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Clinical and Laboratory Investigations in Postmenopusal Women with Unstable Coronary Artery Disease
Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Coronary artery disease (CAD) is the major cause of death in both sexes in the western world. In men with chest pain the diagnostic methods are more useful than in women. An exercise test is considered less reliable in women, mostly due to a high percentage offalse positive tests. Furthermore, 20-40% of women with typical angina have normal vessels at coronary angiography. The mechanisms behind the chest pain in these patients are unknown, but could be due to disturbances in endothelial, thrombogenetic and/or fibrinolytic function.

In a prospective multicentre trial we examined 200 postmenopausal women with unstable CAD and 101 healthy controls. At coronary angiography 15% had normal vessels, 14% had non-significant atherosclerosis and 71% had at least one significant stenosis.

The diagnostic information from basic clinical parameters, ECG and an early exercise test were evaluated. The prevalence of coronary atherosclerosis was high, 85%, and the early exercise test was just as valuable as in men for identifying patients with significant CAD.

Endothelial markers, cyclic GMP (cGMP) and immunoreactive endothelin (irET), were analysed regarding presence or not of coronary atherosclerosis. Patients with normal vessels had low levels of ir-Ef, indicating different mechanisms for ischemia/angina in these patients compared with patients with atherosclerosis. No differences were found regarding cGMP, unless the patient had long-term nitroglycerin treatment, which increased plasma cGMP. Patients with exerciseinduced ischemia had higher cGMP plasma levels compared to those without. This may reflect a general compensatory mechanism.

New lipid variables, apolipoproteins and lipoprotein particles, were no better than the routine lipid examination in separating women with and without coronary atherosclerosis, and the measurement of apolipoproteins and lipoprotein particles on the basis of diagnostic accuracy alone is not justified. Also, elevated triglycerides was most pronounced in women with unstable CAD and coronary atherosclerosis.

Plasma total homocysteine (tHey) is considered a risk factor for CAD, but the relationship between tHey and well-defined CAD in women is still unclear. Mild hyperhomocysteinemia was not related to the risk of unstable CAD in postmenopausal women. Our study stresses the importance of adjusting tHey for the covariates, i.e. age and serum values of folate, vitamin Bl2 and creatinine.

Fibrinolytic and coagulation variables did neither reveal signs of disturbed fibrinolysis nor were in favour of a hypercoagulable/hyperthrombotic state in patients with unstable CAD and normal vessels.

In summary, the prevalence of coronary atherosclerosis in postmenopausal women with signs and symptoms of unstable CAD is high. An early exercise test together with basic clinical parameters is a valuable diagnostic tool. Although there were differences in biochemical markers between patients with and without coronary atherosclerosis, the overlapping between the groups was high. No clinically useful test to separate these two groups was found. Patients with normal vessels were much alike the control group and it is still unclear whether these patients have CAD without atherosclerosis or another mechanism for their chest pain.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2000. , 105 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 615
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27526Local ID: 12182ISBN: 91-7219-572-X (print)OAI: oai:DiVA.org:liu-27526DiVA: diva2:248078
Public defence
2000-02-04, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-06Bibliographically approved
List of papers
1. Unstable coronary artery disease in post-menopausal women: Identifying patients with significant coronary artery disease by basic clinical parameters and exercise test
Open this publication in new window or tab >>Unstable coronary artery disease in post-menopausal women: Identifying patients with significant coronary artery disease by basic clinical parameters and exercise test
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1998 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 19, no 6, 899-907 p.Article in journal (Refereed) Published
Abstract [en]

Background The diagnostic information from an ECG taken while at rest and an exercise test is considered less reliable in women than in men, mostly due to a high percentage offalse-positive tests. This can be explained by a lower pre-test likelihood of coronary heart disease.

Aims To evaluate the diagnostic information that can be gained from basic clinical parameters, an ECG and exercise test in a group of post-menopausal women with symptoms of unstable coronary artery disease in order to identify patients with significant coronary artery stenoses.

Methods and Results We prospectively studied 200 postmenopausal women admitted to the coronary care unit with symptoms of unstable coronary artery disease and ECG changes suggestive of ischaemia. The diagnostic value of common risk factors, myocardial enzymes and an early exercise test were assessed. A coronary angiogram was performed within 60 days. Median age was 67 years. On admission, 38% had ST depression on an ECG taken while at rest, 76% had T-wave inversion, and 41% increased enzyme levels. The coronary angiogram revealed that 15% had no atherosclerosis, 14% had atherosclerosis but no lesion ≥ 50% of luminal diameter and 71 % had at least one significant stenosis. Of patients with known indicators of atherosclerotic disease, all but one had atherosclerosis visualized on the coronary angiogram. A relative ST depression ≥ 0·1 m V and a low maximum workload at exercise test were strong predictors of significant coronary artery disease. The positive predictive value of ST depression was 91% and of low maximum workload 84%.

Conclusion In post-menopausal women with signs of unstable angina and ischaemia on an ECG taken while at rest, the prevalence of coronary atherosclerosis is high, 85%. Contrary to earlier studies, ST T-changes at the early exercise test had a high positive predictive value, especially in combination with a low maximum workload with no false-positive results.

Keyword
women, coronary angiography, unstable angina, exercise test, electrocardiography, risk factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26815 (URN)10.1053/euhj.1997.0867 (DOI)11427 (Local ID)11427 (Archive number)11427 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-09-11Bibliographically approved
2. Plasma levels of cyclic GMP and endothelin in postmenopausal women with unstable coronary artery disease
Open this publication in new window or tab >>Plasma levels of cyclic GMP and endothelin in postmenopausal women with unstable coronary artery disease
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1999 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, Vol. 59, no 5, 325-334 p.Article in journal (Refereed) Published
Abstract [en]

Many women with typical anginal chest pain have normal coronary angiograms, which may be due to altered endothelial function. We evaluated the endothelial markers cyclic GMP (cGMP) and immunoreactive endothelin (ir-ET) regarding presence of coronary atherosclerosis in women with clinical signs of unstable coronary artery disease (CAD). Plasma levels of cGMP and ir-ET were determined in 118 patients and 84 controls. Ischaemia was evaluated at an exercise test. Of the patients 20% had normal vessels, 14% insignificant CAD and 66% significant stenosis at coronary angiography. Mean (95% CI) concentration of cGMP (nmol/l) was higher in patients than in controls (5.05 (4.53; 5.58) vs. 3.79 (3.34; 4.23)). Separating patients according to daily intake of nitroglycerin, only patients with this medication had significantly higher cGMP level (5.73 (4.88; 6.58)), whereas the difference between those without (4.35 (3.76; 4.94)) and controls disappeared. Patients with ischaemia at exercise test had higher cGMP level than those without (6.01 (5.13; 6.88) vs. 4.30 (3.66; 4.94)), even after adjusting for nitroglycerin treatment. ir-ET (pmol/l) was lower in patients with normal vessels than patients with coronary atherosclerosis (0.83 (0.78; 0.88) vs. 0.98 (0.92; 1.04)) and than the control group (0.91 (0.87; 0.94)). The difference between the control group and patients with atherosclerosis was also significant. Patients with unstable CAD and long-term nitroglycerin treatment have increased cGMP level. Patients with exercise-induced ischaemia have higher cGMP level than those without, irrespective of nitroglycerin treatment, which may reflect a general compensatory mechanism. Patients with normal vessels have low level of ir-ET, indicating different mechanisms for ischaemia/angina in these patients compared with patients with atherosclerosis.

Keyword
Coronary atherosclerosis, cyclic GMP, endothelin, exercise test, nitroglycerin, women
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26737 (URN)10.1080/00365519950185517 (DOI)11332 (Local ID)11332 (Archive number)11332 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-09-11Bibliographically approved
3. Plasma lipoprotein particle concentrations in postmenopausal women with unstable coronary artery disease: Analysis of diagnostic accuracy using receiver operating characteristics
Open this publication in new window or tab >>Plasma lipoprotein particle concentrations in postmenopausal women with unstable coronary artery disease: Analysis of diagnostic accuracy using receiver operating characteristics
2000 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 247, no 1, 43-52 p.Article in journal (Refereed) Published
Abstract [en]

Background.The contribution of plasma lipids to cardiovascular risk is usually evaluated by measuring plasma concentrations of total cholesterol, triglycerides and HDL cholesterol, and calculating LDL cholesterol concentration. We investigated plasma concentrations of apolipoproteins and lipoprotein particles in women with unstable coronary artery disease (CAD) to evaluate whether these, better than the routine lipid status, could differentiate women with and without coronary atherosclerosis.

Methods. Blood samples for lipid analyses were collected from 119 angiographically examined postmenopausal 49–79-year-old women with unstable CAD, and from 101 age-matched controls. Mean plasma concentrations were compared and the discriminatory ability of the different variables were tested using receiver operating characteristics (ROC).

Results. At coronary angiography 19% had normal vessels and 81% had coronary atherosclerosis. A disturbed triglyceride metabolism was the most pronounced lipid abnormality in women with unstable CAD and coronary atherosclerosis. ROC showed that none of the evaluated variables had a particularly high discriminatory power regarding unstable CAD or coronary atherosclerosis. The ratio cholesterol/HDL cholesterol was best with an ROC area of 0.79. Furthermore, the newer lipid variables, i.e. lipoprotein particles and apolipoproteins, were no better than the traditional variables.

Conclusion. Lipoprotein changes reflecting a disturbed triglyceride metabolism are most pronounced in women with unstable CAD and coronary atherosclerosis. Lipoprotein particles and apolipoproteins alone were no better than lipids and lipoproteins in separating women with from those without coronary atherosclerosis. Our study does not support the measurement of apolipoproteins and lipoprotein particles on the basis of diagnostic accuracy alone.

Keyword
lipoprotein particles, ROC, unstable CAD, women.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27049 (URN)10.1046/j.1365-2796.2000.00567.x (DOI)11694 (Local ID)11694 (Archive number)11694 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-09-11Bibliographically approved
4. Plasma total homocysteine levels in postmenopausal women with unstable coronary artery disease
Open this publication in new window or tab >>Plasma total homocysteine levels in postmenopausal women with unstable coronary artery disease
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2000 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 151, no 2, 423-431 p.Article in journal (Refereed) Published
Abstract [en]

An elevated plasma total homocysteine (tHcy) level is considered a risk factor for coronary artery disease (CAD), but the relationship between plasma tHcy and well-defined CAD in women is still unclear. Plasma tHcy concentrations and the covariates serum folate, vitamin B12, and creatinine were analysed in 157 angiographically examined postmenopausal women with unstable CAD and in 101 healthy controls. At coronary angiography, 16% had normal vessels and 84% had coronary atherosclerosis. Mean plasma tHcy concentration (μmol/l, 95% confidence interval) did not differ in patients compared to controls (13.1 (12.3–13.8) vs. 12.5 (11.6–13.5)) or in patients with or without coronary atherosclerosis (13.3 (12.4–14.1) vs. 12.0 (10.8–13.2)). A trend to an increasing plasma tHcy with increasing degree of coronary atherosclerosis was attenuated after adjustment for age and the previous mentioned covariates. Odds ratio for the risk of coronary artery disease and coronary atherosclerosis in hyperhomocysteinemic patients (≥90th percentile in controls) was approximately 3. However, the confidence interval included unity in half of the groups and the significance was therefore difficult to judge. Receiver operating characteristics showed age to be the only variable with a significant discriminatory ability regarding the presence of coronary atherosclerosis (area 0.77). Mild hyperhomocysteinemia seems not to be related to the risk of unstable CAD in postmenopausal women. The trend towards higher plasma tHcy with increasing degree of coronary atherosclerosis may be a marker of the disease. In future studies adjustment for age and the other three covariates should be considered.

Keyword
Homocysteine, Women, Unstable coronary artery disease, Coronary angiography, Odds ratio, Covariates, ROC curve
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27048 (URN)10.1016/S0021-9150(99)00416-5 (DOI)11693 (Local ID)11693 (Archive number)11693 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-09-11Bibliographically approved
5. Fibrinolytic Variables in Postmenopausal Women with Unstable Coronary Artery Disease
Open this publication in new window or tab >>Fibrinolytic Variables in Postmenopausal Women with Unstable Coronary Artery Disease
2001 (English)In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 12, no 3, 217-223 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Many women with typical anginal chest pain have normal coronary angiograms. The pathogenetic mechanisms behind the chest pain in these patients is unknown but may be due to altered fibrinolytic function enhancing thrombosis formation. We evaluated the two key components of the fibrinolytic system, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in women with clinical signs of unstable coronary artery disease (CAD).

Methods and results: 158 patients with unstable CAD and 101 controls were examined. Of the patients 16% had normal vessels and 84% coronary atherosclerosis at coronary angiography. Mean plasma concentration of t-PA-ag, but not of PAI-1-act was higher in patients than in controls (t-PA-ag: 2.12 (2.05;2.19) vs. 1.98 (1.89;2.07), p<0.05; PAI-1-act: 1.55 (1.35;1.74) vs. 1.49 (1.24;1.73), p¼n.s.). Patients with coronary atherosclerosis had significantly higher mean plasma levels of both t-PA-ag and PAI-1-act than patients with normal coronary vessels (t-PA-ag: 2.16 (2.08;2.33) vs. 1.94 (1.78;2.10), p<0.05; PAI-1-act: 1.68 (1.47;1.90) vs. 0.82 (0.43;1.21), p<0.01), and these differences were seen whether markers of myocardial damage were elevated or not. Mean plasma levels of PAI-1-act in patients with normal coronary vessels were even lower than in the control group (p<0.05). Almost all significant differences in mean plasma t-PA-ag and PAI-1-act disappeared after adjustments for known covariates.

Conclusion: Our results indicate, regardless of myocardial marker elevation or not, an activated fibrinolytic system in postmenopausal women with unstable CAD and coronary atherosclerosis, but not in the same group of patients with normal coronary vessels. This argues against reduced fibrinolytic capacity in the latter patients and therefore against thrombosis formation as the cause of chest pain in these women. However, we cannot exclude that the differences can be an effect of inequality among some common risk factors between the groups.

Keyword
tissue plasminogen activator, plasminogen activator inhibitor, unstable coronary artery disease, women
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79488 (URN)10.1023/A:1015270907430 (DOI)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
6. Markers of hypercoagulation, von Willebrand factor and anticardiolipin antibodies in postmenopausal women with unstable coronary artery disease: Discriminatory Ability Regarding Unstable Coronary Artery Disease and Coronary Atherosclerosis Using Receiver Operating Characterstics
Open this publication in new window or tab >>Markers of hypercoagulation, von Willebrand factor and anticardiolipin antibodies in postmenopausal women with unstable coronary artery disease: Discriminatory Ability Regarding Unstable Coronary Artery Disease and Coronary Atherosclerosis Using Receiver Operating Characterstics
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Aims - Many women with typical anginal chest pain have normal coronary angiograms. The pathogenetic mechanisms behind the chest pain in these patients are unknown but may be due to increased thrombogenecity. We evaluated markers of hypercoagulation and thrombosis in women with clinical signs of unstable coronary artery disease (CAD).

Methods and results - 158 patients with unstable CAD and 101 controls were examined. 16% of the patients had nonnal vessels and 84% had coronary atherosclerosis at coronary angiography. Mean plasma concentrations of von Willebrand factor-antigen, soluble fibrin (SF), thrombin-antithrombin complex and Ddimer were significantly higher, whereas there was no difference regarding prothrombin fragment 1 +2 between patients and controls. Patients with coronary atherosclerosis had higher mean plasma levels for most variables compared to those with normal coronary vessels, but the only significant difference was for SF. D-dimer was significantly higher in patients with nonnal coronary vessels compared to the control group. Anticardiolipin antibody (ACA) levels were significantly lower in the patient group compared to the control group. Receiver operating characteristics (ROC) showed that none of the variables represented high diagnostic accuracy in distinguishing patients with unstable CAD from healthy controls, or patients with from those without coronary atherosclerosis.

Conclusion - Our results are in favour of a hypercoagulable state in postmenopausal women with unstable CAD and coronary atherosclerosis, even in the absence of myocardial marker elevation, whereas this does not seem to be the case in patients with nonnal vessels. ROC revealed no variable to be particularly clinical useful in separating patients and control or patients with and without coronary atherosclerosis.

Keyword
Coagulation, Unstable Coronary Artery Disease, Women, ROC Curve, Cardiolipin, Coronary Atherosclerosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79489 (URN)
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2013-09-11Bibliographically approved

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