High serum immunoglobulin g and m levels predict freedom from adverse cardiovascular events in hypertension: a nested case-control substudy of the Anglo-Scandinavian cardiac outcomes trial

Aims: We aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination. Methods and Results: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5 years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80 [95% confidence interval, CI 0.72,0.89], p < 0.0001; IgM 0.83[0.75,0.93], p = 0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p < 0.0001, IgM OR 0.81 (0.71,0.93); p = 0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification (17.6% and 7.5% respectively) as well as in the integrated discrimination index. Conclusion: High total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension

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

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

IgM anti-malondialdehyde low density lipoprotein antibody levels indicate coronary heart disease and necrotic core characteristics in the Nordic Diltiazem (NORDIL) study and the Integrated Imaging and Biomarker Study 3 (IBIS-3)

Background: Certain immunoglobulins (Ig) are proposed to have protective functions in atherosclerosis. Objectives: We tested whether serum levels of IgG and IgM autoantibodies against malondialdehyde low density lipoprotein (MDA-LDL) are associated with clinical coronary heart disease (CHD) and unfavorable plaque characteristics. Methods: NORDIL was a prospective study investigating adverse cardiovascular outcomes in hypertensive patients. IBIS-3 analyzed lesions in a non-culprit coronary artery with <50% stenosis using radiofrequency intravascular ultrasound (RF-IVUS) and near-infrared spectroscopy (NIRS). Imaging was repeated after a median of 386 days on rosuvastatin. Associations of antibodies with incident CHD and imaging parameters were assessed in the two sub-studies respectively. Findings: From 10,881 NORDIL patients, 87 had serum sampled at baseline and developed CHD over 4.5 years, matched to 227 controls. Higher titers of IgM anti-MDA-LDL had a protective effect on adverse outcomes, with odds ratio 0.29 (0.11, 0.76; p = 0.012; p = 0.016 for trend). Therefore, the effect was explored at the lesional level in IBIS-3. 143 patients had blood samples and RF-IVUS measurements available, and NIRS was performed in 90 of these. At baseline, IgM anti-MDA-LDL levels had a strong independent inverse relationship with lesional necrotic core volume (p = 0.027) and percentage of plaque occupied by necrotic core (p = 0.011), as well as lipid core burden index (p = 0.024) in the worst 4 mm segment. Interpretation: Our study supports the hypothesis that lower circulating levels of IgM anti-MDA-LDL are associated with clinical CHD development, and for the first time relates these findings to atherosclerotic plaque characteristics that are linked to vulnerability

Placebo-controlled efficacy of percutaneous coronary intervention for focal and diffuse patterns of stable coronary artery disease

Background: Physiological assessment with pressure wire pullback can characterize coronary artery disease (CAD) with a focal or diffuse pattern. However, the clinical relevance of this distinction is unknown. We use data from the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) to test if the pattern of CAD predicts the placebo-controlled efficacy of percutaneous coronary intervention (PCI) on stress echocardiography ischemia and symptom end points. Methods: One hundred sixty-four patients in ORBITA underwent blinded instantaneous wave-free ratio (iFR) pullback assessment before randomization. Focal disease was defined as a ≥0.03 iFR unit drop within 15 mm, rather than over a longer distance. Analyses were performed using regression modeling. Results: In the PCI arm (n=85), 48 were focal and 37 were diffuse. In the placebo arm (n=79), 35 were focal and 44 were diffuse. Focal stenoses were associated with significantly lower fractional flow reserve (FFR) and iFR values than diffusely diseased vessels (mean FFR and iFR, focal 0.60±0.15 and 0.65±0.24, diffuse 0.78±0.10 and 0.88±0.08, respectively, P<0.0001). With adjustment for this difference, PCI for focal stenoses resulted in significantly greater reduction in stress echo ischemia than PCI for diffuse disease (P<0.05). The effect of PCI on between-arm pre-randomization adjusted exercise time was 9.32 seconds (95% CI, −17.1 to 35.7 seconds; P=0.487). When stratified for pattern of disease, there was no detectable difference between focal and diffuse CAD (Pinteraction=0.700). PCI improved Seattle Angina Questionnaire angina frequency score and freedom from angina more than placebo (P=0.034; P=0.0035). However, there was no evidence of interaction between the physiological pattern of CAD and these effects (Pinteraction=0.436; Pinteraction=0.908). Conclusions: PCI achieved significantly greater reduction of stress echocardiography ischemia in focal compared with diffuse CAD. However, for symptom end points, no such difference was observed

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

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. 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. 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. 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.). [Abstract copyright: Copyright © 2023 Massachusetts Medical Society.

Anti-oxidised low density lipoprotein antibodies for the serology and imaging of atherosclerosis

Atherosclerosis and its related major adverse cardiovascular events represent a major worldwide morbidity and mortality burden. The paradigm of identifying ‘vulnerable plaques’ leading to ‘vulnerable patients’ remains challenging despite recent advances in cardiovascular medicine. The project aimed to develop an antibody-based strategy for the translational development of imaging oxidised low density lipoprotein (LDL), a major constituent of vulnerable atherosclerotic plaque. It also aimed to simultaneously develop anti-oxidised LDL antibody-based serological assays for the stratification of individual cardiovascular risk independently of classical risk factors. In this thesis, I first discuss the development of a number of assays for the measurement of anti-oxidised LDL antibodies in serum and plasma. I then describe our findings, using a subpopulation of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) to discover that IgG anti-Malondialdehyde (MDA)-LDL antibody levels are stable, independent biomarkers of freedom from adverse cardiovascular events over a 5.5 year follow up. This is followed by describing LO1 and LO9, both murine monoclonal antibodies, isolated in our laboratory, against MDA-LDL and adherent native LDL respectively. We characterise and sequence both, and take LO1 further into development as an imaging agent. I then progress to discussing the utility of directly labelled LO1 (LO1-750) as a near infra-red fluorescence (NIRF) imaging agent. We use two animal models (Ldlr-/- and rabbit atherosclerosis models), utilising three different modalities (IVIS Spectrum/ computed tomography (CT), Fluorescence molecular tomography (FMT)/CT and intravascular 2D NIRF/intravascular ultrasound (IVUS)). I further discuss the generation of a partially humanised tagged molecular construct (LO1-Fab-Cys), as a first step towards the molecular expression and humanisation of LO1 in an optimised form for targeting of oxidised LDL in humans. Moreover I detail the characterisation of LO9 by delineating in a series of experiments its allosteric epitope on adherent LDL, and describe a potential pathological role for it. We label LO9 with a NIRF agent, and show LO9 localisation in vitro and in vivo in mouse studies.Open Acces