Ramzi Khamis

Imperial College London | Imperial · National Heart and Lung Institute

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 (CAD). In this regard, imaging-based quantification can be improved by choosing the most appropriate imaging modality for diagnosis, treatment and pro...

Background The Standard care vs. Celecoxib Outcome Trial (SCOT) found similar risk of cardiovascular events with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and the COX-2 selective drug celecoxib. Whilst pre-clinical work has suggested roles for vascular and renal dysfunction in NSAID cardiovascular toxicity, our understanding of the...

The preclinical study of atherosclerosis has traditionally centred around the use of small animal models, translating to large animal models, prior to first-in-man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused human limb model. The novel model consists of taking a freshly amputated limb and incorporating it into...

Background Unplanned re-admissions after acute coronary syndrome (ACS) remain high. Telemedicine programmes can provide remote diagnostic information to aid clinical decision that could optimize and reduce the need to access hospital care. Methods TELE-ACS is a randomized controlled trial comparing a telemedicine-based approach versus standard car...

Background Percutaneous coronary intervention (PCI) is frequently performed to improve symptoms of stable angina. Whether PCI without background antianginal medication relieves angina beyond placebo remains unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all...

Introduction Coronary CT-derived valve calcification is becoming increasingly important in the multi-modality assessment of valvular disease, especially in aortic and mitral stenosis, where trans-catheter structural heart interventions may be indicated. Separately, natural antibodies targeted against malondialdehyde-modified LDL (MDA-LDL), an impor...

Introduction The prediction of future cardiovascular events in those at greatest risk is essential to optimise preventative therapies appropriately and effectively. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely assessed biomarker for predicti...

Background Coronary artery high-risk plaque identified on cardiovascular magnetic resonance (CMR) is associated with future coronary events, independent of coronary artery luminal stenosis. We have recently developed a 3-dimensional whole-heart free-breathing non-contrast CMR sequence that allows for simultaneous high-resolution visualisation of th...

Background Coronary artery disease (CAD) is often asymptomatic in patients with chronic obstructive pulmonary disease (COPD) and traditional screening methods may not be as useful in detecting it. A coronary artery calcium score (CACS) can be calculated on CT thorax and predicts future cardiovascular events in COPD.¹ The extent to which this predic...

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 procedura...

Rationale for the Study The prediction of future cardiovascular events in those with vascular risk factors is important to appropriately optimise preventative therapies in those at greatest risk. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely...

Background Coronary CT-derived valve calcification is becoming increasingly important in the multi-modality assessment of valvular disease, especially in aortic and mitral stenosis, where trans-catheter structural heart interventions may be indicated. natural antibodies targeted against oxidised low-density lipoprotein (oxLDL), are related to lower...

Background: Transcatheter Aortic Valve Implantation (TAVI) is associated with 2-3% clinical stroke rate and much higher incidence of silent cerebral infarction. This study investigated the neuroprotective benefits of minimising air emboli in TAVI. It aimed to demonstrate a reduction in vascular brain injury by flushing TAVI valves with CO 2 and sal...

Introduction The preclinical study of atherosclerosis has been traditionally centred around the use of small animal models, translating to large animal models prior to first-in-man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused “live” limb model, to enable the molecular targeting of atherosclerosis. Purpose To d...

Introduction Oxidative modification of low-density lipoprotein (LDL), for example by malondialdehyde (MDA) adduction with subsequent uptake by macrophages to form foam cells and later the plaque necrotic core, is a key initiating event in atherogenesis. Accordingly, a larger lipid necrotic core is a key plaque vulnerability factor, predisposing pla...

Introduction Oxidative modification of low-density lipoprotein (LDL), for example by malondialdehyde (MDA) adduction, with subsequent uptake by foam cells and lipid necrotic core formation, is central in the evolving atherosclerotic plaque. Moreover, greater necrotic core size is a key feature of vulnerable atherosclerotic lesions, that is plaques...

Introduction Translational modelling for the study of atherosclerosis has been traditionally centred around the use of small animal models, translating to large animal models prior to first in man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused ‘live’ limb model, to enable researchers to study molecular targeting...

Objectives The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants. Background Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis. Methods T...

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...

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. Howev...

Background Trends in mortality from aortic stenosis across Europe are not well understood, especially given the significant growth in transcatheter aortic valve replacement (TAVR) in the last 10 years. Purpose To describe trends in mortality from aortic stenosis in European countries from 2000 to 2017. Methods Age-standardised death rates were ex...

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 (PC...

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 Cl...

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 iodinat...

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 pla...

Atherosclerosis is a cardiovascular disease initiated by the deposition of Low Density Proteins (LDL) within the intima and their subsequent oxidation to (oxLDL). Currently, there are no available Positron Emission Tomography (PET) tracers for clinical imaging of atherosclerosis. LO1 and LO9 are novel antibodies that target modified low-density lip...

Background CT coronary angiography (CTCA)-derived low attenuation plaque has recently been identified as the strongest predictor of future myocardial infarction. Antibodies against oxidized low-density lipoprotein (oxLDL)/ malondialdehyde-modified LDL (MDA-LDL) are related to freedom from cardiovascular events. Objectives To investigate possible r...

Objective Near-infrared autofluorescence (NIRAF) of atherosclerosis associates with intraplaque hemorrhage and is detectable in living patients with coronary artery disease. However, further mechanisms underlying NIRAF generation have not been fully characterized. Here, we investigated the role of lipids and oxidative stress in NIRAF generation in...

Objectives The clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK. Method...

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)...

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...

Coronavirus disease 2019 (COVID-19) is forcing cardiology departments to rapidly adapt existing clinical guidelines to a new reality and this is especially the case for acute coronary syndrome pathways. In this focused review, the authors discuss how COVID-19 is affecting acute cardiology care and propose pragmatic guideline modifications for the d...

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)...

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-co...

Evaluation of coronary artery disease (CAD) using coronary computed tomography angiography (CCTA) has seen a paradigm shift in the last decade. Evidence increasingly supports the clinical utility of CCTA across various stages of CAD, from the detection of early subclinical disease to the assessment of acute chest pain. Additionally, CCTA can be use...

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 haemodynam...

Antibodies to oxidized LDL (oxLDL) may be associated with improved outcomes in cardiovascular disease. However, analysis is restricted by heterogenous study design and endpoints. Our objective was to conduct a comprehensive systematic review assessing anti-oxLDL antibodies in relation to coronary artery disease (CAD). Through a systematic literatur...

Background The incremental long-term prognostic value of high-sensitivity C-reactive protein (hsCRP) above troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndromes (ACS) is unknown. Purpose We hypothesised that a mildly elevated hsCRP is associated with mortality risk in patients with suspecte...

Background The incremental long-term prognostic value of high-sensitivity C-reactive protein (hsCRP) above troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndromes (ACS) is unknown. We hypothesised that a mildly elevated hsCRP is associated with mortality risk in patients with suspected ACS, in...

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: NORD...

We provide an up-to-date overview of current topics surrounding oxidized low-density lipoprotein (oxLDL) and its related antibodies in the quest to better identify the individuals at risk of cardiovascular disease and atherosclerotic plaques with unfavorable characteristics. We discuss the potential of oxLDL and anti-oxLDL antibodies as serum bioma...

Background: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. Methods: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure fo...

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...

Introduction Lipoprotein apheresis (LA), an extra-corporeal lipid lowering technique is a promising new therapeutic technique for the treatment of coronary artery disease. Patients with high levels of Lipoprotein(a) but normal cholesterol levels are challenging to treat, and therefore this technique offers a novel therapeutic avenue. Levels of oxLD...

Background Malondialdehyde (MDA)-LDL is one of the main oxidation products involved in atherosclerosis pathogenesis. IgM antibodies against MDA-LDL have been generally regarded as protecting from atherosclerosis. In contrast, the role of IgG antibodies is less clear. How antibody levels relate to coronary atherosclerosis plaque characteristics stil...

Background Atherosclerosis is a disease of global importance. It is a systemic chronic inflammatory disease with a complex aetiology. LDL is primarily oxidised in the subendothelial space, as plasma antioxidants protect circulating LDL from oxidation. However, small amounts of oxidised LDL (oxLDL) have been detected in plasma. Modified LDL is thoug...

Aims Stent deployment causes endothelial cell (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow pertubation on EC injury and repair are incompletely understood. By studying the effects...

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 Irelan...

Supplementary tables.

### Learning objectives The importance of coronary heart disease (CHD) as a disease of both genders tends to be underappreciated, although in 2014 CHD claimed almost three times more lives than breast cancer. Just below one in five male deaths and one in ten female deaths were attributed to CHD. The British Heart Foundation's report in that same y...

Background: We previously demonstrated a significant correlation between higher levels of total IgG anti-malondialdehyde-conjugated low-density lipoprotein (MDA-LDL) and protection from cardiovascular events in a small population. We therefore aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies agains...

Background: Peri-procedural stroke is a serious complication of cardiac catheterisation, with varying incidence and uncertain management. This study determines the incidence and management of cardiac catheterisation-related stroke in a large single centre retrospective cohort.

We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo hu...

Primary percutaneous coronary intervention (PPCI) is the treatment of choice for ST-segment-elevation myocardial infarction. Resources are limited during out of working hours (OWH). Whether PPCI outside working hours is associated with worse outcomes and whether outcomes have improved over time are unknown. We analyzed 11 466 patients undergoing PP...

Background Cardiovascular complications imply a poor prognosis in Takayasu arteritis (TA). TA is a pro-atherogenic condition, but the relationship between vasculitis and atherosclerosis remains elusive. Coronary artery disease (CAD) in TA may be i) vasculitic, ii) atherosclerotic or iii) due to pauci-inflammatory remodelling after revascularisation...

Introduction/Objective: Although IgG autoantibodies reacting with modified LDL have been associated with cardiovascular events, there is controversy as to whether such antibodies can be pathogenic. We set out to generate monoclonal autoantibodies reacting with LDL for further mechanistic studies. Methods/Results: We fused LDL receptor deficient (Ld...