Plasma Lipidomics and Coronary Plaque Changes: A Substudy of the SMARTool Clinical Trial.

AIMS: To date, no studies have investigated the association between lipid species and coronary plaque changes over time, quantitatively assessed by serial imaging. We aimed to prospectively determine the association between lipid species quantified by plasma lipidomic analysis, with coronary plaque changes according to composition assessed by quantitative serial analysis of coronary computed tomography angiography (CTA). METHODS AND RESULTS: Patients with suspected coronary artery disease (CAD) undergoing baseline coronary CTA were prospectively enrolled by 7 EU Centers in the SMARTool study and submitted to clinical, molecular and coronary CTA re-evaluation at follow-up (interscan period 6.39 ± 1.17 years). From the 202 patients that were analysed in the SMARTool main clinical study, lipidomic analysis was performed in 154 patients before the baseline coronary CTA, and this group was included in the present study. Quantitative CTA analysis was performed by a separate core laboratory blinded from clinical data. In univariable analysis, no lipid species were significantly associated with annual total and calcified plaque changes. After adjusting for clinical variables at baseline and statin use, 3 lipid species were significantly associated with non-calcified plaque progression. In detail, cholesteryl ester (CE)(20:3), sphingomyelin (SM)(40:3) and SM(41:1) were found positively related to non-calcified plaque progression (Bonferroni adjusted P-value = 0.005, 0.016 and 0.004, respectively). CONCLUSION: The current study showed an independent relationship between specific lipid species determined by plasma lipidomic analysis, and non-calcified coronary plaque progression assessed by serial, quantitative coronary CTA analysis.

Association of Left Atrial Appendage Morphology and Function With Stroke and Transient Ischemic Attack in Atrial Fibrillation Patients.

We aimed to correlate left atrial appendage (LAA) structure and function with the history of stroke/transient ischemic attack (TIA) in patients with atrial fibrillation (AF). We analyzed the data of 649 patients with AF who were scheduled for catheter ablation. Patients underwent cardiac computed tomography and transesophageal echocardiography before ablation. The LAA morphologies depicted by cardiac computed tomography were categorized into 4 groups: cauliflower, chicken wing, swan, and windsock shapes. The mean age was 61.3 ± 10.5 years, 33.9% were women. The prevalence of stroke/TIA was 7.1%. After adjustment for the main risk factors, the LAA flow velocity ≤35.3 cm/s (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.09 to 4.61, p = 0.033) and the swan LAA shape (OR 2.69, 95% CI 0.96 to 6.86, p = 0.047) independently associated with a higher risk of stroke/TIA, whereas the windsock LAA morphology proved to be protective (OR 0.32, 95% CI 0.12 to 0.77, p = 0.017) compared with the cauliflower LAA shape. Comparing the differences between the LAA morphology groups, we measured a significantly smaller LAA orifice area (389.3 ± 137.7 mm2 in windsock vs 428.3 ± 158.9 ml in cauliflower, p = 0.021) and LAA volume (7.4 ± 3.0 mm2 in windsock vs 8.5 ± 4.8 mm2 in cauliflower, p = 0.012) in patients with windsock LAA morphology, whereas the LAA flow velocity did not differ significantly. Reduced LAA function and swan LAA morphology were independently associated with a higher prevalence of stroke/TIA, whereas the windsock LAA shape proved to be protective. Comparing the differences between the various LAA morphology types, significantly lower LAA volume and LAA orifice area were measured in the windsock LAA shape than in the cauliflower LAA shape.

Relation Between Coronary Plaque Composition Assessed by Intravascular Ultrasound Virtual Histology and Myocardial Ischemia Assessed by Quantitative Flow Ratio.

Coronary plaque composition may play an important role in the induction of myocardial ischemia. Our objective was to further clarify the relation between coronary plaque composition and myocardial ischemia in patients with chest pain symptoms. The study population consisted of 103 patients who presented to the outpatient clinic or emergency department with chest pain symptoms and were referred for diagnostic invasive coronary angiography. Intravascular ultrasound virtual histology was used for the assessment of coronary plaque composition. A noncalcified plaque was defined as a combination of necrotic core and fibrofatty tissue. Quantitative flow ratio (QFR), which is a coronary angiography-based technique used to calculate fractional flow reserve without the need for hyperemia induction or for a pressure wire, was used as the reference standard for the evaluation of myocardial ischemia. Coronary artery plaques with QFR of ≤0.80 were considered abnormal-that is, ischemia-generating. In total, 149 coronary plaques were analyzed, 21 of which (14%) were considered abnormal according to QFR. The percentage of noncalcified tissue was significantly higher in plaques with abnormal QFR (38.2 ± 6.5% vs 33.1 ± 9.0%, p = 0.014). After univariable analysis, both plaque load (odds ratio [OR] per 1% increase 1.081, p <0.001) and the percentage of noncalcified tissue (OR per 1% increase 1.070, p = 0.020) were significantly associated with reduced QFR. However, after multivariable analysis, only plaque load remained significantly associated with abnormal QFR (OR per 1% increase 1.072, p <0.001). In conclusion, the noncalcified plaque area was significantly higher in hemodynamically significant coronary lesions than in nonsignificant lesions. Although an increase in the noncalcified plaque area was significantly associated with a reduced QFR, this association lost significance after adjustment for localized plaque load.

Association of MMP9 with adverse features of plaque progression and residual inflammatory risk in patients with chronic coronary syndrome (CCS).

BACKGROUND AND AIMS: MMP-9 is a predictor of atherosclerotic plaque instability and adverse cardiovascular events, but longitudinal data on the association between MMP9 and coronary disease progression are lacking. This study is aimed at investigating whether MMP9 is associated with atherosclerotic plaque progression and the related molecular basis in stable patients with chronic coronary syndrome (CCS). METHODS: MMP9 serum levels were measured in 157 CCS patients (58 ± 8 years of age; 66% male) undergoing coronary computed tomography angiography at baseline and after a follow up period of 6.5 ± 1.1 years to assess progression of Total, Fibrous, Fibro-fatty, Necrotic Core, and Dense Calcium plaque volumes (PV). Gene expression analysis was evaluated in whole blood using a transcriptomic approach by RNA-seq. RESULTS: At multivariate analysis, serum MMP9 was associated with annual change of Total and Necrotic Core PV (Coefficient 3.205, SE 1.321, P = 0.017; 1.449, SE 0.690, P = 0.038, respectively), while MMP9 gene expression with Necrotic Core PV (Coefficient 70.559, SE 32.629, P = 0.034), independently from traditional cardiovascular risk factors, medications, and presence of obstructive CAD. After transcriptomic analysis, MMP9 expression was linked to expression of genes involved in the innate immunity. CONCLUSIONS: Among CCS patients, MMP9 is an independent predictive marker of progression of adverse coronary plaques, possibly reflecting the activity of inflammatory pathways conditioning adverse plaque phenotypes. Thus, blood MMP9 might be used for the identification of patients with residual risk even with optimal management of classical cardiovascular risk factors who may derive the greatest benefit from targeted anti-inflammatory drugs.

Association between left atrial epicardial fat, left atrial volume, and the severity of atrial fibrillation.

AIMS: Left atrial (LA) volume and LA epicardial fat are both substrates for atrial fibrillation (AF), but may relate with AF at different (early vs. late) stages in the AF disease process. We evaluated associations between LA epicardial fat and LA volume in patients with sinus rhythm (SR), paroxysmal AF (PAF), and persistent/permanent AF. METHODS AND RESULTS: In total, 300 patients (100 with SR, 100 with PAF, and 100 with persistent/permanent AF) who underwent cardiac computed tomography angiography (CTA) were included. The epicardial fat mass posterior to the LA and the LA volume were quantified from CTA and compared between patients with SR, PAF, and persistent/permanent AF. Furthermore, four groups were created by classifying LA epicardial fat and LA volume into large or small according to their median. The mean age of the population was 58.9 ± 10.5 years and 69.7% was male. Left atrial epicardial fat mass was larger in patients with PAF compared with SR, but did not further increase from PAF to persistent/permanent AF. Left atrial volume increased significantly from SR to PAF and to persistent/permanent AF. Left atrial epicardial fat and LA volume were both concordantly large or small in 184 (61%) patients, and discordant in 116 (39%). When both were small, 65.2% of the patients had SR, 23.9% PAF, and 10.9% persistent/permanent AF. When the LA epicardial fat mass was large and the LA volume small (compared with both being small), patients were significantly more often in PAF (55.2 vs. 23.9, P < 0.05), less frequently in SR (32.8% vs. 65.2%, P < 0.05) but showed comparable rates of persistent/permanent AF (12.0% vs. 10.9%, P < 0.05). When the LA volume was large, most patients had persistent/permanent AF. CONCLUSION: Left atrial epicardial fat mass was larger in PAF vs. SR, possibly indicating a marker of early disease, while large LA volumes were associated with a high prevalence of persistent/permanent AF. Elevated LA epicardial fat mass without large LA volume may reflect the early AF disease process.

Abutting Left Atrial Appendage and Left Superior Pulmonary Vein Predicts Recurrence of Atrial Fibrillation After Point-by-Point Pulmonary Vein Isolation.

INTRODUCTION: The role of the spatial relationship between the left superior pulmonary vein (LSPV) and left atrial appendage (LAA) is unknown. We sought to evaluate whether an abutting LAA and LSPV play a role in AF recurrence after catheter ablation for paroxysmal AF. METHODS: Consecutive patients, who underwent initial point-by-point radiofrequency catheter ablation for paroxysmal AF at the Heart and Vascular Center of Semmelweis University, Budapest, Hungary, between January of 2014 and December of 2017, were enrolled in the study. All patients underwent pre-procedural cardiac CT to assess left atrial (LA) and pulmonary vein (PV) anatomy. Abutting LAA-LSPV was defined as cases when the minimum distance between the LSPV and LAA was less than 2 mm. RESULTS: We included 428 patients (60.7 ± 10.8 years, 35.5% female) in the analysis. AF recurrence rate was 33.4%, with a median recurrence-free time of 21.2 (8.8-43.0) months. In the univariable analysis, female sex (HR = 1.45; 95%CI = 1.04-2.01; p = 0.028), LAA flow velocity (HR = 1.01; 95%CI = 1.00-1.02; p = 0.022), LAA orifice area (HR = 1.00; 95%CI = 1.00-1.00; p = 0.028) and abutting LAA-LSPV (HR = 1.53; 95%CI = 1.09-2.14; p = 0.013) were associated with AF recurrence. In the multivariable analysis, abutting LAA-LSPV (adjusted HR = 1.55; 95%CI = 1.04-2.31; p = 0.030) was the only independent predictor of AF recurrence. CONCLUSION: Abutting LAA-LSPV predisposes patients to have a higher chance for arrhythmia recurrence after catheter ablation for paroxysmal AF.

Associations between dyspnoea, coronary atherosclerosis, and cardiovascular outcomes: results from the long-term follow-up CONFIRM registry.

AIMS: The relationship between dyspnoea, coronary artery disease (CAD), and major cardiovascular events (MACE) is poorly understood. This study evaluated (i) the association of dyspnoea with the severity of anatomical CAD by coronary computed tomography angiography (CCTA) and (ii) to which extent CAD explains MACE in patients with dyspnoea. METHODS AND RESULTS: From the international COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 4425 patients (750 with dyspnoea) with suspected but without known CAD were included and prospectively followed for ≥5 years. First, the association of dyspnoea with CAD severity was assessed using logistic regression analysis. Second, the prognostic value of dyspnoea for MACE (myocardial infarction and death), and specifically, the interaction between dyspnoea and CAD severity was investigated using Cox proportional-hazard analysis. Mean patient age was 60.3 ± 11.9 years, 63% of patients were male and 592 MACE events occurred during a median follow-up duration of 5.4 (IQR 5.1-6.0) years. On uni- and multivariable analysis (adjusting for age, sex, body mass index, chest pain typicality, and risk factors), dyspnoea was associated with two- and three-vessel/left main (LM) obstructive CAD. The presence of dyspnoea increased the risk for MACE [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.29-1.90], which was modified after adjusting for clinical predictors and CAD severity (HR 1.26, 95% CI: 1.02-1.55). Conversely, when stratified by CAD severity, dyspnoea did not provide incremental prognostic value in one-, two-, or three-vessel/LM obstructive CAD, but dyspnoea did provide incremental prognostic value in non-obstructive CAD. CONCLUSION: In patients with suspected CAD, dyspnoea was independently associated with severe obstructive CAD on CCTA. The severity of obstructive CAD explained the elevated MACE rates in patients presenting with dyspnoea, but in patients with non-obstructive CAD, dyspnoea portended additional risk.

Left atrial appendage size is a marker of atrial fibrillation recurrence after radiofrequency catheter ablation in patients with persistent atrial fibrillation.

INTRODUCTION: There are no consistently confirmed predictors of atrial fibrillation (AF) recurrence after catheter ablation. Therefore, we aimed to study whether left atrial appendage volume (LAAV) and function influence the long-term recurrence of AF after catheter ablation, depending on AF type. METHODS: AF patients who underwent point-by-point radiofrequency catheter ablation after cardiac computed tomography (CT) were included in this analysis. LAAV and LAA orifice area were measured by CT. Uni- and multivariable Cox proportional hazard regression models were performed to determine the predictors of AF recurrence. RESULTS: In total, 561 AF patients (61.9 ± 10.2 years, 34.9% females) were included in the study. Recurrence of AF was detected in 40.8% of the cases (34.6% in patients with paroxysmal and 53.5% in those with persistent AF) with a median recurrence-free time of 22.7 (9.3-43.1) months. Patients with persistent AF had significantly higher body surface area-indexed LAV, LAAV, and LAA orifice area and lower LAA flow velocity, than those with paroxysmal AF. After adjustment left ventricular ejection fraction (LVEF) <50% (HR = 2.17; 95% CI = 1.38-3.43; p < .001) and LAAV (HR = 1.06; 95% CI = 1.01-1.12; p = .029) were independently associated with AF recurrence in persistent AF, while no independent predictors could be identified in paroxysmal AF. CONCLUSION: The current study demonstrates that beyond left ventricular systolic dysfunction, LAA enlargement is associated with higher rate of AF recurrence after catheter ablation in persistent AF, but not in patients with paroxysmal AF.

A specific plasma lipid signature associated with high triglycerides and low HDL cholesterol identifies residual CAD risk in patients with chronic coronary syndrome.

BACKGROUND AND AIMS: Elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) define a specific lipid profile associated with residual coronary artery disease (CAD) risk independently of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Aim of the present study was to assess whether TG/HDL-C ratio, coronary atherosclerosis and their change over time are characterized by a specific lipidomic profiling in stable patients with chronic coronary syndrome (CCS). METHODS: TG/HDL-C ratio was calculated in 193 patients (57.8 ± 7.6 years, 115 males) with CCS characterized by clinical, bio-humoral profiles and cardiac imaging. Patient-specific plasma targeted lipidomics was defined through a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) strategy. Patients underwent coronary computed tomography angiography (CTA) and an individual CTA risk score, combining extent, severity, composition, and location of plaques, was calculated. All patients entered a follow-up (6.39 ± 1.17 years), including clinical, lipidomics and coronary CTA assessments. RESULTS: Patients were divided in groups according to baseline TG/HDL-C quartiles: IQ (<1.391), IIQ (1.392-2.000), IIIQ (2.001-3.286), and IVQ (≥3.287). A specific pattern of altered lipids, characterized by reduced plasma levels of cholesterol esters, phosphatidylcholines and sphingomyelins, was associated with higher TG/HDL-C both at baseline and follow-up (IVQ vs IQ). The CTA risk score increased over time and this lipid signature was also associated with higher CTA score at follow-up. CONCLUSIONS: In stable CCS, a specific lipidomic signature identifies those patients with higher TG/HDL- C ratio and higher CTA score over time, suggesting possible molecular pathways of residual CAD risk not tackled by current optimal medical treatments.

Triglycerides and low HDL cholesterol predict coronary heart disease risk in patients with stable angina.

We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03-1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30-6.26, P < 0.01) were the only independent predictors of the primary outcome. The TG/HDL-C ratio and the CTA risk score progressed over time despite increased use of lipid-lowering drugs and reduction in LDL-C. In patients with stable angina, high TG and low HDL-C levels are associated with CAD related outcomes independently of LDL-C and treatments.Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

Predictive Added Value of Selected Plasma Lipids to a Re-estimated Minimal Risk Tool.

Background: Lipidomics is emerging for biomarker discovery in cardiovascular disease, and circulating lipids are increasingly incorporated in risk models to predict cardiovascular events. Moreover, specific classes of lipids, such as sphingomyelins, ceramides, and triglycerides, have been related to coronary artery disease (CAD) severity and plaque characteristics. To avoid unnecessary testing, it is important to identify individuals at low CAD risk. The only pretest model available so far to rule out the presence of coronary atherosclerosis in patients with chest pain, but normal coronary arteries, is the minimal risk tool (MRT). Aim: Using state-of-the-art statistical methods, we aim to verify the additive predictive value of a set of lipids, derived from targeted plasma lipidomics of suspected CAD patients, to a re-estimated version of the MRT for ruling out the presence of coronary atherosclerosis assessed by coronary CT angiography (CCTA). Methods: Two hundred and fifty-six subjects with suspected stable CAD recruited from five European countries within H2020-SMARTool, undergoing CCTA and blood sampling for clinical biochemistry and lipidomics, were selected. The MRT was validated by regression methods and then re-estimated (reMRT). The reMRT was used as a baseline model in a likelihood ratio test approach to assess the added predictive value of each lipid from 13 among ceramides, triglycerides, and sphingomyelins. Except for one lipid, the analysis was carried out on more than 240 subjects for each lipid. A sensitivity analysis was carried out by considering two alternative models developed on the cohort as baseline models. Results: In 205 subjects, coronary atherosclerosis ranged from minimal lesions to overt obstructive CAD, while in 51 subjects (19.9%) the coronary arteries were intact. Four triglycerides and seven sphingomyelins were significantly (p < 0.05) and differentially expressed in the two groups and, at a lesser extent, one ceramide (p = 0.067). The probability of being at minimal risk was significantly better estimated by adding either Cer(d18:1/16:0) (p = 0.01), SM(40:2) (p = 0.04), or SM(41:1) at a lesser extent (p = 0.052) to reMRT than by applying the reMRT alone. The sensitivity analysis confirmed the relevance of these lipids. Furthermore, the addition of SM(34:1), SM(38:2), SM(41:2), and SM(42:4) improved the predictive performance of at least one of the other baseline models. None of the selected triglycerides was found to provide an added value. Conclusions: Plasma lipidomics can be a promising source of diagnostic and prognostic biomarkers in cardiovascular disease, exploitable not only to assess the risk of adverse events but also to identify subjects without coronary atherosclerosis, thus reducing unnecessary further testing in normal subjects.

Anatomical Characteristics of the Left Atrium and Left Atrial Appendage in Relation to the Risk of Stroke in Patients With Versus Without Atrial Fibrillation.

[Figure: see text].

Lipid biomarkers in statin users with coronary artery disease annotated by coronary computed tomography angiography.

Molecular markers are suggested to improve the diagnostic and prognostic accuracy in patients with coronary artery disease (CAD) beyond current clinical scores based on age, gender, symptoms and traditional risk factors. In this context, plasma lipids are emerging as predictors of both plaque composition and risk of future events. We aim to identify plasma lipid biomarkers associated to CAD indexes of stenosis severity, plaque lipid content and a comprensive score of CAD extent and its risk. We used a simple high performance liquid chromatography-tandem mass spectrometry method to identify 69 plasma lipids in 132 subjects referred to Coronary Computed Tomography Angiography (CCTA) for suspected CAD, all under statin treatment. Patients were stratified in groups using three different CCTA-based annotations: CTA-risk score, lipid plaque prevalence (LPP) ratio and the coronary artery disease-reporting and data system (CAD-RADS). We identified a common set of lipid biomarkers composed of 7 sphingomyelins and 3 phosphatidylethanolamines, which discriminates between high risk CAD patients and controls regardless of the CAD annotations used (CTA score, LPP ratio, or CAD-RADS). These results highlight the potential of circulating lipids as biomarkers of stenosis severity, non calcified plaque composition and overall plaque risk of events.

Sex differences in coronary plaque changes assessed by serial computed tomography angiography.

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (ß -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (ß -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (ß -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.).

Posterior Left Atrial Adipose Tissue Attenuation Assessed by Computed Tomography and Recurrence of Atrial Fibrillation After Catheter Ablation.

[Figure: see text].

Relationship between coronary artery calcification and myocardial ischemia on computed tomography myocardial perfusion in patients with stable chest pain.

BACKGROUND: Coronary artery calcium (CAC) score has shown to provide incremental prognostic information when added to the Framingham risk score. Although the relation between CAC and myocardial ischemia has been evaluated, there has been little evaluation of the relationship between CAC score and inducible myocardial ischemia on computed tomography myocardial perfusion (CTP). METHODS AND RESULTS: Patients who were referred with stable chest pain from the outpatient clinic and who underwent non-contrast computed tomography scan, coronary computed tomography angiography, and adenosine stress CTP were included in this study. CAC score was subdivided in four groups (1 to 99; 100 to 399, 400 to 999, and ≥ 1000). Inducible myocardial ischemia was considered when reversible perfusion defects were observed in ≥ 1 segment. A total of 131 patients (age 62 ± 9.4 years; 56% male) were included. The median CAC score was 241 (73 to 539). Forty-nine patients (37%) had evidence of inducible myocardial ischemia. The presence of inducible myocardial ischemia increased with increasing CAC score from 22% in the CAC score 1 to 99 subgroup to 35, 47, and 65% in the 100 to 399, 400 to 999, and ≥ 1000 CAC score subgroup, respectively. In multivariable analysis CAC score was the only determinant that significantly predicted the presence of inducible myocardial ischemia on CTP. CONCLUSIONS: In a population of symptomatic patients, the majority of patients with extensive calcification had evidence of inducible myocardial ischemia on CTP. CAC score was the only independent predictor of inducible myocardial ischemia on CTP.

Blood Monocyte Phenotype Fingerprint of Stable Coronary Artery Disease: A Cross-Sectional Substudy of SMARTool Clinical Trial.

BACKGROUND AND AIMS: Atherosclerosis is an inflammatory disease with long-lasting activation of innate immunity and monocytes are the main blood cellular effectors. We aimed to investigate monocyte phenotype (subset fraction and marker expression) at different stages of coronary atherosclerosis in stable coronary artery disease (CAD) patients. METHODS: 73 patients with chronic coronary syndrome were evaluated by CT coronary angiography (CTCA) and classified by maximal diameter stenosis of major vessels into three groups of CAD severity: CAD1 (no CAD/minimal CAD, n° = 30), CAD2 (non-obstructive CAD, n° = 21), and CAD3 (obstructive CAD, n° = 22). Flow cytometry for CD14, CD16, and CCR2 was used to quantify Mon1, Mon2, and Mon3 subsets. Expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1, and CXCR4 was also measured. Adhesion molecules and cytokines were quantified by ELISA. RESULTS: Total cell count and fraction of Mon2 were higher in CAD2 and CAD3 compared to CAD1. By multivariate regression analysis, Mon2 cell fraction and Mon2 expression of CX3CR1, CD18, and CD16 showed a statistically significant and independent increase, parallel to stenosis severity, from CAD1 to CAD2 and CAD3 groups. A similar trend was also present for CX3CR1 and HLA-DR expressions on total monocyte population. A less calcified plaque composition was associated to a higher Mon2 expression of CD16 and higher TNF-α levels. IL-10 levels were lower at greater stenosis severity, while the IFN-γ/IL-10 ratio, a marker of a systemic pro-inflammatory imbalance, was directly correlated to stenosis degree and number of noncalcified plaques. CONCLUSIONS: The results of this study suggest that a specific pattern of inflammation-correlated monocyte marker expression is associated to higher stenosis severity and less calcified lesions in stable CAD. The clinical trial Identifier is NCT04448691.

Impact of Clinical Characteristics and Statins on Coronary Plaque Progression by Serial Computed Tomography Angiography.

Background Progression of coronary artery disease using serial coronary computed tomography angiography (CTA) is of clinical interest. Our primary aim was to prospectively assess the impact of clinical characteristics and statin use on quantitatively assessed coronary plaque progression in a low-risk study population during long-term follow-up. Methods Patients who previously underwent coronary CTA for suspected coronary artery disease were prospectively included to undergo follow-up coronary CTA. The primary end point was coronary artery disease progression, defined as the absolute annual increase in total, calcified, and noncalcified plaque volume by quantitative CTA analysis. Results In total, 202 patients underwent serial coronary CTA with a mean interscan period of 6.2±1.4 years. On a per-plaque basis, increasing age (ß=0.070; P=0.058) and hypertension (ß=1.380; P=0.075) were nonsignificantly associated with annual total plaque progression. Male sex (ß=1.676; P=0.009), diabetes mellitus (ß=1.725; P=0.012), and statin use (ß=1.498; P=0.046) showed an independent association with annual progression of calcified plaque. While hypertension (ß=2.259; P=0.015) was an independent determinant of noncalcified plaque progression, statin use (ß=-2.178; P=0.050) was borderline significantly associated with a reduced progression of noncalcified plaque. Conclusions Statin use was associated with an increased progression of calcified coronary plaque and a reduced progression of noncalcified coronary plaque, potentially reflecting calcification of the noncalcified plaque component. Whereas hypertension was the only modifiable risk factor predictive of noncalcified plaque progression, diabetes mellitus mainly led to an increase in calcified plaque. These findings could yield the need for intensified preventive treatment of patients with diabetes mellitus and hypertension to slow and stabilize coronary artery disease progression and improve clinical outcome.

Clinical risk factors and atherosclerotic plaque extent to define risk for major events in patients without obstructive coronary artery disease: the long-term coronary computed tomography angiography CONFIRM registry.

AIMS: In patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent. METHODS AND RESULTS: Patients from the long-term CONFIRM registry without prior CAD and without obstructive (≥50%) stenosis were included. Within the groups of normal coronary computed tomography angiography (CCTA) (N = 1849) and non-obstructive CAD (N = 1698), the prognostic value of traditional clinical risk factors and atherosclerotic extent (segment involvement score, SIS) was assessed with Cox models. Major adverse cardiac events (MACE) were defined as all-cause mortality, non-fatal myocardial infarction, or late revascularization. In total, 3547 patients were included (age 57.9 ± 12.1 years, 57.8% male), experiencing 460 MACE during 5.4 years of follow-up. Age, body mass index, hypertension, and diabetes were the clinical variables associated with increased MACE risk, but the magnitude of risk was higher for CCTA defined atherosclerotic extent; adjusted hazard ratio (HR) for SIS >5 was 3.4 (95% confidence interval [CI] 2.3-4.9) while HR for diabetes and hypertension were 1.7 (95% CI 1.3-2.2) and 1.4 (95% CI 1.1-1.7), respectively. Exclusion of revascularization as endpoint did not modify the results. In normal CCTA, presence of ≥1 traditional risk factors did not worsen prognosis (log-rank P = 0.248), while it did in non-obstructive CAD (log-rank P = 0.025). Adjusted for SIS, hypertension and diabetes predicted MACE risk in non-obstructive CAD, while diabetes did not increase risk in absence of CAD (P-interaction = 0.004). CONCLUSION: Among patients without obstructive CAD, the extent of CAD provides more prognostic information for MACE than traditional cardiovascular risk factors. An interaction was observed between risk factors and CAD burden, suggesting synergistic effects of both.

Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: Propensity score-based analysis of diabetic and non-diabetic patients.

AIMS: We aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders. METHODS: Out of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability. RESULTS: A total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265). CONCLUSION: Coronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone.