Calvin was first diagnosed with diabetes when he was 10 years old. He had initially responded well to the need to comply with his treatment regimen of dietary control and regular doses of insulin given by self-injection. He was familiar with these problems as both his father and grandfather also had diabetes.

However, by the time Calvin reached 18 years old his diabetes did not fit well with his own self-image. He wanted to be out enjoying life with his friends and did not like to feel he was ‘an invalid’. This led to him becoming lax with his medication and his blood glucose control became less rigorous.

There were a number of occasions on which Calvin felt unwell and over a period of 5 years there was a series of eight emergency hospital admissions. On one such occasion he had been drinking more water than usual (polydipsia) and had been producing greater than normal amounts of urine (polyuria) for about 3 weeks. He had become drowsy and lethargic and, for the 3 days prior to the hospital admission, he had been vomiting.

The doctor in the emergency room noted that he was underweight for his age and build. Initial observations included a pulse rate of 142 beats/min, a blood pressure of 100/60 mm Hg and abnormally deep breathing. A venous blood sample provided the following data:

[Glucose] = 37 mmol/L (3.5–5.5 fasting)

[Na⁺] = 132 mmol/L (135–145)

[K⁺] = 5.5 mmol/L (3.5–5.0)

[Haemoglobin] = 17.5 g/100 mL (13.5–18.0)

Normal reference values are shown in brackets.

A urine dipstick test also showed the presence of glucose and ketones.

This case history raises the following questions:

1. What evidence is there in this history of body fluid volume depletion?

2. What is the link between volume depletion, Calvin’s low blood pressure and his fast heart rate?

3. What aspects of this history give immediate cause for concern and form the basis for clinical management strategies?

Aspects of the answers to these questions are discussed in Case 1.1:2 and in the text of this chapter.

Some fundamental concepts in relation to these opening paragraphs need further explanation.

Textbook person

Textbooks of basic biomedical sciences are inherently sexist, ageist and do not recognize either relatively small or large individuals. They are written primarily about male, 70 kg subjects in the age range 20–25 years. Textbooks contain statements such as ‘cardiac output is 5 L/min’. This is a figure which may well apply to the textbook person at rest, but there are wide variations which all represent perfectly normal values for a given individual within the population at large.

Oxygen consumption

Our textbook subject at rest consumes about 250 mL O₂/min and generates 200 mL CO₂/min. This gives rise to the concept of a respiratory quotient (RQ):

The precise value for RQ in any individual will reflect the composition of their diet but for a typical person consuming a mixed diet of carbohydrate, fat and protein the RQ would be about 0.8. This means that we normally consume more oxygen than we produce carbon dioxide. During exercise oxygen consumption may increase to about 10 times the resting value and the RQ may move closer to a value of 1 due to preferential metabolism of carbohydrate.

Interesting facts

30–40% of all the food we consume in our lifetime is used to generate ATP to drive the sodium pump which maintains the sodium and potassium concentration gradients across cell membranes.

Oxygen is used within the mitochondria of cells to generate adenosine triphosphate (ATP). This provides the energy for movement, for the synthesis of macromolecules and to drive the movement of ions, particularly Na⁺ ions, across cell membranes against a concentration gradient. The distribution of Na⁺ and K⁺ inside and outside cells is summarized in Figure 1.1. The ion gradients are maintained by the sodium pump which expels three Na⁺ ions and pulls two K⁺ ions into the cell each time it operates. As both of these ion movements are against a concentration gradient, an ATP molecule is hydrolysed to provide the energy. For some cells there may be about a million sodium pumps each operating at about thirty times a second. In the body as a whole the sodium pump accounts for about 30% of all of our energy intake over our lifetime. In this way, ionic gradients are maintained which are essential for the continuing function of nerves and muscles, including the heart. Failure to maintain ATP generation in hypoxic tissues leads to osmotic swelling of cells and to a loss of normal cellular function (see p.7). To serve all the requirements, the quantities of ATP which must be synthesized are quite prodigious and amount to something roughly equivalent to an individual’s body weight every day.

Fig. 1.1 The left hand side of this diagram shows typical concentrations of Na and K inside and outside cells. The right hand side depicts the sodium pump which uses ATP to maintain the ionic gradients across cell walls. Concentration units are mmol/L.

Diffusion

Diffusion is the movement of particles from an area of high concentration to an area of low concentration. The concentration of a gas in solution is actually the product of the partial pressure and the solubility coefficient (a constant at a given temperature). Two sets of units are in common usage for gas pressures. The appropriate conversion factors are as follows:

Some important parameters determining rate of diffusion are:

• the diffusive gradient (concentration difference between two points)

• the solubility of the particle in the solvent; if it is not very soluble the concentration will be low

• the size of the solute particle (small particles will diffuse faster than large particles)

• temperature: diffusion is faster at high temperatures than at low temperatures; body temperature is about 37°C in normal human subjects.

Most diffusion in living systems takes place in an environment in which water is the solvent, although molecules such as oxygen and carbon dioxide also have to diffuse through the lipid bilayer which makes up cell membranes. Special provision, in the form of transport proteins and ion channels, is made for ions which carry a charge and are therefore not lipid soluble.

Einstein (1905) showed that the time taken for a molecule to diffuse between two points varies as the square of the distance between the points. In physiological terms, diffusion is fine as a process for moving molecules short distances. A typical cell diameter in the body is about 10 μm and the time taken for an oxygen molecule to diffuse this distance would be a few milliseconds. Diffusion of oxygen over longer distances, however, such as the approximately 10 mm (a thousand times 10 μm) thickness of the ventricular wall of the heart, would take a million times as long, a time measured in hours. This would be inconsistent with maintaining life as, given the composition of the atmosphere, the diffusive gradients of oxygen available to us would be too small. The solution to these problems is to have an amazingly profuse circulatory system which delivers the oxygen and other nutrients very close to the cells where they will be used. Cells in the body are rarely more than 50 μm from a capillary and most are not more than 10–20 μm away.

The diffusive gradients concerned with loading of oxygen into pulmonary capillary blood at the lungs and the delivery of oxygen into the tissues are shown in Figures 1.2 and 1.3. Figure 1.2 shows the events at the interface between an alveolus and a pulmonary capillary. A typical Po₂ in the alveolus is 13.3 kPa (100 mm Hg). Blood returning to the lungs has a Po₂ of about 5.3 kPa (40 mm Hg) and so oxygen diffuses into the pulmonary capillary blood from the alveolus. The diffusive gradient for unloading CO₂ at the lungs is much smaller than for O₂. Mixed venous blood Pco₂ is about 6.1 kPa (46 mm Hg) whilst alveolar Pco₂ is typically 5.3 kPa (40 mm Hg). The diffusive gradient for CO₂ (0.8 kPa) is 10% of the diffusive gradient for O₂ (8 kPa). Both diffuse at about the same rate because CO₂ is 20 times as soluble in water as O₂. The transit time for red blood cells through pulmonary capillaries at rest is about 1 second but the diffusive exchange of O₂ and CO₂ is normally complete in about 0.25 seconds.

Fig. 1.2 Loading of oxygen by diffusion from the alveolae into pulmonary capillaries.

Fig. 1.3 Diffusive gradient. Diffusive gradient for oxygen from arterial blood to the mitochondrion of a cell where the oxygen is used. The interstitial fluid outside the cell is part of the way down this diffusive gradient. When blood leaves the tissue as venous blood it has equilibrated with the interstitial fluid.

Delivery of O₂ into the tissues (Fig. 1.3) starts with the arterial blood which has picked up O₂ in the lungs (Po₂ = 13.3 kPa; 100 mm Hg). Oxygen is used inside the mitochondria and the Po₂ here is of the order of 0.1 kPa (about 1 mm Hg). The interstitial fluid outside a cell is part of the way down a continuous diffusive gradient between the arterial blood and the inside of a mitochondrion. A typical Po₂ in the interstitial fluid is 5.3 kPa (40 mm Hg). Blood leaving a capillary has equilibrated with this fluid and so venous Po₂ is the same as in the interstitial fluid.

Interesting facts

Under normal circumstances, the lungs have spare capacity for several of their functions. For example, completion of the exchange of oxygen and carbon dioxide at the pulmonary capillary: alveolus interface only takes about a quarter of the approximately 1 second available for gas exchange. These safety factors mean that some degree of malfunction of the heart and lungs can be tolerated.

Carriage of oxygen in blood

A further consequence of the poor solubility of oxygen in water is that we have evolved with an oxygen-carrying pigment, haemoglobin (Hb). The oxygen-binding characteristics of haemoglobin are such that it is nearly fully saturated with oxygen at the partial pressure of oxygen normally present in the alveoli of the lungs. Figure 1.4 shows the oxyhaemoglobin dissociation curve. At a Po₂ of 13.3 kPa (100 mm Hg), a typical figure for the alveolus, Hb is 97–98% saturated with O₂. This information can be used to calculate the amount of oxygen carried bound to haemoglobin as follows:

Fig. 1.4 Oxygen–haemoglobin dissociation curve.

Typical values for [Hb] are 120 g/L (women), 140 g/L (men). The figure 1.34 mL/g is the volume (mL) of oxygen bound to 1 g Hb when it is fully saturated. These figures mean that arterial blood contains about 200 mL O₂ bound to Hb per litre blood. A small amount (0.3 mL/L) is carried as dissolved O₂

Reference to the oxyhaemoglobin dissociation curve (Fig. 1.4) shows that venous blood is about 75% saturated with O₂ at Po₂ = 5.3 kPa (40 mm Hg) and therefore about one quarter of the O₂ carried in arterial blood has moved into the tissues. One quarter of the 200 mL O₂/L present in arterial blood is 50 mL. If 50 mL of O₂ is typically deposited in the tissues from each litre of arterial blood, and the textbook person’s cardiac output (volume of blood pumped per minute from each side of the heart—see Chapter 4) is 5 L/min, then 250 mL O₂/min is delivered to the tissues. This is the amount of oxygen identified previously as a figure for O₂ consumption rate for the textbook person at rest.

All tissues do not have the same oxygen consumption rate relative to blood flow. The figure quoted above, that ‘venous blood is typically 75% saturated with oxygen’, refers to ‘mixed venous blood’, i.e. the blood in the right side of the heart which is a mixture of all the venous drainages for the whole body. Venous blood from the kidneys, which have a high flow rate but relatively low O₂ consumption, has an oxygen saturation of about 90%. By contrast, the blood in the venous drainage from the heart is only 25% saturated with O₂. This is an important concept in relation to physiological control mechanisms and to the pathological consequences of disturbances of coronary blood flow (see Chapter 5).

Case 1.1 A design specification for the cardiovascular system: 2

Calvin’s acute circulatory problems

Calvin’s fundamental problem was a lack of insulin, a hormone which moves glucose from the circulation into cells particularly in the liver and skeletal muscle. In addition, in the absence of insulin gluconeogenesis, the conversion of amino acids from the breakdown of protein into glucose is promoted. The high blood [glucose] leads to an osmotic diuresis, excessive urine production and hence body fluid volume depletion. Responses to volume depletion in the form of blood loss (haemorrhage) are discussed in Chapter 14.

The diuresis is the cause of a high [haemoglobin] due to loss of fluid from the extracellular compartment. An appropriate clinical test for volume depletion is to compare standing and lying arterial blood pressure measurements. Normally there will be no substantial difference but in the volume-depleted patient there is a drop in pressure (postural drop) on standing.

In Chapter 4 of this book the links between blood volume and cardiac output (the volume of blood pumped by the heart per minute) are discussed. Basically, the fall in blood volume (a decreased preload on the heart) leads to a decrease in cardiac output and, as a consequence, a fall in arterial blood pressure. The baroreceptor reflex (see Chapter 10) reacts to a fall in blood pressure with an increase in heart rate and constriction of peripheral blood vessels.

Body fluid replacement with a combination of 0.9% saline and 5% glucose is the first priority in order to avoid circulatory collapse. The apparent anomaly of giving extra glucose to a patient with an already high blood [glucose] is explained as follows.

The textbook person contains about 42 L of water. The factors which determine the distribution of this volume between different compartments are described in detail in Chapter 11. Basically, about 14 L is in the extracellular compartment, which includes blood plasma and 28 L is in the intracellular compartment. An increase in the osmotic strength of body fluids, due to high blood [glucose] combined with a decrease in capillary blood pressure associated with volume depletion, means that there is movement of water from the intracellular compartment to the extracellular compartment. As a consequence Calvin suffers both intracellular and extracellular volume depletion. There is a high [Na⁺] in extracellular fluid and a low [Na⁺] in the intracellular fluid. Infusion of saline into a patient will therefore selectively expand the extracellular compartment. Administration of 5% glucose solution initially does not substantially change the osmotic strength of body fluids but, once the glucose has become distributed around the body, insulin supplements will drive the glucose into cells where it can be metabolized to CO₂ and water. Giving 5% glucose is therefore equivalent to an infusion of pure water and will initially dilute the extracellular compartment. The osmotic gradient created will move water into the intracellular compartment. Infusion of 5% glucose will therefore expand both the intracellular and extracellular compartments. These ideas are explained in more detail in Chapters 11 and 14.

A further potential cause for concern is the increase in plasma [K⁺]. This is likely to be a result of a ketoacidosis, a form of metabolic acidosis. At a level of 5.5 mmol/L this is not a significant problem, but further increases in potassium as a result of acidosis-induced movement of K⁺ from inside to outside cells can lead to the development of cardiac arrhythmias and potentially cardiac arrest (see Chapters 2 and 7). Despite a raised plasma [K⁺] there may be whole body depletion of K⁺ as most of the K⁺ is in the intracellular compartment.

Interesting facts

The task of working out the three-dimensional structure of haemoglobin was undertaken by Max Perutz in Cambridge. It took him 23 years but the answer taught us a huge amount about how the oxygen carriage mechanism works. He was awarded the Nobel Prize in 1962.

The shape and position of the oxyhaemoglobin dissociation curve (Fig. 1.4) shows one of the safety factors in relation to lung function. The top of the curve is nearly flat from 13 kPa (100 mm Hg), normal arterial Po₂, down to about 10 kPa (75 mm Hg). This means that a decrease in Po₂ within this range makes little difference to the % saturation of haemoglobin with oxygen, that is little change to the total amount of oxygen carried in arterial blood. Put another way, we can afford to have a certain degree of lung malfunction before it makes any significant difference to oxygen delivery to the tissues.

Cyanosis

Cyanosis is an important clinical sign. It refers to the blue colouration of the skin and mucous membranes produced by the presence of excessive amounts of deoxygenated haemoglobin in arterial blood. It is fundamentally classified into central and peripheral cyanosis.

Central cyanosis is often observed on the lips particularly but is conveniently looked for in a warm environment, the inside of the mouth. It represents a failure of the heart and lungs to ensure adequate oxygenation of the blood during passage through the lungs. There is no agreed quantitative standard for central cyanosis but the presence of 50 g of deoxygenated haemoglobin in 1 L of arterial blood is a commonly used definition. In some laboratories lower levels down to 20 g deoxygenated Hb in 1 L of blood are used to define central cyanosis. In a patient with 150 g Hb in 1 L of blood, 50 g/L as deoxygenated Hb is one third of the total, i.e. a % saturation of 67%. In anaemic patients, despite poor oxygenation of their tissues, a point is reached at which it would be impossible for them to become cyanosed. A patient with 70 g Hb in 1 L blood (about half normal) which is normally saturated with oxygen (97–98%) has enough oxygen delivery to the tissues to support life. However if 50 g Hb/L out of 70 g Hb/L in arterial blood was deoxygenated the patient would be dead not cyanosed.

Peripheral cyanosis which is visible in extremities such as fingers and ears is caused by impaired local blood flow and excessive local extraction of oxygen from the available blood supply. This occurs for example in cold environments (hence the expression ‘blue with the cold’) or in peripheral vascular diseases such as Raynaud’s disease (see Chapter 9).

Interesting facts

Polymorphismsof the haemoglobin molecule are thought to be the most numerous naturally occurring genetically determined variations of any protein in the body.

The battle against the hydrogen ion: acid–base balance

Proteins play many important roles in the body, as structural proteins, membrane ion channels and transporters and as enzymes.

The amino acids which make up proteins have a number of side groups which can bind or release H⁺ ions. These include carboxylic acid groups (COO⁻+H⁺ COOH), amino groups (NH₂+H⁺ NH⁺₃) and the imidazole side group of histidine which can be protonated. Increasing [H⁺] will make it more likely that these sites bind an H⁺ ion and, conversely, decreasing [H⁺] will make it more likely that H⁺ ions are released. These anionic and cationic sites are involved in forming ionic bonds which stabilize the three-dimensional structure of proteins and therefore changes in [H⁺] will alter the shape of proteins and will modify their functional characteristics. For example, altering the shape of ion channels will alter ion permeability and hence bring about changes in the membrane potential of the conducting system of the heart (see Chapter 2), and in the nervous system, which can be lethal. Close regulation of extracellular and intracellular [H⁺] is therefore crucially important.

Under normal conditions extracellular fluid pH is maintained within the narrow range of 7.36–7.44. A pH of 7.4 corresponds to a [H⁺] of 40 nmol/L (40×10⁻⁹ M). This is a very low concentration, especially compared to the other constituents of body fluids. Typical [Na⁺] in plasma, for example, is 140 mmol/L, over three million times the free [H⁺], yet it is commonly changes in [H⁺] which ultimately lead to death. The extremes of pH which are compatible with human life are thought to be pH 6.8–7.8 ([H⁺] = 160 to 16 nmol/L). It must be stressed however that these extremes could only be tolerated for a very short period of time and, clinically, very much smaller deviations from the normal range are a cause for concern.

Although we need to maintain [H⁺] in body fluids at a very low level, oxidative metabolism generates large quantities of H⁺. The major source of this H⁺ is carbon dioxide.

The textbook person generates about 14 moles of CO₂ per day. Failure of the circulation (as the transport system) and the lungs (as the site of excretion) to adequately get rid of this CO₂ leads to respiratory acidosis, a common feature of lung disease. Acutely, complete failure to excrete CO₂ for only a few minutes would lead to a rapid fall in pH and death. Overvigorous excretion of CO₂ (i.e. hyperventilation) leads to respiratory alkalosis, a pH above the normal range. Clinically, alkalosis is much less common than acidosis but is still potentially dangerous when it does occur.

The second form of acid to be excreted comes from the oxidative metabolism of dietary constituents. Complete metabolism of sulphur-containing amino acids, for example, will lead to the generation of sulphuric acid which must be excreted via the kidneys. The total load of such ‘metabolic acid’ for the textbook person is of the order of 50–100 mmol/day. Quantitatively this is a smaller challenge than the excretion of CO₂ but nevertheless it is very significant considering the low [H⁺] in body fluids. Failure to excrete H⁺ adequately via the kidneys leads to metabolic acidosis. Examples of this are renal failure or the overproduction of keto acids which occurs in poorly controlled diabetes mellitus, as in the case history of Calvin described in this chapter. Depletion of metabolic acid, as in vomiting, leads to a metabolic alkalosis.

The roles of the circulatory system in relation to acid–base balance can be summarized as buffering and transport. Buffering of H⁺ is essential to prevent substantial fluctuations in pH during the transport of H⁺ from the site of generation in the cells to the site of excretion in the lungs or kidneys. The most important buffering systems in blood are proteins, especially haemoglobin, and the bicarbonate buffer. Haemoglobin acts as a buffer because the protein component, globin, can absorb or release H⁺ as described earlier. The bicarbonate buffer relies on the generation of HCO⁻₃ by the kidneys each time a hydrogen ion is excreted into the urine. The transport function of the circulatory system is crucial in maintaining acid–base balance. It is essential to have a very profuse circulatory system with a blood capillary close to every cell in the body so that H⁺ ions can be removed immediately they leave the cells where they are generated. Local circulatory failure will lead to local tissue acidosis. This concept is further discussed in relation to shock mechanisms in Chapter 14 of this book.

Case 1.1 A design specification for the cardiovascular system: 3

Arterial blood gas measurements

Calvin provided an arterial blood sample for blood gas analysis, which gave the following results:

Pco₂ = 1.4 kPa (4.7–6.0) = 10.5 mm Hg (35–45)

Po₂ = 15.9 kPa (11–13) = 119 mm Hg (80–100)

pH = 7.15 (7.35–7.45)

[HCO⁻₃] = 3.5 mmol/L (24–30)

Base excess = −22 mmol/L (−2 to +2)

Normal reference values are shown in brackets.

Calvin has a ketoacidosis, a form of metabolic acidosis. This is shown by the large negative base excess. He is hyperventilating as a response to H⁺ ions detected by his peripheral chemoreceptors. The CO₂ produced in his tissues is being diluted into a volume of alveolar gas about three to four times the normal volume and hence Pco₂ is a quarter to a third of normal values. The Po₂ is high as a result of the hyperventilation and there is no indication of lung malfunction. An increase in Po₂ at this level does not significantly increase the volume of oxygen carried in the blood as haemoglobin is already 97–98% saturated at normal arterial Po₂ (Fig. 1.4).

Base excess is a quantitative assessment of the metabolic component of the acid–base disorder. Thus in this case each litre of body fluids has been depleted of bicarbonate (HCO⁻₃) by 22 mmol/L. This can be viewed as the result of bicarbonate binding to hydrogen ions and being excreted at the lungs as CO₂.

Clinical management of the acidosis may involve infusion of sodium bicarbonate but it will often be corrected just by administration of insulin. This will end the ketoacid production and hence help to normalize acid–base status. A danger in the management of the acidosis is the attendant fluctuations in plasma [K⁺]. During an acidosis there is effectively an exchange of H⁺ and K⁺ across cell membranes such that acidosis results in hyperkalaemia. This may itself become life-threatening (see Case 1.1:2). Treatment of the acidosis however brings its own problems. K⁺ ions re-enter cells when the acidosis is corrected but also one of the physiological roles of insulin is to move K⁺ into cells. This happens normally for example after the intake of a K⁺ load, such as a banana, chocolate or orange juice. The combination of a reversal of the acidosis and the effects of insulin administration may cause plasma [K⁺] to fall to dangerously low levels with consequent effects on the membrane potential of pacemaker cells in the heart (see Chapter 2).

Apart from its general role as a nutrient delivery and waste collection system in the body, the circulatory system has other functions in relation to the immune system (see Chapter 11) and in thermoregulation (see Chapter 9).

Cell injury and cell death

Cell injury

Cell injury may be reversible or irreversible. Often a cell/group of cells will initially adapt to a given stimulus and there may be no cellular signs of injury. An example is the cardiac muscle cell in mild hypertension. However, if the stimulus persists or increases in amount/frequency as in severe, long-term hypertension, reversible and ultimately irreversible injury leading to apoptosis or necrosis may occur.

Causes of cell injury

There are numerous causes of cell injury. These include: hypoxia (lack of oxygen), infection (bacteria, viruses, fungi), physical agents (hot or cold temperatures, ultra-violet radiation), chemicals (acids, alkalis), and immuno-logical stimuli such as autoantibodies against, for example, thyroid epithelium.

Cell injury occurs because a cell has to function outside its normal homeostatic capabilities. Thus, if acid is slowly added to the environment of a cell, initial adaptation may occur, but eventually a point of no return will be reached when the adaptive response can no longer protect the cell and cell death occurs.

Mechanisms of cell injury include:

• cell membrane damage such as that caused by complement pathway-related membrane attack complex or free radicals

• mitochondrial damage as seen in hypoxia and cyanide poisoning

• ribosomal damage as in the effect of alcohol on hepatocytes

• nuclear damage caused by radiation or viruses.

Although a particular agent may preferentially target one part of the cell, there is always a wide-ranging cascade of events. Thus, once the cell membrane is damaged, cell pumps such as the sodium pump described earlier will be compromised, also the cytoplasmic composition will change and this will affect mitochondria, the nucleus and other cell organelles.

The response to injurious agents will depend on both the type of cells involved and the type of agent.

Highly specialized cells with a cytoplasm rich in sensitive organelles, such as cardiac muscle cells or renal proximal tubular epithelial cells, may be more prone to cell injury from factors such as hypoxia or drugs than more simple cells such as fibroblasts. In addition, cells which are already compromised, by hypoxia for example, may be more prone to new or further injury than normal cells. The response of a cell population to injury is also dependent on the ability of the cells to divide. In this respect, the cells of the body can be categorized into three groups designated labile, stable and permanent.

• Labile cells divide continuously as they are maintained in the cell cycle (Fig. 1.5). They are often stem cells or precursor cells in a cell population such as basal epidermal or gut lining cells and bone marrow cells. A reduction in labile cell number can, potentially, be quickly reversed.

Fig. 1.5 The cell cycle. G₀, non-dividing (resting) state; G₁ and G₂, gap/preparation phases; S, replication of DNA. Source: Bass et al., 2009.

• Stable cells are usually excluded from the cell cycle and are found in G₀. They can be driven into the cell cycle, at G₁, by an appropriate stimulus. This usually involves growth factor production by the surviving similar or neighbouring different cells. Once in the cell cycle, they can divide and restore cell numbers. Examples of this include renal tubular epithelial cells after acute tubular necrosis or hepatocytes after viral hepatitis.

In both labile and stable cell populations there is a large potential ‘reserve’ for restoring cell numbers and therefore tissue/organ function. This replenishment of a cell population by exactly similar cells is known as ‘regeneration’.

• Permanent cells have no ability to divide and are excluded from the cell cycle. The classic examples are neurones and cardiac myocytes. Thus, after the brain and heart have been fully formed in utero, no new neurones or cardiac muscle cells will appear. These cells cannot replicate when cells are lost as, for example, after significant hypoxia. The body therefore has an alternative strategy. ‘Scarring’ known as gliosis in the brain and fibrosis in the heart, occurs and the dead cells are replaced by inert, non-specialized, fibrous tissue composed mainly of collagen. This is laid down by myofibroblasts found in granulation tissue. The process whereby the cells of a tissue are replaced by scar tissue is known as ‘repair’.

The type of agent causing the injury will also be important. Some cells, such as cardiac myocytes, are more prone to hypoxia than for example fibroblasts. The length of time cells are exposed to the injurious agent is also important, and after a significant time period even fibroblasts will be injured by hypoxia. A further critical variable is the severity of the exposure. Cardiac myocytes are more prone to injury in anoxic (no oxygen) conditions than mild hypoxic (relative lack of oxygen) conditions.

Cell death: apoptosis and necrosis

It is now well established that cell death is actually a spectrum of cellular events and changes. At one end of this spectrum is ‘apoptosis’, a recognized normal physiological event, and at the other is the pathological process of ‘necrosis’.

Apoptosis occurs when cell populations need to be fine-tuned. Although essentially a physiological event, it can occur as part of pathological processes. Physiologically, during fetal development, the digits of the hands and feet develop from solid ‘bars’ of tissue and the interdigital webs are removed by apoptosis. Similarly, the lumen in many hollow viscera is produced by apoptosis of the central cells. Autoreactive T lymphocyte cells are deleted from the young thymus by apoptosis. During the apoptotic process, the cell itself switches on genes which code for new proteins and some of these proteins cause the cell to die. Hence the term ‘cell suicide’ is used to describe apoptosis. Endonucleases cause DNA fragmentation and caspases destroy proteins. The cell is effectively killed from within. Cell membrane pumps may remain viable until the very end of the process. Morphologically, the cell shrinks, the nuclear chromatin condenses and the cell breaks up into a number of apoptotic bodies, which are cleared up (phagocytosed) by macrophages or neighbouring cells. The apoptotic cells are recognized by novel surface signal molecules. The apoptotic process is extremely quick, lasting a few minutes. It often only affects a relatively small number of cells and causes no lasting tissue damage.

At the other end of the cell death spectrum is necrosis. Necrosis is the sum of the morphological changes that result from cell death in a living tissue. Necrosis is pathological, involves large numbers of cells and, importantly, evokes a potentially damaging, inflammatory response. Table 1.1 shows a comparison between apoptosis and necrosis. There are five main types of necrosis and these are outlined in Table 1.2.

Table 1.1

Comparison of apoptosis and necrosis

Feature	Apoptosis	Necrosis
Type of process	Programmed cell death usually physiological	Pathological cell death
Purpose of process	Process used to ‘fine tune’ cell populations—individual cells/groups of cells involved (e.g. finger webs in embryogenesis)	Pathological event, often causing massive tissue destruction with numerous cells dying (e.g. myocardial infarction)
Progression of process	Complex ‘triggered’ series of intracellular biochemical events involving enzyme production and activation (DNA switched on)	Pathological insult tips cells out of limits of adaptability and irreversible cell death occurs
Rate of process	Very rapid	Usually slow
Final result	Ultimately cell shrinks, nucleus condenses and cell fragments into apoptotic bodies which are phagocytosed. No inflammation occurs	Ultimately the cells swell, burst and the intracellular contents often provoke intense inflammation

Table 1.2

Types of necrosis

Overall, therefore, cell death usually results in cessation of function of a tissue or organ. In necrosis, the dead cells rupture and there is spillage of cell contents. Amongst the extruded material there may be enzymes/proteins from the cytoplasm or specific organelles that enter the blood stream. These enzymes/proteins can be used as clinical ‘markers’ to assess which cells are damaged, the extent of the damage and even the timing/duration of the process. Examples of this include enzymes released following myocardial necrosis (see Chapter 5).

Overall functional structure of the cardiovascular system

The gross structure of the cardiovascular system is that we have two populations of blood vessels, the systemic and pulmonary circulations, which are perfused by two pumps mounted in series (Fig. 1.6). The fact that the two pumps are joined together in the heart with a common control system is convenient but is not theoretically essential.

Fig. 1.6 Gross structure of the circulation. The arrows indicate the direction of blood flow.

The relatively high pressure developed in the systemic arterial system, a result of the left ventricle pumping against the resistance to blood flowing through the rest of the systemic circulation, provides the driving force to perfuse all the tissues of the body with blood except the lungs (see Chapter 10). A series of arterial vessels branching from the aorta distribute the blood to the tissues of the body. Within these tissues, distribution of blood flow is primarily controlled at the level of the arterioles and pre-capillary sphincters but exchange of nutrients and waste products takes place in the capillaries (see Chapter 11). Blood then drains through venules into small veins and eventually the great veins (superior and inferior vena cavae) to return to the right side of the heart. The structures and functions of each of these types of blood vessel will be described later in this chapter.

The output from the right side of the heart serves the relatively low pressure pulmonary circuit (Fig. 1.6). Blood leaves the right ventricle in the pulmonary artery and gas exchange between blood and the alveoli of the lungs occurs in the pulmonary capillaries. Carbon dioxide diffuses from the blood into the alveoli and oxygen diffuses in the reverse direction. Blood returns to the left side of the heart in the pulmonary veins.

Blood pressure in the circulation

The systemic loop is a relatively high-pressure circuit. The peak (systolic) pressure generated in the aorta when the left ventricle contracts is typically 120 mm Hg and the trough (diastolic) pressure reached when the ventricle is refilling is typically 80 mm Hg. Mean pressure is 93 mm Hg (see Chapter 10). After passage of blood through a series of resistances, small arteries, arterioles, capillaries, venules and veins, the blood returns to the right atrium where the mean pressure is typically 0–5 mm Hg. There is a continuous drop in pressure going round each of the loop circulations. This is of course essential for blood to flow from one point to the next, that is downhill in pressure terms.

The pulmonary blood supply is a relatively low-pressure loop. The systolic pressure generated in the pulmonary artery is typically 20–25 mm Hg and the diastolic pressure 8–12 mm Hg. Pulmonary capillary blood pressure is about 8–11 mm Hg and any significant increase in this value leads to excessive movement of water out of the pulmonary capillaries and a major clinical problem, pulmonary oedema (see Chapter 11). Pressure in the pulmonary vein and the left atrium is normally about 5–8 mm Hg.

Case 1.1 A design specification for the cardiovascular system: 4

Calvin’s cardiovascular problems later in life

By the time Calvin was 40 he had developed hypertension. His GP told him that this was more common in diabetic than non-diabetic subjects and this was especially true for people of Afro-Caribbean descent such as Calvin. Hypertension affects over half of all people with diabetes. The regulation of arterial blood pressure and the development of hypertension are discussed in Chapter 10. The GP explained to Calvin that he was concerned because the combination of his still poorly controlled diabetes and his hypertension posed a considerable risk of a future heart attack or stroke. These problems are often secondary to the development of atheroma (see Chapters 5 and 8).

The risk of myocardial infarction or angina is between two and four times greater in diabetic patients than in the general population. Cardiovascular disease is the major cause of death in diabetes.

Now 48 years old Calvin began to notice a new set of problems. His feet lost their sensitivity to touch and pain. This meant that his feet were frequently damaged because he bumped into things or cut them. He could not tell whether shoes fitted correctly or not. The damaged area would ulcerate and become infected. The process of healing was very slow and eventually the ends of two of his toes on his right foot became necrotic (gangrenous) and had to be amputated. The loss of sensation in Calvin’s foot is called a neuropathy. It arises because of the altered metabolic state in diabetes and particularly affects the sensory nerve endings in the hands or feet (‘glove’ and ‘stocking’).

Calvin had been referred to a hospital clinic where the team had been monitoring his kidney function regularly. Previously a regular series of urine dipstick tests for albumin conducted in the surgery had failed to show any positive results, although urine samples sent to the local hospital laboratory had provided evidence of microalbuminuria (a raised level of protein in the urine but still below the sensitivity of a dipstick test). He was prescribed an angiotensin converting enzyme inhibitor (ACE I) drug. It was hoped that this would help, in combination with other drugs, to control his raised blood pressure but also would slow the progression of renal failure by attenuating fibrotic mechanisms (see Chapter 9).The situation changed and now the albumin in Calvin’s urine did become detectable by dipstick.

Some of Calvin’s new problems were the result of diabetes-induced vascular damage. The background to this is outlined in Case 4.1:5.

Note: pressures in the circulatory system are measured relative to atmospheric pressure. Thus a pressure of 0 mm Hg in the right atrium means that it is the same as atmospheric pressure. Factors determining arterial blood pressure are described in Chapter 10.

Circulation time

The blood volume of an individual can be estimated to be between 7 and 8% of total body weight. For the textbook person weighing 70 kg, therefore, blood volume would be between 4.9 and 5.6 L. For a lean person, the figure of 8% is more appropriate, whereas 7% would apply to those more generously provided with adipose tissue.

Resting cardiac output for the textbook subject is about 5 L/min (see Chapter 4). This means that, at rest, the average red blood cell is doing a complete circuit of the double loop circulation described above every minute. During exercise (see Chapter 13) cardiac output may increase about fivefold. As blood volume is still the same, the average red cell is now completing the double circuit in 12 seconds.

Arterioles

Arterioles typically have a lumen diameter of about 30 μm and a wall thickness of about 6 μm. Smooth muscle is a major component of the vessel wall and contraction is regulated by a range of mechanisms (see Chapter 9). The arterioles, together with some small arteries, are referred to as ‘resistance vessels’ and are the major site for regulation of the distribution of blood flow and for arterial blood pressure regulation (see Chapter 10). During passage through the arterioles blood pressure drops from about 55 mm Hg to 25 mm Hg at the entrance to the capillary segment. In the resistance vessels the pulsatile blood flow is smoothed out to a constant vessel pressure.

Figure 1.9 is a diagram of the ‘microcirculatory unit’, the arrangement of arterioles, pre-capillary sphincters, capillaries and venules inside a tissue. At the entrance to a capillary bed from an arteriole there is a small cuff of smooth muscle which acts as a pre-capillary sphincter. Closure of the sphincter means that the capillary is not perfused with blood. In resting muscle tissue, of the order of 90% of sphincters may be shut at any one time but will open during exercise (see Chapter 13). The sphincters have no nerve supply but are regulated by local metabolite concentrations.

Fig. 1.9 Microcirculatory unit. The shaded areas represent smooth muscle.

Capillaries

Capillary walls have a single layer of endothelial cells about 0.5 μm thick with a surrounding, non-cellular, basement membrane. Capillary walls do not have smooth muscle but contractile elements within endothelial cells allow them to change shape in response to chemical mediators. This occurs, for example, as part of inflammatory reactions. The cells are not uniform in either structure or function throughout the body and this is discussed in more detail at the start of Chapter 11. Capillaries are the site of exchange of nutrients and waste products between the circulation and the interstitial fluid surrounding cells in the body. This is aided by the low velocity of flow through capillaries. They are the smallest blood vessels and make by far the largest contribution to the 60 000 miles of tubing which comprise the entire circulation. Despite this, only about 6% of total blood volume is flowing through capillaries at any one time (Fig. 1.7).

The capillaries, because they are so profuse, present an enormous cross-sectional area and therefore have a relatively small resistance to blood flow, especially compared to the arterioles. Pressure drop across a typical capillary bed is from 25 mm Hg at the arteriolar end to 15 mm Hg at the venule end.

Venules

These vessels have an internal diameter of the order of 30 μm and a wall about 3 μm thick. The wall comprises an endothelial cell lining together with small amounts of fibrous tissue and an often incomplete layer of smooth muscle. In common with capillaries, venule walls are an important site for the movement of water and nutrients between the circulation and the interstitial fluid (see Chapter 11).

Veins

Small veins typically have an internal diameter of the order of 5 mm and a wall thickness of about 0.5 mm. The walls of veins do contain both elastic and fibrous tissues and also smooth muscle but all of these are in smaller quantities than equivalent-sized arteries.

Veins are very distensible, in other words, if pressure increases inside a vein it will expand easily. Small veins accommodate a high percentage of total blood volume (about 45%) (Fig. 1.7) and have an effective venoconstrictor sympathetic nerve supply. This is important to avoid venous pooling of blood in the lower half of the body, especially during changes in posture (see Chapter 9). Small veins in the lower half of the body have valves which are an important aspect of the venous return mechanisms which move blood against the force of gravity from the legs back to the heart (see Chapter 4).

Pressure drop from the end of the venules (15 mm Hg) through the small veins and vena cava to the right atrium (0–5 mm Hg) is sufficient to ensure flow of blood back to the heart but the small gradient illustrates the fact that these vessels do not pose a major resistance to blood flow.

Box 1.1 Microvascular and macrovascular disease in diabetes

Diabetes increases the risk of both microvascular and macro-vascular complications. This will be made worse by the coexistence of other risk factors such as hypertension, cigarette smoking and hypercholesterolaemia (see Chapter 5).

Poorly controlled diabetes is associated with an increased risk of microvascular complications. Capillary basement membranes become thickened with consequent alterations in their permeability and structural integrity (see Chapter 11). The capillaries of the retina and the kidney are particularly susceptible. Damage to the blood vessels of the retina makes diabetes the commonest cause of blindness in people aged 30–69, a 20-fold increase in risk compared to non-diabetic patients.

In the kidney, glomerular basement membrane changes lead to an increasing permeability to plasma proteins and the entry of increasing amounts of albumin into the nephron. Normally, the small amounts of protein filtered in normal subjects are reabsorbed in the proximal tubule but eventually this mechanism is overwhelmed resulting in proteinuria. This may lead on to the development of oedema (see Chapter 11) and eventually to end-stage renal failure which must be managed by either dialysis or transplantation.

Microvascular problems in diabetes are not however the major cause of cardiovascular death in diabetic patients. Macrovascular complications are 70 times more likely to be fatal. Ischaemic heart disease and peripheral vascular disorders affecting large arterial blood vessels in the legs for example are usually secondary to the development of atheroma (see Chapter 5). About 85% of strokes are atherothrombotic and the risk of this is two to three times higher in patients with diabetes. The remaining 15% of strokes follow an intracranial haemorrhage and the incidence is similar in diabetic and non-diabetic subjects.

Vena cavae and other large veins

The inferior and superior vena cavae are sometimes referred to as the great veins. The inferior vena cava has an internal diameter of about 30 mm, larger than the aorta, but a wall thickness (1.5 mm) which is less than the aorta. The walls of the vena cavae contain quite a lot of fibrous tissue together with some elastic tissue and smooth muscle. These large veins contain about 15% of total blood volume (Fig. 1.7).

The fibrous tissue in the wall of the vena cava provides strength. This is necessary because wall tension in this large vessel is significant. This can be illustrated by reference to the law of Laplace. This law applies to any distensible structure and links wall tension (T), radius (R) and the pressure difference (ΔP) across the wall of the vessel, the transmural pressure (Fig. 1.10):

Fig. 1.10 Law of Laplace applied to a blood vessel.

Although pressure inside the vena cavae is low, the radius is large and so a significant wall tension is developed. Application of this principle to capillaries, which have a very small radius, reveals that capillaries have very low wall tension and so do not tend to burst despite having a wall only one cell thick and containing blood at a higher pressure than the veins.

Angiogenesis

Most of the cells which make up blood vessel walls have a very long turnover time which is measurable in terms of months or years. In the brain capillary turnover time is particularly long.

In certain circumstances, such as in wound repair and in replacing the endometrium of the uterus every 28 days in menstruating women, there is a need for the formation of new blood vessels—angiogenesis. Excessive unwanted angiogenesis also occurs to support tumour growth and in chronic conditions such as psoriasis and rheumatoid arthritis. Conversely, insufficient angiogenesis is thought to be a feature of some aspects of heart disease, strokes and other pathological states.

New blood vessels form as branches (sprouts) from existing capillary blood vessels. The first stage involves the proteolytic digestion of a portion of the basement membrane followed by endothelial cell proliferation. This occurs close to the parent blood vessel and allows the immature blood vessel to grow towards a chemical stimulus generated by, for example, a hypoxic site or developing tumour cells. The migrating endothelial cells have eventually to form a tube and link up with another set of migrating cells before blood circulation can occur.

There are a host of cytokine agents implicated in both promoting and inhibiting angiogenesis. There is much research interest in their role in disease mechanisms and in exercise physiology. The potential therapeutic use of drugs which could, for instance, suppress the development of the new blood vessels which allow tumours to increase in size is widely recognized.

From cradle to grave—the presentation of heart disease

Heart disease may present at any age though there are two clear peaks—the very young and the old. However the range of pathologies is quite distinct. Most children with cardiac problems are born with their heart disease whereas most adults acquire theirs. The Barker hypothesis suggests that in fact we are born with the potential for the acquired forms.

Babies with major heart problems may be diagnosed before birth and antenatal screening methods are improving all the time. The majority of major defects will present within a few hours of birth with symptoms such as breathlessness and poor feeding and signs such as cyanosis and murmurs (see Chapter 12). Incidental findings subsequently become the major route by which cardiac defects are identified, usually when children present to their GP or hospital with other illness which may be exacerbated by underlying heart disease.

An increasing number of conditions are found through screening children where there is a family history of genetically transmitted pathology, such as hypertrophic obstructive cardiomyopathy or long QT syndrome. Some cardiac illnesses are acquired during childhood. The commonest of these is Kawasaki’s disease, an acute vasculitis which may lead to involvement of the coronary arteries with dilatation and stenosis. In the developing world rheumatic heart disease is a common cause of acquired heart disease in childhood triggered by streptococcal infection.

Between the ages of 5 and 40 the incidence of new cardiac disease reaches its nadir. There is a steady trickle through GP’s surgeries and hospital clinics of chest pain, palpitations and exercise intolerance—all associated in the public and physician’s mind with cardiac disease but seldom demonstrating any convincing pathology in this age group. Some will be musculoskeletal in origin, some atypical asthma, the majority nothing at all. Sadly, one of the major presentations of heart disease in this age group is sudden death for which a cardiac cause may be identified. This may trigger the screening of other family members in order to identify those at risk. An important group of patients is those in whom a familial dyslipidaemia is the underlying cause of accelerated atheromatous coronary disease. A carefully taken history looking at the incidence of sudden death or cardiac disease in young people will provide important clues to the likelihood of underlying pathology.

Slowly the classical features of coronary artery disease will begin to dominate the population as it ages. Symptoms such as swollen ankles (see Chapter 11), chest pain (see Chapter 6) or dyspnoea with exertion (see Chapter 5) herald the long-term decline related to progressive obstruc-tion of the coronary arteries. The prevalence of cardiovascular disease rises steadily from the fourth decade. The initial evidence may come in the first acute myocardial infarction or even sudden death (the more common presentation in women over the age of 50). Various risk factors are recognized as increasing the progression of this condition; lifestyle factors such as smoking, obesity, inactivity and alcohol intake; medical problems such as diabetes, hypertension; genetic factors leading to familial predisposition. All must be assessed and factored in to the risk assessment and management of the individual.

Case 1.1 A design specification for the cardiovascular system: 5

Calvin’s macrovascular complications

Calvin is now aged 62. His diabetes is reasonably well controlled but his compliance with the drugs he has been prescribed to reduce his blood pressure is not good. The problems with his feet and the toe amputations have reduced his mobility and this contributes to his being overweight and to a generally depressed approach to life.

Three months ago he started to experience crushing chest pains and to become more breathless. A coronary angiogram showed significant narrowing of his coronary arteries. Further tests are planned but Calvin feels he is just waiting for a heart attack to happen. Coronary blood flow regulation and myocardial infarction are discussed in Chapter 5.

Increasingly the detection of coronary heart disease occurs in screening programmes. So called ‘Well Person Clinics’ check for risk factors. The importance of this type of screening is increasing as it becomes more obvious that risk factors may be modified by interventions such as lifestyle changes and pharmacological therapy including cholesterol-lowering and antihypertensive drugs.

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A DESIGN SPECIFICATION FOR THE CARDIOVASCULAR SYSTEM

A DESIGN SPECIFICATION FOR THE CARDIOVASCULAR SYSTEM

Textbook person

Oxygen consumption

Diffusion

Carriage of oxygen in blood

Cyanosis

The battle against the hydrogen ion: acid–base balance

Cell injury and cell death

Cell injury

Causes of cell injury

Cell death: apoptosis and necrosis

Overall functional structure of the cardiovascular system

Blood pressure in the circulation

Circulation time

Structure and function of blood vessels

Structure of the blood vessel walls

Arteries

Large arteries (elastic arteries)

Small arteries (muscular arteries)

Arterioles

Capillaries

Venules

Veins

Vena cavae and other large veins

Angiogenesis

From cradle to grave—the presentation of heart disease

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A DESIGN SPECIFICATION FOR THE CARDIOVASCULAR SYSTEM

A DESIGN SPECIFICATION FOR THE CARDIOVASCULAR SYSTEM

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