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Importance of peripheral arterial disease as a risk marker in patients with myocardial infarction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. (Kardiologi, Cardiology)ORCID iD: 0000-0001-5726-1226
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

The purpose of this thesis was to describe the true prevalence of widespread arterial disease in a cohort with patients with a recent myocardial infarction (MI) to find valuable clinical methods to detect these patients. Our aim was also to investigate biomarker relationships with peripheral artery disease (PAD) and the importance of PAD in patients’ long-term outcomes.

We studied patients with a recent MI in a prospective observational study, the REBUS ((Relevance of Biomarkers for Future Risk of Thromboembolic Events in Unselected Post-myocardial Infarction Patients) trial. A total of 421 patients were included in the study, 390 of whom had their ankle-brachial index (ABI) measured and a mean-time follow up of 5.5 years. Atherosclerotic changes were assessed in three arterial beds by coronary angiography, measuring the ABI and carotid ultrasound. Ninety-two biochemical biomarkers were assessed at baseline by a proximity extension assay (PEA) chip. 263 out of 421 filled in a self-administered Walking Impairment Questionnaire (WIQ). Polyvascular (PvD) disease was defined as pathological findings in all three arterial beds.

We found that PAD and PvD are underdiagnosed in patients who suffered a recent MI. We also found the ABI to be a strong and useful method to identify patients with PAD as well as patients with more widespread arterial disease, such as PvD (paper I).

The results of the scoring system, the WIQ, showed it is useful for finding patients with PAD and PvD, even when completed soon after an acute MI event (paper II).

We also found that biochemical biomarkers associated with the inflammatory pathway – tumour necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2) and growth differentiation factor 15 (GDF-15) – were able to predict pathological ABI, i.e. PAD, in these MI patients. These results could also be validated in another observational study and cohort of MI patients, the VaMIS cohort (paper III). Pathological ABI was also found to be a strong predictor for cardiovascular events of all-cause mortality, new ACS, and a composite endpoint of all-cause mortality, new ACS, new stroke/TIA or new PAD event. When evaluating the three inflammatory biomarkers as a surrogate marker for ABI, they showed a similar association with all-cause death and the composite endpoint (paper IV).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1612
Keywords [en]
Coronary heart disease, Peripheral artery disease, Polyvascular disease, Inflammatory biomarkers, TNFR-1, TNFR-2, GDF-15, Cardiovascular events.
National Category
Medical and Health Sciences
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-395821ISBN: 978-91-513-0802-9 (print)OAI: oai:DiVA.org:uu-395821DiVA, id: diva2:1365410
Public defence
2019-12-13, Enghoffsalen, Akademiska sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-11-20 Created: 2019-10-24 Last updated: 2019-11-20
List of papers
1. Ankle brachial index most important to identify polyvascular disease in patients with non-ST elevation or ST-elevation myocardial infarction
Open this publication in new window or tab >>Ankle brachial index most important to identify polyvascular disease in patients with non-ST elevation or ST-elevation myocardial infarction
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2016 (English)In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 30, p. 55-60Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Atherosclerosis is a systemic disease. In patients with acute myocardial infarction (MI) the extent of polyvascular disease (PvD) is largely unknown. In this study we investigate the prevalence and clinical characteristics predictive of PvD in patients with non-ST-elevation (NSTEMI) and ST-elevation (STEMI) MI.

METHOD: 375 patients with acute MI included in the REBUS (Relevance of Biomarkers for Future Risk of Thromboembolic Events in Unselected Post-myocardial Infarction Patients) study were examined. Atherosclerotic changes were assessed in three arterial beds by coronary angiography, carotid ultrasound and ankle brachial index (ABI). Results compared findings of atherosclerosis in three arterial beds to fewer than 3 beds. PvD was defined as atherosclerosis in all three arterial beds.

RESULTS: A medical history of MI, peripheral artery disease (PAD) or stroke was reported at admission in 17.9%, 2.1% and 3.7% of the patients, respectively. After evaluation, abnormal ABI was found in 20.3% and carotid artery atherosclerosis in 54.9% of the patients. In the total population, PvD was found in 13.8% of patients with no significant differences observed between NSTEMI and STEMI patients. Age (p<0.001), diabetes (p=0.039), previous PAD (p=0.009) and female gender (p=0.016) were associated with PvD. ABI was the most important predictor of PvD with a positive predictive value of 68.4% (95% CI 57.7-79.2%) and specificity of 92.4% (95% CI 89.5-95.4%).

CONCLUSIONS: PvD is underdiagnosed in patients suffering from MI, both NSTEMI and STEMI. ABI is a useful and simple measurement that appears predictive of widespread atherosclerosis in these patients.

National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-274195 (URN)10.1016/j.ejim.2015.12.016 (DOI)000375919800022 ()26776925 (PubMedID)
Available from: 2016-01-20 Created: 2016-01-20 Last updated: 2019-10-24Bibliographically approved
2. Low Walking Impairment Questionnaire score after a recent myocardial infarction identifies patients with polyvascular disease
Open this publication in new window or tab >>Low Walking Impairment Questionnaire score after a recent myocardial infarction identifies patients with polyvascular disease
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2019 (English)In: JRSM Cardiovascular Disease, ISSN 2048-0040, Vol. 8, p. 1-9Article in journal (Refereed) Published
Abstract [en]

Objectives: To evaluate whether the Walking Impairment Questionnaire score could identify patients with polyvascular disease in a population with recent myocardial infarction and their association with cardiovascular events during two-year follow-up.

Design: A prospective observational study.

Setting: Patients admitted to the acute coronary care unit, the Department of Cardiology, Uppsala University Hospital.

Participants: Patients admitted with acute Non-STEMI- or STEMI-elevation myocardial infarction.

Main outcome measures: The Walking Impairment Questionnaire, developed as a self-administered instrument to assess walking distance, speed, and stair climbing in patients with peripheral artery disease, predicts future cardiovascular events and mortality. Two hundred and sixty-three patients with recent myocardial infarction answered Walking Impairment Questionnaire. Polyvascular disease was defined as abnormal findings in the coronary- and carotid arteries and an abnormal ankle-brachial index. The calculated score for each of all three categories were divided into quartiles with the lowest score in first quartile.

Results: The lowest (worst) quartile in all three Walking Impairment Questionnaire categories was associated with polyvascular disease, fully adjusted; distance, odds ratio (OR) 5.4 (95% confidence interval (CI) 1.8-16.1); speed, OR 7.4 (95% CI 1.5-36.5); stair climbing, OR 8.4 (95% CI 1.0-73.6). In stair climbing score, patients with the lowest (worst) score had a higher risk for the composite cardiovascular endpoint compared to the highest (best) score; hazard ratio 5.3 (95% CI 1.5-19.0). The adherence to medical treatment was high (between 81.7% and 99.2%).

Conclusions: The Walking Impairment Questionnaire is a simple tool to identify myocardial infarction patients with more widespread atherosclerotic disease and although well treated medically, stair climbing predicts cardiovascular events.

Keywords
Peripheral vascular disease, cardiovascular disease, coronary artery disease, polyvascular disease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-382843 (URN)10.1177/2048004019841971 (DOI)000464951000001 ()31019682 (PubMedID)
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-10-24Bibliographically approved
3. Biomarkers in addition to clinical characteristics for prediction of peripheral artery disease in patients with recent myocardial infarction
Open this publication in new window or tab >>Biomarkers in addition to clinical characteristics for prediction of peripheral artery disease in patients with recent myocardial infarction
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(English)In: Article in journal (Other academic) Submitted
Abstract [en]

Abstract

Background Few studies have examined biomarkers in CAD and peripheral artery disease (PAD), their association and the ability to predict PAD.

Methods: Two prospectively observational studies including unselected patients with recent myocardial infarction were used for the analyses. PAD was defined as an abnormal ankle brachial index (ABI) score (<0.9 or > 1.4) on at least one side. The proximity extension assay (PEA) technique was used to simultaneously analyze 92 biomarkers with association to cardiovascular disease in samples early after an acute MI. Random forest was used to identify the biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics were analyzed by the c-statistics.

Results:  Six biomarkers were identified associated with prediction of PAD in the REBUS cohort. Three of these could be validated in the VaMIS cohort; Tumor necrosis factor receptor (TNFR-1),  Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) with an increase in c-statistics; Tnfr1:0.709 (95% CI 0.640, 0.779) and 0.746 (95% CI 0.706,0.787), Tnfr2: 0.703 (95% CI 0.633, 0.773) and 0.745 (95% CI 0.704, 0.785), GDF-15: 0.710 (95% CI 0.640, 0.781) and 0.752 (95% CI 0.711, 0.792) in the REBUS and VaMIS cohort respectively. Adding a group of biomarkers to clinical characteristics further increased the c-statistics compared to a single biomarker.

Conclusions: Three biomarkers out of a panel of 92; TNFR-1, TNFR-2 and GDF-15 were identified associated with PAD in MI patients and could improve prediction of PAD in addition to clinical characteristics.

 

 

Keywords
coronary artery disease, acute coronary syndrome, peripheral artery disease, biochemical biomarker
National Category
Medical and Health Sciences
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-395814 (URN)
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24
4. Biochemical biomarkers associated with peripheral artery disease contribute to prediction of outcome during long-term follow up after myocardial infarction
Open this publication in new window or tab >>Biochemical biomarkers associated with peripheral artery disease contribute to prediction of outcome during long-term follow up after myocardial infarction
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

Background: Few studies have investigated biomarkers and their association to cardiovascular (CV) outcomes in patients with myocardial infarction (MI) and peripheral artery disease (PAD). Tumor necrosis factor receptor 1(TNFR-1), tumor necrosis factor receptor 2(TNFR-2) and growth differentiation factor 15 (GDF-15) are inflammatory biomarkers found to predict PAD.

Aim:  To evaluate whether pathological ankle brachial index (ABI) and the group of biomarkers TNFR-1, TNFR-2 and GDF-15 analyzed early after a MI, were associated with all-cause mortality and the risk of new cardiovascular events during long-term follow up.

Method: 388 patients with MI included in the REBUS (Relevance of Biomarkers for future risk of Thromboembolic Events in Unselected Post-myocardial Infarction Patients) study were examined with ABI to diagnose PAD (defined as an ABI score <0.9 or > 1.4 on at least one side). TNFR-1, -2 and GDF-15 was measured using the Proseek Multiplex CVD III ⁹⁶˟⁹⁶ proximity extension assay (www.olink.com/products/cvd-i and iii-panel).  The composite results for these 3 biomarkers were dichotomized into two groups (i.e high and low values) We evaluated pathological ABI and the group with higher biomarkers values with the association to long-term outcome, and if the group of biomarkers for inflammation could further improve prediction of recurrence of cardiovascular events (mortality, new acute coronary syndrome (ACS) and the composite of mortality, new ACS, stroke/TIA and PAD) after an MI.  

Results:  The mean follow-up time was 5.5 years. After adjustment for established CV risk factors, pathological ABI was associated with a higher risk of new ACS, HR 1.97, 95 % CI 1.12-3.49, p = 0.019, and the composite endpoint; HR 1.97, 95 % CI 1.29-3.01, p=0.002, compared to patients with normal ABI. The group with the higher biomarker value was associated with a higher risk for all-cause mortality; HR 1.84, 95 % CI 1.00-3.38, p=0.049 and the composite endpoint; HR 1.62, 95 % CI 1.03-2.53, p=0.035. In the ROC analyses pathological ABI added to established CV risk factors improved the AUC for a new ACS from 0.753 (95% C.I. 0.684-0.822, p<0.001) to 0.763 (95% C.I. 0.697-0.830, p<0.001). When the group with higher biomarker values was added to  established CV risk factors  AUC for all-cause mortality increased from 0.789 (95% C-I. 0.729-0.849, p<0.001) to 0.805 (95% C.I. 0.746-0.863, p<0.001).

Conclusion: Despite a high proportion of revascularization and guideline-recommended secondary medical treatment, both pathological ABI and the group with higher values of the inflammatory biomarkers (TNFR-1, TNFR-2, GDF-15) predictive for PAD were associated with the risk of new CV events and mortality in patients with a recent MI. The group of inflammatory biomarkers provide additional information to established risk factors in prediction of CV outcome in this cohort with recent MI.

Keywords
coronary artery disease, acute coronary syndrome, peripheral artery disase, biochemial biomarkers, myocardial inafarction, long-term follow up
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-395819 (URN)
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24

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