Acute coronary syndromes

In the UK, there are over 80,000 admissions annually with acute coronary syndromes (ACS). Management of ST-elevation myocardial infarction (STEMI) involves primary percutaneous coronary intervention (PCI), which is delivered via dedicated heart attack centres. Non-ST elevation-ACS (NSTE-ACS) accounts for two-thirds of ACS presentations, affecting an older cohort of patients - often with more complex comorbidities. Initial management is with anti-thrombotic therapy with a view to PCI within 24 hours for the most acute cases and within 72 hours for all others. However, varying management pathways and access to specialist cardiology services results in variable times to definitive treatment. Advances in the sensitivity of cardiac biomarkers and the use of risk assessment tools now enable rapid diagnosis within a few hours of symptom onset. Advances in invasive management and drug therapy have resulted in improved clinical outcomes with resultant decline in mortality associated with ACS

Cardiovascular risk stratification in familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials

Persistent circulating platelet and endothelial derived microparticle signature may explain on-going pro-thrombogenicity after acute coronary syndrome

Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. / Methods & results: Circulating total annexin v + (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) origin were quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls. The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p = 1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. / Conclusions: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of on-going inflammation, endothelial injury and may explain on-going pro-thrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy

Intracoronary platelet and monocyte activation status within platelet-monocyte complexes are determinants of inflammation in ST elevation myocardial infarction1

INTRODUCTION: Platelet Monocyte Complexes (PMCs) are commonly expressed in coronary artery disease but their pathologic significance in ST elevation myocardial infarction (STEMI) is unclear. This study evaluates the relationship between locally activated PMCs and intracoronary inflammation in stable and unstable coronary disease. MATERIAL AND METHODS: Micro catheter aspirated blood samples of 15 STEMI and 7 stable angina patients are collected from the coronary artery (CA), aorta (AO) and right atrium (RA). Samples are labelled with monoclonal antibodies and prepared for flow cytometry. CD 14 and CD 61 double positive cells are identified as PMC. P-selectin expression is identified by additional CD62P positivity and TF expression by additional CD142 positivity. Plasma TNF-alpha and IL-6 are measured using ELISA and CRP is measured in plasma using a high sensitivity automated microparticle enhanced latex turbidimetric immunoassay. RESULTS: No site-specific difference is seen in overall PMC expression in STEMI or stable angina. Surface P-selectin expression in STEMI [median (IQR)] is significantly higher in CA [35.01 (23.15-56.99)] compared with AO [15.99 (10.3-18.85)] or RA [14.02 (10.42-26.08)] (p = 0.003). Intracoronary PMC correlates significantly with intracoronary TNF-alpha (r = 0.87, p = 0.001) and intracoronary IL-6 (r = 0.76, p = 0.03). Bound monocytes within P-selectin positive and tissue factor positive complexes correlate positively with intracoronary TNF-alpha (r = 0.81, p = 0.008 & r = 0.80, p = 0.009 respectively) and IL-6 (r = 0.54, p = 0.16 & r = 0.71, p = 0.05 respectively). No such correlation is observed in the peripheral circulation of STEMI and stable angina patients. CONCLUSION: Inflammation is not attributable to PMC formation per se. However, increased intracoronary P-selectin expression by activated platelets and tissue factor expression by activated monocytes within the complexes are determinants of local intracoronary inflammatory burden in STEMI

Optically Generated Ultrasound for Intracoronary Imaging

Conventional intravascular ultrasound (IVUS) devices use piezoelectric transducers to electrically generate and receive US. With this paradigm, there are numerous challenges that restrict improvements in image quality. First, with miniaturization of the transducers to reduce device size, it can be challenging to achieve the sensitivities and bandwidths required for large tissue penetration depths and high spatial resolution. Second, complexities associated with manufacturing miniaturized electronic transducers can have significant cost implications. Third, with increasing interest in molecular characterization of tissue in-vivo, it has been challenging to incorporate optical elements for multimodality imaging with photoacoustics (PA) or near-infrared spectroscopy (NIRS) whilst maintaining the lateral dimensions suitable for intracoronary imaging. Optical Ultrasound (OpUS) is a new paradigm for intracoronary imaging. US is generated at the surface of a fiber optic transducer via the photoacoustic effect. Pulsed or modulated light is absorbed in an engineered coating on the fiber surface and converted to thermal energy. The subsequent temperature rise leads to a pressure rise within the coating, which results in a propagating ultrasound wave. US reflections from imaged structures are received with optical interferometry. With OpUS, high bandwidths (31.5 MHz) and pressures (21.5 MPa) have enabled imaging with axial resolutions better than 50 μm and at depths >20 mm. These values challenge those of conventional 40 MHz IVUS technology and show great potential for future clinical application. Recently developed nanocomposite coating materials, that are highly transmissive at light wavelengths used for PA and NIRS light, can facilitate multimodality imaging, thereby enabling molecular characterization

Microparticles and their role in coronary artery disease.

Despite significant advances in prevention, medical and interventional management, coronary artery disease (CAD) remains the leading cause of death worldwide. Although the number of people being diagnosed with CAD has plateaued in the western world, it is projected to increase significantly in the developing world reaching epidemic proportions, particularly in South Asia. To better stratify the risk of developing and suffering a cardiovascular event due to CAD, not only plasma biomarkers relating to disease burden but also disease activity in CAD are needed; this will allow targeting of appropriate management to high-risk patients for acute events. Over the last twenty years, data have emerged showing the role of sub-micron vesicles called microparticles (MPs) in the pathogenesis of formation and evolution of atherosclerotic plaques causing either stable angina (SA) or acute coronary syndromes (ACS). Herein we provide an overview of our current knowledge of MP formation, composition and possible mechanisms through which they could be contributing to CAD. We also reviewed currently available methods and their limitations in quantifying MPs and in determining their functional aspects. Role of various treatments ranging from dietary substitutes to oral medicines and intravenous medications to mechanistic procedures such as hemofiltration are elaborated. Although evidence implicating the role of MPs in CAD are mounting large scale prospective studies are still lacking and are the need of the hour prior to establishing the use of MPs as biomarkers for the early detection of CAD and its progression

Agreement of wall shear stress distribution between two core laboratories using three-dimensional quantitative coronary angiography

Wall shear stress (WSS) estimated in models reconstructed from intravascular imaging and 3-dimensional-quantitative coronary angiography (3D-QCA) data provides important prognostic information and enables identification of high-risk lesions. However, these analyses are time-consuming and require expertise, limiting WSS adoption in clinical practice. Recently, a novel software has been developed for real-time computation of time-averaged WSS (TAWSS) and multidirectional WSS distribution. This study aims to examine its inter-corelab reproducibility. Sixty lesions (20 coronary bifurcations) with a borderline negative fractional flow reserve were processed using the CAAS Workstation WSS prototype to estimate WSS and multi-directional WSS values. Analysis was performed by two corelabs and their estimations for the WSS in 3 mm segments across each reconstructed vessel was extracted and compared. In total 700 segments (256 located in bifurcated vessels) were included in the analysis. A high intra-class correlation was noted for all the 3D-QCA and TAWSS metrics between the estimations of the two corelabs irrespective of the presence (range: 0.90–0.92) or absence (range: 0.89–0.90) of a coronary bifurcation, while the ICC was good-moderate for the multidirectional WSS (range: 0.72–0.86). Lesion level analysis demonstrated a high agreement of the two corelabls for detecting lesions exposed to an unfavourable haemodynamic environment (WSS > 8.24 Pa, κ = 0.77) that had a high-risk morphology (area stenosis > 61.3%, κ = 0.71) and were prone to progress and cause events. The CAAS Workstation WSS enables reproducible 3D-QCA reconstruction and computation of WSS metrics. Further research is needed to explore its value in detecting high-risk lesions

Wall-less vascular poly(vinyl) alcohol gel ultrasound imaging phantoms using 3D printed vessels

Vascular phantoms are crucial tools for clinical training and for calibration and validation of medical imaging systems. With current methods, it can be challenging to replicate anatomically-realistic vasculature. Here, we present a novel method that enables the fabrication of complex vascular phantoms. Poly(vinyl alcohol) (PVA) in two forms was used to create wall-less vessels and the surrounding tissue mimicking material (TMM). For the latter, PVA cryogel (PVA-c) was used as the TMM, which was made from a solution of PVA (10% by weight), distilled water, and glass spheres for ultrasonic scattering (0.5% by weight). PVA-c is not water soluble, and after a freeze-thaw cycle it is mechanically robust. To form the wall-less vessels, vessel structures were 3D printed in water-soluble PVA and submerged in the aqueous solution of PVA-c. Once the PVA-c had solidified, the 3D printed PVA vessel structures were dissolved in water. Three phantoms were created, as initial demonstrations of the capabilities of this method: a straight vessel, a stenosed (narrowed), and a bifurcated (branched) vessel. Ultrasound images of the phantoms had realistic appearances. We conclude that this method is promising for creating wall-less, anatomically realistic, vascular phantoms

Prospective comparison of novel dark blood late gadolinium enhancement with conventional bright blood imaging for the detection of scar

BACKGROUND: Conventional bright blood late gadolinium enhancement (bright blood LGE) imaging is a routine cardiovascular magnetic resonance (CMR) technique offering excellent contrast between areas of LGE and normal myocardium. However, contrast between LGE and blood is frequently poor. Dark blood LGE (DB LGE) employs an inversion recovery T2 preparation to suppress the blood pool, thereby increasing the contrast between the endocardium and blood. The objective of this study is to compare the diagnostic utility of a novel DB phase sensitive inversion recovery (PSIR) LGE CMR sequence to standard bright blood PSIR LGE. METHODS: One hundred seventy-two patients referred for clinical CMR were scanned. A full left ventricle short axis stack was performed using both techniques, varying which was performed first in a 1:1 ratio. Two experienced observers analyzed all bright blood LGE and DB LGE stacks, which were randomized and anonymized. A scoring system was devised to quantify the presence and extent of gadolinium enhancement and the confidence with which the diagnosis could be made. RESULTS: A total of 2752 LV segments were analyzed. There was very good inter-observer correlation for quantifying LGE. DB LGE analysis found 41.5% more segments that exhibited hyperenhancement in comparison to bright blood LGE (248/2752 segments (9.0%) positive for LGE with bright blood; 351/2752 segments (12.8%) positive for LGE with DB; p < 0.05). DB LGE also allowed observers to be more confident when diagnosing LGE (bright blood LGE high confidence in 154/248 regions (62.1%); DB LGE in 275/324 (84.9%) regions (p < 0.05)). Eighteen patients with no bright blood LGE were found to have had DB LGE, 15 of whom had no known history of myocardial infarction. CONCLUSIONS: DB LGE significantly increases LGE detection compared to standard bright blood LGE. It also increases observer confidence, particularly for subendocardial LGE, which may have important clinical implications

Micron resolution, high-fidelity three-dimensional vascular optical imaging phantoms

Microscopic and mesoscale optical imaging techniques allow for three-dimensional (3-D) imaging of biological tissue across millimeter-scale regions, and imaging phantom models are invaluable for system characterization and clinical training. Phantom models that replicate complex 3-D geometries with both structural and molecular contrast, with resolution and lateral dimensions equivalent to those of imaging techniques (<20  μm), have proven elusive. We present a method for fabricating phantom models using a combination of two-photon polymerization (2PP) to print scaffolds, and microinjection of tailored tissue-mimicking materials to simulate healthy and diseased tissue. We provide a first demonstration of the capabilities of this method with intravascular optical coherence tomography, an imaging technique widely used in clinical practice. We describe the design, fabrication, and validation of three types of phantom models: a first with subresolution wires (5- to 34-μm diameter) arranged circumferentially, a second with a vessel side-branch, and a third containing a lipid inclusion within a vessel. Silicone hybrid materials and lipids, microinjected within a resin framework created with 2PP, served as tissue-mimicking materials that provided realistic optical scattering and absorption. We demonstrate that optical phantom models made with 2PP and microinjected tissue-mimicking materials can simulate complex anatomy and pathology with exquisite detail