Prognostic/diagnostic testing and a raft of new drug targets from
genomics promise to transform cardiovascular medicine.
Cardiovascular diseases cause more than 15 million deaths in the world
each year, according to the World Health Organization (WHO; Geneva). They
account for 50% of all deaths in several developed countries, and more than
50% in Africa and Western and Southeast Asia. They are also the major cause
of death in adults. In addition, many cardiovascular incidents are not necessarily
fatal, but may impair the ability to lead a normal daily life, resulting in
enormous healthcare costs (estimated at $50−150 billion per year) to
society.
However, despite the huge death and disability tolls, there have been significant
declines in total cardiovascular disease mortality over the past few decades,
due to improved acute and chronic medications and surgical procedures, and
lifestyle and diet changes. Because of the incidence and mortality rates,
cardiovascular diseases are the subject of enormous investment by the biotechnology
and pharmaceutical industries.
Historical perspective In considering the evolution of drug discovery and development in the cardiovascular
area, it is important to realize that the term "cardiovascular disease"
refers to a number of conditions, which WHO classifies into 11 groupings for
the purposes of assembling mortality data. These groupings include hypertension
with or without renal disease, stroke, atherosclerosis, other diseases of
arteries, arterioles, and capillaries, and diseases of veins and lymphatics.
In addition, there are six heart disease groups: rheumatic fever/rheumatic
heart disease, hypertensive heart disease, heart and renal disease, ischemic
heart disease, diseases of pulmonary circulation, and other forms of heart
disease1.
Medicines did not appear for these conditions at the same time, although
herb medicines have been used since antiquity. Perhaps the best known of these
in use today is digitalis, also known as digoxin and digitoxin. It is derived
from the foxglove plant and has been described in medical literature for over
200 years. It is used to treat congestive heart failure, some kinds of congenital
heart defects, and is also used to treat certain arrhythmias, as it functions
to strengthen the contraction of the heart muscle, slowing the heart rate
and promoting the elimination of fluid from body tissues. However, it is not
particularly effective in treating coronary artery disease (CAD), which is
the leading cause of death in the US. Until 30 years ago, there were no drugs
available to treat CAD. However, the concerted efforts of clinicians and the
biopharmaceutical industry have since then produced thrombolytic agents, beta-blockers,
parental nitroglycerine, heparin, aspirin, 2b-3a inhibitors, calcium blockers,
and a variety of anti-platelet agents, all of which gives doctors a potent
arsenal with which to treat cardiovascular diseases.
Nevertheless, medication alone cannot overcome the problems posed by cardiovascular
diseases as a whole, and preventative lifestyle changes have emerged as leading
contributors to the decline of mortality and disability rates now being seen.
For example, the recently completed international Coronary Primary Prevention
Trial (CPPT) was a landmark 10-year study that showed conclusively for the
first time that reducing low density lipoprotein (LDL) cholesterol and total
blood cholesterol can reduce the incidence of coronary heart disease and heart
attacks in men at high risk because of significant amounts of plasma cholesterol.
This and several other studies confirmed the link between lifestyle, diet,
and the chances of having or succumbing to cardiovascular disease, and have
helped direct some of the development of new drugs toward cholesterol-lowering
modes of action and related mechanisms.
Current state Even though the risk factors that increase the chances of cardiovascular
disease are well known (cholesterol and other lipids, cigarette and tobacco
smoke, diabetes mellitus, high blood pressure, obesity, physical inactivity)2 and there is a wide variety of medications to treat or ameliorate
conditions that arise, the number of surgical procedures performed in the
US alone in response to cardiovascular disease is simply staggering.
In 1996 alone, 1.2 million diagnostic cardiac catheterizations, 600,000
coronary artery bypass graft procedures, 150,000 cardiac pacemaker procedures,
450,000 percutaneous transluminal coronary angioplasty procedures, 130,000
endarterectomy procedures, and 80,000 heart valve procedures were performed2. The numbers change in varying degrees over time for each of these
procedures, and most are still increasing, although at lower rates than in
the past.
These types of surgeries can be very expensive, and the associated costs
due to hospitalizations are also enormous, spurring the development of preventative
medications and post-procedure drugs to help with the recovery process. Table 1 is a summary of drugs in development for heart disease
as a whole. There are multiple approaches under development, ranging from
angioplasty gene therapies to monoclonal antibodies to coagulation modulators.
In addition, there are efforts by several companies to develop better imaging
agents for the detection and monitoring of cardiovascular disease progression.
As previously mentioned, cholesterol-lowering drugs are at the forefront
of development, although the American Heart Association recommends that "Drug
therapy can be considered for patients who, in spite of maximal dietary therapy,
regular physical activity and weight loss, need further treatment for elevated
blood cholesterol levels."2
Here, the drugs of choice for elevated LDL cholesterol are the bile acid
sequestrants—cholestyramine and colestipol—and the vitamin nicotinic
acid (niacin), which have been shown to reduce the risk for coronary heart
disease. There are associated side effects; however, they are not considered
serious. Another class of drugs is the 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors, such as lovastatin, pravastatin, and simvastatin.
So-called statin drugs are very effective for lowering LDL cholesterol levels
and have few immediate short-term side effects. They function by interfering
with key events in the synthesis of cholesterol. Other drugs include gemfibrozil,
clofibrate, and probucol, which are effective to varying degrees for lowering
elevated triglyceride levels, and combination therapy for patients who do
not respond adequately to single drug therapy is increasingly being adopted.
Finally, at present, a constant stream of new data support some basic truths
about risk factors and the importance of effective prevention. One recent
report from Australia shows how increased blood pressure is directly responsible
for more than 50% of stroke deaths and for about 25% of deaths from coronary
heart disease in Eastern Asia3. The same study suggests how
even modest reductions in blood pressure could have a very significant impact
on the number of deaths.
Industry challenges Even though there is now significant experience with the various drugs
used to treat cardiovascular diseases, clinicians and the industry are still
challenged by some of the findings. For example, while thrombolytic drugs
(e.g., streptokinase and accelerated tissue plasminogen activator [tPA]) have
been successful since being introduced as the standard management for myocardial
infarction 13 years ago, only about 50% of patients achieve unrestricted flow
within 90 minutes of administration. This has led to a search for better drugs,
including genetically modified tPA and an older agent, staphylokinase4. These efforts highlight the need to balance the discovery of new
drugs and the incremental improvement of already-existing ones. Industry and
clinicians alike are constantly examining the already-existing collection
of available drugs for modified applications or combinations.
Since it is essentially pharmaceutical companies that have developed or
market all the major cardiovascular disease drugs, another challenge for the
industry is whether there are any opportunities for young biotech companies
to be involved in the field. Of course, this question is relevant to all disease
areas. The answer lies in the fact that competition between pharma and biotech
companies is not a bad thing—and more importantly, many of the advances
that will lead to next-generation medicines are increasingly being discovered
and developed through their early stages by biotechs. During the later stages
of clinical trials, when increased expenses necessitate partnerships, biotechs
are then likely to partner with pharmaceutical companies. Thus, the fact that
pharma dominates the commercial exploitation of medicines in this area should
not detract biotech companies from entry. There will always be a need for
better drugs that are effective in a broader population range than currently
available, and biotech companies are ideally suited to discover and develop
these.
Future directions Cardiovascular medicine has had to move with the times, and in addition
to improved surgical procedures and drugs, it is beginning to make use of
the flood of genomic information emerging from tissue-specific sequencing
projects. This has ushered in the field of molecular cardiovascular medicine,
which is based on databases of genomic information from cardiovascular tissue.
For example, a recent report analyzed more than 76,000 expressed sequence
tags (ESTs) from 13 different cDNA libraries of the cardiovascular system5. Northern analysis of the data identified widely expressed genes,
and also ones that were tissue- or development-stage specific.
The future will no doubt see these efforts applied to healthy and diseased
cardiovascular tissue from cross-sections of populations, and is likely to
result in improved understanding of molecular contributors to these diseases.
This, in turn, will be of enormous assistance in the design of new drugs.
In addition, the correlation between gene polymorphisms and specific cardiovascular
diseases is also likely to become increasingly important. A recent report
showed how the Cys242Thr polymorphism of the p22phox gene was related
to angiographic coronary artery disease and endothelial function. The gene
is thought to play a critical role in the generation of superoxide anions
in the vessel wall, which may help control vascular oxidant stress, which
in turn impairs endothelial function which arises during CAD. Although the
Cys242Thr polymorphism was reported to confer a protective effect on CAD risk
in a Japanese study population, in a study of US patients, it did not appear
to confer protection from endothelial dysfunction or CAD6. This
shows the importance of understanding gene variability and the multifactorial
nature of these diseases, and helps prevent making generalizations across
populations. In addition, it helps focus on specific molecular targets on
the basis of these variations, which is the essence of the burgeoning field
of pharmacogenomics (see Pharmacogenomics, pp. 40−42
).
Another future development is the increased identification and use of molecular
markers of cardiovascular disease for early diagnosis and prevention. For
example, cardiac troponins are selectively released by damaged myocardiocytes.
The specificity of this event is high enough that it has resulted in improvements
in the diagnosis of acute cardiac ischemic disorders, and has also enabled
clinicians to predict more reliably the risk and outcome scenarios for patients7.
The future will also see the identification of more new potential molecular
targets for cardiovascular disease. For example, a recent report describes
the correlation between scavenger receptor BI, which is a cell surface receptor
for selective high-density lipoprotein (HDL) cholesterol uptake in the liver
and in other tissues, and the regulation of HDL metabolism, and protection
against atherosclerosis ini animal models8 Should these results
also apply to humans, this will become another new target for drug development
in the future with major potential benefits.
In addition, our understanding of the correlations between cardiovascular
disease and patients in other high-risk groups, such as those receiving renal
transplants, will continue to be refined. These patients often have major
cardiovascular disease complications and left ventricle hypertrophy, which
correlates with adverse prognosis. A recent report shows how certain types
of immunosupression regimens received by these patients may correlate with
increasing risk of cardiovascular disease9. These are significant
clinical correlations whose underlaying reasons are still some time away but
which will continue to be addressed and refined.
Finally, the future will see appropriate emphasis being placed on a third
component of cardiovascular disease propensity, in addition to the traditional
two, which are genetics and the environment. The third component is the prenatal
environment and so-called prenatal "programming", with increasing
research being devoted to it. For example, there are suggestions that the
development of the renin-angiotensin system and its importance in renal development
may be linked to hypertension and thus ultimately cardiovascular disease10. Although still in its infancy, this line of thought and work is
likely to yield significant insights into the full range of factors that affect
the development and progression of heart disease.
Conclusions Cardiovascular disease's effects on world health and the economics
of healthcare are devastating. Nevertheless, a vast array of drugs, improved
surgical procedures, early diagnosis and prevention, and lifestyle and diet
changes are helping to control it to a considerable extent. In the near future,
pharmacogenomic capabilities will help us understand diseases in terms of
specific genetic contributors, and spur the development of effective new drugs
that will help bring this plague under control.
Reprinted from Nature Biotechnology 17, 930−931
(1999).
World Health Organization. World Health Statistics Quarterly46, (1993) & World Health Statistics Quarterly48, (1995); Eur. Heart J.17, 1318-1328 (1996). | ISI |
