A is for Arsenic (14 page)

The complex chain of events that results in a heartbeat must be carefully coordinated. A group of cells in the heart (at the
sinoatrial node in the right atrium), and modified heart cells known as Purkinje fibres are capable of spontaneous self-excitation (meaning they can generate a nervous signal without instructions from the brain); this triggers an impulse, which travels through the heart in a highly coordinated manner. These cells and fibres in the heart act as a pacemaker; they will continue to function so long as there is a supply of oxygen, plus sodium, potassium and calcium ions and a few other key minerals. Strictly speaking, the rest of the body, including the brain, is not really required for the heart to function. Transplanted hearts will begin to beat as soon as they are connected up to the recipient's blood supply; this independent nature of the heart enables the study of its function in isolation from the rest of the body.

Even in the nineteenth century, frog hearts could be kept beating for a considerable time whilst experiments were carried out directly on them by using a relatively simple solution of potassium and sodium salts. However, it was not until 1880 that the importance of calcium ions was appreciated. This discovery was made accidentally by Sydney Ringer (1835–1910), a physician at University College, London, with some inadvertent help from his laboratory assistant. Ringer made up his regular solution of salts in pure distilled water, to ensure he knew the exact composition of the fluid he was bathing the frog hearts in. One day, a solution prepared by his laboratory assistant caused a frog's heart to beat for many hours, far longer than Ringer had ever achieved in the past. It emerged that the assistant had been rather slack in his preparation of the solutions, and had used ordinary tap water instead of distilled water. The calcium dissolved in the tap water was the key ingredient the heart needed.

One of the effects of cardiac glycosides such as digitalis compounds is to increase the availability of calcium ions in heart cells, thereby increasing the force with which the heart contracts. The effect of cardiac glycosides on calcium ions is actually achieved indirectly by the drugs' interaction with an
enzyme, Na
+
/K
+
-ATPase,
⁴⁵
which leads to a higher concentration of calcium ions inside the cell, making the microfibrils contract more strongly.

The combined effects of digitalis compounds on the heart cause slower and more intense contractions of the heart – and an increased efficiency in pumping the blood around the body. This improved efficiency increases the rate of fluid being expelled from tissues and increases urine output, hence Withering's observations of the drug's effectiveness in the treatment of dropsy. But digitalis also has significant side effects because the target enzyme, Na
+
/K
+
-ATPase, is widely distributed throughout the body. The most common side effects are nausea and loss of appetite, though this does not seem to have applied to Mrs Boynton, the victim in
Appointment with Death
, who is described as a large woman. Of course her size may have been due to oedema rather than a healthy appetite. Interactions with Na
+
/K
+
-ATPase in the brain and the eyes produces side effects such as disturbances to vision, which affect many people taking digitalis compounds, and delirium, which tends to affect older patients.

The concentration of Na
+
/K
+
-ATPase is particularly high in the cells of the retina in the eye (there is more of the enzyme there than in brain cells, for example). There are two types of cell in the retina that are sensitive to light and are responsible for our vision: these are rod cells and cone cells. Rod cells are responsible for vision in low light. They can detect a single photon, but cannot distinguish between different wavelengths, making the world appear in shades of grey in low light. Cone cells are less sensitive to light, but the three types present in our retinas are sensitive to three different wavelengths
of light,
⁴⁶
and are responsible for colour perception. Cone cells are maybe 50 times more sensitive to digoxin than rod cells, so it is colour rather than night-vision impairment that most affects patients. Between 20 per cent and 60 per cent of patients with therapeutic levels of cardiac glycosides in their blood report visual disturbances within two weeks of the onset of treatment, and the most common complaint is colour-vision impairment. Everything appears as though through a yellow film (‘xanthopsia'), and there may be hazy or snowy vision. Flickering lights or coloured spots and points of light that appear to have haloes of colour around them are less commonly reported. There can also be effects on the pupil of the eye, such as dilation, constriction or uneven sizes of the pupils, though these are rarer.

Digitalis intoxication may have been responsible for Vincent van Gogh's ‘yellow period', as well as for paintings such as
Starry Night
, which some see as exhibiting the ‘halo' effect around the stars in the sky. Van Gogh may have been treated with digitalis to control the epileptic fits he suffered towards the end of his life. There is some circumstantial evidence to support this theory; there are two portraits of Paul Gachet, the doctor who treated van Gogh in his last months. In both of these, the doctor is portrayed with foxglove flowers. Also, a self-portrait shows van Gogh's pupils being different sizes; could this be a slip of the brush, or evidence of something more sinister? There is no record of digitalis being prescribed to van Gogh, however, and the foxgloves in the doctor's portraits may be a coincidence. The artist may just have had a strong liking for the colour yellow and the artistic effect of haloes around the stars in the sky, rather than being under the vision-warping influence of digitalis.

Digitalis would have had no effect on van Gogh's epilepsy, but at that time drugs that had proved effective in treating one condition were often prescribed for others, in case they proved
to be a panacea for all ills. There is some scientific credibility to this way of thinking. Many drugs originally developed for a specific treatment have been found subsequently to be more effective in treating other conditions. Viagra is a classic example. This drug was originally developed to treat angina, by relaxing the coronary vessels that supply blood to the heart. The target enzyme was phosphodiesterase; this inactivates a messenger molecule
⁴⁷
that causes the dilation of blood vessels, amongst other roles. The drug is effective at increasing blood flow, but it turns out that the heart is not the organ most affected. In addition to its qualities for enhancing men's sex lives, Viagra can affect the dilation of blood vessels throughout the body; those taking heart drugs or who have low blood pressure shouldn't use Viagra as there will still be some interaction with the heart. The drug's effects on blood vessels in the brain can also cause headaches, but its most common side effect is a blue tint to colour perception, caused by its interaction with phosphodiesterase in the cone cells of the eyes.

Is there an antidote?

In an emergency case of digitalis overdose, atropine can be given, to stimulate the heart. In the case of a dose of digitalis that does not kill the patient quickly, potassium chloride (KCl) dissolved in fruit juice can be given every hour until the normal heart rhythm is restored, but the individual must be carefully monitored to avoid potassium toxicity. Complete inactivity is enforced for patients, especially ones with impaired kidney function who cannot process the potassium chloride or other drugs efficiently. The patient is kept completely still until normal heart function is restored.

Today, more drugs are available to treat overdoses of digitalis, and the chances of surviving a huge overdose are much higher. Phenytoin can be given in cases of acute digitalis poisoning, for example, if the patient is unresponsive to potassium therapy.
This drug increases the metabolism of the digitoxin in the body, rendering it ineffective more rapidly than under normal circumstances. Another drug, cholestyramine, reduces the half-life of digitalis drugs in the body. Specific digoxin antibodies are also now available to inactivate the drug in the body.

Some real-life cases

Digitalis-based murder cases are extremely rare – or perhaps, as I mentioned earlier, the murderers have chosen their victims carefully, and the deaths have not been treated as suspicious. Agatha Christie had just one recent case to use as a possible inspiration; it occurred two years before the publication of
Appointment with Death
.

In 1932, Marie Alexandrine Becker was a 55-year-old housewife who had decided that her life needed a little more excitement. Her respectable but dull life in Liège, Belgium, changed one day at the market, when she met Lambert Beyer at the vegetable stall. Beyer was something of a local lothario, and the two embarked on a tempestuous affair. The affair changed Marie from a respectable housewife to a serial killer. Her first victim was her husband, for whom she obtained a substantial payment from a life-insurance policy. Soon Marie tired of her new lover, or perhaps the money he had willed to her was too tempting; in any case, Beyer himself became her second victim.

With the money she had obtained, Marie bought a dress shop to fund her new and extravagant lifestyle. But the income was not enough to pay for the nights out in clubs or the payments to the young men that shared her bed. When one of Marie's friends became ill with a dizzy spell she offered to nurse her. Perhaps unsurprisingly, her friend's health deteriorated, and she died a few weeks later. Marie continued to poison friends to obtain money; when she ran out of friends, she turned to the customers in her shop. Apparently she would drop digitalis into cups of tea in a back room and offer them to the ladies picking out dresses in the shop. After they died, she would take any ready cash and valuables that they had on them.

Rumours had already started about Marie, and anonymous letters had even been sent to the police suggesting that she might have been involved in the deaths of two elderly women. An investigation was started, but it was evidence brought forward by a (surviving) female friend of Marie's that motivated the police to look deeper into the case. The friend had been complaining to Marie about her husband, and how she wished the no-good rascal dead. Marie helpfully offered her friend a powder that would dispatch the man, leaving no trace. After thinking over her options for a few days, the woman went to the police.

Marie was arrested and the bodies of her husband, her lover, her friends and her customers were exhumed. Traces of digitalis were found in the bodies, though no suspicion of foul play had arisen at the time of their deaths. Marie was put on trial in 1936 for the murder of ten people, though it is believed she may have killed twice as many. The jury returned a verdict of guilty and she was sentenced to life imprisonment, there being no death penalty in Belgium at the time. She died in prison during the Second World War. Apparently she revelled in the details of her victims' demise, describing one victim as ‘dying beautifully, lying flat on her back'.

Dame Agatha and digitalis

In
Appointment with Death
Mrs Boynton and her family take a trip to the deserted city of Petra. Mrs Boynton is a monster of a woman; there is no shortage of people who would be happy to see her dead. Mrs Boynton also has a heart condition for which she is taking digitalis medication, in the form of a solution added to water. Her medical condition and treatment provide an excellent opportunity for her killer to cover their tracks. An overdose of digitalis results in failure of the heart to contract properly, ultimately leading to cardiac arrest. Dr Gerard, who is also on the expedition to Petra, correctly points out that ‘A large dose of digitoxin thrown suddenly on the circulation by intravenous injection would cause sudden death by quick palsy of the heart. It has been estimated that 4mg might prove fatal to an adult man.'

There was a plentiful supply of digitalis, despite the fact that the death occurred in an isolated part of the world surrounded by desert, where foxgloves would not grow. The killer had no need to find a local pharmacy and fake a prescription, nor to search for foxglove plants with which they could make their own lethal preparations. The poison could have been obtained from Mrs Boynton's own medication, or from a supply of digitoxin in Dr Gerard's medical bag.

Mrs Boynton's death could have been due to natural causes, or accidental poisoning. When her body is found, Dr Gerard first assumes that her death was due to the exhausting journey to Petra, combined with the hot weather, with this all being too much for her heart. Her death could also have been due to a mistake made by the dispenser when making up her prescription of digitalis medicine (Christie of course knew such blunders were possible from her dealings with Mr P.; see page
here
). In Mrs Boynton's case we will never know if the dispenser made an error, as the bottle containing her medication was inadvertently broken when her body was moved.