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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.

Computed Tomography Coronary Angiography (CTCA)is a technique for imaging coronary arteries with increasing indications in clinical cardiology. AIMS 1.Develop a heart rate (HR) lowering regime for CTCA and to measure its association with image quality. 2.Examine the diagnostic accuracy of 64 slice CTCA (CTCA64) in patients with known coronary artery disease (CAD). 3.Examine the diagnostic accuracy of CTCA64 for assessment of stent restenosis 4.Demonstrate utility of CTCA as an endpoint in assessment of novel diagnostic biomarkers of CAD. METHODS I developed a HR reducing strategy using metoprolol and assessed its effectiveness for improving CTCA64 image quality. The diagnostic value of CTCA in patients with suspected angina was evaluated by comparison with invasive coronary angiography. The diagnostic value of CTCA for quantifying stent restenosis was evaluated by comparison with intravascular ultrasound. The utility of CTCA for evaluating the diagnostic value of B-type natriuretic peptide (BNP) and high sensitivity cardiac troponin I (hs- TnI) was evaluated by blood sampling in patients with suspected angina who subsequently underwent CTCA. RESULTS 1.In 121 patients undergoing CTCA, 75 required rate control. This was achieved (rate ≤60 bpm) in 83% using a systematic regimen of oral and IV metoprolol (n=71) or verapamil (n=4). I demonstrated a significant relation between HR reduction and graded image quality (p<0.001). 2.80 patients underwent CTCA64 and invasive coronary angiography. 724 coronary arterial segments were available for analysis. The sensitivity and specificity of CTCA for significant luminal stenosis was 83.3% (95% CI 67.1-92.5%) and 96.7% (95% CI 95.1-97.9%), respectively, but the positive predictive value was only 63.5% (95% CI 50.4-75.3%). 3.80 patients with 125 stented segments underwent CTCA64 and invasive coronary angiography. Additional intravascular ult rasound (IVUS) examination of stented segments was performed in 48 patients. Using IVUS as the gold-standard for stent restenosis, CTCA and invasive coronary angiography had comparable diagnostic specificities for binary stent restenosis: 82.7% (95% confidence intervals 69.7- 91.84%)and 78.9% (95% confidence intervals 65.3-88.9%), respectively. Sensitivities were lower, particularly the sensitivity of CTCA which was only 11.8% (95% confidence intervals 1.5-36.4%) compared with 58.8% (95% confidence intervals 32.9-81.6%) for invasive coronary angiography. 4. In 93 patients with suspected angina CTCA64 provided a useful endpoint for assessing the diagnostic value of novel circulating biomarkers. BNP levels were higher in the 13 patients shown to have significant (≥50% stenosis) coronary artery disease compared with patients who had unobstructed coronary arteries (18.08pg/ml (IQR 22) vs 9.14pg/ml (IQR 12.62), p=0.024) and increased significantly with exercise, particularly in the group with anatomic coronary artery disease (2.73 ± 5.69 pg/ml vs 1.27±3.29 pg/ml, p=0.16). Conversely I found no association between hs-TnI and the presence of CAD. CONCLUSION Image quality of CTCA64 is enhanced by heart rate reduction below 60 bpm which can be achieved safely by a regimen of oral and intravenous metoprolol. Although CTCA64 is a useful non-invasive method for diagnosis of coronary artery disease, it has a low positive predictive value for identifying severe (≥50%) luminal stenosis which limits its clinical value. Its value for assessment of stent restenosis is even more limited but it finds useful application as an endpoint for diagnostic evaluation of novel biomarkers, allowing confirmation of an association between circulating BNP levels and stable coronary artery disease.

Restenosis is one of the major adverse outcomes of Percutaneous Coronary Intervention (PCI). Previous studies have shown conflicting reports for homocysteine as a predictor of restenosis following PCI. The conflicting reports may be due to oxidative factors (stimulation of polymorphonuclear leukocyte [PMNL]-induced reactive oxygen species generation, xanthine- xanthine oxidase, and arachidonic acid metabolism) other than homocysteine which could cause endothelial cell dysfunction leading to restenosis. Malondialdehyde (MDA), a lipid peroxidation product, is a marker for oxidative stress and is related to all oxidative factors. Therefore, it is possible that serum MDA may be a better predictor of restenosis than plasma homocysteine. The purpose of this study is to determine whether or not the pre-procedural serum MDA and plasma homocysteine levels are elevated in patients who develop restenosis post PCI. <p>The study included fifty-one patients undergoing elective PCI who consented to participate in a protocol that was approved by the Ethics Committee of the University of Saskatchewan. Homocysteine and malondialdehyde were measured in the plasma and serum respectively. Blood samples were collected pre-procedural, 0 time, 8 hours, 24 hours, and 6 months post-procedure. Exercise tolerance tests were performed at two weeks, and six months post-procedure to determine if there was any evidence of restenosis. <p>The results of the study showed that pre-procedural values of plasma homocysteine in the restenosis and non-restenosis groups were 10.37 ± 0.46 and 10.73 ± 0.49 respectively. These values were not significantly different (p=0.60) between the groups. The pre-procedural levels of plasma homocysteine were not significantly different (p=0.08) from the post-PCI values of those patients who did not develop restenosis at the 6-month time interval. However, the pre-procedural levels of plasma homocysteine were significantly different from the post-PCI values of those patients in the restenosis group at the 24hr (p=0.04) and 6-month (p=0.002) time intervals. In the restenosis group there was a significant increase (24%) after six months in the values of homocysteine from the pre-procedural levels. Thus, this indicates that restenosis is associated with higher post-PCI levels of homocysteine. <p>The pre-procedural levels of serum MDA in the restenosis and non-restenosis groups were 0.124± 0.16 and 0.147± 0.02 respectively. There was no significant difference (p=0.60) between the two groups. There was also no significant difference (p=0.053) between the pre-procedural values and the 6-month post-PCI values in those patients who did not develop restenosis. However, there was a significant difference (p=0.001) between the pre-procedural values and the 6-month post-PCI values in those patients who developed restenosis. The levels of serum MDA in patients with restenosis at 6-months increased by 109% and were significantly different (p=0.001) in the restenosis group. <p>The results suggest that pre-procedural levels of plasma homocysteine and serum MDA were not predictors of restenosis following PCI. However, the post-PCI six-month levels of both homocysteine and MDA are predictors of restenosis. Moreover, the post-PCI levels of MDA were better predictors of restenosis than the post-PCI levels of homocysteine because the increase in MDA levels were greater at six months than the rise in homocysteine levels at the same time interval.

Restenosis is one of the major adverse outcomes of Percutaneous Coronary Intervention (PCI). Previous studies have shown conflicting reports for homocysteine as a predictor of restenosis following PCI. The conflicting reports may be due to oxidative factors (stimulation of polymorphonuclear leukocyte [PMNL]-induced reactive oxygen species generation, xanthine- xanthine oxidase, and arachidonic acid metabolism) other than homocysteine which could cause endothelial cell dysfunction leading to restenosis. Malondialdehyde (MDA), a lipid peroxidation product, is a marker for oxidative stress and is related to all oxidative factors. Therefore, it is possible that serum MDA may be a better predictor of restenosis than plasma homocysteine. The purpose of this study is to determine whether or not the pre-procedural serum MDA and plasma homocysteine levels are elevated in patients who develop restenosis post PCI. <p>The study included fifty-one patients undergoing elective PCI who consented to participate in a protocol that was approved by the Ethics Committee of the University of Saskatchewan. Homocysteine and malondialdehyde were measured in the plasma and serum respectively. Blood samples were collected pre-procedural, 0 time, 8 hours, 24 hours, and 6 months post-procedure. Exercise tolerance tests were performed at two weeks, and six months post-procedure to determine if there was any evidence of restenosis. <p>The results of the study showed that pre-procedural values of plasma homocysteine in the restenosis and non-restenosis groups were 10.37 ± 0.46 and 10.73 ± 0.49 respectively. These values were not significantly different (p=0.60) between the groups. The pre-procedural levels of plasma homocysteine were not significantly different (p=0.08) from the post-PCI values of those patients who did not develop restenosis at the 6-month time interval. However, the pre-procedural levels of plasma homocysteine were significantly different from the post-PCI values of those patients in the restenosis group at the 24hr (p=0.04) and 6-month (p=0.002) time intervals. In the restenosis group there was a significant increase (24%) after six months in the values of homocysteine from the pre-procedural levels. Thus, this indicates that restenosis is associated with higher post-PCI levels of homocysteine. <p>The pre-procedural levels of serum MDA in the restenosis and non-restenosis groups were 0.124± 0.16 and 0.147± 0.02 respectively. There was no significant difference (p=0.60) between the two groups. There was also no significant difference (p=0.053) between the pre-procedural values and the 6-month post-PCI values in those patients who did not develop restenosis. However, there was a significant difference (p=0.001) between the pre-procedural values and the 6-month post-PCI values in those patients who developed restenosis. The levels of serum MDA in patients with restenosis at 6-months increased by 109% and were significantly different (p=0.001) in the restenosis group. <p>The results suggest that pre-procedural levels of plasma homocysteine and serum MDA were not predictors of restenosis following PCI. However, the post-PCI six-month levels of both homocysteine and MDA are predictors of restenosis. Moreover, the post-PCI levels of MDA were better predictors of restenosis than the post-PCI levels of homocysteine because the increase in MDA levels were greater at six months than the rise in homocysteine levels at the same time interval.

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Thesis (M.S.)--Florida State University, 2004. / Advisor: Dr. Laurie Grubbs, Florida State University, School of Nursing. Title and description from dissertation home page (viewed June 16, 2004). Includes bibliographical references.