(Circulation. 1995;91:1304-1310.)
© 1995 American Heart Association, Inc.
Articles |
Cardiovascular Health at the Crossroads: Outlook for the 21st Century
Presented at the 67th Scientific Sessions of the American Heart Association November 4, 1994 Dallas, Texas
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Abstract |
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 Top Abstract IntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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There is nothing more vulnerable than entrenched success.
—George Romney
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Introduction |
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TopAbstractIntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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The recent breakthroughs in cardiovascular science and prevention of heart disease and stroke reported at the 67th Scientific Sessions in Dallas are the latest triumphs in a remarkable 50-year success story. Never has our light shone brighter. For example, in 1994, two of our colleagues shared a Nobel Prize for fundamental research that has direct cardiovascular applications.
Yet never in the history of the AHA have we been more anguished about the future. We fear that we may become like large corporations—too expensive to maintain and outcompeted by others who have a different goal or a different bottom line.
Fifty years ago, Franklin D. Roosevelt, one of the most powerful individuals of his time and a person of considerable personal wealth who did not lack access to health care, died of a massive cerebral hemorrhage related to uncontrolled hypertension. His condition, which was complicated by heart failure, had been known for at least 13 years, from the time he entered the White House, but was untreated in its early stages because asymptomatic hypertension was thought to be a benign condition and inadequately treated in its later stages because effective hypertensive drugs had not yet been discovered.1
In the 50 years since Franklin Roosevelt's death we have achieved
some
remarkable victories in the war against heart disease and stroke, but
we have not yet won the war. Our victories include a 49% reduction in
deaths caused by coronary heart disease (CHD) and a remarkable 58%
reduction in deaths due to stroke since 1970 (Fig
1
).2 These triumphs can be attributed to
the efforts of talented and dedicated scientists and enormous
expenditures of public and private funds in the direct support of
research and health promotion and disease prevention.
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Room for Improvement |
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TopAbstractIntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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Because of the work of scientists and researchers, we can assess with considerable precision the risk for cardiovascular disease in both individuals and populations. We have achieved great success in the secondary prevention of cardiovascular disease and are beginning to develop effective strategies for surveillance of community health. Risk assessment and prevention of cardiovascular disease are more effective than risk assessment and prevention of other diseases, except some infectious diseases for which vaccines are available. It is estimated that by modifying the major risk factors for development of cardiovascular disease in the population at large, it is possible to accelerate the rate of decline in CHD mortality to about 6% per year, with an overall reduction of approximately 50% in 10 years.3 This is approximately twice the current rate of decline in heart disease mortality.
However, there is disturbing evidence that this is not happening. All
segments of society are not sharing equally in the benefits of
scientific progress. While mortality trends from CHD and stroke are
similar for men and women, whites and African-Americans, the slope of
the decline in CHD deaths has been steeper in the past decade in men
than in women and in whites than in African-Americans (Fig
2).3 African-Americans have a more marked
reduction in death rates for stroke than whites, but death rates remain
twice as high in African-Americans as in whites (Fig
3).3
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In comparison with other industrialized nations, despite an impressive
59% decrease in CHD mortality rates since 1960, the United States
continues to have substantially higher rates of cardiac death than many
of the major European and Asian nations. The United States currently
ranks 18th of 33 industrialized countries in CHD mortality in men (Fig
4) and 14th of 33 in women (Fig
5).3
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Why are we failing to achieve our potential in prevention of cardiovascular disease and stroke? There is no simple, straightforward answer to that question. It is clear, however, that health practices known to be effective in preventing heart disease and stroke are not being followed by large segments of society. For example, current estimates suggest that the prevalence of smoking is increasing in some important population groups, including African-Americans, women, and youth. Aggressive advertising by the tobacco industry likely plays a role in this. Furthermore, recommendations for heart-healthy diets are often ignored by both consumers and the food and restaurant industries. It is clear that excessive calorie consumption is fostered by any number of societal influences, from one's parents to one's credit card company. In addition, about 60% of the adult population is considered sedentary, reporting irregular or no leisure time physical activity.4 The problem of obesity and sedentary lifestyle has become so great among children and youth that the US Surgeon General recently commissioned a scientific report on the health benefits of physical activity. It is expected that the impact of this report will be similar to the landmark report on smoking hazards of 1964, which set the tone for the major reduction in smoking seen over the past three decades.
The combination of imprudent diet and sedentary lifestyle has resulted
in an alarming increase in the prevalence of overweight, from 25% in
1980 to 33% in 1990 (Fig 6).5 6 Mean
body
weight of men and women in the United States increased by 3.6 kg in the
past decade. Weight gain was dramatic in all races and both sexes. The
overweight epidemic is particularly alarming from a public health
perspective, because there is no satisfactory way to achieve long-term
weight reduction on a population-wide basis. Voluntary weight loss
efforts cost Americans between $30 and $50 billion annually, are
ultimately ineffective because most weight lost is eventually regained,
and may be harmful.7 8 This is yet another area where
prevention is far more effective than treatment and where basic
scientific knowledge is lacking. We know little about the biology of
obesity, including the roles of brain neurotransmitters, gut satiety
hormones, cellular nutrient disposal, and determinants of energy
expenditures. Only fundamental research in this critical area can lead
to the development of coherent strategies for prevention and
treatment.
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To achieve maximal health benefits, we must intervene early and prevent behaviors that foster development of risk factors for cardiovascular disease, which eventually leads to clinical illness and acute events such as heart attack, stroke, disability, and premature death.3 Effective means of preventing risky health behaviors are elusive, and development of improved population-wide preventive strategies is a priority for research, as urgent and compelling as finding a new gene or a new treatment for established cardiovascular disease.
The AHA is in the forefront of organizations seeking to reverse these
alarming trends in risky health behaviors through vigorous public
policy and community program efforts. For example, to discourage
cigarette smoking, a major modifiable risk factor for cardiovascular
disease and stroke, the AHA supports 
An increase in
tobacco excise taxes A ban on tobacco advertising
and promotion, particularly that targeted to women, children, and
minority populations A ban on smoking in
public places FDA regulation of tobacco,
including the manufacture, sale, distribution, labeling, and promotion
of tobacco products
To this end, the AHA has promoted a citizens' petition that asks the government to regulate tobacco products to protect the public, especially children, from the dangers of tobacco use.
The AHA is also leading the way in providing consumers with the information they need to follow a prudent diet. The association actively participates in educating the public about nutrition, responding directly to more than 186 000 queries each year about diet and heart disease and encouraging other organizations to develop nutrition education programs. The AHA also strongly supports food labeling and the establishment of standards for food advertising consistent with the accurate and truthful labeling of food products.
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A Success Story |
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TopAbstractIntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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We have come far in the prevention and treatment of cardiovascular diseases in the past few decades. In 1976 Comroe and Dripps9 published a comprehensive study in which they determined the top 10 clinical advances in patient care since the early 1940s. Comroe and Dripps first surveyed clinicians to select the most important clinical advances, then met with consultants to define the bodies of knowledge and identify the key publications that were essential for each clinical advance. They reported that 41% of the research judged to be essential for later major clinical advances had no clinically oriented goals (Table 1
); knowledge was
sought for the sake of knowledge. Their critical analysis
demonstrated the importance of federal support for creative scientists,
without regard to the immediate relation of their studies to specific
human diseases.
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Hypertension is one field where unfettered basic research and serendipity have led to huge clinical breakthroughs and where the availability of a class of potent drugs with a defined mechanism of action has provided a major tool for unraveling a number of important and unexpected biological processes. Like the origins of man, this adventure began with a serpent. Bothrops jararaca, the Brazilian arrowhead viper, produces a venom that causes generalized vasodilation, hypotension, and hemorrhage. Ferreira10 first demonstrated in 1965 that an extract of this snake venom potentiated the action of bradykinin in vitro by inhibiting its enzymatic degradation. Other groups showed that the snake venom extract also inhibited angiotensin-converting enzyme (ACE), thus blocking the formation of the pressor peptide angiotensin II.11 Ferreira, working first in Brazil and then at Brookhaven National Laboratory, and Miguel Ondetti, working at the Squibb Institute for Medical Research, independently isolated, sequenced, and synthesized a family of ACE-inhibiting and bradykinin-potentiating peptides from Bothrops venom.12-14 One of these, the nine-membered peptide teprotide (SQ 20,881) lowered blood pressure in animal models of hypertension and in hypertensive humans.15 16 The finding that this ACE inhibitor had a potent antihypertensive effect had great impact on hypertension research, shattering the central dogma that the renin-angiotensin system is of minor importance in blood pressure regulation. Teprotide was inactive when given by mouth and therefore not useful in the chronic treatment of hypertension. Accordingly, it was discontinued as a clinical candidate because of lack of commercial interest.17 The research team that had worked on ACE-inhibitor development had been partially dispersed and reassigned to other projects when on March 13, 1974, discussion of a paper describing a potent new inhibitor of carboxypeptidase A, an enzyme that shares catalytic properties with ACE,18 suggested a novel approach to the ACE inhibitor problem. Using this information, SQ 14,225, or captopril, was synthesized and shown to be an orally active ACE inhibitor within a year.19 This is clearly one of the best examples of rational drug development in cardiovascular medicine.
Since that time ACE inhibitors have become one of the most widely
prescribed classes of antihypertensive drugs. ACE inhibitors also have
important beneficial effects that are unrelated to their
antihypertensive actions (Table 2). They reduce
morbidity and mortality and prevent the subsequent development of heart
failure in patients with asymptomatic left ventricular dysfunction
after myocardial infarction20-22 and also reduce mortality
in patients with chronic congestive heart
failure.23 24
ACE inhibitor therapy has recently become part of the standard
treatment regimen for heart failure.25 ACE inhibitors
reduce myocardial and vascular remodeling in the setting of
hypertension to a greater extent than other agents that have comparable
antihypertensive and vasodilator efficacy, suggesting that they have
direct growth-inhibiting effects on the heart and blood vessels. They
also retard progression of diabetic nephropathy26 27
and
vascular pathology of collagen vascular diseases28 in a
manner disproportionate to their antihypertensive effects. When
administered early in life, the ACE inhibitors can cure hypertension
and improve cognitive function in rodent models.29-31 It is
safe to say that their potential uses for human diseases are just
beginning to be explored.
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Perhaps more important than the therapeutic uses of the ACE inhibitors is their immense value as pharmacologic tools to define the role of the tissue renin-angiotensin system in various diseases. Knowledge of the biological importance of ACE, derived in substantial part from use of the ACE inhibitors in both laboratory-based and clinical studies, gave added impetus to the cloning of the ACE gene.32 The ACE gene is linked to blood pressure regulation in the rat.33 34 In a recent, innovative series of experiments the targeted gene transfer technique, homologous recombination, was used to create mice that expressed different copy numbers of the ACE gene.35 These studies demonstrated for the first time the effects of altering doses of the ACE gene on blood pressure, cardiovascular structure and function, and conceivably on noncardiovascular systems.36
Recently a deletion-(D) insertion (I) polymorphism of the human ACE gene with a single base mutation in intron 16 has been identified.37 This mutation appears to affect cardiac growth and development and the level of serum ACE activity but not blood pressure.38 The genotype (DD) with the highest ACE levels is strongly associated with left ventricular hypertrophy and increased risk of myocardial infarction and dilated and hypertrophic cardiomyopathy.39 40 The mechanism of these effects is a popular topic for investigation. More than 40 presentations at the 67th Scientific Sessions focused on ACE inhibitors and the ACE gene, particularly in reference to cardiac hypertrophy and heart failure.
Thus, the product of a 30-year line of investigation— that originated with fundamental pharmacologic studies of snake venom extracts and was fueled by the energy and creativity of scientists working in hypertension research and the innovation, resources, and tenacity of the pharmaceutical industry—is now prolonging the lives of thousands with hypertension, heart attack, and heart failure and promises to help unlock the secrets of the molecular basis of these disorders.
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Outlook for the Future |
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TopAbstractIntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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This wonderful success story required the investment of enormous amounts of capital and manpower. Are success stories of this kind likely to be repeated today? We would like to think so, but the climate for biomedical research and for cardiovascular research in particular is far less favorable than in 1965, when the ACE inhibitor saga began. In 1964 the National Heart, Lung, and Blood Institute (NHLBI) reviewed 782 research project grant applications and funded 378, for a "success rate" of 48.3% (Table 3
). In 1993, 3073
applications were reviewed and 673 were funded, for a success rate of
21.9%. In the last decade alone the number of grants funded by the
NHLBI has decreased dramatically, from 966 in 1987 to 673 in 1993, and
the success rate has declined from a high of 34.8% in 1984 to a low of
21.9% in 1993. In an environment where the probability of funding is
so small, successful applications for funding by the National
Institutes of Health (NIH) require substantial technical and
experimental justification and benefit greatly from extensive
preliminary results, so newly independent researchers and researchers
proposing truly novel projects are at a disadvantage in the
competition. In other words, the NIH seldom funds discovery or truly
new ventures.
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In response to these forbidding odds and the attraction of more secure
careers elsewhere, the number of young scientists (aged 36 years and
younger) who apply for independent NIH grants (RO1s) has plummeted by
more than 50% in the last 8 years (Fig
7).41 42 The actual number of
applications
submitted by young scientists to the NIH was 3040 in 1985 and 1389 in
1993; 1002 awards were given in 1985, for a success rate of 33%, and
302 in 1993, for a success rate of 21.7%. The consequences of this
"brain drain" to other disciplines can scarcely be overstated.
The National Research Council panel that uncovered these disturbing and
unanticipated findings recommended (1) that the NIH increase the amount
of R29 First Independent Research Support and Transition (FIRST) awards
from $70 000 to $125 000 per year, thereby increasing the total amount
of the 5-year award from $350 000 to $625 000, and (2) that the NIH
create a special program for young biologists, including a fixed pool
of money earmarked for R29 grants and a study section devoted to
reviewing R29 applications.41 No mention was made of a
major increase in the NIH budget, a solution deemed impossible in the
current political climate. I believe that this interpretation is
unacceptable.
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There is a clear and urgent need for major increases in our investment
in biomedical research. As AHA volunteers and champions of
cardiovascular health, we have a responsibility to insist that the
federal government provide a more satisfactory solution for the
pandemic of cardiovascular disease in our nation. The total cost of
cardiovascular disease, including stroke, in the United States in 1994
was $128 billion (Fig 8).43 This includes
major expenditures for hospital and nursing home services,
physician/nurse services, and lost productivity because of disability.
These enormous costs dwarf the $855 million budget for research in
heart disease and stroke. Only 0.58% of the expenditures for
cardiovascular health care are being invested in research and
development, an unacceptable ratio for any forward-looking enterprise.
We are jeopardizing our future by failing to support the fundamental
discovery process that paves the way to disease prevention and cure.
This means discovery not only in molecular biology but in social
science research and clinical trials as well.
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President Clinton has expressed a commitment to sustaining America's world leadership in science, mathematics, and engineering in a recent report.44 The report outlines specific goals for accomplishing that purpose but contains little in the way of concrete plans for implementation. We urge you to join your fellow AHA volunteers in communicating to the President the urgent need for major increases in NIH support of cardiovascular disease and stroke research. This is an opportune time for such communications because the President is now preparing the fiscal year 1996 budget for submission to Congress. To achieve our mission, we must be advocates for our own cause. These are difficult times for cardiovascular health; by remaining passive, we risk losing the momentum gathered over the past 50 years. We must act now. Great things sometimes emerge from crisis. The poignant words of Abraham Lincoln also apply to us if we are to further our quest into the 21st century:
The dogmas of the quiet past are inadequate for the stormy present. The occasion is piled high with difficulty and we must rise with the occasion. As our case is new, so we must think anew and act anew.
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Footnotes |
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Requests for reprints should be sent to the American Heart Association, Office of Scientific Affairs, 7272 Greenville Avenue, Dallas, TX 75231-4596.
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References |
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TopAbstractIntroductionRoom for Improvement A Success Story Outlook for the Future...References |
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