CORONARY HEART DISEASE: TREATMENT THAT WORKS
Doctors have known since the nineteenth century that blockages of the coronary arteries cause heart attacks, and that cholesterol-laden material infiltrates the blood vessels of victims, but they knew of no way to prevent the disease and had little to offer patients who suffered from it. Why coronary artery disease struck some individuals and not others was an enigma. Throughout the first half of the twentieth century, death and disability rates rose steadily in most industrialized countries. By the nineteen-sixties, mortality from heart attacks was at an all-time high and getting higher. Coronary disease had become a frightening, baffling modern-day scourge.
If the most tragic manifestation of coronary artery disease was its penchant for striking down seemingly healthy people in the prime of life, the most frustrating to physicians was angina, heart pains brought on by exertion. Men and women who were otherwise robust spent years of their lives debilitated by oppressive chest discomfort triggered by the least physical effort.
The development of the coronary artery bypass operation in the nineteen sixties marked the beginning of an era in which the arterial blockage and narrowing that caused angina could be directly addressed. However, before then there were two treatments that are still used today--nitroglycerin and exercise.
Dynamite pills
In the late nineteenth century, angina sufferers who worked in dynamite factories claimed that the more time they spent around the explosive ingredient of their product, nitroglycerin, the less trouble they had with chest pain. Eventually, they discovered that a pinch of the powder dissolved under their tongue could relieve an angina attack. The chemical was subsequently put into pill form and marketed as a treatment. It is still used today.
No other drug can relieve an attack of angina as quickly as nitroglycerin. Chest pain typically subsides within seconds of placing a pill against the cheek or under the tongue. Doctors often advise coronary patients to keep a bottle of nitroglycerin tablets with them at all times. (This also serves as a means of identification as a coronary patient.)
Pharmaceutical companies have developed long-acting nitroglycerin preparations that can maintain constant levels of the drug in the blood stream for as long as twenty-four hours. Rather than waiting for angina to occur, these drug-delivery systems help forestall attacks.
How nitroglycerin works
The walls of arteries and veins are surrounded by muscle fibers arranged circularly so that when they tighten up the vessels constrict and when they relax the vessels open. The cells lining the walls secrete a chemical called nitric oxide that relaxes those muscle fibers and increases the diameter of the channel. Nitroglycerin is a nitric oxide “donor.” It releases nitric oxide into the muscle fibers causing them to relax.
Until recently, doctors thought that nitroglycerin worked simply by opening up the coronary arteries and allowing more blood to get to the heart. In fact, the drug’s main mode of action is on vessels outside of the heart. By opening the arteries through which the heart must pump blood, nitroglycerin reduces resistance to blood flow. By relaxing veins that carry blood back to the heart, it increases their capacity to hold blood, transiently reducing the amount returning to the heart. Those adjustments lower pressures within the heart, transiently reducing its workload and diminishing its energy needs. Lowering the heart’s oxygen requirements allows the demand for blood in muscle served by narrow arteries to come back into balance with its supply.
There was a time when coronary patients were advised to avoid exercise. In fact, there is little question that heart attacks can be triggered by exertion. However, in the nineteen fifties, some forward-thinking doctors began questioning the conventional wisdom. They noticed that carefully prescribed, gradually increasing exercise made patients feel better. Angina as well as general vitality improved. Over the course of the next two decades, the medical profession slowly changed its attitude about exercise. They began prescribing gentle walks and, later, maximum-intensity aerobic exercise.
Researchers have shown that a program of gradually accelerated exercise increases the amount of exercise a patient can do before having angina. It improves coronary blood flow and favorably affected high cholesterol, high blood pressure and diabetes.
In the long run, exercise reduces the risk of heart attack. However, it can occasionally trigger a heart attack. Exercise-induced heart attacks usually occur in patients who are unaccustomed to exertion. It is advisable to obtain medical clearance when starting an exercise program, and to begin slowly, doing gentle exercises at first and gradually increasing the intensity.
For patients with angina, exercise training increases the level of exertion that can be reached before chest pain occurs. Its main effects are upon muscles outside of the heart. Exercise improves the efficiency of the arm and leg muscles, which allows them to do more work without requiring more blood. That reduces the workload of the heart during exertion.
Exercise reduces mortality from heart attacks. Its main, heart attack preventive effects are upon the heart itself. Patients who exercise regularly have fewer coronary blockages. Exercise also stimulates the growth of “collaterals,” new channels for blood to flow between narrowed and non-narrowed segments of coronary arteries. These pathways are critical for surviving a heart attack.
Those of us who practiced medicine before coronary bypass surgery became available can remember the frustration of trying to treat patients with severe angina. Nitroglycerin and exercise regimens provided some relief, but many patients remained disabled by their pains. Patients and doctors were desperate to find an effective treatment for this stubborn problem.
In the nineteen sixties, advances in bioengineering made it possible to artificially oxygenate blood and mechanically pump it through the body, mimicking the function of the heart and lungs (Figure 1). With that technology, doctors could stop the heart for two or three hours at a time and restart it without damaging organs that depended upon a constant supply of freshly oxygenated blood.
Once the “heart-lung machine” allowed surgeons to stop the heart and work on it, they began to search for a way to relieve the restriction of coronary blood flow that caused angina. Working with laboratory animals, they developed the technique of taking veins from other parts of the body and using them to shunt blood around obstructions. This research ultimately led to the development of the coronary artery bypass operation that is used today to treat angina.
One obstacle had to be overcome before surgeons could use this technology on humans. It is impossible to tell how narrow an artery is by looking at it from the outside during surgery. Surgeons couldn’t bypass obstructions in real patients without knowing where they were. They needed a way to localize and characterize coronary artery obstructions before trying to fix them.
Ultimately, this was accomplished by coronary angiography, a technique in which tiny tubes, i.e., catheters, were inserted into the heart to inject dye to allow them to show up on X-rays. There was a time, however, when the medical profession was resistant to the idea of sticking tubes into people’s hearts. They considered such a thing dangerous, and no prudent hospital administrator would allow a doctor to try it.
In
1929, in a hospital in
Since Forsmann’s experiment heart catheterization has grown to become a mainstay of cardiology. The technique is used today to localize narrowings and blockages of coronary arteries.
How cardiac catheterization is done
Specialists do the procedure in special suites equipped with cardiac monitoring equipment and x-ray machines mounted on swing arms for taking pictures at different angles. Two or three technicians usually assist. The doctor numbs the groin with a local anesthetic, punctures the main artery in the leg with a needle then replaces the needle with a hollow sheath. Under X-ray visualization, he threads a tiny tube, or catheter, through the sheath, back to the main artery leading from the heart (Figure 2).
From there, the catheter is
manipulated into the entrance of each coronary artery and dye injected to
illuminate them on x-ray. The
team usually takes several pictures at different angles, injecting dye and
moving the X-ray machine between each exposure.
By the late nineteen-sixties, the convergence of three technologies, coronary angiography; heart-lung machines and blood vessel grafting, made it possible to perform coronary bypass operations on humans. It rapidly became apparent that coronary artery bypass grafting, or CABG (nicknamed “cabbage”) was, indeed, effective at easing the pain of angina.
How
a coronary bypass operation is done
After the patient is brought to the operating room and anesthetized, the surgeon begins the task of obtaining suitable vessels, or grafts, to be used to construct bypasses. The usual sources are the superficial veins of the lower legs and the arteries that supply the inner chest wall. Surgeons prefer these vessels because they are readily accessible and because other vessels are able to take over their function when they are removed.
To remove veins from the legs, the surgeon cuts the skin along the course of the vessel, frees them from their attachments and lifts them out. The surgeon makes an incision down the middle of the chest and saws the breastbone in half from end to end using a special saw designed not to damage underlying tissue. Mechanical spreaders are used to pry open the chest. If needed, he removes chest wall arteries from inside the chest.
Then the “heart-lung machine” goes into action. The surgeon inserts two tubes into the main veins that bring blood back to the heart and one into the aorta, which supplies blood to the rest of the body. The device sucks out blood returning to the heart, oxygenates it and pumps it back into the aorta, bypassing the heart and lungs.
After the heart-lung machine has taken over, the heart is paralyzed by a solution infused through the coronary arteries. This allows the heart muscle to rest, which reduces its oxygen requirements and helps prevent damage. Getting rid of the beating motion also makes the heart easier to work on.
Using knowledge of the locations of narrowings obtained from the coronary
angiogram beforehand, the surgeon cuts tiny holes into the arteries
downstream from the obstructions. He
sews the mouths of the blood vessels he removed from the legs or chest onto
the holes in the coronary arteries. The
other ends of the grafts are sewn into holes cut into the wall of the aorta.
After the grafts are sewn in, the team warms the heart and gives it an electric shock to start it beating again. The heart-lung machine is stopped, and the heart is allowed to beat on its own. Once the team is sure the heart is working, the surgeon sews the breastbone back together with large wire stitches.
In
its early days, the coronary bypass operation was risky and recovery took
several weeks. Nevertheless,
many angina sufferers were willing to undergo the surgery if it meant they
could get some relief from their pains.
As time has passed and techniques have improved, the risk of the
operation has declined and patients recover more quickly.
Coronary bypass surgery is now one of the most common operations done
in the
In the 1970s, cardiologists and bioengineers developed balloon-tipped catheters that could be inserted into coronary narrowings and inflated to stretch them open (Figure 4.)
While recurrence of narrowing was common and often required a second
angioplasty, in most cases the artery could be made to stay open.
Angioplasty was a suitable substitute for coronary bypass surgery among certain patients without severe disease. PTCA could relieve angina without the discomfort, expense and prolonged hospitalization of major surgery. Patients were usually able leave the hospital within 24 hours and return to normal activities in a few days.
One problem that has plagued angioplasty since its inception has been sudden coronary blockage during the procedure. Emergency coronary bypass surgery is often required to rescue such patients. Recently bioengineers have developed tiny wire coils called “stents” that can be placed in the artery after angioplasty to help hold it open. That technique reduces the danger of sudden blockage and has improved the safety and effectiveness of the procedure.
How
angioplasty and stent placement is done
The cardiologist threads a catheter into the opening of the narrow coronary artery and injects X-ray dye to determine the exact location of narrowing. He then passes a guide-wire through the catheter beyond the obstruction and removes the catheter leaving the guide-wire in place. A balloon-tipped catheter is threaded over the guide-wire and placed across the narrowing. This catheter has two channels, one that slides over the wire, and one through which the balloon can be inflated.
The
balloon is inflated for as long as needed to stretch open the narrowing but
not so long as to dangerously interfere with blood flow.
The stent is a tiny wire tubular device, often likened to the spring of a ballpoint pen. It is wrapped around the balloon tip of an angioplasty catheter. When the balloon is inflated, it stretches open the stent forcing it against the walls of the artery. When the balloon is deflated the stent maintains its shape and holds the artery open after the catheter is removed (Figure 5).
During the nineteen seventies as coronary surgery and angioplasty were gaining in popularity, a quiet revolution in the treatment of coronary disease was taking place. Researchers had found that atherosclerosis was related to several “risk factors,” conditions that raised the odds of heart attacks and angina. Those included cigarette smoking, hypertension, diabetes and elevated blood cholesterol. Perhaps, it was thought, if these could be treated, maybe coronary disease could be prevented or even reversed without having to resort to artery-opening procedures.
The risk factor that most invited intervention was cigarette smoking. In the nineteen sixties, researchers had confirmed a that a strong relationship existed between smoking and lung cancer. Later, the Office of the Surgeon General took the unprecedented step of ordering cigarette manufactures to put cancer warnings on cigarette packs.
The
public was impressed by the bad publicity smoking was getting.
For the first time, the number of cigarette smokers in
In the early seventies studies confirmed that showed that stopping smoking after a heart attack cut the risk of a recurrence in half. Remarkably, the benefits of quitting smoking dwarfed the risk reduction accomplished by any other treatment to date including coronary by-pass. While that discovery was met with little fanfare, those who suspected that coronary disease could be prevented by treating its underlying causes took notice. The ability to prevent heart attacks by quitting smoking reinforced their conviction that changing the body’s metabolic milieu could alter the course of atherosclerosis.
Before the nineteen eighties, the medications available for treating high blood cholesterol worked inconsistently. Some research studies had suggested that the drugs modestly reduced the heart attack rate, but in general, the results were unimpressive. Furthermore, many of the medications caused untoward side effects.
A breakthrough came in the early eighties. Researchers--two of whom were later awarded the Nobel Prize for their work--unraveled the physiological mechanisms responsible for high cholesterol levels in the bloodstream. The pharmaceutical industry used this knowledge to develop a medication that could safely and consistently lower blood cholesterol levels. Instead of reducing cholesterol concentrations by 10 or 15 percent, typical for the old drugs, one pill per day could cut levels by 25 to 50 percent. The first drug of this type to arrive on the market was lovastatin (trade name Mevacor). In the years to follow, other, similar drugs were marketed including pravastatin (Provachol), simvistatin (Zocor), atorvastatin (Lipitor), fluvastatin (Lescol) and cerivastatin (Baychol). While these drugs, collectively known as “statins”, vary in their potency, their chemical structures and mechanisms of actions are similar to lovastatin.
Most cholesterol in the body does not come from dietary sources. The liver manufactures it. The liver is also responsible for removing excess from the bloodstream. High blood levels are usually caused by a logjam in the removal processes that prevents cholesterol from entering the liver and being broken down.
Much of the cholesterol in the bloodstream circulates in small packets called LDL (Low Density Lipoprotein) particles. Liver cells make tiny protein structures called receptors that affix themselves to the cell surface membrane and bind the LDL particles floating by. The cell then engulfs the particles pulling them in to the cell where enzymes can digest them (Figure 6.)
What causes most cases of high blood cholesterol is a deficiency of LDL
receptor activity. Statin drugs
work by stimulating the liver to produce more LDL receptors, improving its
capability to clear cholesterol from the bloodstream.
The way these drugs work is by interrupting cholesterol production within the liver for a few hours each day. Sensing a reduction in internal concentration, liver cells make more receptors to bring cholesterol in from the blood stream. Once inside, the cholesterol is broken down and eliminated.
In
the nineteen-seventies, a new type of medication called beta-blockers came into use as a treatment for angina.
The first drug of this type was propranolol (trade name, Inderal).
Others with advantages in convenience and side effects followed
including atenolol (Tenormin), nadolol (Corgard) and metoprolol (Lopressor).
Beta-blockers
calm the heart. By reducing
heart rate and blood pressure response to exertion or emotional stress, they
lower its oxygen needs. While
they do not increase blood flow through narrow coronaries, they improve the
balance between the oxygen consumption of the heart and its blood supply.
That allows patients to engage in higher levels of physical exertion
without angina. Beta-blockers can be given with nitroglycerin preparations
to provide more effective treatment for angina than either drug alone.
Initially
beta-blockers were given to patients to relieve the symptoms of angina.
After several years, it became apparent that the drugs had another
astonishing effect. They reduced
the heart attack rate by as much as 50 percent--not only among angina
patients but all patients with coronary artery disease.
Guidelines now recommend that that all patients who have angina or
have had a heart attack take a beta-blocker.
The
human nervous system secretes a hormone called adrenalin,
nicknamed the “fight-or-flight hormone” because it serves the
purpose of readying the body for physical action.
Adrenalin and adrenalin-like substances stimulate the heart, raise
the blood pressure, open the windpipes, quicken respiration, increase the
tendency for blood to clot, slow digestion and dilate the
pupils--adjustments that prepare the body for danger.
Beta
blocking drugs inhibit the effects of adrenalin, slowing the heart and
reducing blood pressure during exercise.
Because the amount of work the heart muscle does, and hence its
oxygen needs, are largely determined by how fast it beats and how much
pressure it must pump against, lowering heart rate and blood pressure
reduces the heart’s oxygen requirements.
Those adjustments prevent angina by keeping the heart’s oxygen
needs in balance with its supply.
Since the nineteenth century, pathologists have described clots in the coronaries of patients who died of heart attack. However, stoppage of circulation itself causes blood to coagulate. It was difficult to tell whether the clots they found in the heart occurred before or after death.
One way to tell if something causes a particular condition is to treat it and see what happens. In the nineteen fifties, doctors tried giving heart patients drugs that inhibited clotting but the results were disappointing. The medications, nicknamed “blood thinners,” had no discernible beneficial effect, and plenty of dangerous side effects. Consequently, for years the role for blood clots in causing heart attacks was discounted.
In the nineteen-sixties, investigators discovered that the old, household remedy aspirin had unique blood thinning qualities. Instead of inhibiting coagulation proteins as the other blood thinners did, aspirin worked on platelets, tiny clot-forming cells, in the bloodstream.
Researchers began to study the effects of aspirin on coronary disease. In the nineteen eighties, they discovered that small amounts of aspirin taken daily could reduce the risk of heart attack as much as 50 percent. Guidelines now recommend it to all patients who have angina or who have had a heart attack. Some doctors advocate it for patients without known coronary disease but who have risk factors such as high blood cholesterol, diabetes, cigarette smoking or high blood pressure.
Scientists have developed other platelet-inhibiting drugs that are useful in treating certain complications of coronary disease. However, considering that aspirin was a cliché for a weak and innocuous nostrum, it is remarkable how large of a role it has retained as a preventive as well as therapeutic measure.
Aspirin is, in fact, neither weak nor innocuous. The standard aspirin dose used for treating a headache is 600 milligrams, but only eighty milligrams per day, the children’s dose, is needed to reduce the risk of heart attack. (Some researchers believe 10 milligrams per day may be effective.) Remarkably, the blood thinning effects of a single dose of aspirin lasts for two weeks.
And
aspirin is not without side effects. The
most troublesome complication of regular aspirin use is gastric irritation
and bleeding. In the
Because the beneficial effects of aspirin for coronary disease were discovered somewhat serendipitously, one would expect that focused research efforts would yield even more effective drugs. Indeed, several other medications have been developed that, added to aspirin, improve results in certain situations. One drug, clopidogrel (Pharmaceutical name, Plavix), seems to prevent heart attacks as well as aspirin without as much stomach irritation, and when combined with aspirin it slightly improves aspirin’s heart attack-preventive effects. Whether it deserves its nickname “Super Aspirin” is yet to be determined.
The nickname “blood thinners” is a flagrant misnomer. These drugs do not in any way dilute blood or interfere with its nutritive, warming or oxygen-delivering properties. They do not cause tiredness or intolerance to cold temperatures, as many patients fear.
Platelets are tiny cells that circulate in the bloodstream to protect against bleeding. Whenever blood vessels are damaged, whether externally from traumatic injury or from within as from a ruptured atherosclerotic plaque, platelets adhere to the injured area. While nature’s intent is to form a plug to stifle bleeding, in the case of most heart attacks, the clot gets so big it blocks blood flow through the artery. Aspirin works by interfering with platelet clumping and preventing large clots.
The first platelets to arrive at an area of blood vessel damage release a potent chemical, thromboxane, that attracts others and causes them stick to one another. Aspirin works by deactivating the enzyme that produces that hormone.
Aspirin permanently deactivates thromboxane-producing enzymes in platelets. Their ability to form clots is inhibited for the duration of their life in the blood stream, which is approximately 60 days. One dose of aspirin inhibits blood clotting for several weeks.
Aspirin’s influence on blood clotting is largely separate from its anti-pain and anti-arthritis effects. Indeed, other anti-inflammatory drugs have little effect on platelet clumping and are not used to prevent heart attacks.
The doses of aspirin required to inhibit platelets are much smaller than those needed to relieve headache or arthritis pain. For most patients, one child-strength aspirin per day is enough to do the job.
Another advancement in treating blood clots has been the development of medications to dissolve them once they form. Such drugs, nicknamed “clot busters,” when given within three or four hours of a heart attack, melt clots, restore coronary blood flow and reduce damage to heart muscle. Because the underlying narrowing that causes most heart attacks is often minor, adequate coronary blood flow usually returns when the clot dissolves.
Deciding which treatment to use
Heart specialists have to learn dozens of techniques to manage the complications of coronary artery disease. There are drugs for strengthening damaged heart muscle, quieting erratic rhythms and relieving chest pains. There are operations for fixing damaged heart valves and inserting pacemakers to regulate the heart rhythm. Treating the conditions that contribute to coronary artery disease, such as diabetes and high blood pressure, are as challenging as treating coronary disease itself. However, for treating the actual narrowing and blocking of coronary arteries, there are only a handful of effective treatments.
Which treatment is most appropriate depends upon what aspect of the disease is being addressed. The strategies that have had the greatest benefit on heart attack rates are the cholesterol-lowering medication, smoking cessation, aspirin, and beta-blockers. The techniques that relieve angina most effectively are coronary artery bypass grafting, angioplasty, beta-blockers, nitroglycerin and exercise training. Clot-busters and emergency angioplasty are the most useful in rescuing people from heart attacks.
All of these approaches complement one another. Coronary bypass and angioplasty can relieve angina when medications are unsuccessful. Medications address two major deficiencies of artery opening procedures, their failure to prevent heart attacks and their inability to keep atherosclerosis from progressing.
It is important to address the underlying cause of the condition itself, the infiltration of arteries with cholesterol. Indeed, cholesterol-lowering medications are more effective at preventing heart attacks and reducing mortality than any other type of treatment. If your condition can be comfortably and safely alleviated with medications, effective treatment of high cholesterol will often gradually reopen narrow channels and relieve angina without the need for other artery-opening procedures.
It is hard to argue that wide-open arteries are not a desirable goal even in the absence of chest pain. Indeed, coronary-pass improves survival among patients with extensive coronary narrowing. Advancements in technique have improved tolerability, safety and effectiveness of the operation. Twenty years ago, patients were typically hospitalized for two weeks after cardiac surgery; now the average length of stay is less than five days. Surgeons are increasingly using “minimally invasive” techniques that leave smaller wounds and hasten recovery. A remarkable development in coronary surgery has been the use of chest arteries instead of the leg veins for bypassing narrow coronary arteries. These vessels are more resistant to atherosclerosis and usually stay open several years longer than vein grafts.
Angioplasty techniques are also improving rapidly. The danger of abrupt artery closure during the procedure has been lessened by the use of stents, and doctors are making progress against the recurrence of narrowing that has plagued angioplasty since its inception.
Coronary-bypass and angioplasty will continue to improve, and in the future, it will probably be even easier to bypass or reopen narrowed arteries. However, effective as these techniques are at relieving obstructions, it is important to realize that they treat the effects not the causes of coronary atherosclerosis. While they will likely continue to have important roles in the management of coronary disease, but it will be in addition to medical treatment. The future lies in addressing the underlying causes of atherosclerosis and arterial blockage, cholesterol infiltration of arteries and overactive blood clotting. Not only will strategies to identify and correct such disturbances become even more effective at preventing narrowing and obstruction of blood vessels, they will be used to reverse those conditions once they occur. With each advancement in treatment of the metabolic disturbances that cause cholesterol infiltration, plaque destabilization and blood clot formation, fewer patients will need surgical procedures to reopen narrowed and blocked vessels.