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The societal context of coronary artery disease
O. Færgeman
Department of Internal Medicine and Cardiology, Faculty of Health Sciences, Aarhus University Hospital, AAS, Tage Hansens Gade 2, DK-8000 Aarhus C, Denmark
Corresponding author. Tel: +45 8949 7600; fax: +45 8949 7619. E-mail address: Ole.Faergeman{at}aas.auh.dk
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Abstract
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Our success in reducing risk for coronary heart disease events
with statin therapy should not serve to deflect our attention
from our understanding of the nature of atherogenesis and what
that implies about efforts to eradicate atherosclerosis. The
recently reported Pravastatin or Atorvastatin Evaluation and
Infection Therapy (PROVE-IT) trial showed that a statin regimen
that lowered low-density lipoprotein cholesterol (LDL-C) more
effectively was associated with significantly better prevention
of cardiovascular events than a regimen that was thought to
have greater pleiotropic effects. On the one hand, such findings
should serve to refocus attention on the primary clinical goal
of lowering LDL-C in our at-risk patients; on the other, it
should refocus attention on the conditions that make atherosclerosis
so prevalent in modern society. From the point of view of eradicating
or markedly reducing prevalence of atherosclerosis, political
efforts are required to enhance education and to fashion changes
in policies regulating the agriculture, food, and tobacco industries.
The alternative is to fully embrace the medicalization of society,
whereby we focus on efforts in biotechnology and industrialized
medicine to address the consequences of diseases promoted by
industrialization and urbanization.
Key Words: Coronary heart disease • Atherogenesis • Low-density lipoprotein • Agriculture • Biotechnology • Industrialization
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Introduction
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The statins are among the most useful drugs in modern clinical
medicine. In addition to effectively preventing coronary heart
disease (CHD) events in some at-risk individuals, they have
been used to confirm the dynamic nature of atherosclerosis (for
example, by showing the potential for halting or reversing the
disease process), and their use has largely settled the issue
of whether cholesterol is causative in atherogenesis. However,
our recent discussions of the benefits of statin drugs have
deflected our attention from two basic elements of our understanding
of atherosclerosis. One is that we do understand the process
of atherogenesis quite well, although our view of what we know
well is often obscured by enthusiasm for novel research into
what we know less well. The second is that the disease is, in
principle, eradicable. The sobering conclusion to be drawn from
considering statins within this context is that while they are
effective in preventing disease events in many individuals,
they have little utility in terms of eradicating atherosclerotic
disease even if complete medicalization of society could be
achieved.
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Coronary artery disease: pathophysiology
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A myriad of complexities notwithstanding, atherogenesis is understood
to consist of a gradual (decades-long) deposition in the blood
vessel walls of cholesterol, derived especially from the low-density
lipoproteins (LDL) in plasma.
1 Lowering of low-density lipoprotein
cholesterol (LDL-C) by diet, drugs, or surgery is rapidly followed
(in months) by a reduction in risk of clinical disease, such
as myocardial infarction (MI). We seem, nevertheless, to be
confused by the striking evidence of rapid salutary effects
against a slowly working agent of disease like LDL-C. Thus,
many of us have sought to explain the rapid reduction in risk
demonstrated in the clinical endpoint statin trials by invoking
pleiotropic effects of statins—effects other than lowering
of plasma LDL, including improvement in endothelial function,
antioxidant effects, anti-inflammatory effects, and antiproliferative
effects.
2 The recently reported Pravastatin or Atorvastatin
Evaluation and Infection Therapy (PROVE-IT) trial should lead
to a simpler understanding of atherogenesis, one that could
reinforce the importance of appropriate treatment goals in reducing
CHD risk—i.e. lowering of LDL-C—and also heighten
awareness of steps that must be taken to truly combat the epidemic
of atherosclerosis. This trial was performed to compare the
ability of a less effective statin (pravastatin), weaker in
its LDL-C-lowering effects, with that of a more powerful statin
(atorvastatin) to reduce rates of death or major cardiovascular
events in patients who had recently been hospitalized with acute
coronary syndromes.
3 The hypothesis was that the greater beneficial
pleiotropic (anti-inflammatory) effects of pravastatin would
at least negate the greater LDL-C reduction achieved with atorvastatin,
the more powerful statin. However, the results of PROVE demonstrated
a rapidly emerging superiority of the drug that lowered LDL-C
the most. Among 4162 patients followed for 18–36 months
(mean, 24 months), median LDL-C levels reached during treatment
were 95 mg/dL in patients receiving pravastatin 40 mg
vs. 62 mg/dL in those receiving atorvastatin 80 mg
(
P<0.001); at 2 years, rates of the primary end-point (any-cause
mortality, MI, documented unstable angina requiring hospitalization,
revascularization, or stroke) were 26.3% in the pravastatin
group vs. 22.4% in the atorvastatin group, a 16% reduction in
hazard ratio favouring atorvastatin (
P=0.005) (
Figure 1). The
fourteenth-century thinker William of Occam proposed the principle,
known as Occam's razor, that when confronted with rival theories,
we should choose the simplest one that fits the facts. The result
of PROVE-IT is consistent with the simpler understanding of
atherogenesis, supporting the view that LDL-C is causative in
the disease process and that reducing LDL-C inhibits the disease.
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Figure 1 Median LDL-C during treatment with pravastatin 40 mg or atorvastatin 80 mg (left) and Kaplan–Meier estimate of probability of study endpoint (death, major cardiovascular event) in the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial. (Reproduced with permission from Cannon et al.3)
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Similarly, C-reactive protein (CRP), a marker of inflammation,
has recently received much attention as a marker of cardiovascular
risk that has been proposed to be more accurate than LDL-C in
risk discrimination.
4 There is no question that there are elevated
levels of CRP in atherosclerosis, as well as in infectious diseases,
cancer, and several immunological diseases; the issue that has
gained attention is how well it compares with other risk factors
in prediction of risk and treatment-related risk reduction.
The largest analysis to date of the ability of CRP to predict
CHD events is a recently reported analysis from the prospective
Reykjavik Study,
5 in which measurements were obtained at baseline
from up to 2459 patients who had a non-fatal MI or died of CHD
during the study as well as from 3969 control subjects. Follow-up
was 17.5 years in cases and 20.6 years in controls; measurement
of CRP in paired samples from 379 participants taken an average
of 12 years apart showed a within-person correlation coefficient
of 0.59 for CRP values. After adjustment for age, gender, period,
CHD risk factors, and socioeconomic status, the odds ratio for
a CHD event (non-fatal MI or CHD death) among patients in the
top third versus the bottom third of control baseline CRP values
was 1.45, somewhat higher than that observed for another inflammatory
marker, von Willebrand factor (1.11), but lower than the odds
ratios for such established risk factors as elevated total cholesterol
(2.38), current smoking (vs. never smoking, 1.75), and elevated
systolic blood pressure (1.50) (
Figure 2). The areas under the
receiver-operating-characteristic curves indicated CRP measurements
that provided little additional predictive value over that already
provided by the established risk factors. As stated by the investigators,
these findings indicate that CRP is a relatively moderate predictor
of CHD and that recommendations regarding its use in this regard
may need to be reviewed.
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Figure 2 Odds ratio for CHD event among patients (non-fatal myocardial infarction or CHD death) and controls (no CHD events) in an analysis in the Reykjavik Study population. Comparisons are between patients and controls, with values in the top third and those in the bottom third of the distribution of values for controls, except for smoking vs. non-smoking comparison. Shown are odds ratios with 95% confidence interval (CI) (horizontal lines) and (right) area under the receiver-operating-characteristic (ROC) curve with 95% CI. See text. (Reproduced with permission from Danesh et al.5)
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Thus, in risk assessment as well as in risk reduction, for the
time being at least, we can do with a fairly simple understanding
based on classical risk factors, including LDL-C.
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Eradicability of coronary artery disease
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Atherosclerotic disease is, in principle, eradicable. Atherosclerosis
has been with us for at least 3500 years, but it appears to
have been rare until industrialization and use of fossil fuels
enabled farmers to raise huge amounts of livestock for meat
and milk and permitted the population of industrialized countries
to become increasingly sedentary. The onset of industrialization
marks the first time in human history that several conditions
conducive to the disease, including the mass cultivation of
tobacco, were present at the same time, and under these conditions
it did not take long before atherosclerotic diseases were common.
1 There are few data available on the beginning of the epidemic,
yet a picture of its growth can be sketched from coded data
from death certificates available in the United States since
around 1900
6 and from data on a large Dutch kindred with familial
hypercholesterolaemia (FH) available from 1850
7 (
Figure 3).
The US data show a rapid rise in CHD mortality rate through
the early part of the twentieth century, peaking at around 1960,
when efforts to improve lifestyle and to devise treatments for
atherosclerosis were initiated. The Dutch data, obtained by
calculating standardized mortality rates for individuals with
FH and using excellent public registries indicating dates of
birth and death, show that increased mortality rates were already
evident in the later decades of the nineteenth century, coincident
with onset and growth of industrialization; mortality peaked
along with that in the general US population around 1960. These
data suggest that individuals with FH, who are more susceptible
to early and aggressive atherosclerotic disease due to mutation
of the LDL receptor gene, served much as miners' canaries, dying
off earlier and at greater rates as industrialization and urbanization
wrought their pro-atherogenic changes on society.
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Figure 3 Mortality from coronary heart disease in a Dutch FH kindred, calculated from standardized mortality rates (SMR) and public registries and in the general US population, based in part on coded data from death certificates indicating the growth of the atherosclerosis epidemic. (Dutch FH data are from Sijbrands et al.7 US data are from Stallones.6)
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The onset and growth of the atherosclerosis epidemic were much
too rapid to be the product of changes in the human genome.
Genetic variation typically determines individual susceptibility
to disease within a population, not whether the disease is rare
or common. Prevalence is a composite function of genetic variation
and environment. As an example, consider the distributions of
serum cholesterol levels in Japan, where CHD was rare, and in
Finland, where CHD was common, as shown in
Figure 4.
8 A theoretical
genetic variation conferring relatively high CHD risk via higher
cholesterol level in the Japanese population would yield about
the same overall risk as a genetic variation associated with
low cholesterol level and low risk in the Finnish population.
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Figure 4 Genetic variation determines individual susceptibility to disease within the population, not disease prevalence. Population distribution of serum cholesterol values in Japan, where CHD was rare, and Finland, where CHD was common. A theoretical genetic variation (GV2) in the Japanese population that confers higher cholesterol levels and increased CHD risk would be associated with cholesterol levels and risk similar to those conferred by a theoretical genetic variant (GV1), resulting in reduced cholesterol levels in the Finnish population. (Adapted with permission from Rose.8)
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How can we shift population distributions of cholesterol levels?
In the setting of clinical trials, at least, we manage to do
this by providing statin treatment.
Figure 5 shows the shift
in LDL-C levels from baseline after 12 months of treatment with
simvastatin in the 4S study, which was reported 10 years ago
9;
newer, more powerful statins such as rosuvastatin and atorvastatin
would produce even greater shifts in LDL-C distributions. The
late Geoffrey Rose noted two decades ago, however, that disease
prevention directed at individuals can be expected to have only
a minor effect on population health.
9,10 Lifestyle changes can
protect those individuals who adopt them, and increasingly effective
medical treatments continue to emerge from medical and biotechnical
research, but neither of these approaches to prevention in individuals
can remove the societal conditions responsible for epidemic
atherosclerosis. Rose argued that rendering atherosclerotic
disease less common can be achieved only by removing the conditions
that make it common, and the North Karelia project in Finland
showed that a population-based approach to prevention—based
on collaboration among government, heart foundations, the food
industry, and agriculture—can in fact reduce the burden
of cardiovascular disease.
11 It is therefore very disappointing
that recent studies in the United States
12 and Europe
13 have
indicated that both government policy and the interests of the
food industry continue to promote atherosclerotic disease.
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Figure 5 Shift in concentration distribution of LDL-C after 12 months of treatment with simvastatin 20–40 mg in the 4S trial.9
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Substantial societal obstacles confront any efforts at eradication
of atherosclerotic disease. As shown in
Table 1, the composition
of the average diet in modern society reflects huge increases
in fat and sugar intake at the expense of complex carbohydrates,
when compared with agrarian or hunter–gatherer diets.
14 An example of how such trends are actually reinforced by agricultural
policy can be seen in
Figure 6.
13 The fate of most of the
surplus of butter produced in the European Union is to replace
healthier vegetable fats in the production of pastry. In contrast,
most of the fruits and vegetables, eligible for European Union
withdrawal compensation, are ultimately composted. These and
other examples in the Swedish report
13 indicate that the Common
Agricultural Policy of the European Union, conceived in the
very different European situation that prevailed just after
World War II, serves to promote rather than prevent some of
the most important diseases now afflicting Europeans.
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Figure 6 Top: Mechanisms for disposal of surplus European Union butter. Bottom: Destiny of withdrawn fruits and vegetables eligible for European Union withdrawal compensation. (Adapted with permission from Elinder.13)
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As a clinician, Geoffrey Rose acknowledged ‘the enormous
difficulty for medical personnel to see health as a population
issue and not merely as a problem for individuals’.
10 He argued, correctly I believe, that coronary artery disease
is a societal problem and that it requires a political solution.
The approach of changing the conditions that make atherosclerotic
disease prevalent requires political action, including changes
in urban planning, education, and policies regarding the agriculture,
food, and tobacco industries.
11 A problem with this approach
is that social engineering is no longer as fashionable or as
politically correct as it was even a quarter of a century ago.
An alternative approach is the full medicalization of society,
an approach that was still unrealistic when Geoffrey Rose lived.
He could not have foreseen the full potential of drugs such
as the statins. In this case, we would rely on biotechnology
(including, for example, gene therapy and stem-cell therapy)
and industrialized medicine (with its ever-improving drug and
surgical therapies) to bail us out of the consequences of diseases
promoted by industrialized agriculture and our inadequate adaptation
to life as city dwellers.
15 With regard to atherosclerotic disease,
some portion of this could be achieved fairly readily by, for
example, offering statins over the counter or incorporating
them into a poly-pill with other drugs to combat cardiovascular
disease.
16 The not-too-distant future might even offer a vaccination
against atherosclerosis.
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Conclusion
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The basics of atherogenesis are well understood. Recognition
of the causes of disease and its prevalence should serve to
focus efforts on the correct treatment of such disease in individuals
and on the difficult steps that must be taken if we wish to
eradicate the disease. Our notions about statin pleiotropy should
not deflect clinical attention from lowering LDL-C in individual
patients, but in managing our patients with coronary artery
disease using statins and all the other wonderful means at our
disposal, we must also initiate or at least support the political
efforts necessary to eradicate atherosclerotic disease or make
it less common.
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Discussion
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Professor Cobbe: In terms of societal issues, one point you
did not mention is that of exercise and how public policy can
encourage exercise.
Professor Færgeman: I used the composition of food and food policy as only one important example, but calorie intake/output and exercise are equally important. I think that every time a politician decides not to build a bicycle path, he has made a modest contribution to heart disease. There are ways to encourage exercise that are really quite easy to accomplish, at least in some societies. Emphasizing physical education in schools and creating more facilities for exercise that are available to the public are examples. Yes, counteracting sedentary lifestyle is another part of the equation, along with food policy and agricultural policy.
Audience Question: I enjoyed the talk very much, Ole. I was intrigued by your comment regarding the potential for a vaccine—could you expand on that?
Professor Færgeman: It is one of the directions of research at present, although not one in which I am directly involved. I know that Swedish researchers and investigators at the University of California at La Jolla and Los Angeles, for example, are working on this issue. The basis of one approach is that injection of oxidized LDL in apo E (apolipoprotein E)-deficient mice sometimes proved to retard rather than promote atherosclerosis. So far as I understand it, there is evidence that components of the oxidized LDL modulate the immunologic response to the oxidized LDL in different ways, with some of the components promoting inhibition of atherosclerosis. I do not think that vaccination is just around the corner; but, perhaps in a decade or two, we will be seeing serious public health attempts in this area.
Professor Cobbe: The issue of CRP is probably of great interest to many. What is your understanding of the relationship between LDL-C and CRP? Does LDL-C reduction directly drive down CRP? Does the presence of less atheroma mean less generation of CRP?
Professor Færgeman: I think I should defer to others here who might know more about the potential relationship, since I do not do research in this area. One view is that CRP perhaps reflects the metabolic syndrome: the hepatic synthesis of CRP is stimulated by cytokines produced in visceral fat, and perhaps the artery wall also produces agents that promote hepatic synthesis of CRP.
Professor Kastelein: We have initiated research in this area only recently, and some of our findings will be reported soon. In some studies, we infused recombinant CRP into humans, and we found that CRP is not just an innocent bystander but has biological properties that are associated with atherosclerosis. The potential role of CRP is even more evident when recombinant CRP is infused in FH heterozygotes with elevated LDL-C. It seems that there is some interaction between LDL and CRP at the vessel wall that augments atherogenic processes. So, I think that there is a biological interaction between LDL and CRP.
Dr Ballantyne: We do not understand the full mechanisms, but there does appear to be a relationship between the degree of LDL-C reduction and degree of CRP reduction. Initially, we thought that there was not a dose-response effect between LDL-C reduction and CRP reduction with statins, but newer data appear to indicate otherwise. It also has been found that there is additional reduction in CRP when the addition of ezetimibe to a statin results in additional LDL-C reduction; ezetimibe alone produces a very modest reduction in LDL-C and does not reduce CRP. There are a lot of issues that we need to explore in this area, but I think the greatest likelihood is that the relationship reflects a hepatic effect; cholesterol homeostasis involves regulation of a lot of processes and pathways in the liver down to the transcription level, and CRP may be partially regulated by these mechanisms.
Audience Question: Regarding the different serum cholesterol distributions in the Japanese and Finnish populations, should the different populations therefore have different LDL-C levels set for prevention of coronary artery disease?
Professor Færgeman: From the point of view of preventing atherosclerosis on a population level, I would not think so. Many years ago, Brown and Goldstein wrote that physiological concentrations of LDL-C, based inter alia on cell culture experiments, are probably 0.6 to 1.6 mmol/L, or 25 to 75 mg/dL. If everyone's serum cholesterol were in this concentration range, atherosclerosis and coronary artery disease would probably be very rare. The setting of LDL-C goals for lipid-lowering therapy in order to reduce risk of CHD events in individuals who already have underlying atherosclerosis, whether it is clinically evident or not, is a somewhat different issue. Currently, our LDL-C targets in medical treatment are not those physiological levels, except perhaps in the high-risk patients without severe hypercholesterolaemia. It is of interest that the reductions seen with atorvastatin 80 mg in the PROVE-IT trial got down to the upper end of what would be considered the physiological range of LDL-C. But, with regard to preventing development of disease, I would think that physiological LDL-C levels in the Japanese and Finns are probably similar. The data I showed on cholesterol distributions show that, from this particular point of view, it is a bad thing to be in Finland. I should note, however, that those data were obtained before the North Karelia project was conducted, and that the picture in Finland has changed for the better since then.
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Abstract
Introduction