Ivo A. Joosen

Elevated Levels of Circulating DNA and Chromatin Are Independently Associated With Severe Coronary Atherosclerosis and a Prothrombotic State

Objective—Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state. Approach and Results—In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase–DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase–DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26–3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase–DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. Conclusions—Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.

The Extent of Coronary Atherosclerosis Is Associated With Increasing Circulating Levels of High Sensitive Cardiac Troponin T

Objective—This study explored the relationship between coronary atherosclerotic plaque burden and quantifiable circulating levels of troponin measured with a recently introduced high sensitive cardiac troponin T (hs-cTnT) assay. Methods and Results—Cardiac patients suspected of having coronary artery disease (CAD) but without acute coronary syndrome were studied. Cardiac troponin T levels were assessed using the fifth-generation hs-cTnT assay. All patients (n=615) underwent cardiac computed tomographic angiography (CCTA). On the basis of CCTA, patients were classified as having no CAD or mild (<50% lesion), moderate (50% to 70% lesion), severe (>70% lesion), or multivessel CAD (multiple >70% lesions). As a comparison, high-sensitivity C-reactive protein levels were measured. Progressively increasing hs-cTnT levels were found in patients with mild (median, 4.5 ng/L), moderate (median, 5.5 ng/L), severe (median, 5.7 ng/L), and multivessel (median, 8.6 ng/L) CAD compared with patients without CAD (median, 3.7 ng/L) (all P<0.01). For high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide, no such relationship was observed. In patients without CAD, 11% showed hs-cTnT levels in the highest quartile, compared with 62% in the multivessel disease group (P<0.05). Multivariance analysis identified hs-cTnT as an independent risk factor for the presence of CAD. Conclusion—In patients without acute coronary syndrome, even mild CAD is associated with quantifiable circulating levels of hs-cTnT.

Patients originally diagnosed with idiopathic atrial fibrillation more often suffer from insidious coronary artery disease compared to healthy sinus rhythm controls

BACKGROUND Idiopathic atrial fibrillation (AF) refers to a clinically lacking cardiovascular or pulmonary disease generating the pathophysiologic substrate for the arrhythmia. However, because idiopathic AF is associated with an increased event rate, it could be a harbinger of as-yet undetected underlying heart disease. OBJECTIVE The purpose of this study was to determine the prevalence of coronary artery disease (CAD) in patients diagnosed with idiopathic paroxysmal AF. METHODS Of the 3243 patients who underwent cardiac computed tomographic angiography (CTA) in our center between January 2008 and March 2011, we identified a total of 115 consecutive idiopathic paroxysmal AF patients who underwent CTA before electrophysiologic ablation. Patients were compared with 275 age-, sex-, and PROCAM risk score-matched healthy controls in permanent sinus rhythm. All patients were free of hypertension, diabetes, congestive heart failure, previous known coronary artery and peripheral vascular disease, previous stroke, thyroid, pulmonary, and renal disease, and structural abnormalities on echocardiography. RESULTS Controls more often showed a family history of CAD (38% vs 15%, P <.001), had a higher prevalence of smoking (25% vs 14%, P = .021), higher fasting blood glucose levels (5.5 ± 0.7 mmol/L vs 5.4 ± 0.6 mmol/L, P = .025), and smaller atrial diameters (37 ± 4 mm vs 40 ± 5 mm, P <.001) compared to AF patients. Notwithstanding the above, idiopathic AF patients significantly more often suffered from subclinical CAD compared to controls (49% vs 34%, P = .008). Multivariable regression analysis revealed that beside (as expected) age and gender, a history of AF and left atrial diameter were significant predictors of underlying CAD. CONCLUSION Half of patients originally diagnosed with idiopathic paroxysmal AF show concealed underlying CAD. The detection and treatment of CAD at an early stage could improve the prognosis of these patients.

Accelerated in vivo thrombin formation independently predicts the presence and severity of CT angiographic coronary atherosclerosis.

OBJECTIVES This study sought to investigate the association between thrombin generation in plasma and the presence and severity of computed tomography angiographically defined coronary atherosclerosis in patients with suspected coronary artery disease (CAD). BACKGROUND Besides its pivotal role in thrombus formation, experimental data indicate that thrombin can induce an array of pro-atherogenic and plaque-destabilizing effects. Although thrombin plays a role in the pathophysiology of atherosclerosis progression and vascular calcification, the clinical evidence remains limited. METHODS Using 64-slice coronary computed tomographic angiography, we assessed the presence and characteristics of CAD in patients (n = 295; median age 58 years) with stable chest pain. Coronary artery calcification was graded as absent (Agatston score 0), mild (Agatston score 1 to 100), moderate (Agatston score 101 to 400), and severe (Agatston score >400). Calibrated automated thrombography was used to assess endogenous thrombin potential in plasma in vitro. Thrombin-antithrombin complex (TATc) levels were measured as a marker for thrombin formation in vivo. RESULTS TATc plasma levels were substantially higher in patients with CAD versus patients without CAD (p = 0.004). Significant positive correlations were observed between steadily increasing TATc levels and the severity of CAD (r = 0.225, p < 0.001). In multinomial logistic regression models, after adjusting for established risk factors, TATc levels predicted the degree of coronary artery calcification: mild (odds ratio: 1.56, p = 0.006), moderate (odds ratio: 1.56, p = 0.007), and severe (odds ratio: 1.67, p = 0.002). Trends were comparable between the groups when stratified according to the degree of coronary luminal stenosis. CONCLUSIONS This study provides novel clinical evidence indicating a positive independent association between enhanced in vivo thrombin generation and the presence and severity of coronary atherosclerosis, which may suggest that thrombin plays a role in the pathophysiology of vascular calcification and atherosclerosis progression.

Combined use of exercise electrocardiography, coronary calcium score and cardiac CT angiography for the prediction of major cardiovascular events in patients presenting with stable chest pain

BACKGROUND The usual diagnostic work-up of chest pain patients includes clinical risk profiling and exercise-ECG, possibly followed by additional tests. Recently cardiac computed tomographic angiography (CCTA) has been employed. We evaluated the prognostic value of the combined use of exercise-ECG and CCTA for the development of cardiovascular endpoints. METHODS In 283 patients (143 male, mean age 54 ± 10 years) with intermediate pre-test probability for coronary artery disease presenting with stable chest pain, exercise-ECG, CCTA and calcium score were performed. Patients were followed-up for combined endpoint of acute coronary syndrome (ACS) and revascularization. RESULTS After a median follow-up of 769 days (interquartile range 644-1007), 6 ACS and 9 revascularizations were recorded. A positive exercise-ECG predicted for the combined endpoint, [hazard ratio (HR) 5.14 (95% confidence interval (CI) 1.64-16.13), p=0.005], as well as a positive calcium score [HR 4.59 (95% CI 1.30-16.28), p=0.02] and a ≥ 50% stenosis on CCTA [HR 45.82 (95% CI 6.02-348.54), p<0.001]. ROC-analysis showed an area under the curve (AUC) of 0.79 (95% CI 0.67-0.90) for exercise-ECG, which increased significantly when CCTA was added: 0.91 (95% CI; 0.86-0.97; p=0.006). Multivariable Cox regression showed exercise-ECG predicted independently [HR 3.6, (95% CI 1.1-11.2), p=0.03], as well as CCTA [HR 31.4 (95% CI 4.0-246.6), p=0.001], but not calcium score [HR 0.6 (95% CI 0.2-2.3), p=0.5]. CONCLUSIONS The combined subsequent use of exercise-ECG for functional information and CCTA for anatomical information provides a high diagnostic yield in stable chest pain patients with an intermediate pre-test probability for coronary artery disease.

High-sensitivity cardiac troponin t: Risk stratification tool in patients with symptoms of chest discomfort

Background Recent studies have demonstrated the association between increased concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and the incidence of myocardial infarction, heart failure, and mortality. However, most prognostic studies to date focus on the value of hs-cTnT in the elderly or general population. The value of hs-cTnT in symptomatic patients visiting the outpatient department remains unclear. The aim of this study was to investigate the prognostic value of hs-cTnT as a biomarker in patients with symptoms of chest discomfort suspected for coronary artery disease and to assess its additional value in combination with other risk stratification tools in predicting cardiac events. Methods We studied 1,088 patients (follow-up 2.2±0.8 years) with chest discomfort who underwent coronary calcium scoring and coronary CT-angiography. Traditional cardiovascular risk factors and concentrations of hs-cTnT, N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP) were assessed. Study endpoint was the occurrence of late coronary revascularization (>90 days), acute coronary syndrome, and cardiac mortality. Results Hs-cTnT was a significant predictor for the composite endpoint (highest quartile [Q4]>6.7 ng/L, HR 3.55; 95%CI 1.88–6.70; P<0.001). Survival analysis showed that hs-cTnT had significant predictive value on top of current risk stratification tools (Chi-square change P<0.01). In patients with hs-cTnT in Q4 versus <Q4, a 2- to 3-fold increase in cardiovascular risk was noticed, either when corrected for high or low Framingham risk score, coronary calcium scoring, or CT-angiography assessment (HR 3.11; 2.73; 2.47; respectively; all P<0.01). This was not the case for hsCRP and NT-proBNP. Conclusions Hs-cTnT is a useful prognostic biomarker in patients with chest discomfort suspected for coronary artery disease. In addition, hs-cTnT was an independent predictor for cardiac events when corrected for cardiovascular risk profiling, calcium score and CT-angiography results.

Relation between Mild to Moderate Chronic Kidney Disease and Coronary Artery Disease Determined with Coronary CT Angiography

Background Both end-stage and milder stages of chronic kidney disease (CKD) are associated with an increased risk of adverse cardiovascular events. Several studies found an association between decreasing renal function and increasing coronary artery calcification, but it remains unclear if this association is independent from traditional cardiovascular risk factors. Therefore, the aim of this study was to investigate whether mild to moderate CKD is independently associated with coronary plaque burden beyond traditional cardiovascular risk factors. Methods A total of 2,038 patients with symptoms of chest discomfort suspected for coronary artery disease underwent coronary CT-angiography. We assessed traditional risk factors, coronary calcium score and coronary plaque characteristics (morphology and degree of luminal stenosis). Patients were subdivided in three groups, based on their estimated glomerular filtration rate (eGFR) Normal renal function (eGFR ≥90 mL/min/1.73 m2); mild CKD (eGFR 60–89 mL/min/1.73 m2); and moderate CKD (eGFR 30–59 mL/min/1.73 m2). Results Coronary calcium score increased significantly with decreasing renal function (P<0.001). Coronary plaque prevalence was higher in patients with mild CKD (OR 1.83, 95%CI 1.52–2.21) and moderate CKD (OR 2.46, 95%CI 1.69–3.59), compared to patients with normal renal function (both P<0.001). Coronary plaques with >70% luminal stenosis were found significantly more often in patients with mild CKD (OR 1.67 (95%CI 1.16–2.40) and moderate CKD (OR2.36, 95%CI 1.35–4.13), compared to patients with normal renal function (both P<0.01). After adjustment for traditional cardiovascular risk factors, the association between renal function and the presence of any coronary plaque as well as the association between renal function and the presence of coronary plaques with >70% luminal stenosis becomes weaker and were no longer statistically significant. Conclusion Although decreasing renal function is associated with increasing extent and severity of coronary artery disease, mild to moderately CKD is not independently associated with coronary plaque burden after adjustment for traditional cardiovascular risk factors.

Epicardial adipose tissue volume as a predictor for coronary artery disease in diabetic, impaired fasting glucose, and non-diabetic patients presenting with chest pain

AIMS Epicardial adipose tissue (EAT) volume has been associated with coronary artery disease (CAD). As diabetes mellitus type 2 (DM2) patients have higher EAT volumes, it has been suggested that EAT may play a role in promoting CAD in these patients. The aim of this study was to examine the association between EAT and CAD in DM2, impaired fasting glucose (IFG) and control patients presenting with stable chest pain. METHODS AND RESULTS A total of 410 stable chest pain patients underwent multidetector cardiac computed tomography angiography (CCTA) to assess the presence of CAD. The extent of CAD was expressed as the number of affected segments. The EAT volume was measured using three-dimensional volumetric quantification. The EAT was compared using ANOVA, logistic and linear regression models were used to assess its predictive value. Multivariable regression analysis corrected for traditional risk factors was performed. Eighty-three patients had DM2, 118 IFG and there were 209 controls. DM2 as well as IFG patients had higher EAT volumes compared with controls (98 ± 41, 92 ± 39, and 75 ± 34 cm(3), respectively; P < 0.001). EAT predicted the presence (OR: 1.01; P < 0.001) and the extent of CAD (B: 0.01; P < 0.001). The associations were equal in all subgroups. However, in a multivariable regression model corrected for traditional cardiovascular risk factors, EAT was not an independent predictor for the presence or extent of CAD (OR: 1.00; P = 0.88 and B: -0.11; P = 0.68, respectively). CONCLUSION The EAT volume is associated with CAD in DM2, IFG, and control patients. However, EAT is not an independent predictor for CAD in patients presenting with stable chest pain.

High-Sensitivity Cardiac Troponin Concentrations in Patients with Chest Discomfort: Is It the Heart or the Kidneys As Well?

Background High-sensitivity cardiac troponins (hs-cTn) are the preferred biomarkers to detect myocardial injury, making them promising risk-stratifying tools for patients with symptoms of chest pain. However, circulating hs-cTn are also elevated in other conditions like renal dysfunction, complicating appropriate interpretation of low-level hs-cTn concentrations. Methods A cross-sectional analysis was performed in 1864 patients with symptoms of chest discomfort from the cardiology outpatient department who underwent cardiac computed tomographic angiography (CCTA). Serum samples were analyzed using hs-cTnT and hs-cTnI assays. Renal function was measured by the estimated glomerular filtration rate (eGFR), established from serum creatinine and cystatin C. On follow-up, the incidence of adverse events was assessed. Results Median hs-cTnT and hs-cTnI concentrations were 7.2(5.8–9.2) ng/L and 2.6(1.8–4.1) ng/L, respectively. Multivariable regression analysis revealed that both assay results were more strongly associated with eGFR (hs-cTnT:stβ:-0.290;hs-cTnI:stβ:-0.222) than with cardiac imaging parameters, such as coronary calcium score, CCTA plaque severity score and left ventricular mass (all p<0.01). Furthermore, survival analysis indicated lower relative risks in patients with normal compared to reduced renal function for hs-cTnT [HR(95%CI), 1.02(1.00–1.03) compared to 1.07(1.05–1.09)] and hs-cTnI [1.01(1.00–1.01) compared to 1.02(1.01–1.02)] (all p<0.001). Conclusion In patients with chest discomfort, we identified an independent influence of renal function on hs-cTn concentrations besides CAD, that affected the association of hs-cTn concentrations with adverse events. Estimating renal function is therefore warranted when interpreting baseline hs-cTn concentrations.

Gender Difference in the Prognostic Value of CTA

The prognostic value of coronary computed tomographic angiography (CTA) is emerging, and especially detected obstructive coronary artery disease (CAD) is a strong independent predictor for events [(1)][1]. Meanwhile, the pathophysiology of acute coronary syndromes in men and women differs. In