Fibrinogen levels had a modest direct association with the number of AMIs and also with the number of total arterial occlusions demonstrated angiographically, and the score of wall motion abnormalities (LVS) (Table 6.2). Those patients who had evidence of left ventricular damage as measured by wall motion abnormalities on the ventriculogram had a higher level of fibrinogen than those with normal function (Table 6.4). The group with the highest levels of fibrinogen had on average a signif icantly greater degree of LV dysfunction as supported by a direct univariate correla tion between fibrinogen and LVS (Table 6.2). Those with LV damage also had a greater volume of cigarette intake during their life (Table 6.4). None of the other major risk factors assessed were related to the LVS. Furthermore, there was no relation between fibrinogen level and the time since the last AMI.
Multiple regression analysis failed to confirm an independent association between LV damage and fibrinogen levels when the severity score and other risk factor variables were taken into account. The only independent variable associated with the LVS determined by multiple regression analysis was the measure of severity of CAD (CSS).
6.1.4 Discussion
In males with established CHD, a modest direct linear association exists between fibrinogen levels and the severity of CAD but not the extent of coronary atheroma. The fibrinogen level in this group of CAD patients is partly dependent on other risk factors (age, smoking and HDL cholesterol level) as well as the presence of severe stenoses. Given this last observation, it is feasible that an underlying disease process may concomitantly cause severe intraluminal obstructive lesions and increased fibri nogen levels, such as recurrent mural thrombosis and fibrin formation within and/or over atherosclerotic plaques.639,714
A descriptive assessment of the relationship between fibrinogen and other variables was made by dividing fibrinogen into 4 groups with an increasing range of values. This descriptive illustration supports the modest linear relationships shown in the correlation assessment, and, more importantly, demonstrates the poor clinical utility of the fibrinogen level for predicting severity or extent of disease in an individual. Other studies have also shown a marked overlap of the fibrinogen levels between
groups having increasing CAD severity.374 The fibrinogen level in such groups also had a large standard error of the mean.374
Previous studies evaluating the relationship between fibrinogen and angiographically defined CAD have made conflicting observations. A significant association between fibrinogen and a measure of CAD has been documented previously711 and multive ssel CAD disease patients have higher fibrinogen levels than patients with single vessel disease.712 Another study, using multiple linear regression, failed to show any predictive relationship between fibrinogen and angiographic CAD.713 The disparities between these reports, and with the current study, most likely arise from methodo logical differences, particularly in relation to the method of defining CAD. For example, the scoring system criteria used in one study713 was derived from clinical requirements and lesion haemodynamics, and does not provide a broad gradient measure of overall extent and severity of atherosclerosis. In a more recent study,374 which reported plasma fibrinogen as being an independent predictor of CAD severi ty, a number of methodological anomalies exist. For example, alcohol intake was entered into the multivariate analysis used in the study even though it was not corre lated with fibrinogen levels and it is an equivocal risk factor for CAD. Yet triglyce ride levels, which may influence the relationship,713 were not entered. Furthermore, patients with severe left main stem arterial lesions were excluded, ex-smokers of 5 years or more were considered non-smokers, controlled diabetics were included, and, even though the blood sugar univariately correlated with fibrinogen, it was not entered into the multiple regression analysis. Also, approximately 33% of the male group studied did not have significant obstructive CAD (Gensini score of zero). Despite these patient population and methodological differences, both our observa tions and this report374 support the presence of an independent association between severe disease and fibrinogen level, with fibrinogen as the dependent variable. Unfortunately neither study can clarify whether the association provides an aetiolog- ical link between plasma fibrinogen and obstructive CAD.
The degree of functionally impaired myocardium has a direct and proportional asso ciation with fibrinogen. A negative correlation has previously been demonstrated between fibrinogen and left ventricular ejection fraction.713 This observation is in agreement with the positive association between the LVS and fibrinogen level. However, this association would appear to be indirect rather than causal, since the only variable independently associated with our measure of left ventricular dysfunc tion (LVS) by multivariate analysis is disease severity, the fibrinogen level only being related by association with disease severity (CSS).
An increase in fibrinogen occurs in the acute phase of a MI.715'717 In general fibrino gen reaches a maximum level within the first week715,716 and in most cases returns to pre-infarct levels within 3 to 4 weeks.715 This time course parallels that for the healing of necrotic tissue within the myocardium following an infarct.11 This study has demonstrated an association between fibrinogen and left ventricular segmental dysfunction present beyond such a time frame. However, our multiple regression analysis would suggest that chronically elevated levels are more directly related to the underlying disease severity. Similarly, the univariate relationship of fibrinogen with the number of AMI probably arises indirectly via disease severity, or by mechanisms simultaneously leading to severe lesion development, AMI, and in-
creased fibrinogen production.
Previous studies have established an association between fibrinogen and a number of th e m a jo r risk fa c to rs fo r C H D . T h e se fa c to rs in c lu d e a g e ,705,718'720 to b a c c o use,327,703,718'721 blood cholesterol level,372,631,721 and lower socioeconomic status.722 We have confirm ed the presence of an independent direct relationship betw een the fibrinogen level and previous cigarette use by an individual. This study cannot eval uate the acute effects o f cigarette smoking on fibrinogen levels. The association was with the total volume o f cigarette intake during the life of the patient, supporting the observation that it may take more than 5 years for fibrinogen to return to pre-sm ok ing levels.60 It is of relevance that ex-sm okers m ay be at higher risk o f acute coro nary events for at least 15 years after stopping.723 Furtherm ore, it has been suggest ed that a substantial p art o f the relatio n sh ip betw een sm oking and CHD m ay be m ediated through fibrinogen.60 Equally, the converse may be true. O ur findings do not resolve this question but do dem onstrate that long-term smoking directly results in a d ose dep en d en t in crease in fib rin o g en . H ow ever, the a p p aren t re la tio n sh ip b etw een the chronic use o f c ig arettes and fib rin o g en lev el m ay be the re s u lt o f observer/selection bias. There was no validation o f the accuracy of the self-reporting o f tobacco intake, including the current use o f cigarettes. Therefore, the association may feasibly be related to acute smoking effects that were unreported.
An unexpected observation was the relatively strong and independent inverse asso ciation with HDL cholesterol levels. M ost previous reports concerning individuals with or without CHD have not examined such a possible relationship, or possibly did not rep o rt the lack o f association,705,711'713 and little is available from population based studies.372,373,703,718,722 A lack o f association has been rep o rted for a norm al population group,719 and also for CHD patients.374,704 A negative but insignificant association using the ’clottable’ fibrinogen method but not with the heat precipitation method for fibrinogen measurement has been demonstrated in CHD patients random ly selected from a specific population.704 The relationship m ust rem ain a tentative possibility but does highlight the importance of validation techniques for self report ing o f tobacco intake to assess under-reporting of past and current tobacco use. This is o f further im portance with regard to the HDL cholesterol level association with fibrinogen. Sm oking has a well know n inverse association w ith H D L cholesterol levels, and under-reporting may introduce sufficient bias to give a false independent association between fibrinogen and HDL cholesterol, and reduce the possibility o f m easuring an association between sm oking and the severity o f CAD. The inverse association observed in our study indicates an area for further study. N evertheless, the observation has subsequently been confirmed in other studies.724'729, although the reason has not been elucidated. The later uniform confirm ation of the positive asso ciation between HDL cholesterol and fibrinogen level adds further validation to the observations of this study.
Increasing age is one o f the m ost pow erful predictors for the developm ent o f both CAD and CHD.202 This is reflected in the results o f our univariate and multivariate analysis. Population based fibrinogen levels have a positive relationship with age,730 which also occurs in aging CHD patients.731 It is possible that any increase in fibri nogen with age noted in population based studies may in part be due to the develop m ent o f subclinical severe obstructive disease. This would increase the likelihood of
the fibrinogen level being a reliable prospective predictor of CHD and symptomatic events in a "normal" population group.
Apart from age, the risk factors analysed in the present study do not significantly contribute to the variance of disease severity or extent within a group of males with established CHD. This observation does not negate their possible influence as risk factors for the initiation of CHD in a susceptible individual or group, and this ap plies equally to the fibrinogen level. However, within such a group they do not appear to contribute substantially to the severity and extent of disease expression as interpreted angiographically. If the study sample number were to be increased great ly in order to detect possible weak associations which were significant in the multi ple linear regression analysis, their contribution to the variance of the dependent variable would not be remarkably altered. Therefore, even if the sample size con tributed to a type II statistical error, increasing the number would not result in a relationship that had a substantial clinical value.
A potentially major confounding methodological problem with most angiographic studies, including the presently reported observations, is the lack of incident cases used to assess the relationship. Lipid measures, hypertension, weight and tobacco use will all have undergone possible modification following the initial diagnosis, leading to a selection bias and hence limiting the likelihood of necessarily finding significant associations. In addition, modification of both the underlying disease as well as the risk factors may occur following the long-term use of cardiovascular active drugs, such as beta-blockers and calcium entry blockers. This potential prob lem may also apply to this assessment of fibrinogen despite the exclusion of individ uals with known confounding factors. A possible important association between diet and fibrinogen may exist. A direct relation between linoleic acid intake660 and an inverse association with dietary cereal719 have been reported. No major influence over fibrinogen levels has been noted for cardiovascular medications.60,418 Those drugs recorded as being able to modify fibrinogen levels732 were not used by the patients with CAD evaluated in this study. A prospective angiographic study is required to more appropriately evaluate the observations from our cross-sectional study, but with current angiographic methodology a prospective study on normals to more reliably evaluate a causal relationship cannot presently be performed.
6.1.5 Summary
1. The above observations do not verify the proposition that an increased fibrinogen level is causally associated with a greater extent and/or increased severity of CAD. Elevated fibrinogen levels do have a modest relationship with severe CAD. This relationship, however, may be due to another process simultaneously leading to increased fibrinogen levels and the development of severe stenotic CAD, such as in creased platelet reactivity. The plasma fibrinogen level must be taken into account when evaluating differences in platelet function between any two groups.
2. They indicate that any relationship existing between fibrinogen and CAD is unlikely to be due to a non-specific response to atherosclerotic involvement of the coronary arteries. An independent association between fibrinogen and the extent of coronary arterial wall involvement, and by inference, atherogenesis, was
not able to be demonstrated.
3. The fibrinogen level for an individual with CAD is in part directly pre dicted by the volume of previous cigarette use, the age of the individual, the severity o f underlying CAD, and inversely by HDL cholesterol level.
4. The results rem ain co n sisten t w ith the observation that a priori high fibrinogen levels may be predictive o f an increased incidence o f CHD events. This p red ictiv e relationship w ould appear to be m ediated through an association w ith other risk factors and with CAD severity. W hether there is any causal relationship between CHD events and fibrinogen levels still remains to be determined.
6.2 FIBRINOGEN LEVELS IN YOUNG MALES WITH CORONARY