Commentary: Lifelong prevention of atherosclerosis: the critical importance of major risk factor exposures

Philip Greenlanda, Samuel S Giddingb and Russell P Tracyc

a Department of Preventive Medicine and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
b The Nemours Cardiac Center, Alfred I. DuPont Hospital for Children, Wilmington, Delaware, USA.
c Departments of Pathology and Biochemistry, University of Vermont, Burlington, VT, USA.

Correspondence: Philip Greenland, MD, Department of Preventive Medicine, The Feinberg School of Medicine, Northwestern University, 680 N Lake Shore Drive, Suite 1102, Chicago, IL 60611, USA. E-mail: p-greenland{at}northwestern.edu

More than 40 years ago, a model that expressed then-prevailing concepts about atherogenesis1 proposed that atherosclerosis begins relatively early in life (ages 10–20 years) with deposition of the fatty streak, progresses (ages 20–30 years) to the fibrous plaque, and further advances from ages 30–50 years by the action of traditional risk factors such as cigarette smoking, unfavourable blood lipid and blood pressure levels, overweight and insulin resistance (or glucose intolerance related factors) and eventually results in occlusive plaques and clinical manifestations of the atherosclerotic diseases from approximately age 50 onward. In this issue of the International Journal of Epidemiology, Beaglehole and Magnus2 remind us that ‘traditional’ risk factors explain perhaps as much as 85% or more of the world’s experience with atherosclerosis. They state that research on further refinements of this model cannot add much to epidemiological knowledge of this disease, and they argue that more energy should be expended in lowering the prevalence of tobacco use, unfavourable cholesterol levels, dyslipidaemia, physical inactivity, and the obesity/insulin resistance syndrome.

The 1960s model was plausible, based on accrued wisdom to that point, and has increased in force over time. In a recent re-examination of this issue, one of us (PG) showed that nearly 100% of people who developed clinical coronary events during 20+ years of follow-up in three large American cohorts (including the Framingham Heart Study,3 the Chicago Heart Association Detection Project cohort,4 and the 360 000 screenees of the Multiple Risk Factor Intervention Trial5) had been previously exposed to unfavourable levels of blood cholesterol, blood pressure, cigarette smoking, and/or diabetes.6 Thus, as noted by Beaglehole and Magnus,2 the major risk factors were present and represented putative precursors in nearly all cases of clinical coronary heart disease (CHD).

However, questions about the atherosclerotic process remained unanswered by this model and troubled researchers for many years. Why do so many people exposed to unfavourable blood cholesterol and blood pressure levels and/or cigarette smoking not develop clinical atherosclerosis?7,8 In the same study cited above,6 85% of men and women in these three large US cohorts who did not develop clinical CHD events in long term follow-up had also been previously exposed to unfavourable levels of the major risk factors; many had prior exposure to two, three or all four factors. We have very little understanding of what affords protection to the many exposed individuals who escape clinical CHD. And, in those who eventually develop cardiovascular disease, is it possible that the timing of more aggressive preventive interventions can be improved in high risk individuals?

The 1960s model of chronic progression of atherosclerosis also failed to explain how people whose plaques were non-occlusive and caused no symptoms, even when challenged by exercise or other stress, could suddenly die from CHD or suffer an unheralded myocardial infarction. Recent concepts of plaque vulnerability,9 the role of haemostatic and thrombogenic factors in the complications of atherosclerosis,10 and the potential role of inflammation11 in both atherogenesis and its complications appear to explain some of these clinical observations. It is now generally understood that inflammation is likely involved in the progression of atherosclerosis, though whether it is the first step in the process, or a reaction to the earliest steps, remains unclear. Cardiac events are the sum of early atherogenesis, progression mediated by inflammation (probably promoted by traditional risk factor exposures), and acute thrombosis. Beaglehole and Magnus2,12 are concerned that intense current interest in these new concepts has diverted attention from older and still relevant observations that major risk factors were present in nearly everyone who developed clinical CHD.

We propose a model that unifies the recent and older concepts and affirms targeting major risk factors as the key primary prevention strategy. This model (Figure and Table) recognizes that atherosclerosis evolves over a lifetime and that rates of progression may vary in different individuals based on their risk exposures. This model further recognizes that diagnostic advances allow us to identify some individuals where rapid rates of progression make medical intervention not only feasible but of greater benefit than diet and behavioural treatment alone. There are three components to the model corresponding to early atherogenesis, aggressive plaque growth, and impending or present end organ injury. At each stage of the process, different approaches are warranted. The model recognizes relatively recent research on prenatal and early childhood exposures that may also justify attention to nutrition and other risk exposures even as early as conception.13 However, as these exposures are as yet largely unclear,14 they are acknowledged in the model for completeness but are not discussed here in further detail.

Evidence supporting the major role of ‘traditional’ risk factors in the process of atherogenesis and clinical CHD is reviewed in some depth by Beaglehole and Magnus.2 A great deal of what we know on this topic derives from the American PDAY (Pathobiological Determinants of Atherosclerosis in Youth) Study of collected arteries, blood, and other tissues from approximately 3000 people aged 15–34 years who died from external causes and were subjected to autopsies in forensic laboratories. Reports from this study confirm observations made during the Korean War that atherosclerotic plaques are already present in about 15% of people by age 20. More importantly, major ‘adult’ risk factors such as overweight and obesity,15 smoking, hypertension, diabetes and impaired glucose tolerance,16 and blood lipid levels including low high density lipoprotein (HDL)-cholesterol and high non-HDL cholesterol,17 are strongly related to the occurrence of fatty streaks and of early-onset plaques seen in adolescents and young adults with coronary atherosclerosis. Individuals with the most extensive plaques had the greatest number of major risk factors in their early years.

Longitudinal studies of children through adolescence and young adulthood convincingly show that increases in obesity and adverse health behaviours contribute to worsening lipid profiles, higher blood pressure, and insulin resistance.18–20 In these studies secular trends in obesity, progressive weight gain from adolescence to adulthood, and participation in adverse health behaviours (diet, tobacco use, weight gain) all contributed to worsening risk status over time. Thus, pathological studies such as PDAY and the Bogalusa Heart Study,21 taken in conjunction with data on changes in cardiovascular risk with growth and development, convincingly demonstrate that primary prevention could have a large impact on the development of atherosclerosis in the maturing vascular system.

The concept that early risk factor exposure may be critical in predicting the consequences of atherosclerosis has also surfaced in long-term follow-up studies of young adults. Klag et al.22 studied prospectively 1017 young men (mean age, 22 years) followed for 27 to 42 years to quantify risk of cardiovascular disease and total mortality associated with serum cholesterol levels measured in early adult life. During a median follow-up of 30 years, the young adult mean serum cholesterol level was strongly associated with the incidence of CHD events and of all cardiovascular disease, as well as with total mortality and mortality due to cardiovascular disease. Risks were similar whether the events occurred before or after the age of 50. Similar results have been reported from a Chicago cohort of nearly 11 000 men aged 18–39, examined initially from 1967 to 1973, and followed for over 20 years.23 In this cohort, the major adult risk factors, measured only once in young adulthood, were highly predictive of future coronary death before age 60. Additional supportive data concerning the predictive capacity of early life exposure to the adult CHD risk factors comes from studies of late adolescents and young adults from a cohort of university students in Glasgow, Scotland, followed for several decades after measurement of smoking habits and blood pressure.24,25

Conversely, as noted by Beaglehole and Magnus,2 absence of exposure to the major risk factors appears to be strongly protective against developing the clinical consequences of CHD. Only limited data are available on this topic since few people in long-term cohort studies have been unexposed to major risk factors. In a 1999 report by Stamler et al.,26 from a Chicago cohort, men aged 18–39 at initial examination were classified into ‘low-risk’ status (n = 942) based on favourable levels of four major risk factors (serum cholesterol <200 mg/dl; systolic/ diastolic blood pressure <=120/80; non-smoking; non-diabetic) and were compared to the remainder of cohort (n = 9083). During 22 years follow-up, only one of the 942 in the ‘low-risk’ stratum experienced a death attributed to CHD. Age-adjusted relative risk for CHD mortality comparing the low-risk group to all others in the cohort was 0.08, i.e. 92% lower. In the same report, 7163 low-risk men aged 35–39 from the MRFIT screening study were compared to the 64 981 men aged 35–39 who had at least one risk factor in an unfavourable level. Relative risk for CHD mortality in 16 years follow-up was 0.14 (95% CI: 0.08–0.25), i.e. 86% lower. Absolute CHD mortality rates in the subgroups not exposed to any of the major risk factors in these younger men were very low, far below epidemic levels typically found in Western countries.

What is the evidence that inflammatory markers, or other ‘new’ risk factors add prognostic information? Do they predict the early development of CHD or its long-term outcome in young people? Thrombotic/inflammatory markers, especially fibrinogen, have been shown to predict CHD in middle-aged men (healthy men as well as those with clinical cardiovascular disease), women, and older individuals, as reviewed by Tracy.11 The issue of whether fibrinogen’s ability to predict CHD events represents a causal factor, or simply a marker of subclinical atherosclerosis, remains uncertain.11 Hypothetically, fibrinogen may participate in the causal pathway because it is a clotting factor, and elevated levels could contribute to an acceleration of CHD. Alternatively, fibrinogen may be associated with CHD risk because it is an acute phase reactant, and increased levels may simply reflect severity of the underlying atherosclerosis. Fibrinogen’s role in predicting the very earliest onset of CHD, as in the PDAY studies, has not been demonstrated to date.

In terms of inflammatory markers of CHD risk, C-reactive protein (CRP) is one of the most extensively studied. As recently reviewed,11,27 CRP has been shown to predict CHD events in patients with clinical cardiovascular disease (e.g. unstable angina), in healthy middle-aged men and women, and in older men. C-reactive protein predicted CHD risk over long periods in middle-aged men in several studies lasting between 10 and 20 years.11,28 A recent report suggests that CRP levels at the upper-end of the childhood range (but still well below adult levels) are related to abnormal endothelial function and early onset of carotid artery intimal-medial thickening in children, mean age 10 years.29 Thus, CRP appears to play an early role in the pathogenesis of atherosclerosis, but it remains unclear whether these levels are predictive of long-term risk and whether these early levels are independent of risk factor exposures. Tracy has proposed11 that the long-term predictive capacity of CRP in middle-aged people is likely a reflection of accumulated disease associated with atherosclerotic risk. In other words, in middle-aged people, CRP is a marker of the underlying inflammatory process and atherosclerotic burden that develops after initiation in youth.

In contrast to findings in the middle-aged, Tracy et al.30 have found an interaction between inflammation and time to death from all causes in the elderly. For example, for death within 2.5 years of blood collection, those in the upper quintile of fibrinogen values had a relative risk of approximately 7 compared to those in the lowest quintile. However, beyond 2.5 years, fibrinogen was far less predictive. Similar results have been noted for CRP and several other markers of the inflammation-thrombosis complex.31,32 These observations have led to an hypothesis that older individuals may enter a time of destabilization accompanied by rapid worsening over a 6-month to 2-year period to a clinical event. While the ability of CRP to predict CHD events over long periods of time in middle-aged people suggests that CRP predominantly reflects accumulating damage, it appears that in older age, with an increased atherosclerotic burden, there is a time immediately prior to a lesion-dependent thrombotic event accompanied by increased inflammatory and coagulant activation. Thus, CRP and fibrinogen levels may represent different pathophysiological processes at different times in a person’s life. Nevertheless, these processes appear to be relatively late phenomena in the lifespan of an atherosclerotic plaque.

Based on the observations summarized here, and building on the comments of Beaglehole and Magnus,2 we have revised the model of atherosclerosis developed some 40 years ago by McGill and colleagues.1 In this new model (Figure and Table), we propose that major risk factors (including unfavourable blood lipid levels, unfavourable blood pressure levels, cigarette smoking, and diabetes-insulin resistance) act upon the endothelium and alter its biology in a way that initiates the atherosclerotic process.33 Continued exposure to these major risk factors early in life converts the fatty streak to the fibrous plaque that is often present by age 20 in exposed and susceptible people. Continued risk factor exposure throughout young adulthood leads to further plaque growth and occlusive plaques by ages 40–50 in susceptible people (e.g. those with genetic disorders of lipid metabolism, diabetes mellitus, tobacco use, early onset renal disease). With sustained risk exposure, inflammation ensues and increases risk for plaque progression, plaque rupture, and clinical events. Later, by about age 60, inflammatory processes may contribute more strongly than in middle-age to the initiation of acute events. Tracy previously termed this latter process the hypothesis of ‘proximate pathophysiology’.11 The model also suggests the role of prenatal and early childhood exposures in risk development, as noted earlier.

Based on the proposed integrative model, several conclusions emerge. We agree with Beaglehole and Magnus2 that the major risk factors deserve the greatest attention as a preventive strategy. Primary prevention of atherosclerosis is critical for health. Delaying or preventing exposure delays the onset of endothelial damage and plaque development. We propose that the critical time for initiating primary prevention is in adolescence and early adulthood and should be continued throughout life. Based on previous work, we propose that non-smoking, combined with (low density lipoprotein [LDL]-cholesterol <100 mg/dl (or total cholesterol <180 mg/dl), body mass index <25 kg/m2, systolic blood pressure <120 mm Hg, and diastolic <80 mm Hg are healthful.4,34 Individuals who exceed these levels should strive to improve health by working towards these goals, including in youth.35

However, some individuals, either through early intense risk exposure, particular susceptibility, or long and sustained chronic exposure will develop atherosclerosis. Attention and treatment, if necessary, to traditional risk factors later in life (middle-age and older) represents an effort to avert the clinical consequences of plaque burden that might have been prevented by avoiding traditional risks earlier in life. Efforts to identify and reverse the inflammatory process and/or the thrombotic process become critical because events are that much more likely. New research has made the identification and treatment of high risk individuals feasible and effective. These efforts need to be further refined and improved.

Finally, we should not abandon the idea that protection against atherosclerosis can be achieved. New knowledge about the importance of traditional risk factors, new risk factors in disease progression, and protective factors, many now unknown, which contribute to a healthy vasculature should be sought. However, we cannot abandon what we know to be true in this search. Many impediments exist to effective implementation of lessons already learned; some, based on our pathological staging of the atherosclerotic process, are listed in the Table. The future for the public health approach lies in the co-ordination of new knowledge with the successful implementation of what is known to improve health and well-being.


View this table:
[in this window]
[in a new window]
 
Table 1 Prevention of atherosclerosis-related morbidity by pathological stage of the process
 


View larger version (42K):
[in this window]
[in a new window]
 
Figure 1 Atherosclerosis: A progressive process

 
References

1 McGill HC Jr, Greer JC, Strong JP. Natural history of human atherosclerotic lesions. In: Standler M, Bourne GH (eds). Atherosclerosis and Its Origin. New York, Academic Press, 1963.

2 Beaglehole R, Magnus P. The search for new risk factors for coronary heart disease: occupational therapy for epidemiologists? Int J Epidemiol 2002;32:1177–22.

3 Kannel WB. The Framingham Study: Its 50-year legacy and future promise. J Atheroscler Thromb 2000;6:60–66.[Medline]

4 Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts. Cardiology 1993;82:191–222.[ISI][Medline]

5 Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA 1982;248:1465–77.[Abstract]

6 Greenland P, Deloria-Knoll M, Dyer AR, Garside D. How often does coronary death occur in the absence of traditional risk factors? Presented, 42nd Annual Conference on Cardiovascular Epidemiology and Prevention, American Heart Association, Honolulu, Hawaii, 23–26 April 2002.

7 Marmot M, Winkelstein W Jr. Epidemiologic observations on intervention trials for prevention of coronary heart disease. Am J Epidemiol 1975;101:177–81.[ISI][Medline]

8 Rosenman RH, Friedman M. Neurogenic factors in pathogenesis of coronary heart disease. Med Clin North Am 1974;58:269–79.[ISI][Medline]

9 Kolodgie FD, Burke AP, Farb A et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 2001;16:285–92.[CrossRef][ISI][Medline]

10 Zaman AG, Helft G, Worthley SG, Badimon JJ. The role of plaque rupture and thrombosis in coronary artery disease. Atherosclerosis 2000;149:251–66.[CrossRef][ISI][Medline]

11 Tracy RP. Inflammation markers and coronary heart disease. Curr Opin Lipidol 1999;10:435–41.[CrossRef][ISI][Medline]

12 Magnus P, Beaglehole R. The real contribution of the major risk factors to the coronary epidemics: time to end the ‘only-50%’ myth. Arch Intern Med 2001;161:2657–60.[Free Full Text]

13 Barker DJ. A new model for the origins of chronic disease. Med Health Care Philos 2001;4:31–35.[CrossRef][Medline]

14 McCarron P, Okasha M, McEwen J et al. respond to ‘height-cardiovascular disease relation‘: are all risk factors equal? Am J Epidemiol 2002;155:690–91.[Free Full Text]

15 McGill HC Jr, McMahan CA, Herderick EE et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 2002;105:2712–18.[Abstract/Free Full Text]

16 Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study. Pediatr Pathol Mol Med 2002;21:213–37.[CrossRef][ISI][Medline]

17 McGill HC Jr, McMahan CA, Zieske AW et al. Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol 2000; 20:1998–2004.[Abstract/Free Full Text]

18 Gidding SS, Bao W, Srinivasan S, Berenson GS. Effects of secular trends in obesity on coronary risk factors in children: The Bogalusa Heart Study. J Pediatr 1995;127:868–74.[ISI][Medline]

19 Sinaiko AR, Donahue RP, Jacobs DR Jr, Prineas RJ. Relation of weight and rate of increase in weight during childhood and adolescence to body size, blood pressure, fasting insulin, and lipids in young adults. The Minneapolis Children’s Blood Pressure Study. Circulation 1999; 99:1471–76.[Abstract/Free Full Text]

20 Stuhldreher WL, Orchard TJ, Donahue RP, Kuller LH, Gloninger MF, Drash AL. Cholesterol screening in childhood: sixteen-year Beaver County Lipid Study experience. J Pediatr 1991;119:551–56.[ISI][Medline]

21 Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998;338:1650–56.[Abstract/Free Full Text]

22 Klag MJ, Ford DE, Mead LA et al. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med 1993;328:313–18.[Abstract/Free Full Text]

23 Navas-Nacher EL, Colangelo L, Beam C, Greenland P. Risk factors for coronary heart disease in men 18 to 39 years of age. Ann Intern Med 2001;134:433–39.[Abstract/Free Full Text]

24 McCarron P, Smith GD, Okasha M, McEwen J. Blood pressure in young adulthood and mortality from cardiovascular disease. Lancet 2000;355:1430–31.[CrossRef][ISI][Medline]

25 McCarron P, Smith GD, Okasha M, McEwen J. Smoking in adolescence and young adulthood and mortality in later life: prospective observational study. J Epidemiol Community Health 2001;55:334–35.[Free Full Text]

26 Stamler J, Stamler R, Neaton JD et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA 1999;282:2012–18.[Abstract/Free Full Text]

27 Lagrand WK, Visser CA, Hermens WT et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 1999;100:96–102.[Abstract/Free Full Text]

28 Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996; 144:537–47.[Abstract]

29 Jarvisalo MJ, Harmoinen A, Hakanen M et al. Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol 2002;22:1323–28.[Abstract/Free Full Text]

30 Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19:1776–83.[Abstract/Free Full Text]

31 Cushman M, Lemaitre RN, Kuller LH et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999;19:493–98.[Abstract/Free Full Text]

32 Tracy R, Lemaitre R, Psaty B et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121–27.[Abstract/Free Full Text]

33 Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 1994;93:50–55.[ISI][Medline]

34 Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000;343:16–22.[Abstract/Free Full Text]

35 Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: A statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 2002;106:143–60.[Free Full Text]