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AbstractBackgroundObjectiveMethodsResultsConclusionsReliable typing of amyloid is essential. Amyloid extraction from tissue enables immunochemical typing of the precursor protein using an enzyme-linked immunosorbent assay (ELISA).To assess the diagnostic accuracy of a panel of ELISAs for typing the four main types (AA, ATTR, AL-kappa and AL-lambda amyloid).From 1996 to 2023 subcutaneous abdominal fat tissue aspirates were obtained from 1339 amyloidosis patients and 868 controls. Amyloid was visually graded 0–4+ in Congo red-stained smears. Amyloid extracted from tissue by Guanidine was typed using a panel comprising four ELISAs.All amyloid protein concentrations in extracts correlated with amyloid grade in smears. Typing sensitivity was low (23.3%) in samples with grade 1+/2+ amyloid. Overall typing sensitivity of the panel was 81.6% for all easily visible amyloid (grade 3+/4+): high for AA (98.8%) and ATTR (96.8%) and fair for AL-kappa (66.7%) and AL-lambda (75.9). Overall typing specificity was 98.0% and the overall positive predictive value was 98.0%.We describe a highly specific ELISA panel for routine typing of the main amyloid types in fat tissue. Until more sensitive typing techniques will become generally available, typing easily visible amyloid in fat tissue using this ELISA panel is reliable, affordable and straightforward. [ABSTRACT FROM AUTHOR]

This document reports on two patients, a father and daughter, who both developed AA amyloidosis as a complication of the PAMI syndrome, which stands for PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome. The father had a history of various health issues, including acute rheumatic fever, furunculosis, and neutropenia. He eventually developed renal failure and died. The daughter experienced sterile pyogenic arthritis, neutropenia, and hepatosplenomegaly before developing renal failure and receiving a kidney transplant. Both patients were found to have a mutation in the PSTPIP1 gene. This case highlights the challenges in diagnosing AA amyloidosis and suggests that genetic testing for PSTPIP1 gene mutations should be considered in patients with unexplained neutropenia and a history of chronic inflammation. [Extracted from the article]

Aims Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. Methods and results From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10−12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10−8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10−18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. Conclusion In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies. [ABSTRACT FROM AUTHOR]

To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNP+ and AL/PNP–, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNP+), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age- and sex-matched to both AL/PNP– (HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. sNfL levels were increased both in 10 AL/PNP+ patients (p <.001) and in 10 AL/PNP– patients (p <.005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNP+ patients than in AL/PNP– patients (p <.005). sNfL levels were also increased in 15 ATTRv/PNP+ patients, compared to both 15 HC/TTRv (p <.0001) and 15 TTRv carriers (p <.0001). ATTRv/PNP+ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p =.05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis. [ABSTRACT FROM AUTHOR]

From a clinical perspective, there is a need for a reliable and comprehensive list of diseases causing AA amyloidosis. This list could guide clinicians in the evaluation of patients with AA amyloidosis in whom an obvious cause is lacking. In this systematic review, a PubMed, Embase and Web of Science literature search were performed on causes of AA amyloidosis published in the last four decades. Initially, 4066 unique titles were identified, but only 795 full-text articles and letters were finally selected for analysis. Titles were excluded because of non-AA type of amyloidosis, language, no full-text publication or irrelevance. Hundred and fifty diseases were initially reported to be associated with the development of AA amyloidosis. The presence of AA amyloid was proven in 208 articles (26% of all) of which 140 (67%) showed a strong association with an underlying disease process. Disease associations were categorized and 48 were listed as strong, 19 as weak, 23 as unclear, and 60 as unlikely. Most newly described diseases are not really unexpected because they often cause longstanding inflammation. Based on the spectrum of identified causes, a pragmatic diagnostic approach is proposed for the AA amyloidosis patient in whom an obvious underlying disease is lacking. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are very common conditions, particularly in the elderly. However, the mechanisms underlying the two disorders, including their intricate interaction have not been fully resolved. Here, our aim is to review the evidence on the role of the two types of senile amyloidosis in this connection. Two types of senile amyloidosis can be identified: wild-type transthyretin (TTR)-derived amyloidosis (ATTRwt) and isolated atrial amyloidosis (IAA). ATTRwt is an underlying condition that is being increasingly recognized in patients with HFpEF and often accompanied by AF. IAA is an established cause of AF, adding to the mechanism problem. New diagnostic and therapeutic possibilities have emerged that may facilitate clinical management of (senile) amyloidosis, which in turn may have implications for the management of HFpEF and AF. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

We report a case of wild type ATTR (ATTRwt) amyloidosis in an 81-year-old man with a positive family history of hereditary ATTR (ATTRv) amyloidosis. Taking this family history into account, a diagnosis of ATTRv amyloidosis based on the TTRV30M variant was strongly suspected and this was shared with the patient. Subcutaneous abdominal fat tissue did show amyloid in the Congo red stain and bone scintigraphy showed increased cardiac uptake (Perugini grade 2) [[1]], clinically confirming the diagnosis ATTR amyloidosis with cardiomyopathy. [Extracted from the article]

Purpose: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality.This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied.ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality.Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.Methods: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality.This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied.ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality.Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.Results: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality.This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied.ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality.Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.Conclusion: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality.This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied.ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality.Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality. [ABSTRACT FROM AUTHOR]

Aims: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights., Methods and Results: In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61-0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65-0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers., Conclusion: ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM., Competing Interests: Conflict of interest: Alwin Tubben: none. George Markousis-Mavrogenis: none. Laura M.G. Meems: none. Bart van Essen: none. Lukas Baumhove: none. Milou Berends: none. Hendrea S.A. Tingen: none. Johan Bijzet: none. Bouke P.C. Hazenberg: none. Adriaan A. Voors: The UMCG, which employs AAV, received consultancy fees or research support from Anacardio, AstraZeneca, BMS, Bayer, Boehringer Ingelheim, Cytokinetics, Corteria, EliLilly, Merck, Moderna, Novartis, NovoNordisk, Roche Diagnostics. Dirk-Jan van Veldhuisen: none. Riemer H.J.A. Slart: The UMCG, which employs RHJAS, received grant support of Pfizer and Siemens Healthineers. Hans L.A. Nienhuis: The UMCG, which employs HLAN, received consultancy fees and speaking honorarium from Pfizer and Alnylam. Peter van der Meer: PvdM is supported by a grant from the European Research Council (ERC CoG 101045236, DISSECT-HF). The UMCG, which employs PvdM, received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Boehringer Ingelheim and Ionis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT-proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The clinical description of a novel TTR gene mutation characterized by a late onset amyloid cardiomyopathy., Methods and Results: A 78-year-old man of Dutch origin with recent surgery for bilateral carpal tunnel syndrome (CTS) was admitted to our hospital because of heart failure with preserved ejection fraction (55%). Cardiac ultrasound showed thickened biventricular walls, and cardiac magnetic resonance imaging also showed late gadolinium enhancement. Early signs of a polyneuropathy were found by neurophysiological testing. A few months later, his 72-year-old sister was admitted to an affiliated hospital because of heart failure caused by a restrictive cardiomyopathy. In both patients, a subcutaneous abdominal fat aspirate was stained with Congo red and DNA was analyzed by direct sequencing of exons 1 to 4 of the transthyretin (TTR) gene. Both fat aspirates revealed transthyretin-derived (ATTR) amyloid. 99m Tc-diphosphonate scintigraphy further confirmed cardiac ATTR amyloidosis in the male patient. DNA analysis of both patients showed a novel TTR mutation c.194C>G that encodes for the gene product TTR (p.A65G) ending up as the mature protein TTR A45G. The 56-year-old daughter of the male patient had the same TTR mutation. A full diagnostic workup did not reveal any signs of amyloidosis yet., Conclusions: A novel amyloidogenic TTR mutation was found in a Dutch family. The clinical presentation of ATTR A45G amyloidosis in the affected family members was heart failure due to a late-onset cardiomyopathy. The systemic nature of this disease was reflected by bilateral CTS and by early signs of a polyneuropathy in the index patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Amyloidosis has been a mystery for centuries, but research of the last decennia has clarified many of the secrets of this group of diseases. A protein-based classification of amyloidosis helps to understand problems that were part of the obsolete clinical classification in primary, secondary, and familial amyloidosis. All types of amyloid are secondary to some underlying precursor-producing process: each type is caused by a misfolded soluble precursor protein that becomes deposited as insoluble amyloid fibrils., Summary: The incidence of amyloidosis is not well documented, but probably falls between 5 and 13 per million per year. Prevalence data are scarce, but one UK study indicates about 20 per million inhabitants. Amyloidosis can be localized (amyloid deposited in the organ or tissue of precursor production) or systemic (amyloid at one or more sites distant from the site of precursor production). The major systemic types of amyloidosis are AL (associated with a light chain-producing plasma cell dyscrasia), AA (associated with longstanding inflammation), wild-type ATTR (associated with normal transthyretin and old age), and hereditary ATTR (associated with a transthyretin mutation) amyloidosis. Imaging techniques, such as cardiac ultrasound, magnetic resonance imaging, bone scintigraphy, and serum amyloid P component scintigraphy, are useful both for diagnosing amyloidosis and for assessing disease severity. Serologic markers are useful for detecting organ disease and disease monitoring during follow-up. Current treatment modalities are directed against the ongoing supply of precursor proteins and thereby aim to stop further accumulation of amyloid. Novel treatment modalities, such as interference with amyloid formation and even removal of amyloid, are being studied. A well-thought and planned monitoring during follow-up helps to assess the effect of treatment and to early detect possible progression of amyloidosis., Key Messages: Clinical management comprises histologic proof of amyloid, evidence of systemic deposition, reliable typing, precursor assessment, severity of organ disease, risk assessment and prognosis, choice of treatment, and planned monitoring during follow-up., Facts From East and West: (1) AL amyloidosis is the most prevalent type of amyloidosis accounting for 65% of the amyloidosis-diagnosed patients in the UK and for 93% of the amyloidosis-diagnosed patients in China. The predisposition of men over women to develop AL amyloidosis might be higher in China than in Western countries (2:1 vs. 1.3:1). Both in the East and West, incidence increases with age. At the time of diagnosis, edema is twice as frequent and the proportion of renal involvement is higher in Chinese compared to Western patients. (2) Melphalan followed by autologous stem cell transplantation (ASCT) is the current standard therapy but is restricted to eligible patients. The efficacy and safety of bortezomib combined with dexamethasone were proven in Western patients and recently confirmed in a Chinese cohort. Recent studies in China and the US indicate that bortezomib induction prior to ASCT increases the response rate. Thalidomide and lenalidomide have shown benefit, but toxicity and lack of clinical evidence exclude these agents from first-line therapy. The green tea extract epigallocatechin-3-gallate is under investigation as an inhibitor of AL amyloid formation and a compound that might dissolve amyloid.

Objective: To determine small artery elasticity (SAE) in patients with longstanding rheumatoid arthritis (RA) in comparison to healthy controls, and to investigate its relation to markers of endothelial cell activation, disease activity, joint damage, and the presence of atherosclerosis., Methods: Forty-nine patients with RA and 50 age- and sex-matched healthy controls were studied. Traditional cardiovascular risk factors and disease-related factors were recorded. SAE was measured noninvasively by pulse-wave analysis (PWA). Endothelial activation was assessed by measuring levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor (vWF). Carotid intima-media thickness (IMT), as an indicator of subclinical atherosclerosis, was assessed using ultrasonography., Results: Patients with RA had higher body mass index, blood pressure, and triglyceride levels and were more often cigarette smokers compared to controls. SAE was decreased in RA patients compared to controls and was inversely related with age, smoking, blood pressure, vWF, sVCAM-1, high sensitivity C-reactive protein, and IMT. Presence of RA was independently related to SAE in multivariate linear regression analysis. SAE was inversely related with the Health Assessment Questionnaire score. No correlation was found between SAE and other disease activity markers and damage. IMT in patients and controls was not different., Conclusion: Small artery elasticity was decreased in patients with longstanding RA. The presence of RA was independently associated with SAE. Whereas IMT in patients with RA was not increased, we hypothesize that endothelial dysfunction, reflected by decreased SAE, is present prior to IMT thickening in these patients.

Introduction: The objectives of this study were to determine small arterial elasticity (SAE) in systemic lupus erythematosus (SLE) and to investigate its relationship with intima media thickness (IMT), accumulation of advanced glycation end products (AGEs), endothelial activation and inflammation., Methods: Thirty SLE patients with inactive disease and 30 age- and sex-matched healthy controls were included. Twenty patients with essential hypertension (EH) served as positive control. SAE was assessed by pulse-wave analysis using tonometric recordings of the radial artery. IMT of the carotid arteries was measured by ultrasound. AGE accumulation was assessed with an AGE-reader. Endothelial activation markers and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA)., Results: SAE was decreased in SLE (P = 0.01) and further decreased in EH (P < 0.01) compared to healthy controls. IMT was increased in EH (P < 0.05), but not in SLE. AGE accumulation was increased in SLE (P < 0.05) and further increased in EH (P < 0.01) compared to healthy controls. Endothelial activation markers and CRP were increased in SLE but not in EH. SAE related to AGE accumulation (r = -0.370, P < 0.05), CRP (r = -0.429, P < 0.05) and creatinine clearance (r = 0.440, P < 0.05), but not to IMT and endothelial activation markers. In multivariate analysis SLE was an independent predictor of SAE., Conclusions: SAE is decreased in SLE patients without increased IMT, independently of traditional cardiovascular risk factors. Longitudinal studies are needed to investigate whether SAE, endothelial activation and AGE accumulation are early markers for cardiovascular disease in SLE.

Objective: To assess endothelial cell (EC) function of the cutaneous microcirculation in patients with Wegener's granulomatosis (WG) and to relate EC function to EC activation and presence of atherosclerosis., Methods: We studied 28 WG patients with inactive disease and 28 age and sex matched controls. Common carotid intima-media thickness (IMT), as a measure of atherosclerosis, was determined by ultrasonography. EC function of microcirculation in the fingers was assessed using laser Doppler fluxmetry in combination with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), which are endothelium-dependent and endothelium-independent vasodilators, respectively. In addition to vascular responses, traditional cardiovascular risk factors were recorded, and EC activation was assessed by serological measures., Results: WG patients had increased IMT compared to controls (0.71 mm vs 0.66 mm; p < 0.05). In WG patients IMT correlated positively with age and body mass index (BMI), and negatively with duration of prednisolone use and cumulative prednisolone dose. Levels of von Willebrand factor and C-reactive protein were increased in patients with WG (p < 0.05). ACh-induced but not SNP-induced vasodilatation was enhanced in WG patients compared to controls. When patients and controls with increased IMT were excluded, the difference in relative response to ACh became significant (median 567% vs 334%; p = 0.007). The response to ACh correlated negatively with age., Conclusion: We confirmed that WG patients have accelerated atherosclerosis as measured by IMT. EC activation and disturbed microvascular endothelium-dependent vasodilatation were present in the microcirculation of WG patients with inactive disease and without signs of atherosclerosis, indicating and contributing to a proatherogenic state.