillaries termed preferential channels (or thoroughfare channels). These channels shunt the blood to the veins. The small true capillaries have only a thin endothelial cell layer making the wall ideal for exchange.

Figure 1.5

The diameter of true capillaries is only 5-10 mm, barely enough for erythrocytes to squeeze through. The average length of capillaries is 1 mm, and the linear red cell velocity at rest varies around 1 mm each s. The capillary density is high in cardiac and striated muscle tissue and low in subcutis and in cartilage. Endothelial cells contain actin and myosin. It is uncertain whether capillaries may be able to alter their shape according to the needs of the tissues.

Important exchange vessels are thin-walled vessels with a large surface area. Exchange vessels comprise true capillaries, parts of preferential channels, and venules (Fig. 1.5). The number of pores is high in the venous ends of capillaries and in venules. Exchange vessels are any blood vessels, which allow transport of substances through its wall in both directions. The velocity of the blood flow in capillaries varies, sometimes with rhythmic pulsation, at other times random.

At rest the intracapillary pressure varies from arteriole to venule between 3.3 and 1.6 kPa (25 and 12 mmHg), during arteriolar vasoconstriction between 1.6 and 1 kPa (12 and 8 mmHg), and during vasodilatation between 5.3 and 1.6 kPa (40 and 25 mmHg). Arterial pressure fluctuations have been recorded even in the most distal parts of the capillaries. In venules and veins, however, the flow is smooth without fluctuations.

The capillary wall consists of a layer of endothelial cells (0.1 - 1 mm of thickness) resting on a basement membrane. At least three types of capillaries are present in humans:

1. Continuous capillaries are the most abundant. The distance between endothelial cells is 5-30 nm (Fig. 1.6). Tight junctions with narrow clefts are difficult to pass for the dissolved molecules and ions. In the continuous capillaries, the water filled pore surface area comprises only 10-4 of the total surface.

The continuous capillaries in the brain are low permeable to ions and most hydrophilic molecules, because their tight junctions are really tight (the blood-brain barrier).

2.  Fenestrated capillaries contain tight junctions and pores or fenestrations, which are fluid filled channels with a diameter of 50-100 nm. These are formed by two adjacent cell membranes that have fused during removal of the lipid bilayers, so only a diaphragm of protein lattice is left allowing bulk flow without colloids (Fig. 1.6). Fenestrations are round windows found in the capillaries of organs that transport lots of water (the bowels, glomerular capillaries of the kidneys, pancreas and salivary glands). In each fenestration bush-like filaments can be demonstrated by electron micrography.  The filaments are composed of a protein core with glycosaminoglycan side chains. The filaments and the protein lattice in the fenestrae keep plasma proteins back (Fig. 1.6). In the glomerular capillaries, water filled fenestrations cover 20% of the surface.

Figure 1.6:  Three types of capillary walls

3.  Sinusoid capillaries have very broad openings between the endothelial cells (Fig. 1.6). These large fenestrations have no diaphragm. Sinusoid capillaries are often found in tissues that are bathed in plasma (liver, spleen and bone marrow).

The circumventricular organs of the brain contain an abundance of fenestrations in the walls. The circumventricular organs are located close to the control centers of the hypothalamus and the brainstem. Any penetration of signal molecules in the neighborhood of these control centers is of physiological importance. In other areas with continuous capillaries, most substances cannot bypass the blood-brain barrier and reach the brain cells.

 

1.4     Transcapillary Fluid Exchange

 

Starling hypothesized that the fluid exchange across the capillary wall was determined by the hydrostatic (Pc) and the colloid osmotic pressure (pc) in the capillary (Fig. 1.7).

 

Figure 1.7: Transcapillary fluid exchange (Starling) is shown over a capillary wall. 

 

The flux of substance (J) over the capillary membrane is determined by (P × DC).

Fluid moves out of the arterial end of the capillary by filtration, because the net hydrostatic pressure (35-5 = 30 mmHg) is higher than the colloid osmotic pressure (pc= 26 mmHg), and most of the fluid (9/10) passes again into the blood by reabsorption in the venous end (Fig. 1.7). Here, the colloid osmotic pressure (26 mmHg) supersedes the hydrostatic pressure (15-1 mmHg equals14 or 1.9 kPa).

The net diffusion of water molecules across the capillary wall is approximately zero. Instead, the transvascular exchange is caused by a combination of an outward ultrafiltration and an inward colloid osmotic force. Ultrafiltration is caused by a hydrostatic pressure gradient created by the heart. The hydrostatic pressure gradient is a net outward force, moving water through pores in the capillary wall. Plasma contains dissolved protein, which cannot pass the small pores in capillary walls readily. The plasma proteins create a colloid osmotic pressure of about 3.3-3.7 kPa (25-28 mmHg). This pressure is much larger than the interstitial colloid osmotic pressure, so that the colloid osmotic gradient across the capillary wall is a net inward force, which draws water into the capillaries.

Starling described the transvascular water flow as early as in 1896. The driving forces are the so-called Starling forces.  The capillary protein reflection coefficient is symbolized s. s is the fraction of plasma protein molecules reflected off the capillary wall. The protein reflection coefficient is 0.9-1.0 for many capillaries, expressing that the colloid osmotic pressure gradient is not reduced over time by diffusion of proteins over the capillary wall.

The capillary filtration coefficient (Capf) corresponds to the permeability of the capillary wall. In the legs Capf is around 0.075 ml of fluid per min per kPa in 100 g of tissue (at body temperature). The combined pressures in the Starling equation ([(Pc - Pt) - s(pc - pt)]) determine, if there is a net pressure for water movement across the capillary wall.

In conclusion, water moves out of the arterial end of the capillary by filtration, and near the venule end, water moves into the blood by reabsorption. This transport along the capillary is called Starling´s paracapillary circulation. Thus there is normally a net filtration of water and some proteins into the interstitial space. This water and protein, returns to the blood via the lymphatic system (1/10 of the total filtration in Fig. 1.7). The lymph volume amounts to approximately 3-5 l daily, and is mainly produced in the liver and intestine. Starling presumed – erroneously - that proteins were unable to leave the blood in the capillaries (Fig. 1.8: A).

 

Figure 1.8:  Two models of transcapillary fluid exchange.  The capillary pressure (Pc) is protected                                     from large changes in MAP, but is sensitive to changes in venous pressure

This assumption is wrong. The capillaries are almost universally permeable to proteins and macromolecules that resemble proteins.

Another physiologist Drinker found protein in lymphatic fluid. Drinker developed a model, which presumed that capillaries to a variable degree were permeable to proteins (Fig. 1.8: B). Within a single capillary, the protein permeability increases from the arterial towards the venous end.

Let us assume that the heart is pumping out about 9000 l of blood every day. With a packed cell volume of 45% there is 55% plasma. This means that 4950 l is plasma. With a 6% protein concentration there is a total of 297 kg of protein. If less than 0.1 per cent (1/1440) of this protein is filtered into the interstitial fluid and lymph, it amounts to 206 g of protein daily. This amount of protein leaves the blood in the capillaries, and returns almost completely to the blood through the lymph and not the veins (Fig. 1.8: B). Hence, Starling’s paracapillary circulation obviously plays a dominating role in the transport of crystalloids (small molecules of nourishment and waste products) through the capillary wall.

The capillary hydrostatic pressure (Pc) varies from tissue to tissue. It is low in the lungs and intestine (1 kPa) and particularly high in the renal glomerular capillaries (6-8 kPa). In resting skeletal muscle capillaries, the pressure is 4.3 kPa (32 mmHg) at the arterial end and 1.6 kPa (12 mmHg) at the venous end. In general, Pc increases whenever the mean arterial pressure (MAP) increases, venule pressure (Pv) or resistance (Rv) increases, or when arteriolar resistance (Ra) decreases, according to the formula: Pc = [(Rv/Ra) MAP + Pv] developed in Fig. 1.8.  Normally, Rv/Ra is approximately 1/10. Thus Pc is protected from large changes in MAP, but is sensitive to changes in venous pressure including the central venous pressure (CVP).

In tissues, where the perfusion pressure is reduced to a value below a so-called critical closing pressure, the blood flow ceases due to vessel collapse. This is explained by the Laplace model (Fig. 1.9C).

Figure 1.9:  Laplace models for the relaxed ventricle (A), the spherical alveole (B), and the cylindrical blood capillary (C). 

The myogenic response also causes an important deviation from Poiseuille´s law. The myogenic response covers reactions where the vascular smooth muscle contracts in response to increased transmural pressure and vice versa. A decrease in transmural pressure (intravascular minus extravascular pressure) of the precapillary vessels elicits precapillary relaxation. A rise in transmural pressure elicits precapillary contraction. Perhaps the stretch of smooth muscle cells opens Ca2+-channels, whereby a Ca2+-influx increases the intracellular Ca2+ concentration sufficiently for contraction.

 

1.5     The Lymphatic System:

 

Macromolecules do penetrate the capillary wall and the content of lymph derives from plasma. Less than 0.1 per cent of all the plasma proteins that are being ejected from the heart in a 24-hour period escape from the capillaries. Pores of 40 - 60 nm permeate the venous end of the capillaries. Here, macromolecules can pass by filtration in a pressure determined fluid transport. Passage as a whole plasma portion (bulk flow) through fenestrations is also possible.

Transepithelial solvent transport can also draw solutes by solvent drag. Gradient dependent transport concepts such as filtration, bulk flow and solvent drag are used by different groups of scientists. When large amounts of lymph are being produced, solvent drag dominates over diffusion. At low lymph production, half of the protein transport is caused by diffusion. Fluid passes through the cell by pinocytosis. 

Capillary filtration predominates over capillary reabsorption resulting in an overshoot (a net filtration) of interstitial fluid. Most of the net filtration is reabsorbed into the blood of end-capillaries or venules (Starling´s paracapillary circulation).

The lymphatic vessels drain the remaining filtered fluid (See Fig. 1.7). The lymphatics are composed of endothelium-lined vessels similar to blood capillaries. Some lymphatics are equipped with one-way valves, so rhythmic activity in nearby skeletal muscles returns the lymph to the circulation via the thoracic duct. Lymph vessels originate as blind-ended sacs close to the blood capillaries. Lymph vessels are permeable to proteins, macromolecules and even to cells from the interstitial fluid. The lymphatic drainage is particularly important for transporting chylomicrons absorbed from the intestine, and to return plasma proteins that leak from several blood capillary systems. Lung tissue has no lymphatics, because the lymphatic vessels end at the terminal bronchioli. The lymph from the liver provides us with 50% of the daily lymph produced.

Lymphatic fluids from liver and kidney have a protein concentration equal to plasma’s (6-8 g per 100 ml), and lymphatic fluid from the bronchial tree has a similar concentration of protein.

Lymphatic fluids from skin and muscles contain only 2% protein, and brain lymph contains no protein at all.

 

1.6     Electrical Conduction:

The pattern of conduction for contraction of the heart is an electrical coupling event between cardiac muscle cells. Cardiac cells can be divided into three functional classes: myocardial or contractile cells, pacemakers or nodal cells, and conducting cells. The myocardial cells make up about 99% of the heart’s mass and are responsible for contraction and force generation. The second class of cells, pacemaker cells, provide the rhythmic electrical signals that will spread across the whole heart, causing a wave of contractions (heartbeats). Pacemaker cells can be found at the sinoatrial (SA) node and the atrioventricular (AV) node of the heart. The SA node has the highest rate of rhythmic discharge and is considered the heart’s natural pacemaker. This cluster of pacemaker cells determines the frequency of heartbeats, or heart rate. The signal that initiates in the SA node travels to the AV node where it is delayed. The third class of cells, conducting cells, form a conduction system specialized for conducting a signal rapidly from one part of the heart to another. From the AV node the signal follows a tight network of conducting cells known as the bundle of His. The bundle of His is comprised of one right, and two, left bundle branches that direct the signal to the lower tip (apex) of the heart. These branches curve back up to form a complex network of Purkinje fibers beneath the endocardium of the two ventricles, causing synchronized contraction throughout the heart (Fig. 1.10).

 

Figure 1.10

 

An electrocardiogram (ECG or EKG) is too used to measure and record the combined effect of all the cardiac action potentials or electrical activity of the heart.  By placing electrodes to measure voltage changes on the outside of the body, this type of recording gives information about electrical conduction in the heart.

 

The normal ECG has the following features:

 

1.7 The Cardiac Cycle:

 

The cardiac cycle constitutes the succession of atrial and ventricular electromechanical events. It is classically divided in ventricular systole and diastole, but these two phases are further subdivided as it is described below. During the cycle, gradient pressures are generated between the cardiac chambers and the great vessels, so they can be recorded and plotted on a diagram (Fig. 1.11). Here only the mechanical features of the cardiac cycle will be discussed.

The mechanical events of the cardiac cycle can be divided in seven phases. The description below is about the left heart, although it can be the same for the right heart. The difference is in the lower pressures reached by the right ventricle and pulmonary artery pressures.

·  Phase 1 - It is the onset of ventricular systole and coincides with the R wave peak in the ECG. According to the Starling’s Law of the heart, tension will be developed in cardiac muscle fibers proportionally to their previous stretching or clinically, end-diastolic-volume (the preload). The end diastolic volume (EDV) is about 135 mL. The ventricular pressure becomes higher than atrial one and the mitral valve close. The phonocardiogram at this moment must show the first heart sound (S1), also audible on auscultation. The origin of the first heart sound is complex and it is still debated. But for clinical purposes, it is well acceptable if one says it is originated by the closure of atrioventricular valves. The intraventricular pressure rises sharply while the mitral and aortic valves keep closed. This phase 1 is so called isovolumetric contraction. The term isometric should not be used since some fibers do lengthen while others shorten as the ventricular shape changes during systole. The aortic pressure curve shows an oscillation, reflecting the mechanical effect of the ventricle on the aorta during this period.

·  Phase 2 - When the intraventricular pressure overcomes the aortic diastolic pressure, the aortic valve opens and the left ventricle and the aorta become a common cavity. The pressure tracings during this period follow one another closely. This phase is called early or rapid ejection period. The aorta blood flow increases with time and blood coming into the aorta exceeds the peripheral runoff (blood leaving aorta from its branches). When the peripheral run-off becomes equal to ejection, the pressure curves flatten (rounded summit). The intraventricular volume reduces substantially. The venous pulse curve shows the c wave originated by the bulgement of tricuspid valve into the right atrium in the previous phase. The subsequent fall on the tracing is due to the descent of the base of the ventricle, the x wave.

 

·  Phase 3 - The aortic and ventricular pressure declines, while the peripheral run-off is still high. This is the reduced ejection period. The aortic pressure is slightly greater then ventricular one but the blood flow is still forward. This is explained by the momentum or inertia of blood: during the previous phase, the velocity was increasing with time and the blood gained some inertia, sufficient to keep it forward, despite the reversal gradient between aorta and ventricle. The aortic blood flow reduces sharply. Meanwhile, the venous return fills the right atrium gradually, originating the v wave on the venous pulse.

 

·  Phase 4 - When the momentum is over (equal to zero), there is virtually a reversal of blood flow in the aorta. Some blood “falls down” in the sinus of Valsalva and the aortic cusps come together preventing the regurgitation of blood into the ventricle. The second heart sound (S2), for clinical purposes, is due to the closure of aortic and pulmonic valves. There is a sharp decline in the ventricular pressure while the aortic and mitral valves keep closed and this period of time is so called the isovolumetric relaxation phase. The ventricular volume remains virtually constant and this is the residual volume (about 50 mL). The aortic curve shows a brief and sharp rise due to abrupt closure of the aortic valve: when the cusps come together, vibrations are generated and transmitted to the aorta wall. This is the dichrotic incisura or dichrotic knob that can be seen in another peripheral artery pressure recordings.

 

·  Phase 5 - The ventricular pressure becomes lesser than atrium pressure and the mitral valve opens. This is the onset of the rapid ventricular filling period. The right atrium pressure declines and produces the y descent on the venous pulse tracing. The third sound (S3) is recorded and it can be audible in a variety of diseases (as in heart failure) or sometimes, in healthy children. Blood coming from the atrium quickly fills the ventricle. The pressures in these two chambers decline sharply. There is a common cavity again and pressure curves are very similar, with the atrium pressure being slightly greater than ventricle.

 

·  Phase 6 - This is the reduced ventricular filling phase. The atrium and ventricle pressures rise gradually. Some authors call it the diastasis phase. The ventricular volume curve rises.

 

·  Phase 7 - The end of the cardiac cycle is the atrial systole: it accounts for approximately 25% of ventricular filling. The fourth heart sound (S4), (just as the a wave on the venous pulse), is due to atrial systole and is recorded in the phonocardiogram. It can be audible on auscultation in athletes or in some diseases, which the most common is systemic arterial hypertension, where the left ventricular compliance is reduced and a forceful atrium contraction is present. In fast heart rates (tachycardia), atrial systole is very important because the phases 5 and 6 are reduced. So the blood coming from the atrium will contribute with great importance to the ventricular filling, preventing low cardiac output (heart failure) and reduced coronary blood flow, since this occurs mainly at diastole.

In clinical practice, some terms are largely used and they are derived from the cardiac cycles events: stroke volume (SV) is the volume of blood the ventricle ejects at systole. The product of SV with the heart rate (HR) gives us the cardiac output (CO) (about 5 L/min). The ejection fraction (EF) is calculated dividing the SV by the EDV (usually 60-70%) and is an index of the contractile status of the heart.

Figure 1.11

Click Here To See The Volume/Pressure and Electrical Relationships in a Normal Cardiac Cycle

(The University of Utah’s HyperHeart web site)

 

1.8 Hemopoiesis and Blood Components:

 

Hemopoiesis is the formation of blood cells. All blood cells are derived from the multipotent stem cells. Stem cells produce erythroid cells, granulocytes, lymphoid cells, megacaryocytes and monocytes by a number of differentiation steps. Stem cells maintain normal cell populations in a healthy bone marrow controlled by hemopoietic growth factors, and stem cells have the capacity for self-renewal. Hemopoietic growth factors include erythropoietin, interleukins, glucocorticoids, sex hormones and thyroid hormones.

Stem cells and red cell precursors contain ribosomal RNA along with cell organelles. The cells lose organelles during maturition. Pronormoblasts, normoblasts and reticulocytes at each stage contain less RNA and increasing amounts of hemoglobin. Reticulocytes can still synthesise hemoglobin, have lost the nucleus, and remain in the bone marrow a few days before they enter the peripheral blood. Here, they lose their RNA after a couple of days and become mature red cells. The reticulocyte count is normally less than 2.5% of the red cell count, but following hemorrhage or hemolysis the reticulocyte-% increases reflecting increased erythropoiesis. When the bone marrow fails to respond to anaemia, the reticulocyte count may fall below 0.5%.

The normal hematological ranges are given in Box 1-2, together with other values of interest.

Box 1-2: Normal hematology values. The normal range varies from one laboratory to another.

Red cell count

4-6*1012 l-1

Leukocyte count

4-11*109  l-1.

Reticulocytes

0.5-2.5% of red cells

Platelet count

150-400*109 l-1

Mean Corpuscular Volume (MCV)

80-96 fl

Mean Cell Hemoglobin Concentration

320-350 g l-1

Mean erythrocyte lifespan

120 days

Hemoglobin (mol. weight monomer)

16 115 Dalton

Hemoglobin concentration (mean)

9.18 mM (149 g l-1 = 100%).

Packed cell volume (PCV, hematocrit)

40-50%.

Oxygen binding capacity (hemoglobin)

1.34 ml g-1 (60 mmol kg-1)

Oxygen concentration in arterial blood

200 ml STPD l-1

Erythrocyte sedimentation rate (ESR)

Less than 20 mm in the first hour

Osmolality of plasma

290 mOsmol (kg water)-1

When normal kidneys are perfused with hypoxaemic blood, the peritubular interstitial cells release large amounts of the glycoprotein hormone, erythropoietin, with a strong effect on the haemopoietic stem cells in the red bone marrow. The stem cells are stimulated to produce proerythroblasts, which speed up the production of new red cells after a few days. The increased erythrogenesis improves tissue oxygenation, which decreases erythropoietin production and the balance is re-established.

Chronic renal failure leads to erythropoietin deficiency, and thus to anaemia, which is of the normochromic, normocytic type.

 

The Red Cells

Hemoglobin is synthesized in the mitochondria of the maturing red cells. Vitamin B6 is a co-enzyme for the formation of d-amino-laevulinic acid (ALA) by ALA-synthetase. The reaction is stimulated by erythropoietin. One hemoglobin molecule binds 4 oxygen molecules at most. Hemoglobin consists of globin (2 a and 2 b polypeptide chains) and 4 prostetic haem-groups (Fig. 1.12). Hemoglobin A (for Adult) has a molecular weight of 64 460 g per mol (Dalton). Hemoglobin A comprises almost all haemoglobin in adults, supplied with only a minimum of hemoglobin A2.

The polypeptide chains are not covalently linked but are held together by hydrophobic forces. Each hem group is connected to one polypeptide chain, which contain a ring of 4 imidazol-groups. In the centre of the porphyrin ring the one iron atom is coordinated by 6 ligands, four of which bind the metal to the porphyrin chain, one to histidin on either the a- or the b-chains. The last is an open binding, which is able to bind either O2 or carbon monoxide (CO).

In the lung capillaries hemoglobin is saturated with oxygen at high tensions, where the affinity of (oxy)hemoglobin for more oxygen is high (Fig. 1.12). The affinity between oxygen and hemoglobin is defined by P50, an affinity index. A low P50 equals a high standard affinity and vice versa. The successive change in affinity during binding of the 4 oxygen molecules to each hemoglobin is caused by molecular interactions among the 4 hem groups. This explains the sigmoid shape of the oxygen dissociation curve. Oxygen is released at the low tensions of the tissues, where the affinity of (deoxy)hemoglobin for oxygen is low. The oxygen tension in the tissue mitochondria may reach extremely low values (zero to 1 mmHg or 0.133 kPa).

Red cells do not contain mitochondria, so they survive on anaerobic metabolism (glycolysis) and the anaerobic intermediate, 2,3-diphosphoglycerate (2,3-DPG), is produced by the help of a red cell enzyme. As the 4 hem units successively unload oxygen, the b-chains of deoxyhemoglobin are pulled apart, and 2,3-DPG binds strongly to the 2 b-chains of deoxyhemoglobin (Fig. 1.12). This electrostatic binding substantially reduces the affinity between oxygen and hemoglobin. Individuals with high arterial pH (chronic alkalosis) or with low arterial oxygen tension (hypotonic hypoxaemia) increase their concentration of 2,3-DPG in their red cells. Storage of blood reduces the 2,3-DPG concentration with time.

Figure 1.12: Model of oxyhemoglobin’s (oxyhaemoglobin) relaxed binding structure and deoxyhemoglobin’s (deoxyhaemoglobin) tight binding structure. The circular disk with Fe is hem

 

When hem is bound to O2 or CO, it has a cherry-red color, and hem is dark red when it is in the deoxygenated form. The breakdown of hemoglobin liberates CO and produces bilirubin that is yellow in color. Bilirubin is normally excreted with the bile. Failure of bile excretion leads to accumulation of bilirubin in the body. Jaundice (icterus) is a yellow pigmentation of the skin, plasma, cell membranes and secretions with accumulated bilirubin and other bile-pigments. Bilirubin and other pigments are also found in the blue-yellow skin-spots following lesions with subcutaneous bleeding.

Notice that when blood is saturated under the normal, ambient O2 partial pressure (20 kPa = 150 mmHg), the oxygen capacity of hemoglobin is 1.34 and not 1.39 ml STPD g-1 (Fig. 1.12). The latter holds only for extremely high partial pressures (above 45 kPa), when breathing pure oxygen or oxygen-enriched air, where the oxygen capacity is equal to the theoretical.

The rate of fall of red cells is called the erythrocyte sedimentation rate (ERS). The ERS is measured in a glass column of whole blood with anticoagulant. ERS is measured in mm as the cell free yellow zone above the red cells following 60 min of sedimentation. ERS is an estimate of the acute phase response. The acute phase response produces high levels of large sticky proteins (C-reactive protein, immunoglobulins, fibrinogen) that form rapidly falling piles of red cells. ERS is abnormally increased (above 20 mm) in infections, immunology reactions, ischaemia, malignancy or traumas. Normally, the level is only a few mm per first hour, 15-20 with a common cold, and 50-100 during pregnancy.

 

Viscosity of Blood

Viscosity is the inner friction in the fluid, which is due to the interaction between molecules and particles in the blood passing a cylindrical vessel. Telescope cylinders (laminae) of blood sliding against each other (Fig. 1.13) can illustrate this inner friction. The outermost blood cylinder rests against the vessel wall (velocity is zero), and the central cylinder moves (laminar flow) with the greatest velocity (v). The velocity profile is parabolic. The velocity gradient, with the distance x from the center of the blood vessel towards the outermost blood cylinder, is called the shear rate (dv/dx). The tangential force (F) between these blood cylinders depends upon the area (A) sliding against each other, and the relation to viscosity (h) is given by the equation in the legend to Fig 1.13.

Figure 1.13: Blood vessel with red cells and arrows showing different velocity (v).

F/A = h × dv/dx. The viscosity (h) one Pascal sec (1 Pa s) is the tangential force, working on 1 m2 of surface area, when dv/dx is 1 (s-1).  

This simplified description is valid for water, gas, and other homogenous fluids that are Newtonian fluids. Newtonian fluids are defined as fluids with a viscosity that is independent of the shear rate. Newtonian fluids move streamline or with so-called ideal laminar flow.

The viscosity of non-Newtonian fluids decreases with increasing shear rate, according to the equation above. Blood is namely not homogenous with a viscosity that is independent of shear rate. On the contrary, at low shear rates (low blood flow), the viscosity of blood can be ten-fold higher than normal. The typical normal viscosity of body warm blood is 5 centiPoise, equal to 5 milli-Pascal seconds (or 5 mPa*s).

Blood viscosity depends upon the concentration of red cells (the hematocrit).

A patient with anaemia and a PCV of 30% has a low blood viscosity and a poor oxygen transport capacity (Fig. 1.14). On the contrary, a patient with polycythaemia and a PCV of 60% has a high oxygen transport capacity, but the blood viscosity is dangerously high and he may develop thrombosis and emboli (Fig. 1.14).

Figure 1.14: Hemotocrit (PCV) and relative viscosity varies along the green line. A normal PCV of 45% is shown with the normal absolute viscosity of body-warm blood

With increasing blood flow (and shear rate), an increasing fraction of red cells is being pulled into the axial stream of small vessels, so that friction is being minimized. At high shear rates in large vessels, blood therefore mainly behaves like a Newtonian fluid, with a low and almost constant viscosity, as well as a linear relation between blood flow and the driving pressure.

The viscosity of blood apparently decreases in tubes with a diameter less than 0.5 mm (the small-diameter effect - or the Fåhraeus-Lindqvist phenomenon - see Fig. 1.15).

Figure 1.15: The viscosity of blood decreases abruptly in tubes with diameters decreasing from 0.5 mm (Fåhræus-Lindquist effect)

This is because the packed cell volume (PCV) is low in small vessels, since red cells have a tendency to accumulate and pass as a single plug in the fast axial stream, where there is a negligible friction. The slower layers along the vessel wall are passed mainly by plasma. This falling viscosity in the small resistance vessels and in the precapillaries and capillaries reduces the work of the heart. This is why the blood flow frequently rises linearly with the driving pressure and thus actually follows Poiseuille´s law, as if blood was a Newtonian fluid.

Blood flow tends to become turbulent in irregular vessels, where the flow velocity is high and the viscosity is low. Turbulence means irregular movements of the fluid elements - an energy demanding transport process.

Plasma viscosity is sometimes measured instead of erythrocyte sedimentation rate (ESR), because it is dependent of the same large sticky protein molecules as ESR, but is independent of the hemoglobin concentration and obtainable within 15-20 min.

 

Blood Coagulation

Whole blood consists of a fluid (plasma) in which blood cells and platelets are suspended. Blood cells consist of red cells (erythrocytes) and white cells (leukocytes). A small amount of anticoagulant to a blood sample blocks the coagulation process, and whole blood sediments into three layers: Below the heavy red cells, then a thin grey-white layer of white cells, and above a yellow fluid (plasma) with an invisible content of most of the platelets. A blood sample without anticoagulants normally sediments with coagulation (fibrin formation) within 5 min. A firm red mass is formed, and after some time it retracts and forms a red cone (a fibrin clot of blood cells and fibrin) surrounded by yellow serum.

Healthy humans possess both a fast extrinsic and a slow intrinsic clotting system. The coagulation process involves at least 3 systems, all of which contribute to the hemostasis. Firstly, a vasoconstriction occurs following release of serotonin from damaged endothel cells. Secondly, the fast extrinsic system goes into action, and thirdly, the slow intrinsic system contributes. Finally, the 2 coagulation systems operate together and converge for common reactive steps in order to produce thrombin (Fig. 1.16).

Disruption of the endothelial barrier by injury initiates a cascade of catalytic events through either or both clotting systems. At each reaction in the chain of events, a proenzyme coagulation factor is activated to its enzymatic form, which can activate the next reaction in the chain. The letter a stands for the active form. The enzymes are all endopeptidases (proteases), and their catalytic sites include a serine moiety.  By these many steps in the cascade, the process escalates until large amounts of thrombi are released. - Factor IV (Ca2+), factor V (proaccelerin), kininogen, kallikrein, and factor VIII are coagulation co-factors without enzymatic activity.

Thrombin is a protease that is responsible for the formation of fibrin monomers, and thus for formation of a fibrin clot. Its parent molecule is prothrombin (factor II), which is present in normal plasma. Thrombin formation from prothrombin goes through certain cleavage stages, the first of which is by activated factor Xa (Stuart). These reactions are augmented by factor IV (Ca2+), factor V (proaccelerin), and phospholipid (see green oval in Fig. 1.16). Thrombin initiates blood platelet aggregation, and disintegrates the plasma membrane of the platelets so phospholipid is provided. The coagulation factors are synthesised mainly in the liver. - An exception is the large Von Willebrands factor (vWf) complex, which is synthesized in the vascular endothelial cells and in megakaryocytes.

The fast extrinsic thrombin formation is initiated by the contact of blood with injured cells (Fig. 1.16). The damaged cells liberate a clot-promoting agent, factor III or tissue thromboplastin. Factor III interacts with a plasma protein, factor VII, to start a cascade of reactions by prothrombin activators leading to formation of thrombin within seconds (Fig. 1.16).

Clotting of blood implies conversion of a soluble plasma protein, factor I (or fibrinogen), into an insoluble network of fibrin. First, fibrinogen undergoes limited proteolysis by thrombin. The formed fibrin monomers polymerize into insoluble strands of fibrin polymers (Fig. 1.16). Finally the monomers of the fibrin strands are cross-linked by the enzyme activated (a) fibrin-stabilizing factor (XIIIa).