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

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. Prevention of atherosclerosis-related morbidity by pathological stage of the process Disease associated with premature atherosclerosis (e.g. diabetes mellitus, familial hypercholesterolaemia) High risk clinical states based on consensus guidelines (hypertension, dyslipidaemias, metabolic syndrome) Target organ injury (LV hypertrophy, coronary calcium, microalbuminuria, ?proinflammatory states) Status post myocardial infarction or cerebrovascular accident Unstable angina Positive stress test, coronary angiography, carotid stenoses, other markers of subclinical atherosclerosis Nutrition (appropriate caloric intake, saturated fat, cholesterol, fibre, salt) Physical activity Avoidance of tobacco Risk screening (blood pressure, obesity, cholesterol, glucose tolerance) Smoking cessation programmes Public health strategies to minimize unrecognized risk states Assessment of target organ injury (left ventricular mass, urinary protein, inflammatory markers, carotid intima media thickness, coronary calcium, endothelial function) when indicated Implementation of treatment for risk Inadequate funding for community-based research Inadequate regulation of industry Lack of proactive public health requirements equivalent to immunization programs (e.g. fitness in schools) Race/ethnic/socioeconomic status barriers to Inadequate for risk factor Lack of with of when indicated risk Inadequate or requirements for at for patients and/or the Disease associated with premature atherosclerosis (e.g. diabetes mellitus, familial hypercholesterolaemia) High risk clinical states based on consensus guidelines (hypertension, dyslipidaemias, metabolic syndrome) Target organ injury (LV hypertrophy, coronary calcium, microalbuminuria, ?proinflammatory states) Status post myocardial infarction or cerebrovascular accident Unstable angina Positive stress test, coronary angiography, carotid stenoses, other markers of subclinical atherosclerosis Nutrition (appropriate caloric intake, saturated fat, cholesterol, fibre, salt) Physical activity Avoidance of tobacco Risk screening (blood pressure, obesity, cholesterol, glucose tolerance) Smoking cessation programmes Public health strategies to minimize unrecognized risk states Assessment of target organ injury (left ventricular mass, urinary protein, inflammatory markers, carotid intima media thickness, coronary calcium, endothelial function) when indicated Implementation of treatment for risk Inadequate funding for community-based research Inadequate regulation of industry Lack of proactive public health requirements equivalent to immunization programs (e.g. fitness in schools) Race/ethnic/socioeconomic status barriers to Inadequate for risk factor Lack of with of when indicated risk Inadequate or requirements for at for patients and/or the Prevention of atherosclerosis-related morbidity by pathological stage of the process Disease associated with premature atherosclerosis (e.g. diabetes mellitus, familial hypercholesterolaemia) High risk clinical states based on consensus guidelines (hypertension, dyslipidaemias, metabolic syndrome) Target organ injury (LV hypertrophy, coronary calcium, microalbuminuria, ?proinflammatory states) Status post myocardial infarction or cerebrovascular accident Unstable angina Positive stress test, coronary angiography, carotid stenoses, other markers of subclinical atherosclerosis Nutrition (appropriate caloric intake, saturated fat, cholesterol, fibre, salt) Physical activity Avoidance of tobacco Risk screening (blood pressure, obesity, cholesterol, glucose tolerance) Smoking cessation programmes Public health strategies to minimize unrecognized risk states Assessment of target organ injury (left ventricular mass, urinary protein, inflammatory markers, carotid intima media thickness, coronary calcium, endothelial function) when indicated Implementation of treatment for risk Inadequate funding for community-based research Inadequate regulation of industry Lack of proactive public health requirements equivalent to immunization programs (e.g. fitness in schools) Race/ethnic/socioeconomic status barriers to Inadequate for risk factor Lack of with of when indicated risk Inadequate or requirements for at for patients and/or the Disease associated with premature atherosclerosis (e.g. diabetes mellitus, familial hypercholesterolaemia) High risk clinical states based on consensus guidelines (hypertension, dyslipidaemias, metabolic syndrome) Target organ injury (LV hypertrophy, coronary calcium, microalbuminuria, ?proinflammatory states) Status post myocardial infarction or cerebrovascular accident Unstable angina Positive stress test, coronary angiography, carotid stenoses, other markers of subclinical atherosclerosis Nutrition (appropriate caloric intake, saturated fat, cholesterol, fibre, salt) Physical activity Avoidance of tobacco Risk screening (blood pressure, obesity, cholesterol, glucose tolerance) Smoking cessation programmes Public health strategies to minimize unrecognized risk states Assessment of target organ injury (left ventricular mass, urinary protein, inflammatory markers, carotid intima media thickness, coronary calcium, endothelial function) when indicated Implementation of treatment for risk Inadequate funding for community-based research Inadequate regulation of industry Lack of proactive public health requirements equivalent to immunization programs (e.g. fitness in schools) Race/ethnic/socioeconomic status barriers to Inadequate for risk factor Lack of with of when indicated risk Inadequate or requirements for at for patients and/or the A progressive process