Evaluation of an in vitro coronary stent thrombosis model for preclinical assessment.

Stent thrombosis remains an infrequent but significant complication following percutaneous coronary intervention. Preclinical models to rapidly screen and validate therapeutic compounds for efficacy are lacking. Herein, we describe a reproducible, high throughput and cost-effective method to evaluate candidate therapeutics and devices for either treatment or propensity to develop stent thrombosis in an in vitro bench-top model. Increasing degree of stent malapposition (0.00 mm, 0.10 mm, 0.25 mm and 0.50 mm) was associated with increasing thrombosis and luminal area occlusion (4.1 ± 0.5%, 6.3 ± 0.5%, 19.7 ± 4.5%, and 92.6 ± 7.4%, p < 0.0001, respectively). Differences in stent design in the form of bare-metal, drug-eluting, and bioresorbable vascular scaffolds demonstrated differences in stent thrombus burden (14.7 ± 3.8% vs. 20.5 ± 3.1% vs. 86.8 ± 5.3%, p < 0.01, respectively). Finally, thrombus burden was significantly reduced when healthy blood samples were incubated with Heparin, ASA/Ticagrelor (DAPT), and Heparin+DAPT compared to control (DMSO) at 4.1 ± 0.6%, 6.9 ± 1.7%, 4.5 ± 1.2%, and 12.1 ± 1.8%, respectively (p < 0.01). The reported model produces high throughput reproducible thrombosis results across a spectrum of antithrombotic agents, stent design, and degrees of apposition. Importantly, performance recapitulates clinical observations of antiplatelet/antithrombotic regimens as well as device and deployment characteristics. Accordingly, this model may serve as a screening tool for candidate therapies in preclinical evaluation.

Target-vessel versus multivessel revascularisation in ST-elevation myocardial infarction: a meta-analysis of randomised trials.

INTRODUCTION: In acute ST-segment elevation myocardial infarction (STEMI), coronary reperfusion with percutaneous coronary intervention (PCI) to treat the culprit lesion responsible for infarction improves clinical outcomes in nearly all patients. The concurrent treatment of non-infarct vessels with significant stenoses during initial angiography remains an area of controversy. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane Library, Google Scholar, Science Direct, and Web of Science. Original data were abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Only four randomised trials comprising 775 patients met full criteria for analysis. The incidence of non-fatal MI (3.25% vs 8.51%, OR: 0.376, 95% CI: 0.192-0.763), refractory angina (4.01% vs 9.57%, OR: 0.400, 95% CI: 0.241-0.741) and repeat revascularisation (10.52% vs 24.20%, OR: 0.336, 95% CI: 0.202-0.661) was lower in the multivessel revascularisation cohort. Death from cardiac causes or refractory angina or non-fatal MI (11.78% vs 28.86%, OR: 0.336, 95% CI: 0.223-0.505) and death from cardiac causes or non-fatal MI (5.26% vs 12.76%, OR: 0.420, 95% CI: 0.245-0.722) were significantly lower in the multivessel revascularisation cohort. The Median Contrast Volume and Procedure Length were similar in both cohorts. CONCLUSIONS: In patients with acute STEMI who undergo primary PCI, a strategy of treatment of significant non-infarct stenosis (preventive PCI) in addition to the culprit lesion responsible for infarction may result in improved cardiovascular outcomes and reduced overall mortality; however there is insufficient data to fully validate this from currently published literature.

Evaluation of a Rabbit Model of Vascular Stent Healing: Application of Optical Coherence Tomography.

Percutaneous coronary intervention (PCI) is a management strategy for symptomatic obstructive coronary artery disease (CAD). Despite advancements, in-stent restenosis (ISR) still imparts a 1-2% annual rate of repeat revascularization-a focus of ongoing translational research. Optical coherence tomography (OCT) provides high resolution virtual histology of stents. Our study evaluates the use of OCT for virtual histological assessment of stent healing in a rabbit aorta model, enabling complete assessment of intraluminal healing throughout the stent. ISR varies based on intra-stent location, stent length, and stent type in a rabbit model-important considerations for translational experimental design. Atherosclerosis leads to more prominent ISR proliferation independent of stent-related factors. The rabbit stent model mirrors clinical observations, while OCT-based virtual histology demonstrates utility for pre-clinical stent assessment. Pre-clinical models should incorporate clinical and stent factors as feasible to maximize translation to clinical practice.

Trends in Transcatheter Aortic Valve Implantation in Australia.

Aortic valve stenosis is the most common valvular lesion in Australia, with a rising prevalence in line with the ageing population. Recent trials have demonstrated the efficacy of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement in consecutively lower surgical risk patient cohorts. Despite this, the current indication for TAVI in Australia is for the treatment of severe symptomatic aortic stenosis in patients who are of prohibitive or high surgical risk and ultimately deemed suitable by a heart team. This article summarises the trends in TAVI in Australia over the last 5 years in terms of funding, accreditation and service delivery, as well as advances in technique, technology, patient selection and local outcomes.

3D Printing for Cardiovascular Applications: From End-to-End Processes to Emerging Developments.

3D printing as a means of fabrication has seen increasing applications in medicine in the last decade, becoming invaluable for cardiovascular applications. This rapidly developing technology has had a significant impact on cardiovascular research, its clinical translation and education. It has expanded our understanding of the cardiovascular system resulting in better devices, tools and consequently improved patient outcomes. This review discusses the latest developments and future directions of generating medical replicas ('phantoms') for use in the cardiovascular field, detailing the end-to-end process from medical imaging to capture structures of interest, to production and use of 3D printed models. We provide comparisons of available imaging modalities and overview of segmentation and post-processing techniques to process images for printing, detailed exploration of latest 3D printing methods and materials, and a comprehensive, up-to-date review of milestone applications and their impact within the cardiovascular domain across research, clinical use and education. We then provide an in-depth exploration of future technologies and innovations around these methods, capturing opportunities and emerging directions across increasingly realistic representations, bioprinting and tissue engineering, and complementary virtual and mixed reality solutions. The next generation of 3D printing techniques allow patient-specific models that are increasingly realistic, replicating properties, anatomy and function.

Platelet Quiescence in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Bypass Graft Surgery.

Background The optimal antiplatelet strategy for patients with acute coronary syndromes who require coronary artery bypass surgery remains unclear. While a more potent antiplatelet regimen will predispose to perioperative bleeding, it is hypothesized that through "platelet quiescence," ischemic protection conferred by such therapy may provide a net clinical benefit. Methods and Results We compared patients undergoing coronary artery bypass surgery who were treated with a more potent antiplatelet inhibition strategy with those with a less potent inhibition through a meta-analysis. The primary outcome was all-cause mortality after bypass surgery. The analysis identified 4 studies in which the antiplatelet regimen was randomized and 6 studies that were nonrandomized. Combining all studies, there was an overall higher mortality with weaker strategies compared with more potent strategies (odds ratio, 1.38; 95% CI, 1.03-1.85; P=0.03). Conclusions Our findings support the concept of platelet quiescence, in reducing mortality for patients with acute coronary syndrome requiring coronary artery bypass surgery. This suggests the routine up-front use of potent antiplatelet regimens in acute coronary syndrome, irrespective of likelihood of coronary artery bypass graft.

Physician prediction of 1-year mortality in the cardiac catheterization laboratory: comparison to a validated risk score.

BACKGROUND: Physician perception of procedural risk and clinical outcome can affect revascularization decision making. Public reporting of percutaneous coronary intervention outcomes accentuates the need for accuracy in risk prediction in order to avoid a treatment paradox of undertreating the highest risk patients. Our study compares a validated risk score to physician prediction (PP) of 1-year mortality based on clinical impression at the time of invasive angiography. METHODS AND RESULTS: We performed a cohort study between August 2015 and May 2018 to determine the discriminative accuracy of interventional cardiologists on one-year mortality of the treated patient. PP of one-year mortality was compared to the New York State Percutaneous Coronary Intervention Reporting System (NYPCIRS) score in predicting mortality. Three thousand seven hundred ninety-two patients were followed with a median follow-up period of 14.4 months (interquartile range 12.4-18.1 months) and 165 patients (4.4%) died within one-year. PP of mortality was associated with one-year mortality with a hazard ratio of 8.78 (95% confidence interval 5.24-14.71, P < 0.0001). Clinical presentation in the form of cardiogenic shock, return of spontaneous circulation, and liver and renal dysfunction were associated with PP. Diagnostic accuracy and specificity were improved in PP compared to NYPCIRS. The combination of PP to NYPCIRS improved the overall c-statistic and diagnostic yield. CONCLUSION: PP appears to be especially specific and accurate for prediction of mortality compared to NYPCIRS though it lacks sensitivity. Furthermore, the combination of PP with NYPCIRS improved the c-statistic and diagnostic yield. Overall, the utility of PP with an objective risk score improves the diagnostic accuracy of mortality prediction.

Modifiable Risk Factors and Residual Risk Following Coronary Revascularization: Insights From a Regionalized Dedicated Follow-Up Clinic.

OBJECTIVE: To ensure compliance with optimal secondary prevention strategies and document the residual risk of patients following revascularization, we established a postrevascularization clinic for risk-factor optimization at 1 year, with outcomes recorded in a web-based registry. Although coronary revascularization can reduce ischemia, medical treatment of coronary artery disease (CAD) remains the cornerstone of ongoing risk reduction. While standardized referral pathways and protocols for revascularization are prevalent and well studied, post-revascularization care is often less formalized. PATIENTS AND METHODS: The University of Ottawa Heart Institute is a tertiary-care center providing coronary revascularization services. From 2015 to 2019, data were prospectively recorded in the CAPITAL revascularization registry, and patient-level procedural, clinical, and outcome data are collected in the year following revascularization. Major adverse cardiovascular event (MACE) was defined as death, myocardial infarction, unplanned revascularization, or cerebrovascular accident. Kaplan-Meier curves were generated to evaluate time-to-event data for clinical outcomes by risk-factor management, and comparisons were performed using log-rank tests and reported by hazard ratio (HR) and 95% confidence intervals (CIs). RESULTS: A cohort of 4147 patients completed 1-year follow-up after revascularization procedure that included 3462 undergoing percutaneous coronary intervention (PCI), 589 undergoing coronary artery bypass graft (CABG), and 96 undergoing both PCI and CABG. In the year following revascularization (median follow-up 13.3 months-interquartile range [IQR]: 11.9-16.5) 11% of patients experienced MACE, with female patients being disproportionately at risk. Moreover, 47.7% of patients had ≥2 risk factors (diabetes, dyslipidemia, overweight, active smoker) at the time of follow-up, with 45.0% of patients with diabetes failing to achieve target hemoglobin (Hb) A1c, 54.8% of smokers continuing to smoke, and 27.1% of patients failing to achieve guideline-directed lipid targets. CONCLUSION: Patients who have undergone revascularization procedures remain at elevated risk for MACE, and inadequately controlled risk factors are prevalent in follow-up. This highlights the need for aggressive secondary prevention strategies and implementation of programs to optimize postrevascularization care.

Contrast-free optical coherence tomography:Systematic evaluation of non-contrast media for intravascular assessment.

BACKGROUND: Coronary revascularization using imaging guidance is rapidly becoming the standard of care. Intravascular optical coherence tomography uses near-infrared light to obtain high resolution intravascular images. Standard optical coherence tomography imaging technique employs iodinated contrast dye to achieve the required blood clearance during acquisition. We sought to systematically evaluate the technical performance of saline as an alternative to iodinated contrast for intravascular optical coherence tomography assessment. METHODS AND RESULTS: We performed bench top optical coherence tomography analysis on nylon tubing with sequential contrast/saline dilutions to empirically derive adjustment coefficients. We then applied these coefficients in vivo in an established rabbit abdominal stenting model with both saline and contrast optical coherence tomography imaging. In this model, we assessed the impact of saline on both quantitative and qualitative vessel assessment. Nylon tubing assessment demonstrated a linear relationship between saline and contrast for both area and diameter. We then derived adjustment coefficients, allowing for accurate calculation of area and diameter when converting saline into both contrast and reference dimensions. In vivo studies confirmed reduced area with saline versus contrast [7.43 (5.67-8.36) mm2 versus 8.2 (6.34-9.39) mm2, p = 0.001] and diameter [3.08 mm versus 3.23 mm, p = 0.001]. Following correction, a strong relationship was achieved in vivo between saline and contrast in both area and diameter without compromising image quality, artefact, or strut assessment. CONCLUSION: Saline generates reduced dimensions compared to contrast during intravascular optical coherence tomography imaging. The relationship across physiologic coronary diameters is linear and can be corrected with high fidelity. Saline does not adversely impact image quality, artefact, or strut assessment.

Evaluation of plasminogen activator inhibitor-1 as a biomarker of unplanned revascularization and major adverse cardiac events in coronary angiography and percutaneous coronary intervention.

BACKGROUND: The stented coronary artery remains at high-risk of complications, particularly in the form of stent thrombosis and in-stent restenosis. Improving our ability to identify patients at high-risk for these complications may provide opportunities for intervention. PAI-1 has been implicated in the pathophysiology of stent complications in preclinical studies, suggesting it may be a clinically valuable biomarker to predict adverse events following percutaneous coronary intervention. METHODS: Plasma PAI-1 levels were measured in 910 subjects immediately after coronary angiography between 2015 and 2019. The primary outcome was the incidence of unplanned revascularization (UR) at 12 months. The secondary outcome was the incidence of major adverse cardiac events (MACE). RESULTS: UR and MACE occurred in 49 and 103 patients in 12 months. Reduced plasma PAI-1 levels were associated with UR (4386.1 pg/mL [IQR, 2778.7-6664.6], n = 49, vs. 5247.6 pg/mL [IQR, 3414.1-7836.1], n = 861; p = 0.04). Tertile PAI-1 levels were predictive of UR after adjustment for known clinical risk factors associated with adverse outcomes. In post-hoc landmark analysis, UR was enhanced with low plasma PAI-1 levels for late complications (beyond 30 days). Finally, an updated systematic review and meta-analysis did not reveal an association between plasma PAI-1 and MACE. CONCLUSION: PAI-1 levels are not independently associated with UR nor MACE in patients undergoing angiography but associated with UR following adjustment with known clinical factors. In our landmark analysis, low PAI-1 levels were associated with UR for late stent complications. As such, future studies should focus on the mediatory role of PAI-1 in the pathogenesis of stent complications.

Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective.

Adenosine, a purine nucleoside, is produced broadly and implicated in the homeostasis of many cells and tissues. It signals predominantly via 4 purinergic adenosine receptors (ADORs) - ADORA1, ADORA2A, ADORA2B and ADOosine signaling, both through design as specific ADOR agonists and antagonists and as offtarget effects of existing anti-platelet medications. Despite this, adenosine has yet to be firmly established as either a therapeutic or a prognostic tool in clinical medicine to date. Herein, we provide a bench-to-bedside review of adenosine biology, highlighting the key considerations for further translational development of this proRA3 in addition to non-ADOR mediated effects. Through these signaling mechanisms, adenosine exerts effects on numerous cell types crucial to maintaining vascular homeostasis, especially following vascular injury. Both in vitro and in vivo models have provided considerable insights into adenosine signaling and identified targets for therapeutic intervention. Numerous pharmacologic agents have been developed that modulate adenmising molecule.

Evaluation of Plasma Adenosine as a Marker of Cardiovascular Risk: Analytical and Biological Considerations.

Background Adenosine is a ubiquitous regulatory molecule known to modulate signaling in many cells and processes vital to vascular homeostasis. While studies of adenosine receptors have dominated research in the field, quantification of adenosine systemically and locally remains limited owing largely to technical restrictions. Given the potential clinical implications of adenosine biology, there is a need for adequately powered studies examining the role of plasma adenosine in vascular health. We sought to describe the analytical and biological factors that affect quantification of adenosine in humans in a large, real-world cohort of patients undergoing evaluation for coronary artery disease. Methods and Results Between November 2016 and April 2018, we assessed 1141 patients undergoing angiography for evaluation of coronary artery disease. High-performance liquid chromatography was used for quantification of plasma adenosine concentration, yielding an analytical coefficient of variance (CVa) of 3.2%, intra-subject variance (CVi) 35.8% and inter-subject variance (CVg) 56.7%. Traditional cardiovascular risk factors, medications, and clinical presentation had no significant impact on adenosine levels. Conversely, increasing age (P=0.027) and the presence of obstructive coronary artery disease (P=0.026) were associated with lower adenosine levels. Adjusted multivariable analysis supported only age being inversely associated with adenosine levels (P=0.039). Conclusions Plasma adenosine is not significantly impacted by traditional cardiovascular risk factors; however, advancing age and presence of obstructive coronary artery disease may be associated with lower adenosine levels. The degree of intra- and inter-subject variance of adenosine has important implications for biomarker use as a prognosticator of cardiovascular outcomes and as an end point in clinical studies.

Coronary artery stenting in acute coronary syndrome associated with giant cell arteritis.

Coronary vasculitis is a rare but devastating complication of giant cell arteritis, otherwise known as temporal arteritis. Originally named for its propensity to attack the superficial temporal arteries, it is now recognized that it commonly involves a number of medium and large arteries throughout the body. Here we describe two cases of giant cell arteritis affecting the coronary arteries, one discovered at post-mortem and one which was successfully treated with immunosuppressive therapy and drug-eluting coronary stents. .