杏吧原创

Heart disease still kills more people in developed countries than any other
medical problem. But in recent decades researchers have unravelled many of the
underlying causes, raising hopes for more effective drugs

IN INDUSTRIALLY developed countries heart attacks kill one in four people.
So the chances are that most of us will witness one at some point in our
lives. But while the expression 鈥渉eart attack鈥� is familar to everyone, how
many people actually know what it means?

Over the past few decades scientists and doctors have built up an
impressively detailed picture of the way the heart works and of what goes
wrong during a heart attack. The cellular basis of the heart鈥檚 ability to pump
blood is now clear, and researchers are homing in on the biochemical processes
that control the responses of heart cells to various drugs. New insights into
the causes of heart attacks have also come from a less likely quarter: the
world of mathematics, where chaos theory is being used to understand the
abnormal rhythms that are sometimes produced by damaged hearts and which can
prove lethal. But before delving into this, we must understand what the heart
does and how it does it.

The heart鈥檚 function is to pump blood around the body, supplying oxygen and
other nutrients to organs and muscles and removing waste products from them.
In fact, as a quick look at its architecture reveals, the heart is two pumps
working in parallel.

The right side of the heart receives deoxygenated blood from all over the
body and supplies it to the lungs for oxygenation, while the left side of the
heart receives oxygenated blood from the lungs and distributes it around the
body. The flow of blood from the right ventricle through the lungs to the left
atrium is called the pulmonary circulation; the flow from the left ventricle
through the body to the right atrium is called the systemic circulation.

William Harvey gave the first accurate description of these interlinked
circulations in 1628. His superb treatise remains one of the most influential
scientific papers ever written and is still well worth reading.

Early anatomists observed that the left ventricle is much larger than the
right. The reason for this follows from understanding the circulation:
although both sides of the heart move the same amount of blood, the left
ventricle must send the blood further, to vessels supplying many different
organs, not just the lungs. This also explains why pressure in the systemic
circulation 鈥� normally known as the 鈥渂lood pressure鈥� 鈥� is higher than in the
pulmonary circulation.

To keep the circulation going, the heart pumps about seventy times each
minute. The pressure wave accompanying each beat travels down the arteries and
is called the pulse. The pulse can be felt at several places in the body
including the wrist (radial pulse), the groin (femoral pulse) and the neck
(carotid pulse).

Although all the organs of the body require a blood supply, some depend
more critically than others on a continuous flow. Muscles, for example,
especially if they are not being used, remain unscathed even when deprived of
their blood supply for many minutes. But interrupt blood flow to the brain,
and it begins to malfunction within seconds, causing loss of consciousness. If
the supply is not restored within two to three minutes, irreversible damage
can occur.

Another organ which is particularly sensitive to having its blood supply
interrupted is the heart itself. If a part of the heart loses its blood supply
鈥� or, as physiologists describe it, becomes ischaemic 鈥� its ability to
function as a pump falls within seconds and fails completely within minutes.
This ischaemic heart disease is the underlying cause of most heart attacks.
Ischaemia is usually triggered by the clogging up of an artery serving a
particular area of the heart. To understand the heart鈥檚 response to the
subsequent loss of blood flow, one must look at its cellular structure.

The heart is composed of a specialised type of muscle, cardiac muscle.
Individual heart cells, or cardiac myocytes, are electrically coupled to each
other by membrane structures called gap junctions 鈥� small pores through which
electrical currents can flow from cell to cell. This coupling ensures that all
muscle cells contract synchronously when stimulated by excitation waves.

The heart has an intrinsic rhythm of about seventy beats per minute. This
rhythm 鈥� which continues even when the heart has been removed from the body if
conditions are suitable 鈥� is driven by successive waves of electrical
excitation, similar to nerve impulses, which spread through conducting tissues
in the heart muscle. These electrical waves originate in the sinoatrial node,
a small cluster of specialised muscle fibres in the atrial wall which acts as
the heart鈥檚 pacemaker. As well as stimulating the atria to contract, the waves
are conducted into the ventricles, causing these muscles to contract. The
contractions start at the bottom and have the effect of squeezing blood out of
each ventricle.

The intrinsic rhythm, though important, does not explain the ability of the
heart to respond to changes in the body鈥檚 requirements. Why do our hearts beat
more strongly when we exercise, for example? It turns out that both the
excitation waves driving the heart and the strength with which myocytes
contract in response to these waves are sensitive to a variety of control
mechanisms. Nerves from the sympathetic nervous system speed up the heart rate
(see Inside Science Number 19), while other nerves, from the parasympathetic
nervous system, slow it down. The contraction strength is influenced by
cellular mechanisms that adjust the activation level of myocytes (see Box 2).

Like all muscle cells, cardiac myocytes 鈥渂urn up鈥� oxygen as they contract,
converting it to carbon dioxide. But only the innermost layers of myocytes,
adjacent to the blood in the cardiac chambers, can rely on diffusion of oxygen
directly from the blood. The rest of the heart depends on blood supplied by
the coronary arteries.

The main coronary arteries emerge at the beginning of the aorta and pass
along the outer surface of the heart, the epicardium, for a few centimetres
before sprouting smaller branches. These then enter the main body of the heart
to supply the myocytes. There are three principal coronary artery branches,
all of which can be involved in producing heart attacks. Blockages leading to
ischaemia most commonly occur in the left anterior descending artery, which is
implicated in about 50 per cent of cases, followed by the right main coronary
artery (30 per cent of cases) and the circumflex artery (20 per cent). In most
instances, the blockage occurs in the epicardial part of one of these arteries
and is due to atherosclerosis.

Atherosclerosis involves the build-up of fatty deposits on the inner
surfaces of arteries. It can affect large and medium-sized arteries throughout
the body, and can thus cut-off blood flow to other organs as well as the
heart. Most strokes, for example, are caused by atherosclerosis in cerebral
arteries. An individual鈥檚 risk of developing atherosclerosis depends both on
lffestyle factors, such as smoking and diets rich in saturated fats, and on
traits influenced by genetic makeup, such as high blood pressure and hyper-
cholesterolaemia 鈥� a condition in which excessive amounts of cholesterol are
present in blood.

Risks for the young

Lipid-rich cell clumps

ATHEROSCLEROSIS is by no means confined to middle-aged or older people.
Researchers have long known that small atherosclerotic lesions called fatty
streaks can form even in the arteries of children and young adults. These are
little more than a shallow bulge on the inner surface of an artery 鈥� a bulge
made of lipid-rich cells clumped together just under the lining of the artery.
Lipid is a general term for the substances found in storage fat and the more
complex fatty molecules, such as cholesterol, that make up cell membranes.

Fatty streaks cause little if any narrowing of coronary arteries and so
have no adverse effects. However, research shows that fatty streaks in
coronary arteries can develop into more serious lesions. Known as fibrofatty
plaques, these are composed of a pool of lipids covered by a fibrous cap,
containing smooth muscle cells, immune cells known as macrophages and the
protein collagen. Whereas fatty streaks are seldom deeper than 1 millimetre,
fibrofatty plaques can be several millimetres deep and can cause dangerous
narrowing of the bores of arteries. This narrowing can be monitored with a
special type of X-ray known as a coronary angiogram, where coronary arteries
are visualised by injecting into them a marker substance which appears white
on the X-ray.

Plaques vary in the proportion of lipid and fibrous material they contain.
Those that are mainly fibrous produce ischaemia by gradual, progressive
narrowing of the artery and seldom rupture. Plaques rich in lipids, on the
other hand, are more likely to produce sudden ischaemia. Usually this occurs
when blood flowing through the artery ruptures a very thin fibrous cap,
exposing the lipid pool below. The exposed lipid then stimulates the formation
of a blood clot, which continues to grow until it completely blocks the
artery. The whole process may take only a few minutes and the end result is a
coronary thrombosis.

Gradual narrowing of a coronary artery is likely to cause angina, a severe,
crushing chest pain often described as 鈥渁 band round the chest鈥�. The pain
usually occurs only when patients start to exercise or engage in physically
demanding activities. This is because the constriction in the artery prevents
blood flowing through it at the rate needed to fuel the extra work of the
heart.

In some cases, angina can be alleviated by drugs that act to dilate
arteries, usually by 鈥渞elaxing鈥� the smooth muscle tissue that forms the walls
of arteries. But often the fibrous tissue of a plaque encircles the whole
artery, producing a blockage that is stubbornly unresponsive to drugs.

In general, the more severe the narrowing, the less physical activity a
patient can do without suffering angina. In extreme cases, patients experience
chest pains even when they are not exerting themselves physically 鈥� a sign
that the affected region of heart is teetering on the brink of survival. The
diagnosis of such so-called 鈥渞est pain鈥� often leads to surgery designed to
bypass the narrowed segment, an operation known as a coronary artery bypass
graft (CABG, or 鈥渃abbage鈥�). Here, surgeons remove part of a vein or artery,
usually the saphenous vein in the leg or the internal mammary artery in the
chest, and join it to the blocked coronary artery before and after the
blockage, creating a bypass. A patient may have a single, double or triple
bypass operation, depending on how many principal coronary arteries are
blocked.

Myocardial infarction

Death in the heart

IF A coronary artery causing rest pain is allowed to narrow further, or a
patient suffers coronary thrombosis due to an unstable plaque, the result is
usually severe and irrepressible pain. If the blockage is not cleared, the
myocytes whose blood is supplied by the affected artery will die. Death of a
region of heart is known as a myocardial infarction.

Putting together what has been said so far, we can begin to understand what
happens when someone has a heart attack. In the first stage, a coronary
thrombosis forms on an atherosclerotic plaque. As soon as the flow of blood in
the affected artery begins to slow, the patient will begin to experience
severe chest pain: the region of the heart normally served by the artery is
being deprived of oxygen. Sometimes this pain is the first sign that the
person has heart disease, but usually it comes after a history of angina.
Unlike most angina pains, though, this one is unrelenting and unresponsive to
anti-angina drugs.

If a severe chest pain of this kind lasts more than 5 to 10 minutes, call a
doctor immediately because treatment needs to be started as soon as possible.
Surprisingly, research shows that the average period from the beginning of a
heart attack to the calling of a doctor is two hours. As many as one in four
heart attack victims will die within that period, mostly due to abnormal
rhythms, or arrhythmias.

Chest pain is by no means the only problem for someone suffering a heart
attack. Deprived of oxygen, the ischaemic region of the heart rapidly stops
functioning as a pump. The bigger size of the left ventricle and the fact that
it has to pump blood further than the right means that most common symptoms
stem from ischaemic malfunction of the left, rather than right, ventricle.

These include a fall in blood pressure and a faster heart rate. The first
of these leads to a weaker pulse, while the second is one of the body鈥檚 ways
of trying to compensate for the fact that the heart is pumping less
efficiently with each beat. The inefficiency of the heart, combined with the
severe pain, means that patients usually appear pale and sweaty, with cold,
moist hands. Also, their lips and fingernails may appear blue due to cyanosis
caused by poor circulation. And because blood is being pumped so sluggishly
into the systemic circulation, it tends to accumulate in the pulmonary
circulation. This impairs the function of the lungs and contributes to the
breathlessness which patients often experience.

What can be done for a person suffering a heart attack? The first thing a
doctor can do is to give drugs which relieve the pain. But a more important
goal is to clear the thrombus from the affected artery. The longer that the
blood supply is cut off, the more muscle will die. One useful drug is aspirin.
Researchers have discovered that the humble aspirin, as well as relieving
aches and pains, helps to slow the growth of blood clots.

Thrombolytic agents

Dissolving the clots

IN RECENT years, biomedical research has led to the development of
powerful agents for dissolving a thrombus within blood vessels. These
thrombolytic agents include an enzyme called streptokinase and a protein known
as tissue plasminogen activator. Both these substances work by converting a
blood protein called plasminogen into plasmin, an enzyme which digests fibrin,
one of the main components of blood clots. Whereas streptokinase can only
perform this biochemical conversion in fluid, tissue plasminogen activator can
release plasmin in the clot itself. These drugs must be given to patients
within 2 hours if they are to have a chance of clearing the thrombus before
any permanent damage is done. If they are given between 2 and 4 hours after
the heart attack began, myocytes will almost cetainly die but the damage will
be less severe than it would be otherwise.

Unfortunately, it is not safe to give thrombolytic agents to all patients.
With people who are prone to suffering from internal bleeding 鈥� due to recent
surgery for example, or high blood pressure or an active stomach ulcer 鈥� there
is a danger that thrombolytic agents will cause internal haemorrhage by
interfering with the normal blood-clotting mechanisms at sites outside the
heart. In this situation, doctors can attempt to strengthen the heart with
other drugs. Most of these, including agents that mimic the action of the
hormone adrenaline, strengthen contractions by boosting levels of calcium
inside myocytes. Unfortunately, these drugs also tend to make arrhythmias more
likely. An exciting recent advance is the development of calcium-sensitising
compounds. These are still at an experimental stage but the signs are that
they will be able to strengthen heart contractions without causing
arrhythmias.

Another valuable measure is to connect the patient to a cardiac monitor, by
attaching the monitor鈥檚 detection wires to sticky, round plasters placed on
the chest. The tiny electrical impulses associated with each heartbeat cause
currents to flow in the wires and can be displayed on the monitor as the
electrocardiogram, or ECG. The pattern of an ECG can help to confirm that a
patient has suffered a myocardial infarction and can indicate which region of
the heart has been damaged. ECGs also allow doctors and nurses to detect
arrhythmias.

The most common fatal arrhythmia is known as ventricular fibrillation, in
which electrical impulses from damaged cardiac muscle cause the normally
synchronous contractions of the heart to break down. Instead of acting as a
single muscle, each ventricle becomes a collection of muscle fibres
contracting independently and out of phase. At first sight the ECG produced by
ventricular fibrillation appears to consist of randomly generated impulses 鈥�
quite unlike the apparently regular pattern seen in healthy people. But recent
research tells a more complicated story. Using chaos theory, an American
cardiologist Ary Goldberger has shown that the contractions of a normal heart
have attributes consistent with chaotic behaviour 鈥� their rate varies in a
complex manner that cannot be easily predicted. When analysed mathematically,
the result is a broad frequency spectrum. In contrast, ventricular
fibrillation lacks the fingerprint of chaos: it produces impulses that are
more regular and have a much narrower frequency spectrum. Diseased hearts
ofren have a pattern of heart-rate variability lying between these two
extremes. This research suggests that loss of chaotic variability may be a
marker of heart disease. If this is so, doctors may in future be able to use
chaos theory to identify people at risk of sudden death.

The normal pumping action of the heart is abolished by ventricular
fibrillation and the circulation of blood stops. This is known as cardiac
arrest. With no blood flowing to the brain, the patient rapidly loses
consciousness and collapses. Unless circulation is rapidly restored, death is
inevitable. If the patient is in hospital, there is a chance that the
ventricular fibrillation will be seen on the monitor seconds before the
patient actually collapses. In this situation, the treatment is to
鈥渄efibrillate鈥� the heart 鈥� that is, to rapidly apply electrodes to the front
of the chest and pass a controlled electric current through the patient. If
successful, defibrillation resynchronises the heart, allowing effective
pumping action to begin again. A patient may have to be defibrillated several
times in the early stages of a heart attack. In cases where the heart is
severely damaged, defibrillation is not always possible.

When someone collapses outside hospital, defibrillation must wait until an
ambulance arrives. In this situation the circulation must be kept going by
artificial means (cardiac massage), or the person will die. Also, because
people often stop breathing when they suffer a cardiac arrest, it is usually
necessary to give them artificial respiration (the so-called 鈥渒iss of life鈥�).

The consequences of a heart attack depend mainly on how much heart muscle
is damaged or destroyed and the severity of the underlying lesion in the
coronary arteries. If only a small amount of muscle is damaged and the
arteries are only mildly affected by atherosclerosis, the patient is likely to
recover and lead a normal life. On the other hand, if the heart is severely
damaged, the patient may develop heart failure, a serious condition which
tends to worsen with time. If the coronary arteries are severely diseased,
surgery may be required to prevent further heart attacks.

Having a heart attack can be a dramatic incentive to adopt a more healthy
lifestyle. Some of the more important things to do are to exercise regularly,
eat a low fat, high fibre diet and stop smoking. But prevention is much better
than a cure: rather than adopting a healthy lifestyle afrer you have a heart
attack, do it now.

1: Monitoring rhythms

THE ECG was first recorded in 1887. But it was not until a Dutch
physiologist called Willem Einthoven began using a sensitive string
glavameter in 1913 that any real progress was made. The early equipment was
cumbersome and difficult to use, but modern electronics has made today鈥檚
machines portable and versatile. The arbitrary names Einthoven gave to the
various parts of a normal ECG pattern are still in use: the P wave, the QRS
complex and the T wave. But today the physiological basis of these waves is
understood. For example, the QRS complex occurs when the ventricles are
electrically excited and contracting.

When a region of heart becomes ischaemic it not only fails as a pump but
its electrical properties change. This is because the lack of oxygen and blood
disrupts the biochemical processes which control the balance of ions across
myocyte membranes 鈥� a balance crucial to their electrical behaviour.

One outcome of this is that an electric current known as the injury current
flows between damaged and normal heart muscle. In the early phase of a heart
attack this current can be detected as elevation of the ST region of an ECG 鈥�
the part of an ECG between the end of the QRS complex and the beginning of the
T wave. Exactly which ECG wires detect such changes will depend on which part
of the heart has been injured. Experienced observers can use this information
to identify the affected area of the heart.

The damaged area of the heart can also produce abnormal pacemaker signals
which excite the rest of the heart and disrupt its pumping action. Examples of
abnormal rhythms include very rapid heart rates, of more than 200 beats per
minute, and ventricular fibrillation, in which the whole heart contracts
asynchronously causing a chaotic ECG pattern. In severely ischaemic hearts,
pacemaker activity and pumping action may cease altogether. This is called
asystole and usually leads to death.

2: Activating cardiac muscles

EACH contraction of a heart muscle cell is the end result of a complex
chain of events. The initial signal to contract comes from the cardiac
pacemaker, specialised areas of heart muscle found in the right atrium and at
the atrioventricular junction. These areas generate impulses automatically,
though the rate at which they discharge can be varied by nerves supplying the
heart. These impulses cause the voltage across the membranes of cardiac
myocytes to change dramatically, and this opens up tiny channels through which
calcium ions can move into the cells. Myocytes respond to this modest influx
of calcium by releasing a much larger amount of calcium from a store which is
known as the sarcoplasmic reticulum.

Each myocyte now has a higher concentration of calcium ions in its
cytoplasm, with the result that some of these ions bind to a muscle protein
called troponin. Troponin is one of a team of proteins which collaborate to
make muscle fibres contract 鈥� an event which involves the minute protein
filaments, or myofilaments, that make up muscle fibres sliding past one
another to shorten the fibre.

Troponin responds to calcium by changing its shape. And in turn this change
of shape allows the two main myofilament proteins, actin and myosin, to engage
in cross-bridge cycling 鈥� the biochemical process which enables myofilaments
to slide past one another. Once the voltage across myocyte membranes has
returned to normal, calcium stops moving into the cells and calcium ions are
taken back into the sarcoplasmic reticulum. As a result, troponin reverts to
its original shape, cross-bridge cycling is switched off and the muscle
relaxes. All this happens about 70 times a minute throughout your life.

The heart can vary the amount of force produced in any given contraction by
altering the amount of calcium that is released from the sarcoplasmic
reticulum. Under normal conditions, enough calcium is released to activate
myocytes to the halfway point. When a greater cardiac output is required, for
example during exercise, natural adjustments such as an increased heart rate
and adrenaline production cause more calcium to be released, and hence fuller
activation of the muscle. Drugs such as digitalis, which can be used to treat
heart failure, also stimulate greater force production by increasing calcium
release. Another way in which the heart can strengthen its contractions is by
increasing the force myocytes generate in response to a given amount of
calcium. This is how calcium sensitisers (see main text) work.

Other factors have the opposite effect: for example, build up of phosphate
or hydrogen ions in the cytoplasm reduces the force produced in response to a
given level of calcium. These substances accumulate in ischaemic cardiac
muscle and are largely responsible for the rapid pump failure seen when
regions of heart become ischaemic.

Further Reading

An Anatomical Disputation Concerning the Movement of the Heart and Blood in
Living Creatures, by William Harvey, translated by G. Whitteridge (Blackwell
Scientific Publications, 1976). A well-written translation with an excellent
introduction.

Vital Circuits, by S. Vogel (Oxford University Press, 1992). An
entertaining introduction to hearts and the blood circulation.

Modulation of Cardiac Calcium Sensitivity: a New Approach to Increasing the
Strength of the Heart, edited by J.A. Lee and D.G. Allen (Oxford University
Press, 1993). Contains chapters describing control of muscle activation, the
effects of ischaemia and the actions of calcium sensitisers on heart muscle.