Gross anatomy: The mammalian heart is a double pump in which the right side operates as a low-pressure system delivering de-oxygenated blood to the lungs, while the left side is a high pressure system delivering oxygenated blood to the rest of the body. The walls of the right ventricle are much thinner than those of the left, because the work load is lower for the right side of the heart.
There is a dense cartilaginous ring between the atria and the ventricles, which forms a secure connection for the aorta and the pulmonary artery, and provides mechanical support for the four cardiac valves. The compact semilunar valves in the two outflow tracts operate without external help, but the mitral and tricuspid valves between the atria and the ventricles require the assistance of the papillary muscles and chordae tendineae to prevent them everting into the atria at the peak of the ventricular contraction (systole). This band of connective tissue also isolates the atria electrically from the ventricles, so that the atrioventricular node is the only signalling route between the four chambers.
The ventricular muscle is relatively stiff, and would take some time to fill spontaneously with venous blood during diastole. The thin, flexible atria serve to buffer the incoming venous supply, and their initial contraction at the begining of each cardiac cycle fills the ventricles efficiently in a short space of time.
Ultrastructure: In contrast to the huge polynucleate cells found in voluntary skeletal muscles, cardiac muscle cells are small with only one or two nuclei. The regular arrangement of sarcomeres within the myofibrils gives the tissue a striated pattern (like voluntary muscle) but the cardiac cells are not separately innervated. They lack motor end plates and rely instead on communicating gap junctions to transmit electrical signals directly from one cell to the next. This means that in a normal healthy heart, every cell depolarises every beat. This precludes the progressive fibre recruitment and twitch summation mechanisms that regulate contractile force in skeletal muscles, and requires a completely different system for internal signalling and biochemical control.
Cardiomyocytes are often "X"- or "Y"-shaped and make end-to-end contact with several neighbours. This may help to spread the load more evenly. Mechanical tension is transmitted from cell to cell by intercalated disks, which are specialised load-bearing structures in the plasmalemma. These always interrupt the regular sequence of tension-generating sarcomeres at one of the Z-lines. The cytoskeletal protein dystrophin is involved in a separate load bearing system along the length of the cells, and a severe inherited cardiomyopathy eventually develops in patients where the dystrophin gene (or its cardiac promoter) is missing or damaged.
Metabolism: Cardiac muscle can achieve the highest sustained metabolic rate of all the tissues in the human body. Up to 40% of the cell volume may be occupied by mitochondria, and most of the remainder is taken up by contractile fibrils. Adult cardiomyocytes are incapable of cell division and are totally specialised for energy production and mechanical work. The biochemistry of muscle contraction is described in the separate muscle pages.
The continuous energy demand can only be satisfied by aerobic metabolism. The heart's capacity to generate ATP by anaerobic glycolysis is severely limited, and it will not support normal contractile or electrical activity. Glucose entry into cardiac cells is insulin-dependent, and under normal circumstances the organ shows a distinct preference for free fatty acids, ketone bodies and (to a lesser extent) blood lactate, all of which are completely oxidised to carbon dioxide and water.
The heart muscle is supplied with blood via the coronary arteries, which arise from the aorta immediately behind the aortic valves. Most of the cardiac veins drain into the coronary sinus, which empties directly into the right atrium. Cardiac muscle has a very high arteriovenous oxygen extraction, which may exceed 90%. Most tissues extract only about 30% of the available oxygen from the blood. The lack of reserve capacity, and the near absence of any any colateral circulation from vessels supplying other areas of the heart, can lead to catastrophic problems if a major branch of a coronary artery becomes blocked through atherosclerosis, leading to a heart attack. Myocytes downstream of the block die and release their contents into the cardiac veins and lymph ducts. This leads to a charteristic elevation of cardiac enzymes in blood plasma. The dead tissue is known as a myocardial infarct. If the patient survives the affected area is invaded by macrophages and fibroblasts. It is eventually re-organised as scar tissue, with a permanent loss of cardiac capacity.
Laplace's law: is an important physical constraint on cardiac performance. It relates the internal pressure "P" inside a spherical bubble of radius "R" to the surface tension "T" in the walls. The law states that
Bubbles will swell or shrink until this relationship is precisely satisfied. It is very easily derived. If the cross sectional area of the bubble across its equator is A, and its circumference is L, then the total pressure P.A developed across the equator must be exactly balanced by the tension L.T in the bubble walls. But
The law follows directly from the two equations above. The practical effect is that it requires more wall tension to generate the same internal pressure in a large sphere than it does in a small one. Laplace's law governs fluid pumping by any approximately spherical chamber, including hearts. [It would not, for example, apply to a linear piston pump.] It implies that as the heart fills up with blood then the muscle will find itself at an increasing mechanical disadvantage and the chambers will become more difficult to empty. This has obvious implications for dilated cardiomyopathy, but without some very effective countervailing mechanism, even healthy hearts could not operate successfully.
The Starling mechanism: If the heart chambers are initially distended with blood, the ensuing beat is much more forceful than if the chambers were initially empty. This more than compensates for the mechanical disadvantage imposed by Laplace's law, so that the aortic output pressure actually rises as the venous filling pressure is increased. It is essential that heart muscle should respond to stretching in this way, since otherwise the circulatory system would be unstable and pumping would become impossible whenever the ventricles were full. The relationship was first reported by Starling about 80 years ago, although the precise mechanism has been disputed. The most likely explanation is that calcium ion release from the sarcoplasmic reticulum is greatly increased when the SR is mechanically stretched.
Starling's "law" is often illustrated with a graph relating end diastolic pressure (reflecting the initial passive ventricular stretch) to the peak systolic pressure developed during the ensuing beat. The relationship is not fixed and the shape of the curve depends on the outflow resistance. The graph will be shifted to the left by inotropic agents such as catecholamines which increase the inherent contractility of the heart. Negative inotropes like acetyl choline will move the curve to the right.
The curve "turns over" at very high filling pressures, but this descending limb of the Starling curve is not attained under physiological conditions.
Congestive heart failure is characterised by inadequate contractility, so that the ventricles have difficulty in expelling sufficient blood. This leads to a rise in venous blood pressures, which may, temporarily, achieve a new equilibrium where cardiac output is maintained through the Starling mechanism. However, the raised venous pressures impair fluid drainage from the tissues and produce a variety of serious clinical effects.
Right sided heart failure causes lower limb oedema. Blood pooling in the lower extremities is associated with intravascular clotting and thromboembolism. Left sided heart failure produces pulmonary oedema and respiratory distress. Very frequently both sides of the heart may fail at the same time. It might be imagined that treatment with inotropic drugs (e.g. digitalis, catecholamines) would be sufficient to resolve the problem. In some circumstances such treatment might be appropriate, but it is likely to increase the cardiac oxygen demand. This may not be helpful in patients suffering from ischaemic heart disease.
Cardiac oxygen consumption and work output depend on both the preload (i.e the initial passive stretch) and the afterload (i.e the aortic outflow resistance). However, it makes very little difference to the oxygen requirement whether or not the heart actually succeeds in emptying. The principal determinant for cardiac oxygen consumption is the P*T integral (the area under the left ventricular pressure versus time curve) and the volume of blood pumped has only a minor influence on the result. It may therefore be more effective to treat congestive heart failure with diuretics (which relieve venous congestion by reducing the total blood volume) and by lowering the peripheral vascular resistance. These measures will assist ventricular emptying by reducing the work load on the heart.
Electrical activity: Unlike voluntary skeletal muscles, cardiac muscle does not require any nervous stimulation in order to contract. Each beat is initiated by the spontaneous depolarisation of pacemaker cells in the sino-atrial (SA) node, located where the great veins empty into the right atrium. These cells trigger the neighbouring atrial cells by direct electrical contacts and a wave of depolarisation spreads out over the atria, eventually exciting the atrio-ventricular (AV) node, located at the top of the interventricular septum. Contraction of the atria precedes that of the ventricles, forcing extra blood into the ventricles and eliciting the Starling response. The electrical signal from the AV node is carried to the ventricles by a specialised bundle of conducting tissue (the bundle of His) which divides into several bundle branches within the interventricular septum. [Damage to these conducting bundles, or to the AV node, produces the clinical conditions of partial or complete heart block, where the atria and the ventricles contract independently.] The conducting tissues are derived from modified cardiac muscle cells, and are known as Purkinje fibres. They have a reduced content of contractile proteins, and a much higher conduction velocity, than ordinary cardiomyocytes. The conducting bundles divide repeatedly as they spread out through the myocardium to coordinate electrical and contractile activity across the heart. Although each cardiac muscle cell is in electrical contact with most of its neighbours, the message normally arrives first via the Purkinje system.
these cells have a high glycogen content, but few contractile proteins
photograph: Dr Robyn Brown, School of Biomedical Sciences, University of Leeds
Autonomic control: Hearts do not require innervation in order to beat, but the autonomic nervous system controls the force and frequency of cardiac contraction. Acetyl choline, acting through M2 muscarinic receptors, reduces the spontaneous firing rate of the sinoatrial node, and also depresses conduction velocity through the Purkinje fibres and the force of the ensuing ventricular contractions. Catecholamines, acting through beta-1 receptors and adenyl cyclase have the opposite effects.
The cardiac cycle: The diagram below shows the principal events in the normal cardiac cycle, for an individual with a blood pressure of 120/80 and a heart rate of 75 beats/min. The papillary muscles are activated early during systole, and prevent the eversion of the delicate leaflets of the mitral and tricuspid valves. [Infarcts that involve these muscles can lead to valvular incompetence.] The first heart sound "lub" is associated with the closure of the mitral and tricuspid valves near point 1 and the second sound "dup" with the closure of the aortic valve at point 2. Three important indices of cardiac contractility are the left ventricular end-diastolic pressure [edp] (measured just before the mitral valve closes), the maximum rate of left ventricular pressure increase [dP/dT (max)] and the peak systolic pressure [psp]. Ventricular activation is actually spread over about 75 msec, and the action potential therefore represents a "typical" cell. Note the very different voltage scales used for the ECG and the action potential recording.
The electrocardiogram [ECG] is an important non-invasive source of diagnostic information. Although a constant cardiac membrane potential produces no measurable electrical effect at the surface of the body, the spread of excitation through the heart generates small resultant voltages which can be detected by electrodes attached to the skin. The spread of excitation is affected by many disease processes, and therefore provides important clues about the nature of the underlying defects. The ECG signal is about one hundred times smaller than the action potentials recorded using microelectrodes from individual cells. It reflects the summation of innumerable tiny currents from billions of cardiac cells, and is broadly proportional to muscle mass: the left ventricular signals, for example, are much bigger than the atrial effects. The amplitude of the signal is reduced in dilated cardiomyopathy, although the reasons for this are not entirely clear.
The initial P wave is produced by the atrial depolarisation. This is followed by the QRS complex as electrical excitation spreads through the ventricles, and finally by the T wave as the ventricles repolarise towards the end of each beat. By convention the main upstroke on each trace is always called the "R" wave. It does not always reflect exactly the same event - the precise shape of the ECG varies with the position of the recording electrodes, and there are considerable anatomical variations from one subject to the next.
The heart is a complex three-dimensional structure, but it is convenient to represent the source of the ECG waveforms by a simple electrical dipole that changes both its size and orientation as the wave of depolarisation spreads through the muscle. It is important to realise that we are observing a vector quantity - one that has both magnitude and direction, although we can only record its scalar projections on the surface of the skin. The usual locations of the recording electrodes for a full diagnostic ECG are marked on the diagram below, but for routine patient monitoring only two electrodes are normally employed.
For reasons of practical convenience the electrodes for right arm (RA) and left arm (LA) are normally attached at the wrists, and the "midline" (LL) electrode is actually attached to the left ankle. This has only minor effects on the results. Three channels [often called "leads"] are usually recorded simultaneously, and the equipment can be used in three distinct ways:
To compare the signal from one limb electrode with the average signal from the other two. Thus the aVR lead compares the signal from the right arm electrode with the left arm and left leg connected together, aVL analogously with the left arm, and aVF with the left foot. This yields similar information to leads I, II and III but the coordinate system is effectively rotated through 30 degrees, and the signals are generally larger, which may be more convenient.
To compare the signals in the precordial leads V1 through V6 with a reference provided by all three limb electrodes connected together. The particular utility of this approach is in the diagnosis of acute myocardial infarction [AMI] in the anterior wall of the heart. Infarcts forming in other locations produce changes in the nearest limb leads. The leads recording from the opposite side of the heart may show reciprocal effects, as might be expected for a vector source. The time course of the ECG changes during AMI may be more informative than a single recording.
Numerous pathological changes can be diagnosed from the ECG, but for this exercise only five will be distinguished: (1) ST segment depression in angina pectoris, (2) ST segment elevation in acute myocardial infarction, (3) atrioventricular dissociation seen in heart block, (4) the wide abnormal QRS complexes produced by an ectopic focus, and (5) the complete absence of organised electrical activity seen in ventricular fibrillation (VF).
Angina pectoris: Milder forms of cardiac ischaemia typically affect the sub-endocardium more than the epicardium and produce transient chest pain without myocardial infarction. ATP levels fall in the affected cells, leading to the opening of ATP-dependent potassium channels, and an abbreviation of the action potentials. This reduces work output by the affected region and may have a cardioprotective effect. ECG recordings over the ischaemic area show ST segment depression. Anginal pain is often induced by exercise and relieved by rest and nitroglycerine therapy. The ECG changes are similarly reversible.
Acute myocardial infarction: Severe ischaemia leading to infarction typically affects the full thickness of the ventricular wall. The ischaemic area ceases to contract, and a characteristic sequence of ECG changes is observed over the affected region. The first indication is a marked ST segment elevation and enlargement of the T waves. The effect is greatly diminished within one hour, and by 24 hours the ST segment has returned to the baseline, the Q waves are greatly enlarged, and the T waves are inverted. If the patient survives the ST and T wave changes gradually return to normal, but the enhanced Q wave may persist indefinitely.
Heart block: Infarction or other disease processes may interrupt the normal conduction of impulses through the bundle of His or the bundle branches, leading to partial or complete heart block. Atrial contractions may be normal, but the ventricular rhythm is very slow. In supraventricular tachycardias a rapid atrial rate coupled with the long refractory period of the normal healthy AV node may produce a 2:1 or 3:1 heart block where the ventricles contract every second or third atrial beat.
Ectopic beats: All subjects experience an occasional premature ventricular complex [PVC] which is often precipitated by tiredness, nicotine, caffeine or alcohol. Their incidence increases with age and they are much more common in the presence of cardiac disease. They are caused by sporadic pacemaker-like activity within the ventricular muscle. The QRS complex is often bizarre and much wider than a normal beat, because they rely on cell to cell transmission, instead of the normal Purkinje system. Atrial premature beats are also known, which may or may not be transmitted to the ventricles, depending on their timing in relation to the depolarisation of the sinus and atrioventricular nodes.
Ventricular fibrillation: This condition is characterised by disorganised ventricular activity, and a complete absence of QRS complexes. Unless treated it is fatal within 3 - 5 minutes. The most effective treatment is a DC shock from an electronic defibrillator which simultaneously depolarises all the myocardial cells, and allows the pacing and conduction system to reset itself.
Control of cardiac output: Aortic output varies over a twenty-fold range between sleeping and vigorous exercise, and is also increased during pregnancy. The Starling mechanism is important in allowing the heart to adapt to an increased venous return. In addition, both circulating adrenalin, and noradrenalin released by cardiac nerve terminals, have inotropic effects, enhancing cardiac contractility via cyclic AMP and protein kinase A. Increased contractility means that the same peak systolic pressure can be achieved with a lower end diastolic pressure, i.e. with a lower degree of ventricular stretch. Increased contractility does not necessarily produce a rise in arterial pressure, but may produce a fall in the central venous pressure. Ion channel phosphorylation in response to catecholamines and sympathomimetic drugs increases calcium entry during the action potential, calcium release from the SR during systole (contraction), and calcium uptake by the SR during diastole (relaxation). [Direct electrical connections between adjacent cardiac muscle cells preclude the progressive fibre recruitment seen in voluntary muscles: in the heart every muscle cell depolarises every beat.] Catecholamines from the sympathetic nerves acting on cardiac beta-1 adrenoceptors make the beats more rapid and forceful, while acetylcholine from the parasympathetic nerves acting on muscarinic M2 receptors has the opposite effect.
It is not practicable to run every physiological system at full capacity all the time: it is more efficient to concentrate scarce resources on the most pressing problems. This is particularly true for the distribution of the overall cardiac output, where the maximal blood flow through all the organs added together is many times greater than the maximal pumping capacity of the heart. Blood flow to the tissues is regulated by smooth muscle in the walls of the small arterioles, which normally restrict the perfusion to a small fraction of its maximal value. Arteriolar smooth muscle is responsible for most of the peripheral vascular resistance.
There is a second reason to carefully ration blood flow: molecular oxygen is a di-radical and at high concentrations is an extremely toxic substance, damaging proteins and cell membranes and necessitating frequent repairs. There is a very steep oxygen concentration gradient between the red cell interior and the surrounding tissues, where the Km of cytochrome oxidase for oxygen is correspondingly low. Although the free oxygen concentration in arterial blood is around 0.25mM (and the protein-bound oxygen is about 7.5mM) most tissue oxygen concentrations are in the micromolar range. Local blood flow is adjusted to achieve this target value.
Every property of the cardiovascular system is affected by multiple interlocking feedback loops. If any aspect is altered, the whole system will re-adjust, sometimes responding in most unexpected ways with long-term effects far removed from the initial site of interest.
Although this is a restricted list, the following features are thought to be important:
The right side of the heart (pumping blood to the lungs) is a low pressure pump, while the left side of the heart (serving the rest of the body) operates at a much higher blood pressure. This is reflected in the chamber dimensions and wall thickness.
The Starling mechanism is very important, and allows even a totally denervated heart to achieve a reasonable degree of autoregulation. This should be considered in conjunction with the next point.
About 70% of the blood volume resides in the great veins, which have muscular walls. Contraction of venous smooth muscle, or an expansion in blood volume, raises central venous pressures and transfers some of this reserve blood supply into the heart chambers, stretching the heart and greatly increasing the cardiac output.
Most of the resistance to blood flow arises from smooth muscle compressing the walls of the arterial tree. The main effects are in the small arterioles, and in the pre-capillary sphincters which ration blood flow into the capillary beds.
Local control of blood flow relies mainly on nitric oxide produced by vascular endothelial cells and adenosine released by ischaemic tissues. Capillary loops seem to be folded back on themselves so as to bring the inflow and outflow vessels into close juxtaposition, and thereby facilitate this local signalling.
Blood osmolarity is monitored by osmoreceptor cells in the hypothalamus which control overall water balance through the pituitary peptide vasopressin (= anti-diuretic hormone, or ADH). These sensors are also connected to the behavioural systems controlling thirst and salt craving. Stretch receptors in the right atrium and the arterial tree monitor total blood volume, and this neurally transmitted information is also used to modulate ADH release.
There is interaction between the control of blood volume and blood osmolarity. Stretching the right atrium stimulates the release of atrial natriuretic peptide from the atrium, which promotes sodium excretion by the kidney, ultimately reducing blood volume and salt content. Conversely, low salt concentration in the distal convoluted tubule, or inadequate perfusion of the kidney, both stimulate release of renin into the bloodstream. This short half-life protease cleaves circulating angiotensinogen producing angiotensin I. Subsequent proteolysis by the lung endothelium yields angiotensin II which has a powerful vasoconstrictor effect on arteriolar smooth muscle. This raises systemic blood pressure, restores kidney perfusion, and stimulates release of the salt-retaining hormone aldosterone from the adrenal cortex, which promotes renal sodium retention and potassium loss.
In many tissues there is a local angiotensin metabolism superimposed on the whole body mechanisms described above.
The whole ensemble is monitored and regulated by the autonomic nervous system. There are blood pressure receptors (baroreceptors) in the great veins and in the aorta and the arterial tree. The baroreceptor signals are integrated with information on body position from the system controlling voluntary movements, and with information from chemical sensors, ultimately regulating renin production, cardiac contractility and arterial and venous smooth muscle tone. The physical position of the body is important, because the hydrostatic pressures associated with an upright posture are greater than arterial blood pressures, and very much greater than the pressure in the veins.