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| 2. |
- Broen, J. C. A., et al.
(author)
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A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators
- 2012
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In: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:1, s. 264-271
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Journal article (peer-reviewed)abstract
- Objective To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). Methods. We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. Results. In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P = 0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P = 0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P = 0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P = 0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor alpha and interleukin-6) upon TLR-2-mediated stimulation (both P < 0.0001). Conclusion. Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.
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| 3. |
- Holm, Niels R, et al.
(author)
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OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions.
- 2023
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In: The New England journal of medicine. - 1533-4406. ; 389:16, s. 1477-1487
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Journal article (peer-reviewed)abstract
- Imaging-guided percutaneous coronary intervention (PCI) is associated with better clinical outcomes than angiography-guided PCI. Whether routine optical coherence tomography (OCT) guidance in PCI of lesions involving coronary-artery branch points (bifurcations) improves clinical outcomes as compared with angiographic guidance is uncertain.We conducted a multicenter, randomized, open-label trial at 38 centers in Europe. Patients with a clinical indication for PCI and a complex bifurcation lesion identified by means of coronary angiography were randomly assigned in a 1:1 ratio to OCT-guided PCI or angiography-guided PCI. The primary end point was a composite of major adverse cardiac events (MACE), defined as death from a cardiac cause, target-lesion myocardial infarction, or ischemia-driven target-lesion revascularization at a median follow-up of 2 years.We assigned 1201 patients to OCT-guided PCI (600 patients) or angiography-guided PCI (601 patients). A total of 111 patients (18.5%) in the OCT-guided PCI group and 116 (19.3%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. At 2 years, a primary end-point event had occurred in 59 patients (10.1%) in the OCT-guided PCI group and in 83 patients (14.1%) in the angiography-guided PCI group (hazard ratio, 0.70; 95% confidence interval, 0.50 to 0.98; P=0.035). Procedure-related complications occurred in 41 patients (6.8%) in the OCT-guided PCI group and 34 patients (5.7%) in the angiography-guided PCI group.Among patients with complex coronary-artery bifurcation lesions, OCT-guided PCI was associated with a lower incidence of MACE at 2 years than angiography-guided PCI. (Funded by Abbott Vascular and others; OCTOBER ClinicalTrials.gov number, NCT03171311.).
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| 7. |
- Danad, I., et al.
(author)
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Hybrid imaging using quantitative H2 15O PET and CT-based coronary angiography for the detection of coronary artery disease
- 2013
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:1, s. 55-63
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Journal article (peer-reviewed)abstract
- Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H 2 15O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H2 15O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H 2 15O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H 2 15O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H2 15O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H2 15O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H 2 15O PET/CTCA is superior to either H2 15O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.
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| 9. |
- Hoek, Roel, et al.
(author)
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Determining Hemodynamically Significant Coronary Artery Disease : Patient-Specific Cutoffs in Quantitative Myocardial Blood Flow Using [15O]H2O PET Imaging
- 2024
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 65:7, s. 1113-1121
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Journal article (peer-reviewed)abstract
- Currently, cutoffs of quantitative [15O]H2O PET to detect fractional flow reserve (FFR)-defined coronary artery disease (CAD) were derived from a single cohort that included patients without prior CAD. However, prior CAD, sex, and age can influence myocardial blood flow (MBF). Therefore, the present study determined the influence of prior CAD, sex, and age on optimal cutoffs of hyperemic MBF (hMBF) and coronary flow reserve (CFR) and evaluated whether cutoff optimization enhanced diagnostic performance of quantitative [15O]H2O PET against an FFR reference standard. Methods: Patients with chronic coronary symptoms underwent [15O]H2O PET and invasive coronary angiography with FFR. Optimal cutoffs for patients with and without prior CAD and subpopulations based on sex and age were determined. Results: This multicenter study included 560 patients. Optimal cutoffs were similar for patients with (n = 186) and without prior CAD (hMBF, 2.3 vs. 2.3 mL center dot min-1 center dot g-1; CFR, 2.7 vs. 2.6). Females (n = 190) had higher hMBF cutoffs than males (2.8 vs. 2.3 mL center dot min-1 center dot g-1), whereas CFRs were comparable (2.6 vs. 2.7). However, female sex-specific hMBF cutoff implementation decreased diagnostic accuracy as compared with the cutoff of 2.3 mL center dot min-1 center dot g-1 (72% vs. 82%, P , 0.001). Patients aged more than 70 y (n = 79) had lower hMBF (1.7 mL center dot min-1 center dot g-1) and CFR (2.3) cutoffs than did patients aged 50 y or less, 51-60 y, and 61-70 y (hMBF, 2.3-2.4 mL center dot min-1 center dot g-1; CFR, 2.7). Age-specific cutoffs in patients aged more than 70 y yielded comparable accuracy to the previously established cutoffs (hMBF, 72% vs. 76%, P = 0.664; CFR, 80% vs. 75%, P = 0.289). Conclusion: Patients with and without prior CAD had similar [15O]H2O PET cutoffs for detecting FFR-defined significant CAD. Stratifying patients according to sex and age led to different optimal cutoffs; however, these values did not translate into an increased overall accuracy as compared with previously established thresholds for MBF.
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| 10. |
- Lubberink, Mark, et al.
(author)
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Myocardial Oxygen Extraction Fraction Measured Using Bolus Inhalation of O-15-Oxygen Gas and Dynamic PET
- 2011
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:1, s. 60-66
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Journal article (peer-reviewed)abstract
- The aim of this study was to determine the accuracy of oxygen extraction fraction (OEF) measurements using a dynamic scan protocol after bolus inhalation of O-15(2). The method of analysis was optimized by investigating potential reuse of myocardial blood flow (MBF), perfusable tissue fraction, and blood and lung spillover factors derived from separate O-15-water and (CO)-O-15 scans. Methods: Simulations were performed to assess the accuracy and precision of OEF for a variety of models in which different parameters from O-15-water and (CO)-O-15 scans were reused. Reproducibility was assessed in 8 patients who underwent one 10-min dynamic scan after bolus injection of 1.1 GBq of O-15-water, two 10-min dynamic scans after bolus inhalation of 1.4 GBq of O-15(2), and a 6-min static scan after bolus inhalation of 0.8 GBq of (CO)-O-15 for region-of-interest definition. Results: Simulations showed that accuracy and precision were lowest when all parameters were determined from the O-15(2) scan. The optimal accuracy and precision of OEF were obtained when fixing MBF, perfusable tissue fraction, and blood spillover to values derived from a O-15-water scan and estimating spillover from the pulmonary gas volume using an attenuation map. Optimal accuracy and precision were confirmed in the patient study, showing an OEF test-retest variability of 13% for the whole myocardium. Correction of spillover from pulmonary gas volume requires correction of the lung time-activity curve for pulmonary blood volume, which could equally well be obtained from a O-15-water rather than (CO)-O-15 scan. Conclusion: Measurement of OEF is possible using bolus inhalation of O-15(2) and a dynamic scan protocol, with optimal accuracy and precision when other relevant parameters, such as MBF, are derived from an additional O-15-water scan.
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| 11. |
- van den Hombergh, Wieneke M.T., et al.
(author)
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Prediction of organ involvement and survival in systemic sclerosis patients in the first 5 years from diagnosis
- 2020
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In: Journal of Scleroderma and Related Disorders. - : SAGE Publications. - 2397-1983 .- 2397-1991. ; 5:1, s. 57-65
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Journal article (peer-reviewed)abstract
- Background: Organ involvement often occurs in early systemic sclerosis and has been related to premature death. Identifying patients at diagnosis at risk of developing early organ involvement would be useful to optimize screening and management strategies. Objective: To develop prediction models for the 5-year development of interstitial lung disease, pulmonary arterial hypertension and death. Methods: A European multicentre inception cohort was created. For modelling, predefined clinical variables with known predictive value at diagnosis were used. Univariate and multivariate regression analysis were done to select baseline predictors and build the prediction models. The models were tested using the area under the receiver operating characteristic curve comparing observed and expected frequencies. Results: Of 735 patients, 23% developed interstitial lung disease, 8% developed pulmonary arterial hypertension 12% died. The interstitial lung disease model included diffuse cutaneous systemic sclerosis (OR = 1.8), systemic sclerosis disease duration < 3 years (OR = 1.4), puffy fingers (OR = 1.6), and anti-topoisomerase-I-antibodies (OR = 1.8). The pulmonary arterial hypertension model included age > 65 years (OR = 3.2), forced vital capacity < 70% (OR = 2.5) and diffusing capacity of the lung for carbon monoxide < 55% (OR = 1.9). Death was predicted best by age > 65 years (OR = 4.1), male gender (OR = 1.9), no anti-centromere antibodies (OR = 0.5), proteinuria (OR = 1.9), forced vital capacity < 70% (OR = 1.8) and pulmonary arterial hypertension at diagnosis (OR = 10.1). The area under the receiver operating characteristic was 0.66 (95% CI 0.64–0.67), 0.66 (95% CI 0.64–0.68) and 0.70 (95% CI 0.69–0.72), respectively. Conclusion: We have shown that it is possible to predict interstitial lung disease, pulmonary arterial hypertension and death using established variables already available at the moment of systemic sclerosis diagnosis. Discriminatory performance of the models was suboptimal. Further research including new variables is necessary to improve performance.
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