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Insights into the relationship between coronary calcification and atherosclerosis risk factors
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction

Coronary artery disease (CAD) is the most common cause of death in Europe and North America and early detection of atherosclerosis is a clinical priority. Diagnosis of CAD remains conventional angiography, although recent technology has introduced non-invasive imaging of coronary arteries using computed tomographic coronary angiography (CTCA), which enables the detection and quantification of coronary artery calcification (CAC). CAC forms within the arterial wall and is usually found in or adjacent to atherosclerotic plaques and is consequently known as sub-clinical atherosclerosis.

 The conventional cardiovascular (CV) risk factors used to quantify the estimated 10-year coronary event risk comprise dyslipidaemia, hypertension, diabetes mellitus, obesity, smoking and family history of CAD. Nevertheless, their relationship with significant (>50%) stenosis, their interaction with the CAC score and their predictive ability for CAC presence and extent has not been fully determined in symptomatic patients.

 

Methods 

 For Papers 1-4 we took patients from the Euro-CCAD cohort, an international study established in 2009 in Umeå, Sweden. The study data gave us the CAC score and the CV risk factor profile in 6309 patients, together with angiography results for a reduced cohort of 5515 patients. In Papers 1 and 2 we assessed the risk factors for significant stenosis, including CAC as a risk factor. Paper 2 carried out this analysis by geographical region: Europe vs USA and northern vs southern Europe. Paper 3 investigated the CV risk factors for CAC presence, stratified by age and gender, while Paper 4 assessed the CV risk factors for CAC extent, stratified by gender.

 In paper 5 we carried out a systematic review and meta-analysis of all studies of the risk factor predictors of CAC presence, extent and progression in symptomatic patients. From a total of 884 studies, we identified 10 which fitted our inclusion criteria, providing us with a total of 15,769 symptomatic patients. All 10 were entered in the systematic review and 7 were also eligible for the meta-analysis.

 

Results

Paper 1:           Among risk factors alone, the most powerful predictors of significant coronary stenosis were male gender followed by diabetes, smoking, hypercholesterolaemia, hypertension, family history of CAD and age; only obesity was not predictive. When including the log transformed CAC score as a risk factor, this proved the most powerful predictor of >50% stenosis, but hypercholesterolaemia and hypertension lost their predictive ability. The conventional risk factors alone were 70% accurate in predicting significant stenosis, the log transformed CAC score alone was 82% accurate but the combination was 84% accurate and improved both sensitivity and specificity.

 Paper 2:           Despite some striking differences in profiles between Europe and the USA, the most important risk factors for >50% stenosis in both groups were male gender followed by diabetes. When the log CAC score was included as a risk factor, it became by far the most important predictor of >50% stenosis in both continents, followed by male gender. In the northern vs southern Europe comparison the result was similar, with the log CAC score being the most important predictor of >50% stenosis in both regions, followed by male gender.

 Paper 3:           Independent predictors of CAC presence in males and females were age, dyslipidaemia, hypertension, diabetes and smoking, with the addition of family history of CAD in males; obesity was not predictive in either gender. The most important predictors of CAC presence in males were dyslipidaemia and diabetes, while among females the most important predictors of CAC presence were diabetes followed by smoking. When analysed by age groups, in both males and females aged <70 years, diabetes, hypertension and dyslipidaemia were predictive, with diabetes being the strongest; in females aged <70 years, smoking was also predictive. Among those aged ≥70 years, the results are completely different, with only dyslipidaemia being predictive in males but smoking and diabetes were predictive in females.

 Paper 4:           In the total cohort, age, male gender, diabetes, obesity, family history of CAD and number of risk factors predicted an increasing CAC score, with the most important being male gender and diabetes. In males, hypertension and dyslipidaemia were also predictive, although diabetes was the most important predictor. Diabetes was similarly the most important risk factor in females, followed by age and number of risk factors. Among patients with CAC, hypertension, dyslipidaemia and diabetes predicted CAC extent in both males and females, with diabetes being the strongest predictor in males followed by dyslipidaemia, while diabetes was also the strongest predictor in females, followed by hypertension. Quantile regression confirmed the consistent predictive ability of diabetes.

 Paper 5:           In the systematic review, age was strongly predictive of both CAC presence and extent but not of CAC progression. The results for CAC presence were overwhelmed by data from one study of almost 10,000 patients, which found that white ethnicity, diabetes, hypertension and obesity were predictive of CAC presence but not male gender, dyslipidaemia, family history or smoking. With respect to CAC extent, only male gender and hypertension were clearly predictive, while in the one study of CAC progression, only diabetes and hypertension were predictive. In the meta-analysis, hypertension followed by male gender, diabetes and age were predictive of CAC presence, while for CAC extent mild-moderate CAC was predicted by hypertension alone, whereas severe CAC was predicted by hypertension followed by diabetes.

 

Conclusion

Our investigation of the Euro-CCAD cohort showed that the CAC score is far more predictive of significant stenosis than risk factors alone, followed by male gender and diabetes, and there was little benefit to risk factor assessment over and above the CAC score for >50% stenosis prediction. Regional variations made little difference to this result. Independent predictors of CAC presence were dyslipidaemia and diabetes in males and diabetes followed by smoking in females. The risk factor predictors alter at age 70. The most important risk factor predictors of CAC extent were male gender and diabetes; when analysed by gender, diabetes was the most important in both males and females. Our studies have consistently shown the strong predictive ability of male gender in the total cohort and diabetes in males and females and this is reflected in the meta-analysis, which also found hypertension to be independently predictive. Interestingly, dyslipidaemia does not appear to be a strong risk factor.

 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1830
Keyword [en]
Coronary artery calcification, risk factors, atherosclerosis, stenosis
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:umu:diva-124909ISBN: 978-91-7601-535-3OAI: oai:DiVA.org:umu-124909DiVA: diva2:956505
Public defence
2016-09-22, Hörsal D, UnodT9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-09-01 Created: 2016-08-30 Last updated: 2016-09-09Bibliographically approved
List of papers
1. The coronary calcium score is a more accurate predictor of significant coronary stenosis than conventional risk factors in symptomatic patients: Euro-CCAD study
Open this publication in new window or tab >>The coronary calcium score is a more accurate predictor of significant coronary stenosis than conventional risk factors in symptomatic patients: Euro-CCAD study
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2016 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 207, 13-19 p.Article in journal (Refereed) Published
Abstract [en]

Aims: In this retrospective study we assessed the predictive value of the coronary calcium score for significant (>50%) stenosis relative to conventional risk factors. Methods and Results: We investigated 5515 symptomatic patients from Denmark, France, Germany, Italy, Spain and the USA. All had risk factor assessment, computed tomographic coronary angiogram (CTCA) or conventional angiography and a CT scan for coronary artery calcium (CAC) scoring. 1539 (27.9%) patients had significant stenosis, 5.50 of whom had zero CAC. In 5074 patients, multiple binary regression showed the most important predictor of significant stenosis to be male gender (B = 1.07) followed by diabetes mellitus (B = 0.70) smoking, hypercholesterolaemia, hypertension, family history of CAD and age but not obesity. When the log transformed CAC score was included, it became the most powerful predictor (B = 1.25), followed by male gender (B = 0.48), diabetes, smoking, family history and age but hypercholesterolaemia and hypertension lost significance. The CAC score is a more accurate predictor of >50% stenosis than risk factors regardless of the means of assessment of stenosis. The sensitivity of risk factors, CAC score and the combination for prediction of >50% stenosis when measured by conventional angiogram was considerably higher than when assessed by CTCA but the specificity was considerably higher when assessed by CTCA. The accuracy of CTCA for predicting >50% stenosis using the CAC score alone was higher (AUC 0.85) than using a combination of the CAC score and risk factors with conventional angiography (AUC 0.81). Conclusion: In symptomatic patients, the CAC score is a more accurate predictor of significant coronary stenosis than conventional risk factors.

Keyword
Atherosclerosis, Coronary calcification, Risk factors
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-118774 (URN)10.1016/j.ijcard.2016.01.056 (DOI)000371271400004 ()26784565 (PubMedID)
External cooperation:
Available from: 2016-05-25 Created: 2016-04-04 Last updated: 2016-08-31Bibliographically approved
2. Coronary calcification and male gender predict significant stenosis in symptomatic patients in northern and southern Europe and the USA: A Euro-CCAD study
Open this publication in new window or tab >>Coronary calcification and male gender predict significant stenosis in symptomatic patients in northern and southern Europe and the USA: A Euro-CCAD study
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2016 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645Article in journal (Refereed) Submitted
Abstract [en]

Background: Significant stenosis is the principal cause of stable angina but its predictors and their variation by geographical region are unclear.

Methods and Results: From the European Calcific Coronary Artery Disease (Euro-CCAD) cohort, we retrospectively investigated 5515 symptomatic patients from northern Europe (Denmark, France, Germany), southern Europe (Italy, Spain) and USA. All had conventional cardiovascular risk factor assessment, angiography and CT scanning for coronary artery calcium (CAC) scoring. There were considerable differences in the patient characteristics between the groups, with the USA patients being younger and having more diet and lifestyle-related risk factors, although hypertension may have been better controlled than in Europe. USA patients had a two-fold increase in prevalence of significant stenosis and a three-fold increase in median CAC score. In all three groups, the log CAC score proved to be the strongest predictor of >50% stenosis followed by male gender. In the USA group there were no additional independently predictive risk factors, although in northern Europe obesity, hypertension, smoking and hypercholesterolaemia remained predictive, with all risk factors other than age and hypertension proving to be predictive in the southern Europe group. Without the CAC score as a variable, male gender followed by diabetes were the most important predictors in all three regions, with hypertension also proving predictive in northern Europe.

 Conclusion:  In symptomatic patients, the CAC score and male gender were the most important predictors of significant stenosis in symptomatic patients in northern and southern Europe and the USA.

Place, publisher, year, edition, pages
Oxford: Oxford University Press, 2016
Keyword
Stenosis, coronary artery calcification, risk factors, geographical region
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-124924 (URN)
External cooperation:
Available from: 2016-08-30 Created: 2016-08-30 Last updated: 2016-08-31
3. Gender and age effects on risk factor-based prediction of coronary artery calcium in symptomatic patients: a Euro-CCAD study
Open this publication in new window or tab >>Gender and age effects on risk factor-based prediction of coronary artery calcium in symptomatic patients: a Euro-CCAD study
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2016 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 252, 32-39 p.Article in journal (Refereed) Published
Abstract [en]

Background and aims: The influence of gender and age on risk factor prediction of coronary artery calcification (CAC) presence in symptomatic patients is unclear.

Methods: From the European Calcific Coronary Artery Disease (EURO-CCAD) cohort, we retrospectively investigated 6309 symptomatic patients, 62% male, from Denmark, France, Germany, Italy, Spain and USA. All had risk factor assessment and CT scanning for CAC scoring.

 Results: The prevalence of CAC among females was lower than among males in all age groups. Using multivariate logistic regression, age, dyslipidaemia, hypertension, diabetes and smoking were independently predictive of CAC presence in both genders. In addition to a progressive increase in CAC with age, the most important predictors of CAC presence were dyslipidaemia and diabetes (β = 0.64 and 0.63 respectively) in males and diabetes (β = 1.08) followed by smoking (β = 0.68) in females; these same risk factors were also important in predicting increasing CAC scores. There was no difference in the predictive ability of diabetes, hypertension and dyslipidaemia in either gender for CAC presence in patients aged <50 and 50-70 years. However, in patients aged >70, only dyslipidaemia predicted CAC presence in males and only smoking and diabetes were predictive in females. 

 

Conclusion:  In symptomatic patients, there are significant differences in the ability of conventional risk factors to predict CAC presence between genders and between patients aged <70 and ≥70, indicating the important role of age in predicting CAC presence.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Coronary calcification, age, gender, risk factors
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-124925 (URN)10.1016/j.atherosclerosis.2016.07.906 (DOI)
External cooperation:
Available from: 2016-08-30 Created: 2016-08-30 Last updated: 2016-08-31Bibliographically approved
4. Diabetes and male gender are key risk factor predictors of CAC extent: a Euro-CCAD study
Open this publication in new window or tab >>Diabetes and male gender are key risk factor predictors of CAC extent: a Euro-CCAD study
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2016 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and aims: Although much has been written about the risk factor predictors of CAC extent, few studies have been carried out on symptomatic patients. Similarly, no study has directly compared predictors of CAC extent and zero CAC.

Methods: From the European Calcific Coronary Artery Disease (Euro-CCAD) cohort, we retrospectively investigated 6309 symptomatic patients, 62% male, from Denmark, France, Germany, Italy, Spain and USA. All had risk factor assessment and CT scanning for CAC scoring.

 Results: Among all patients, male gender (β = 1.36, p<0.001) and diabetes (β = 0.47, p<0.001) were the most important risk factors of CAC extent, with age, diabetes (DM), obesity, family history of CAD and number of risk factors also being predictive. Among patients with CAC, DM, hypertension (HT) and dyslipidaemia (DL) were predictors of an increasing CAC score in males and females, with DM being the strongest (p<0.001 for both). These results were echoed in quantile regression, where DM was consistently the most important predictor of CAC extent in every quantile in both males and females. HT and DL were also predictive but to a lesser extent, with HT being predictive in the high CAC quantiles and DL in the low CAC quantiles.

 Conclusion: In addition to male gender, DM is the most important predictor of CAC extent in both genders.  

Keyword
Coronary calcification extent, risk factors, diabetes, gender
National Category
Public Health, Global Health, Social Medicine and Epidemiology Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-124926 (URN)
External cooperation:
Available from: 2016-08-30 Created: 2016-08-30 Last updated: 2016-08-31
5. Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis
Open this publication in new window or tab >>Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis
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2016 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067Article in journal (Refereed) Accepted
Abstract [en]

Background: The relationship of conventional cardiovascular risk factors (age, gender, ethnicity, diabetes, dyslipidaemia, hypertension, obesity, exercise, and the number of risk factors) to coronary artery calcification (CAC) presence and extent has never before been assessed in a systematic review and meta-analysis.

Methods: We included only English language studies that assessed at least three conventional risk factors apart from age, gender, and ethnicity, but excluded studies in which all patients had another confirmed condition such as renal disease.

Results: In total, 10 studies, comprising 15,769 patients, were investigated in the systematic review and seven studies, comprising 12,682 patients, were included in the meta-analysis, which demonstrated the importance of diabetes and hypertension as predictors of CAC presence and extent, with age also predicting CAC presence. Male gender, dyslipidaemia, family history of coronary artery disease, obesity, and smoking were overall not predictive of either CAC presence or extent, despite dyslipidaemia being a key risk factor for coronary artery disease (CAD).

Conclusion: Diabetes and hypertension consistently predict the presence and extent of CAC in symptomatic patients.

 

Place, publisher, year, edition, pages
Basel, Switzerland: MDPI, 2016
Keyword
meta-analysis, systematic review, coronary calcification, risk factors
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-124923 (URN)
External cooperation:
Available from: 2016-08-30 Created: 2016-08-30 Last updated: 2016-08-31

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