Foreword
State University of New York, Downstate Medical Center, NY, USA
Aker University Hospital, Oslo, Norway
* Correspondence: J.C. LaRosa, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 1, Brooklyn, NY 11203, USA. Fax: +1-718-270-4732.
lrosbruck{at}netmail.hscbklyn.edu
Human life expectancy at birth has steadily increased from the beginning of recorded history to the present time. In ancient Rome, it was approximately 20 years, and it took 4000 years, to the mid-19th century, to double. From the mid-19th century to the present, it has almost doubled again. The prevention of atherosclerosis, however, has not played much of a role in that life extension. On the contrary, atherosclerosis, on a worldwide basis, is becoming more, rather than less, of a problem.
The first written description of atherosclerosis was by Joseph Conrad Bruner who, in 1695, described `hardening' of the aorta and major blood vessels in an autopsy. In 1768, William Heberden described angina pectoris, based on 20 observed cases, which increased to 100 cases by 1782. In 1852, Carl Von Rokitansky described the pathology of atheroma and originated the `thrombogenic' or `encrustation' theory of atherosclerosis, and in 1856 Rudolf Virchow described the `inflammatory' theory – atherosclerosis as a result of intimal inflammation and subsequent fibrosis.
However, it was not until the early 1900s that A. Ignatowsky, S. Saltykow and N.N. Anitschkow first put forward the `lipid' theory of atherogenesis, and described the importance of the relationship between circulating cholesterol levels and atherosclerosis. The lipid, thrombogenic and inflammatory theories have subsequently been amalgamated into our modern concept of atherogenesis. Although these ideas were being discussed at the beginning of the 20th century, atherosclerosis was not then a common disease. In 1910, Sir William Osler, who practiced medicine in the late 19th and early 20th centuries, and who founded the idea of what we now term internal medicine, described angina pectoris as a rare disease. This point of view was echoed several decades later by Paul Dudley White, who pointed out that, `until the first 2–3 decades of the twentieth century, coronary heart disease was rare and not missed by ignorance'.
This situation changed radically as the 20th century progressed. For the past several decades, coronary heart disease (CHD) has been the leading cause of death in the world. In 1990, it accounted for 6.3 million deaths worldwide.1 Although mortality rates from CHD and stroke have declined in most developed countries since 1970, there has been a staggering increase in developing countries. A recent analysis predicted that CHD will continue to grow on a global scale, and will remain the leading cause of death in 2020 (Table 1).2
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The factors for atherosclerosis increase
The events underlying the increase in cardiovascular disease in developed countries during the 20th century are being repeated in developing countries at the beginning of the 21st century.2 Then, and now, an increase in atherosclerosis has been due to two primary factors. The first is the ageing of the population, a phenomenon that continues in both the developed and developing worlds (Fig. 1).2 This is largely due to improvements in public health programmes, and a decline in mortality due to infectious agents. For example, in urban China over the last 30 years, fatal infectious disease rates, particularly in children, have fallen, while death rates from cardiovascular disease have increased markedly (Fig. 2).3
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The second factor that contributes to increased coronary risk is urbanization and the resultant decline in physical activity, accompanied by increases in dietary animal fat and caloric intake, which in turn lead to an increase in the prevalence of obesity and type 2 diabetes. This has been demonstrated in studies showing that when Indian men move from rural to urban areas, their cholesterol levels increase;4 and when they move from an urban area in India to an urban area in Europe, their cholesterol levels become indistinguishable from those of Europeans5 (Table 2). These processes have also been dramatically illustrated in Japan since the end of the Second World War, where increases in dietary animal fat have been accompanied by marked increases in deaths from CHD and malignancies (Fig. 3).6
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How can the medical community meet the challenge presented by the global burden of cardiovascular disease? In the developed world, it seems that the potential to reduce CHD by encouraging individuals to change dietary habits and be more physically active has, for the time being, been exhausted. In the United States, for example, dietary fat intake has decreased over the past 40 years, but overall caloric intake has increased, and it is now estimated that, in the near future, obesity will result in greater health expenditure than cigarette smoking.7 Despite clear observational and epidemiological evidence demonstrating that the relative risk of developing CHD falls as activity levels increase, and that stroke survival rates increase with exercise, activity levels continue to decline in the increasingly elderly and urbanized societies of today.
Therefore, the medical profession is likely to focus on patient-based strategies. As a result, identification of patients at risk of developing CHD will become increasingly important, and individual tailoring of preventive measures will dominate the field. Along with greater utilization of advanced technologies to treat symptomatic disease, such as percutaneous coronary intervention and thrombolysis, preventive drugs are also likely to be more widely used in the future.
Statins for cholesterol lowering
Trials of cholesterol lowering with statin drugs have clearly demonstrated that coronary events can be reduced by approximately one-third.8 However, viewed another way, two-thirds of individuals will go on to have their next coronary event, despite having their cholesterol lowered. This may, of course, be related to a number of factors, including the presence of other coronary risk factors that are untreated, and the possibility of additional benefit from more aggressive cholesterol lowering. A third possibility, however, is that the burden of atherosclerosis accumulated by middle age may be too extensive to be overcome. Indeed, mathematical modelling has demonstrated that the ideal time for cholesterol intervention to provide the most event-free years is somewhere between age 35 and 45 (Fig. 4).9 Intervention with drugs in a large number of younger adults would, however, not only be expensive, but could potentially expose populations to many more years of cholesterol-lowering drugs with unknown effects.
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Nevertheless, in terms of medical intervention, the remarkable efficacy of statins, combined with their excellent safety profile, suggests that they will be one of the major pillars in the prevention and treatment of CHD in future decades. As the cost of statins gradually decreases (as has the cost of ß-blockers and angiotensin-converting enzyme inhibitors), they will become more widely prescribed. It is possible that genetic science, such as stem-cell research, will provide therapies that will have a major impact on the prevention and management of CHD in the future. For the next decade, however, it is unlikely that such remedies will become widely available to the millions of people worldwide who are at risk of developing CHD.
The papers in this supplement arise from the central plenary sessions, collectively entitled `New Frontiers in Atherosclerotic Disease Management', of the Second Atorvastatin Global Investigators Meeting, which was held in Paris, France, from April 28–30, 2002. The objective of the supplement is to address key issues relating to the challenges faced by physicians in effectively managing and treating CHD in the 21st century.
The importance of global risk factor management, and guidelines for its effective implementation, are outlined from the perspective of physicians in Europe by Richard Hobbs, respectively. Steven Nissen discusses the use of novel diagnostic techniques to identify patients at risk of CHD, and Cornelis Kluft examines the potential role of biological markers in identifying such patients.
There then follows a series of papers concerned with extending the benefits of lipid-lowering therapy to special patient populations: John Betteridge discusses the treatment of dyslipidaemia in patients with type 2 diabetes; Michael Welch the rationale for using statin therapy to prevent cerebrovascular disease; Henrik Sillesen the future treatment and management of the patient with peripheral arterial disease; and David Waters the management of patients with acute coronary syndromes.
The final paper focuses on the effects of statin therapy that extend beyond the lowering of low-density lipoprotein cholesterol: John Chapman discusses whether the effects of statins on high-density lipoprotein cholesterol are clinically relevant.
It is important to remember that the key to the prevention of CHD lies in the combination of medical interventions and public health measures. Central to this must be the understanding that human beings are not anatomically, physiologically or biochemically suited to take in large amounts of animal fat. Humans have flat, grinding teeth, long intestines and low levels of cholesterol, the great majority of which is carried in low-density lipoprotein. In other words, humans are not natural carnivores. We must face the fact that high-calorie, high-animal-fat diets, which may at one time have enabled us to survive as a species, have become counterproductive. Cholesterol-lowering drug interventions, while important, will not be sufficient to stem the growing epidemic of atherosclerosis in the world unless they are accompanied by major changes in dietary and exercise habits.
References
- Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;349:1269–1276[CrossRef][Web of Science][Medline]
- Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet. 1997;349:1498–1504[CrossRef][Web of Science][Medline]
- Chonghua Y, Zhaosu W, Yingkai W. The changing pattern of cardiovascular diseases in China. World Health Statist. Quart. 1993;46:113–118
- Srinath PK. Lessons from Contrasting Worlds. 1997;:71–75
- McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet. 1991;337:382–386[CrossRef][Web of Science][Medline]
- Toshima H. Coronary artery disease trends in Japan. Jpn. Circ. J. 1994;58:166–172[Medline]
- Wickelgren I. Obesity: how big a problem. Science. 1998;280:1364–1367
[Abstract/Free Full Text] - LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999;282:2340–2346
[Abstract/Free Full Text] - Ulrich S, Hingorani AD, Martin J, et al. What is the optimal age for starting lipid-lowering treatment? A mathematical model. BMJ. 2000;320:1134–1140
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