A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome: A cohort study.

BACKGROUND: There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS. METHODS AND FINDINGS: We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, the exclusion of those with abnormal WCC or hsCRP levels >15 mg/L makes it unlikely that sepsis was a major contributor. CONCLUSIONS: These multicentre, real-world data from a large cohort of patients with suspected ACS suggest that mildly elevated hsCRP (up to 15 mg/L) may be a clinically meaningful prognostic marker beyond troponin and point to its potential utility in selecting patients for novel treatments targeting inflammation. TRIAL REGISTRATION: ClinicalTrials.gov - NCT03507309.

Near-Infrared Autofluorescence in Atherosclerosis Associates With Ceroid and Is Generated by Oxidized Lipid-Induced Oxidative Stress.

[Figure: see text].

Vulnerable plaques and patients: state-of-the-art.

Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term 'vulnerable plaque' was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of 'vulnerability' of a specific lesion to the more comprehensive goal of identifying patient 'cardiovascular vulnerability'. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and 'local' diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of 'high-risk' plaques occurring in 'vulnerable' patients.

Adapting the role of handheld echocardiography during the COVID-19 pandemic: A practical guide.

The COVID-19 pandemic has altered our approach to inpatient echocardiography delivery. There is now a greater focus to address key clinical questions likely to make an immediate impact in management, particularly during the period of widespread infection. Handheld echocardiography (HHE) can be used as a first-line assessment tool, limiting scanning time and exposure to high viral load. This article describes a potential role for HHE during a pandemic. We propose a protocol with a reporting template for a focused core dataset necessary in delivering an acute echocardiography service in the setting of a highly contagious disease, minimising risk to the operator. We cover the scenarios typically encountered in the acute cardiology setting and how an expert trained echocardiography team can identify such pathologies using a limited imaging format and include cardiac presentations encountered in those patients acutely unwell with COVID-19.

Developing a Strategy for Interventional Molecular Imaging of Oxidized Low-Density Lipoprotein in Atherosclerosis.

The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological imaging by focusing on the immunobiology hidden in and behind the endothelium and therefore may be able to improve the identification of prospective culprit lesions. Our focus has been on identifying arterial accumulation of oxidized low-density lipoprotein (oxLDL) by exploiting advances in knowledge of vascular pathobiology. Here, we reflect on our work developing near-infrared fluorescence imaging of oxLDL using LO1, a monoclonal autoantibody generated in our laboratory. We detail progress to date and discuss our vision on taking the work through the early translational pipeline toward a multitargeted approach in imaging rupture-prone atherosclerotic plaques. Ultimately, molecular imaging of coronary arteries should be able to assess the regional risk that is specific to a lesion, which can then be used in concert with global risk factors to personalize the therapeutic strategy for patients in a way that goes beyond generalized population-based therapies.

Disturbed flow promotes endothelial senescence via a p53-dependent pathway.

OBJECTIVE: Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow-generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence. APPROACH AND RESULTS: LDLR(-/-) (low-density lipoprotein receptor(-/-)) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated ß-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated ß-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated ß-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow-induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow-induced senescence. CONCLUSIONS: Disturbed flow promotes endothelial senescence via a p53-p21-dependent pathway which can be inhibited by activation of sirtuin 1. These observations support the principle that pharmacological activation of sirtuin 1 may promote cardiovascular health by suppressing EC senescence at atheroprone sites.

The cardiovascular effects of GLP-1 receptor agonists beyond obesity and type 2 diabetes: An anti-atherosclerotic action.

Obesity and overweight affect almost one third of the European population. Obesity and its associated conditions, including type 2 diabetes, significantly impact healthcare systems, life expectancy and quality of life. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity, with or without diabetes, has provided an effective alternative to metabolic surgery and dietary interventions. We are now beginning to understand their pleiotropic effects beyond weight loss, such as their favourable impact on cardiovascular profiles. The aim of this review is to summarize available preclinical and clinical data on the beneficial effects of GLP-1 receptor agonists on atherosclerosis and cardiovascular disease which has the potential to substantially broaden the scope of their clinical applications.

Randomized Trial of Remote Assessment of Patients After an Acute Coronary Syndrome.

BACKGROUND: Telemedicine programs can provide remote diagnostic information to aid clinical decisions that could optimize care and reduce unplanned readmissions post-acute coronary syndrome (ACS). OBJECTIVES: TELE-ACS (Remote Acute Assessment of Patients With High Cardiovascular Risk Post-Acute Coronary Syndrome) is a randomized controlled trial that aims to compare a telemedicine-based approach vs standard care in patients following ACS. METHODS: Patients were suitable for inclusion with at least 1 cardiovascular risk factor and presenting with ACS and were randomized (1:1) before discharge. The primary outcome was time to first readmission at 6 months. Secondary outcomes included emergency department (ED) visits, major adverse cardiovascular events, and patient-reported symptoms. The primary analysis was performed according to intention to treat. RESULTS: A total of 337 patients were randomized from January 2022 to April 2023, with a 3.6% drop-out rate. The mean age was 58.1 years. There was a reduced rate of readmission over 6 months (HR: 0.24; 95% CI: 0.13-0.44; P < 0.001) and ED attendance (HR: 0.59; 95% CI: 0.40-0.89) in the telemedicine arm, and fewer unplanned coronary revascularizations (3% in telemedicine arm vs 9% in standard therapy arm). The occurrence of chest pain (9% vs 24%), breathlessness (21% vs 39%), and dizziness (6% vs 18%) at 6 months was lower in the telemedicine group. CONCLUSIONS: The TELE-ACS study has shown that a telemedicine-based approach for the management of patients following ACS was associated with a reduction in hospital readmission, ED visits, unplanned coronary revascularization, and patient-reported symptoms. (Telemedicine in High-Risk Cardiovascular Patients Post-ACS [TELE-ACS]; NCT05015634).

Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: a Consensus Statement from the Quantitative Cardiovascular Imaging Study Group.

The detection and characterization of coronary artery stenosis and atherosclerosis using imaging tools are key for clinical decision-making in patients with known or suspected coronary artery disease. In this regard, imaging-based quantification can be improved by choosing the most appropriate imaging modality for diagnosis, treatment and procedural planning. In this Consensus Statement, we provide clinical consensus recommendations on the optimal use of different imaging techniques in various patient populations and describe the advances in imaging technology. Clinical consensus recommendations on the appropriateness of each imaging technique for direct coronary artery visualization were derived through a three-step, real-time Delphi process that took place before, during and after the Second International Quantitative Cardiovascular Imaging Meeting in September 2022. According to the Delphi survey answers, CT is the method of choice to rule out obstructive stenosis in patients with an intermediate pre-test probability of coronary artery disease and enables quantitative assessment of coronary plaque with respect to dimensions, composition, location and related risk of future cardiovascular events, whereas MRI facilitates the visualization of coronary plaque and can be used in experienced centres as a radiation-free, second-line option for non-invasive coronary angiography. PET has the greatest potential for quantifying inflammation in coronary plaque but SPECT currently has a limited role in clinical coronary artery stenosis and atherosclerosis imaging. Invasive coronary angiography is the reference standard for stenosis assessment but cannot characterize coronary plaques. Finally, intravascular ultrasonography and optical coherence tomography are the most important invasive imaging modalities for the identification of plaques at high risk of rupture. The recommendations made in this Consensus Statement will help clinicians to choose the most appropriate imaging modality on the basis of the specific clinical scenario, individual patient characteristics and the availability of each imaging modality.

Depletion of Homeostatic Antibodies against Malondialdehyde-Modified Low-Density Lipoprotein Correlates with Adverse Events in Major Vascular Surgery.

We aimed to investigate if major vascular surgery induces LDL oxidation, and whether circulating antibodies against malondialdehyde-modified LDL (MDA-LDL) alter dynamically in this setting. We also questioned relationships between these biomarkers and post-operative cardiovascular events. Major surgery can induce an oxidative stress response. However, the role of the humoral immune system in clearance of oxidized LDL following such an insult is unknown. Plasma samples were obtained from a prospective cohort of 131 patients undergoing major non-cardiac vascular surgery, with samples obtained preoperatively and at 24- and 72 h postoperatively. Enzyme-linked immunoassays were developed to assess MDA-LDL-related antibodies and complexes. Adverse events were myocardial infarction (primary outcome), and a composite of unstable angina, stroke and all-cause mortality (secondary outcome). MDA-LDL significantly increased at 24 h post-operatively (p < 0.0001). Conversely, levels of IgG and IgM anti-MDA-LDL, as well as IgG/IgM-MDA-LDL complexes and total IgG/IgM, were significantly lower at 24 h (each p < 0.0001). A smaller decrease in IgG anti-MDA-LDL related to combined clinical adverse events in a post hoc analysis, withstanding adjustment for age, sex, and total IgG (OR 0.13, 95% CI [0.03-0.5], p < 0.001; p value for trend <0.001). Major vascular surgery resulted in an increase in plasma MDA-LDL, in parallel with a decrease in antibody/complex levels, likely due to antibody binding and subsequent removal from the circulation. Our study provides novel insight into the role of the immune system during the oxidative stress of major surgery, and suggests a homeostatic clearance role for IgG antibodies, with greater reduction relating to downstream adverse events.

Monoclonal Autoantibody Against a Cryptic Epitope on Tissue-Adherent Low-Density Lipoprotein for Molecular Imaging in Atherosclerosis.

BACKGROUND: Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis. OBJECTIVES: The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants. METHODS: The authors created hybridomas from an unimmunized low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mouse and selected an IgG2b isotype autoantibody, LO9, for further characterization. RESULTS: LO9 reacted well with native LDL bound to immobilized matrix components and less well to oxidized LDL. LO9 binding to immobilized native LDL was not neutralized by fluid-phase native LDL, indicating an adhesion-dependent epitope. The authors localized the epitope to a 20 amino-acid peptide sequence (P5) in the globular amino-terminus of apolipoprotein B. LO9 reacted with antigen in mouse atherosclerosis and in both human stable and ruptured coronary atherosclerosis. Furthermore, in vivo near-infrared fluorescence molecular tomographic imaging, and ex vivo confocal microscopy showed that intravenously injected LO9 localized beneath endothelium of the aortic arch in Ldlr-/- mice, in the vicinity of macrophages. CONCLUSIONS: The authors believe LO9 is the first example of an IgG autoantibody that reacts with a native LDL epitope revealed by adherence to tissue matrix. Antibodies against adherent native LDL have potential as molecular targeting agents for imaging of and therapeutic delivery to atherosclerosis.

Impact of white blood cell count on clinical outcomes in patients treated with aspirin-free ticagrelor monotherapy after percutaneous coronary intervention: insights from the GLOBAL LEADERS trial.

AIMS: The aim of this study was to investigate the efficacy and safety of ticagrelor monotherapy in patients undergoing percutaneous coronary intervention (PCI) stratified according to the baseline white blood cell (WBC) count. METHODS AND RESULTS: This is a post hoc analysis of the GLOBAL LEADERS trial, a multi-centre, open-label, randomized all-comer trial in patients undergoing PCI, comparing the experimental strategy (23-month ticagrelor monotherapy following 1-month dual anti-platelet therapy [DAPT]) with the reference strategy (12-month aspirin monotherapy following 12-month DAPT). Patients were stratified into two WBC groups, either < or ≥median WBC count of 7.8 × 109 cells/L (lower or higher WBC group, respectively). The primary endpoint was a composite of all-cause mortality or new Q-wave myocardial infarction at 2 years. Of 14 576 patients included in the present study, 7212 patients (49.5%) were classified as the lower WBC group, who had a significantly lower risk of both ischaemic and bleeding outcomes at 2 years. At 2 years, the experimental strategy was associated with a significant lower incidence of the primary endpoint compared with the reference strategy in the lower WBC group [2.8% vs. 4.2%; hazard ratio (HR): 0.67; 95% confidence interval (CI): 0.52-0.86] but not in the higher WBC group (4.8% vs. 4.7%; HR: 1.01; 95% CI: 0.82-1.25; Pinteraction=0.013). There were no significant differences in the risks of Bleeding Academic Research Consortium type 3 or 5 bleeding between two anti-platelet strategies regardless of the WBC groups. CONCLUSION: Increased WBC counts, which may reflect degree of inflammation, at the time of index procedure may attenuate the anti-ischaemic benefits of ticagrelor monotherapy observed in patients with lower WBC counts.

Oxidised LDL and Anti-Oxidised LDL Antibodies Are Reduced by Lipoprotein Apheresis in a Randomised Controlled Trial on Patients with Refractory Angina and Elevated Lipoprotein(a).

Aims: An abundance of epidemiological evidence demonstrates that elevated lipoprotein(a) (Lp(a)) represents a significant contributing risk factor towards the development of cardiovascular disease. In particular, raised Lp(a) may play a mechanistic role in patients with refractory angina. Studies have also shown a correlation between oxidised LDL (oxLDL) levels and atherosclerotic burden as well as rates of cardiovascular events. Antibodies against oxLDL (anti-oxLDL) are involved in the removal of oxLDL. Lipoprotein apheresis (LA), which removes lipoproteins using extra-corporeal processes, is an established means of reducing Lp(a), and thereby reduces cardiovascular events. The aim of this study was to investigate the effect of LA on oxLDL and anti-oxLDL levels amongst those with refractory angina in the context of raised Lp(a). Methods: We performed a sub-study within a randomised controlled crossover trial involving 20 patients with refractory angina and raised Lp(a) > 500 mg/L, comparing the effect of three months of blinded weekly LA or sham, followed by crossover to the opposite study arm. We utilized enzyme-linked immunosorbent assays (ELISA) to quantify oxLDL and IgG/ IgM anti-oxLDL antibody levels at baseline and following three months of active LA or sham sessions. Results: Following three months of LA, there was a 30% reduction in oxLDL from 0.37 ± 0.06 to 0.26 ± 0.04 with a mean drop of -0.11 units (U) (95% CI -0.13, -0.09) compared to no significant change with sham therapy (p < 0.0001 between treatment arms). LA also led to a 22% reduction in levels of IgG and IgM anti-oxLDL, again with no significant change demonstrated during sham (p = 0.0036 and p = 0.012, respectively, between treatment arms). Conclusion: Amongst patients with refractory angina in the context of elevated Lp(a), LA significantly lowers levels of oxLDL and anti-oxLDL antibodies, representing potential mechanisms by which LA yields symptomatic and prognostic benefits in this patient cohort.

Trends in Mortality From Aortic Stenosis in Europe: 2000-2017.

Background: Trends in mortality from aortic stenosis across European countries are not well-understood, especially given the significant growth in transcatheter aortic valve implantation (TAVI) in the last 10 years. Methods: Age-standardised death rates were extracted from the World Health Organisation Mortality Database, using the International Classification of Diseases 10th edition code for non-rheumatic aortic stenosis for those aged > 45 years between 2000 and 2017. The UK and countries from the European Union with at least 1,000,000 inhabitants and at least 50% available datapoints over the study period were included: a total of 23 countries. Trends were described using Joinpoint regression analysis. Results: No reductions in mortality were demonstrated across all countries 2000-2017. Large increases in mortality were found for Croatia, Poland and Slovakia for both sexes (>300% change). Mortality plateaued in Germany from 2008 in females and 2012 in males, whilst mortality in the Netherlands declined for both sexes from 2007. Mortality differences between the sexes were observed, with greater mortality for males than females across most countries. Conclusions: Mortality from aortic stenosis has increased across Europe from 2000 to 2017. There are, however, sizable differences in mortality trends between Eastern and Western European countries. The need for health resource planning strategies to specifically target AS, particularly given the expected increase with ageing populations, is highlighted.

Coronary Magnetic Resonance Angiography in Chronic Coronary Syndromes.

Cardiovascular disease is the leading cause of mortality worldwide, with atherosclerotic coronary artery disease (CAD) accounting for the majority of cases. X-ray coronary angiography and computed tomography coronary angiography (CCTA) are the imaging modalities of choice for the assessment of CAD. However, the use of ionising radiation and iodinated contrast agents remain drawbacks. There is therefore a clinical need for an alternative modality for the early identification and longitudinal monitoring of CAD without these associated drawbacks. Coronary magnetic resonance angiography (CMRA) could be a potential alternative for the detection and monitoring of coronary arterial stenosis, without exposing patients to ionising radiation or iodinated contrast agents. Further advantages include its versatility, excellent soft tissue characterisation and suitability for repeat imaging. Despite the early promise of CMRA, widespread clinical utilisation remains limited due to long and unpredictable scan times, onerous scan planning, lower spatial resolution, as well as motion related image quality degradation. The past decade has brought about a resurgence in CMRA technology, with significant leaps in image acceleration, respiratory and cardiac motion estimation and advanced motion corrected or motion-resolved image reconstruction. With the advent of artificial intelligence, great advances are also seen in deep learning-based motion estimation, undersampled and super-resolution reconstruction promising further improvements of CMRA. This has enabled high spatial resolution (1 mm isotropic), 3D whole heart CMRA in a clinically feasible and reliable acquisition time of under 10 min. Furthermore, latest super-resolution image reconstruction approaches which are currently under evaluation promise acquisitions as short as 1 min. In this review, we will explore the recent technological advances that are designed to bring CMRA closer to clinical reality.

The Placebo-Controlled Effect of Percutaneous Coronary Intervention on Exercise Induced Changes in Anti-Malondialdehyde-LDL Antibody Levels in Stable Coronary Artery Disease: A Substudy of the ORBITA Trial.

Aim: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) forms a significant component of oxidised LDL. The effects of exercise on levels of MDA-LDL and anti-MDA-LDL antibodies are not well-understood. Furthermore, it is not known whether these can be modified in patients with coronary artery disease by percutaneous coronary intervention (PCI). Methods: The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial was the first blinded, multi-centre randomised trial of PCI vs. placebo procedure for angina relief. Serum samples were available at four time-points: pre-randomisation pre- (P1) and post- (P2) exercise and post-randomisation (6-weeks following the PCI or placebo procedure), pre- (P3) and post- (P4) exercise. ELISAs were performed using laboratory-developed assays for MDA-LDL (adjusted for Apolipoprotein B) and anti-MDA-LDL antibodies. Results: One hundred ninety-six of the 200 patients (age 66.1 [SD 8.99] years, 28% female) with severe single vessel coronary artery disease suitable for PCI enrolled in the ORBITA trial had blood available for analysis. With exercise at pre-randomisation (P2-P1) there was no significant change in adjusted MDA-LDL (-0.001, 95% CI -0.004 to 0.001; p = 0.287); however, IgG and IgM anti-MDA-LDL significantly declined (-0.022, 95% CI -0.029 to -0.014, p < 0.0001; -0.016, 95% CI -0.024 to -0.008, p = 0.0002, respectively). PCI did not have a significant impact on either the pre-exercise values (P3 controlling for P1) of MDA-LDL (p = 0.102), IgG (p = 0.444) or IgM anti-MDA-LDL (p = 0.909). Nor did PCI impact the exercise induced changes in these markers (P4 controlling for P1, P2, and P3) for MDA-LDL (p = 0.605), IgG (p = 0.725) or IgM anti-MDA-LDL (p = 0.171). Pre-randomisation ischaemia on stress echo did not impact these interactions. Conclusions: Exercise results in an acute reduction in anti-oxLDL antibodies in patients with severe single vessel coronary disease, possibly indicating an induction in homoeostatic clearance via the innate immune system. However, PCI did not ameliorate this effect.

A Novel Immunoassay for Malondialdehyde-Conjugated Low-Density Lipoprotein Measures Dynamic Changes in the Blood of Patients Undergoing Coronary Artery Bypass Graft Surgery.

Oxidized low-density lipoproteins play an important role in tissue pathology. In this study, we report a sensitive novel enzyme-linked immunosorbent assay for the detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a key component of oxidized LDL. The assay is capable of measuring a variable presence of MDA-LDL within human plasma and serum. We demonstrate the robust nature of the assay on samples stored for over 20 months, as well as high inter-operator reproducibility (r = 0.74, p < 0.0001). The assay was capable of detecting dynamic changes in patient blood samples after coronary artery bypass graft surgery, indicating synthesis or release of MDA-LDL with the oxidative stress of surgery, followed by homeostatic clearance. This robust, sensitive and specific assay for circulating MDA-LDL will serve as a valuable translational tool for the improved detection of oxidative forms of LDL in response to a range of physiological or pathological stimuli, with potential clinical applicability.

Placebo-Controlled Efficacy of Percutaneous Coronary Intervention for Focal and Diffuse Patterns of Stable Coronary Artery Disease.

[Figure: see text].