LEVELS, LIPOPROTEINS AND BLOOD GLUCOSE IN YOUNG MALES WITH CORONARY HEART DISEASE
6.3.1 Introduction
It is clear from the results presented in this Chapter, and from the literature, that the epidem iological evidence for an elevated blood fibrinogen level being a risk indica tor for CHD is unequivocal. Nevertheless, a mechanism for the relationship has not been elucidated and the question as to whether there is a causal relationship has not been fully established.62,372,373,701'707 M oreover, there exists a clustering of the other m ajor risk factors that are associated with plasm a fibrinogen level, the mechanisms o f w hich also rem ain unexplained. An association betw een fibrinogen and other m ajor risk factors for CHD has been well established.62,143,372,374,631,703,705,718'722,738. In addition, an independent inverse association between plasma fibrinogen and HDL cholesterol levels in males with CHD was noted in the prelim inary studies for this thesis.61 At that tim e most previous reports concerning individuals with or without CHD had not exam ined the relationship.61 Indeed, review articles made no mention o f a relationship.62,738,740 One possible explanation was that a negative association had not been re p o rte d .705,711'713 T here was also little av ailab le inform ation from population based studies.372,373,703,718,722 There were reports dem onstrating no asso ciation in a normal population group719 and in CHD patients.374 A positive associa tion with CHD patients using the ’clo tta b le ’ fibrinogen m easurem ent m ethod had been dem onstrated, but not with the heat precipitation m ethod.704 H ow ever, since then the association has been substantiated by a num ber o f studies which recently have been reported in prelim inary form .724'729 In population studies, the fibrinogen level correlated positively with total cholesterol,724 also with LDL cholesterol,725,728 and inversely with HDL cholesterol levels.724,725,727,728
A ssociations betw een plasm a fibrinogen level and obesity738 and diabetes143,738 are w ell recognised, and even with the blood glucose level in n o n -d iab etics.374,143 O f additional interest is an apparent association betw een plasm a fibrinogen and blood insulin lev els,727,728 as w ell as body fat d istrib u tio n .724,727,741'743 H ow ever, not all studies dem onstrate an association with fat distribution744 or do so only with univar iate analysis 727
T h erefo re, in lig h t o f the above in fo rm atio n , in this section the re la tio n sh ip s o f plasm a fibrinogen levels in non-diabetic young males with prem ature CHD and the w ell m atch ed c o n tro l group are fu rth er e v a lu a te d in o rd e r to fu rth er refin e our
understanding of the relationships.
6.3.2 Methods
6.3.2.1 Patient Population. The case and control groups consisted of the young males defined in Chapter 3. The exclusion criteria are described in section 6.1.2.1. 6.2.2.2 Laboratory measurements. The laboratory methods have been described previously61 in Chapter 2.
6.3.2.3 Anthropomorphic Measures. These measurements are described in full in Appendix 2.
6.3.2.4 Glycosylated Haemoglobin. A colourimetric method was used for the estimation of Hb glycosylation364'366 and is described in Chapter 2.
6.3.2.5 Statistical Analysis. Associations were evaluated by univariate analysis and the details are given in Chapter 2.
6.3.3 Results
6.3.3.1 Group comparisons. The mean values for the major risk factors are summarised and comparisons made between the groups in Chapter 3. Of particular note, was that all tobacco users were cigarette smokers and there were 7 and 4 current smokers in the control and case groups respectively. In addition, the non diabetic case group had a significantly higher BSL (5.3+/-0.10 vs 4.9+/-0.08 mmoles/1, p=0.02) and H bA lC level (7.8+/-0.2 vs 7.3+/-0.1, p=0.03) than the controls, although the levels were within the normal range. Moreover, the scapular skin fold thickness was significantly higher in the case group (17.1+/-0.9 vs 1.8+/- 0.7 cm, p=0.006), but there was no difference in the weight, height, BMI and tri ceps skin fold thickness. Finally the plasma fibrinogen level was also significantly greater in the case group (275+/-10 vs 230+/-8 mg/100ml, p=0.001).
6.3.3.2 Correlations. The fibrinogen level in both groups correlated weakly with age but the age distribution of both groups was narrow (Table 6.5). The correlation with other factors is described in section 6.2.
6.3.33 Multivariate analysis. Multivariate analysis was performed with the plasma fibrinogen level as the dependent variable. Those CHD risk factors which had a univariate association were entered into the regression equation as the inde pendent variables. The Hb remained predictive of fibrinogen levels in the control group. Scapular skin fold thickness was independently predictive of fibrinogen level in the CHD group (Table 6.7).
6.3.4 Discussion
An independent inverse association between plasma fibrinogen and HDL cholesterol levels has been documented in a broad age group of patients with CHD (Section 6.1).61 This observation has been supported by the early reports from a number of
other studies.724'729 In the present report of a younger group of males with premature CHD, an inverse univariate association was similarly demonstrated, but was not independently predictive of the risk factors measured. More importantly, the associa tion was not demonstrated in the normal controls. However, in the preliminary study described in section 6.1,61 HbAlC and scapular skin fold thickness were not meas ured, and hence not included in the multivariate analysis. From the present results, it would appear that the relationship between fibrinogen and HDL cholesterol levels may be due to a co-morbidity bias. That is, both are associated with each other through an association with the cluster of risk factors of central body obesity, abnormal glucose homeostasis, hypertension and abnormal lipoproteins. Indeed, that link could also be the reason that they are risk factors for CHD.
The inverse association between fibrinogen and HDL cholesterol levels can also be supported by a plausible biological explanation, and may well be a direct associa tion. A strong positive relationship between plasma lipoprotein lipase (LPL) and HDL cholesterol levels has previously been documented.745 Thrombin inhibits LPL210 and also appears to stimulate fibrinogen synthesis by an enzymatic mechan ism independent of fibrinogenolysis or disseminated intravascular clotting.746 There fore, increased thrombin activity, for whatever reason, may increase fibrinogen production and increased fibrin breakdown products will further stimulate fibrinogen synthesis. The increased thrombin activity will also inhibit LPL activity possibly leading to decreased HDL cholesterol levels. Furthermore, fatty acids significantly increase the production of fibrinogen,208 while polyunsaturated fatty acids and trigly cerides decrease HDL cholesterol levels.747
An association between the blood glucose and fibrinogen levels in a non-diabetic population has been documented in the past,143 and an association between fibrino gen and HbAlC values had been previously predicted.143 There exists a cluster of CHD risk factors (blood glucose level, HbAlC, BMI, body weight and scapular skin fold thickness), which together are measures of a group of risk factors which are well recognised predictors for CHD.748,749 However, the fibrinogen level univariate- ly correlated with the factors in this grouping only in the CHD group, and the asso ciation was not present in the control group. Furthermore, the strength of this rela tionship was demonstrated when a measure of central body obesity, namely scapular skin fold thickness, was independently predictive of the fibrinogen level, an observa tion also unique to the CHD group.
An elevated fibrinogen level in populations with a low incidence for CHD is not a risk factor for CHD.60 High fibrinogen levels occur in groups where CHD disease is rare, suggesting that if increased fibrinogen levels cause CHD, high levels must interact with some other characteristic.60 Fibrinogen has a strong relationship with hyperglycaemia in diabetics143 and clusters, along with other CHD risk factors, with an abnormal lipoprotein profile.750 As discussed, the fibrinogen level, in addition, directly correlates with a number of other risk factors. These facts, in combination with the observations made in this report, that the fibrinogen level in CHD patients with premature CHD is related to specific risk factors and is not related to the same factors in a normal group, supports the concept that an elevated fibrinogen level is possibly only a causal risk factor for CHD (that is the clinical expression of the disease) in individuals with developed CAD having preexisting atheroma, as pre-
viously suggested.60 Alternatively, the association may be through mechanisms giving abnormal glucose homeostasis, abnormal lipoproteins (including low HDL cholesterol levels), hypertension and central body obesity, which so often cluster together in individuals with CHD.
6.3.5 Summary
1. An inverse association between HDL cholesterol and fibrinogen levels in patients with CHD was demonstrated in preparatory study of this Thesis and con firmed in the main case-control study. This was a novel observation which has also been reported independently by others. The mechanism of this association remains to be elucidated.
2. In CHD patients the fibrinogen level appears to have an association with other more recently recognised risk factors which cluster together, viz central body obesity, abnormal glucose homeostasis and lipid abnormalities. Given these observations, the impact of such potential relationships on the results of this Thesis are examined in Appendix 2.
6.4 FIBRINOGEN AND IN VITRO PLATELET AGGREGATION