By Fredarick L. Gobel, MD
As a new intern in the emergency room at St. Luke's Hospital in Duluth, Minnesota, in 1959, I had the opportunity to care for a man who was brought to the hospital with chest pain. He was a previously healthy and active 46-year-old director of theater at the University of Minnesota in Duluth.
He had experienced the onset of crushing chest pain, radiating into both arms just a few hours earlier while at work. Persistent pain, nausea and profuse sweating prompted him to call an ambulance and he was promptly taken to the emergency room where I met him for the first time. He had been in good health all of his life with no important medical problems. His parents were alive and well and both had an age well into the late 80's. His blood pressure was a bit low but his physical examination was otherwise unremarkable except for an opened, half-full, package of Camel cigarettes in his shirt pocket.
He was treated with oxygen and morphine. An electrocardiogram demonstrated an acute anterior myocardial infarction (a heart attack on the front wall of the heart). His pain eased with the morphine and oxygen and he was placed on a gurney in preparation for transfer to a hospital bed.
A short time later the transferring nurse came running back to the emergency room and asked me to return to see the patient immediately as he had stopped breathing. Indeed, when I arrived he was pulseless and appeared lifeless. He was quickly returned to the emergency room where an electrocardiogram verified that he had ventricular fibrillation (a chaotic heart rhythm not capable of sustaining life). I opened his chest with a scalpel, massaged his heart to try to restore a normal rhythm; but the cardiac massage was not successful and he died. A lasting impression was created in my mind when I told his young wife and two beautiful daughters, ages 8 and 10, that their husband and father was dead. He died a sudden death from ventricular fibrillation secondary to an acute myocardial infarction - a heart attack caused by a cholesterol and blood clot obstruction in one or more of the major coronary arteries which supply blood to the heart muscle.
What I did was the standard of care, all that was available, in 1959. In this article, I'd like to discuss the progress that we have made since that time and how this young college professor might have been treated differently today, or how his children might be treated if they should suffer a similar heart attack.
Reduction in Mortality After reaching a peak in 1963 the age adjustable death rates from coronary heart disease have declined by nearly 50% in the past four decades and we have been the beneficiaries of that improvement.
Percentage change in age adjusted mortality for stroke and
coronary artery disease 1950-1995
We've come a long way from the tragic death of that young man, 40 years earlier, but not yet far enough.
The Early Years After World War II, the industrialized nations turned their attention from the war effort toward domestic matters, including health care and, in the United States, the National Heart Act was passed. As a result of this act in 1948, the National Heart Institute (now the National Heart, Lung and Blood Institute, NHLBI) was formed to support teaching and research. One of the most important research efforts of the National Heart Institute was organization of the Framingham Heart Study, an epidemiological study of the population of Framingham, Mass. In 1961, two years after the death of the young man that I cared for, the Framingham Study made their first report. This now classic study clearly established the concept of risk factors for coronary artery disease. High blood pressure, high cholesterol and cigarette smoking were identified as major contributors to the pandemic of coronary artery disease which had been recognized as the major cause of death in the United States since the mid century. Over the next decade several other risk factors were identified and the list now includes:
Risk factors for coronary heart disease
1. High cholesterol
2. Cigarette smoking
3. Hypertension
4. Diabetes
5. Genetic factors
6. Obesity
The presence of a risk factor does not indicate that you will develop obstruction in the coronary arteries, coronary artery disease, or a heart attack, only that you are more likely to develop this problem. In order to be certain about a causal relationship, moreover, the removal or reduction of a risk factor must be proved to result in the reduction of the incidence of coronary artery disease.
Photomicrograph of a normal coronary artery
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Photomicrograph of a coronary artery with 80% of its lumen obstructed by an atherosclerotic plaque
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Coronary Care Units Although acute myocardial infarction was recognized as an entity as early as 1912, it wasn't until mid-century that it was recognized as the most common cause of death in the United States. In the 1960's the development and rapid dissemination of coronary care units reduced the in-hospital mortality from 30% to 15%. Coronary care units (CCU) are disease-specific, specially equipped areas within the hospital, staffed by people with advanced skills in the care of patients with coronary artery disease. The development of the external defibrillator allowed the prompt treatment of ventricular fibrillation. Ventricular fibrillation is the cause of death in many patients with acute myocardial infarction. The external defibrillator delivers an electrical shock to the heart through externally applied paddles. This shock stops the fibrillating heart and allows resumption of a normal heart rhythm. The ability to stop an abnormal heart rhythm with an electrical jolt must rank among the most important advances in medical history. Lidocaine is a powerful medication that can be given intravenously to "stabilize" the heart rhythm when irregular, and it helps prevent ventricular fibrillation. Finally, the coronary care unit nurse was empowered to treat ventricular fibrillation with electric shocks on an emergency basis in the absence of a physician. The coronary care unit, a nurse empowered to administer emergency defibrillation, the external defibrillator and lidocaine all contributed to the reduction in mortality in patients with acute myocardial infarction.
Thrombolytic Therapy or "Clot Busters" The next major advance in the treatment of acute myocardial infarction was the introduction of medicines powerful enough to break up blood clots within the coronary arteries - thrombolytic therapy. Cholesterol deposition in the coronary artery, atherosclerosis, is not evenly distributed but occurs in focal areas leading to the formation of plaques. A myocardial infarction results when there is disruption or rupture of an atherosclerotic plaque in the lining of the coronary artery.
Atherosclerotic plaque within a coronary artery
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Rupture of an atherosclerotic coronary artery plaque
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Occlusion of a coronary artery by a thrombus
adjacent to a ruptured plaque
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This ruptured plaque leads to the development of a blood clot within the coronary artery adjacent to the site of rupture. The blood clot is referred to as a thrombus. When there is sufficient volume the thrombus may obstruct the entire coronary artery and stop the blood flow to the heart muscle. Heart muscle cells begin to die within one hour without blood flow, and by six hours the process is nearly complete. Administration of a clot "dissolving" drug may lead to a breakup of the thrombus (which we call lysis) and restore patency to the artery (hence "thrombolysis") and thereby improve coronary blood flow, thus saving heart muscle. Thrombolytic therapy has led to a further reduction in mortality of approximately 20%, and when given very early to some patients by as much as 45%. In the past several years balloon angioplasty and coronary artery stents have been used in selected patients to break up the clot and to restore arterial patency.
The short term mortality of patients hospitalized with acute myocardial infarction before and after development of coronary care units and thrombolytic drugs
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Beta Blockers In the first half of the century, not only was the early mortality of acute myocardial infarction very high, but survivors of acute myocardial infarction were also at risk of re-infarction and sudden death after hospital discharge. In the early 1970's, a number of new pharmacologic agents were shown to be of benefit when given to survivors of acute myocardial infarction. As an example beta-adrenergic receptor blockers (beta blockers or adrenaline blockers) were shown to reduce mortality not only when given directly in the vein during acute myocardial infarction, but also when taken by mouth after discharge from the hospital. Currently, beta blockers are routinely prescribed to eligible patients following acute myocardial infarction. Commonly prescribed beta blockers would include propranolol (Inderal®), atenolol (Tenormin®) and metoprolol (LoPressor®).
Heart Failure Acute myocardial infarction, even when treated promptly, results in necrosis or death of previously contracting (squeezing) heart muscle. In many cases this decreases the ability of the heart to pump blood to the rest of the body. This may limit the blood supply to vital organs such as the brain, lungs, liver, and skeletal muscle resulting in the development of symptoms. Heart failure is present when the heart does not function sufficiently to meet the needs of the body. Deleterious remodeling of the heart from the dead heart muscle following a heart attack, such as aneurysm formation, may then occur, further interfering with the ability to pump blood.
In the 1990's drugs that block a specific enzyme have been shown to benefit patients with acute myocardial infarction. This medication dilates the blood vessels in the arms and legs and leads to decreased resistance to blood flow; which in turn allows the heart to propel blood forward to the rest of the body. The enzyme blocked is the angiotensin converting enzyme (ACE) and consequently this family of drugs is referred to as ACE inhibitors. Prolongation of life was first demonstrated with the use of beta blocks in acute myocardial infarction and, next, improved survival was demonstrated with the use of ACE inhibitors in patients who have weakened ability to pump blood. Currently both medicines are important agents in our therapeutic armamentarium.
Aspirin and Blood Platelets A blood platelet is a small colorless disc, which is about half the size of a red blood cell. They are normal components of blood. Platelets are involved in the coagulation of the blood and when activated they clump together, or aggregate, and form a blood clot. For example, they stop the bleeding of a cut finger. An important development in our knowledge was the recognition and the appreciation of the importance of activated aggregating platelets in the formation of a blood clot in the coronary artery leading to the development of acute myocardial infarction and other coronary events. Equally important was the demonstration that aspirin, previously known to prevent platelet aggregation, was effective in reducing deaths from acute myocardial infarction either when given alone or when given with a thrombolytic agent. Aspirin, the same medicine that you take for a headache, has been shown to reduce by half the incidence of heart attacks in healthy men. It is also effective in patients with angina pectoris (chest pain from a temporary insufficient blood supply to the heart) and for preventing recurrent heart attacks in patients with a history of previous heart attacks. It also helps prevent strokes. The benefits of this widely available and inexpensive drug are present regardless of age, gender or the presence of other risk factors.
High Blood Pressure In the 1960's high blood pressure was controlled in only 15% of patients and half of patients with high blood pressure were unaware of its presence. Two decades later, following a Herculean educational effort, the percentage of patients unaware of the presence of high blood pressure had decreased to 15% and the control of high blood pressure had more than tripled to 55%. This improvement in the recognition and treatment of high blood pressure has had a profound effect on the well being of patients with heart failure, the prevention of strokes, the development of coronary artery disease and heart attacks.
Cholesterol and the "statins" Another very important development during this past half century has been the introduction of pharmaceutical agents capable of markedly lowering blood cholesterol levels. Recognition of the importance of high cholesterol as a risk factor for coronary artery disease, primarily from the same Framingham project (referred to earlier) led to a national campaign to reduce the amount of cholesterol and saturated fat in the diet. This campaign was led by the NHLBI and the American Heart Association. As a result the number of Americans with high (>240mg%) cholesterol decreased from 34 to 19 percent during a two decade period. Our current goal is less than 200mg%. Diet therapy is limited, however, as only 20% of the blood cholesterol level is determined by dietary intake. The past decade has led to the development of a number of agents which reduce LDL cholesterol (low-density lipoprotein cholesterol - the "bad" cholesterol). Most (80%) of the cholesterol in our blood is manufactured in the liver and these agents block a liver enzyme - coenzyme A reductase - which leads to a dramatic fall in total cholesterol, and LDL cholesterol. The first of these agents was lovastatin or Mevacor, the second simvistatin or Zocor, and the third pravastatin or Pravachol. Hence they are referred to as "statins." Several very large randomized trials have demonstrated that the statins dramatically and safely lower LDL cholesterol, and consequently lead to reduction in deaths from coronary artery disease, and heart attacks in patient with established coronary heart disease as well as in patients with high cholesterol but without obvious heart disease. They also prevent progression of cholesterol build up in surgically implanted saphenous vein bypass grafts. By reducing the fat in cholesterol plaques the statins may stabilize the plaque and prevent plaque rupture and subsequent heart attacks. This may well be one of the most important pharmacologic advances this half century.
Blood fat and 'statins'
- Total Cholesterol
LDL cholesterol ("bad")
- HDL cholesterol ("good")
- Triglycerides
- 'Statins' Commonly Used for Treatment
- Mevacor
- Zocor
- Pravachol
- Lescol
- Lipitor
- Baycol
Bioengineers World War II led to enormous advances in mechanical and electrical engineering and electronics which have continued this half-century. These disciplines lend themselves to the treatment of cardiovascular problems characterized by disturbances in hydraulic or electrical function and, hence a new army of bioengineers developed. This led, in turn, to remarkable synergy and cooperation between industry, teaching hospitals and universities, and the practicing physician. The diagnosis of heart disease was facilitated first by invasive techniques such as coronary arteriography and more recently by noninvasive techniques such as cardiac ultrasound (echocardiography), magnetic resonance imaging (MRI), and fast computer tomographic (CT) scanning. The development and the growth of open-heart surgery for congenital and acquired heart disease is worthy of an article in its own right.
In 1944, Dr. Blalock performed the first "blue-baby operation." In 1953, the heart lung machine was invented and in 1960, the first successful aortic valve replacement was completed. Other notable advances include coronary angioplasty and stenting, cardiac pacemakers and internal defibrillators. In 1960, the first successful pacemaker implantation was reported. Internal cardiodefibrillators allow patients to have their own implanted defibrillator which delivers an internal electric heart shock to the heart when it recognizes the presence of ventricular fibrillation. Most of the world's implantable devices were and are being developed in Minnesota. These procedures are now used to treat over a million people in the United States each year and they have improved the quality and duration of life. None of these advances and developments were available in 1959. In fact most of them were not even conceivable to me at that time.
At the turn of the millennium, then, a number of developments might have allowed our 46-year-old theater director to have reached his four score years of life. First, the heart attack might have been prevented by modification of risk factors, especially cessation of cigarette smoking and alteration of his blood cholesterol level. Secondly, he would be transferred to a CCU where ventricular fibrillation would be treated immediately with an external defibrillator, and the recurrence of ventricular fibrillation prevented with lidocaine. Thirdly, the obstructed coronary artery would be approached more aggressively by thrombolysis, potent antiplatelet agents, angioplasty, coronary artery stenting, or bypass graft surgery. Lastly, his course following the heart attack would be improved with beta blockers, aspirin, and ACE inhibitors. None of these pharmacologic agents or procedures were available to me in 1959. This is remarkable progress in so short a time.
We're Not Finished But we have not yet come far enough. These rapid and effective developments have led to some complacency on the part of the public whose fear of heart disease has lessened. Today's adolescents are heavier, smoke more, and exercise less than their parents did at the same age. In addition, 260 billion dollars are spent annually for the treatment of heart disease, which will soon climb to be the leading cause of death in the entire world.
Annual deaths for various diseases in 1996.
(National Center for Health Statistics)
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There are reasons for our incomplete victory. First, we have inadequate knowledge - for example half of all patients with coronary artery disease do not have any of the established risk factors. Second, there is inadequate use of established strategies. For example, smoking continues to increase in teenage women and 45% of patients still have uncontrolled hypertension. Third, the established strategies are inadequate as many patients continue to die of cardiovascular disease in spite of our best efforts. Fourth, new epidemics of cardiovascular disease emerge such as atrial fibrillation and heart failure.
With continued effort, however, we can prevail and modern science can lead to a true victory against cardiovascular disease. This is likely to occur by identifying new risk factors for coronary artery disease such as high levels of homocysteine in the blood, insulin resistance in diabetes, and estrogen deficiency in postmenopausal women. New advances in cardiac imaging will likely be developed such as ways to find and identify atherosclerotic plaques that are likely to rupture. A molecular approach to vascular disease may lead to a limitation in coronary events. Finally, learning to manipulate genes, transgenic techniques, advances in molecular genetics and gene transfer allow us to be optimistic as we move into the 21st Century. Just this past year, it was demonstrated that vascular endothelial growth factor (VEGF) could promote new blood vessel growth. So, the war on cardiovascular disease continues its advance on many fronts from the molecule to the total population. Each of us can contribute to this effort by staying knowledgeable and actively supporting education and research.
References:
Braunwald E.: Shattuck Lecture NEJM 1997; 337:19, 1360-1369
Scandinavian Simvistatin Survival Study Group (45) Lancet 1994; 334: 1383-1389
Shepherd J., Cobbe S.M., Ford I. et. al. NEJM 1995; 333: 1301-1307
The Post Coronary Artery Bypass Graft Trial Investigators NEJM 1997; 336: 153-162
Kannel W.B., Dawber T.R. et. al. Annals of Internal Medicine 1961; 55:33-50
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