Ferdinand Flores

Mortality Incidence and the Severity of Coronary Atherosclerosis Assessed by Computed Tomography Angiography

OBJECTIVES This study investigated whether cardiac computed tomography angiography (CTA) can predict all-cause mortality in symptomatic patients. BACKGROUND Noninvasive coronary angiography is being increasingly performed by CTA to assess for obstructive coronary artery disease (CAD), and minimal outcome data exist for coronary CTA. We have utilized a cohort of symptomatic patients who underwent electron beam tomography to allow for longer follow-up (up to 12 years) than currently available with newer 64-slice multidetector-row computed tomography studies. METHODS In all, 2,538 consecutive patients who underwent CTA by electron beam tomography (age 59 +/- 14 years, 70% males) without known CAD were studied. Computed tomographic angiography results were categorized as significant CAD (> or =50% luminal narrowing), mild CAD (<50% stenosis), and normal coronary arteries. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and coronary artery calcification (CAC). RESULTS During a mean follow-up of 78 +/- 12 months, the death rate was 3.4% (86 deaths). The CTA-diagnosed CAD was an independent predictor of mortality in a multivariable model adjusted for age, gender, cardiac risk factors, and CAC (p < 0.0001). The addition of CAC to CTA-diagnosed CAD increased the concordance index significantly (0.69 for risk factors, 0.83 for the CTA-diagnosed CAD, and 0.89 for the addition of CAC to CAD, p < 0.0001). Risk-adjusted hazard ratios for CTA-diagnosed CAD were 1.7-, 1.8-, 2.3-, and 2.6-fold for 3-vessel nonobstructive, 1-vessel obstructive, 2-vessel obstructive, and 3-vessel obstructive CAD, respectively (p < 0.0001), when compared with the group who did not have CAD. CONCLUSIONS The primary results of our study reveal that the burden of angiographic disease detected by CTA provides both independent and incremental value in predicting all-cause mortality in symptomatic patients independent of age, gender, conventional risk factors, and CAC.

Aged garlic extract supplemented with B vitamins, folic acid and l-arginine retards the progression of subclinical atherosclerosis: A randomized clinical trial

OBJECTIVES Previous studies demonstrated that aged garlic extract reduces multiple cardiovascular risk factors. This study was designed to assess whether aged garlic extract therapy with supplements (AGE+S) favorably affects inflammatory and oxidation biomarkers, vascular function and progression of atherosclerosis as compared to placebo. METHODS In this placebo-controlled, double-blind, randomized trial (conducted 2005-2007), 65 intermediate risk patients (age 60+/-9 years, 79% male) were treated with a placebo capsule or a capsule containing aged garlic extract (250 mg) plus Vitamin B12 (100 microg), folic acid (300 microg), Vitamin B6 (12.5 mg) and l-arginine (100 mg) given daily for a 1 year. All patients underwent coronary artery calcium scanning (CAC), temperature rebound (TR) as an index of vascular reactivity using Digital Thermal Monitoring (DTM), and measurement of lipid profile, autoantibodies to malondialdehyde (MDA)-LDL, apoB-immune complexes, oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL/apoB), lipoprotein (a) [Lp (a)], C-reactive protein (CRP), homocysteine were measured at baseline and 12 months. CAC progression was defined as an increase in CAC>15% per year and an increase in TR above baseline was considered a favorable response. RESULTS At 1 year, CAC progression was significantly lower and TR significantly higher in the AGE+S compared to the placebo group after adjustment of cardiovascular risk factors (p<0.05). Total cholesterol, LDL-C, homocysteine, IgG and IgM autoantibodies to MDA-LDL and apoB-immune complexes were decreased, whereas HDL, OxPL/apoB, and Lp (a) were significantly increased in AGE+S to placebo. CONCLUSION AGE+S is associated with a favorable improvement in oxidative biomarkers, vascular function, and reduced progression of atherosclerosis.

Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients.

Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.

Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography.

It was previously reported that event-free survival rates of symptomatic patients with coronary artery disease (CAD) diagnosed by computed tomographic angiography decreased incrementally from normal coronary arteries to obstructive CAD. The aim of this study was to investigate the clinical outcomes of symptomatic patients with nonobstructive CAD with luminal stenoses of 1% to 49% on the basis of coronary plaque morphology in an outpatient setting. Among 3,499 consecutive symptomatic subjects who underwent computed tomographic angiography, 1,102 subjects with nonobstructive CAD (mean age 59 ± 14 years, 69.9% men) were prospectively followed for a mean of 78 ± 12 months. Coronary plaques were defined as noncalcified, mixed, and calcified per patient. Multivariate Cox proportional-hazards models were developed to predict all-cause mortality. The death rate of patients with nonobstructive CAD was 3.1% (34 deaths). The death rate increased incrementally from calcified plaque (1.4%) to mixed plaque (3.3%) to noncalcified plaque (9.6%), as well as from single- to triple-vessel disease (p <0.001). In subjects with mixed or calcified plaques, the death rate increased with the severity of coronary artery calcium from 1 to 9 to ≥ 400. The risk-adjusted hazard ratios of all-cause mortality in patients with nonobstructive CAD were 3.2 (95% confidence interval 1.3 to 8.0, p = 0.001) for mixed plaques and 7.4 (95% confidence interval 2.7 to 20.1, p = 0.0001) for noncalcified plaques compared with calcified plaques. The areas under the receiver-operating characteristic curve to predict all-cause mortality were 0.75 for mixed and 0.86 for noncalcified coronary lesions. In conclusion, this study demonstrates that the presence of noncalcified and mixed coronary plaques provided incremental value in predicting all-cause mortality in symptomatic subjects with nonobstructive CAD independent of age, gender, and conventional risk factors.

Effect of statin treatment on coronary plaque progression - a serial coronary CT angiography study.

OBJECTIVES Statins have been shown to reduce plaque progression using data on intravascular ultrasound, carotid intima-media thickness and coronary artery calcium scans. However, there is little data on effects of statins on plaque progression using Coronary CTA. The objective is to evaluate the effect of statin therapy on plaque progression using serial Coronary CTA (CCTA). METHODS The study included 100 consecutive patients who underwent serial Coronary CTA (mean follow up: 406 ± 92 days) for evaluation of CAD without known prior heart disease or revascularization. We performed volumetric assessment of low attenuation plaque (LAP < 30 Hounsfield units), non-calcified (NCP) and calcified plaque volumes at baseline and follow up scans for vessels >2 mm in diameter. Patients who received statins were compared to those that did not. RESULTS Total plaque progression was significantly reduced among statin user compared to non-statin users (-33.3 mm(3) ± 90.5 vs. 31.0 mm(3) ± 84.5, p = 0.0006). Statin users had significantly reduced progression of NCP volume (-47.7 mm(3) ± 71.9 vs. 13.8 mm(3) ± 76.6, p < 0.001) and significantly reduced progression of LAP volume (-12.2 mm(3) ± 19.2 vs. 5.9 mm(3) ± 23.1, p < 0.0001). When we compared for remodeling index, no statistical difference was found between the two groups (p = 0.25) and a non-significant trend toward calcium progression (29.3 mm(3) ± 67.9 vs. 10.0 mm(3) ± 53.2, p = 0.133). After adjustment for cardiovascular risk factors, mean plaque volume difference between statin and non-statin users was statistically significant for both LAP and NCP volumes (-18.1, 95% CI: -26.4, -9.8 for LAP; -101.7, 95% CI: -162.1, -41.4 for NCP; p < 0.001) respectively. CONCLUSION Statin therapy resulted in significantly lower progression of LAP and NCP plaques compared to non-statin users.

Effects of Sevelamer and Calcium-Based Phosphate Binders on Lipid and Inflammatory Markers in Hemodialysis Patients

Introduction: Cardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients. Methods: We examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005. Results: Of the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP <10 mg/l [odds ratio (OR): 1.06, 95% CI: 1.02–1.11] and LDL cholesterol <70 mg/dl (OR: 1.33, 95% CI: 1.19–1.47) when compared to the calcium binder group independent of age, vintage, body mass index, statin use or other variables. Conclusion: The improvements in multiple surrogate markers of inflammation and lipids in the NIED study make sevelamer a promising therapy for treatment in MHD patients with high risk of cardiovascular disease and mortality.

Increased Epicardial, Pericardial, and Subcutaneous Adipose Tissue Is Associated with the Presence and Severity of Coronary Artery Calcium

RATIONALE AND OBJECTIVES Epicardial adipose tissue (EAT), pericardial adipose tissue (PAT), and subcutaneous adipose tissue (SAT) are mediators of metabolic risk and may be involved in the pathogenesis of coronary artery disease. The aim of this study was to investigate the association of visceral and subcutaneous fat depots with the presence and severity of coronary artery calcium (CAC) in asymptomatic individuals. MATERIALS AND METHODS One hundred eleven consecutive subjects underwent CAC assessment, and their Framingham risk scores were measured. EAT, total thoracic adipose tissue, and SAT volumes were measured from slice level 15 mm above to 30 mm below the ostium of the left main coronary artery. PAT was calculated as thoracic adipose tissue - EAT. SAT was defined as the volume of fat depot anterior to the sternum and posterior to the vertebra. CAC was defined as 0, 1 to 100, 101 to 400, or ≥ 400. Relative risk regression analysis was used to assess the association between fat depots and CAC. RESULTS There were modest correlations between EAT (r = 0.58), PAT (r = 0.47), SAT (r = 0.34), and CAC (P < .01). EAT, PAT, and SAT increased proportionally with the severity of CAC in both genders (P < .05). After adjustment for cardiovascular risk factors and body mass index, the relative risks for each standard deviation increase in EAT, PAT, and SAT were 3.3 (95% confidence interval, 1.9-5.6), 2.7 (95% confidence interval, 1.6-3.9), and 2.6 (95% confidence interval, 1.5-4.4) for CAC ≥ 100 compared to CAC 0, respectively (P < .05). The area under the receiver-operating characteristic curve to predict CAC ≥ 100 was higher in each fat depot compared to Framingham risk score, and addition of fat depots to Framingham risk score provided maximum prognostication value to detect CAC ≥ 100. CONCLUSIONS Increased EAT, PAT, and SAT are associated with the severity of CAC independent of risk factors.

Prognostic Value of Number and Site of Calcified Coronary Lesions Compared With the Total Score

OBJECTIVES This study sought to evaluate the long-term prognostic value of the number and sites of calcified coronary lesions and to compare the accuracy of number of calcified lesions with the extent of total calcium score. BACKGROUND There is a strong relationship between mortality and total coronary artery calcium (CAC) score. It is not known whether the number of calcified lesions or their location influences outcome. METHODS A total of 14,759 asymptomatic patients were referred for evaluation of CAC scanning using electron beam tomography. Univariable and multivariable Cox proportional hazards models were developed to estimate time to all-cause mortality at, on average, 6.8 years (n = 281). RESULTS Risk-adjusted annual mortality was 0.19% (95% confidence interval 0.18% to 0.21%) for patients without any calcified lesions. For patients with >20 lesions, annual risk-adjusted mortality exceeded 2% per year. Mortality rates were significantly higher for left main lesions as compared to other coronary arteries with annual mortality rates of 1.3%, 2.1%, 9.2%, and 13.6% for 1 to 2, 3 to 5, and > or =6 lesions, respectively (p < 0.0001). For left main CAC scores of 0 to 10, 11 to 100, 101 to 399, and 400 to 999, annual risk-adjusted mortality was 0.33%, 0.81%, 1.73%, and 7.71%, respectively (p < 0.0001). All 4 patients with a CAC score of > or =1,000 in the left main died during follow-up. However, patients with more frequent calcified lesions also had higher CAC scores. Specifically, > or =81% of patients with >10 calcified lesions also had a CAC score > or =100. With exception, for patients with CAC scores > or =1,000, annual mortality was dramatically higher at 3.0% to 4.5% for those with 1 to 5 calcified lesions as compared with 1.1% to 2.0% for those with 6 or more lesions (p < 0.0001). CONCLUSIONS We report that mortality rates increased proportionally with the number of calcified lesions. Although predictive information is contained in the number of calcified lesions, its added statistical value is minimal. With exception, patients with frequent lesions in the left main or those with a few large calcified lesions have a particularly high mortality risk.

Relation of oxidative biomarkers, vascular dysfunction, and progression of coronary artery calcium.

The relation between oxidative stress and coronary artery calcium (CAC) progression is currently not well described. The present study evaluated the relation among the biomarkers of oxidative stress, vascular dysfunction, and CAC. Sixty asymptomatic subjects participated in a randomized trial evaluating the effect of aged garlic extract plus supplement versus placebo and underwent measurement of CAC. The postcuff deflation temperature-rebound index of vascular function was assessed using a reactive hyperemia procedure. The content of oxidized phospholipids (OxPL) on apolipoprotein B-100 (apoB) particles detected by antibody E06 (OxPL/apoB), lipoprotein(a), IgG and IgM autoantibodies to malondialdehyde-low-density lipoprotein and apoB-immune complexes were measured at baseline and after 12 months of treatment. CAC progression was defined as an annual increase in CAC >15%. Vascular dysfunction was defined according to the tertiles of temperature-rebound at 1 year of follow-up. From baseline to 12 months, a strong inverse correlation was noted between an increase in CAC scores and increases in temperature-rebound (r(2) = -0.90), OxPL/apoB (r(2) = -0.85), and lipoprotein(a) (r(2) = -0.81) levels (p <0.0001 for all). The improvement in temperature-rebound correlated positively with the increases in OxPL/apoB (r(2) = 0.81, p = 0.0008) and lipoprotein(a) (r(2) = 0.79, p = 0.0001) but inversely with autoantibodies to malondialdehyde-low-density lipoprotein and apoB-immune complexes. The greatest CAC progression was noted with the lowest tertiles of increases in temperature-rebound, OxPL/apoB and lipoprotein(a) and the highest tertiles of increases in IgG and IgM malondialdehyde-low-density lipoprotein. In conclusion, the present results have documented a strong relation among markers of oxidative stress, vascular dysfunction, and progression of coronary atherosclerosis. Increases in OxPL/apoB and lipoprotein(a) correlated strongly with increases in vascular function and predicted a lack of progression of CAC.

Cardiac computed tomographic angiography in an outpatient setting: An analysis of clinical outcomes over a 40-month period

BACKGROUND Cardiac computed tomographic angiography (CTA) provides for accurate noninvasive diagnosis of coronary artery disease (CAD). OBJECTIVES We analyzed the clinical outcomes over 40 months in patients with and without CAD as determined by CTA in an outpatient setting. METHODS Consecutive symptomatic patients (n = 493; mean age, 58 +/- 15 years; 70% men) with an intermediate likelihood of CAD referred for outpatient CTA evaluation were prospectively followed for a mean of 40 +/- 9 months. RESULTS Results of CTA included as normal (defined as normal coronary lumen), found in 32% (157), nonobstructive disease (<50% luminal stenosis) in 41% (204), obstructive disease (>or=50% luminal stenosis) in 19% (93). Eight percent (n = 39) had >or=1 major nondiagnostic coronary artery segment. Follow-up identified 21 patients with myocardial infarction (MI) in the significant obstructive CAD and nondiagnostic group. No patients with either normal coronary arteries or nonobstructive disease experienced an MI during follow-up. The 40-month event-free survival was 100% for both the normal and nonobstructive disease groups, 97.5% for the nondiagnostic study group, and 79% for the group with obstructive CAD. After adjustment for age, sex, diabetes mellitus, hypertension, hypercholesterolemia, and baseline coronary artery calcium (CAC), a stepwise multivariable model (Cox regression) showed that obstructive CAD was an independent predictor of cardiac events and had significant incremental value over clinical risk factors and CAC (HR = 16.6; 95% CI, 4.9-55.2; P = 0.0001). CONCLUSION In symptomatic patients with an intermediate likelihood of CAD referred for CTA, normal coronary arteries or nonobstructive CAD portends an excellent prognosis. The finding of obstructive CAD identifies patients at higher risk of subsequent MI, independent of cardiovascular risk factors and coronary artery calcium.