Plaque Progression Differences Between Apixaban and Rivaroxaban in Patients With Atrial Fibrillation Measured With Cardiac Computed Tomography and Plaque Quantification.

BACKGROUND: Direct oral anticoagulants (DOACs) have been associated with less calcification and coronary plaque progression than warfarin. Whether different DOACs have different effects on coronary plaque burden and progression is not known. We compared the 12-month effects of apixaban and rivaroxaban on plaque characteristics and vascular morphology in patients with atrial fibrillation through quantitative cardiac computed tomographic angiography. STUDY QUESTION: In patients with nonvalvular atrial fibrillation using apixaban or rivaroxaban, are there differences in plaque quantification and progression measured with cardiac computed tomography? STUDY DESIGN: This is a post hoc analysis of 2 paired prospective, single-centered, randomized, open-label trials with blinded adjudication of results. In total, 74 patients were prospectively randomized in parallel trials: 29 to apixaban (2.5-5 mg BID) and 45 to rivaroxaban (20 mg QD). Serial cardiac computed tomographic angiography was performed at baseline and 52 weeks. MEASURES AND OUTCOMES: Comprehensive whole-heart analysis was performed for differences in the progression of percent atheroma volume (PAV), calcified plaque (CP) PAV, noncalcified plaque (NCP) PAV, positive arterial remodeling (PR) ≥1.10, and high-risk plaque (Cleerly Labs, New York, NY). RESULTS: Both groups had progression of all 3 plaque types (apixaban: CP 8.7 mm 3 , NCP 69.7 mm 3 , and LD-NCP 27.2 mm 3 ; rivaroxaban: CP 22.9 mm 3 , NCP 66.3 mm 3 , and LD-NCP 11.0 mm 3 ) and a total annual plaque PAV change (apixaban: PAV 1.5%, PAV-CP 0.12%, and PAV-NCP 0.92%; rivaroxaban: PAV 2.1%, PAV-CP 0.46%, and PAV-NCP 1.40%). There was significantly lower PAV-CP progression in the apixaban group compared with the rivaroxaban group (0.12% vs. 0.46% P = 0.02). High-risk plaque characteristics showed a significant change in PR of apixaban versus rivaroxaban ( P = 0.01). When the propensity score weighting model is applied, only PR changes are statistically significant ( P = 0.04). CONCLUSIONS: In both groups, there is progression of all types of plaque. There was a significant difference between apixaban and rivaroxaban on coronary calcification, with significantly lower calcific plaque progression in the apixaban group, and change in positive remodeling. With weighted modeling, only PR changes are statistically significant between the 2 DOACs.

Coronary CTA With AI-QCT Interpretation: Comparison With Myocardial Perfusion Imaging for Detection of Obstructive Stenosis Using Invasive Angiography as Reference Standard.

BACKGROUND. Deep learning frameworks have been applied to interpretation of coronary CTA performed for coronary artery disease (CAD) evaluation. OBJECTIVE. The purpose of our study was to compare the diagnostic performance of myocardial perfusion imaging (MPI) and coronary CTA with artificial intelligence quantitative CT (AI-QCT) interpretation for detection of obstructive CAD on invasive angiography and to assess the downstream impact of including coronary CTA with AI-QCT in diagnostic algorithms. METHODS. This study entailed a retrospective post hoc analysis of the derivation cohort of the prospective 23-center Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) trial. The study included 301 patients (88 women and 213 men; mean age, 64.4 ± 10.2 [SD] years) recruited from May 2014 to May 2017 with stable symptoms of myocardial ischemia referred for nonemergent invasive angiography. Patients underwent coronary CTA and MPI before angiography with quantitative coronary angiography (QCA) measurements and fractional flow reserve (FFR). CTA examinations were analyzed using an FDA-cleared cloud-based software platform that performs AI-QCT for stenosis determination. Diagnostic performance was evaluated. Diagnostic algorithms were compared. RESULTS. Among 102 patients with no ischemia on MPI, AI-QCT identified obstructive (≥ 50%) stenosis in 54% of patients, including severe (≥ 70%) stenosis in 20%. Among 199 patients with ischemia on MPI, AI-QCT identified nonobstructive (1-49%) stenosis in 23%. AI-QCT had significantly higher AUC (all p < .001) than MPI for predicting ≥ 50% stenosis by QCA (0.88 vs 0.66), ≥ 70% stenosis by QCA (0.92 vs 0.81), and FFR < 0.80 (0.90 vs 0.71). An AI-QCT result of ≥ 50% stenosis and ischemia on stress MPI had sensitivity of 95% versus 74% and specificity of 63% versus 43% for detecting ≥ 50% stenosis by QCA measurement. Compared with performing MPI in all patients and those showing ischemia undergoing invasive angiography, a scenario of performing coronary CTA with AIQCT in all patients and those showing ≥ 70% stenosis undergoing invasive angiography would reduce invasive angiography utilization by 39%; a scenario of performing MPI in all patients and those showing ischemia undergoing coronary CTA with AI-QCT and those with ≥ 70% stenosis on AI-QCT undergoing invasive angiography would reduce invasive angiography utilization by 49%. CONCLUSION. Coronary CTA with AI-QCT had higher diagnostic performance than MPI for detecting obstructive CAD. CLINICAL IMPACT. A diagnostic algorithm incorporating AI-QCT could substantially reduce unnecessary downstream invasive testing and costs. TRIAL REGISTRATION. Clinicaltrials.gov NCT02173275.

Endothelial microparticles: sophisticated vesicles modulating vascular function.

Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation.

Atherosclerosis Imaging Quantitative Computed Tomography (AI-QCT) to guide referral to invasive coronary angiography in the randomized controlled CONSERVE trial.

AIMS: We compared diagnostic performance, costs, and association with major adverse cardiovascular events (MACE) of clinical coronary computed tomography angiography (CCTA) interpretation versus semiautomated approach that use artificial intelligence and machine learning for atherosclerosis imaging-quantitative computed tomography (AI-QCT) for patients being referred for nonemergent invasive coronary angiography (ICA). METHODS: CCTA data from individuals enrolled into the randomized controlled Computed Tomographic Angiography for Selective Cardiac Catheterization trial for an American College of Cardiology (ACC)/American Heart Association (AHA) guideline indication for ICA were analyzed. Site interpretation of CCTAs were compared to those analyzed by a cloud-based software (Cleerly, Inc.) that performs AI-QCT for stenosis determination, coronary vascular measurements and quantification and characterization of atherosclerotic plaque. CCTA interpretation and AI-QCT guided findings were related to MACE at 1-year follow-up. RESULTS: Seven hundred forty-seven stable patients (60 ± 12.2 years, 49% women) were included. Using AI-QCT, 9% of patients had no CAD compared with 34% for clinical CCTA interpretation. Application of AI-QCT to identify obstructive coronary stenosis at the ≥50% and ≥70% threshold would have reduced ICA by 87% and 95%, respectively. Clinical outcomes for patients without AI-QCT-identified obstructive stenosis was excellent; for 78% of patients with maximum stenosis < 50%, no cardiovascular death or acute myocardial infarction occurred. When applying an AI-QCT referral management approach to avoid ICA in patients with <50% or <70% stenosis, overall costs were reduced by 26% and 34%, respectively. CONCLUSIONS: In stable patients referred for ACC/AHA guideline-indicated nonemergent ICA, application of artificial intelligence and machine learning for AI-QCT can significantly reduce ICA rates and costs with no change in 1-year MACE.

Relation of Gender to Atherosclerotic Plaque Characteristics by Differing Angiographic Stenosis Severity.

It is unknown whether gender influences the atherosclerotic plaque characteristics (APCs) of lesions of varying angiographic stenosis severity. This study evaluated the imaging data of 303 symptomatic patients from the derivation arm of the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial, all of whom underwent coronary computed tomographic angiography and clinically indicated nonemergent invasive coronary angiography upon study enrollment. Index tests were interpreted by 2 blinded core laboratories, one of which performed quantitative coronary computed tomographic angiography using an artificial intelligence application to characterize and quantify APCs, including percent atheroma volume (PAV), low-density noncalcified plaque (LD-NCP), noncalcified plaque (NCP), calcified plaque (CP), lesion length, positive arterial remodeling, and high-risk plaque (a combination of LD-NCP and positive remodeling ≥1.10); the other classified lesions as obstructive (≥50% diameter stenosis) or nonobstructive (<50% diameter stenosis) based on quantitative invasive coronary angiography. The relation between APCs and angiographic stenosis was further examined by gender. The mean age of the study cohort was 64.4 ± 10.2 years (29.0% female). In patients with obstructive disease, men had more LD-NCP PAV (0.5 ± 0.4 vs 0.3 ± 0.8, p = 0.03) and women had more CP PAV (11.7 ± 1.6 vs 8.0 ± 0.8, p = 0.04). Obstructive lesions had more NCP PAV compared with their nonobstructive lesions in both genders, however, obstructive lesions in women also demonstrated greater LD-NCP PAV (0.4 ± 0.5 vs 1.0 ± 1.8, p = 0.03), and CP PAV (17.4 ± 16.5 vs 25.9 ± 18.7, p = 0.03) than nonobstructive lesions. Comparing the composition of obstructive lesions by gender, women had more CP PAV (26.3 ± 3.4 vs 15.8 ± 1.5, p = 0.005) whereas men had more NCP PAV (33.0 ± 1.6 vs 26.7 ± 2.5, p = 0.04). Men had more LD-NCP PAV in nonobstructive lesions compared with women (1.2 ± 0.2 vs 0.6 ± 0.2, p = 0.02). In conclusion, there are gender-specific differences in plaque composition based on stenosis severity.

Diabetes, Atherosclerosis, and Stenosis by AI.

OBJECTIVE: This study evaluates the relationship between atherosclerotic plaque characteristics (APCs) and angiographic stenosis severity in patients with and without diabetes. Whether APCs differ based on lesion severity and diabetes status is unknown. RESEARCH DESIGN AND METHODS: We retrospectively evaluated 303 subjects from the Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia (CREDENCE) trial referred for invasive coronary angiography with coronary computed tomographic angiography (CCTA) and classified lesions as obstructive (≥50% stenosed) or nonobstructive using blinded core laboratory analysis of quantitative coronary angiography. CCTA quantified APCs, including plaque volume (PV), calcified plaque (CP), noncalcified plaque (NCP), low-density NCP (LD-NCP), lesion length, positive remodeling (PR), high-risk plaque (HRP), and percentage of atheroma volume (PAV; PV normalized for vessel volume). The relationship between APCs, stenosis severity, and diabetes status was assessed. RESULTS: Among the 303 patients, 95 (31.4%) had diabetes. There were 117 lesions in the cohort with diabetes, 58.1% of which were obstructive. Patients with diabetes had greater plaque burden (P = 0.004). Patients with diabetes and nonobstructive disease had greater PV (P = 0.02), PAV (P = 0.02), NCP (P = 0.03), PAV NCP (P = 0.02), diseased vessels (P = 0.03), and maximum stenosis (P = 0.02) than patients without diabetes with nonobstructive disease. APCs were similar between patients with diabetes with nonobstructive disease and patients without diabetes with obstructive disease. Diabetes status did not affect HRP or PR. Patients with diabetes had similar APCs in obstructive and nonobstructive lesions. CONCLUSIONS: Patients with diabetes and nonobstructive stenosis had an association to similar APCs as patients without diabetes who had obstructive stenosis. Among patients with nonobstructive disease, patients with diabetes had more total PV and NCP.

Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease.

Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.

Interobserver variability among expert readers quantifying plaque volume and plaque characteristics on coronary CT angiography: a CLARIFY trial sub-study.

BACKGROUND: The difference between expert level (L3) reader and artificial intelligence (AI) performance for quantifying coronary plaque and plaque components is unknown. OBJECTIVE: This study evaluates the interobserver variability among expert readers for quantifying the volume of coronary plaque and plaque components on coronary computed tomographic angiography (CCTA) using an artificial intelligence enabled quantitative CCTA analysis software as a reference (AI-QCT). METHODS: This study uses CCTA imaging obtained from 232 patients enrolled in the CLARIFY (CT EvaLuation by ARtificial Intelligence For Atherosclerosis, Stenosis and Vascular MorphologY) study. Readers quantified overall plaque volume and the % breakdown of noncalcified plaque (NCP) and calcified plaque (CP) on a per vessel basis. Readers categorized high risk plaque (HRP) based on the presence of low-attenuation-noncalcified plaque (LA-NCP) and positive remodeling (PR; ≥1.10). All CCTAs were analyzed by an FDA-cleared software service that performs AI-driven plaque characterization and quantification (AI-QCT) for comparison to L3 readers. Reader generated analyses were compared among readers and to AI-QCT generated analyses. RESULTS: When evaluating plaque volume on a per vessel basis, expert readers achieved moderate to high interobserver consistency with an intra-class correlation coefficient of 0.78 for a single reader score and 0.91 for mean scores. There was a moderate trend between readers 1, 2, and 3 and AI with spearman coefficients of 0.70, 0.68 and 0.74, respectively. There was high discordance between readers and AI plaque component analyses. When quantifying %NCP v. %CP, readers 1, 2, and 3 achieved a weighted kappa coefficient of 0.23, 0.34 and 0.24, respectively, compared to AI with a spearman coefficient of 0.38, 0.51, and 0.60, respectively. The intra-class correlation coefficient among readers for plaque composition assessment was 0.68. With respect to HRP, readers 1, 2, and 3 achieved a weighted kappa coefficient of 0.22, 0.26, and 0.17, respectively, and a spearman coefficient of 0.36, 0.35, and 0.44, respectively. CONCLUSION: Expert readers performed moderately well quantifying total plaque volumes with high consistency. However, there was both significant interobserver variability and high discordance with AI-QCT when quantifying plaque composition.

The effect of scan and patient parameters on the diagnostic performance of AI for detecting coronary stenosis on coronary CT angiography.

OBJECTIVES: To determine whether coronary computed tomography angiography (CCTA) scanning, scan preparation, contrast, and patient based parameters influence the diagnostic performance of an artificial intelligence (AI) based analysis software for identifying coronary lesions with ≥50% stenosis. BACKGROUND: CCTA is a noninvasive imaging modality that provides diagnostic and prognostic benefit to patients with coronary artery disease (CAD). The use of AI enabled quantitative CCTA (AI-QCT) analysis software enhances our diagnostic and prognostic ability, however, it is currently unclear whether software performance is influenced by CCTA scanning parameters. METHODS: CCTA and quantitative coronary CT (QCT) data from 303 stable patients (64 ± 10 years, 71% male) from the derivation arm of the CREDENCE Trial were retrospectively analyzed using an FDA-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination. The algorithm's diagnostic performance measures (sensitivity, specificity, and accuracy) for detecting coronary lesions of ≥50% stenosis were determined based on concordance with QCA measurements and subsequently compared across scanning parameters (including scanner vendor, model, single vs dual source, tube voltage, dose length product, gating technique, timing method), scan preparation technique (use of beta blocker, use and dose of nitroglycerin), contrast administration parameters (contrast type, infusion rate, iodine concentration, contrast volume) and patient parameters (heart rate and BMI). RESULTS: Within the patient cohort, 13% demonstrated ≥50% stenosis in 3 vessel territories, 21% in 2 vessel territories, 35% in 1 vessel territory while 32% had <50% stenosis in all vessel territories evaluated by QCA. Average AI analysis time was 10.3 ± 2.7 min. On a per vessel basis, there were significant differences only in sensitivity for ≥50% stenosis based on contrast type (iso-osmolar 70.0% vs non isoosmolar 92.1% p = 0.0345) and iodine concentration (<350 mg/ml 70.0%, 350-369 mg/ml 90.0%, 370-400 mg/ml 90.0%, >400 mg/ml 95.2%; p = 0.0287) in the context of low injection flow rates. On a per patient basis there were no significant differences in AI diagnostic performance measures across all measured scanner, scan technique, patient preparation, contrast, and individual patient parameters. CONCLUSION: The diagnostic performance of AI-QCT analysis software for detecting moderate to high grade stenosis are unaffected by commonly used CCTA scanning parameters and across a range of common scanning, scanner, contrast and patient variables. CONDENSED ABSTRACT: An AI-enabled quantitative CCTA (AI-QCT) analysis software has been validated as an effective tool for the identification, quantification and characterization of coronary plaque and stenosis through comparison to blinded expert readers and quantitative coronary angiography. However, it is unclear whether CCTA screening parameters related to scanner parameters, scan technique, contrast volume and rate, radiation dose, or a patient's BMI or heart rate at time of scan affect the software's diagnostic measures for detection of moderate to high grade stenosis. AI performance measures were unaffected across a broad range of commonly encountered scanner, patient preparation, scan technique, intravenous contrast and patient parameters.

Relationship of age, atherosclerosis and angiographic stenosis using artificial intelligence.

OBJECTIVE: The study evaluates the relationship of coronary stenosis, atherosclerotic plaque characteristics (APCs) and age using artificial intelligence enabled quantitative coronary computed tomographic angiography (AI-QCT). METHODS: This is a post-hoc analysis of data from 303 subjects enrolled in the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial who were referred for invasive coronary angiography and subsequently underwent coronary computed tomographic angiography (CCTA). In this study, a blinded core laboratory analysing quantitative coronary angiography images classified lesions as obstructive (≥50%) or non-obstructive (<50%) while AI software quantified APCs including plaque volume (PV), low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), calcified plaque (CP), lesion length on a per-patient and per-lesion basis based on CCTA imaging. Plaque measurements were normalised for vessel volume and reported as % percent atheroma volume (%PAV) for all relevant plaque components. Data were subsequently stratified by age <65 and ≥65 years. RESULTS: The cohort was 64.4±10.2 years and 29% women. Overall, patients >65 had more PV and CP than patients <65. On a lesion level, patients >65 had more CP than younger patients in both obstructive (29.2 mm3 vs 48.2 mm3; p<0.04) and non-obstructive lesions (22.1 mm3 vs 49.4 mm3; p<0.004) while younger patients had more %PAV (LD-NCP) (1.5% vs 0.7%; p<0.038). Younger patients had more PV, LD-NCP, NCP and lesion lengths in obstructive compared with non-obstructive lesions. There were no differences observed between lesion types in older patients. CONCLUSION: AI-QCT identifies a unique APC signature that differs by age and degree of stenosis and provides a foundation for AI-guided age-based approaches to atherosclerosis identification, prevention and treatment.

Glycosylated hemoglobin, but not advanced glycation end products, predicts severity of coronary artery disease in patients with or without diabetes.

BACKGROUND: The association between coronary artery disease (CAD) and diabetes mellitus (DM) is strong but the physiologic mechanisms responsible for this association remain unclear. Patients with DM exhibit high circulating levels of glycated proteins and lipoproteins called advanced glycation end products (AGEs) which have been implicated in the development of oxidative damage to vascular endothelium. We examined the relationships between the presence and extent of CAD and AGEs in patients undergoing elective coronary artery catheterization in an urban teaching hospital. METHODS: Patients with possible CAD (n = 364) were recruited prior to elective cardiac catheterization (52% male, 48% diabetic). Regression and correlation analyses were used to examine the relationship between serum AGE concentrations, soluble AGE receptor (sRAGE) concentration, HbA1c, LDL and the presence of obstructive CAD along with the burden of CAD measured by SYNTAX and SYNTAX II scores. RESULTS: AGE and sRAGE levels did not significantly correlate with any of the studied coronary artery disease parameters. HbA1c showed positive correlation with both SYNTAX and SYNTAX II scores in patients with and without diabetes. CONCLUSION: In this cross-sectional study of patients with possible CAD, serum AGEs and sRAGE concentrations did not correlate with SYNTAX or SYNTAX II scores regardless of diabetic status. HbA1C correlated positively with the SYNTAX and SYNTAX II scores in both diabetic and non-diabetic populations.

Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment.

CXCR1 and CXCR2 chemokine receptors and their ligands (CXCL1/2/3/7/8) play an important role in tumor progression. Tested to date CXCR1/2 antagonists and chemokine-targeted antibodies were reported to affect malignant cells in vitro and in animal models. Yet, redundancy of chemotactic signals and toxicity hinder further clinical development of these approaches. In this pre-clinical study we investigated the capacity of a novel small molecule dual CXCR1/2 inhibitor, Ladarixin (LDX), to attenuate progression of experimental human melanomas. Our data showed that LDX-mediated inhibition of CXCR1/2 abrogated motility and induced apoptosis in cultured cutaneous and uveal melanoma cells and xenografts independently of the molecular defects associated with the malignant phenotype. These effects were mediated by the inhibition of AKT and NF-kB signaling pathways. Moreover, systemic treatment of melanoma-bearing mice with LDX also polarized intratumoral macrophages to M1 phenotype, abrogated intratumoral de novo angiogenesis and inhibited melanoma self-renewal. Collectively, these studies outlined the pre-requisites of the successful CXCR1/2 inhibition on malignant cells and demonstrated multifactorial effects of Ladarixin on cutaneous and uveal melanomas, suggesting therapeutic utility of LDX in treatment of various melanoma types.

Chemokine-enhanced DNA vaccination in cancer immunotherapy.

We have demonstrated that priming of intratumoral and intradermal vaccination sites with chemokines enhances cytotoxic immune response against established neoplasms. Additional insights into the molecular mechanisms that underlie these findings and the optimization of such an approach may lead to the development of cost-effective and generic immunotherapeutic regimens against cancer.

Personalized cytomic assessment of vascular health: Evaluation of the vascular health profile in diabetes mellitus.

BACKGROUND: An inexpensive and accurate blood test does not currently exist that can evaluate the cardiovascular health of a patient. This study evaluated a novel high dimensional flow cytometry approach in combination with cytometric fingerprinting (CF), to comprehensively enumerate differentially expressed subsets of pro-angiogenic circulating progenitor cells (CPCs), involved in the repair of vasculature, and microparticles (MPs), frequently involved in inflammation and thrombosis. CF enabled discovery of a unique pattern, involving both MPs and CPCs and generated a personalized signature of vascular health, the vascular health profile (VHP). METHODS: Levels of CPCs and MPs were measured with a broad panel of cell surface markers in a population with atherosclerosis and type 2 diabetes mellitus (DM) and age-similar Healthy controls (HC) using an unbiased computational approach, termed CF. RESULTS: Circulating hematopoietic stem and progenitor cell (CHSPCAng) levels were detected at significantly lower concentrations in DM (P < 0.001), whereas levels of seven phenotypically distinct MPs were present at significantly higher concentrations in DM patients and one MP subset was present at significantly lower concentration in DM patients. Collectively, the combination of CHSPC(Ang) and MP levels was more informative than any one measure alone. CONCLUSIONS: This work provides the basis for a personalized cytomic vascular health profile that may be useful for a variety of applications including drug development, clinical risk assessment and companion diagnostics.