The Spark of Life: Electricity in the Human Body (21 page)

Fortunately, LQT syndrome can now be treated, enabling patients to lead a relatively normal life. Drugs known as beta-blockers prevent the effects of stress on the heart and are usually highly effective. Many people are also given an implantable defibrillator, which can detect an abnormal heart rhythm and apply a shock to reset it back to normal.

The Tale of Terfenidine

Mutations in many different genes are known to cause LQT syndrome, including at least six different kinds of ion channel (most are potassium channels). But LQT syndrome is not always genetic in origin. It can also be induced by drugs that block cardiac ion channels. The drug terfenidine is a very effective anti-allergy agent that used to be sold over the counter in the UK. In 1985 it was approved for use in the USA, where it was marketed as Seldane. It quickly became widely accepted and by 1991 it was the ninth most prescribed medication in the United States. But by that time several cases of cardiac problems in patients taking the prescribed dose of terfenidine had been reported, including prolongation of the QT interval and sudden death. In most cases, affected patients were also taking certain antibiotics, had liver dysfunction, or had pre-existing cardiovascular disease. Consequently, the pharmaceutical company who manufactured the drug issued 1.6 million letters to physicians and pharmacists recommending it should not be used in patients with these conditions. It was later removed from the market.

Terfenidine has this effect because it blocks HERG potassium channels. In most people terfenidine does not produce problems as it is rapidly broken down in the liver to a metabolite that does not block HERG, but remains an effective anti-allergy agent. As the drug is taken orally, it passes through the liver first, so little terfenidine ever reaches the heart. However, individuals with liver disease, who may be deficient in the enzymes that break down the drug, or people taking drugs or substances (such as grapefruit juice) that inhibit these enzymes, are at risk of developing cardiac arrhythmias.

The tale of terfenidine does not end here. It was quickly recognized that many other drugs were also able to block HERG and thereby predispose people towards heart problems. Thus in 2001 Japan, the USA and the European Community ruled that all novel drugs must be screened for their effects on HERG. The most recent guidelines dictate that studies must be performed not only on isolated cells and tissues but also on people (thousands of ECGs are required). This ruling led to a plethora of small biotech companies that carry out HERG screening and to a sharp rise in the cost of drug development because many drugs fail at this stage. Some drug companies who had drugs in the later stages of the development pipeline that turned out to interact with HERG lost very considerable amounts of money.

My Heart Goes Pit-a-pat

          Her: Oh doctor, I’m in trouble.

          Him: Well, goodness gracious me!

          Her: For every time a certain man

          Is standing next to me.

          Him: Mmm?

          Her: A flush comes to my face

          And my heart begins to race,

          It goes boom boody-boom boody-boom boody-boom

          Boody-boom boody-boom boody-boom-boom-boom.

So begins the hilarious duet famously sung by Sophia Loren and Peter Sellers. It’s a familiar feeling: all of us have experienced the speeding of the heart when we are excited or afraid, and the thumping beat that makes us feel as if our heart is about to burst.

This is caused by the ‘fight or flight’ hormone adrenaline, which primes the body to cope with an adverse situation by increasing both the rate and the force of contraction. It does so by opening additional calcium channels in heart cell membranes. This speeds up the rate at which the sinus node cells fire, so that the heart rate is increased, and it also boosts the amount of calcium that is released from the intracellular stores and thereby enhances the strength of contraction. Adrenaline is made by the adrenal glands that lie just above the kidney, and is secreted into the bloodstream in response to stress or exercise; a related substance with a similar action, noradrenaline, is released from nerves that innervate the heart.

Although an increased heart rate during exercise is essential in order to ensure that the limb muscles are adequately supplied with fuel and oxygen, too fast a rate is deleterious. This is because the heart muscles themselves cannot be supplied with oxygen fast enough. The consequence is angina – a severe incapacitating chest pain that can extend down the left arm. Angina is more easily precipitated in people whose coronary blood vessels are narrowed as a result of atherosclerotic plaques (fatty deposits in the vessel walls). Consequently, an exercise test, which increases the heart rate and thus its oxygen demand, is often used to test the health of the coronary vessels. Angina is not only brought on by exertion: it can also be triggered by anger, excitement or emotional stress. I vividly remember the time I was sailing a small yacht up the Ijmuiden canal to Amsterdam and debris became entangled around our propeller, rendering the engine useless. This canal is a major shipping route and it was extremely busy. Huge, heavily loaded commercial barges, with very limited ability to manoeuvre, were bearing down on us. As I struggled to put up the sails and the other crew member dived overboard with a knife to free the propeller, the skipper had an angina attack. He retired below deck to crush a glass capsule of amyl nitrate (nitroglycerin) under his nose and inhale the vapour. This eased his pain by dilating the coronary vessels and increasing blood flow to his heart.

Nitroglycerin acts by releasing a natural gas called nitric oxide, which stimulates the production of a chemical called cyclic GMP that causes blood vessels to relax. Viagra (sildenafil citrate) works in a similar way: by elevating cyclic GMP levels in the blood vessels of the penis it causes them to dilate, resulting in an erection. However, if both drugs are taken together their effects can summate, causing blood vessels throughout the body to relax so much it leads to a severe drop in blood pressure. Consequently, men taking nitroglycerin for their angina should avoid Viagra. It is a fascinating fact that Viagra was discovered fortuitously by scientists seeking drugs to treat angina. It wasn’t very effective in clinical trials and would have been abandoned, but for the fact that a few men taking part in the trials were reluctant to stop taking it because of an unusual (and unexpected) side-effect.

Beta-blockers are often taken to decelerate a racing heart. They work by blocking the action of adrenaline, preventing it binding to beta-adrenoreceptors in the heart membrane and so speeding up the heart. However, they can have an unfortunate side-effect, as some men quickly find out when the drug renders them impotent.
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The incidence is relatively low, although, interestingly, some studies suggest that it is higher in men who are aware of this side-effect of beta-blockers, suggesting that at least part of the problem is caused by anxiety. One case, perhaps, where too much knowledge may indeed be a dangerous thing.

Be Still, my Heart

Chemicals released by the nerves innervating the heart can also slow its rate, and sometimes even stop it completely. In 1994, I was visiting Houston in Texas for a scientific conference. It had been a long and tiring flight and it was terribly hot, but I was determined to go to the welcome party. I had had one (well, maybe two) glasses of wine when suddenly I felt wobbly, dizzy and my head seemed to explode. The next thing I remember was staring down a black tunnel at an enormous polished mound, which I slowly became aware was the tip of a man’s shoe. And then there were many of them, filling my vision. I was on the floor – cold, sweaty and with a mouse’s-eye view of the feet of my colleagues. I had fainted for the first time in my life. The reason was simple: a sudden increase in the activity of the inhibitory nerves supplying my heart had temporarily stopped it. Consequently, my brain ceased to receive any oxygen and I blacked out. Once on the floor, however, with the blood supply restored, I revived.

The chemical transmitter acetylcholine is responsible for slowing the heart rate. It is released from the terminal branches of the vagal nerve, which runs from the brain to the heart (among other organs). Acetylcholine binds to muscarinic receptors on the sinus node cells. These receptors derive their name from the fact that they are also activated by muscarine, a compound found in certain mushrooms, including the familiar red-and-white-spotted flycap
Amanita muscaria
. Binding of acetylcholine to muscarinic receptors (which are different from the acetylcholine receptors found in skeletal muscle) triggers a chain of reactions that ultimately leads to opening of potassium channels. This allows potassium ions to flow out of the cell, making the interior of the cell more negative. As in the case of the nerve cells, this switches off the sodium and calcium channels, so decreasing electrical activity and slowing the heart rate.

The heart is under a small but continual amount of inhibition by the vagal nerve, which explains why the resting heart rate is actually slower than the spontaneous firing rate of the pacemaker cells in the sinus node. People who have had a heart transplant lack any nervous input as the vagal nerve is severed during the operation and so their resting heart rate is higher than normal.

Atropine antagonizes the action of acetylcholine at muscarinic receptors and is used clinically to reduce the effect of the transmitter in patients with a very slow heart rate, or whose heart has actually stopped. This helps speed up the heart. In large amounts, however, atropine is a deadly poison. It is named after Atropos, the most terrible and feared of the three Fates in Greek mythology, who cut the thread of life, and whose hand could never be stayed.

Atropine also inhibits muscarinic acetylcholine receptors in other tissues. One of its most celebrated effects is to dilate the pupil of the eye. Brilliant eyes, due to dilated pupils, are perceived as more sexually attractive, perhaps because orgasm also induces widening of the pupil. Atropine was widely used as a cosmetic by ladies of the Elizabethan court who obtained it by crushing the shiny black berries of the deadly nightshade plant, which explains its Latin name –
Atropa belladonna
(meaning ‘beautiful lady’). Every part of the plant is poisonous to humans, although birds can eat the seeds with impunity. Atropine and its derivatives are used clinically today to dilate the pupil in eye examinations and enable the ophthalmologist to examine the back of the eye more easily. You may even have experienced its effects yourself – this is the drug that makes your eyes super-sensitive to light (because the iris muscle can no longer contract in bright light), so that you tend to screw up your eyes in the sunshine and should not drive.

A Racing Heart

You have only to run for the bus to recognize that exercise has a dramatic effect on the heart rate. The maximum human heart rate is around 200 beats a minute, about threefold greater than at rest. It can be very much higher in other creatures – that of the hummingbird during flight is a staggering 1,200 beats a minute. This increase in rate is triggered by the release of noradrenaline from the sympathetic nerves innervating the heart and by a rise in the circulating levels of adrenaline. Although people with heart transplants increase their heart rate in response to exercise, they do so more slowly as they respond only to adrenaline in the blood, which takes longer to get there. The brake on the heart rate produced by acetylcholine released from the vagal nerve is also removed during exercise and reinstated when exercise ceases: this does not happen in transplant patients, which explains why their heart rate takes longer to return to normal after exercise.

The maximum heart rate is age-dependent (decreasing with age) but similar in all people, independent of their fitness. What varies is the maximum amount of blood they can pump. Athletes have lower resting heart rates because regular exercise produces an increase in the size of the heart and thus enhances the amount of blood that it can pump with each beat. Consequently, the heart needs to beat less frequently to pump the same amount of blood around the body. Although their maximal heart rate is similar, athletes are able to pump far more blood when exercising than couch potatoes because their hearts are larger, giving them a competitive advantage.

The Silent Killer

Potassium chloride is a very effective way of stopping the heart. It is fast, silent, leaves little evidence behind, and is said to be painless (although who is telling?). It is thus a favourite method of murder in detective stories, such as in the Dick Francis novel,
Comeback
, in which horses, and humans, are killed by infusing them with a potassium chloride solution. In
Comeback
, the chemical is obtained from a specialist company, but it is actually very easy for anyone to get it, because it is widely sold as a low-sodium salt substitute. Nor is murder with potassium chloride confined to fiction: a number of hospital nurses have been charged with, and even convicted of, unlawful killing of patients in their care by injections of potassium chloride.

Intravenous injections of potassium chloride, following an anaesthetic to put the victim to sleep, have also been used legally in state executions of criminals. Dr Jack Kevorkian famously used them in his thanatron machine,
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a euthanasia device he used to help terminally ill patients die (he was jailed for second-degree murder in 1998) and rather improbably, potassium chloride has also been promoted as a self-administered suicide aid by the German ex-politician Roger Kusch.