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P-selectin antagonism reduces thrombus formation in humans.
BACKGROUND: Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. AIM: To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans. METHODS AND RESULTS: In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2 m) and high-dose (20 m) PSI-697 and the glycoprotein IIb-IIIa receptor antagonist tirofiban (50 ng mL(-1)) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb-IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2 m) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20 m), PSI-697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low-shear and high-shear chambers, respectively. CONCLUSIONS: P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.
Vascular B1 kinin receptors in patients with congestive heart failure.
Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.
Role of brain natriuretic peptide (BNP) in risk stratification of adult syncope.
AIMS: To assess the value of a near-patient brain natriuretic peptide (BNP) test to predict medium term (3 month) serious outcome for adult syncope patients presenting to a UK emergency department (ED). METHODS: This was a prospective cohort pilot study. Consecutive patients aged > or = 16 years presenting with syncope over a 3 month period were eligible for prospective enrolment. All patients who were medium or high risk according to our ED's existing syncope guidelines underwent near-patient BNP testing using the Triage point of care machine. RESULTS: 99 patients were recruited. 72 of 82 high and medium risk patients underwent BNP measurement. 11 patients had a serious outcome, 9 of whom had BNP measured. In 25 (35%) patients, BNP was > or = 100 pg/ml, and in 3 of these it was > 1000 pg/ml. 6 of the 25 patients (24%) with a BNP > 100 pg/ml, and all 3 patients with a BNP > 1000 pg/ml, were in the serious outcome group. BNP was raised over 100 pg/ml in 6 of the 9 serious outcome patients having a BNP measured (66%), and over 1000 pg/ml in 3 (33%). CONCLUSIONS: This early work suggests that BNP may have a role in the risk assessment of syncope patients in the ED. Further work is required to see how BNP interacts with other clinical variables. Near-patient BNP testing may be shown to be an independent predictor of adverse outcome either alone or incorporated into existing syncope clinical decision rules and scores in order to improve their sensitivity and specificity. Further studies are required to evaluate this.
Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin.
OBJECTIVES: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet-monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet-monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI). DESIGN: Platelet-monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 microg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet-monocyte aggregation was assessed with specific blocking antibodies. RESULTS: Addition of unfractionated heparin in vitro was associated with a higher level of platelet-monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet-monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet-monocyte aggregates (absolute Delta 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Delta -1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet-monocyte aggregates associated with heparin. CONCLUSIONS: In vitro and in vivo unfractionated heparin is associated with increased platelet-monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.
Calcific aortic stenosis: same old story?
Calcific aortic stenosis is the commonest adult valvular heart condition seen in the western world. Its prevalence is continuing to rise, with predominance in older patients who are frequently undergoing successful aortic valve replacement. This review discusses the natural history of calcific aortic stenosis, highlights recent insights into its pathogenesis, and outlines current medical and surgical management. The potential role of novel therapeutic interventional strategies is discussed.
Endothelin-1[1-31] is not elevated in men with chronic heart failure.
Endothelin-1[1-31] is a recently discovered member of the endothelin family with vasoactive properties in several animal models and in man in vivo. It is generated from big endothelin-1 by human mast cell chymase and may be a novel intermediary peptide in the production of endothelin-1[1-21]. Given that both big endothelin-1[1-38] and chymase activity are increased in chronic heart failure, the aim of this study was to determine whether plasma endothelin-1[1-31] concentrations are elevated in patients with chronic heart failure. Plasma endothelin-1[1-31] concentrations were measured by enzyme-linked immunosorbent assay in nine patients with chronic heart failure, and nine age- and sex-matched control subjects. Consistent with previous studies, plasma concentrations of big endothelin-1[1-38] were elevated in patients compared with controls (17.1 +/- 4.4 pg/mL vs 8.9 +/- 3.4 pg/mL, P = 0.002), although there were no differences in plasma endothelin-1[1-21] (3.3 +/- 0.4 pg/mL vs 3.4 +/- 0.7 pg/mL, P = 0.7) or endothelin-1[1-31] (both 1.1 +/- 0.1 pg/mL, P = 0.2) concentrations. We have demonstrated that patients with chronic heart failure have normal plasma endothelin-1[1-31] concentrations. This suggests that, in contrast to big endothelin-1[1-38], plasma endothelin-1[1-31] is unlikely to be a useful prognostic marker in patients with chronic heart failure.
Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man.
OBJECTIVE: Cigarette smoking impairs peripheral endothelium-dependent vasodilatation and acute tissue plasminogen activator (t-PA) release in man. The aim of the study was to determine if this endothelial dysfunction is, in part, mediated by the effects of nicotine. METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms of eight healthy male non-smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min). Endothelium-independent vasodilatation was assessed using intra-arterial infusion of sodium nitroprusside (2 to 8 microg/min). Subjects attended after 7 days treatment with transdermal nicotine or placebo in a double blind randomised crossover design. RESULTS: Plasma cotinine concentrations rose from 0.4+/-0.1 (placebo) to 125+/-25 ng/ml during nicotine administration (P<0.001). On both treatment days, substance P caused dose-dependent increases in blood flow and plasma t-PA antigen and activity concentrations (P<0.001 for all) but had no effect on plasma plasminogen activator inhibitor type 1 (PAI-1) concentrations. Compared with placebo, nicotine administration increased the substance-P-induced release of t-PA antigen and activity (P<0.05 for both) without an effect on endothelium-dependent or -independent vasodilatation. CONCLUSIONS: Short-term transdermal nicotine treatment does not affect endothelium-dependent vasomotion but does increase substance-P-induced t-PA release in vivo in man. This suggests that nicotine administration alters specific aspects of endothelial function and enhances the acute endogenous fibrinolytic capacity in vivo. The long-term effects of nicotine exposure, including the potential to cause depletion of endothelial t-PA stores, now needs to be assessed.
Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man.
OBJECTIVE: Both endothelin-1 and nitric oxide make important contributions to the maintenance of basal peripheral arteriolar tone. However, the role of angiotensin II, a key hormone regulating cardiovascular and renal function, in the regulation of peripheral vascular tone has not been fully characterised. METHODS: Using local intra-arterial administration of losartan, a selective angiotensin II type 1 (AT1) receptor antagonist, we examined the contribution of endogenous angiotensin II to the maintenance of basal and sympathetically stimulated vascular tone in the forearm of healthy man under conditions of sodium repletion and depletion. The effects of losartan on responses to exogenous angiotensin I, angiotensin II, bradykinin and noradrenaline were also determined. RESULTS: Losartan, in keeping with its actions as a selective AT1 receptor antagonist, inhibited responses to angiotensin I and II, but had no effect on responses to bradykinin or noradrenaline. The dose of angiotensin II required to cause a 20% vasoconstriction was 40- and 250-fold greater with 30 and 300 micrograms/min of losartan, respectively. However, in sodium replete subjects, losartan alone caused no significant changes in basal forearm blood flow (95% confidence interval of -7.2 to +8.0%), forearm vascular resistance or sympathetically stimulated forearm vasoconstriction. Sodium depletion elevated plasma renin activity and angiotensin II concentrations (p < or = 0.002) after which acute local administration of losartan increased forearm blood flow in a dose dependent manner (maximum of 69 +/- 17%; p < 0.001). CONCLUSIONS: Endogenous angiotensin II does not contribute to the acute local maintenance of basal peripheral vascular tone in healthy man except under conditions of renin-angiotensin system activation such as sodium depletion.
Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.
AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p
Distinguishing Type 1 from Type 2 Myocardial Infarction by Using CT Coronary Angiography.
PURPOSE: To determine whether quantitative plaque characterization by using CT coronary angiography (CTCA) can discriminate between type 1 and type 2 myocardial infarction. MATERIALS AND METHODS: This was a secondary analysis of two prospective studies (ClinicalTrials.gov registration nos. NCT03338504 [2014-2019] and NCT02284191 [2018-2020]) that performed blinded quantitative plaque analysis on findings from CTCA in participants with type 1 myocardial infarction, type 2 myocardial infarction, and chest pain without myocardial infarction. Logistic regression analyses were performed to identify predictors of type 1 myocardial infarction. RESULTS: Overall, 155 participants (mean age, 64 years ± 12 [SD]; 114 men) and 36 participants (mean age, 67 years ± 12; 19 men) had type 1 and type 2 myocardial infarction, respectively, and 136 participants (62 years ± 12; 78 men) had chest pain without myocardial infarction. Participants with type 1 myocardial infarction had greater total (median, 44% [IQR: 35%-50%] vs 35% [IQR: 29%-46%]), noncalcified (39% [IQR: 31%-46%] vs 34% [IQR: 29%-40%]), and low-attenuation (4.15% [IQR: 1.88%-5.79%] vs 1.64% [IQR: 0.89%-2.28%]) plaque burdens (P < .05 for all) than those with type 2. Participants with type 2 myocardial infarction had similar low-attenuation plaque burden to those with chest pain without myocardial infarction (P = .4). Low-attenuation plaque was an independent predictor of type 1 myocardial infarction (adjusted odds ratio, 3.44 [95% CI: 1.84, 6.96]; P < .001), with better discrimination than noncalcified plaque burden and maximal area of coronary stenosis (C statistic, 0.75 [95% CI: 0.67, 0.83] vs 0.62 [95% CI: 0.53, 0.71] and 0.61 [95% CI: 0.51, 0.70] respectively; P ≤ .001 for both). CONCLUSION: Higher low-attenuation coronary plaque burden in patients with type 1 myocardial infarction may help distinguish these patients from those with type 2 myocardial infarction.Keywords: Ischemia/Infarction, CT Angiography, Quantitative CTClinical trial registration nos. NCT03338504 and NCT02284191 Supplemental material is available for this article. © RSNA, 2022.
Cardiovascular 18F-fluoride positron emission tomography-magnetic resonance imaging: A comparison study.
BACKGROUND: 18F-Fluoride uptake denotes calcification activity in aortic stenosis and atherosclerosis. While PET/MR has several advantages over PET/CT, attenuation correction of PET/MR data is challenging, limiting cardiovascular application. We compared PET/MR and PET/CT assessments of 18F-fluoride uptake in the aortic valve and coronary arteries. METHODS AND RESULTS: 18 patients with aortic stenosis or recent myocardial infarction underwent 18F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as tissue-to-background ratios (TBRs). Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58 ± 0.34, P = 0.66; 95% limits of agreement - 27% to + 25%) but performed less well with Dixon AC (1.38 ± 0.44, P = 0.06; bias (-)14%; 95% limits of agreement - 25% to + 53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT; however, stents caused artifact on PET/MR making assessment of 18F-fluoride uptake challenging. CONCLUSION: Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artifacts currently limiting clinical application.
Iterative reconstruction incorporating background correction improves quantification of [18F]-NaF PET/CT images of patients with abdominal aortic aneurysm.
BACKGROUND: A confounding issue in [18F]-NaF PET/CT imaging of abdominal aortic aneurysms (AAA) is the spill in contamination from the bone into the aneurysm. This study investigates and corrects for this spill in contamination using the background correction (BC) technique without the need to manually exclude the part of the AAA region close to the bone. METHODS: Seventy-two (72) datasets of patients with AAA were reconstructed with the standard ordered subset expectation maximization (OSEM) algorithm incorporating point spread function (PSF) modelling. The spill in effect in the aneurysm was investigated using two target regions of interest (ROIs): one covering the entire aneurysm (AAA), and the other covering the aneurysm but excluding the part close to the bone (AAAexc). ROI analysis was performed by comparing the maximum SUV in the target ROI (SUVmax(T)), the corrected cSUVmax (SUVmax(T) - SUVmean(B)) and the target-to-blood ratio (TBR = SUVmax(T)/SUVmean(B)) with respect to the mean SUV in the right atrium region. RESULTS: There is a statistically significant higher [18F]-NaF uptake in the aneurysm than normal aorta and this is not correlated with the aneurysm size. There is also a significant difference in aneurysm uptake for OSEM and OSEM + PSF (but not OSEM + PSF + BC) when quantifying with AAA and AAAexc due to the spill in from the bone. This spill in effect depends on proximity of the aneurysms to the bone as close aneurysms suffer more from spill in than farther ones. CONCLUSION: The background correction (OSEM + PSF + BC) technique provided more robust AAA quantitative assessments regardless of the AAA ROI delineation method, and thus it can be considered as an effective spill in correction method for [18F]-NaF AAA studies.
Peri-Coronary Adipose Tissue Density Is Associated With 18F-Sodium Fluoride Coronary Uptake in Stable Patients With High-Risk Plaques.
OBJECTIVES: This study aimed to assess the association between increased lesion peri-coronary adipose tissue (PCAT) density and coronary 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) in stable patients with high-risk coronary plaques (HRPs) shown on coronary computed tomography angiography (CTA). BACKGROUND: Coronary 18F-NaF uptake reflects the rate of calcification of coronary atherosclerotic plaque. Increased PCAT density is associated with vascular inflammation. Currently, the relationship between increased PCAT density and 18F-NaF uptake in stable patients with HRPs on coronary CTA has not been characterized. METHODS: Patients who underwent coronary CTA were screened for HRP, which was defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP) (<30 Hounsfield units [HU]) and spotty calcification; and obstructive coronary stenosis ≥50% (plaque volume >100 mm3). Patients with HRPs were recruited to undergo 18F-NaF PET/CT. In lesions with stenosis ≥25%, quantitative plaque analysis, mean PCAT density, maximal coronary motion-corrected 18F-NaF standard uptake values (SUVmax), and target-to-background ratios (TBR) were measured. RESULTS: Forty-one patients (age 65 ± 6 years; 68% men) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronary 18F-NaF activity. Lesions with 18F-NaF uptake had higher surrounding PCAT density than those without 18F-NaF uptake (-73 HU; interquartile range -79 to -68 HU vs. -86 HU; interquartile range -94 to -80 HU; p < 0.001). 18F-NaF TBR and SUVmax were correlated with PCAT density (r = 0.63 and r = 0.68, respectively; all p
Global burden of atherosclerotic cardiovascular disease in people with hepatitis C virus infection: a systematic review, meta-analysis, and modelling study.
BACKGROUND: More than 70 million people worldwide are estimated to have hepatitis C virus (HCV) infection. Emerging evidence indicates an association between HCV and atherosclerotic cardiovascular disease. We aimed to determine the association between HCV and cardiovascular disease, and estimate the national, regional, and global burden of cardiovascular disease attributable to HCV. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, Ovid Global Health, and Web of Science databases from inception to May 9, 2018, without language restrictions, for longitudinal studies that evaluated the risk ratio (RR) of cardiovascular disease in people with HCV compared with those without HCV. Two investigators independently reviewed and extracted data from published reports. The main outcome was cardiovascular disease, defined as hospital admission with, or mortality from, acute myocardial infarction or stroke. We calculated the pooled RR of cardiovascular disease associated with HCV using a random-effects model. Additionally, we calculated the population attributable fraction and disability-adjusted life-years (DALYs) from HCV-associated cardiovascular disease at the national, regional, and global level. We also used age-stratified and sex-stratified HCV prevalence estimates and cardiovascular DALYs for 100 countries to estimate country-level burden associated with HCV. This study is registered with PROSPERO, number CRD42018091857. FINDINGS: Our search identified 16 639 records, of which 36 studies were included for analysis, including 341 739 people with HCV. The pooled RR for cardiovascular disease was 1·28 (95% CI 1·18-1·39). Globally, 1·5 million (95% CI 0·9-2·1) DALYs per year were lost due to HCV-associated cardiovascular disease. Low-income and middle-income countries had the highest disease burden with south Asian, eastern European, north African, and Middle Eastern regions accounting for two-thirds of all HCV-associated cardiovascular DALYs. INTERPRETATION: HCV infection is associated with an increased risk of cardiovascular disease. The global burden of cardiovascular disease associated with HCV infection was responsible for 1·5 million DALYs, with the highest burden in low-income and middle-income countries. FUNDING: British Heart Foundation and Wellcome Trust.
Global Longitudinal Strain Analysis Using Cardiac MRI in Aortic Stenosis: Comparison with Left Ventricular Remodeling, Myocardial Fibrosis, and 2-year Clinical Outcomes.
PURPOSE: To use global longitudinal strain (GLS) as a marker of left ventricular decompensation in aortic stenosis and to investigate the relationship of GLS measured with cardiac MRI with markers of myocardial fibrosis, symptom development, remodeling, and clinical outcomes. MATERIALS AND METHODS: Patients with aortic stenosis and healthy control subjects were assessed. GLS was assessed by using cardiac MRI feature tracking, diffuse fibrosis by T1 mapping, and replacement fibrosis using late gadolinium enhancement. Follow-up was prospective for the primary endpoint of all-cause mortality. RESULTS: GLS was reduced in aortic stenosis (n = 159) compared with control subjects (n = 41) (-17.6% ± 3.1 [standard deviation] vs -18.9% ± 2.6, P = .02). GLS demonstrated weak associations with aortic stenosis severity (Vmax; r = 0.24, P = .0005) but showed moderate correlation with T1 mapping measures of myocardial fibrosis (eg, indexed extracellular volume [iECV]; r = 0.43, P < .0001). Moreover, GLS was reduced in patients with midwall fibrosis compared with control subjects (P < .001), although values were similar to those of patients with myocardial infarction (P = .25). In adjusted analyses, GLS was associated with total myocardial fibrosis burden (iECV) and ejection fraction (both P < .001). GLS offered poor discrimination between disease states, inability to distinguish between control subjects and patients (area under the curve [AUC], 0.60), presence or absence of fibrosis (AUC, 0.63), or symptomatic severity (left ventricular decompensation AUC, 0.64). At follow-up (median, 1466 days), 21 patients died. GLS did not independently predict clinical outcomes. CONCLUSION: GLS correlates with established markers of myocardial fibrosis. However, widespread utility of single GLS measurements may be limited by overlap between disease states and its inability to predict clinical outcomes beyond current established markers.© RSNA, 2019Supplemental material is available for this article.
Pneumonia risk with inhaled fluticasone furoate and vilanterol in COPD patients with moderate airflow limitation: The SUMMIT trial.
RATIONALE: Pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been thoroughly assessed in patients with moderate airflow limitation. OBJECTIVES: To determine the incidence of pneumonia and risk factors in COPD patients with moderate airflow limitation who had, or were at high risk for cardiovascular disease. METHODS: In the Study to Understand Mortality and MorbidITy in COPD (SUMMIT), 16,590 subjects with moderate airflow limitation (50% ≤ FEV1 ≤ 70% predicted) and heightened cardiovascular risk were randomized double-blind 1:1:1:1 to inhaled once-daily vilanterol 25 μg (VI), fluticasone furoate 100 μg (FF), vilanterol 25 μg combined with 100 μg fluticasone furoate (FF/VI), or matched placebo. In a pre-specified analysis, we assessed investigator-reported adverse pneumonia events, and independently-adjudicated fatal events. MEASUREMENTS AND MAIN RESULTS: The safety population comprised 16,568 subjects who actually received study medication. There were 1017 pneumonia events reported from 842 subjects. For placebo, FF, VI and FF/VI, reported pneumonia incidence was 5%, 5%, 4% and 6%, respectively. When adjusted for time on treatment, event rates were similar in the placebo, FF and FF/VI containing arms (3.84, 4.24 and 3.95/100 treatment years, respectively) but lower in the VI group (2.77/100 treatment years). Risk factors for pneumonia risk included: greater degree of airflow limitation (i.e. FEV1 <60% predicted), prior exacerbation history, and BMI <25 kg/m2. CONCLUSIONS: In contrast to previous studies in patients with severe disease, increased pneumonia risk with inhaled corticosteroid use was not evident in COPD subjects with moderate airflow limitation and heightened cardiovascular risk.
Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.
Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.