- Email: [email protected]
High cholesterol and coronary heart disease in younger men: The potential role of stress induced exaggerated blood pressure response
Medical Hypotheses (2008) 70, 543–547
http://intl.elsevierhealth.com/journals/mehy
High cholesterol and coronary heart disease in younger men: The potential role of stress induced exaggerated blood pressure response William R. Ware
*
14 Metamora Crescent, London, ON, Canada N6G 1R3 Received 18 June 2007; accepted 26 June 2007
Summary It is well known that by far the strongest association between serum cholesterol levels and the risk of coronary heart disease or related adverse events is found in younger men. The question is what is different about this age-gender subgroup? It has been suggested that this enhanced risk is seen in younger men because of unique exposure to stress. While stress is known to raise cholesterol levels, the magnitude of the elevation appears insufficient to account for the observed association between cholesterol levels and CHD in young men. An hypothesis is presented which suggests that part and perhaps all of this association is due to the relationship between cholesterol levels and exaggerated blood pressure response to stress, i.e. individuals who exhibit this hyper-response also tend to have significantly elevated cholesterol levels. Given that both stress and an exaggerated blood pressure response to stress are also risk factors for CHD, this could influence the relationship between CHD risk and cholesterol in this age group even if multivariate analysis includes casual blood pressure. This is important since in risk assessment, especially among young men, cholesterol levels play an important role. c 2007 Elsevier Ltd. All rights reserved.
Introduction The association of serum cholesterol and the risk of coronary heart disease (CHD), CHD related events, and CHD mortality has been found to vary with both gender and age, and by far the strongest association has been observed with men under about the age of 50 [1–4]. This is clear when one examines just age and total cholesterol in the Framingham risk calculation. The age factor contribution to * Tel.: +1 519 472 2359; fax: +1 519 472 2932. E-mail address: [email protected]
the score increases strongly with age and the contribution from cholesterol decreases strongly in an age dependent manner yielding a modest or even very small contribution to the resultant risk in older men. A recent very large study confirms what is seen in the Framingham algorithm, i.e. this association in women and the elderly who were initially free of CHD is statistically insignificant or at least much weaker than in young men [3]. Thus the cholesterol–CHD risk association in younger men can be viewed as anomalous [5,6]. This leads to the interesting question – what is different just in younger men that produces this apparently
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.06.031
544 anomalous association of risk with serum cholesterol when the endpoints are CHD or adverse CHD events? It has been suggested that an explanation might be found in the stress environment that appears to be unique to younger men [6]. High levels of stress might be expected to peak during the age period prior to 50. This is the age where some men are in the midst of their professional careers, in many cases subject to great stress, even harassment. It is well known that many individuals, both professionals and non-professionals, hate their jobs, their boss, the part of the country where they work, etc. There is the ever present risk of being fired, losing ones job because of downsizing, or failing to achieve success or to be promoted. Men who own their own businesses may well be exposed to extreme stress since mistakes or bad luck can result in bankruptcy and the loss of everything. At the upper end of this age range, there is the worry about job loss when it could prove difficult if not impossible to find equivalent employment. In addition, this is the age when marital break-ups are common and generally highly stressful, when teenage children may drive their parents to distraction or cause them to become frantic with worry. It is when children may have problems with drugs and alcohol. Work-place stress also interacts with domestic stress and it is obvious that stress can not only be intense but chronic. Thus it can be argued that younger men are exposed to higher levels of stress than older men. But if stress is involved, why the correlation with cholesterol? There are a number of studies over several decades that show a positive correlation between stress and either total cholesterol or LDL levels [7–12]. Cholesterol would then be simply a marker for stress. However, in most studies the magnitude of cholesterol elevation associated with stress is small and typically only a few percent. Higher elevations reported occasionally in the older literature appear to be the exception. Cholesterol elevation attributable to stress appears to be an unlikely explanation for the correlation between CHD and cholesterol found in younger men.
Exaggerated response to stress and cholesterol levels There is another correlation of cholesterol with stress that might provide an answer to the question posed above. A recent paper Borghi et al. report an investigation of serum cholesterol levels and the incidence of exaggerated blood pressure response to stress [13]. It is well known that the response
Ware to stress involving blood pressure varies considerably from individual to individual and some, the so-called hyper-responders, exhibit an exaggerated response. Borghi et al. found significantly greater increases in both systolic and diastolic BP changes induced by mental stress between individuals with high cholesterol as compared those with normal cholesterol or controls. In addition, the changes were slower to normalize after the stress was removed with those having high cholesterol maintaining somewhat BP elevated levels while the controls returned to normal. In the high-normal BP group with high cholesterol, 83% exhibited BP hyper-response, whereas in the high-normal BP group with normal cholesterol levels only 38.1% were hyper-responsive. High normal BP was defined as systolic BP between 130 and 139 mm Hg and diastolic BP between 85 and 89 mm Hg. High cholesterol was 246 ± 4.4 mg/dL whereas for the low cholesterol group it was 177 ± 3.5 mg/dL. The controls had normal BP and low cholesterol. In the study of Borghi et al. baseline cholesterol levels were not correlated with blood pressure. The study group was predominantly males in their late 20 s. These results are consistent with two previous studies that showed BP response to mental stress is exaggerated in patients with hypercholesterolaemia and that the effect can be significantly blunted with hydroxymethylglutaryl-CoA reductase inhibitors (statins) [14,15]. In addition, enhanced vasoconstrictive and pressor response to angiotensin II and norepinephrine has been observed in patients with hypercholesterolaemia [16]. Borghi et al. also point out that impaired endotheliumdependent vascular relaxation has been seen in patients with high serum levels of cholesterol and that this can be observed long before the development of manifest atherosclerotic lesions, and could significantly impact BP regulation. In studies of the association of serum cholesterol and the risk of CHD or CHD events, BP is of course recognized as a major factor. However, adjustment of results to take this into account employs resting BP data. In fact, in most studies it would be entirely out of the question to obtain data on exaggerated response. Therefore it can be argued that the corrections for confounding by BP are incomplete and that the relationship between cholesterol levels and CHD risk could be due to residual confounding. In addition, Borghi et al. found approximately the same low percentage of hyperresponders in both the high-normal BP and normal BP groups when cholesterol levels were low and Minami et al. [14] also found that in normotensive patients with hypercholesterolaemia, exaggerated BP response to stress was present. This provides
High cholesterol and coronary heart disease in younger men: The potential role additional evidence that introducing resting BP into multivariate models will fail to correct for the influence of hyper-response.
Stress and exaggerated BP response to stress and the risk of CHD This hypothesis of course depends of an association between stress and stress induced exaggerated BP response and the risk of CHD and CHD events. This connection with stress in general appears to be well established and the effect is large, in fact much larger than enhanced risk associated with serum cholesterol levels [8,17,18]. Also, so-called Type A behavior is closely related to stress levels and has been shown to be a strong predictor of early coronary events [19]. Likewise, studies reveal that abnormal anger in young men is associated with an increased risk of future cardiovascular disease, and in particularly myocardial infarction [20]. The connection between exaggerated BP response to stress and the risk cardiovascular disease and atherosclerosis has also received attention. In a recent review [21], Treiber et al. concluded that published studies are broadly consistent with the proposition that exaggerated BP response may be predictive of the presence [22–24] and progression [25] of atherosclerosis as determined by intimamedial thickness. The relationship between exaggerated stress response and CHD and CHD events has also been investigated. Either psychological [26,27] or exercise [28–30] induced stress was used and the presence of hyper-response was found to be a significant risk factor, and in some cases the enhancement was dramatic. There in fact appears to be growing interest in studying detailed psycho-physiological mechanisms associated with this phenomenon [31]. Thus it is suggested that a reason for what some regard as an anomalous relationship between CHD risk and cholesterol in young men may in part be due enhanced and prolonged exposure to high levels of psychological stress and to the presence within this age-gender group of a significant number of individuals with BP hyper-response to stress. The propensity for exhibiting this exaggerated response to stress happens to be rather strongly correlated with serum cholesterol levels, and this could be responsible for all or part of the observed association between cholesterol levels and CHD risk in young men. Put another way, it is suggested that an important factor involved in the incidence of CHD in young men is high exposure to stress but if BP hyper-responders to stress were absent
545
from the cohorts studied, little or no correlation with cholesterol might have been found because, as pointed out, stress per se only elevates cholesterol by a small amount. Given that exaggerated BP response is itself a risk factor for CHD, the hyper-responders among this age-gender group would experience enhanced risk attributable to stress. Since this exaggerated response is seen most frequently in individuals with high cholesterol, an association would be observed between CHD risk and cholesterol. Correcting for the presence of BP hyper-response might then eliminate cholesterol as a significant risk factor for this age group. Reduced risk found with lipid lowering could then be attributed in part to the action of statin drugs mentioned above, i.e. the blunting of the stress induced BP hyper-response. The mechanism associated with this blunting is not clear and may be due to pleiotropic properties of statins [32]. If it indeed turns out to be the case that this hypothesis is correct, then this would focus more attention on exaggerated BP response to stress in the context of CHD risk in younger men and diminish the emphasis on cholesterol levels. The importance of stress reduction and stress management would also be strengthened.
Testing the proposed association This hypothesis could be tested in a subgroup of the placebo arm of a drug intervention trial. While it seem impossible to artificially induce the intensity or duration of stress encountered in the real-life situations described above, a short protocol exists based on psychological stress induction that identifies hyper-responders [13] and could be introduced as part of baseline assessment. Hyper-responders could also be identified in case-control studies and anyone contemplating a study of the association of stress or BP and CHD might find it informative to add this characteristic to the baseline assessment. It is acknowledged that familial hypercholesterolaemia, while rare, might contribute to the association between CHD and cholesterol observed in young men, especially at the lower end of the age range, and individuals with this condition would be expected on average to fall into the highest percentiles of serum cholesterol. The presence of individuals with the genetic defect associated with this condition have not in general been identified or segregated during the data analysis in large studies of the relationship between cholesterol and CHD and this could contribute to correlations. Ideally, studies designed to test the hypothesis
546 presented here should attempt to take this factor into account. Familial hypercholesterolaemia is a complex issue, if for no other reason than that individuals with this condition may live as long as normal people and have a similar risk of CHD [33].
Conclusions Evidence seems to support the suggestion that coexistence of high serum cholesterol and the propensity for exaggerated blood pressure response to stressful events could be a significant factor when the association between CHD incidence or the risk of adverse CHD events is studied as a function of cholesterol levels in individuals initially free of CHD. Multivariate models that merely incorporate resting or casual BP would not adjust for this factor. This could explain why only young men, a group that might well be exposed to unusually high levels of stress both at work and at home, almost exclusively exhibit this modest but significant association between cholesterol and CHD. The strong relationship between stress and CHD and especially adverse CHD events adds to the plausibility of the hypothesis. This appears to be an important issue. The Framingham Score system reflects enhanced risk associated with elevated cholesterol for younger men by stratifying the scoring for cholesterol by age, but this association may mostly or even entirely due to the relationship between exaggerated BP response and hypercholsterolaemia, and if this is indeed true, attention should be focused on this risk factor rather than on cholesterol levels. The fact that emphasis today centers on LDL cholesterol rather than total cholesterol should not decrease the potential significance of this hypothesis since the most pronounced association is seen at high total cholesterol levels which also imply for the most part high LDL levels since triglycerides and especially HDL make a rather small contribution to the total.
References [1] Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA 1987;257(16):2176–80. [2] Stamler J et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000;284(3):311–8. [3] Ulmer H et al. Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health (Larchmt.) 2004;13(1):41–53.
Ware [4] Jacobs D et al. Report of the conference on low blood cholesterol: mortality associations. Circulation 1992;86(3):1046–60. [5] Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM 2002;95(6):397–403. [6] Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM 2003;96(12):927–34. [7] Peter R et al. High effort, low reward, and cardiovascular risk factors in employed Swedish men and women: baseline results from the WOLF study. J Epidemiol Community Health 1998;52(9):540–7. [8] Kivimaki M et al. Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees. BMJ 2002;325(7369):857. [9] Vrijkotte TG, van Doornen LJ, de Geus EJ. Work stress and metabolic and hemostatic risk factors. Psychosom Med 1999;61(6):796–805. [10] Stoney CM et al. Lipid reactivity to stress: I. Comparison of chronic and acute stress responses in middle-aged airline pilots. Health Psychol 1999;18(3):241–50. [11] McCann BS, Warnick GR, Knopp RH. Changes in plasma lipids and dietary intake accompanying shifts in perceived workload and stress. Psychosom Med 1990;52(1):97–108. [12] Bijlani RL et al. Relationship of examination stress to serum lipid profile. Indian J Physiol Pharmacol 1986;30(1): 22–30. [13] Borghi C et al. Serum cholesterol levels, blood pressure response to stress and incidence of stable hypertension in young subjects with high normal blood pressure. J Hypertens 2004;22(2):265–72. [14] Minami M et al. Pressor hyperreactivity to mental and hand-grip stresses in patients with hypercholesterolemia. J Hypertens 1999;17(2):185–92. [15] Sung BH, Izzo Jr JL, Wilson MF. Effects of cholesterol reduction on BP response to mental stress in patients with high cholesterol. Am J Hypertens 1997;10(6):592–9. [16] Straznicky NE et al. Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension. Am J Cardiol 1995;75(8):582–6. [17] Smith TW et al. Hostility, anger, aggressiveness, and coronary heart disease: an interpersonal perspective on personality, emotion, and health. J Pers 2004;72(6): 1217–70. [18] Smith TW, Ruiz JM. Psychosocial influences on the development and course of coronary heart disease: current status and implications for research and practice. J Consult Clin Psychol 2002;70(3):548–68. [19] Gallacher JE et al. Is type A behavior really a trigger for coronary heart disease events? Psychosom Med 2003;65(3): 339–46. [20] Chang PP et al. Anger in young men and subsequent premature cardiovascular disease: the precursors study. Arch Intern Med 2002;162(8):901–6. [21] Treiber FA et al. Cardiovascular reactivity and development of preclinical and clinical disease states. Psychosom Med 2003;65(1):46–62. [22] Jae SY et al. Exaggerated blood pressure response to exercise is associated with carotid atherosclerosis in apparently healthy men. J Hypertens 2006;24(5):881–7. [23] Jennings JR et al. Exaggerated blood pressure responses during mental stress are prospectively related to enhanced carotid atherosclerosis in middle-aged Finnish men. Circulation 2004;110(15):2198–203. [24] Kamarck TW et al. Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from
High cholesterol and coronary heart disease in younger men: The potential role
[25] [26]
[27] [28]
[29]
the Kuopio Ischemic Heart Disease Study. Circulation 1997;96(11):3842–8. Barnett PA et al. Psychological stress and the progression of carotid artery disease. J Hypertens 1997;15(1):49–55. Alderman MH et al. Blood pressure reactivity predicts myocardial infarction among treated hypertensive patients. J Clin Epidemiol 1990;43(9):859–66. Keys A et al. Mortality and coronary heart disease among men studied for 23 years. Arch Intern Med 1971;128(2):201–14. Mundal R et al. Exercise blood pressure predicts cardiovascular mortality in middle-aged men. Hypertension 1994;24(1):56–62. Kjeldsen SE et al. Supine and exercise systolic blood pressure predict cardiovascular death in middle-aged men. J Hypertens 2001;19(8):1343–8.
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[30] Laukkanen JA et al. Systolic blood pressure response to exercise testing is related to the risk of acute myocardial infarction in middle-aged men. Eur J Cardiovasc Prev Rehabil 2006;13(3):421–8. [31] Lovallo WR. Cardiovascular reactivity: mechanisms and pathways to cardiovascular disease. Int J Psychophysiol 2005;58(2–3):119–32. [32] Minami M et al. Effects of cholesterol-lowering therapy on pressor hyperreactivity to stress in hypercholesterolemic patients. Hypertens Res 2003;26(4): 273–80. [33] Sijbrands EJ et al. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. BMJ 2001;322(7293): 1019–23.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
High cholesterol and coronary heart disease in younger men: The potential role of stress induced exaggerated blood pressure response William R. Ware
*
14 Metamora Crescent, London, ON, Canada N6G 1R3 Received 18 June 2007; accepted 26 June 2007
Summary It is well known that by far the strongest association between serum cholesterol levels and the risk of coronary heart disease or related adverse events is found in younger men. The question is what is different about this age-gender subgroup? It has been suggested that this enhanced risk is seen in younger men because of unique exposure to stress. While stress is known to raise cholesterol levels, the magnitude of the elevation appears insufficient to account for the observed association between cholesterol levels and CHD in young men. An hypothesis is presented which suggests that part and perhaps all of this association is due to the relationship between cholesterol levels and exaggerated blood pressure response to stress, i.e. individuals who exhibit this hyper-response also tend to have significantly elevated cholesterol levels. Given that both stress and an exaggerated blood pressure response to stress are also risk factors for CHD, this could influence the relationship between CHD risk and cholesterol in this age group even if multivariate analysis includes casual blood pressure. This is important since in risk assessment, especially among young men, cholesterol levels play an important role. c 2007 Elsevier Ltd. All rights reserved.
Introduction The association of serum cholesterol and the risk of coronary heart disease (CHD), CHD related events, and CHD mortality has been found to vary with both gender and age, and by far the strongest association has been observed with men under about the age of 50 [1–4]. This is clear when one examines just age and total cholesterol in the Framingham risk calculation. The age factor contribution to * Tel.: +1 519 472 2359; fax: +1 519 472 2932. E-mail address: [email protected]
the score increases strongly with age and the contribution from cholesterol decreases strongly in an age dependent manner yielding a modest or even very small contribution to the resultant risk in older men. A recent very large study confirms what is seen in the Framingham algorithm, i.e. this association in women and the elderly who were initially free of CHD is statistically insignificant or at least much weaker than in young men [3]. Thus the cholesterol–CHD risk association in younger men can be viewed as anomalous [5,6]. This leads to the interesting question – what is different just in younger men that produces this apparently
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.06.031
544 anomalous association of risk with serum cholesterol when the endpoints are CHD or adverse CHD events? It has been suggested that an explanation might be found in the stress environment that appears to be unique to younger men [6]. High levels of stress might be expected to peak during the age period prior to 50. This is the age where some men are in the midst of their professional careers, in many cases subject to great stress, even harassment. It is well known that many individuals, both professionals and non-professionals, hate their jobs, their boss, the part of the country where they work, etc. There is the ever present risk of being fired, losing ones job because of downsizing, or failing to achieve success or to be promoted. Men who own their own businesses may well be exposed to extreme stress since mistakes or bad luck can result in bankruptcy and the loss of everything. At the upper end of this age range, there is the worry about job loss when it could prove difficult if not impossible to find equivalent employment. In addition, this is the age when marital break-ups are common and generally highly stressful, when teenage children may drive their parents to distraction or cause them to become frantic with worry. It is when children may have problems with drugs and alcohol. Work-place stress also interacts with domestic stress and it is obvious that stress can not only be intense but chronic. Thus it can be argued that younger men are exposed to higher levels of stress than older men. But if stress is involved, why the correlation with cholesterol? There are a number of studies over several decades that show a positive correlation between stress and either total cholesterol or LDL levels [7–12]. Cholesterol would then be simply a marker for stress. However, in most studies the magnitude of cholesterol elevation associated with stress is small and typically only a few percent. Higher elevations reported occasionally in the older literature appear to be the exception. Cholesterol elevation attributable to stress appears to be an unlikely explanation for the correlation between CHD and cholesterol found in younger men.
Exaggerated response to stress and cholesterol levels There is another correlation of cholesterol with stress that might provide an answer to the question posed above. A recent paper Borghi et al. report an investigation of serum cholesterol levels and the incidence of exaggerated blood pressure response to stress [13]. It is well known that the response
Ware to stress involving blood pressure varies considerably from individual to individual and some, the so-called hyper-responders, exhibit an exaggerated response. Borghi et al. found significantly greater increases in both systolic and diastolic BP changes induced by mental stress between individuals with high cholesterol as compared those with normal cholesterol or controls. In addition, the changes were slower to normalize after the stress was removed with those having high cholesterol maintaining somewhat BP elevated levels while the controls returned to normal. In the high-normal BP group with high cholesterol, 83% exhibited BP hyper-response, whereas in the high-normal BP group with normal cholesterol levels only 38.1% were hyper-responsive. High normal BP was defined as systolic BP between 130 and 139 mm Hg and diastolic BP between 85 and 89 mm Hg. High cholesterol was 246 ± 4.4 mg/dL whereas for the low cholesterol group it was 177 ± 3.5 mg/dL. The controls had normal BP and low cholesterol. In the study of Borghi et al. baseline cholesterol levels were not correlated with blood pressure. The study group was predominantly males in their late 20 s. These results are consistent with two previous studies that showed BP response to mental stress is exaggerated in patients with hypercholesterolaemia and that the effect can be significantly blunted with hydroxymethylglutaryl-CoA reductase inhibitors (statins) [14,15]. In addition, enhanced vasoconstrictive and pressor response to angiotensin II and norepinephrine has been observed in patients with hypercholesterolaemia [16]. Borghi et al. also point out that impaired endotheliumdependent vascular relaxation has been seen in patients with high serum levels of cholesterol and that this can be observed long before the development of manifest atherosclerotic lesions, and could significantly impact BP regulation. In studies of the association of serum cholesterol and the risk of CHD or CHD events, BP is of course recognized as a major factor. However, adjustment of results to take this into account employs resting BP data. In fact, in most studies it would be entirely out of the question to obtain data on exaggerated response. Therefore it can be argued that the corrections for confounding by BP are incomplete and that the relationship between cholesterol levels and CHD risk could be due to residual confounding. In addition, Borghi et al. found approximately the same low percentage of hyperresponders in both the high-normal BP and normal BP groups when cholesterol levels were low and Minami et al. [14] also found that in normotensive patients with hypercholesterolaemia, exaggerated BP response to stress was present. This provides
High cholesterol and coronary heart disease in younger men: The potential role additional evidence that introducing resting BP into multivariate models will fail to correct for the influence of hyper-response.
Stress and exaggerated BP response to stress and the risk of CHD This hypothesis of course depends of an association between stress and stress induced exaggerated BP response and the risk of CHD and CHD events. This connection with stress in general appears to be well established and the effect is large, in fact much larger than enhanced risk associated with serum cholesterol levels [8,17,18]. Also, so-called Type A behavior is closely related to stress levels and has been shown to be a strong predictor of early coronary events [19]. Likewise, studies reveal that abnormal anger in young men is associated with an increased risk of future cardiovascular disease, and in particularly myocardial infarction [20]. The connection between exaggerated BP response to stress and the risk cardiovascular disease and atherosclerosis has also received attention. In a recent review [21], Treiber et al. concluded that published studies are broadly consistent with the proposition that exaggerated BP response may be predictive of the presence [22–24] and progression [25] of atherosclerosis as determined by intimamedial thickness. The relationship between exaggerated stress response and CHD and CHD events has also been investigated. Either psychological [26,27] or exercise [28–30] induced stress was used and the presence of hyper-response was found to be a significant risk factor, and in some cases the enhancement was dramatic. There in fact appears to be growing interest in studying detailed psycho-physiological mechanisms associated with this phenomenon [31]. Thus it is suggested that a reason for what some regard as an anomalous relationship between CHD risk and cholesterol in young men may in part be due enhanced and prolonged exposure to high levels of psychological stress and to the presence within this age-gender group of a significant number of individuals with BP hyper-response to stress. The propensity for exhibiting this exaggerated response to stress happens to be rather strongly correlated with serum cholesterol levels, and this could be responsible for all or part of the observed association between cholesterol levels and CHD risk in young men. Put another way, it is suggested that an important factor involved in the incidence of CHD in young men is high exposure to stress but if BP hyper-responders to stress were absent
545
from the cohorts studied, little or no correlation with cholesterol might have been found because, as pointed out, stress per se only elevates cholesterol by a small amount. Given that exaggerated BP response is itself a risk factor for CHD, the hyper-responders among this age-gender group would experience enhanced risk attributable to stress. Since this exaggerated response is seen most frequently in individuals with high cholesterol, an association would be observed between CHD risk and cholesterol. Correcting for the presence of BP hyper-response might then eliminate cholesterol as a significant risk factor for this age group. Reduced risk found with lipid lowering could then be attributed in part to the action of statin drugs mentioned above, i.e. the blunting of the stress induced BP hyper-response. The mechanism associated with this blunting is not clear and may be due to pleiotropic properties of statins [32]. If it indeed turns out to be the case that this hypothesis is correct, then this would focus more attention on exaggerated BP response to stress in the context of CHD risk in younger men and diminish the emphasis on cholesterol levels. The importance of stress reduction and stress management would also be strengthened.
Testing the proposed association This hypothesis could be tested in a subgroup of the placebo arm of a drug intervention trial. While it seem impossible to artificially induce the intensity or duration of stress encountered in the real-life situations described above, a short protocol exists based on psychological stress induction that identifies hyper-responders [13] and could be introduced as part of baseline assessment. Hyper-responders could also be identified in case-control studies and anyone contemplating a study of the association of stress or BP and CHD might find it informative to add this characteristic to the baseline assessment. It is acknowledged that familial hypercholesterolaemia, while rare, might contribute to the association between CHD and cholesterol observed in young men, especially at the lower end of the age range, and individuals with this condition would be expected on average to fall into the highest percentiles of serum cholesterol. The presence of individuals with the genetic defect associated with this condition have not in general been identified or segregated during the data analysis in large studies of the relationship between cholesterol and CHD and this could contribute to correlations. Ideally, studies designed to test the hypothesis
546 presented here should attempt to take this factor into account. Familial hypercholesterolaemia is a complex issue, if for no other reason than that individuals with this condition may live as long as normal people and have a similar risk of CHD [33].
Conclusions Evidence seems to support the suggestion that coexistence of high serum cholesterol and the propensity for exaggerated blood pressure response to stressful events could be a significant factor when the association between CHD incidence or the risk of adverse CHD events is studied as a function of cholesterol levels in individuals initially free of CHD. Multivariate models that merely incorporate resting or casual BP would not adjust for this factor. This could explain why only young men, a group that might well be exposed to unusually high levels of stress both at work and at home, almost exclusively exhibit this modest but significant association between cholesterol and CHD. The strong relationship between stress and CHD and especially adverse CHD events adds to the plausibility of the hypothesis. This appears to be an important issue. The Framingham Score system reflects enhanced risk associated with elevated cholesterol for younger men by stratifying the scoring for cholesterol by age, but this association may mostly or even entirely due to the relationship between exaggerated BP response and hypercholsterolaemia, and if this is indeed true, attention should be focused on this risk factor rather than on cholesterol levels. The fact that emphasis today centers on LDL cholesterol rather than total cholesterol should not decrease the potential significance of this hypothesis since the most pronounced association is seen at high total cholesterol levels which also imply for the most part high LDL levels since triglycerides and especially HDL make a rather small contribution to the total.
References [1] Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. JAMA 1987;257(16):2176–80. [2] Stamler J et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000;284(3):311–8. [3] Ulmer H et al. Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health (Larchmt.) 2004;13(1):41–53.
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