Use of Carotid IMT in risk stratification of hypogonadal men with atherosclerosis and coronary artery disease - Essay Example

1) Introduction Coronary heart disease (CHD) is one of the most common causes of death in the Western World. It results from coronary atherosclerosis, which is directly associated with several well defined risk factors, including smoking, diabetes mellitus, hypertension, obesity, hyperlipidemia, lack of exercise, and familial predisposition. Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex (Jones, 141). Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD as their female counterparts (Jones, 141, English et, al., 890). Is it possible that a male hormone like testosterone is partly responsible for this It is well known that serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Testosterone exhibits a number of potential cardioprotective actions. Testosterone administration is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1, tumor necrosis factor (TNF ) and to increase levels of the anti-inflammatory cytokine IL-10 among others (Jones, 142-145, Malkin et al., 3313) Lower testosterone levels have also been correlated with carotid atherosclerosis as shown by Jones (146). Most epidemiological studies of risk factors for atherosclerosis and clinical trials for the prevention of disease have used the morbidity and mortality that results from coronary artery disease (CAD), stroke, and peripheral vascular disease as measures of the disease process in older adults. But this does not mean that the younger population is immune to atherosclerotic process. There is a larger subset of population that is prone to presenile atherosclerosis, particularly those with a family history. This is a very important group of patients that need to be identified early, so that preventive and remedial measures may be suitably instituted, before occlusive process occurs. Traditionally this screening process has used blood investigations like lipid analysis, blood sugar analysis, cardiac evaluations tests like cardiac enzymes, and echo. But is there a possibility of a test, simple enough to be easily reproducible, done quickly and noninvasively, and which carries a prognostic significance Carotid IMT studies using Doppler is increasingly been seen as an important marker for prediction of CAD. This is a new field, which has assumed great significance. It is increasingly being identified as a screening procedure and a marker to assess prognosis. This is an office procedure, noninvasive, simple enough to be reproducible, with least patient discomfort. Is it possible to link somehow, the use of testosterone, carotid IMT and the risk of atherosclerosis so that a combined analysis gives us greater confidence in patient management We know now that carotid IMT is significant in atherosclerosis. We know that testosterone levels are lower in elderly males, possibly being a cause in development of CAD. Studies have linked low testosterone levels with greater IMT. Thus it seems plausible to use low testosterone levels and carotid IMT in the screening and follow up of patients at risk for development of CAD and patients who have had CAD and are being managed for prevention of further events. 2) Use of carotid IMT as risk stratification tool and how it is measured Carotid IMT is a noninvasive procedure based on the use of the common Ultrasound technology with suitable modification. The technique uses a B-mode real-time ultrasound with a high resolution. B-mode ultrasound imaging technology has evolved to the extent that the walls of superficial arteries can be imaged non-invasively, in real-time, and with high resolution. Bots has shown the use of The Meijer's Arc, which allows a standardized circumferential scan of the left and right carotid artery (2986). In his article he has used the Meijer Arc to standardize the points of examination on both sides of the neck, and also as a reference for future examination. Since this technique is a dynamic technique, unlike angiography or 'luminology', ultrasound imaging can visualize the arterial wall at every stage of atherosclerosis, from 'normal' arterial wall to complete arterial occlusion. Arterial wall thickness can therefore be measured as a continuous variable from childhood to old age, in patients and healthy controls. Espeland states that, "strong association between carotid IMT and cardiovascular events has been demonstrated repeatedly. For example, the Cardiovascular Health Study, found it to be the risk factor most strongly associated with incident cardiovascular events" (5). Carotid IMT was shown to be highly predictable for future cardiovascular events. In the Rotterdam Study, Del Sol, et al. found that a single carotid IMT measurement was of the same importance as a battery of commonly used risk factors in the prediction of CHD and CVD (Espeland, 5). It is of importance for the success of carotid IMT and its acceptance more widely that there be standardized values which can be used as reference values, rather than different studies using arbitrary values. The Atherosclerosis Risk in Communities (ARIC) study found that carotid IMT of 1 mm or more was associated with two to five times the increased hazard of CHD and four to eight times the increased hazard of stroke (Chambless, 485-86). This is a highly significant development and has strong prognostic significance. This study implied that not only was the Carotid IMT associated with CAD, but it could be a predictor for cerebrovascular accidents as well, and for the first time a figure of 1 mm was given, which they felt was significant enough to be used as reference. Further Rotterdam Study found that per standard deviation increase (0.16 mm) in IMT, the odds ratio for myocardial infarction was 1.43 (Del Sol, 1535). Thus if the carotid IMT increased, it was associated with a proportionately increases risk of CAD but does a decrease in IMT allow a decrease in risk of CAD. This question will be answered in the following sections. In the next section, the methodology of the technique is outlined. Measurement of CIMT The CIMT is noninvasively and reproducible assessed in the carotid artery by B-mode ultrasound (Simon, 159). The common carotid artery bifurcates into its terminal branches, the internal and t he external carotid artery. So which 'carotid' artery is measured, the common, the internal, or the external or all Simon has categorized the evaluation into two approaches: (i) measurement at multiple extra cranial carotid sites in near and far walls and (ii) computerized measurement restricted to the far wall of the distal common carotid artery. In the first technique the artery is studied at multiple points at the level of the common, external and internal, and both the near and far walls are studied, and an average of the readings is taken. In the second technique, just the distal CCA is studied at the level of the far wall. Sakaguchi et al., suggest that multiple studies at the carotid bulb and ICA, are more strongly associated with coronary lesions than CCAIMT alone (368,370). This implies that multiple sites of measurement including ICA are more important as compared to CCA IMT alone. Thus the study should not be just limited to the CCA, but an effort should be made to measure ICAIMT as well. Sakaguchi has also developed a plaque score (plas) to grade the type of atherosclerotic plaque. They feel that a combination of both Plas and IMT is more predictive that IMT alone (370). 3) Increased carotid IMT and atherosclerosis (and CAD) Carotid IMT is now being increasingly linked as a predictive tool to follow patients of CAD. There is need to study its role in younger at risk patients also. Aminbaksh carried out a study where he collected data of all previous studies linking IMT with risk factors in CAD patients and normal persons (150). In his analysis he writes that the risk of first myocardial infarction increases with an IMT of 0.822 mm or more, and a progression rate of 0.034 m per year or more increases the risk significantly (154). He has linked carotid IMT not only with the development of atherosclerosis, but with the actual development of MI. This paper is also significant as it focused on the evaluation of IMT in normal persons and those yet asymptomatic as well. This puts us on a stronger footing as we discuss the role of IMT in atherosclerosis. CIMT has also been shown to be significant in predicting early onset atherosclerosis in individuals with family history, thus underlying the need for greater surveillance (Wang et al. 575) A definite relation of IMT has been shown with atherosclerosis if IMT is above 1 mm (Sinha, 529) even in low to intermediate risk individuals. This figure, previously mentioned, is now not only significant for elderly patients, but also for younger, at risk individuals. Thus in the younger age group at risk individuals, there is a case for early institution of carotid IMT study, and a regular follow up if the IMT is more than 1 mm. It also implies that the need for lifestyle modification and treatment for CAD much before the IMT approaches this magical figure of 1 mm. It is now beyond doubt the relation of carotid IMT with atherosclerosis. It follows that IMT may be related also to the risk factors for CAD. In an excellent paper by Poredos, an analysis of CIMT with risk factors of atherosclerosis has been made (48). Not only a positive correlation with age, sex, lifestyle (obesity, smoking) has been shown, an association with insulin resistance has been shown (48). Thus IMT may be suggested to have a role in the prediction of CAD in diabetics. There was a mention previously of the possibility of improvement in CIMT if intervention is undertaken. Poredos also highlights the improvement in CIMT once anti atherosclerotic measures are taken (50). The author has shown reversal of IMT with cessation of smoking, antilipidemic agents, and lifestyle modification (50-51). Thus if the patient is compliant with his treatment and modification of his lifestyle, carotid IMT can be used a predictor of decrease in risk. It quantifies the absolute decrease in risk for development of cardiovascular and cerebrovascular event. This paper lies to rest any queries regarding a correlation of CIMT with atherosclerosis and CAD. There are three dimensions to the role of IMT. The first is its role in the evaluation of elderly, symptomatic and asymptomatic patients. The second is its role in the younger patient who is prone to atherosclerosis, but is as yet asymptomatic. But can this procedure be used as a risk predictor, in those who have already undergone CABG Yes, according to O'Leary et al, who quote Hodis et al, in finding an association between intima- media thickness and further coronary events. In a study of patients who had undergone coronary-artery bypass graft surgery (O'Leary, 20, Hodis, 267-8), O'Leary et al., found carotid- artery intima-media thickness is a strong predictor of new cardiovascular events even after statistical adjustment for other risk factors (20), thus proving this index to be an independent risk factor. They clarified that carotid IMT is an independent risk factor in addition to the traditional risk factors which are known to all of us, implying that there is a need to include IMT study in the investigative work up of the at risk patient. 5) Increased carotid IMT and low testosterone (hypogonadism) There is a growing body of evidence to prove that low testosterone levels are an independent factor in increase of CIMT. Svatberg et al., found in a study an inverse association between total testosterone levels and IMT of the carotid artery in men that was present also after excluding men with CVD (581). This implies that low testosterone level is an independent risk factor for intimal thickening in the carotids, and this increase is not due to coincident atherosclerosis giving credence to the opening statement. But how clinically relevant is this In the human body it is the level of the free enzyme which is more significant as the form which is bound to body proteins is usually unavailable to exert its action, and testosterone is no exception. The role of free testosterone has been investigated by Yang et al. In their study where they studied the levels of free testosterone in the elderly patients and those with CAD, they conclude that the normal levels of Free testosterone (FT) has a beneficial role in atherosclerosis, and the low levels seen in elderly have a contributory role in development of CAD ( 556). This could imply that if a normal level of testosterone is maintained in the body, it may prevent the onset of CAD. Of particular significance is the study of Yang in Sep 2005,where he previously studied the role of FT in atherosclerosis using carotid IMT by Doppler technique. He found Free testosterone was in negative correlation with atherosclerosis in old-age male (931). What is the role of free testosterone There is evidence to suggest that free testosterone may have the role of anti-atherosclerosis. Barud explains that fall of testosterone concentration in ageing men can influence either oxidative modification of LDL or the immune response to these lipoproteins which may be important in the pathogenesis of atherosclerosis (283) In another study, Yang found that low free testosterone level was followed by increased level of inflammatory cytokines, which accelerate the process of atherosclerosis (Yang, 932). Makinen studied middle aged males and found common carotid IMT correlated inversely with serum testosterone (p = 0.003) in multivariate models adjusted for age, total cholesterol, body mass index, blood pressure, and smoking (1603, abstract). This finding is significant as it brings into focus the role of low levels of testosterone in middle aged males, and not just elderly males. Does this have implications for use of testosterone in management of CAD Muller studied 195 asymptomatic men and found Low free testosterone levels were related to IMT of the common carotid artery in elderly men independently of cardiovascular risk factors (2074), giving further credence to the role of these factors in screening. Low testosterone is therefore being linked with IMT across all ages, and independent of status of CAD. With further studies the combined role of testosterone and IMT becomes clearer, as both are now being associated in diabetic patients also. Diabetes is itself a major risk factor in development of CAD. De Pergola studied the role of FT in 127 overweight and obese glucose-tolerant (NGT) young adult men, indicating that IMT-CCA is negatively associated with FT levels, independent of age, total body fat, central fat accumulation, and fasting glucose concentrations in overweight and obese NGT patient and concluded that hypotestosteronemia may accelerate the development of atherosclerosis and increase the risk for CHD in obese men (806-7). Thus low testosterone has been correlated with carotid IMT across all age groups in patients asymptomatic for CAD, but having all the risk factors, including diabetes as suggested by Fukui (1029) 6) Prevalence of coronary artery disease in men with low testosterone It is increasingly being recognized that patients coronary artery disease have lower levels of testosterone as compared to age matched persons without CAD (Dobrzycki, 876). In his study Dobrzycki estimated levels of testosterone in patients with and without CAD, and came to the conclusion of the causative role of testosterone in CAD. However there are few studies that have actually demonstrated this. The current literature is full of data which focuses on role of testosterone in development and progression of atherosclerosis. Whether CAD is more common in patients of hypogonadism is still not clear. Also is not clear, the incidence of CAD in patients with low testosterone levels. These are areas of current research. However there is a role of testosterone, is a fact which is being gradually accepted. Yang et al, have clearly demonstrated the prevalence of low testosterone level in patients of atherosclerosis (556). Sieminska also suggests the role of low testosterone in CAD development. He studied 105 documented CAD patients and found low testosterone levels in all patients as compared to controls (164-65). Low testosterone can now be directly linked to CAD, and not just the process of atherogenesis. What is the incidence of hypogonadism in patients of CAD An answer to this question could indicate the relative causative importance of low testosterone levels in CAD. Jones studied 831 men with CHD and concluded that prevalence of hypogonadism in CAD patients was between 23.4% to 52.6%, using different cut off limits for testosterone levels (148). In his study, where he used very low levels of testosterone for cut off , he found an incidence of about 23%, but the same figure rose to greater than 50% when the cutoffs used in other studies were used. This could mean that up to half of the patients of CAD have low testosterone levels. This is a very significant figure. Van den Beld et al. demonstrated a strong inverse association between serum levels of total testosterone and the degree of carotid atherosclerosis in a population of 403 independently-living elderly men, aged 73-94 years (25). They found that the incidence of carotid atherosclerosis was higher if there were lower testosterone levels. Now it is known that carotid atherosclerosis is associated with CAD, so this study has significant importance. In another significant study English et al, assayed testosterone in angiographically proven CAD patients and found significantly lower levels than in patients with normal angiograms (892-93). There is thus irrefutable evidence to suggest the role of testosterone in CAD. Summary To summarize, there is abundant literature to prove that CIMT has a definite and positive correlation with atherosclerosis and CAD. Not only is this procedure of significance in patients of CAD, it also has the potential to pick up asymptomatic patients, especially those with preexistent risk factors. CIMT has the ability to predict new cardiac events. Its greatest benefit can be shown in individuals where treatment and lifestyle modification has been instituted. CIMT is also increase independently in individuals with low testosterone, either due to age or pathology. Testosterone, on the other hand is now being increasingly linked to development of CAD. It is now known that low testosterone levels in elderly males maybe a risk factor for development of CAD. These facts open up an exciting area of research which focuses on the combined role of CIMT and hypogonadism in CAD. On one hand is the prospect of therapeutic benefit of testosterone, and on the other is the role of CIMT and low testosterone levels in the early diagnosis and follow up of CAD patients. These issues need to be addressed with randomized controlled trials. The answers that these trials give may cause a sea change in the management of CAD patients. References 1. Aminbakshi A, Mancini John GB. Carotid Intima - Media Thickness Measurements: What Defines an Abnormality A Systematic Review. Clin Invest Med;22(4):149-57 1999 2. Barud W, Palusinski R, Beltowski J, Wojcicka G. Inverse Relationship between Total Testosterone and Anti-Oxidized Low Density Lipoprotein Antibody Levels in Ageing Males. Atherosclerosis. Oct;164(2):283-8. 2002 3. Beld Van Den AW, Bots ML, Janssen JA, Et Al. Endogenous Hormones and Carotid Atherosclerosis In Elderly Men. Am J Epidemiol; 157: 25-31. 2003 4. Bots Michiel L, Evans Gregory W, Ward A. Riley, Grobbee Diederick E., Carotid Intima-Media Thickness Measurements in Intervention Studies Design Options, Progression Rates, and Sample Size Considerations: A Point Of View. Stroke.;34:2985-2994. 2003 5. Chambless LE, et al.,Carotid Wall Thickness is Predictive of Incident Clinical Stroke: The Atherosclerosis Risk In Community(ARIC) Study. Am J Epidemiol, 151:478-487. 2000 6. de Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R. Free Testosterone Plasma Levels are Negatively Associated with the Intima-Media Thickness of the Common Carotid Artery in Overweight and Obese Glucose-Tolerant Young Adult Men. 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IntimaMedia Thickness: Indicator of Cardiovascular Risk and Measure of the Extent of Atherosclerosis. Vascular Medicine; 9: 46:54. 2004 19. Sakaguchi et al., Equivalence of Plaque Score and Intima-Media Thickness of Carotid Ultrasonography for Predicting Severe Coronary Artery Lesion. Ultrasound In Med. & Biol., Vol. 29, No. 3, Pp. 367-371, 2003 20. Sieminska L et al., Serum Free Testosterone in Men with Coronary Artery Atherosclerosis. Med Sci Monit. May;9(5):CR162-6. 2003. 21. Simon A, Je Rome Gariepy, Gilles Chironi, Jean-Louis Megnien, Jaime Levenson. Intima- Media Thickness: A New Tool for Diagnosis and Treatment of Cardiovascular Risk. Journal of Hypertension, 20:159169. 2002 22. Sinha A, Eigenbrodt Marsha, Mehta Jawahar L., Does Carotid Intima Media Thickness Indicate Coronary Atherosclerosis Current Opinion in Cardiology, 17:526-530. 23. Svartberg J et al., Low Testosterone Levels Are Associated With Carotid Atherosclerosis In Men. J Intern Med. Jun;259(6):576-82. 2006 24. Wang et al., Carotid Intima-Media Thickness Is Associated With Premature Parental Coronary Heart Disease The Framingham Heart Study. Circulation.;108:572-576.. 2003 25. Yang YM, Lv XY, Huang WD, Xu ZR, Wu LJ. Study of Androgen and Atherosclerosis in Old-Age Male. J Zhejiang Univ Sci B. Sep;6(9):931-5. 2005 26. Yang YM, Xu ZR, Wu LJ, Li Z, Gu HF, Zhao XH. Atherosclerosis And Androgen Levels In Elderly Maleszhejiang Da Xue Xue Bao Yi Xue Ban. Nov;34(6):547-50, 556. 2005 Read More