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Ovid: Oxford Handbook of Medical Sciences

Editors: Wilkins, Robert; Cross, Simon; Megson, Ian; Meredith, David Title: Oxford Handbook of Medical Sciences, 1st Edition Copyright ©2006 Oxford University Press, 2006, except ‘Clinical aspects’ section of Chapter 2 (Copyright by Keith Frayn) > Table of Contents > Chapter 6 – Respiratory and cardiovascular systems Chapter 6 Respiratory and cardiovascular systems The Thorax Anatomy of the thorax and lungs The thoracic cavity extends from the neck to the diaphragm. It is bounded by an osteocartilaginous framework and contains the lungs and associated structures, as well as the great vessels, the heart, and part of the oesophagus. The lungs are spongy elastic tissue made up of alveoli, which are fed air via the bronchial tree of branching bronchi. The thoracic cage contains two lungs, one on either side of the mediastinum. The hilum is the root of each lung and the point where all the important vessels (including nerves, pulmonary vessels, bronchial vessels, lymph vessels) enter and leave. The lung is divided into lobes by the visceral fissures. Right lung The right lung comprises the superior, middle, and inferior lobes. The middle and inferior lobes are separated by the oblique fissure. This runs from the spinous process of the 2nd thoracic vertebra posteriorly to the 6th costal cartilage anteriorly. The horizontal fissure separates the superior and middle lobes. It runs from the point where the 4th rib crosses the oblique fissure and around to the 4th costal cartilage anteriorly. Left lung The left lung comprises the superior and inferior lobes. The two lobes are divided by the oblique fissure which follows the corresponding surface markings to those of the right oblique fissure. Borders of the lungs

  • Anteriorly: costal and mediastinal surfaces of the lungs
  • Inferiorly: diaphragmatic surface of the lungs
  • Posteriorly: costal and mediastinal surfaces of the lungs.

The cardiac notch is found on the medial surface of the left lung, where the lateral heart border indents on the lung surface. Lung surface markings Posteriorly, starts at T12, moving laterally along the 12th rib to the mid-scapular point, and to the 10th rib at the mid-axillary line. It reaches theth costal cartilage at the mid-clavicular line. On the right, it moves medially to cross the 6th costal cartilage and end at the 4th costal cartilage. On the left, the heart border causes a steeper drop from the 4th costal cartilage to the 6th costal cartilage at the cardiac notch. Lymphatic drainage of the lungs The lymph drains inwards, from the pleura to the hilum of the lung to the bronchopulmonary lymph nodes. From there, it drains into the tracheobronchial nodes which are found at the bifurcation of the trachea; then to the paratracheal and mediastinal lymph trunks, and, finally, into the brachiocephalic veins. P.351
Nerve supply of the lungs At the root of the lung, a pulmonary nerve plexus is comprised of parasympathetic fibres from the vagus nerve and sympathetic fibres from the sympathetic trunk. Parasympathetic ganglia are located in the pulmonary plexuses and bronchial tree. Sympathetic ganglia (paravertebral ganglia) are located along the sympathetic trunk. Parasympathetic fibres innervate smooth muscle found in the bronchial tree and pulmonary vessels and innervate secretory glands of the bronchial tree. Parasympathetic fibres also carry sensation from stretch receptors in bronchial muscles, interalveolar connective tissue, baroreceptors in pulmonary arteries, and chemoreceptors in pulmonary veins. Sympathetic fibres provide innervation to the smooth muscle of the bronchial tree and pulmonary vessels and innervate secretory glands of the bronchial tree. The parietal pleura of the lungs is innervated by the phrenic and intercostal nerves. Blood supply of the lungs The pulmonary arteries carry deoxygenated blood to the lungs for gas exchange in the alveoli. The re-oxygenated blood returns to the heart via the pulmonary veins. The lungs themselves receive oxygenated blood from the bronchial arteries (branches of the descending aorta) which perfuse lung tissue. The mediastinum The mediastinum is located between the two lungs. It contains:

  • The heart in its pericardial sac
  • The great vessels entering and leaving the heart
  • The thymus gland.

It is divided into superior and inferior areas by the lower border of the T4 vertebra (the angle of Louis). The inferior area is subdivided into the anterior, middle (contains the heart and great vessels), and posterior areas adjacent to the thoracic vertebrae T5–T12. The thoracic duct Lymph from the lower limbs and abdomen drains towards the cisterna chyli which lies within the abdomen at the level of L1 and L2. This becomes the thoracic duct as it pierces the diaphragm at the aortic opening. It runs behind the oesophagus, moving to the left of the oesophagus at the level of T5. It drains into the start of the left bracheocephalic vein after ascending behind the carotid sheath, then turning back downwards over the subclavian artery. Lymph drains from the head and neck, upper limbs, and thorax via the left jugular, subclavian, and mediastinal trunks either into the thoracic duct or directly back into large veins at the base of the neck. This is similar to the right side where the right jugular, subclavian, and mediastinal veins may drain into the large veins on the right side of the neck draining into the right brachiocephalic trunk. P.352
Skeletal and soft tissue framework of the thorax (Colour Plate 7) The thorax is bounded by a variety of structures (12 pairs of ribs, costal cartilages, thoracic vertebrae, intercostal muscles, sternum) which participate in ventilation as well as protecting the thoracic organs. Together they form the thoracic cage. The diaphragm is attached to the inferior margins of the thoracic cage and separates the thoracic cavity from the abdomen. The ribs (Fig. 6.1) A typical rib comprises several distinct parts:

  • Head: articulates with the corresponding vertebra and the one above
  • Neck: separates the head and the tubercle
  • Tubercle: articulates with the transverse process of the corresponding vertebra
  • Angle of the rib: divides the rib into two halves and is the weakest point of the rib
  • Shaft: forms the flattened main portion of the rib
  • Ribs 1–7 are true ribs (vertebrosternal ribs; the rib is fused anteriorly to the sternum via costal cartilages)
  • Ribs 8–10 are floating ribs (vertebrochondral ribs; the rib is fused to the costal cartilage of the above rib)
  • Ribs 11 and 12 are false ribs (the rib is not fused to the sternum by any means).

Costal cartilage increases the elasticity of the thoracic cage, making it less fragile and liable to fracture following trivial trauma.

Fig. 6.1 (a) First rib; (b) sixth rib; (c) twelfth rib.

The 1st rib Owing to its superior location, the first rib is associated with other structures and muscle attachments. It is also the most curved rib. Scalenus medius attaches to its upper surface posteriorly. Scalenus anterior attaches to its tubercle on the upper medial side of the rib. The subclavian vein runs in front of this attachment, and the subclavian artery and lowest branch of the brachial plexus run behind the attachment of scalenus anterior. The 10th rib The tenth rib only articulates with T10 and, hence, only has one articular facet. The 11th and 12th ribs These two ribs are short, have no necks or tubercules, and only have one large facet which articulates with the corresponding vertebra. Cervical and lumbar ribs 0.5% of the population have an extra rib, known as a cervical rib (since it articulates with the seventh cervical vertebra). Sometimes this can cause lower brachial plexus compression. The sternum This is a flat, long bone which articulates anteriorly with the ribs via costal cartilages. The sternum comprises three fused bones (manubrium, body, xiphisternum). The manubrium is a flat, wide and triangular-shaped bone, found at the level of T3 and T4 vertebrae. It articulates with the clavicle and the first two ribs. At the superior end is found the suprasternal notch as well as two notches either side of this where the head of the clavicle articulates. The sternal angle (or angle of Louis) defines the point where the manubrium fuses with the body of the sternum. The body is the largest part of the sternum and comprises four fused segments. It extends from T5–T9 and articulates with the cartilage of ribs 2–7. The xiphisternum is found inferiorly and is the smallest sternal bone. Musculature of the thorax The intercostal muscles are located between neighbouring ribs. They comprise three layers of muscle, from inside to outside:

  • Innermost intercostal muscles are separated incompletely from the middle intercostals by the neurovascular bundle. This layer may cross more than one rib, forming an incomplete fibrous layer
  • Middle or internal intercostal muscles run obliquely away from the sternum
  • External intercostal muscles form a membrane anteriorly (the external intercostal membrane). Fibres pass down and inwards, towards the sternum.

Several other muscles attach to the thoracic cage, including the accessory muscles of respiration such as sternocleidomastoid and some of the scalene muscles. P.354
Nerves and vessels of the thoracic cage Each thoracic spinal nerve (associated with the corresponding rib) gives off two nerve branches on leaving the intervertebral foramina. The dorsal roots supply the muscles, bones, joints, and skin of the back. The anterior roots form the intercostal nerves (T1–T11) and the subcostal nerve (T12). The intercostal nerves give off muscular branches and two cutaneous branches (lateral and anterior branches) and supply the muscular walls of the thorax and abdomen and the corresponding cutaneous area of skin (dermatome). The intercostal muscles are supplied by branches of the intercostal nerves called collateral nerves. The neurovascular bundle (intercostal bundle) consists of the anterior and posterior vessels (arteries and veins) and the intercostal nerves. The intercostal bundle runs below the corresponding rib and includes, from top to bottom: vein, artery, and nerve. They enter the intercostal space between the pleura and the internal intercostal membrane posteriorly. Initially, the neurovascular bundle runs in the middle of the intercostal space, along the internal surface of the internal intercostal membrane. This neurovascular bundle runs under the rib in the costal groove at the angle of the rib where it gives off the collateral branch. The lateral cutaneous branch supplies the intercostal muscles. The anterior cutaneous branch runs on the inner surface of the internal intercostal muscle and ends anteriorly near the sternum as anterior cutaneous branches. The blood supply of the thoracic cage The thoracic cage is supplied by the anterior and posterior intercostal arteries. The 1st-6th anterior intercostal arteries are branches from the internal thoracic artery (from the subclavian artery). The 7th-9th anterior intercostal arteries are supplied by the musculophrenic artery. The 10th and 11th intercostal muscles only have a posterior supply. The 1st and 2nd superior intercostal arteries are supplied by the costocervical trunk (a branch from the second part of the subclavian artery). The 3rd-11th posterior intercostal arteries are supplied by the thoracic aorta. Branches of the posterior intercostal arteries supply the skin, muscles, and the spinal cord. All posterior arteries run forwards and anastamose with the corresponding anterior intercostal artery. The anterior abdominal wall is supplied by the subcostal artery (a branch of the thoracic aorta). P.355
Venous drainage of the thoracic cage Veins follow the course of the corresponding artery. There are 11 intercostal veins and one subcostal vein on each side of the thorax. Generally, anterior and posterior intercostal veins anastomose to drain into the internal thoracic and then azygous vein, which drains into the superior vena cava, back to the heart. The 1st posterior intercostal vein drains into the left brachiocephalic or vertebral vein. The left 2nd and 3rd intercostal veins drain into the superior intercostal vein which crosses the aorta to drain into the left brachiocephalic vein. Ventilatory movements During inspiration, the ribs move upwards and outwards like bucket handles lifting upwards. This increases the thoracic diameter in all directions. During expiration, the thoracic cage shrinks as the bucket handle-like motion of the ribs sinking reduces the volume of the thoracic cage. The diaphragm moves downwards with inspiration by contraction at the central tendon, and upwards with expiration. The diaphragm The diaphragm is a muscular, dome-like structure which separates the abdominal contents from the thorax. It should be considered in two parts: a peripheral muscular part and a central aponeurosis. It is involved in ventilation of the lungs. Attachments of the diaphragm:

  • Costally to the inner sides of the lower six costal cartilages and ribs
  • Inside surface of xiphisternum
  • Front of upper three lumbar vertebrae and intervertebral discs form the attachment of the right crus
  • 1st and 2nd lumbar vertebrae form the attachment of the left crus
  • The central tendon formed by the insertions of the muscular attachments of the diaphragm (a trefoil-shaped area which partially fuses with the base of the pericardium).

The diaphragm is supplied by the phrenic nerve from the cervical roots 3, 4, and 5. Since sensory innervation to the diaphragm is via the phrenic nerve, when the diaphragm is inflammed, pain is referred to the shoulder tip which is the cutaneous portion of the phrenic nerve. Penings of the diaphragm Several important structures past through the diaphragm between the thorax and the abdomen. The inferior vena cava and the right phrenic nerve pierce the diaphragm at the level of the 8th thoracic vertebra. The oesophagus, the left and right vagus nerves, and the left gastric artery and vein pierce the diaphragm at the level of the 10th thoracic vertebra. The aorta, azyous vein, and thoracic duct pierce the diaphragm at the level of the 12th thoracic vertebra. The diaphragm is also pierced by the sympathetic chain and greater and lesser splanchnic nerves. P.356
The Pulmonary System Pleura and pleural cavities The lungs are each surrounded by membranous pleural sacs which are entirely separate from each other. The pleural sac comprises an inner layer of visceral pleura (pulmonary pleura), closely adhered to the lung’s surface, and an outer layer of parietal pleura, closely adhered to the inside of the thoracic cavity. The parietal pleura is further subdivided into costal pleura (inner thoracic wall), mediastinal pleura (mediastinum), diaphragmatic pleura (diaphragm), and cervical pleura (apex of lung in the neck) in different regions of the thorax. Pleural reflections are junctions between different parts of pleura where a marked change in direction occurs (e.g. costal pleura merging with mediastinal pleura). Visceral and parietal pleura are continuous with each other at the hilum of the lung and, at this point, a double layer of parietal pleura extends inferiorly forming the pulmonary ligament which provides space for the pulmonary vessels to move during ventilation. Between the two layers of pleura exists a potential space, the pleural cavity, which is normally filled with pleural fluid. This aids the movement of the pleural layers against each other during inspiration and expiration. At certain points, when the volume of the thoracic cavity is submaximal (during expiration), larger spaces known as recesses are formed (Fig. 6.2). These are pronounced where costal pleura is in contact with diaphragmatic pleura (costodiaphragmatic recess) and where costal pleura is in contact with mediastinal pleura (costomediastinal recess). These cavities can become filled with pus or blood during pulmonary infection (OHCM6 p.172) or injury and this is visible on a chest X-ray (OHCM6 p.166, Plates 5, 8) as a blunting of the angles of, for example, the costodiaphragmatic recess. When fluid needs to be drained from the pleural cavity, it is usually done by inserting a needle into theth intercostal space, anterior to the mid-axillary line, over the border of the lower rib to avoid damage to nerves or blood vessels (OHCM6 p.748). The visceral pleura receives innervation from the anterior and posterior pulmonary plexuses. Parietal pleura is innervated by intercostal and phrenic nerves and inflammation of this layer frequently results in referred pain to other areas supplied by the same spinal segments. For example, inflammation of diaphragmatic pleura can result in abdominal wall pain, and inflammation of mediastinal pleura can be referred to the neck and shoulder. In contrast, visceral pleura receives no sensory innervation.

Fig. 6.2(a) Radiograph of the chest in inspiration; (b) in full expiration.

Upper airways The upper airways comprise those parts of the respiratory tract above the trachea. However, it must be remembered that the same term is also used to refer to all airways which conduct inspired gases from the atmosphere to the terminal bronchioles, where gas exchange starts. Here, the former definition will be used. The upper airways are lined by respiratory epithelium which is characteristically pseudostratified and ciliated. Frequent goblet cells secrete mucous which absorbs smaller inhaled particles not excluded by the nose. The continuous beating motion of cilia prevents these particles from entering the lungs by shifting mucous upwards and out of the respiratory tract where it is swallowed or expectorated (mucociliary escalator). This is an important defence against the entry of foreign, potentially pathogenic, particles. The nose (Fig. 6.3) As well as playing an important role in the sense of smell, the nose moistens and warms inhaled air whilst preventing particulate matter from entering the airways. Air enters the nose through the anterior nares (nostrils), passing the anterior nasal hairs (vibrissae). These trap and prevent inhalation of larger foreign particles. The epithelial lining changes shortly after entering the nose from keratinized to respiratory epithelium. The nasal septum, which is formed from part of the ethmoid bone of the skull, the septal cartilage, and the vomer, separates the nasal airway into left and right halves. Conchae are swirl-like bony structures found on the lateral aspect of each side of the nasal airway which moisten and warm air passing past them by increasing the surface area of the nasal passage. There are three conchae on each side—an inferior, a middle, and a superior concha. Olfactory epithelium is found in the upper regions of the nasal airway above the superior conchae and is specialized for the detection of smell. Olfactory nerves are hair-like projections which line the roof and lateral walls of the nose where olfactory epithelium is found. They sense smell as air circulates past them by binding to specific odour-producing molecules in inhaled gases. Inhaled air exits the nose through its posterior openings–the right and left choanae (posterior nares)—to enter the nasopharynx (the area lying behind the nasal passage and above the soft palate). The paranasal sinuses (Fig. 6.4) There are four pairs of paranasal sinuses: the maxillary, frontal, ethmoidal, and sphenoidal sinuses. They are hollow, air-filled bony cavities that surround the nose. They are lined with respiratory epithelium and produce mucous which drains into the nasal cavity via ostia (cavities or holes below each concha, also called meati). There is a meatus associated with each concha, as well as a spheno-ethmoidal recess above the superior concha.

Fig. 6.3 Lateral wall of nasal cavity.
Fig. 6.4 Lateral wall of nose with conchae removed to show drainage of paranasal sinuses.


  • The spheno-ethmoidal recess drains the sphenoidal sinuses
  • The superior meatus drains the posterior ethmoidal sinuses
  • The middle meatus drains the rest of the ethmoidal sinuses, and all of the maxillary and frontal sinuses
  • The inferior meatus receives drainage from the naso-lacrimal duct. This duct drains tears from the medial angle of the eye into the nose.

Blood supply to the nose (Fig. 6.5) The nose is supplied by several different arteries which anastamose at Little’s area in the anterior part of the nasal septum. The roof, anterior, and lateral walls are supplied by the anterior and posterior ethmoidal arteries, whilst the meati, septum, and conchae are supplied by the sphenopalatine arteries, superior labial artery, and a branch of the greater palatine artery. The pharynx (Fig. 6.6) The pharynx is a muscular tube which extends from the oesophagus to the base of the skull. Anteriorly, the pharynx opens into the back of the nose, mouth, and larynx. It provides transport of food and air to the trachea and oesophagus respectively. The pharynx is divided into three regions:

  • Nasopharynx is the area behind the nose and above the soft palate
  • Oropharynx is the area behind the mouth, between the soft palate and the hyoid bone
  • Laryngopharynx is the area behind the larynx, from the epiglottis to C5, terminating at the start of the oesophagus.

The pharynx is made of three muscles—the superior, middle, and inferior pharyangeal constrictor muscles. These fan-like muscles stack one inside the other and interdigitate with each other. They are attached to the side walls of the three orifices into which the pharynx opens anteriorly. All three muscles attach to the median raphe (fusion of the muscles) as they fan out and attach to the posterior wall of the pharynx. The nasopharynx plays an important role in respiration. It is protected from the regurgitation of food during swallowing by the soft palate rising upwards and closing it off from the rest of the pharynx. The pharyngeal tonsil (a collection of lymphoid tissue commonly known as the adenoids) is found in the posterior wall and roof of the nasopharynx. The Eustachian tube enters the nasopharynx at the level of the floor of the nose on the lateral walls. This tube forms a communication between the nasopharynx and the middle ear, accounting for the common concurrence of throat and middle ear infections. The oropharynx is important in digestion and as part of the immune response. It receives food boluses during deglutition (swallowing) and is part of the conduit between the mouth and the oesophagus. It involuntarily contracts on receiving food, thus squeezing the bolus into the laryngopharynx and into the oesophagus. The oropharynx contains the palatine tonsils (a collection of lymphoid tissue), between the palatoglossal and palatopharyngeal arches at the back of the throat.

Fig. 6.5 Arterial supply of nose. Area of anastomosis (ringed).
Fig. 6.6 Sagittal section of head and neck to show pharynx.

A continuous lymphoid ring is formed by the palatine tonsils, Waldeyer’s ring (lymphoid tissue on the dorsum of the tongue), and the adenoids (pharyngeal tonsil). Together, they act as one of the first lines of defence in the immune system. Blood supply and innervation of the pharynx (Fig. 6.7) The pharynx is supplied by branches from the external carotid and the superior thyroid arteries. The pharyngeal venous plexus drains into the internal jugular vein. Sensory innervation of the pharynx is via cranial nerve IX (via pharyngeal branches) and cranial nerve V (via the maxillary division) which supplies the nasopharynx. Motor innervation is by cranial nerve X (via pharyngeal branches). The larynx (Fig. 6.8) The larynx plays an important role in producing speech and sound, allows for ventilation, and protects the trachea and bronchial tree during swallowing. It is a tube which conveys air to the lungs from the pharynx. It is made of a framework of nine cartilages, bound together by ligaments and muscles, and contains the vocal cords which are responsible for vocalization. The U-shaped hyoid bone within the neck is the framework by which the larynx is attached to other structures within the neck, including the pharynx, mandible, and the tongue. The hyoid bone lies at the level of cervical vertebrae 3 and 4. The larynx is attached to the hyoid bone by the thyrohyoid muscle and membrane. The epiglottis is an elastic flap of cartilage which lies behind the tongue and forms the entrance to the larynx. It attaches to the hyoid bone (in front) and posteriorly to the back of the thyroid cartilage. Laterally, the epiglottis is attached to the arytenoids by aryepiglottic folds which form the opening of the larynx. These arytenoid cartilages are pyramid-shaped. The thyroid cartilage is V-shaped and, in men, forms the prominence in the neck called the ‘Adam’s apple’. The thyroid cartilage is attached to the hyoid bone by the thyrohyoid membrane. The cricoid cartilage is the only complete ring of cartilage in the respiratory system and is signet ring-shaped. The widest part of the ring faces posteriorly and, either side of it, sit the arytenoid cartilages. The corniculate and cuneiform cartilages are small, paired cartilages which support the aryepiglottic folds and are found within them. The cricothyroid membrane (cricovocal membrane) runs on the posterior surface of the thyroid cartilage, behind the vocal processes of the arytenoids, connecting the thyroid, cricoid, and arytenoid cartilages. This membrane is thickened between the thyroid and the cricoid and, anteriorly, it becomes the cricothyroid ligament. This is easily palpable since it is subcutaneous and, in an emergency, can be pierced to provide an airway during laryangeal obstruction (OHCM6 p.756).

Fig. 6.7 Arterial supply to pharynx.
Fig. 6.8 Interior of larynx, coronal section viewed from posterior.

Laryngeal muscles Muscles of the larynx are divided into the intrinsic and extrinsic muscles. Extrinsic muscles consist of the infra- and supra-hyoid muscles and stylopharyngeus. The infra-hyoid muscles are sternohyoid, omohyoid, thyrohyoid, and sternothyroid and are responsible for depressing the larynx and hyoid bone. The supra-hyoid muscles are digastric, stylohyoid, mylohyoid, and geniohyoid and, together with stylopharyngeus, elevate the larynx and hyoid bone. The intrinsic muscles of the larynx control movements within the larynx, such as tension on the vocal cords. The muscles include: thyroarytenoid, posterior and lateral cricoarytenoid, interarytenoid, aryepiglottic, and cricothyroid. Cricothyroid is the only exterior muscle and tightens the vocal cords by tilting the cricoid cartilage. It is supplied by the superior laryngeal nerve. All the intrinsic muscles are supplied by the recurrent laryngeal nerve and have a common sphincter action, since they form an encircling sheet. They have different attachments which are evident in their names:

  • Thyroarytenoid relaxes the vocal cords
  • The posterior cricoarytenoid abducts the vocal cords
  • The lateral cricoarytenoids adduct the vocal cords
  • The interarytenoids and aryepiglottic muscle close off the larynx during swallowing by forming a sphincter.

The vocal cords The vocal cords are formed by two different folds of mucosa to form a triangular-shaped membrane either side of the opening between them. The superior vestibular fold forms the false vocal cord; the inferior vestibular fold forms the true vocal cord. They have a pearly white avascular appearance, as there is no submucosa between them, and only consist of tightly fused mucosa. The opening between the cords is called the rima glottidis. The shape of this area is constantly changing with vocalization. The true cords are important for vocalization, while the false cords have a purely protective role. The larynx is divided into three areas by these folds of mucosa:

  • Supraglottic compartment (above the vocal cords)
  • Glottic compartment (between the two types of vocal cords)
  • Subglottic compartment (below the true cords and terminating at the start of the trachea).

Nerves, blood, and lymphatic supply of the larynx (Figs. 6.9, 6.10) Sensory innervation, blood supply, and lymphatic drainage are different above and below the vocal cords. The superior laryngeal nerve provides sensory innervation for laryngeal structures above the vocal cords and the recurrent laryngeal nerve below. The superior laryngeal branch from the superior thyroid artery supplies structures above the cords, whilst the inferior laryngeal branch from the inferior thyroid artery supplies structures below the cords. Lymphatic drainage below the cords is to the lower group of deep cervical nodes, whilst the upper group of deep cervical nodes drain structures above the cords.

Fig. 6.9 Arterial supply and lymphatic drainage of larynx.
Fig. 6.10 Nerve supply to larynx.

The trachea The trachea starts just below the cricoid cartilage, at the level of C6. It has c-shaped cartilaginous rings, with a fibrous muscular band (trachealis) over the cartilage-deficient area posteriorly. It is lined with respiratory epithelium, which acts as an escalator, wafting particulate matter in the mucous upwards, away from the lower airways. Nerves, blood, and lymphatic supply of the trachea The inferior thyroid artery supplies the trachea. The postero-inferior deep cervical nodes drain the trachea. Parasympathetic innervation is from the vagus and recurrent laryngeal nerve, whilst sympathetic innervation is from the sympathetic trunk. P.367
Lower airways (Fig. 6.11) The distal segments of the pulmonary tree conduct gases between the upper airways and those areas of the lung which are highly specialized for gas exchange. The airways divide 20–25 times before reaching the alveoli (where most gas exchange occurs) and, between each division, become smaller in length and diameter than more proximal segments. In healthy subjects, the upper airways contribute most to total pulmonary resistance because their total cross-sectional area is markedly less than for more distal segments. The angle of Louis lies at the level of thoracic vertebrae 4 and 5 and marks the bifurcation of the trachea into right and left main bronchi. The right main bronchus is wider, more vertical, and shorter, making foreign bodies more likely to lodge in this tract. The right upper lobe bronchus is given off before the right main bronchus enters the hilum of the lung, below and anterior to the pulmonary artery. The left main bronchus has an infero-lateral pathway to the root of the lung. It is inferior to the arch of the aorta, but anterior to the thoracic aorta and oesophagus. It gives off no branches before entering the lung at the level of T6. These main bronchi enter each lung at the hilum which demarcates extrapulmonary and intrapulmonary bronchi. Inside the lungs, bronchi divide into branches (lobar bronchi), each of which supplies a pulmonary lobe (two in the left lung, three in the right lung). The lobar bronchi continue to divide and, after approximately four divisions, form bronchioles which each supply a single lobule. Each bronchiole divides into 5–7 terminal bronchioles which then form 2–5 respiratory bronchioles (characterized by the presence of sporadic alveoli). Distally, respiratory bronchioles form 2–11 alveolar ducts, from which most alveoli lead via alveolar sacs. Bronchopulmonary segments are (Fig. 6.12) wedge-shaped areas within the lung (smaller than a lobe) which are supplied by an individual bronchus, artery, and vein.

  • The superior secondary bronchus supplies the apical, posterior, and anterior bronchopulmonary segments of the superior lobe
  • The middle lobe includes the lateral and medial bronchopulmonary segments
  • The lower lobe includes the superior, anterior basal, medial basal, lateral basal, and posterior basal bronchopulmonary segments.

On the left, there are two main lobes–the superior and inferior lobes and the lingular lobe (a tiny attachment which is the remnant of the middle lobe found on the right side). After entering the lung hilum, the left main bronchus divides into two secondary bronchi.

  • The superior bronchi supplies the apical, posterior, superior and inferior bronchopulmonary segments of the superior lobe
  • The inferior bronchi supplies the anterior basal, medial basal, lateral basal, posterior basal bronchopulmonary segments of the inferior lobe.
Fig. 6.11 Lungs and great vessels after removal of the anterior thoraic wall.
Fig. 6.12 Bronchopulmonary segments in (a) the right and (b) the left lung. Arrows, likely course of inhaled material: (a) in upright position and (b) in recumbent position.

Alveoli The alveoli form the major compartment specialized for gas exchange between blood and air. There are approximately 300 million alveoli in the two lungs, with a combined surface area of 80m2-140m2. This, coupled with their proximity to pulmonary capillaries, enhances the rapid exchange of gases between blood and air. Adjacent alveoli are separated by a thin wall, the interalveolar septum, which comprises epithelial layers from each of the alveoli sandwiching a connective tissue matrix and dense network of pulmonary capillaries. The alveoli and capillary blood are separated by the blood-air barrier. This comprises the thin, single-layered alveolar epithelial cells, the fused basal laminae of the epithelial layer and capillary endothelial cells, and the endothelial cells themselves. Together, these three layers are only about 1.5µm thick and greatly facilitate diffusional gas exchange. Alveoli from adjacent alveolar ducts are linked by interalveolar pores of Kohn—10µm openings in the interalveolar septum which are an alternative route for movement of gases between alveoli during local bronchiolar obstruction. Type I alveolar cells comprise about 95% of the alveolar surface and are characteristically squamous. Type II alveolar cells are more rounded and account for the remaining 5% of alveolar surface area. They secrete pulmonary surfactant which lines alveoli, reducing surface tension, maintaining their stability and minimizing work required to inflate the lungs. Type I cells are involved in the absorption of surfactant, promoting its turnover. Type II cells are also a stem cell population, and can divide and differentiate into type I cells in the event that the alveolar epithelium is damaged. Blood and nerve supply, and lymphatic drainage of the lungs The airways and parenchymal tissue of the lungs are supplied by bronchial arteries which arise from the descending thoracic aorta and enter the lungs at each hilum. Corresponding bronchial veins drain blood from the lungs. Branches of the pulmonary artery deliver deoxygenated blood to the alveolar capillaries, and these are returned to the left side of the heart by the pulmonary veins. Autonomic nerve plexi (containing sympathetic and parasympathetic fibres) exist at the root of the right and left lungs. The lungs receive both efferent and afferent innervation. Lymph drains from the lungs to the hilar tracheobronchial nodes. P.371
Respiratory mechanics—static Respiratory mechanics is the study of the forces, pressure and work involved in ventilating alveoli. Air flow into and out of the lungs can only occur down pressure gradients and it is the function of the respiratory muscles to create these gradients and permit respiration. Lung volumes The measurement of lung volumes is an important clinical test of lung function. They vary between individuals and are influenced by age, gender, size, and posture. However, standard values are available and variations from this can be useful in the diagnosis of lung pathology—restrictive and obstructive lung diseases (OHCM6 p.168) affect these volumes differently. The most important examples are shown in Table 6.1. Certain lung volumes can be measured by spirometry (OHCM6 p.168, 169) (Fig. 6.13), which involves the subject breathing into a sealed container and, in so doing, measuring the volume of inhaled and exhaled gases under variable conditions. These volumes can be recorded by a pen recording apparatus. Of the lung volumes described in Table 6.1, residual capacity (and any other lung volumes including it) cannot be measured, since this is the volume that cannot be exhaled (e.g. into a spirometer). In order to assess these volumes, an alternative technique (e.g. nitrogen washout or helium dilution) is required. Nitrogen washout involes the subject breathing 100% O2 and collecting expired gases until expired N2 is zero. At this P.373
point, the N2content of all of the expired gas is measured and, since N2 content of air in the lungs is about 80%, total lung volume can be determined. Helium dilution involves allowing a known amount of helium (which is not absorbed by the pulmonary circulation) to equilibrate in the lungs. Since the concentration of helium in expired air can then be measured, functional residual capacity can be determined from the relationship:

Table 6.1 Lung volumes—descriptions (OHCM6 p.171)
Name (abbreviation)Description
Residual volume (RV)Volume of gas in the lungs after a maximal expiration
Functional residual capacity (FRC)Volume of gas in the lungs after a normal expiration
Inspiratory reserve volume (IRV)Volume of extra gas that can be inhaled at the end of a normal inspiration by a maximal inspiratory effort
Expiratory reserve volume (ERV)Volume of extra gas that can be exhaled at the end of a normal expiration by a maximal expiratory effort
Inspiratory capacity (IC)Volume of gas that can be inhaled following a normal expiration by a maximal inspiratory effort
Tidal volume (TV)Amount of gas inhaled or exhaled during one normal breath
Vital capacity (VC)Amount of gas that can be inhaled by a maximal inspiratory effort following a maximal expiration
Total lung capacity (TLC)The total volume of the lungs at the end of a maximal inspiratory effort
Fig. 6.13 The subdivisions of the lung volumes. Idealized spirometry record of the changes in lung volume during normal breathing at rest, followed by a large inspiration to total lung capacity, followed by a full expiration to the residual volume. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Intrapleural pressure At the end of a normal expiration, intrapleural pressure (the pressure of fluid inside the pleural cavity) is negative relative to atmospheric pressure(-5cm H2O). This is because of the inherent mechanical tendency of the lungs to collapse inwards and the chest wall to recoil outwards. (A collapsed lung, or pneumothorax (OHCM6 p.194, 798), where air is introduced into the pleural space results in the lungs collapsing inwards and the chest wall outwards.) During inspiration, the muscles of chest wall and diaphragm expand the chest and increase intrathoracic volume, thus reducing intrapleural pressure further. In this way, alveolar pressure is reduced (by up to 5cm H2O in normal subjects) and inspiration is initiated. Conversely, during normal expiration, the muscles of the chest wall and diaphragm relax, decreasing intrathoracic volume, increasing alveolar pressure above atmospheric pressure, and causing expiration. A forced expiration, during which contraction of certain chest wall muscles results in an even higher increase in intrapleural pressure, obviously increases expiratory rate further. Intra-oesophageal pressure is approximately equal to intrapleural pressure and can be recorded by introducing a pressure transducer into the oesophagus. Compliance Compliance is a measure of the pressure required to inflate the lungs by a certain incremental volume and is therefore expressed in units of, for example, LkPa-1. This pressure is acting against forces working to deflate the lung which include the inherent elasticity of the lung as well as forces which arise as a result of the surfactant which lines the alveoli. Furthermore, during normal breathing, airways resistance and other frictional forces reduce the compliance of the lungs. Total compliance is, therefore, a combination of lung compliance and chest wall compliance. Surfactant and surface tension Alveoli are small (approximately 100µm in diameter), gas-filled spheres lined with liquid. Laplace’s Law relates the pressure (P) of the gas inside such a sphere to the surface tension of the liquid concerned (T) and its radius (r): It follows, therefore, that significant pressures are required to open closed alveoli. This is reflected in the magnitude of the pressures required to hold a pair of excised lungs at increasing volumes during inflation. Little increase in volume is measured until the holding pressure reaches about 1kPa. As pressure is increased further, the static volume of the lungs similarly increases until a maximum value is reached. During deflation, the volume of the lungs remains high until pressure has dropped significantly. The difference in holding pressures required for any given lung volume during inflation and deflation is referred to as hysteresis (Fig. 6.14). Hysteresis is only marked for excised lungs which are initially collapsed. P.375
For lungs inflated with saline, no such hysteresis exists and the holding pressure required to maintain any given volume is much lower. This is because both effects arise as a result of the surfactant-air interface. In contrast with other liquids, the surface tension of a film of surfactant increases, as the relative area of that film increases and can fall to very low levels. Furthermore, the static surface tension of a film of surfactant is greater when measured during expansion of that film than during contraction (i.e. there is hysteresis). Surfactant, therefore:

  • Reduces the overall compliance of the lung
  • Stabilizes alveoli by preventing small alveoli from emptying into larger ones
  • Prevents suction of fluid from pulmonary capillaries into alveoli.

Surfactant is secreted by type II alveolar cells from about 30 weeks gestation (humans). Insufficient surfactant is believed to account for infant respiratory distress syndrome in premature babies.

Fig. 6.14 The pressure—volume relationship for a single respiratory cycle. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Respiratory mechanics—dynamic Airways resistance The resistance of the airways to airflow determines the rate of laminar flow in the face of an applied pressure gradient and is given by the equation: This relationship can be used to calculate airways resistance where mouth pressure (measurable by a manometer), alveolar pressure (measurable by a body plethysmograph), and the rate of airflow are known. Resistance is given by Poiseuille’s law and is described by the equation: where l and r are the length and the radius of the tube, R is the resistance, and η is the viscosity of the gas (or liquid) in the tube. It is clear from these two equations that flow rate is critically dependent on the radius of the tube. In vivo, the uppermost parts of the bronchiolar tree contribute most to the total resistance because, although individually their radius is large, small bronchioles and terminal bronchioles are much greater in number. Bronchiolar contraction (e.g. during anaphylaxis (OHCM6 p.780)) increases airways resistance and, similarly, decreases in lung volume compress the airways and increase resistance. About one third of total airway resistance arises from the nose, pharynx, and larynx. Mouth breathing (e.g. during exercise) significantly reduces this value. Of the lower bronchial tree, the greatest resistance to airflow occurs in medium-sized bronchi. During a forced expiration, intrapleural pressure rises to positive levels as described above. Whilst this increases the driving force for air to exit the lungs, it also causes compression of the airways, which increases their resistance and decreases airflow. Since the effect on airways resistance is greater, there is a certain peak expiratory flow rate (OHCM6 p.168, 169)(measurable using a peak flow meter) above which increases in expiratory effort do not result in increases in expiratory rate. This peak flow rate decreases as lung volume decreases, since airway resistance increases. Obstructive airway disease (e.g. asthma OHCM6 pp.184–7, 794–5) reduces peak flow rate, whereas it is unchanged in restrictive airways disease (e.g. pulmonary fibrosis OHCM6 p.202). Turbulent flow in the airways, which can be heard as wheezing under certain pathological conditions, is governed by different pressure—flow relationships. Whether airflow in a given tube is laminar or turbulent is determined by the Reynolds number. In healthy subjects, the airflow in the bronchial tree exhibits a combination of laminar and turbulent characteristics. In addition to airway resistance, the tissues of the lung also provide some resistance to breathing as they move. Normally, this value is a relatively low contributor to total pulmonary resistance compared to airway resistance (about 20%). P.377
Work done by breathing Mechanical work done by breathing is given by the product of the total change in volume and the total change in pressure. Normally, inspiration is an active process requiring muscular contraction, and expiration is passive (the required energy is obtained from the stretched elastic tissues of the lung and chest wall). Usually this value is low, although it is increased when airways resistance is increased (obstructive lung disease) or during forced inspiration and expiration. P.378
Diffusion Under normal conditions, the process of ventilation continuously fills the alveoli with atmospheric air, whilst mixed venous blood enters the pulmonary circulation. The gases in these two compartments are broughtinto close contact with each other and O2 and CO2 move in opposite directions, across the blood—gas barrier, by simple diffusion (Fig. 6.15). The blood—gas barrier is formed of the alveolar epithelium, the capillary endothelium, and their fused basement membranes and associated structures. The rate at which gas moves from a region of high partial pressure to a region of low partial pressure is proportional to the partial pressure difference and solubility of the gas concerned and the surface area of the barrier to be traversed. It is also inversely proportional to the thickness of the barrier and the square root of the molecular weight of the gas under consideration (Fick’s law). The total surface area of the alveoli taking part in gas exchange in the lungs is large (80–140m2) and the thickness of this barrier is only 0.3µm. The structure of the blood—gas barrier is therefore optimized for rapid gasexchange. At 37°C, CO2 is some 20 times more soluble in water than O2, and, since they are of similar molecular weight, the rate of diffusion ofCO2 is much greater, even though the partial pressure gradient for CO2 is not so great. It must be remembered that the mechanisms that exist in redblood cells for increasing the solubility of O2 and CO2 do not exist in the blood—gas barrier and do not speed up the rate of diffusion. On average, it takes approximately 0.75sec for blood to traverse the length of an alveolar capillary. This is sufficient time for rapidly diffusinggases (e.g. CO2, normally O2) to equilibriate across the blood—gas barrier, and they are said to be ‘perfusion limited’. In other words, the level of perfusion in the capillary limits the amount of the gas that can cross the blood—gas barrier and the alveoli are in equilibrium with the blood atthe end of the capillary. More slowly diffusing gases (CO, O2 under certain pathological conditions) are said to be ‘diffusion limited’. That is to say that the alveoli are not in equilibrium with the capillary blood at the point at which the capillary ends. Whether a gas is perfusion or diffusion limited depends on the relative solubility of that gas in the blood and the alveolar wall. At altitude (when the partial pressure gradient for O2 is reduced) or during diseases which lead to thickening of the alveolar wall, the transport of O2 can become diffusion limited. Exercise significantly reduces the length of time taken for blood to traverse the length of a pulmonarycapillary, although in healthy subjects, the rate of diffusion of O2 is still sufficiently high to prevent its transport from becoming diffusion limited. P.379
The transport of CO across the blood—gas interface is always diffusion limited and is, therefore, used to measure the properties of the blood—gas interface. The amount of CO disappearing from an inhaled sample over 10sec is measured and, assuming that the amount of starting CO in the blood is negligible, reflects the area and thickness of the blood—gas barrier. Owing to its high solubility, the transport of CO2 is rarely diffusion limited. Certain pathological conditions (e.g. pulmonary oedema OHCM6 pp.136–8, 786) can significantly alter the rates at which gases can diffuse out of the lungs.

Fig. 6.15 Diagrammatic representation of the layers separating the alveolar air space from the blood in the pulmonary capillaries. (Reproduced with permission from Pocock G and Richards CD (2004), 2004), Human Physiology: The Basis of Medicine, 2nd edn, University Press.)

Ventilation Ventilation is the process by which inspired gases reach the alveoli and the blood—gas barrier, as well as the removal of expired gases. Alterations in the rate and depth of ventilation affect the composition of alveolar gas and, therefore, the composition of the gases entering the blood. The airways comprise conducting airways (which deliver gas to the alveoli) and exchange zones (where transfer of gases to and from the pulmonary circulation occurs). In a healthy individual, the conducting airways are approximately 150ml and this volume is frequently referred to as dead space (i.e. the volume of each breath which does not ventilate the exchange zones). Anatomical dead space refers to the volume of the lung that is not alveoli; physiological dead space is the volume of the lung that does not exchange gases with the pulmonary circulation. In healthy individuals, these values are approximately equal. However, during lung disease, physiological dead space may be significantly increased as a result of reduced efficiency of pulmonary gas exchange. Anatomical dead space can be measured by the nitrogen content in the expired gas from an individual inhaling 100% pure oxygen for a singlebreath. Initially, N2 content will be zero as gas from the non-alveolar regions is exhaled (last in, first out) but, after a certain volume is exhaled, N2 will rise to 80% (the same as N2 content of alveolar gas). From this, the volume of anatomical dead space can be measured. Physiological dead space can be measured from the Bohr equation which relies uponthe fact that, in expired air, all CO2 comes from the alveoli (the CO2 content of atmospheric air and, therefore, the dead space is zero): where VD is the dead space volume; VE is the volume of expired gas inone breath; and FE and FA are the fractions of expired air and alveolar air, respectively, which are CO2. Tidal volume is approximately 500ml min-1 and 15 breaths per minute. Total ventilation is therefore 7500ml min-1. However, the physiological dead space volume of the lungs is approximately 150ml and, therefore, only 5250ml min-1 is useful ventilation. 2250ml min-1 is simply ventilation of the dead space. Composition of alveolar gases The composition of alveolar gas is determined by rate at which O2 is added to the alveoli by ventilation and removed by the blood, as well asthe rate at which CO2 is removed from the alveoli by ventilation and added by the blood. It follows from this that an increase in ventilationwill be accompanied by an increase in alveolar O2 and a decrease in alveolar CO2. P.381
The composition of alveolar gases can be calculated from the alveolar gasequation which, if the concentration of CO2 in inspired air is close to zero, is given by: where PA O2, PIO2, and PACO2 are the partial pressures of oxygen in alveolar and inspired air, and carbon dioxide in alveolar air, respectively.R is the respiratory quotient, which is the ratio of CO2 production to O2 utilization. R is dependent upon dietary status and other factors but is normally about 0.8. Regional differences in ventilation In an upright subject, the apices of the lungs are ventilated less efficiently than the bases. This can be seen by analysing the distribution of inhaled radioactive gas (e.g. 133Xe). This is primarily because the base of the lung undergoes a larger volume change during ventilation than the apex since at the beginning of an inspiration it is relatively less inflated and thus more compliant. In contrast, the apex of the lung must support the lungs’ and weight is, therefore, more distended and less compliant. In other words, for a given pressure difference, the base of the lung is ventilated more than the apex. This effect is gravity dependent and, if the subject lies on their back, posterior regions of the lung become the best ventilated. P.382
Pulmonary perfusion Blood enters the pulmonary circulation from the right ventricle of the heart. The right and left pulmonary arteries progressively divide and accompany the airways as far as the terminal bronchioles, and from here they form the capillary network supplying the alveoli. The very large surface area of the pulmonary capillaries and the alveoli, as well as the close apposition between them, make the lungs a very efficient device for mediating gas exchange. The capillary network ultimately drains into pulmonary veins and into the left atria of the heart. The mean pressure within the pulmonary system is 15mmHg, with systolic and diastolic pressures of 25mmHg and 8mmHg respectively. This is lower than the systemic circulation, largely because the height through which blood is required to ascend is significantly less. There are two sorts of blood vessel in the lung:

  • Alveolar vessels which include capillaries and slightly larger vessels
  • Extra-alveolar vessels—all arteries and veins which run through the lung parenchyma.

In addition to pulmonary blood pressure, the volume of alveolar vessels is determined by alveolar pressure, while the volume of extra-alveolar vessels is determined by lung volume and consequent pull of lung parenchyma on their walls. This distinction is critical to understanding the regulation of pulmonary blood flow. The total pressure drop across the pulmonary circulation is only 10mmHg, compared to 100mmHg for the systemic circulation. It follows, therefore, that the total resistance of the system is much lower. This is largely because the muscular arterioles which are the major resistance vessel of the systemic circulation are not present in the pulmonary circulation. Increased pressure within the pulmonary circulation (e.g. from increases in either pulmonary arterial or venous pressure) causes its low resistance to fall even further. This is due to recruitment of normally closed vessels, as well as distension of already open vessels. Recruitment and distension normally occur together. High lung volumes also reduce vascular resistance by opening vessels (pull of parenchymal tissue on capillary wall). If vessels are collapsed, the pressure in pulmonary arterial vessels must reach a critical opening pressure before blood flow can occur. During a deep inspiration, alveolar pressure rises with respect to capillary pressure and the capillaries tend to be squashed. This is because the blood pressure falls. Measurement of pulmonary blood flow The amount of O2 taken up by lungs can be measured (spirometry), ascan the concentration of O2 in arterial (brachial or radial artery) and mixed venous blood (catheter in pulmonary artery). Therefore, the total amount of blood perfusing the lungs can be determined (Fick principle). Distribution of blood flow Considerable inequality of perfusion exists within the human lung. Radioactive xenon dissolved in saline injected into a peripheral vein and P.383
autoradiography can be used to measure this. When xenon reaches alveolar capillaries, it evolves into gas (because of low solubility), then counters over the chest will determine the magnitude of perfusion. In the upright human, lung blood flow decreases linearly from base to apex. This is affected by changes in posture and activity. Gravity is the major determinant of perfusion. The lower regions of the lung are perfused to a greater extent since hydrostatic pressure here is higher, allowing greater recruitment and distension of blood vessels. The relative changes are much greater for the pulmonary circulation than for the systemic circulation, since the ambient pressure in the pulmonary circulation is much lower. The lung is divided into zones according to the perfusion pattern seen in the upright lung:

  • Zone 1: alveolar pressure greater than pulmonary arterial pressure—no flow (i.e. dead space)
  • Zone 2: pulmonary arterial pressure is greater than alveolar pressure. Blood flow is therefore determined by arterial alveolar difference (not arterial venous difference—because venous pressure is so low and much lower than alveolar pressure)
  • Zone 3: venous pressure exceeds alveolar pressure (flow determined by arterial venous pressure difference in usual way). As one moves down this zone, perfusion increases due to distension of blood vessels.

Control of the pulmonary circulation Hypoxic regions of the lungs undergo vascular vasoconstriction. The precise mechanism underlying this is unknown but it still occurs in excised lungs and is, therefore, presumably an effect which is intrinsic tothe lung. PO2 of alveolar gas is chiefly responsible for determining thisresponse. Above 100mmHg PO2, little vasoconstriction is seen. Below this level, rapid vasoconstriction occurs. K+ channels, and/or nitric oxide may be involved. It is believed that this response directs blood flow away from underventilated (hypoxic) areas of the lung. At high altitude, this increases pulmonary blood pressure and can cause oedema. It is also responsible for the vascular changes seen at birth. Low blood pH also causes pulmonary vasoconstriction. Water balance in lung The distribution of fluid between pulmonary capillaries and the pulmonary extracellular space is, of course, determined by Starling forces. There is probably a net fluid outflow of approximately 20ml/hour. Increases in pulmonary capillary pressure (e.g. during hypoxic vasoconstriction or left ventricular failure OHCM6 pp.136–8) increase this net fluid outflow and can cause pulmonary oedema (OHCM6 p.786) in which fluid crosses alveolar epithelium and enters the alveolar spaces. Alveolar oedema is a serious problem as it interferes with gas exchange. Other functions of the pulmonary circulation The pulmonary circulation is also a reservoir for blood and has several metabolic functions. It is well suited to modifying blood—borne substances since it receives the entire circulation. P.384
Ventilation—perfusion relationships (Fig. 6.16) The matching of ventilation and perfusion in all regions of the lung is a critical determinant of healthy gas exchange. The ventilation—perfusion ratio is a useful measure of this. Regions of the lung which are under-perfused (resulting in an increased V/Q ratio) exhibit a gas composition approaching that of inspired air and, similarly, under-ventilated areas(decreased V/Q ratio) result in decreased PO2 and increased PCO2 in pulmonary venous blood. In other words, the gas composition approaches that of mixed venous blood. The effect of a regional mismatch in ventilation and perfusion on wholelung function is to reduce its efficiency as a gas exchanger (increase PCO2 and decrease PO2). However, in vivo, the raised PCO2 results in anincrease in ventilation. Whilst this can help to eliminate extra CO2, it is afar less efficient mechanism for compensating for reduced O2 transfersince, whereas the CO2 dissociation curve is linear, the O2 dissociation curve is flat at high PO2 values. Consequently, whilst it is possible to increase the excretion of CO2 by increasing ventilation, it is not possibleto increase O2 loading into blood that is already saturated. For perfusion-limited gases, the composition of alveolar gas and endcapillary blood is identical. For O2 this is determined by the rate at which it is delivered to the alveoli by ventilation and removed by the blood and, for CO2, by the rate at which it is delivered by the blood and removed by ventilation. The effect of alterations in V/Q ratio can be plotted on an O2—CO2 diagram. This gives all of the possible compositions of alveolar gas (or end-capillary blood) in a particular lung unit as the V/Q ratio is altered, assuming that the composition of inspired air and mixed venous blood remains constant. There is a greater increase in perfusion from the apex of the lung to its base than there is for ventilation (in the upright lung). This is primarily because the density of blood is greater than inspired air. The V/Q ratio is therefore greatest at the apex of the lung and least at its base. Using anO2—CO2 diagram, one can determine the contents of alveolar and end-capillary blood at various different levels of the lung. Near the apex, the Po2 is high and the PCO2 is low. The reverse situation occurs at the base.There is a greater difference in PO2than there is for PCO2. An uneven V/Q ratio results in a decrease in the oxygenation of the blood for two reasons:

  • The well-ventilated, apical regions of the lung are only weakly perfused and, therefore, the basal regions, which are poorly ventilated, dominate the PO2 of blood leaving the lung
  • P.385

  • The Hb—O2 dissociation curve is flat at high PO2 values. Therefore, although well-ventilated regions of the lung can increase PO2, they do not increase the concentration by a corresponding amount, and can certainly not compensate for under-ventilated regions of the lung. TheCO2 dissociation curve is linear in the physiological range and, therefore, under-ventilated regions of the lung do not contribute tothe elevation of total CO2 in blood leaving the lungs.

In healthy, upright subjects, the depression of PO2 in blood leaving the lung by V/Q mismatch is trivial. It can become more significant in disease where the degree of mismatch can be far greater. Shunt Shunt is an extreme form of ventilation perfusion mismatch caused by the passage of blood through the pulmonary circulation which is not fully ventilated (e.g. bronchial artery blood which supplies the lung parenchyma and drains into the pulmonary veins, as well as coronary venous blood which drains into the left ventricle). An abnormal connection between the pulmonary artery and pulmonary vein (pulmonary arteriovenous fistula), as well as defects allowing blood to pass from the right to the left hand sides of the heart, can also produce a shunt. The shape of O2—Hb dissociation curve is such that the addition of asmall amount of under-oxygenated shunted blood greatly reduces PO2.Hypoxaemia in a shunted patient cannot be abolished by giving 100% O2 to breathe since the ventilated and perfused regions of the lung are already fully oxygenating the blood. A shunt does not normally affectPCO2 in arterial blood since the chemoreceptors sense increased arterial PCO2 and make the appropriate adjustments (increase ventilatory rate).

Fig. 6.16 Distribution of ventilation, blood flow, and the ventilation—perfusion ratio in the normal upright lung. (Reproduced with permission from Pocock G and Richards CD (2004), Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Oxygen transport in the blood Introduction Oxygen is transported in the blood from the alveolar capillaries of thelungs (where blood is loaded with O2) to the peripheral capillaries in thetissues (where O2 is off-loaded). It is transported in two distinct forms— dissolved in solution in the intracellular and extracellular compartments and complexed to haemoglobin (Hb). Hb is packaged in red blood cells (erythrocytes) to prevent its filtration by the glomerulus and to limit the rises in blood viscosity which would arise were Hb dissolved in plasma. The amount of oxygen dissolved in the blood is proportional to its partial pressure (Henry’s law). At 37°C, 0.003ml O2 are dissolved in each 100ml blood per mmHg. Resting O2 consumption is approximately 300L O2 min-1 and, even if all of the O2 in arterial blood (100mmHg) were extracted by the tissues, cardiac output would have to be approximately 100L min-1 to support the body’s O2 requirement. This is clearly not possible and the amount of O2 transported in the blood in this way is normally negligible. However, dissolved O2 represents the major pathway for transport of O2 across capillary walls to respiring cells, and the only pathway from the alveoli to red blood cells. Haemoglobin Haemoglobin (Hb) is a 64,500 MW tetramer. Each protein subunit (globin) is bound to a haem group containing four pyrroles and a ferrous (Fe2+) iron ion at the centre. Neither haem nor globin alone are able to bind O2. Each Fe2+ can bind one O2 molecule and, therefore, eachmolecule of haemoglobin may bind up to four O2 molecules. Normal adult haemoglobin is made up of 2α (141 AAs) and 2β (146AAs) subunits, although a number of physiological and pathological variants exist (OHCM6 p.643) (p.388). Hb—O2 dissociation curve The O2 carrying capacity of Hb is limited by the number of O2 binding sites on each molecule of Hb and, therefore, the amount of O2 bound to a sample of Hb can be expressed either as aconcentration (normally ml O2/100ml blood) or, alternatively, as apercentage saturation of maximalO2 capacity. Once Hb is 100% saturated, the amount of O2 bound to itcannot be increased by increasing the partial pressure of O2. The reaction between Hb and O2 is both rapid and reversible. Binding of O2 toHb is co-operative such that the binding of each O2 molecule to the Hb tetramer facilitates the binding of the next (Figs. 6.17, 6.18). This positive co-operativity is a particular property of tetrameric Hb and is not exhibited by the monomer. The Hb—O2 dissociation (or association) curve istherefore sigmoidal rather than hyperbolic, which facilitates O2 loading atthe lungs and O2 unloading at the tissues. P.387
Factors affecting O2 binding to Hb Increases in H+, CO2, and temperature each shift the Hb—O2 dissociationcurve to the right and favour the unloading of O2. This is clearly of physiological benefit in, for example, a metabolically active muscle whichwill have a high demand for O2 and where pH will be decreased, CO2 production raised, and at an increased temperature. The effects of pH and CO2 on the Hb—O2 dissociation curve are known collectively as the Bohr effect. 2, 3-diphosphoglycerate (2, 3-DPG) produced by erythrocytes duringglycolysis, binds to Hb and reduces its affinity for O2. The production of2, 3-DPG is raised during hypoxic conditions, favouring the delivery of O2 to the tissues.

Fig. 6.17 Comparison between the oxygen dissociation curves for myoglobin and haemoglobin. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
Fig. 6.18 Positive co-operativity in binding of O2 to haemoglobin.

Variant forms of Hb Many variant and modified forms of haemoglobin have been described, only a few of which will be detailed here;

  • Sickle haemoglobin (HbS) (OHCM6 pp.640—1) results from a mutation of the globin polypeptide. HbS polymerizes, especially under conditions where O2 is low or acidity is high (e.g. in respiring tissues). The polymerized protein distorts the shape of the erythrocyte, making it sickle-shaped, and causes it to obstruct small capillaries, triggering sickling crises
  • Foetal haemoglobin (HbF) (OHCM6 p.643) has a raised affinity forO2 compared to adult haemoglobin. This facilitates delivery of O2 to the foetus from maternal uterine blood which is at a lower partial pressure than normal arterial blood. HbF tends to disappear from foetal red blood cells a few months after birth
  • Myoglobin is a monomeric form of haemoglobin expressed in striatedmuscle fibres. It has a much higher affinity for O2 than haemoglobin anddoes not demonstrate co-operativity in its binding of O2 (p.387). Myoglobin acts as a store of O2 available in hypoxic conditions, and also allows O2 to be delivered to respiring cells when muscle is contracted and perfusion reduced
  • Carboxyhaemoglobin CO (OHCM6 p.830) has an affinity for Hbapproximately 200 times that of O2. Consequently, inhaling even a low concentration of CO causes anaemia by reducing the amount of Hbavailable to bind O2. Carboxyhaemoglobin is red in colour, so patients suffering from CO poisoning do not appear anaemic
  • Methaemoglobin contains Fe3+ ions in its haem groups, rather than Fe2+. Oxidizing agents like nitrites and sulphonamides can cause this tooccur. Methaemoglobin does not carry O2 efficiently. Erythrocytes contain an enzyme, methaemoglobin reductase, which catalyses the reduction of Fe3+ ion back to its Fe2+ form.

Carbon dioxide transport in the blood Carbon dioxide is transported in the blood from the tissues to the lungs where it is excreted from the body (Fig. 6.19). It exists in the blood in three forms: dissolved CO2, HCO-3, and complexed to the terminal amine groups of blood proteins as carbamino CO2. In arterial blood, HCO-3 makes up 90% of total CO2 carried; dissolved CO2, 5%, and carbamino CO2, 5%. In venous blood, the equivalent proportions are 60%, 10%, and 30%. Dissolved CO2 Obeys Henry’s law and, since it is 20 times more soluble in blood thanO2, accounts for a significant proportion of total CO2 transported by blood. Dissolved CO2 is carried in the blood in both intracellular and extracellular compartments. Bicarbonate Formed by the hydration of dissolved CO2 to form carbonic acid which subsequently dissociates into H+ and HCO-3. The hydration reaction is accelerated 13,000-fold by the enzyme, carbonic anhydrase, which is found within erythrocytes, both intracellularly and on their surface. CO2 diffuses across red blood cell membranes into the cytosol where the hydration reaction to form carbonic acid proceeds. The carbonic acid generated subsequently dissociates into H+ + HCO3-. In order to allow this reaction to proceed, HCO-3 is transported out of the erythrocyte in exchange for extracellular Cl- ions on AE1 (anion-exchanger isoform 1) and protons are buffered by intracellular buffers (primarily Hb, whose deoxygenated form is a more powerful proton buffer than its oxygenated form). The erythrocyte intracellular chloride concentration is therefore higher for venous erythrocytes than for arterial erythrocytes (chloride shift). Carbamino CO2 CO2 can bind to the terminal amine groups of blood proteins, either intracellularly or extracellularly. Hb is the most significant protein forcarrying CO2 in this way and deoxygenated Hb binds CO2 more readilythan oxygenated CO2. The CO2 dissociation curve (Fig. 6.20) The carbon dioxide dissociation curve is right-shifted (promoting off-loading of CO2) by the presence of oxyhaemoglobin. This is known asthe Haldane effect and is analogous to the Bohr effect for O2 carriage. The Haldane effect arises because deoxyhaemoglobin is a weaker acid than oxyhaemoglobin and more readily binds either H+ (allowing thedissociation of carbonic acid to proceed) or the weak acid, CO2 (allowing the formation of carbamino CO2). Similarly, under acid conditions, theoff-loading of O2 from oxyhaemoglobin is promoted (Bohr effect). The Haldane effect and the Bohr effect both arise because deoxygenated haemoglobin is a weaker acid (better proton acceptor) than oxygenated haemoglobin.

Fig. 6.19 A schematic representation of: (a) the exchange of CO2 and O2 that occurs between the blood and tissues; (b) the exchange that occurs in the lungs between the blood and the alveolar air. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
Fig. 6.20 The carbon dioxide dissociation curve for whole blood and the Haldane effect. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Regulation of breathing In healthy individuals, the act of breathing is largely automated and isregulated to meet the body’s requirements for O2 uptake and CO2 excretion. In addition, certain activities (such as sneezing, coughing, swallowing, or speech) also require short-term adjustments to breathing pattern. Of course, one can voluntarily override automated breathing for short periods as well. Central control The respiratory rhythm is generated in respiratory centres in the medulla. Sectioning of the brainstem above these areas abolishes voluntary (cortical) control of breathing but leaves its normal rhythmicity intact. Two groups of upper motor neurones are relevant: the dorsal respiratory group initiate inspiration, whilst the ventral respiratory group are responsible for inspiration and expiration. Reciprocal inhibition is evident between inspiratory and expiratory cells. Both of these groups of neurones exhibit action potentials with a frequency that corresponds to the ventilatory cycle. Higher inputs from the pons and the cortex can modify the rhythm of the respiratory group neurones. Furthermore, afferent fibres (largely from chemoreceptors, see below) can also regulate their activity. Certain reflex responses from the lungs modify breathing behaviour. The Herring—Breuer reflex describes the inhibition of inspiration as the lungs are stretched. This reflex pathway limits the depth of inspiration, particularly during heavy breathing. Irritant receptors in the nasal mucosa and other airways result in a reflex sneeze or cough. This response helps to clear the airways of the original irritant. J-receptors, located in the lung interstitium, respond if the lungs become congested, and limit the rate and depth of breathing. Chemical control of breathing The most important function of the lungs is to regulate the levels of O2 and CO2 within the blood. An increase in ventilatory rate will tend to increase PAO2 and have the reverse effect on PACO2. Sensing of PO2 and PCO2 is performed by central and peripheral chemoreceptors which are located in the ventral surface of the medulla (central) and the aortic arch and carotid artery (peripheral). These organs respond to changes in blood gases and initiate rapid changes in respiratory rate in response. Central chemoreceptors are responsive to changes in the pH of the extracellular fluid of the brain (Fig. 6.21). In turn, the pH of this compartment is determined by the pH of blood and cerebrospinal fluid (CSF). The blood—brain barrier and the CSF—brain barrier are relatively impermeable to charged proton equivalents (e.g. H+ or HCO-3) and, therefore, it is PCO2 which is the major determinant of pH of the brain interstitium. Increases in CO2shift the equilibrium: P.393
to the right and thus decrease pH. Central chemorecptors respond to this by increasing actional potential frequency in their afferent nerve, resulting in an increase in ventilatory rate and reduction of PCO2. It is important to note that the pH of the CSF is more senstive to changes in PCO2 than the pH of the brain interstitium. This is because the proton-buffering capacity of the CSF is lower. Consequently, ventilatory rate is most sensitive to the composition of this compartment.

Fig. 6.21 Schematic diagram illustrating how the PCO2 of the capillary blood in the brain stimulates the central chemoreceptors. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Peripheral chemoreceptors are small (7mm × 5mm), encapsulated organs which receive a high blood supply and, in contrast to central chemoreceptors, sample PO2, pH and PCO2 in arterial blood. The afferent nerve fibres of peripheral chemoreceptors fire more frequently in response tolowered PaO2 or arterial pH, or raised PaCO2. They are the only part of the respiratory system which is able to elicit an increase in ventilation inresponse to reduced PaO2. The firing rate of the afferent nerve shows alarge increase as PO2 is lowered below about 100mmHg—above this value, the peripheral chemoreceptors are relatively insensitive to changes in oxygen tension. Although peripheral chemoreceptors are responsiveto alterations in PCO2, this effect is quantitatively less important thantheir response to PO2. The carotid bodies (although not the aortic arch chemoreceptors) arealso responsive to decreases in pH not elicited by an alteration to PCO2. This response explains the hyperventilation observed in patients suffering from, for example, diabetic ketoacidosis (OHCM6 pp.818—19). Whole-body regulation of gas tensions In general, CO2 tensions are a more important determinant of ventilatoryrate than O2 tensions. This can be demonstrated experimentally by precisely controlling the composition of inspired gas whilst simultaneously recording ventilatory rate. Until a threshold value is reached (about 100mmHg), reducing oxygen tensions has only a minor effect on ventilation. In contrast, even small increases in CO2 tensions dramatically increase ventilatory drive. Hypoxia does increase the sensitivity of ventilatory rate to PCO2. P.395
Respiratory disorders There are a number of disorders that, at best are an irritant, but can be debilitating or even fatal in serious cases. Cough (OHCM6 p.49)

  • Coughing is a reflex that is activated to remove mucus and extraneous material (e.g. dirt) in order to prevent occlusion of the airway
  • It is sometimes overstimulated in response to local inflammation caused by viral or bacterial infection, or a persistent irritant such as cigarette tar
  • The mechanism underlying cough is very poorly understood but non-addictive analogues of morphine reduce the symptoms of coughing. Codeine (methylmorphine) is the most commonly used opiate for symptomatic treatment of cough but it causes sputum to thicken, preventing its use in conditions such as chronic bronchitis and asthma, where thick sputum might exacerbate breathlessness.

Asthma (OHCM6 pp.184—7, 794—5) An inflammatory disorder resulting in episodic constriction of the bronchioles (bronchoconstriction), leading to acute breathlessness, wheezing, and cough.

  • Affects up to 10% of the population in Western countries and is increasing both in prevalence and severity
  • Although there is likely to be a genetic predisposition to asthma, an attack is generally prompted by an environmental stimulus (e.g. allergens, atmospheric pollutants, or even cold air)
  • Episodes can be broadly divided into two phases, although the severity of each varies enormously between individual cases: the first phase is characterized by rapid bronchoconstriction in response to inflammatory cell-derived release of histamine, platelet-activating factor (PAF), prostanoids (PGD2), and leukotrienes (e.g. LTC4, LTD4) caused by the irritant stimulus (Fig. 6.22). Activation of the inflammatory cells also releases chemokines that attract specific T-lymphocytes (Th2 cells) together with other inflammatory cells (eosinophils are particularly important). These cells generate increasing amounts of the inflammatory mediators, resulting in lung epithelial cell damage, bronchial hyperreactivity, and inflammation (the late phase), culminating in an asthma attack (Fig. 6.22)
  • There is no cure for asthma. Bronchodilators (e.g β2-adrenoceptor agonists like salbutamol and terbutaline and, to a lesser extent, caffeine-related compounds like theophylline or muscarinic receptor antagonists such as ipatropium) are an effective means of alleviating the symptoms of bronchospasm associated with asthma
  • Chronic inflammatory asthma is best treated with glucocorticoids (e.g. prednisolone, hydrocortisone) which inhibit production of many of the cytokines and inflammatory mediators that are important in the recruitment and activation of inflammatory cells.
Fig. 6.22 Cellular events in asthma.

Chronic obstructive pulmonary disorder (COPD OHCM6 pp.188–9, 796–7; chronic bronchitis and emphysema) COPD is a term that is often attributed to conditions that cause constant breathlessness and wheezing, such as chronic bronchitis and emphysema. Chronic bronchitis

  • Inflammation of the bronchi in response to the permanent damage caused to the lungs by the effects of smoking, pollution, or infection
  • Symptoms include constant breathlessness and a persistent, chesty cough. Both symptoms are brought about by inflammation-induced increases in mucus secretions, reducing the accessibility of air to the alveolae. The condition deteriorates with infections such as colds and influenza.


  • In reality, can only be fully diagnosed histologically post-mortem
  • Involves the destruction of supporting structures in the lung, leading to the collapse of airways. Trapped air in the alveolae results in over-inflation of the lungs. Smoking is again the primary cause of the disease.

Like asthma, COPD is not curable but the symptoms can be eased by:

  • Stopping smoking
  • Administration of bronchodilators (e.g. salbutamol)
  • Administration of muscarinic antagonists to reduce sputum production
  • Long-term oxygen therapy.

Adult (or acute) respiratory distress syndrome (ARDS) OHCM6 pp.190–1 ARDS is not a specific disease but is the result of lung injury caused by a direct insult to the lung (e.g. inhalation of smoke or corrosive gas) or as a result of severe systemic inflammation in response to infection (e.g. sepsis) that leads to multi-organ dysfunction. ARDS is attributed to massive capillary leak as a result of the recruitment and activation of large numbers of inflammatory cells at the site of injury. This over-response leads to endothelial damage and increases the permeability of alveolar capillaries, resulting in the flooding of alveolae. The syndrome is associated with the following symptoms:

  • Alveolar collapse
  • Poor lung compliance
  • Gas exchange problems, leading to hypoxaemia (lack of oxygen in the blood)
  • Pulmonary hypertension (exacerbating the capillary leak and the resulting pulmonary oedema).

In the long term, inflammation gives way to fibrotic remodelling—the laying down of the fibrous structures associated with scar tissue. Lung function is yet more compromised because the scar tissue leads to yet more destruction of the microcirculation and reduced compliance. P.399
Treatment The prognosis for ARDS is very poor (mortality rate of 50–75%). Therapeutic interventions are limited, but current management practice is as follows:

  • Provide respiratory support (oxygen)
  • Use inhaled nitric oxide (NO) to reduce pulmonary hypertension (p.383)
  • Treat underlying infection with antibiotics, if applicable.

Pneumonia (OHCM6 pp.172–6, 800) Pneumonia is the collective term to describe infection of lung parenchymal tissue. The source of the infection is most often bacterial, but can also be viral or fungal. Before the advent of antibiotics, pneumonia was often fatal. Even today, mortality is ~10%, but most patients can be treated in the community and do not require hospitalization. Symptoms include:

  • Breathlessness
  • Fever
  • Chest pain (especially on deep breaths)
  • Cough (mucus can contain blood in severe cases)
  • Anorexia
  • Fatigue.

Management and treatment involve provision of oxygen and treatment with appropriate antibiotics (OHCM6 p.176) (e.g. amoxicillin for Streptococcus pneumoniae, also known as Pneumococcus) and fluids, in severe cases. Preventative measures include vaccination against pneumococcus and influenza in vulnerable groups. Pneumonia is classified as follows:

  • Community acquired pneumonia: most commonly caused by Streptococcus pneumoniae bacteria, but can be the result of a secondary infection in patients with COPD (pseudomonas infection) or through viral infection (influenza)
  • Nosocomial pneumonia: acquired >48hr after hospital admission. Often gram-negative enterobacterial infection orStaphylococcus aureus
  • Aspiration pneumonia: aspiration is defined as the entry of a foreign substance into the respiratory tract and the associated pneumonia can refer to the resulting physical damage or to a subsequent infection of damaged parenchymal tissue. This condition most often affects people in unconscious states (e.g. alcohol-induced) but can also be related to oesophageal disorders such as reflux, or even poor dental hygiene. Streptococcus pneumoniae is the primary infective agent in this form of pneumonia
  • Immunocompromised pneumonia: pneumonia is a common cause of death in patients with compromised immune systems (e.g. AIDS). A wide range of infective agents, including Streptococcus pneumoniae, gram-negative bacteria, and influenza virus proliferate rapidly in the absence of a weakened immune response and can ultimately result in respiratory collapse.

Cystic fibrosis (OHCM6 p.178) Genetics Cystic fibrosis is transmitted by an autosomal recessive gene and this gene is the most frequent seriously deleterious recessive gene in the Northern European gene pool with a frequency of 1 in 25 in the UK and a disease incidence of 1 in 2500 live births. Molecular mechanisms The gene which is defective in cystic fibrosis codes for a protein which controls a chloride channel in the apical membrane of epithelial cells. The defective protein does not transport chloride into the epithelial cells from the surface and this has different effects in different epithelia. In the airways, there is reduced secretion of chloride into the surface mucus with subsequent sodium and water resorption into the cells causing dehydration of the surface mucus which is then much more viscid and is not cleared by the mucociliary escalator, leading to recurrent respiratory infections. Different mutations in the cystic fibrosis gene produce proteins with a range of function from none through to moderately reduced, so the phenotype of the disease varies with the extent of the protein dysfunction. Complications of cystic fibrosis

  • Bronchiectasis and recurrent respiratory infection: the viscid secretions in the bronchi cause obstruction leading to permanent dilation (bronchiectasis) and recurrent infection by organisms such as Pseudomonas aeruginosa. Respiratory failure is the cause of death in cystic fibrosis
  • Malabsorption: viscid secretions block the pancreatic ducts with subsequent atrophy of the exocrine glands. The resultant lack of digestive enzymes leads to malabsorption, especially of fats and fat-soluble vitamins. Oral supplements of enzymes can improve this
  • Hepatic cirrhosis: again secondary to viscid secretions obstructing the biliary tree
  • Male infertility.

Potential of gene therapy Since the airways are easily accessible to fluids dispersed as aerosols, it seems that a potential therapy for cystic fibrosis would be to inhale aerosols containing DNA fragments with a normal cystic fibrosis gene. If this could enter the epithelial cells lining the respiratory tract and encode mRNA, then these cells could produce a normal protein and the disease could be alleviated at this site. Whilst there has been some progress, there are still problems with finding a vector that will mediate large-scale take-up of the DNA. A more promising, though less sophisticated, molecular therapy is inhalation of recombinant human DNAase which breaks down the polymerized DNA from neutrophils which makes a large contribution to the increased viscosity of bronchial secretions in cystic fibrosis. P.401
Pulmonary embolism (OHCM6 p.194, 802) Another cause of respiratory disorder is pulmonary embolism due to the occlusion of one or more pulmonary arteries by an embolus (usually a displaced thrombus—p.460) originating from the large veins in the pelvis or legs (deep vein thrombosis—p.460). When the thrombus becomes dislodged, it travels relatively unimpeded through the veins (which increase in diameter as they approach the heart) and through the right side of the heart. Once the thrombus passes out of the right ventricle into the pulmonary artery, the arteries that it encounters are of progressively reducing diameter. Ultimately, the thrombus is unable to progress and lodges in a vessel, preventing blood flow to areas of the lung downstream of the occlusion. The severity of the effect is determined by the size of the area served by the occluded artery: a large thrombus will block a large vessel, causing severe lung tissue damage and is usually fatal; smaller emboli (microemboli) may not inflict sufficient damage to induce symptoms. On occasion, the embolus may not be thrombotic in origin: fat or air can be similarly transported to the lung through the venous system, although this is usually only associated with surgery or scuba diving, respectively. Symptoms and treatments Diminshed perfusion of the lungs results in reduced blood available for gas exchange, resulting in breathlessness and hypoxaemia. Treatments include immediate oxygen therapy and anticoagulant therapy (e.g. warfarin and low molecular weight heparin) to prevent further events. P.402
Altitude and pulmonary oedema With increasing altitude, air pressure falls, resulting in a fall in the amount of oxygen present in a given volume. Therefore, less oxygen is inhaled with each breath and the breathing rate has to increase to compensate. This short-term solution to the problem of reduced oxygen levels is accompanied by slower adaptive changes to help improve blood oxygenation, including an increase in red blood cell generation in response to kidney-derived erythropoeitin (p.594). These adaptive changes are termed ‘acclimatization’ and can take several days; high altitude climbers will progress slowly to give sufficient time for their bodies to acclimatize. Nevertheless, many climbers experience ‘altitude sickness’ above altitudes of 10,000 feet (3000m), complaining of headaches, nausea, and breathlessness. In more serious cases, severe pulmonary or cranial oedema can ensue as a result of increased permeability of capillaries in the lungs or brain respectively—the mechanism remains largely unknown. Pulmonary oedema results in severe breathlessness that is rapidly alleviated by taking the patient back to low altitude. Cranial oedema is more serious because the patient is often unaware of their condition, even if their delirious behaviour is obvious to others. Failure to return to low altitude very rapidly can result in death. Susceptibility is not predictable and is not related to fitness; susceptible individuals are probably genetically predisposed to altitude sickness. P.403
Blood—plasma Blood consists of a suspension of a number of different types of cells in an aqueous medium called plasma (Table 6.2). The primary function of blood is the transport of oxygen in red blood cells and essential nutrients in the plasma to tissues and organs for use in cellular respiration. Conversely, the waste products of cellular metabolism are also carried away from tissues by the blood. However, the transport function of blood extends well beyond the requirements for cellular metabolism: many hormones and other signalling molecules are transported from the glands where they are synthesized to their target tissues by the blood, whilst white blood cells and platelets are carried in the blood to help protect against infection and to repair tissue damage. Plasma is an iso-osmotic aqueous medium, the basic constituents of which are sodium and potassium salts, glucose, and plasma proteins (see table). Plasma is isolated from the cellular fractions of blood by centrifugation in the presence of an anticoagulant to prevent the blood from clotting. Serum is similar to plasma but is isolated by allowing the blood to clot; as a result, serum does not include clotting proteins. The concentration of the plasma constituents is regulated primarily by the kidney, where water, sodium, and urea are excreted (p.482). Plasma glucose is tightly regulated by the actions of the pancreatic hor-mones—insulin and glucagon (pp.584—5)—but can more than double immediately following a meal containing carbohydrates. The plasma proteins, of which albumin is most abundant, are mainly synthesized in the liver and they perform a number of functions, including the maintenance of osmotic balance in the plasma and removal of potentially toxic chemical entities that might enter the bloodstream, (e.g. transition metal ions and some drugs and toxins). Plasma proteins do not normally pass through blood vessel walls into tissues.

Table 6.2 Blood composition and constituent function
Blood constituentContent/cell countFunction
Transport, electrolytic, and osmolarity balance
Red blood cells5 × 109/mlO2, CO2 transport
White blood cells9 × 106/mlDefence
Platelets3 × 108/mlHaemostasis

The Cardiovascular System Red blood cells Red blood cells (also known as erythrocytes) are the most abundant cell type in the blood (Table 6.2, p.403). These cells do not have nuclei (they are anucleate) and account for ~40% of total blood volume (haematocrit) in healthy adults. They develop in the bone marrow from large, nucleated normoblastic cells that differentiate into mature red cells in response to the kidney-derived hormone, erythropoietin. Healthy red blood cells conform to a biconcave discoid shape (~8µm in diameter) that is sufficiently flexible to allow them to pass through capillaries that can be as narrow as 3µm. Red blood cells are packed with the specialized, pigmented protein, haemoglobin, the primary function of which is to bind molecular oxygen(O2) in vascular beds where O2 is abundant (the lungs) and deliver it to regions where the oxygen is needed to maintain cellular respiration. Haemoglobin is a complex protein comprising four subunits (2α and 2β in adults), each of which contains a haem group. The haem groups are synthesized in the mitochondria of maturing red blood cells in a processrequiring vitamin B6 and circulating iron bound to transferrin. In order to bind O2 efficiently, haem iron is kept in its reduced (Fe2+) form as opposed to the met (Fe3+) form by NADPH-fuelled methaemoglobin reductase and the abundant endogenous antioxidant, glutathione (GSH). The interaction of haemoglobin with O2 is covered in detail on pp.386–7. P.405
Blood groups Red blood cells, along with many other cells in the body, express antigens on their cell membranes. These antigens are glycoproteins (proteins linked to carbohydrate chains), the precise structure of which are determined at a genetic level. In humans, there are two types of antigen that can be expressed, each with a different sugar residue at a specific locus in its carbohydrate chain: type A has an acetylgalactosamine, whereas type B has galactose. Blood groups are assigned according to which of these antigens is expressed in an individual, hence the blood groups A, B, AB (where both are expressed) and O (where neither is expressed). Blood groups are inherited according to Mendelian principles, with A and B co-dominant, whilst O is recessive. The blood group of an individual also determines the antibodies that they will produce against red blood cell antigens—the overriding determining factor for compatibility of blood used in transplants. Should plasma containing anti-A antibody come into contact with red blood cells expressing the A antigen, they congeal or agglutinate, making them functionally inactive. This provides the basis for the simple test that is routinely conducted to determine blood group to enable cross-matching before transfusions (covered in detail elsewhere). The rhesus system A and B antigens do not constitute the only types of antigen that are expressed on red blood cells. Indeed, there are a great number of antigens on red blood cells, the combination of which are probably unique to any given individual. Many of these antigens have not yet been fully characterized, but those associated with the rhesus system are recognized, alongside the ABO antigens, as important identification tags. Rhesus system antigens constitute a group of glycoproteins that are expressed in most people (85% Caucasians and 99% Orientals are rhesus positive, Rh+). The rhesus system only becomes an issue when a Rh mother gives birth to a Rh+ child that is of the same ABO blood group as the mother. In the event of some red blood cells from the foetus crossing into the mother’s circulation during childbirth, the cells will not be destroyed by the mother’s immune system because they are of the same ABO group. However, the surviving cells will induce the mother to produce antibodies against Rh antigens and, whilst the first child is unaffected, should the mother have a second Rh+ child, her immune system will destroy the red blood cells of the child, leading to haemolytic disease. The issue is overcome in modern medicine by screening pregnant women for Rh and injecting them with Rh+ antibodies within 36 hours of childbirth to destroy any foetal red blood cells before the immune system has time to generate antibodies of its own. P.406
White blood cells The comparatively large nucleated cells found in the blood are collectively known as the white blood cells or leucocytes, whose primary function is defence against infection. The white blood cell population can broadly be divided into two classes of cell:

  • The lymphocytes that act in concert with immunoglobulins and the complement system to instigate immunity
  • The phagocytes that contribute to inflammatory processes and actively ingest invading pathogens, diseased host cells, and cellular debris.

The function of white cells is covered in detail on p.810. The origins and localization of white blood cells are outlined in Fig. 6.23. Lymphocytes and natural killer cells Like all blood cells, lymphocytes are ultimately derived from pluripotent stem cells in the bone marrow, which differentiate into lymphoid stem cells in response to specific inflammatory mediators (e.g interleukin 3, IL-3) and growth factors (e.g. granulocyte-macrophage colony stimulating factor, GM-CSF), release of which is stimulated by infection. In this way, the body responds rapidly to infection by generating more white blood cells to help deal with the crisis. The next stage of development is differentiation of lymphoid stem cells into B lymphocytes (in the bone marrow) and T lymphocytes (in the thymus). B lymphocytes are responsible for generating antibodies for immunity and are characterized by expression of specific surface markers (CD19, 20, and 22). T lymphocytes express CD4 or CD8 surface markers (amongst others) and have the ability to distinguish between healthy cells that belong to the host individual (‘self’) and foreign or diseased cells (‘non-self’). CD4-expressing lymphocytes help to produce antibodies (‘helper cells’), whilst CD8-expressing lymphocytes initiate cell-mediated immunity against intracellular organisms. Mature B and T cells circulate in the bloodstream but are able to migrate into tissues to fight infection and also gravitate towards the lymph nodes and spleen, via the lymphatic system, resulting in localized swelling of the nodes during infection. Lymphocytes flow back into the bloodstream, via the thoracic duct, into the superior vena cava. Natural killer (NK) cells are also derived from lymphoid stem cells in the bone marrow. NK cells are designed to search and destroy cells that are infected by viruses or are cancerous. The phagocytes Phagocytes are also derived from pluripotent stem cells that differentiate into myeloid stem cells, via haemopoeitic stem cells in the bone marrow. The fate of myeloid stem cells is determined by the relative abundance of specific monocyte, granulocyte, or eosinophil-derived growth factors and interleukins. This system results, therefore, in sophisticated self-regulation whereby generation of cells of a particular type is only initiated if the existing cells of that type are highly activated and in need of reinforcements.

Fig. 6.23 The origin of blood cells.

Monocytes and macrophages Monocytes are derived directly from myeloid cells and pass into the bloodstream, where they circulate in a quiescent form for up to two days before they migrate into the tissue and differentiate into mature phagocytic macrophages. Macrophages are the scavengers of the immune system and are particularly prevalent in the liver (where they are sometimes called Kupffer cells) and the lungs. However, they accumulate in specific sites of infection to help kill invading pathogens and to clear cellular debris from the site. Neutrophils These granulocytes have a very distinctive nuclear arrangement consisting of densely packed chromosomal material in 2–5 distinct lobes. Like monocytes, mature neutrophils also differentiate from myeloid progenitor cells via granulocyte stem cells. The cytoplasm of neutrophils is packed with granules of different types:

  • Primary granules contain a range of enzymes (e.g. myeloperoxidase) that generate highly toxic, oxygen-related species, including superoxide and hydrogen peroxide
  • Secondary granules contain enzymes (e.g. lysozyme, collagenase) that act to lyse cells and digest their contents, or deprive them of essential iron (lactoferrin).

The primary function of neutrophils is the identification, phagocytosis, and killing of invading pathogens (p.804). Mature neutrophils only circulate for about 10hr before they undergo programmed cell death (p.71) and are cleared by macrophages. Eosinophils Eosinophils are very similar in structure, function, and origin to neutrophils. The distinguishing feature of eosinophils is their 2–3-lobed dense nucleus. They are often associated with allergic reactions and defence against parasites. Basophils Basophils are rarely found in peripheral blood and when they enter tissues, they become mast cells that are involved in the recruitment of other inflammatory cells to sites of infection or damage. These cells are packed with histamine and heparin-containing granules that can obscure the nucleus. Platelets Platelets are very small (1–2µm diameter), discoid, subcellular fragments that do not contain nuclei but have most of the other features associated with cells, including mitochondria, endoplasmic reticulum, and a crude microfilament and actin-based cytoskeleton. Platelets are derived from megakaryocytes in the bone marrow in response to thrombopoietin synthesized in the kidneys and liver. Their generation is auto-regulated on account of clearance of circulating thrombopoietin by platelets. P.409
The function of platelets is to stop blood loss after injury by forming a plug in damaged blood vessels and releasing agents (e.g. thrombin) that contribute to rapid clot formation. They also release signals to recruitand activate further platelets (e.g. ADP, thromboxane A2, 5-HT) and to attract inflammatory cells (e.g. platelet-derived growth factor; PDGF) to the site of injury in order to ward off any potential infection. This process of haemostasis is covered in detail on pp.446–7. P.410
Heart morphology (Colour Plate 8) The heart is a four-chambered, muscular pump responsible for perfusing the vascular network with blood. The left and right sides of the heart effectively operate as two pumps, sending blood through the serially arranged systemic and pulmonary circulations respectively. Gross anatomy The outline of the heart, which is roughly conical in shape, can be consistently defined on the surface of the chest according to the following guidelines:

  • The superior border of the heart is defined as a line following the 2nd intercostal space approximately 4cm either side of the sternum
  • The right border runs from the 3rd right costal cartilage to the 6th right costal cartilage
  • The apex of the heart is located in the 5th intercostal space in the mid-clavicular line. Its inferior border runs from this point to the right border
  • The left border of the heart connects the apex to the superior border.

These relationships are of importance to clinicians during auscultation and palpation (OHCM6 pp.40–1). The heart is located in the middle mediastinum within the pericardium: a double layered sac which completely surrounds the heart apart from the points where the great vessels enter and leave. The external pericardial layer is referred to as fibrous pericardium—a structure which prevents excessive distension of the heart. It is lined on its internal face by a parietal layer of serous pericardium. This is continuous with the visceral layer of serous pericardium (epicardium) forming a potential space (pericardial cavity), which contains a thin layer of fluid permitting the heart to move within the pericardial sac. Pericardial sinuses are formed by the reflection of the pericardium around the heart. These sinuses are small, blind-ending spaces between the heart and the great vessels (oblique sinus) and around the aorta and pulmonary trunk posterior to the heart (transverse sinus). The heart is fist-sized and lies obliquely within the thorax such that its anterior surface is formed largely of the right atrium and the right ventricle, while the left atrium and the left ventricle are orientated posteriorly. The wall of the heart is made up of three layers: the epicardium is the most superficial of these and is lined by the muscular myocardium which in turn is separated from the chambers by a layer of endocardium. The fibrous skeleton of the heart is formed by a cartilaginous ring at the level of the membranous ventricular septum, separating the atria from the ventricles. It contains the atrioventricular, aortic, and pulmonary orifices. It provides electroinsulation, so that electrical impules cannot pass directly from the atria to the ventricles except via the atrioventricular node. This fibrous skeleton also supports the cardiac valves at the base of the cusps, preventing stretching and incompetence of the valves. P.411
Blood flow through the heart The systemic circulation drains into the right atrium via the superior and inferior venae cavae, while the cardiac veins enter the right atrium via the coronary sinus. The right atrium is separated from the left atrium by the interatrial septum within which can be found the fossa ovalis—a vestige of the foramen ovale which permits the shunting of blood from the right to the left atrium in the foetus. Right atrial contraction forces blood into the right ventricle through the right atrioventricular orifice. This structure is bounded by the right atrioventricular (tricuspid) valve which prevents any backflux of blood during ventricular contraction. The papillary muscles which arise from the ventricular wall are attached to the loose edges of the cusps of the right atrioventricular valve (usually one per cusp) via chordae tendinae which maintain the direction of the cusps. The three cusps of this valve are attached to a fibrous ring surrounding the atrioventricular orifice. Right ventricular contraction forces blood into the pulmonary trunk via the infundibulum. The interventricular septum separates the right and left ventricles and bulges into the right ventricle because of higher pressure in the left ventricle. Backflux of blood from the pulmonary circulation into the right ventricle is prevented by the presence of the pulmonary valve; this comprises three semi-lunar cusps. Stenosis of the pulmonary valve, frequently occurring alongside infundibular pulmonary stenosis, narrows the outflow from the right ventricle and causes right ventricular hypertrophy. The left atrium receives the four pulmonary veins (two inferior and two superior). Its wall is slightly thicker than that of the right atrium owing to the higher pressures within the systemic circulation. The fossa ovalis is a visible part of the interatrial septum. Blood is expelled from the left atrium past the mitral valve, via the atrioventricular orifice, to the left ventricle. The mitral valve is analogous in structure and function to the tricuspid valve, although it comprises only two cusps and its papillary muscles are larger than their counterparts in the right side of the heart. The wall of the left ventricle is approximately twice as thick as the right ventricle. It pumps blood into the aorta via the aortic orifice. The three semi-lunar cusps of the aortic valve guard this opening. Aortic sinuses are formed behind the cusp of each valve as a bulge in the aortic wall. The posterior sinus supplies the origin of the left coronary artery, and the anterior cusp provides the origin of the right coronary artery, which supplies the heart. P.412
Blood and nerve supply to the heart (Colour Plate 8) The coronary circulation must provide the myocardium with sufficient blood to meet its high basal oxygen consumption, with the capacity to increase during exercise. The high pressure which develops in the ventricular wall during systole transiently shuts off the coronary circulation. This effect means that 80% of coronary blood flow occurs during diastole. In order to cope with these challenges, myocardium contains a high capillary density, increasing the efficiency with which nutrients and waste products can be exchanged. Furthermore, the total oxygen extraction from the coronary circulation is high. The branches of the coronary arteries are particularly sensitive to obstruction (e.g. during atherosclerosis OHCM6 p.114; pp.442–5), since anastomoses are infrequent and inefficient (functional end arteries). Such events underlie myocardial infarction and angina. Sites of obstruction can be localized by coronary angiography (OHCM6 pp.108–9). Arterial supply (Fig. 6.24) (OHCM6 p.109) The right and left coronary arteries arise from the aorta just distal to the aortic valve at the coronary sinus. These vessels supply the myocardium and the epicardium. The right coronary artery passes from the anterior aortic sinus anteriorly, past the pulmonary trunk in the right atrioventricular groove, in which it passes under the inferior border of the heart; ultimately it anastomoses with the circumflex branch of the left coronary artery at the posterior interventricular groove. A branch of the right coronary artery (the posterior interventricular artery) runs in the inferior interventricular groove and anastomoses with the anterior interventricular artery near the apex of the heart, which arises from the left coronary artery. This right posterior interventricular artery supplies the AV node in 90% of people, while in the remaining 10%, the AV node is supplied by a branch of the left coronary artery. Clearly, this is of significance following myocardial ischaemia. A marginal branch also arises from the right coronary artery and passes along the inferior border of the heart. The left coronary artery passes from the posterior aortic sinus and runs in the left atrioventricular groove to anastomose with the right coronary artery. It gives off several key branches analogous to those from the right coronary artery—the anterior interventricular artery (which runs in the anterior interventricular groove) and the circumflex artery (which anastomoses with the right coronary artery). The left marginal artery follows the left margin of the heart. In general, the right and left ventricles are supplied by the right and left coronary arteries, respectively, while the atria and interventricular septum can be supplied by both. There can be considerable variations from this scheme, however.

Fig. 6.24 The arterial supply of the heart.

Venous drainage (Fig. 6.25) The majority of the venous drainage of the heart empties into the coronary sinus, although a certain amount passes directly into the right atrium (largely from anterior cardiac veins which drain the anterior aspect of the heart). The coronary sinus runs in the posterior atrioventricular groove and receives:

  • The great cardiac vein (from the anterior interventricular groove) at its left end
  • The middle cardiac vein (from the inferior interventricular groove)
  • The small cardiac vein (from the lower border of the heart) at its right end.

Nerve supply (Table 6.3) The heart receives innervation from parasympathetic, sympathetic, and sensory fibres which together form superficial and deep cardiac plexuses below the aortic arch. Sensory fibres innervating the heart run in close proximity to cervical and thoracic spinal nerves. This explains the phenomenon of referred cardiac pain to the chest, arms, and neck during myocardial ischaemia (pp.92–3).

Fig. 6.25 The venous drainage of the heart.
Table 6.3 Nerve supply to the heart
TypeNerveInnervated siteFunction
Parasympathetic (efferent)Vagus nerve
  • SA node
  • AV node
  • Coronary arteries
  • Decreases heart rate
  • Constriction of coronary arteries
  • No appreciable effect on contractility
Sympathetic (efferent)Cervical and upper thoracic spinal nerves via sympathetic ganglia
  • SA node
  • AV node
  • Cardiac muscle fibres
  • Coronary arteries
  • Increases heart rate
  • Increases force of contraction
  • Dilation of coronary arteries
Sensory (afferent)Follows sympathetic ganglia via white rami communicantes and spinal nerves
  • Myocardium
  • Pain from myocardium ischaemic

Conducting system of the heart (Fig. 6.26) As for all striated muscle, membrane depolarization is the stimulus for contraction of cardiac myocytes to occur, and the co-ordinated and regulated spread of electrical excitation from the atria to the ventricles is essential for efficient pumping activity. The cells of the heart are arranged as a branching functional syncitium in which electrical depolarization passes from one cell to the next via gap junctions. Certain cardiac muscle cells contain few myofibrils and are specialized conducting fibres which allow a wave of depolarization to spread throughout the heart in a rapid, co-ordinated manner. Unlike skeletal muscle, electrical impulses within the heart are generated intrinsically and are not dependent on external nervous input, although cardiac function can be modulated by the activity of the autonomic nervous system. The sino-atrial node (SA node)—an area of specialized cardiac tissue on the posterior wall of the right atrium—is the normal pacemaker region of the heart where electrical depolarization is initiated. SA node cells contain few myofibrils and are not specialized for contraction. Instead, they spontaneously depolarize in a rhythmic manner, triggering action potentials which are conducted to the surrounding atrial tissue. The frequency of SA node depolarizations determines the frequency of cardiac contraction. The SA node is the usual pacemaker in the heart since it exhibits the highest frequency of spontaneous activity and overrides other potential pacemaker regions (ectopic pacemakers). Following an action potential, the resting membrane potential of an SA node cell is —55 to —60mV. A slow inward leak of Na+ ions (If, ‘funny’ current) then depolarizes SA node cells until an action potential is fired at about —40mV. The upstroke of the action potential in an SA node cell is a result of the influx of Ca2+ ions through voltage-gated Ca2+ channels. The atria are almost completely electrically insulated from the ventricles by the annulus fibrosus and electrical impulses can only pass between them via the atrio-ventricular node (AV node). This is a specialized area of conducting tissue within the atrial septum which slows the conduction of the electrical impulse, allowing the atria to contract before the ventricles. Electrical impulses arrive at the AV node via conducting pathways from the SA node. From here, the bundle of His transmits depolarization across the annulus fibrosus and along the interventricular septum. The bundle of His divides into anterior and posterior, left and right bundle branches which pass down the left or right side of the interventricular septum and transmit impulses initially to the endocardial regions of the left and right ventricles respectively. Fibres from the left and right bundle branches transmit impulses to Purkinje fibres which are made up of large-diameter cells which conduct electrical impulses very rapidly. In general, large-diameter fibres propagate electrical impulses more quickly since their internal resistance is lower. From the endocardium, contractile cells transmit impulses to each other. This network of rapid conducting fibres therefore allows all parts of the ventricles to contract virtually simultaneously. P.417
The function of the pacemaker and conducting system of the heart can be modulated by autonomic nervous system activity. Sympathetic nerve activity to the SA node increases the magnitude of the funny current, thereby decreasing the time taken for depolarization to occur and increasing heart rate (positive chronotropic effect—tachycardia). This is mediated by catecholamines binding to β1 adrenoceptors, leading to an increase in intracellular cAMP which increases the open-state probability of channels which conduct the funny current. Similarly, sympathetic activity decreases the time taken for conduction through the AV node. Parasympathetic (vagal) nervous activity slows heart rate (bradycardia) by slowing the rate of depolarization of the pacemaker potential in SA node cells. Furthermore, pacemaker cells are hyperpolarized, increasing the time required to reach threshold for an action potential. Both of theseeffects are the result of acetylcholine binding to muscarinic (M2) receptors. Reduced pacemaker potential is the result of reduced intracellular cAMP concentration; hyperpolarization is the result of activation of K+-channels.

Fig. 6.26 The conducting system of the heart. The fibrous skeleton of the heart separates the muscle of the atria from that of the ventricles, which are connected only by the bundles of His.

The electrocardiogram (ECG) (OHCM6 pp.94–107) The ECG is a record of the electrical events associated with depolarization and repolarization of the myocardium, measured as changes in the surface potential of the skin. During the cardiac cycle, as the atria and then the ventricles undergo sequential depolarization followed by repolarization, the extracellular myocardial compartment can be treated as two moving dipoles of opposite charge. Each dipole is essentially an aggregation of the depolarized (negative) and hyperpolarized (positive) regions of the heart. Charge flows between these two dipoles and it is the potential arising from these minute currents that can be picked up as small (up to 1mV) potential differences at the skin. Normally, only potentials arising from myocardial depolarization and repolarization can be recorded—the conducting system is too small to produce potential changes of sufficiently large magnitude to be measurable by ECG. The ECG is routinely used clinically and allows abnormalities in the electrical activity of the myocardium to be detected and diagnosed. It must remembered that the ECG is a record of electrical, not contractile events. Properties of the ECG The nature of the ECG trace varies according to the ‘limb leads’ used to record it (see below), although certain features are invariant in healthy subjects (Fig. 6.27):

  • The P wave is the first event of the cardiac cycle observable by ECG. It arises from depolarization of the atria and lasts approximately 0.08sec
  • The PR interval is the period from the start of the P wave to the start of the QRS complex (it should more logically be known as the PQ interval). A large proportion of the PR interval is flat (after the P wave) and this represents the time taken for conduction through the AV node—the heart is essentially isoelectric during this period. The PR interval lasts approximately 0.2sec
  • The QRS complex is a record of ventricular depolarization and, as such, is analogous to the P wave for the atria. It lasts for only a short time, approximately 0.1sec, demonstrating the almost synchronous depolarization of the ventricular myocardium
  • The ST segment corresponds to the plateau phase of the ventricular action potential and, like the major part of the PR interval, represents the heart in an isoelectric state
  • The T wave is a record of ventricular repolarization. It is normally in the same orientation as the QRS complex (large upward deflection), since repolarization occurs in the opposite direction to depolarization.

Standard limb leads The ECG is traditionally recorded using three electrodes—one on each arm and one on the left leg. Together, these three points make up Eintho-ven’s triangle. An ECG trace is generated by resolving the electrical vector arising from the electrical dipole onto one of the three leads connecting P.419
the above three electrodes. During the cardiac cycle, this electrical dipole changes in magnitude and direction and, therefore, its resolution onto each of the three leads is continually changing. Each of the three leads is in a different orientation and emphasizes different features of the ECG:

  • Lead I: right arm (—) to left arm (+)—horizontal
  • Lead II: right arm (—) to left leg (+)—60° below horizontal
  • Lead III: left arm (—) to left leg (+)—120° below horizontal.

The standard leads are therefore designed such that a positive deflection results when a positive dipole points towards the left arm (lead I) or the left leg (lead II or III).

Fig. 6.27 The relationship between the onset and duration of the action potentials of cardiac cells during a single cardiac cycle and the ECG trace. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

Normal cardiac rhythm and arrhythmias The action potential in the heart There are a number of features that make the action potentials of the heart different from those seen in other excitable tissue. Most importantly, there are special pacemaker cells (found primarily in the sino-atrial node) that spontaneously generate action potentials in a cyclical fashion, thanks to their unusually high Na+ permeability. The key events in the cardiac action potential (Fig. 6.28):

  • A slow leak of Na+ into pacemaker cells (pacemaker potential), gradually causing depolarization until the threshold potential is reached
  • Phase 0: at threshold, voltage-dependent Na+ channels open, leading to rapid depolarization
  • Phase 1: Na+ channels only remain open for a few milliseconds and quickly de-activate when the cell is depolarized, leading to a partial repolarization
  • Phase 2: voltage-gated Ca2+ channels are then activated, allowing an influx of Ca2+ which maintains depolarization
  • Phase 3: delayed, outwardly rectifying K+ channels (as well as other potassium channels) open to allow an efflux of K+, ultimately repolarizing the cell
  • Phase 4: no sooner have pacemaker cells repolarized than they start to depolarize again on account of the pacemaker potential. Pacemaker cells tend to have a less polar ‘resting’ membrane potential than other cells (—60mV as opposed to ~—80mV for most cells) because of their inherent leakiness to Na+
  • The rate at which the pacemaker potential develops is accelerated bynoradrenaline and adrenaline acting on β1 adrenoceptors and is slowedby vagus-derived acetylcholine acting on muscarinic M2 receptors.

The pacemaker potential is transmitted to surrounding cells in the atrium because the cells are electrically coupled. These cells do not usually have pacemaker activity and action potentials are only triggered by depolarization of adjacent cells. Depolarization of atrial cells is of shorter duration (200msec) than that in Purkinje fibres and ventricles, where Ca2+ channel activation is prolonged, leading to a longer plateau phase and action potentials that last for 300— 400 msec (Fig. 6.28). Refractory period The refractory period is the time taken between action potentials for the cell to prepare itself for another depolarization (e.g. re-activation of Na+ channels that are inactivated during depolarization). During the refractory period, cells cannot be activated, even if a stimulus arrives—a crucial factor in ensuring that the action potential is propagated in one direction only and cannot double-back on itself to create chaotic contractile patterns (p.222).

Fig. 6.28 (a) Cardiac action potential and membrane permeability; (b) change in action potential response profile across cardiac tissue—longer depolarizations correspond to protracted Ca2+ channel opening.

Arrhythmias (also known as dysrhythmias) (pp.126–33, 790–3) Maintenance of a consistent rhythm is central to efficient cardiac function. The electrical conductance system described above is cleverly designed to only allow electrical waves to travel in one direction and to prevent their arriving too close together, making for inefficient contraction of cardiac muscle. However, an injury to the heart muscle (caused, for example, by a heart attack (p.120–4, 782–3)—(p.432) results in the death of a discrete area of the muscle, as defined by the location of the thrombus of the coronary artery that led to the heart attack. The infarcted area is dominated by scar tissue, which alters the electrical conduction properties of that region. The site of the infarct has serious implications for the efficient transmission of the electrical activity across the heart and can lead to potentially fatal changes in heart rhythm—so-called arrhythmias.

  • Abnormal pacemaker activity: the heart rate is normally determined by the pacemaker cells in the sino-atrial (SA) node, but other cells in the heart can undertake pacemaker activity during or after ischaemic damage. The cellular mechanisms have not been fully elucidated but may involve a decrease in Na+/K+—ATPase pump activity leading to membrane depolarization, and pain-mediated adrenaline release might play a part during a heart attack
  • Heart block: if an infarct encompasses the atrio-ventricular (AV) node, the wave of activity may not be properly transmitted from the atria to the ventricles. The atria will continue to beat at the rate set by the SA node; the ventricles will beat independently, at a rate set by ventricular pacemaker cells. Sequential contraction of the atria, followed by the ventricles, is crucial for efficient pumping of blood and ‘heart block’ is best treated by implantation of an artificial pacemaker (OHCM6 pp.134–5)
  • Re-entry: the refractory nature of cardiac muscle immediately after depolarization normally ensures that the impulse wave only travels in one direction. Re-entry applies to a ‘ring’ of cardiac tissue, which can be anatomically distinct from the surrounding tissue, but is more commonly only functionally distinct. The concept dictates that an impulse arising from any point in the ring will propagate in both directions, until the waves of depolarization meet and both impulses are cancelled out (Fig. 6.29). However, if part of the ring is damaged, such that the impulse is not transmitted in the normal (anterograde) direction but can still be conducted in the retrograde direction, the impulse can cycle around the ring continuously, if the time taken for each cycle exceeds the refractory period. Although the re-entrant circuit may only occupy a small area of cardiac tissue, its effects are transmitted to the surrounding cardiac muscle and the impact on heart rhythm can be dramatic. Drugs that are useful in treating re-entry prolong the refractory period (see Table 6.4)
  • Delayed after-depolarization: normally, myocardial cells do not contract when they are stimulated by the wave of activity that originates in the SA node. Inbetween times, the cells are first refractory and then P.423
    quiescent, until the arrival of the next wave of depolarization. However, if intracellular Ca2+ levels increase excessively during depolarization, an after-depolarization can result from a net influx of Na+ ions in exchange for the Ca2+ (in the ratio 3 Na+ in: 1 Ca2+ out) and the opening of Ca2+-sensitive non-selective cation channels. If the heart rate is slow, the after-depolarization may not be sufficient to elicit an action potential, and it gradually subsides. However, as the heart rate increases, the after-depolarization increases until it is sufficiently high to elicit an action potential: the effect is self-perpetuating, leading to an indefinite chain of action potentials in quick succession (tachycardia).
Fig. 6.29 Circus movement caused by re-entry in cardiac tissue.

Bradycardia and atrial fibrillation Bradycardia (pp.126–7) is an unusually slow heart rate that can be brought on by sinus dysfunction (sick sinus syndrome) or hypothyroidism and exacerbated by heart-slowing drugs (β-blockers and cardiac glycosides). Severe cases can lead to cardiac arrest, atrial fibrillation, or thromboembolism. Mild cases can be effectively treated with the muscarinic ACh receptor antagonist, atropine, which prevents the slowing effect of parasympathetic (vagal) stimulation of the heart. More serious cases may require temporary or permanent implantation of pacemaker devices (pp.134–5). Atrial fibrillation (AF) (pp.130–1) is defined as irregular and extremely rapid (300–600/min) contractions of the atria. The AV node is only intermittently activated by this chaotic activity, giving rise to irregular ventricular function. The cause is often myocardial infarction, but heart failure, hypertension, bronchitis, and hyperthyroidism can also result in AF. The main risk is thromboembolism (p.355), which is prevented by the anticoagulant, warfarin (p.648) (p.461). The key to treatment of AF is to deal with the underlying cause, if possible, and to use drugs to slow the atrial contractions (digoxin, β-blockers, verapamil, amiodorone). If patients fail to respond to drug treatment or in emergency, cardioversion (p.754) (electrical shock treatment) might help to restore normal rhythm. Treatment of arrhythmias Some arrhythmias are best treated by implantation of an artificial pacemaker (abnormal pacemaker activity), by surgical intervention to ablate re-entry circuits (e.g. accessory pathways between the atria and ventricles in Wolff—Parkinson—White syndrome), or by cardioversion in serious acute cases. Drug therapies, however, are primarily aimed at the electrophysiological events of cardiac contractility and crudely fit into the Vaughan Williams’ classification. As can be seen in Table 6.4, the overall effect is generally a reduction in cardiac contractility, but the underlying cause of this effect varies with the different classes of drug.

Table 6.4 Vaughan Williams’ classification of anti-arrhythmic drugs
ClassExampleMechanismRate of depolarizationAction potential durationRefractory periodAtrio-ventricular conductionCardiac contractility
IaProcainamideUse-dependent inhibition of Na+ channelsReducedIncreasedIncreasedReducedReduced
IbLidocaine (p.226)Inhibition of fast-dissociation Na+ channelsReducedReducedIncreasedNo effectNo effect
IcFlecainideInhibition of slow-dissociation Na+channelsReducedNo effectNo effectReducedReduced
IIPropranololβ-blockNo effectNo effectNo effectReducedReduced
IIIAmiodoroneK+-channel blockNo effectIncreasedIncreasedReducedNo effect
IVVerapamilCa2+-channel blockNo effectReducedNo effectReducedReduced

The heart as a pump The role of the heart is to supply sufficient blood to the tissues to satisfy their O2 and nutrient requirements and to remove waste products, including urea and CO2. This role is fulfilled due to the synchronized contraction of the cardiac myocytes that constitute the walls of the heart chambers in response to the wave of electrical activity that is conducted by the myocytes themselves. Below (and in Figs. 6.30, 6.31) is a summary of the mechanical events that contribute to the cardiac cycle; we join the cycle during the relaxation phase (diastole), just before the next wave of excitation is initiated in the SA node. Under resting conditions in humans, the whole cycle is complete in ~ 1 second:

  • The atria and ventricles are relaxed and the pressure in the heart chambers is low. Blood from the large systemic veins (superior and inferior vena cava) and that returning from the lungs (pulmonary vein) flows into the right and left atria respectively. The atrio-ventricular (AV) valves are open at this stage of the cycle, so the majority of blood passes passively from the atria to the ventricles.
  • The wave of depolarization emitted from the SA node in the right atrium sweeps across the atria and causes the cardiac myocytes in their walls to contract, forcing most of the remaining blood from the atria into the ventricles via the open AV valves. The volume of the ventricles increases as they fill (to a maximum of about 130ml under resting conditions).
  • The conduction wave has now passed through the AV node and been conducted, via the fast Purkinje fibres in the bundle of His, to the apex of the ventricles, whereupon it sweeps across the ventricles from bottom to top, initiating ventricular contraction (systolic phase).
  • As soon as ventricular contraction starts, the AV valves snap shut, trapping the blood in the ventricles and causing ventricular pressure to rise without any significant change in ventricular volume.
  • Pressure in the ventricles continues to rise until it exceeds that in the outflow arteries (pulmonary artery and the aorta; ~80mmHg). Now the valves at the openings to these arteries are forced open by the pressure, and blood flows down its pressure gradient into the arteries. Ventricular volume falls as the blood is forced out. Ultimately, the pressure in the ventricles will fall below that in the arteries and the pulmonary and aortic valves will shut. Under resting conditions, only about half of the total volume of blood in the ventricles is ejected (i.e. the ejection fraction is about 50%).
  • The wave of contraction is followed by a relaxation phase. The refractory nature of the cardiac myocytes at this stage prevents another contraction occurring too soon after the first; it is essential that sufficient time is given between heartbeats to allow the chambers of the heart to fill properly. The relaxation (diastolic) phase of the cycle therefore allows blood to flow back into the heart, via the atria, before the start of another cycle.
Fig. 6.30 Cardiac cycle at rest: pressure, volume, and heart sounds.
Fig. 6.31 The cardiac cycle.

Each stroke of a healthy adult human heart under resting conditions ejects ~70ml into the systemic circulation, via the aorta. This volume is known as the ‘stroke volume’. The heart rate under the same conditions is usually ~70 beats/min. Knowing these two parameters, we are able to calculate the amount of blood that is pumped out of the heart every minute (the cardiac output): Stroke volume × heart rate = cardiac output 70ml × 70 beats/min = 4900ml/min (4.9litres/min) Preload and the Frank-Starling Law The force generated by contraction of cardiac myocytes is dependent on their length—just as it is for skeletal muscle fibres. The ‘length—tension’ relationship for cardiac tissue therefore bears a close similarity to that for skeletal muscle, but the length of the muscle is uniquely determined by the amount of blood in the ventricle when the heart is fully relaxed (the end diastolic volume; Fig. 6.32). The Frank—Starling Law establishes that the force of contraction of the heart is related to the end diastolic volume (Fig. 6.32). Sympathetic nervous stimulation of the heart increases the efficiency of contractility—more force is generated for a given end diastolic volume. The end diastolic volume is dependent on the amount of blood returning to the heart, also known as preload. In a non-compliant, fixed-volume, closed system, this would necessarily equal the amount of blood leaving the heart, meaning that increased cardiac output would be reflected in increased preload and increased force of contraction. Cardiac output is indeed a determinant of preload, but the issue is complicated by the fact that contraction of veins alters the volume of the vascular system and influences preload (Fig. 6.32): venous contraction reduces venous volume and increases preload and vice versa. Therefore, whilst arterial tone is regarded as the primary determinant of blood pressure, venous tone has an impact on cardiac work and output, hence the ability of veno-selective dilators (e.g. nitrates) to reduce O2 consumption by the heart by reducing cardiac work. Heart valve disease (OHCM6 pp.146–8) Effective valves in the heart are essential for optimal pumping conditions because they prevent backflow of blood against the desired direction of flow. Valves are found between the atria and ventricles (the atrioventricular valves; mitral—left, tricuspid—right) and between the ventricles and the major arteries (aortic valve—left; pulmonary valve—right). There are a number of potential causes of valve malfunction which can be crudely divided into those that cause narrowing of the valve opening (stenosis) and those that cause the valve to leak, leading to regurgitation.

Fig. 6.32 Preload and the Frank—Starling Law (a) Ventricular volume determines cardiac muscle strength; (b) the Frank—Starling relationship between ventricular volume (muscle length) and force of contraction; (c) venoconstriction is a determinant of ventricular volume (preload).


  • Excessive calcification
  • Congenital malformation
  • Rheumatic fever (p.144) (autoimmune damage to valve tissue—more common in developing countries)
  • Atherosclerotic degeneration.


  • Bacterial infection (endocarditis) (pp.152–4) or inflammation
  • Prolapse (poorly supported or weak valve leaflets)
  • Ventricular (atrioventricular valve disease) or aortic dilatation.

The physiological impact of heart valve disease is a loss of effective pumping in the heart resulting in symptoms consistent with reduced cardiac output:

  • Fatigue
  • Breathlessness
  • Angina (left-side valve disease)
  • Oedema (pulmonary oedema for right-side valve disease, systemic oedema for left-side).

Diagnosis Dysfunctional valves are often first diagnosed by GPs, who detect abnormal heart noises (or murmurs). The normal ‘click’ of heart valves closing becomes a prolonged flutter on account of the valve leaflets fluttering or blood regurgitating through an insufficiently closed valve. The time and duration of the murmur is indicative of the valve that is damaged and the type of valve dysfunction (e.g. stenosis or regurgitation). However, diagnosis can only be confirmed with an ECG. Treatment Advanced deterioration of valve function usually requires cardiological or surgical intervention, depending on the nature of the disease. Valvuloplasty (p.150) is a procedure conducted by a cardiologist in patients with stenosed pulmonary or mitral valves; it does not require general anaesthesia. A balloon-tipped catheter is inserted into the femoral artery in the leg and manipulated remotely using X-ray imaging until the tip is across the stenosed valve, where it is inflated to increase the size of the opening and improve blood flow through it. Valve replacement (p.150) involves open-heart surgery. Damaged valves can be replaced by artificial valves or valves taken from cadavers (homografts) or from pigs (porcine xenografts). Artificial valves have the advantage of durability but patients with artificial grafts have to be maintained on anti-thrombotic drugs, whilst grafts from natural sources require replacement after ~10 years but do not require antithrombotics. P.431
Heart failure (pp.136–9) The inability of the heart to meet the supply needs of the body is known as heart failure. Heart failure is often precipitated by a heart attack, which leads to the death of an area of ventricular myocardium and a reduction in the efficiency of ventricular contraction. In patients with heart failure, the ejection fraction at rest falls considerably, with critical effects on cardiac output. For example, if the ejection fraction falls to 25%, only ~35ml is ejected with every heartbeat and cardiac output falls to ~2.5 litres/min (from the usual ~5 litres/min) leading to the following chain of events (see also Fig. 6.33):

  • Blood pressure falls and is sensed by the baroreceptors and through a fall in renal blood flow
  • Signals from the baroreceptors result in the stimulation of the sympathetic nervous system, which restores blood pressure to normallevels by increasing heart rate (via cardiac β1 adrenoceptors), blood volume (β adrenoceptors in the kidney), and vascular resistance (α1 receptors in arterioles)
  • The shortfall in cardiac output is therefore compensated for at the expense of increased heart rate, peripheral vascular resistance (afterload), and blood volume (preload).

The vicious cycle Unfortunately, this short-term solution has long-term consequences. The increased work rate of the heart, coupled with the increased resistance against which it has to pump blood, leads to the thickening of the ventricular walls (remodelling). Whilst cardiac remodelling might be conceived to be advantageous on account of the strengthening of the muscle, it also leads to a further reduction in the volume of the ventricular chamber, reducing the stroke volume further. Simultaneously, the reduction in renal perfusion activates the renin-angiotensin-aldosterone pathway (Fig. 6.33), leading to Na+ and water retention in the tissue (oedema) and pooling of blood in the central veins. The increase in central venous pressure constitutes an increase in cardiac preload, which might be predicted to improve cardiac contractility according to the Frank—Starling law (Fig. 6.32). However, the sympathetic compensation that has already taken place means that increasing the preload fails to increase contractility—instead, the heart becomes overloaded with blood (dilated). This vicious cycle (Fig. 6.33) means that the initial reduction in stroke volume is compensated for by mechanisms that, ultimately, lead to a further reduction in stroke volume and a gradual deterioration in the condition. Heart failure is classified according to symptoms (New York Classification of Heart FailureOHCM6 p.137):

  • Class I: heart disease diagnosed but no breathlessness during ordinary activity
  • Class II: comfortable at rest but breathless with ordinary activity (e.g. walking)
  • Class III: breathlessness apparent with very mild activity; moderately debilitating
  • Class IV: breathless at rest; highly uncomfortable and debilitating.
Fig. 6.33 The vicious cycle of heart failure is triggered by ischaemic damage to the ventricle.

Treatment of heart failure (OHCM6 pp.138–9) The aim of treatment of heart failure is to break the vicious cycle to slow progression of the disease and prolong the life of sufferers:

  • Reduce volume overload: as with hypertension, the kidney is a major target for therapeutic intervention in heart failure. Diuretics (e.g. furosemide) or angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril) are the first-line drugs in heart failure. ACE inhibition has a secondary benefit of causing vasodilatation and reducing afterload (see below), and may also slow or prevent the processes involved in cardiac remodelling
  • Veno-/vasodilatation: organic nitrates (e.g. isosorbide mononitrate) are veno-selective nitric oxide (NO) donor drugs that reduce cardiac workload primarily through reducing preload (although they may have some impact on afterload through vasodilatation as well). These drugs have been shown to reduce mortality
  • Increase the force of ventricular contraction: cardiac glycosides (e.g. digoxin) can be prescribed if none of the above treatments are showing benefit. These drugs are especially effective in patients with a dilated heart and work primarily by inhibiting the Na+/K+ —ATPase, leading to an increase in intracellular Na+, which exchanges with calcium through the Na+/Ca2+ exchange pump. Ultimately, the extra Ca2+ swells the intracellular Ca2+ stores in the sarcoplasmic reticulum, meaning that more Ca2+ is released when the cells are stimulated. Cardiac glycosides can also slow the heart and improve rhythm. In acute heart failure, where a rapid increase in contractility is imperative, β1 adrenoceptor agonists (e.g. dobutamine) can be used
  • Inhibit sympathetic activity: increased sympathetic activity contributes to the vicious cycle that exacerbates heart failure. Inhibition of β-adrenoceptors in the heart has long been avoided on account of the perceived danger of reducing the force of contraction. However, it is now recognized that low doses of the β-blocker, carvedilol, in conjunction with a cardiac glycoside, ACE inhibitor, and diuretic can reduce mortality, although the precise mechanism of this action is still unknown. Physicians are advised to proceed cautiously with β-blockers in heart failure.

The vascular system Blood is transported between the heart and the tissues by blood vessels (Fig. 6.34).

  • Arteries carry blood from the heart to the tissues. They have thick, muscular walls to cope with the high pressures that they are exposed to, and to facilitate their constriction and dilatation to modulate blood pressure and flow distribution. Arteries become progressively smaller but more numerous with distance from the heart; the smallest arteries are called arterioles and are the primary determinant of resistance to flow, often termed peripheral vascular resistance or afterload
  • Capillaries are very fine vessels (<50µm) that distribute blood from the arterioles throughout tissues. The walls of capillaries are only one endothelial cell in thickness and do not contract. The thin walls facilitateeasy diffusion of O2 and glucose necessary for cellular respiration down the concentration gradient from the incoming blood, into the tissues.Waste metabolites (CO2, urea) diffuse in the opposite direction. An exception to this basic rule applies in the lungs (pulmonary circulation), where capillaries come into close contact with alveolar air to facilitategaseous exchange, with the loss of CO2 to the atmosphere and theuptake of O2 into the red blood cells, where it is transported bound to haemoglobin (p.386)
  • Veins carry blood away from tissues and back to the heart. They have some vascular smooth muscle, but not as much as arteries; as a result they can contract and relax, but the changes in diameter are far less dramatic than in arteries. Blood leaving the capillaries enters small veins (venules), which progressively converge, pooling blood into increasingly large vessels. There is little pressure difference across the venous circulation, meaning that unaided flow of blood would be very slow. As a result, veins contain valves to prevent retrograde flow (backflow) and the venous return of blood to the heart is aided by contraction of the surrounding skeletal muscles. This is particularly important in humans, where our upright stance means that the effects of gravity have to be overcome to ensure the return of blood to the heart from our feet. The amount of blood returning to the atria of the heart determines preload (p.428).

Modulators of vascular tone An important feature of our blood vessels is that they contract and dilate in response to numerous signalling molecules in the body. The mechanism by which these effects occur are summarized below and the cellular mechanisms are illustrated in Fig. 6.35. Systemic vasoconstriction

  • The primary stimulus for vascular smooth muscle contraction is activation of the sympathetic nervous system that innervates blood vessels. Increased sympathetic drive results in release of noradrenaline(NA) from sympathetic nerve terminals, which activates α1 and β2adrenoceptors on the smooth muscle cells. Most arteries and arterioles have α1 receptors and contract in response to NA; α2 P.435
    adrenoceptors are also found in these arteries, but they are probably stimulated by circulating adrenaline rather than by sympathetic nerve-derived NA. Arteries that supply skeletal muscle and some veinshave a predominance ofB2 adrenoceptors, which causes them to dilate in response to NA and circulating adrenaline. The net effect of increased sympathetic nervous system activity is to redistribute blood flow away from the internal organs to the skeletal muscles to prepare for ‘fight or flight’ (p.597)
    Fig. 6.34 Characteristics of different blood vessel types, showing the relative proportions of smooth muscle.
  • P.436

  • ATP and neuropeptide Y are co-transmitters that are often released, with NA, to cause rapid or long-lasting vasoconstrictor effects respectively. Stimulation of β-adrenoceptors in the kidney also increases the amount of renin available to catalyse the first step in the renin—angiotensin–aldosterone system. One of the products of this system is angiotensin II, which is a powerful vasoconstrictor through stimulation of angiotensin (AT) receptors on the smooth muscle (primarily AT1 receptors).

Local vasoconstrictors

  • The endothelins (ET-1, ET-2, ET-3—of which ET-1 is the most abundant) are endothelium-derived vasoconstrictor peptides, actingthrough ETA and ETB receptors on the smooth muscle. However, theaction of ET-1 is modulated through stimulation of ETB receptors on the endothelium, which leads to the release of an endothelium-derived vasodilator, nitric oxide (NO—see below)
  • Thromboxane A2 (TXA2) is a prostanoid synthesized in platelets in response to vascular injury (p.456). As well as stimulating platelet activation, TXA2 is a powerful local vasoconstrictor, which helps to reduce blood loss after injury

Local vasodilators (Figs. 6.35, 6.36)

  • Adenosine is primarily produced as a by-product of ATP breakdown, and can either be seen as a local or systemic vasodilator throughstimulation of A2 receptors on the smooth muscle (except in the kidney, where stimulation of A1 receptors causes vasoconstriction). Adenosine is important in the heart, where it blocks AV conduction and reduces the force of contraction; adenosine release might be partly responsible for the pain associated with heart attacks. Adenosineis also a neuromodulator (A1 receptors), a bronchoconstrictor (A1), and a pro-inflammatory mediator (A3)
  • Nitric oxide (NO) is one of a number of endothelium-derived vasodilators that are generated to cause local vasodilatation. Stimuli for NO generation include shear stress (the lateral stress experienced by endothelial cells due to blood flow), hypoxia, and circulating neurohormonal factors (e.g. substance P, bradykinin) that act to increase endothelial intracellular Ca2+. Endothelium-derived NO also acts as a powerful inhibitor of platelet activation and inflammatory cell adhesion. Dysfunction in NO production has been implicated in many cardiovascular diseases, including atherosclerosis. NO is the most important endothelium-derived relaxing factor in large arteries
  • Prostacyclin (PGI2) is a product of arachidonic acid metabolism, stimulated in response to many of the same mediators as NO. PGI2 acts synergistically with NO (the effect of combined release is greater than the sum of the two parts)
  • Endothelium-derived hyperpolarizing factor (EDHF) is the dominant endothelium-derived factor in small (resistance) arteries. Its identity is still an unresolved issue, but K+ ions appear to play a prominent role.
Fig. 6.35 Some of the cellular mechanisms underlying vascular smooth muscle contraction and dilation in response to endogenous signals. Key: Ach — acetylcholine; ANP — atrial natriuiretic peptide; Adr — adrenaline; α2 -α2 adrenoceptor; AC — adenylate cyclase; Ang II — angiotensin II; BK — bradykinin; β2 — β2 adrenoceptor; ETA and ETB — endothelin receptors A and B; ET-1 — endothelin-a; eNOS — endothelial nitric oxide synthase; COX — cyclo-oxygenase; EDHF — endothelium-derived hyperpolarizing factor; GPCR — G-protein-coupled receptor; MLCK — myosin light chain kinase; sGC/pGC — soluble and particiculate guanylate cyclase; NA — noradrenaline; PLA2 — phospholipase A2; PER — prostaglandin receptor; PGI2 — prostacyclin; ROC — receptor-operated channel; Subs P — substance P; TXA2 — thromboxane A2; VGC — voltage-gated channel.

Signal integration and intracellular contractile processes The extent of constriction of any artery depends on the balance of vasoconstrictor and vasodilator stimuli. In the interests of efficiency, the signals from all of the different mediators are almost exclusively channelled through a single intracellular entity—the concentration of cytoplasmic calcium (Ca2+i: vasoconstrictors stimulate an increase in intracellular Ca2+i and vasodilators reduce Ca2+i, thus avoiding the potentially inefficient stimulation of two or more competing pathways (Fig. 6.35). Ca2+i derived from intracellular stores in the sarcoplasmic reticulum and through voltage-gated Ca2+ channels binds to calmodulin, which stimulates myosin light chain kinase (MLCK) to phosphorylate myosin—an essential step in the interaction of smooth muscle myosin with actin.

Fig. 6.36 Some of the endothelium-derived local regulators of vascular tone.

Haemodynamics Blood pressure detection Blood pressure is constantly monitored by special receptors (baroreceptors). There are ‘high pressure receptors’ in the aortic arch, pulmonary artery, and carotid arteries (carotid sinus), and ‘low pressure receptors’ in the atria and adjacent large veins. Signals from both high- and low-pressure receptors are integrated in the ‘cardiovascular centres’ in the upper medulla and responded to by appropriate stimulation of the parasympathetic (to slow the heart in response to high blood pressure) or sympathetic (to accelerate heart rate, constrict blood vessels, and increase blood volume in response to low blood pressure) branches of the autonomic nervous system (Fig. 6.37). Blood pressure determination The relationship between blood flow, resistance, and pressure bears close similarity to Ohm’s law for electricity (Fig. 6.38). The blood system is a closed circuit and the pressure within the system is determined by a number of parameters, all of which can be controlled from the cardiovascular centres in the medulla.

  • Blood volume: the volume of fluid within a system with fairly rigid walls is an important determinant of pressure. Just as pumping more air into a tyre increases the tyre pressure, so increasing the volume of blood increases blood pressure. Indeed, the effect is far more dramatic in the blood system because, unlike air, blood is virtually incompressible—the molecules cannot be forced to come closer together by external force. However, the impact of changes in blood volume are partially damped out by the fact that arteries (and tyres) are compliant—the walls are able to stretch to accommodate more fluid without a proportional increase in pressure. As we age, our arteries stiffen (become less com-pliant—arteriosclerosis OHCM6 p.114)—a factor that contributes to the gradual increase in blood pressure that we experience with age. The kidney controls the blood volume by modulating the amount of salt and, consequently, water that is reabsorbed in the distal tubule (pp.488–9). Blood volume-mediated changes are slow in onset and are not responsible for rapid compensatory changes in blood pressure, but are central to hypertension (OHCM6 p.140—3) (p.448)
  • Cardiac output: as mentioned previously, cardiac output is determined both by heart rate and stroke volume (p.428). The relationship between cardiac output and blood pressure is a proportional one: if all other parameters remain unchanged (and ignoring compliance), doubling cardiac output would be expected to double blood pressure
  • Vascular resistance: the resistance against which the heart has to work to drive blood through the arteries (or afterload) is a crucial determinant of blood pressure. The most important blood vessels involved in blood pressure determination are the arterioles (p.434) because they are the smallest vessels in the arterial tree and are responsible for the resistance to flow (hence the term ‘resistance arteries’). The importance of arteriolar contraction is demonstrated in P.441
    the simple model shown in Fig. 6.39: in this case, contraction of an isolated arteriole, so that the diameter is halved (decreased by a factor of 2), causes the pressure in the system to rise by a factor of 24 (=16). Although the diameter of the large arteries is not the primary determinant on blood pressure, their contraction reduces their compliance, leading to a small increase in systolic blood pressure.
Fig. 6.37 Baroreceptor reflex responsible for blood pressure homeostasis.
Fig. 6.38 Relevance of Ohm’s law to fluid dynamics in the cardiovascular system. BP — blood pressure; BF — blood flow; R — resistance.

Reflex responses The rapid and integrated response to changes in blood pressure in humans is best illustrated with the example of what happens when we stand up (Fig. 6.40):

  • The action of standing leads to a rapid pooling of venous blood in the legs due to gravity, leaving less blood in the large central veins for return to the heart. More than 0.5 litres of blood is redistributed in this way upon standing.
  • The reduction in preload leads to a reduction in stroke volume (Frank—Starling law; Fig. 6.32) and, consequently, cardiac output. Arterial pressure falls momentarily. Baroreceptors in the large veins and atria detect the fall in central venous pressure.
  • Signals from the low-pressure baroreceptors are processed in the cardiovascular centres of the medulla and the sympathetic nervous system is stimulated (Fig. 6.40).
  • Heart rate increases, peripheral vascular resistance increases, central veins contract—all of which returns arterial and venous pressure to near-normal levels within a few seconds.
Fig. 6.40 Cardiovascular effects of: (a) change in posture; (b) exercise.

The importance of the sympathetic nervous system in this process is highlighted by the fact that a major side-effect of inhibitors of the synthesis of noradrenaline (NA) is postural hypotension (OHCM6 p.80) (low blood pressure on standing, which can cause fainting) (p.440). The cardiovascular reflex to posture is an example of our response to a sudden change in blood pressure—a similar response would be experienced if blood volume fell suddenly due to blood loss through haemorrhage. For the most part, however, this reflex system responds to minor changes in blood pressure induced by our environment. It is comparable to a thermostatically controlled heating system, switching on and off in response to moment-by-moment changes in blood pressure. The effects are widespread—low pressure stimulates the entire sympathetic nervous system, which impacts on all our arteries and veins as well as the heart and kidney. High blood pressure stimulates the parasympathetic nervous system, which slows the heart and reduces cardiac output, affecting blood flow to all parts of the body. Regional blood flow is under local control Although there is some modification of the pattern of blood flow upon sympathetic stimulation, determined by the distribution of α and β adrenoceptors in blood vessels of different tissues (pp.434–5), there is little or no capability for responding to the specific needs of a particular organ or tissue. Therefore, superimposed on these systemic mechanisms that keep a tight grip on blood pressure, are local control systems that react to the immediate metabolic requirements of a given tissue. Control of regional flow—the endothelium There are several key features that are shared by local mediators:

  • They are generated in response to detectable changes in the local environment (e.g. ischaemia, increased levels of metabolites, increased shear stress caused by elevated blood flow)
  • They are generated very rapidly in order that they can execute a rapid response
  • They are metabolized or inactivated rapidly so that their effects remain local.

The endothelium that lines all blood vessels is ideally situated to detect and respond to changes in the local environment, as it is the interface between the flowing blood and the vessel wall. It is not surprising, therefore, that the endothelium is a hotbed for the production of local modulators of blood vessel tone, particularly vasodilators. The importance of the endothelium is highlighted by the fact that so-called ‘endothelial dysfunction’ has been implicated in a range of cardiovascular disease, including atherosclerosis (OHCM6 p.114). Nitric oxide (NO) is synthesized in response to an increase in Ca2+ within the endothelial cells, triggered by ischaemia, shear stress, or circulating modulators (including bradykinin and substance P). Ca2+ binds to calmodulin and stimulates the endothelial isoform of the enzyme, nitric oxide synthase (eNOS), leading to increased generation of the free radical NO (see Fig. 6.35 on p.437). This is a small molecule and diffuses P.445
rapidly into both the vessel wall and the lumen to cause vasodilatation and inhibition of platelet and monocyte function. Endothelial NO is usually generated in very low concentrations (low nM range), indicating its potency as a signalling molecule. Its nature as a free radical means that it is highly reactive, with a biological half-life of only a few seconds. Most of the effects of NO are cGMP-mediated (see Fig. 6.35 on p.437), but there is evidence of cGMP-independent mechanisms, particularly when NO is generated in higher concentrations. Organic nitrates that are often used in angina (p.455) undergo tissue-mediated metabolism to release NO. NO is also known to be the non-adrenergic, non-cholinergic (NANC) neurotransmitter found in specific nerves (p.246) and an inducible isoform of the enzyme (iNOS) is expressed in response to inflammatory stimuli; local concentrations of NO from iNOS are believed to be ~1000 times higher than those from eNOS, reflecting its change in function from a highly controllable local mediator to a cytotoxic agent for use by the immune system. Prostacyclin (PGI2) acts synergistically with NO and is generated in response to similar stimuli. It has a relatively short half-life (<5min), but its dilution in flowing blood reduces its activity as it is washed away from itssite of production. PGI2 is synthesized from arachidonic acid by a three-step process involving phospholipase A2, cyclo-oxygenase 1 (COX-1), and prostacyclin synthase (see Fig. 6.36 p.439). PGE2 is a closely related prostanoid that also causes vasodilatation. P.446
Exercise Exercise is defined as an increase in skeletal muscle activity, which requires modifications to the cardiovascular system to accommodate the increased metabolic needs of muscular tissue (see Fig. 6.40 p.443). In the first instance, this might be achieved simply by activation of local mediators in response to the hypoxia that rapidly develops during exercise. However, exercise is also associated with an increase in sympathetic drive, resulting in release of NA and adrenaline, with the following effects:

  • Vasodilatation of arteries that supply skeletal muscle through β2 adrenoceptors (partly mediated by the endothelium)
  • Vasoconstriction of blood vessels supplying the major organs and thegut through α1 adrenoceptors
  • Increased heart rate and stroke volume through stimulation of β1 adrenoceptors
  • Bronchodilatation mediated by circulating adrenaline acting on β2 adrenoceptors in the bronchi; the breathing rate will also increase in response to oxygen and carbon dioxide chemoreceptors (p.392).

These processes combine to cause a considerable increase in cardiac output to account for the massive increase in oxygen consumption and a prioritization of blood distribution to favour muscles at the expense of other tissues. In a trained athlete, heart rate can easily treble (from ~50 beats/min to >150 beats/min), stroke volume can more than double (80→160ml/min), resulting in an increase in cardiac output from ~4 li-tres/min to up to ~40 litres/min. If peripheral resistance were to remain constant, systolic blood pressure under these conditions would rise above 1000mmHg, which would clearly exceed the limits of blood vessel strength. In the event, blood pressure usually only reaches approximately double the normal values (~200mmHg), indicative of an overall decrease in peripheral resistance. Clearly, the signals from the higher centres that are driving the exercise overcome the signals from the high-pressure baroreceptors, which would normally act to return blood pressure to normal by reducing heart rate through vagal stimulation. The body relinquishes its tight grip on blood pressure in order to meet the immediate metabolic needs of the muscles. P.447
Hypertension (OHCM6 pp.140–3) Hypertension is a condition that is characterized by chronically elevated blood pressure and is a risk factor for other cardiovascular diseases including coronary artery disease, myocardial infarction, stroke, and heart failure. Diagnosis In reality, an artificial limit has to be defined to enable the distinction between hypertension and normal blood pressure. From the clinical perspective, two levels have now been set:

  • Patients with blood pressure >160/100mmHg should be treated
  • Blood pressures of 140/90–159/99mmHg are in the ‘grey area’: the physician must decide whether the elevated blood pressure constitutes a significant risk of heart disease on a case by case basis. In order to make this judgement, other risk factors (e.g. diabetes, smoking, high LDL) will be taken into account. The more risk factors, the greater the need to treat.

Mild hypertension is asymptomatic and regular blood pressure measurements conducted by GPs is sufficient to ensure early diagnosis and improved prognosis in hypertension. Originally, it was assumed that diastolic pressure was the best indicator of hypertension but, more recently, it has become generally accepted that risk of conditions like coronary artery disease is more closely linked to systolic blood pressure, leading to this measure being the prime consideration in diagnosis of hypertension. Causes of hypertension The specific cause of hypertension can only be clearly identified in a small percentage of cases (~5%)—so-called ‘secondary’ hypertension, which can be due to:

  • Renal disease e.g. renal stenosis (blockage of the renal arteries), glomerular nephritis (inflammation of the glomerulus), diabetic nephropathy (damage to the nephron induced by diabetes)
  • Endocrine diseases e.g. tumour-related overproduction of aldosterone (Cushing’s (OHCM6 p.310, Conn’s syndromes (OHCM6 p.314) or adrenaline (phaeochromocytoma (OHCM6 p.314))
  • Other clearly identifiable causes e.g. monoamine oxidase inhibitors (amphetamines), pregnancy.

The remaining vast majority of hypertensive cases (~95%) are collectively diagnosed as essential hypertension, for which the cause is undefined. However, it is a broadly held view that sufferers are genetically predisposed to the condition through a renal disorder. Treatment Irrespective of the cause of hypertension, the primary aim of treatment is to reduce blood pressure in order to lower the risk of accelerated atherosclerotic disease (see Fig. 6.43 on p.453) that can lead to heart attack or stroke (see Fig. 6.42 on p.452). P.449
As with most cardiovascular disorders, the primary target for drug intervention in hypertension is not necessarily the heart. Instead, it has proved more profitable to target drugs at the kidney (as renal dysfunction is intrinsically linked to the pathogenesis of the condition) or the blood vessels: Diuretics Thiazides (e.g. bendroflumethiazide) are the first-line drugs for use in hypertension. These drugs inhibit the Na+/Cl- transporter in the distal convoluted tubule (p.490), resulting in an increase in sodium excretion, which is associated with increased water excretion and reduced blood volume. Side-effects include K+ loss (OHCM6 p.692) (hypokalaemia) and postural hypotension (OHCM6 p.80) (low blood pressure when upright, leading to dizziness or fainting). β-blockers Although β1-adrenoceptors in the heart are a logical target for β-blockers, these receptors are only significantly activated during stress, exercise, or heart failure, when the sympathetic nervous system is stimulated. β-blockers are, therefore, only likely to have an inhibitory effect on heart rate when there is increased sympathetic drive; they will have little impact on the heart at rest, when its rate and force of contraction is primarily determined by the parasympathetic nervous system (vagus nerve). In reality, the primary effect of β-blockers is not mediated by inhibition of cardiac β-receptors but those in the kidney that ordinarily activate synthesis of the enzyme renin, which is required to convert angiotensinogen to angiotensin I in the renin—angiotensin—aldosterone system (RAAS; Fig. 6.41). Angiotensin I is subsequently converted to angiotensin II, which P.450
increases blood pressure by the combined effect of increased systemic vasoconstriction and through salt and water retention. The immediate benefit of β-blockers in reducing blood pressure is likely to be coupled to long-term benefits through inhibition of angiotensin II-mediated vascular hypertrophy and hyperplasia, which exacerbates hypertension and plays a role in the progression of conditions like arteriosclerosis and atherosclerosis.

Fig. 6.41 The renin—angiotensin—aldosterone system.

ACE inhibitors, angiotensin receptor antagonists The RAAS is clearly an important therapeutic target in hypertension because of its dual impact on salt handling by the kidney and vasoconstriction of blood vessels (Fig. 6.41). Whilst β-blockers act on the first step in this process, ACE inhibitors act on the enzyme that converts angiotensin I to angiotensin II—angiotensin converting enzyme (ACE). Like β-blockers, these drugs ultimately reduce the amount of circulating angiotensin II that can activate angiotensin (AT) receptors in the kidney and in the blood vessels to cause salt retention and vasoconstriction respectively. ACE inhibitors will also share the long-term benefits of β-blockers, by inhibiting vascular remodelling that plays a role in the progression of hypertension and other vascular diseases. The side-effects of ACE inhibitors include increased K+ retention and cough, which is due to the fact that ACE also mediates the metabolism of the peptide, bradykinin, through its neutral endopeptidase activity. Increased bradykinin in the bronchial mucosa is responsible for stimulation of the cough reflex. Some of the side-effects of ACE inhibitors are avoided by inhibition ofthe RAAS at the AT receptors. AT1 receptors mediate most of the pro-hypertensive effects of angiotensin II (Fig. 6.41) (AT2 receptor function isstill largely unknown) and a number of AT1-specific receptor antagonists (e.g. losartan) are increasingly popular in hypertensive therapy. An added benefit of AT1 receptor antagonists over ACE inhibitors surrounds a possible alternative route for angiotensin II synthesis via the enzyme chymase. Whilst it is unclear whether the chymase route of synthesis is clinically relevant, the possibility remains that ACE inhibition might be partially circumnavigated by this route. Calcium antagonists Ca2+ is central to contraction of both smooth and cardiac muscle. Inhibition of the mechanisms that cause the levels of cytoplasmic Ca2+ to rise and mediate contraction, are legitimate therapeutic targets in hypertension because they might cause vasodilatation (reduced afterload) and reduced cardiac output. A reduction in cytoplasmic Ca2+ can be effected by a number of means:

  • Inhibition of release from endoplasmic reticulum
  • Inhibition of activation of voltage-gated (e.g. L-type) Ca2+ channels in the plasma membrane
  • Increased sequestration into the endoplasmic reticulum
  • Increased extrusion via calcium pumps or exchange mechanisms.

The majority of therapeutic agents act to prevent stimulation of L-type voltage-gated Ca2+ channels. These drugs fall into three broad categories: dihydropyridines (e.g. nifedipine, amlodipine; vessel selective) benzothiazepines (e.g. diltiazem; fairly non-selective); and phenylalkylamine (e.g. verapamil; cardiac selective). Dihydropyridines are favoured in hyperten-sion—particularly amlodipine which has a long plasma half-life. Their action is primarily on resistance arteries that determine blood pressure (peripheral vascular resistance, afterload) but their use is often associated with reflex tachycardia (compensatory increase in heart rate), unless administered in conjunction with β-blockers. Side-effects of Ca2+ antagonists used in hypertension are mainly associated with their vasodilator action: headache, flushing, and oedema (swelling), particularly in the ankles. Other drugs Many of the drugs (other than β-blockers) that reduce blood pressure through actions on the sympathetic nervous system, have been used as anti-hypertensives in the past. However, these usually carry fairly severe side-effects, particularly with respect to postural hypotension. Nevertheless, methyl-dopa, which is metabolized to the false transmitter, α-methylnoradrenaline, is still occasionally used in pregnancy; the α2agonist, clonidine (which enhances the negative feedback system in sympathetic nerve terminals), is sometimes used in refractory cases; and α1-receptor antagonists (e.g. doxazosin) might have an added benefit on the plasma lipid profile (LDL/HDL). Hydralazine can be used as an alternative vasodilator to reduce afterload; its mechanism of action is poorly understood but might involve the inhibition of Ca2+ release from the smooth muscle sarcoplasmic reticulum. Like Ca2+ antagonists, its use is associated with reflex tachycardia and it should be given with a β-blocker. Mixed endothelin receptor antagonists (e.g. bosentan) are showing promise in the treatment of pulmonary hypertension, by preventing the powerful vasoconstrictor action of the endothelium-derived peptide, endothelin-1 (pp.436–9). There are considerable differences in sensitivity of patients to these drugs and it is often a case of trial and error to find the most suitable drug, or combination of drugs, for a patient. This is an area of medicine that might realise considerable benefit from pharmacogenomics (p.210). P.452
Atherosclerosis (OHCM6 p.114) Atherosclerosis is a complex disease process that results in the deposition of lipids in discrete lesions (plaques) found in the walls of large conduit arteries. Although atherosclerotic lesions are found in almost all of us from an early age, their prevalence is greatly increased by a number of risk factors, including genetic predisposition, gender (male), a high lipid diet, smoking, hypertension, and diabetes (Fig. 6.42). Plaque distribution is not random: plaques are absent from veins and the microvasculature and their distribution in large arteries coincides with bifurcations, bends, and branch points, where blood flow is disturbed (turbulent). Coronary arteries are particularly susceptible to plaque formation because, as well as their being tortuous and highly branched, the flow is particularly disturbed by the beating heart in which they are embedded. The following response to injury model is widely accepted to explain the initiation and progression of the disease (Fig. 6.43).

Fig. 6.42 Inter-relationships between risk factors and disease processes: interventional strategies.
Fig. 6.43 Pathogenesis of atherosclerosis—response to injury: (a) healthy endothelium; (b) damaged/dysfunctional endothelium; (c) inflammatory phase; (d) unresolved inflammation; plaque rupture; thrombosis.

Response to injury 1. Endothelial injury Disturbed flow leads to endothelial dysfunction or erosion, with the loss of the protective effects of NO in particular. The affected endothelium becomes ‘activated’, expressing a range of adhesion molecules (e.g. vascular cell adhesion molecule 1; VCAM-1), which ‘capture’ circulating monocytes. Endothelial erosion exposes the collagen-rich prothrombotic subendothelium, to which platelets adhere, forming microthrombi. There may also be increased release of proatherogenic endothelium-derived ET-1. A further consequence is the generation of the oxidizing free radical, superoxide, from NAD(P)H oxidases in the endothelial membrane. 2. Inflammation Captured monocytes infiltrate through the endothelium, where they differentiate into macrophages in response to growth factors, cytokines, and chemoattractants generated by infiltrating T-lymphocytes (e.g. granulocyte colony stimulating factor; G-CSF), which go on to generate high concentrations of several pro-oxidant species (superoxide, NO, peroxynitrite) designed to kill pathogens. The inflammatory process is exacerbated by adherent platelets, which degranulate, releasing a number of pro-inflammatory mediators (e.g. platelet derived growth factor). Neighbouring smooth muscle cells begin to proliferate and migrate to form the ‘neointima’ in response to growth factors and in the absence of anti-mitogenic NO. The smooth muscle cells of the neointima conform to a non-contractile, secretory phenotype, generating extracellular matrix to stabilize the developing plaque (fibrosis). 3. Lipid accumulation Normally, circulating lipids, in the form of low-density lipoproteins (LDL), diffuse readily in and out of the vessel wall without consequence. However, in the highly oxidizing environment of a developing atherosclerotic lesion, LDL is rapidly oxidized (forming ox-LDL), which is recognized by scavenger receptors on macrophages, prior to phagocytosis. The ox-LDL is trapped in the vessel wall in macrophages (now called foam cells), which ultimately die, releasing their contents to form the lipid-rich core of the plaque. Calcification is also a feature of mature plaques in humans. It is this stage of the atheroscleortic process for which the most effective treatments have been targeted. Firstly, lowering plasma LDL levels is known to reduce mortality in patients with atherosclerosis-related conditions: moderate benefits can be seen with improved diets, but the recent introduction of the drug class known as statins (OHCM6 p.114) (which inhibit de novo synthesis of cholesterol in the liver resulting in up-regulation of LDL receptors that effectively reduce circulating LDL) have shown dramatic improvements in lipid lowering and are routinely prescribed to ‘at risk’ patients. It has since transpired that statins also have a range of other benefits, particularly with respect to the restoration of a healthy endothelium, anti-platelet effects, and plaque stabilization. Other primary prevention is aimed at reducing the prevalence of pro-oxidant species by stopping smoking and treating diabetes and hypertension. Intuitively, increased dietary intake of antioxidant vitamins C and E might be expected to have some benefit to this end, but trials to date have been disappointing. P.455
Most atherosclerotic plaques stabilize at this point, as inflammation is resolved. A stable plaque will partially occlude the lumen of the artery and the extent and site of the occlusion (or ‘stenosis’) will determine whether the subject suffers from symptoms. Stable angina pectoris (OHCM6 p.118) is caused by restricted blood flow through a stenosed coronary artery. Patients with angina, therefore, suffer severe chest pain caused by hypoxia associated with insufficient blood supply to part of the myocardium in response to increased demand (e.g. exercise). Symptoms can be successfully managed using organic nitrate drugs (glyceryl trinitrate spray or sublingual tablet) immediately before exercise. Sufferers are also recommended to take low-dose aspirin daily to reduce the chance of thrombosis, as well as β-blockers to reduce the work rate and oxygen demand of the heart. Severe cases may be treated with balloon angioplasty (OHCM6 pp.108–9) or bypass surgery (OHCM6 pp.150–1), although both procedures carry risks of re-occlusion (due to restenosis or thrombosis). Stenoses in the large conduit arteries of the leg (e.g. femoral arteries) can lead to ischaemia (lack of oxygen) to the affected limbs, causing severe pain and, in some cases, infection or gangrene. Treatments for this so-called peripheral vascular disease include angioplasty and stenting, or bypass grafting. Very severe cases require amputation to prevent sepsis and gangrene. 4. Plaque rupture Plaques that remain inflamed can become unstable (prone to rupture). The mechanism that determines the stability of atherosclerotic plaques is not yet fully understood, but the consequences of plaque rupture can be devastating. Material from the core bursts through the weakened neo-intima, where it comes into contact with the blood. This material is highly thrombogenic, leading to rapid platelet adhesion and aggregation, with the associated activation of the coagulation cascade. The resulting thrombus can either completely occlude the artery at the site of the plaque or become dislodged, forming an embolus that passes further down the arterial tree before occluding a smaller vessel. The result is an acute ischaemic event: in the heart (coronary arteries), this causes myocardial infarction (MI) (OHCM6 pp.354–9); in the brain (carotid arteries), a stroke; and in the leg, acute peripheral ischaemia (OHCM6 pp.490–1) (femoral arteries, although this may also be caused by an embolus from elsewhere). All are extremely serious and require emergency treatment, although the severity of the event is entirely dependent on the site of the thrombus, the size of the ischaemic area, and the speed at which the correct medical attention is provided. Treatment in all cases involves immediate anti-thrombotic therapy—(aspirin (MI), warfarin (embolic events), or heparin (peripheral ischaemia) (p.460). Patients with MI should also be prescribed thrombolytic therapy (OHCM6 p.782) (t-PA, streptomycin) as soon as possible, and ACE inhibitors and β-blockers have both been shown to reduce subsequent mortality. P.456
Haemostasis Platelets play a central role in haemostasis—the process that stops blood loss after blood vessels injury. There are three components of haemostasis:

  • Platelet activation to form a loose plug as a stop-gap measure
  • Local vasoconstriction to reduce blood flow to the affected area
  • Activation of the coagulation cascade to convert soluble fibrinogen to fibrin strands that form a mesh around the platelet plug and trap other blood cells, to generate a more permanent repair to the damaged vessel.

These processes are closely interlinked. Platelet activation in response to exposed collagen at the wound results in their synthesizing the vasoconstrictor and platelet activator, thromboxane A2 (TXA2), and their release of granules containing the vasoconstrictors (adrenaline and 5-hydroxy-ryptamine (5-HT), as well as inflammatory mediators (e.g. platelet-activating factor (PAF), platelet-derived growth factor (PDGF)). Meanwhile, collagen and platelets stimulate the intrinsic pathway for blood coagulation, whilst the tissue damage stimulates the extrinsic pathway. These pathways converge to convert prothrombin (so-called factor II) to thrombin (factor II activated; IIa), which acts to convert fibrinogen to fibrin and to further recruit platelets. The processes of platelet activation and coagulation will now be looked at in more detail. Platelet activation There are a range of different glycoprotein (GP) receptors on platelet membranes, which recognize and bind to a variety of ligands, including collagen and von Willebrand factor (vWF)—ma factor secreted by the endothelium in response to injury). Stimulation of these receptors triggers the platelet activation pathway (Fig. 6.44), resulting in an increase in intracellular Ca2+—the trigger responsible for the following cellular effects:

  • Change of shape: pseudopodia emerge from the normal smooth discoid platelet surface, vastly increasing the surface area and, consequently, the adhesiveness of the platelets
  • Degranulation: release of vasoconstrictor and platelet-activating factors to cause vasoconstriction and platelet recruitment respectively
  • GPIIb/IIIa exposure: a conformational change in the membrane leads to the exposure of the otherwise hidden glycoprotein, GPIIb/IIIa, which binds to fibrinogen to help stabilize the platelet plug.
Fig. 6.44 Platelet activation pathways and therapeutic interventions.

Coagulation Coagulation consists of two cascade pathways (Fig. 6.45(a)) that converge to generate the activated serine protease, thrombin (factor IIa), which is responsible for the polymerization of soluble fibrinogen into fibrin strands. The purpose of the cascade systems is to amplify the signal: activation of a small amount of one factor in the cascade generates large amounts of the next factor downstream, and so on. The result is rapid formation of large amounts of fibrin in response to what may have been a fairly weak initial signal. Each step in the cascade involves the activation of normally inactive circulating enzymes (known as ‘factors’), most of which are serine proteases. As each factor becomes activated, it catalyses a specific proteolytic event in the subsequent factor in the cascade to activate it. Fibrin formed from soluble fibrinogen is finally stabilized by the action of factor XIIIa. Haemophilia (OHCM6 p.644) Haemophilia is a sex-linked genetic disorder that affects men only and constitutes an inability to synthesize factor VIII (classical haemophilia) or, more rarely, factor IX (haemophilia B or Christmas disease). Until recently, transfusions of whole plasma, or purified, concentrated preparations of missing factors (from the blood of healthy donors) has been the means of factor supplementation. However, with the risk of transfusion-transmitted infectious diseases (e.g. HIV and hepatitis), recombinant factor VIII and IX are now available, although their manufacture has proved difficult because of the need for post-translational modification of the proteins. Genetically modified animals offer hope in this area: they can be genetically manipulated to produce essential coagulation factors in their milk. Thrombosis and endogenous anti-thrombotic mechanisms Haemostasis is clearly a crucial process in the very rapid formation of a temporary patch in damaged blood vessels, in advance of the healing process effecting a permanent repair. However, it is essential that the haemostatic process is only stimulated in damaged vessels and that inappropriate clotting (known as thrombosis), that would prevent blood flowing to tissues and organs, is avoided.

  • Antithrombin III (ATIII) is central to preventing thrombosis by binding to the active site of all of the factors involved in the coagulation cascade and inhibiting their action (Fig. 6.45(b))
  • The endothelial lining of blood vessels is now recognized to be central to preventing thrombosis in undamaged vessels by a number of mechanisms (Fig. 6.46)
    • Presenting a physical barrier that seperates platelets and coagulation factors in the blood from stimulatory collagen in the sub-endothelial layers of the boold vessel
    • Secretion of heparan sulphate on the luminal surface to activate ATIII and prevent activation of the clotting factors
    • Synthesis of powerful inhibitors of platelet activation. Prostacyclin(PGI2) and nitric oxide (NO) act synergistically to prevent the increase in intra-platelet Ca2+ that is essential for activation
      Fig. 6.45 (a) The coagulation cascade; (b) inhibition of coagulation by antithrombin III—effect of heparin.
      Fig. 6.46 Anti-platelet and anti-coagulation properties of the endothelium.
    • P.459

    • Expression of the enzyme CD39 on the luminal surface to convert the platelet activator, ADP, to inactive AMP
    • Release of tissue plasminogen activator (t-PA) to convert plasminogen to plasmin, which cleaves fibrin strands, earning t-PA the title ‘clot-buster’.

Damage to, or dysfunction of, the endothelium compromises some or all of these protective effects and also leads to the release of the platelet activator, vWF, and the t-PA inhibitor, plasminogen activator inhibitor-1 (PAI-1). This is believed to be a vital step in a number of pathological conditions that cause thrombosis, with potentially fatal consequences. The site (arterial or venous) of thrombus generation is important in determinining the morphology and cardiovascular impact of thrombosis:

  • Arterial thrombi are predominantly composed of activated platelets (so-called ‘white thrombus’) with some fibrin. They can be caused by atherosclerotic plaque rupture (p.455) or release of pro-thrombotic debris during vascular surgery or interventional cardiology procedures. They may remain at the initial site of thrombosis or be carried downstream as an embolus where they will block a smaller artery in the same vascular tree
  • Venous thrombi are mainly fibrin with few platelets and a large proportion of red blood cells that become trapped in the mesh (red thrombus). Venous thrombi tend to form in conditions where venous flow has stopped (deep vein thrombosis caused by extended physical inactivity, such as long flights in cramped conditions) or atrial fibrillation, where blood pools in the atrial chambers of the heart (p.424). Venous thrombi are of little consequence whilst they remain at their site of origin, but at some point, they will become dislodged and will pass through the heart into the arterial circulation as an embolus, with potentially catastrophic effects. Those that originate in the systemic venous circulation will pass through the heart into the pulmonary artery, causing pulmonary thrombosis (p.401), those that originate in the left atrium will pass into the systemic arterial circulation, where will they cause thrombosis in whatever tissue or organ chance takes them (e.g. the brain to cause a stroke, the heart to cause myocardial infarction or the limbs to cause acute ischaemia (p.455)). A recognized side-effect of some oral contraceptive pills is an increased risk of venous thromboembolism.

Anti-thrombotic therapies Anti-platelet agents Anti-platelet agents are a particularly useful therapeutic approach to prophylaxis against arterial thrombotic events associated with atherosclerotic disease (p.452). Indeed, low dose aspirin is recognized to be a cheap and effective means of reducing the risk of thrombotic events and is routinely prescribed for patients with a history of cardiovascular disease. Platelet activation pathways provide several points for drug intervention (see Fig. 6.44 on p.457):

  • Cyclo-oxygenase-1: Conversion of arachidonic acid to the TXA2 precursor, prostaglandin H2, is an essential intermediate step in P.461
    collagen-stimulated platelet activation. Aspirin and ibuprofen inhibit the enzyme by covalent modification (acetylation) of a critical serine residue in the enzyme. The inhibition is irreversible and, uniquely in platelets, will persist for the lifetime of the platelet because, unlike other cells, they have no DNA from which to synthesise replcement COX. The lack of abilit for platelets to replace inhibited COX may contribute to the apparent platelet selectivity of COX inhibitors. Their use is limited by gastric irritation, which can lead to gastric ulcers
  • ADP receptors: Clopidogrel is an ADP receptor antagonist that is emerging as a desirable anti-platelet agent with clinical benefit in a number of settings, particularly in the prevention of thrombosis related to interventional cardiology (e.g. balloon angioplasty and stenting). Given that ADP is unlikely to be the initial trigger for activation, it is likely that these agents block the recruitment phase of thrombosis that is in part mediated by ADP secreted in granules from activated platelets (see Fig. 6.44 on p.457). To date, few side-effects have been reported although there is at least a theoretical risk of bleeding
  • GPIIb/IIIa receptors: These agents (e.g. abciximab) have been developed to block the receptors that bind to fibrinogen. They have been found to be particularly powerful and are associated with an increased risk of haemorrhage. ADP antagonists appear to have a preferable therapeutic profile
  • Other possible targets: TXA2 receptor antagonists are under investigation as antiplatelet agents. NO donor drugs that inhibit the increase in Ca2+ through CGMP and cAMP production respectively, might be highly effective inhibitors of platelet activation. Combined NO/aspirin drugs are under development, with the possible advantage of reduced gastric toxicity.

Anticoagulants (OHCM6 pp.648–9) Drug interventions that impact on the coagulation pathway focus on the following targetsxs:

  • Inhibition of the vitamin K-dependent post-translational modification of clotting factors: factors II, VII, IX, and X require post-translational γ-carboxylation before they are functional. This conversion involves the carboxylation of glutamic acid toγ-carboxyglutamic acid and requires the co-factor, vitamin K (Fig. 6.47), which is oxidized to an epoxide in the process. Reconstitution of vitamin K to the reduced form involves the enzyme, vitamin K reductase. Warfarin is an oral anticoagulant (first developed as a rat poison) that inhibits vitamin K reductase and reduces the amount of available vitamin K for posttranslational modification of clotting factors. The effects of warfarin are slow in onset (~40hr) and reversal by oral vitamin K supplementation is also slow. As a result, careful dose titration is critical to ensure that sufficient drug is available to inhibit synthesis of functional clotting factors without causing potentially fatal haemorrhage by preventing the clotting process altogether
  • Potentiation of the inhibitory effects of the endogenous anticoagulant, ATIII: each step in the coagulation cascade is inhibited by ATIII, which acts to prevent inappropriate coagulation in vivo. Heparin has long been P.462
    recognized to potentiate the effects of ATIII by simultaneously binding to it and the target activated clotting factor (Fig. 6.47). Factor Xa is an exception, where it appears that binding of heparin to ATIII alone is sufficient to modulate its activity. Low molecular weight heparins (LMWHs) have been developed to act primarily on factor Xa. Heparin and LMWHS carry the side-effect of an increased risk of bleeding, but prolonged use of heparin can trigger an immune response which causes paradoxical thrombotic thrombocytopaenia (a pro-thrombotic state)
  • Thrombin inhibitors: a number of direct inhibitors of thrombin are under development. Hirudin is the anticoagulant used by the medical leech to prevent blood clotting and facilitate continuous feeding. Trials of hirudin have been disappointing to date, but several other thrombin inhibitors are under trial, including hirugin and PPAK, both of which are able to inhibit thrombin even once it has bound to fibrinogen.

Fibrinolytic drugs (clot-busters) (OHCM6 p.645, 782) In the unfortunate event of a thrombotic event, it is essential to restore blood flow to the ischaemic area as soon as possible to minimize the area of infarct. The drugs of choice are recombinant tissue plasminogen activators (t-PA; alteplase, duteplase, reteplase) and streptokinase, which act to support endogenous fibrinolytic agents, t-PA and urokinase-type plasminogen activator (u-PA) in converting inactive plasminogen in clots to the active fibrinolytic enzyme, plasmin (Fig. 6.48). Plasmin induces the lysis of fibrin, fibrinogen, and many of the clotting factors. Fibrinolytic agents administered within 12hr of myocardial infarction and 3hr of stroke have shown real clinical benefit in terms of the post-trauma impairment suffered by patients. However, fibrinolytics can cause severe bleeding and it is recommended that they are not used again in the same patient for 1yr. Bleeding complications can be reversed by tranexamic acid.

Fig. 6.47 Role of vitamin K in post-translational modification of clotting factors—effect of warfarin.
Fig. 6.48 Interventional strategies for preventing thrombosis.

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