Hidróxidos

The “classical” cardiovascular risk factors (cholesterol, hypertension, diabetes, smoking and family history) do not fully account for CAD risk. Furthermore, they do not account for the gender differences in prognosis in those with proven CAD.^‘°. Women who present with MI have been shown to have a poorer prognosis than men who present similarly. Fibrinogen, FVII:C, PAI-1 and vWF have been shown in large studies to predict acute coronary events.^"*' The question arises as to whether sex differences between these haemostatic parameters could explain the differences in disease presentation and prognosis.

As in the CASS study^"^\ we found that nearly half o f the female patients undergoing coronary angiography had insignificant coronary disease or apparently normal coronary arteries compared to only 20% in our male subjects. This indicates the need for other non-invasive markers that may better predict the presence of significant coronary atheroma

As expected, women presenting for angiography were older and had higher plasma cholesterol levels than men. They were also more likely to be hypertensive,^*®’ and less likely to smoke cigarettes. In the whole study group and in those subjects with atheroma, females had higher levels o f both fibrinogen and factor VII with no differences in vWF concentrations. PAI-1 concentrations were elevated in females with atheroma compared to both men with atheroma and to females with normal coronary angiography. vWF was also increased in females with atheroma compared to those without, whilst factor VII did not appear to be related to the presence of atheroma. These results indicate that elevated factor VII and fibrinogen in females is gender rather than disease related, whilst PAI-1 and vWF appear to be associated with underlying atheroma rather than gender.

Higher levels of fibrinogen in women than men have been described in the healthy general population notably in the Scottish Heart Health Study o f 8824 subjects, and our findings in this study would support the view that in women, fibrinogen reflects gender rather than the presence o f atheroma. By contrast, in men, fibrinogen appears to be related to the presence o f coronary disease. The EC AT study^**®^ reported no sex difference in fibrinogen levels in subjects who had been investigated for CAD by angiography. Fibrinogen is an acute phase protein, and circulating levels are affected by

a number factors including age, smoking, BMI, and cholesterol It is unclear from the EC AT study whether adjustments were made for these possible confounders nor did the study look at men and women separately. In our study after adjusting for a large number o f possible confounders the sex differences in fibrinogen remained. The reason for these sex differences is not immediately apparent, although it is possible that sex hormones play a role. If fibrinogen is not associated with the presence o f atheroma in women, it may not influence the differences in prognosis between the sexes in subjects with evidence of CAD.

Previous studies that have investigated sex differences in the fibrinolytic system in healthy populations have yielded conflicting r e s u l t s . L a r g e cross-sectional studies suggest that PAI-1 levels are similar in men and women, and our study finding in the total population is in agreement with this. As in the ECAT study we have found higher PAI-1 levels in women with significant coronary stenosis than men. A recent study reported higher PAI-1 levels in diabetic women compared to diabetic men.^‘^ Suppression of fibrinolysis through raised PAI-1 is related to the syndrome of insulin resistance’^* and it has been suggested that sex-specific interference of the haemostatic system in association with insulin resistance may be the explanation for this finding.

Insulin resistance without clinical diabetes appears to be a factor in coronary artery disease, although our results imply that increased PAI-1 in females is related to atheroma, either causally or secondary to the underlying disease.

In the Framingham Offspring Study,^^’ postmenopausal women and men of similar age did not differ significantly in their PAI-1 levels. However, healthy women with higher oestrogen levels, or those on hormone replacement therapy (HRT) had lower PAI-1 levels than other women not on HRT. In the present study, we made no assessment of the sex hormone levels, nor did we assess the use o f HRT in our female population. However, examination of the age group in the female population suggests that the majority o f the women would be postmenopausal. Furthermore, the use o f HRT in this population at the time of recruitment was 3%. Despite this there was a substantial difference in PAI-1 levels to indicate that hormonal status does not fully account for the observed gender difference.

The majority o f studies of vWF in healthy white subjects, and those with angina,^^^ show no sex differences, and this was our finding in the total study population

and in the subgroup with significant coronary stenosis. However, vWF levels were related to the presence of CAD in women but not in men. Hence, despite the similarity in the levels of vWF between the sexes, vWF levels may contribute to the differences in prognosis.

Higher levels in FVII:C in women than men have also been described in the general population,^^'* and as with fibrinogen, our finding in the total study population and in the subgroup with significant atheroma would not therefore be unexpected. Raised FVIIiC levels have been described in women but not men in a small study of subjects with unstable angina compared to a normal control population.^"^^ The EC AT study also found higher circulating levels of FVII:C in women compared to men with significant coronary stenosis^^^ These findings with our observation that FVILC levels were similar in women regardless of the presence o f atheroma indicates that the increased levels reflect gender rather than atheroma . In a recent report among diabetic subjects women had higher levels of FVILC than men.^*^ A gender-specific influence of insulin resistance on the coagulation system was suggested. As with circulating PAI-1, a contribution of insulin resistance on the gender difference in circulating FVILC cannot be excluded. FVILC levels may therefore not contribute to the differences in prognosis between the sexes.

The importance o f haemostatic factors on the pathogenesis o f CAD in women has gained further support by the recent finding that Factor V Leiden increases the risk of myocardial infarction in young women.(quote246) However, the authors make it clear that the finding is unlikely to be applicable to populations of older women (as in our study population) in whom the overall baseline risk is higher. We have not measured Factor V Leiden in our study and are therefore unable to comment further on this finding.

In conclusion, we have shown in this study that in patients undergoing angiography for investigation of chest pain, women have a worse classical risk factor profile, and increased levels of fibrinogen, FVILC and PAI-1 compared to men. However, in women with atheroma only PAI-1 and vWF levels were related to the presence o f CAD which may be part of the explanation for the poorer prognosis in women than their male counterparts.

In the search for non-invasive markers o f CAD, large prospective trials are needed to evaluate the role of circulating levels o f these coagulation and fibrinolytic

factors and whether they may provide an additional means o f predicting the likelihood for the presence of significant atheroma, particularly in women. This may be of use in selecting female patients who require a coronary angiogram. It may help reduce the number of female patients who present with chest pain and are subsequently found to have a normal coronary angiogram. The evidence for an association o f PAI-1 with the presence of significant disease is growing, and the striking differences o f PAI-1 levels in our study between females with and without significant stenosis raises the possibility that PAI-1 may fulfil such a role as a non-invasive marker at least in women. A prospective study is now underway to examine this.

The present study has some limitations. Firstly, it is retrospective, and therefore unable to yield sensitivity, specificity and predictive values for the possible non- invasive markers. Secondly, we have not measured insulin resistance which may be the explanation for some o f the differences seen. Thirdly, the lack of data on the use of HRT presents a further limitation, as HRT use has been shown to influence fibrinolytic factors. Further studies are underway to address this. This study supports the growing body of evidence that the coagulation and fibrinolytic system needs to be considered in the assessment of risk factor profiles in patients (especially in women) who present for the assessment of chest pain.