Aims/hypothesisEndothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.MethodsMale participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability.ResultsBoth sublingual dimensions (0.64 [0.57–0.75] μm vs 0.78 [0.71–0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88–6.59] μm vs 8.89 [4.74–11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83–0.99] μm and to 5.88 [5.33–6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.Conclusion/interpretationType 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.Trial registrationwww.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186FundingAn unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)
This proposal for standardization of (123)I-metaiodobenzylguanidine (iobenguane, MIBG) cardiac sympathetic imaging includes recommendations for patient information and preparation, radiopharmaceutical, injected activities and dosimetry, image acquisition, quality control, reconstruction methods, attenuation, scatter and collimator response compensation, data analysis and interpretation, reports, and image display. The recommendations are based on evidence coming from original or scientific studies whenever possible and as far as possible reflect the current state-of-the-art in cardiac MIBG imaging. The recommendations are designed to assist in the practice of performing, interpreting and reporting cardiac sympathetic imaging. The proposed standardization does not include clinical indications, benefits or drawbacks of cardiac sympathetic imaging, and does not address cost benefits or cost effectiveness; however, clinical settings of potential utility are mentioned. Standardization of MIBG cardiac sympathetic imaging should contribute to increasing its clinical applicability and integration into current nuclear cardiology practice.
Background
Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor but the underlying mechanisms responsible for its pathogenicity are poorly defined. Since Lp(a) is the prominent carrier of pro-inflammatory oxidized phospholipids (OxPL), part of its atherothrombosis might be mediated through this pathway.
Methods
In vivo imaging techniques MR imaging, 18F-FDG-PET/CT and SPECT/CT were used to measure subsequently atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed using FACS analysis, inflammatory stimulation assays and transendothelial migration assays. In vitro studies to the pathophysiology of Lp(a) on monocytes were performed using an in vitro model for trained immunity.
Results
We show that subjects with elevated Lp(a) (108 [50–195] mg/dL; n=30) have increased arterial inflammation and enhanced PBMCs trafficking to the arterial wall, compared with subjects with normal Lp(a) (7 [2–28] mg/dL; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce pro-inflammatory cytokines upon stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the pro-inflammatory response in monocytes derived from healthy controls (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apo(a).
Conclusions
These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.
Clinical Trial Registration
URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5006 Unique Identifier: NTR5006 (VIPER study)
Cardiovascular diseases are the leading cause of death not only in Europe but also in the rest of the World. Preventive measures, however, often fail and cardiovascular disease may manifest as an acute coronary syndrome, stroke or even sudden death after years of silent progression. Thus, there is a considerable need for innovative diagnostic and therapeutic approaches to improve the quality of care and limit the burden of cardiovascular diseases. During the past 10 years, several retrospective and prospective clinical studies have been published using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to quantify inflammation in atherosclerotic plaques. However, the current variety of imaging protocols used for vascular (arterial) imaging with FDG PET considerably limits the ability to compare results between studies and to build large multicentre imaging registries. Based on the existing literature and the experience of the Members of the European Association of Nuclear Medicine (EANM) Cardiovascular Committee, the objective of this position paper was to propose optimized and standardized protocols for imaging and interpretation of PET scans in atherosclerosis. These recommendations do not, however, replace the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual study protocols used and the individual patient, in consultation with the patient and, where appropriate and necessary, the patient’s guardian or carer. These recommendations suffer from the absence of conclusive evidence on many of the recommendations. Therefore, they are not intended and should not be used as "strict guidelines" but should, as already mentioned, provide a basis for standardized clinical atherosclerosis PET imaging protocols, which are subject to further and continuing evaluation and improvement. However, this EANM position paper might indeed be a first step towards "official" guidelines on atherosclerosis imaging with PET.
accurate recognition at earlier stages. Imaging provides non-invasive tools for follow-up of disease remission/progression complementing clinical evaluation. Additional areas not defined include appropriate clinical indications for imaging, optimal imaging utilization by clinical presentation, accepted imaging methods, accurate image interpretation, and comprehensive and clear reporting. Prospective randomized clinical trial data for the diagnosis of amyloidosis and for imaging-based strategies for treatment are not available. A consensus of expert opinion is greatly needed to guide the appropriate clinical utilization of imaging in cardiac amyloidosis.
Our results indicate that patients with HF and decreased late H/M or increased myocardial MIBG washout have a worse prognosis compared with those with normal semi-quantitative myocardial MIBG parameters.
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