Long-term results of percutaneous coronary intervention in no-touch vein grafts are significantly better than in conventional vein grafts.

INTRODUCTION: Conventional vein grafts have a high risk of thrombosis and early atherosclerosis. Percutaneous coronary intervention (PCI) in conventional vein grafts is associated with a higher incidence of late adverse cardiac events. The aim of this study was to evaluate the long-term results after PCI in saphenous vein grafts (SVG) harvested with the no-touch technique compared to the conventional technique. METHODS: This was a single-center, retrospective, cohort study, based on data from the Swedeheart register. The inclusion criterion was individuals who underwent CABG using different vein graft techniques between January 1992 and July 2020, and who required a PCI in SVGs between January 2006 and July 2020. The primary end point was long-term in-stent restenosis. The secondary endpoints were long-term major adverse cardiac events (MACE) and 1-year re-hospitalization rates. The associations between the graft types and the endpoints were evaluated using the Fine and Gray competing-risk regression analysis. RESULTS: The study included 346 individuals (67 no-touch, 279 conventional). The mean clinical follow-up time was 6.4 years with a standard deviation of 3.7 years. The long-term in-stent restenosis rate for the no-touch grafts was 3.2% compared to 18.7% for the conventional grafts (p < .01), with a subdistribution hazard ratio (SHR) of 0.16 (p = .010). The long-term MACE rate was 27.0% in the no-touch group and 48.3% in the conventional group (p < .01) with a SHR of 0.53 (p = .017). The short-term results were similar in both groups. CONCLUSIONS: Percutaneous coronary intervention in a no-touch vein graft was associated with statistically significantly fewer in-stent restenoses and MACE at long-term follow-up compared to a conventional SVG.

Superior long-term patency of no-touch vein graft compared to conventional vein grafts in over 1500 consecutive patients.

OBJECTIVES: To evaluate the long-term angiographic patency of saphenous vein grafts (SVG) harvested using the no-touch technique compared to the conventional technique. METHODS: This was a single-center, retrospective, cohort study. The inclusion criteria were individuals who underwent a CABG (coronary artery bypass grafting) between January 1995 and July 2020, and who successively needed a clinically-driven angiography. The primary endpoint was long-term patency. The secondary endpoints were differences in patency based on sub-group analysis (single vs. sequential graft, divided by target vessel). RESULTS: The study included 1520 individuals (618 no-touch, 825 conventional and 77 arterial grafts). The mean clinical follow-up time was 8.4 years ± 5.5 years. The patency per patient was 70.7% in the no-touch grafts vs. 46.7% in the conventional grafts (p < 0.001, OR = 2.8). The graft patency was 75.9% in the no-touch grafts vs. 62.8% in the conventional grafts (p < 0.001, OR = 1.8). CONCLUSIONS: The no-touch vein grafts were associated with statistically significantly higher patency at long-term compared to the conventional grafts. CLINICAL TRIAL REGISTRATION: NCT04656366, 7 December 2020.

Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo.

We have previously shown that angiomotin (Amot) mediates angiostatin inhibition of endothelial migration and tube formation in vitro. A crucial role of angiomotin in regulating endothelial cell motility is indicated by the findings that knockdown of Amot in zebrafish reduces the number of filopodia of endothelial tip cells and severely impairs the migration of intersegmental vessels. In addition, targeting angiomotin using DNA vaccination inhibits angiogenesis and tumor growth in vivo. In this report, we have generated antibodies that, similar to angiostatin, bind to angiomotin on the endothelial cell surface. These antibodies inhibited FGF-2 and vascular endothelial growth factor (VEGF) -induced endothelial migration in the Boyden chamber assay. Furthermore, the anti-Amot B06 antibody significantly reduced the number of endothelial filopodia and inhibited vessel migration during retinal angiogenesis in vivo. We also show that systemic or local treatment with this antibody inhibits pathological blood vessel formation associated with tumor growth or laser-induced choroid neovascularization of the eye. These findings provide a rationale for using angiomotin antibodies for specifically targeting endothelial migration in angiogenesis-dependent diseases.

Inhibition of injury-induced arterial remodelling and carotid atherosclerosis by recombinant human antibodies against aldehyde-modified apoB-100.

OBJECTIVE: The immune system plays an important regulatory role in the development of atherosclerotic plaques and neointima formation following various types of angioplasty. In the present study we investigated the effect of antibodies against aldehyde-modified apolipoprotein B-100 (apoB-100), a component of oxidized LDL, on atherosclerosis and response to arterial injury in mice. METHODS: The ability of a high affinity human recombinant antibody (2D03), specific for malondialdehyde-modified apoB-100, to influence formation of atherosclerosis as well as remodelling and neointima formation after a collar-induced injury of the carotid artery was studied in LDL receptor(-/-) mice over-expressing human apoB-100. RESULTS: The antibody recognized epitopes present in mouse plasma and reduced the plasma level of oxidized LDL by 34%. Antibody treatment inhibited injury-induced restrictive vascular remodelling but did not influence the size of the neointima. Atherosclerosis in the uninjured contra lateral carotid artery was determined by computerized image analysis and the mean plaque area in animals given control IgG1 was 7608+/-10,336 micro m(2). In contrast, essentially no plaques were present in animals treated with the 2D03 antibody (397+/-235 micro m(2), P<0.01 versus control IgG1). CONCLUSIONS: Treatment with antibodies against aldehyde-modified apoB-100 dramatically reduces atherosclerosis and inhibits restrictive vascular remodelling in mice expressing human apoB-100.

Antibodies against oxidized low-density lipoprotein for the treatment of vulnerable plaques.

Inflammation caused by the accumulation of oxidized low-density lipoprotein (oxLDL) in the arterial wall is a key factor in the development of atherosclerosis. Accumulating evidence suggests that adaptive immune responses to oxLDL are of major importance in regulating the inflammatory response, and that humoral immunity largely has a protective effect in this process. This concept is supported by animal studies demonstrating that treatment with antibodies against oxLDL inhibits atherosclerosis. Human antibodies with high affinity and specificity for epitopes on oxLDL have been developed and are now, after appropriate safety testing and non-clinical toxicology, ready to be tested in humans. Patients that may benefit front antibody treatment are most likely to be high-risk individuals in which conventional treatments, including lipid-lowering statins, do not provide sufficient protection.

Long-Term Outcome of Incomplete Revascularization After Percutaneous Coronary Intervention in SCAAR (Swedish Coronary Angiography and Angioplasty Registry).

OBJECTIVES: The aim of this study was to describe current practice regarding completeness of revascularization in patients with multivessel disease undergoing percutaneous coronary intervention (PCI) and to investigate the association of incomplete revascularization (IR) with death, repeat revascularization, and myocardial infarction (MI) in a large nationwide registry. BACKGROUND: The benefits of multivessel PCI are controversial. METHODS: Between 2006 and 2010 we identified 23,342 patients with multivessel disease in the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) and merged data with official Swedish health data registries. IR was defined as any nontreated significant (60%) stenosis in a coronary artery supplying >10% of the myocardium. RESULTS: Patients with IR (n = 15,165) were older, had more extensive coronary disease, and more often had ST-segment elevation MI at presentation than those with complete revascularization (CR) (n = 8,177). All-cause 1-year mortality, MI, and repeat revascularization were higher in IR than CR: 7.1% versus 3.8%, 10.4% versus 6.0%, and 20.5% versus 8.5%, respectively. Propensity score methodology was used in the adjusted analyses. Adjusted hazard ratio (HR) for the composite of death, MI, or repeat revascularization at 1 year was higher in IR than CR: 2.12 (95% confidence interval [CI]: 1.98 to 2.28; p < 0.0001). Adjusted HR for death and the combination of death/MI were 1.29 (95% CI: 1.12 to 1.49; p = 0.0005) and 1.42 (95% CI: 1.30 to 1.56; p < 0.0001), respectively. CONCLUSIONS: Incomplete revascularization at the time of hospital discharge in patients with multivessel disease undergoing PCI is associated with a high risk of recurrent 1-year adverse cardiac events.

Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis.

BACKGROUND: Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis. Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. METHODS AND RESULTS: Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE-/- mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. CONCLUSIONS: These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.

Targeting angiogenesis with antibodies for the treatment of cancer.

The treatment of cancer by targeting angiogenesis and depriving growing tumors of their blood supply has been recognized as an interesting therapeutic possibility for several decades. A multitude of development programs investigating both low-molecular-weight substances and biologicals, in particular monoclonal antibodies (mAbs), have been instigated. The generation of human or human-like mAbs has led to the recent development of therapeutic antibodies that are potentially highly beneficial in the treatment of cancer. Avastin, which binds to the pro-angiogenic factor vascular endothelial growth factor, is one of the most promising of these antibodies, and has proved beneficial in the treatment of colorectal, lung and breast cancer, with a potential to be used also in other types of cancer. However, as angiogenesis is a complex process controlled by both pro-angiogenic as well as anti-angiogenic factors, several research and development programs targeting different pro-angiogenic factors, receptors and antigens that are selectively expressed on cells in newly formed blood vessels are under way. At BioInvent International AB, research is focused on angiomotin, a newly discovered receptor for the anti-angiogenic factor angiostatin, and on the pro-angiogenic factor placenta growth factor.

Follow-up of ischaemic heart disease in patients with coeliac disease.

Patients with coeliac disease and myocardial infarction have a more favourable atherosclerotic risk factor profile than controls with myocardial infarction (MI). Therefore, MI prognosis and treatment may differ according to coeliac status. This paper reports on the study of Swedish MI patients with and without coeliac disease (equal to villous atrophy; Marsh histopathology stage 3) based on duodenal or jejunal biopsy data. We used the Swedish Quality Register (SWEDEHEART) to identify individuals with a record of MI from 2005 to 2008 and to obtain data on medication, coronary interventions, and clinical and laboratory parameters at 6-10 weeks and one year after first MI. One-year mortality and coronary interventions were assessed for 430 coeliac patients and 1988 controls. For other outcome variables, we compared 42 coeliac patients with MI and 201 general population controls with MI. Odds ratios (ORs) were calculated by logistic regression. The results showed that compared with controls with MI, coeliac individuals with MI had significantly higher one-year all-cause mortality (OR = 1.43; 95% confidence interval (CI) = 1.04-1.95) but less often underwent a percutaneous coronary intervention (OR = 0.77; 95% CI = 0.61-0.96). Coeliac patients were more often prescribed warfarin but less often aspirin and statins. The readmission rate due to cardiac events in coeliac patients was 15.2% vs. 12.6% in controls (p-value = 0.69). Other clinical and laboratory parameters were similar. We conclude that the follow up of MI does not seem to differ between coeliac patients and controls, and is unlikely to explain the excess mortality from cardiovascular disease noted in Swedish patients with CD.

Study of Patient Information after percutaneous Coronary Intervention (SPICI): should prevention programmes become more effective?

AIMS: This cross-sectional observational study was designed to evaluate the uptake and outcome of patient education after percutaneous coronary intervention (PCI). METHODS AND RESULTS: A questionnaire containing 41 items was handed out to consecutive patients from randomly selected Swedish hospitals after PCI. Questions concerned the patient's attribution of the cause of the cardiac event, perception of the information provided by physicians and nurses, and a self-assessment of changes in lifestyle post PCI regarding tobacco, physical activity, food habits and stress. Replies were obtained from 1,073 patients (reply rate 67%). Non-modifiable risk factors (age, heredity) were attributed a higher rate as the cause of disease compared to modifiable factors (smoking, physical activity, food habits). Most patients (67%) perceived they were cured, and 38% perceived from the given information that there was no need to change their habits. A mere 27% reported that they still had cardiovascular disease and needed behavioural change. After PCI, 16% continued to use tobacco; half of these were offered smoking cessation support. In spite of an 80% referral rate to cardiac rehabilitation, one out of two patients did not enrol. Fewer than half were regularly physically active. Nutritional counselling was provided to 71%, but only 40% changed food habits. Stress management programmes were rarely provided. CONCLUSIONS: Current preventive practice scarcely meets the challenge posed by the progress in modern invasive cardiology. The Study of Patient Information after percutaneous Coronary Intervention (SPICI) motivates an in-depth revision and adaptation of cardiac rehabilitation programmes in order to improve patient understanding of the disease, and to support greater compliance with a cardioprotective lifestyle.

Automated screening procedure for high-throughput generation of antibody fragments.

In the emerging field of proteomics, there is an urgent need for catcher molecules such as antibodies for detecting the proteome or parts of the proteome in a microarray format. A suitable source for providing a large diversity of binders is obtained by combinatorial libraries, such as phage display libraries of single chain antibody fragments (scFv) or Fab fragments. To find novel binders from the n-CoDeR libraries with a high throughput, we have automated the screening process with robotics. The automated system is configured to screen tens of thousands of clones per day to target antigens in various formats, including peptides and soluble proteins, as well as cell-bound targets; thus, it is well designed to meet demands from the proteomics area.

Oxidized LDL antibodies in treatment and risk assessment of atherosclerosis and associated cardiovascular disease.

Immune responses against oxidized forms of LDL play a critical role in activation and regulation of the inflammatory process that characterizes all stages of atherosclerosis. In humans oxidized LDL is targeted by both IgM and IgG autoantibodies. Immunization of hypercholesterolemic animals with oxidized LDL has been shown to inhibit atherosclerosis demonstrating that at least some of these immune responses have a protective effect. The identification of the structures in oxidized LDL that are responsible for activation of immunity has made it possible to develop novel therapeutic approaches for treatment of atherosclerosis based on active (vaccines) and passive (antibodies) immunization. Studies performed in atherosclerosis-prone mice demonstrate that both peptide-based vaccines and recombinant IgG targeting epitopes in oxidized LDL significantly reduce atherosclerosis. There is also evidence antibodies against oxidized LDL could also be used for imaging atherosclerosis.

Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.

OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence. RESULTS: At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes. CONCLUSIONS: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.

Rapid induction of apoptosis in B-cell lymphoma by functionally isolated human antibodies.

Novel panning and screening methodology was devised to isolate high affinity human recombinant scFv antibody fragments with functionally associated properties in B lymphoma cells. The approach was used to generate a panel of apoptosis-inducing antibodies specific for antigens differentially expressed in B lymphoma vs. T leukaemia cells. The selections resulted in an antibody pool with near perfect selectivity (>99%) for the B lymphoma target cells. Randomly picked clones (72) revealed 7 unique antibody genotypes. Six of these rapidly induced apoptosis in target cells. Following the conversion to full IgGs, the antibodies were shown to be specific for HLA-DR/DP, the B-cell receptor mu chain and for CD54/ICAM-1. The latter receptor was not previously associated with apoptotic properties in B-cell lymphomas. Anti-ICAM-1 IgG induced apoptosis in a broad range of B lymphoma cell lines and were shown by immunohistochemistry to bind strongly to B lymphoma tissue obtained from 5 different B lymphoma patients. The recombinant IgG antibodies had affinities in the subnanomolar (0.3 nM) to nanomolar (3 nM) range. The described technology is generally applicable for the rapid isolation of high affinity human antibodies with specificity for differentially expressed cell surface receptors with intrinsic negative or positive signalling properties from naïve phage libraries.