Severity Of Microangiopathy Research Articles

Improvement of microangiopathy after haematopoietic stem cell transplantation in systemic sclerosis.

Haematopoietic stem cell transplantation (HSCT) is a treatment option for patients with severe systemic sclerosis (SSc), but the efficacy of the procedure in remodelling the nailfold microvascular array is largely unknown. Therefore, this study aimed to evaluate the effect of HSCT on microangiopathy assessed through nailfold capillaroscopy (NC) and to compare the results with findings in patients receiving conventional immunosuppression. We included SSc patients with severe SSc and whose pre- and post-treatment NC images were available. Findings in patients treated with HSCT were compared with patients not treated with HSCT. Images were scored by two independent observers blinded for clinical data and treatment history. Capillary pattern was determined and semiquantitative scores from 0 (no changes) to 3 (>66% alterations per millimetre) were used to quantify the degree of specific microvascular characteristics. Changes in severity of microangiopathy between baseline and post-treatment were compared between groups. Images of 18 HSCT patients and 21 controls were scored. From baseline to follow-up, 33% of HSCT patients showed improvement from scleroderma pattern to normal NC, compared to 6% of controls (p=0.15). Pre- to post-treatment differences in semiquantitative scores showed significant improvement in HSCT patients compared to controls regarding capillary loss (-0.5 vs. 0.0, p<0.05) and disorganisation (-0.8 vs. 0.0, p<0.05). The degree of microangiopathy improved significantly in severe SSc patients treated with HSCT compared with patients receiving conventional immunosuppressive therapy.

Do different lipid components accelerate the pathogenesis and severity of Diabetic Retinopathy?

BackgroundTo assess the association of lipid and lipid-derived toxic molecules in pathogenesis and severity of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM).MethodsThe present cross-sectional study included 14 healthy individuals (HC) without T2DM, 22 T2DM subjects without DR (DNR), 24 T2DM subjects with mild non-proliferative DR (MNPDR), and 24 T2DM subjects with high-risk proliferative DR (HRPDR). All subjects underwent plasma and vitreous analysis for estimation of total lipid (TL), free fatty acid (FFA), lipid peroxides (LPOs) like malondialdehyde (MDA), 4-Hydroxy-noneal (HNE), the advanced lipoxidation end product (ALE) like Hexanoyl-lysine (HLY) and vascular endothelial growth factor (VEGF) following standard spectrophotometric and enzyme-linked immunosorbent assay (ELISA) methods respectively.ResultsThe concentration of TL, FFA, markers of lipid peroxidation and lipoxidation as well as VEGF in plasma and vitreous were found to be significantly elevated stepwise inT2DM subjects (HRPDR > MNPDR > DNR) compared to healthy controls (HC).Further, plasma conventional lipid components like total cholesterol (TCH), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), FFA and TL showed their significant positive correlations with vitreous level of different LPOs, ALE and VEGF in the DR group.ConclusionTotal lipid and lipid-derived detrimental biomolecules ultimately result in increased secretion of VEGF and thus not only add as associated mediators in the pathogenesis of DR, these also accelerate the severity of microangiopathy in T2DM.

Association Between Centromere- and Topoisomerase-specific Immune Responses and the Degree of Microangiopathy in Systemic Sclerosis.

Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentromere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc). ACA and ATA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed. In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity. We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc.

CD40-mediated HIF-1α expression underlying microangiopathy in diabetic nerve pathology.

ABSTRACTTo understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy was observed, as evidenced by reduced capillary luminal area, increased capillary basement membrane thickness and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves. In diabetic nerves, there was also significant macrophage and T cell infiltration, and cluster of differentiation 40 (CD40) expression was increased. The molecular alterations observed were upregulation of hypoxia-inducible factor-1α (HIF-1α), mitogen-activated protein kinase-activated protein kinase 2 (MK2; MAPKAPK2) and phosphatase and tensin homolog (PTEN). In addition, HIF-1α was correlated with small myelinated fiber density and capillary luminal area, while both MK2 and PTEN were correlated with capillary basement membrane thickness. The molecular cascades were further demonstrated and replicated in a cell model of microangiopathy on human umbilical vein endothelial cells (HUVECs) exposed to high-glucose medium by silencing of CD40, PTEN and HIF-1α in HUVECs using shRNA. These data clarified the hierarchy of the molecular cascades, i.e. upregulation of CD40 leading to HIF-1α expression in endothelium and nerve fibers. In conclusion, this study revealed the association of microangiopathy, thrombosis and inflammatory infiltrates with nerve degeneration in diabetic nerves, demonstrating that CD40 is a key molecule for the upregulation of HIF-1α and PTEN underlying the severity of microangiopathy.

FRI0498 A Quantitative Videocapillaroscopic Study about the Relationship of Avascular Areas with the Clinical Characteristics and Disease Severity in Patients with Systemic Sclerosis

BackgroundSeveral studies have been carried out in systemic sclerosis (SSc) in order to correlate the microvascular damage with the clinical features and/or organ involvement, most of them by using the...

C0147: Homocysteine Levels in Patients with Primary and Secondary Raynaud’s Phenomenon. Its Association with Microangiopathy Severity

C0147: Homocysteine Levels in Patients with Primary and Secondary Raynaud’s Phenomenon. Its Association with Microangiopathy Severity

Homocysteine levels in patients with primary and secondary Raynaud's phenomenon. Its association with microangiopathy severity

The association between hyperhomocysteinemia (HHcy) and Raynaud's phenomenon (RP) remains a matter of debate. In 18 primary RP, 23 secondary RP and 41 controls, we investigated homocysteine (Hcy) levels along with biochemical and inflammatory parameters. The Hcy levels in both primary and secondary RP were elevated when compared with controls (p < 0.05 and p < 0.01, respectively). As age was higher in secondary RP as compared with controls (p < 0.01), both primary and secondary RP were age-matched with a corresponding control group, and with Hcy maintaining its statistical significance (p < 0.05). No differences in creatinine, B12 vitamin or folic acid were observed between groups (p > 0.05), or in the prevalence of cardiovascular risk factors (p > 0.05). When patients were classified according to presence or absence of digital ulcers, as a sign of microangiopathy severity, the former showed higher Hcy levels than the latter (p = 0.035). Our results indicate that both primary and secondary RP patients show a mild increase in Hcy levels, which is not related to age, vitamin deficiencies or impaired renal function, but is related to microangiopathy severity. Therefore the association of HHcy and RP suggest that Hcy may contribute to endothelial dysregulation, which characterizes this disease. Specific studies should be designed to elucidate the pathogenesis of HHcy in these patients.

Hemorheological profile in primary and secondary Raynaud's phenomenon. Influence of microangiopathy

Raynaud's phenomenon (RP) is an episodic peripheral circulatory disorder characterized by local artery spams in subjects exposed to cold or emotional stress. It is not well-established whether RP patients show an altered rheological profile, mostly due to patient classification and clinical severity. We aimed to compare the hemorheological profile in patients with primary and secondary RP with a healthy control group. Eighteen primary RP, 22 secondary RP and 22 healthy controls, were included in the study. RP patients were also divided according to the presence of digital ulcers (7 with, 33 without). Biochemical and hemorheological variables were analyzed, including glucose, triglycerides, total-cholesterol, immunoglobulins, fibrinogen, plasma viscosity, erythrocyte aggregation, erythrocyte deformability and blood viscosity. Age was higher in secondary RP as compared with primary (p = 0.049), while glucose, triglycerides IgA, IgG and plasma viscosity were higher in secondary RP than in healthy subjects (p < 0.05). RP patients with digital ulcers presented higher IgA (p = 0.012), lower erythrocyte aggregation time (p = 0.008) and a trend for higher fibrinogen levels and plasma viscosity (p = 0.064, p = 0.069, respectively). The results of the present study indicate that secondary RP patients show a mild impairment of the rheological profile that aggravates with microangiopathy severity.

SAT0215 Microvascular Involvement in Systemic Sclerosis (SSC): A Preliminary Quantitative Videocapillaroscopic Study About the Type and Extent of the “Scleroderma Pattern” and Correlation with Clinical Characteristics.

BackgroundSeveral studies have been carried out in systemic sclerosis (SSc) in order to correlate the microvascular changes with the clinical features and organ involvement, most of them through qualitative or...

AB0487 Scoring the correlations between nailfold microangiopathy severity and finger dermal thickness in systemic sclerosis patients

BackgroundPeripheral microangiopathy and increased dermal thickness (DT) are typical clinical aspects of systemic sclerosis (SSc) (1-3).ObjectivesThe aim of this study was to identify and score possible correlations between nailfold microangiopathy...

Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients

ObjectiveThe aim of this study was to identify possible correlations between nailfold microangiopathy severity, finger dermal thickness (DT) and fingertip blood perfusion (FBP) in systemic sclerosis (SSc) patients.MethodsFifty-seven SSc patients...

Progression of Nailfold Microvascular Damage and Antinuclear Antibody Pattern in Systemic Sclerosis

This study evaluates possible correlations between the pattern of antinuclear antibodies (ANA) on indirect immunofluorescence (IIF) testing and nailfold microangiopathy stage (early, active, and late stage) in systemic sclerosis (SSc). Patients with SSc were followed prospectively to monitor progression of microvascular damage. The ANA pattern on IIF was searched in 42 patients with SSc showing an early pattern of nailfold microangiopathy at baseline, and was followed using nailfold videocapillaroscopy (NVC) for a median time of 91 months. Among patients whose microangiopathy showed a rapid progression from early to late pattern on NVC, the IIF pattern was fine-speckled + nucleolar (Scl-70+) in 44%, centromeric in 33%, nucleolar in 11%, and homogeneous in 11% of patients with SSc. Antitopoisomerase I antibodies were significantly more frequent (57%) in patients with late pattern of microangiopathy on NVC. The median time of progression from early to active disease was significantly lower in patients with both fine-speckled + nucleolar and nucleolar ANA positivity. The severity of microangiopathy was higher in patients with the nucleolar pattern on IIF. Patients already showing a slight reduction of capillary number at baseline were likely to have either the nucleolar or the fine-speckled + nucleolar pattern on IIF. Of note, 37% of patients still showing the early microangiopathy pattern on NVC at the end of the followup were ANA-negative. ANA-negative patients with SSc display a slower progression of nailfold microangiopathy characterized by the early pattern on NVC. Progression to the late NVC pattern (more advanced stage of microvascular damage) seems to be associated with a different autoantibody pattern on IIF (fine-speckled + nucleolar pattern being the most prevalent).

Plasma Homocysteine is Not Related to the Severity of Microangiopathy in Secondary Raynaud Phenomenon

Introduction:The role of elevated homocysteine in primary and secondary Raynaud phenomenon (RP) and in patients with atherosclerosis has been reported controversially. In secondary RP due to connective tissue disease specific alterations of nailfold capillaries might be present. An association between these microvascular changes and homocysteine has been suggested.Aim:The aim of this study was to determine whether homocysteine level differs between patients with primary and secondary RP and to test the hypothesis that homocysteine or other cardiovascular risk factors are associated with specific features of microangiopathy in secondary RP.Patients and MethodsEighty-one consecutive patients with RP referred for vascular assessment were studied by nailfold capillaroscopy. Homocysteine, C-reactive protein and cholesterol were measured and other cardiovascular risk factors and comorbidities assessed.Results:Homocysteine, C-reactive-protein and cholesterol levels did not differ between patients with primary (n=60) and secondary RP (n=21). Likewise, no differences in the prevalence of cardiovascular risk factors and comorbidities were found. In secondary RP no correlation was found between microvascular involvement and homocysteine or C-reactive protein.Conclusion:Plasma homocysteine is not different in patients with either primary or secondary RP and is therefore not a marker for the distinction of these diseases. The extent of microvascular involvement in secondary RP does not correlate with plasma homocysteine.

Parameters of metabolism and hemostasis in patients with type 1 diabetes mellitus and microgiopathy of different severity

Aim. To identify risk factors of macro-microvascular lesions at different stages of pathological process in patients with type 1 diabetes mellitus andmicrogiopathy of different severity. Materials and methods. Comprehensive analysis of parameters of metabolism, hemogram, platelet and plasma hemostasis in 121 patients (67 menand 54 women of mean age 28.2?10.7 years) with type 1 diabetes mellitus and angiopathy of different severity. Results. All patients had hyperglycemia along with dysproteinemia and altered lipid spectrum. Mean platelet volume and aggregation activity increasedwhile activated partial thromboplastic time decreased compared with control subjects regardless of the presence and severity of microangiopathy. Conclusion. Morphological and functional characteristics of platelets and activated partial throm-boplastic time are differently related to metabolicchanges.

Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes

Background and aims Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. Methods and results Common carotid artery intima–media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p < 0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. Conclusion In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications.

Cerebrovascular Reactivity, Intima-Media Thickness, and Nephropathy Presence in Patients With Type 1 Diabetes

OBJECTIVECerebrovascular reactivity impairment was reported as a marker of cerebral microangiopathy in long-term type 1 diabetes. Intima-media complex thickening reflects early stages of macroangiopathy in type 1 diabetes. The analysis of the relationship between these variables and other microangiopathic complications might serve as a beneficial indicator for early prophylaxis in these patients.RESEARCH DESIGN AND METHODSVasomotor reactivity reserve (VMRr) and breath-holding index (BHI) of the middle cerebral artery were measured with transcranial Doppler in 59 patients (median age 32.0 years, range 20–51, 36 females) with type 1 diabetes, without history of cerebrovascular events, and 30 healthy control subjects (median age 31.5 years, range 25–39, 15 females). The relationships between the presence of selected vascular complications of type 1 diabetes and biochemical parameters, intima-media thickness (IMT), and VMRr and BHI in patients were analyzed.RESULTSVMRr and BHI were lower in patients with type 1 diabetes when compared with healthy subjects (81.5 vs. 100%, P < 0.01, and 1.6 vs. 2.2, P = 0.04, respectively), whereas IMT was significantly higher in patients then in healthy control subjects (0.36 vs. 0.30 mm, P = 0.001). However, no association of IMT with VMRr was found. We found a significant reduction of VMRr and BHI in patients with diabetic nephropathy.CONCLUSIONSThe presence of diabetic nephropathy, but not IMT, can be regarded as an indicator of cerebral microangiopathy severity in patients with type 1 diabetes.

Serum resistin is associated with the severity of microangiopathies in type 2 diabetes

Resistin, secreted from adipocytes, causes insulin resistance and diabetes in rodents. To determine the relation between serum resistin and diabetic microangiopathies in humans, we analyzed 238 Japanese T2DM subjects. Mean serum resistin was higher in subjects with either advanced retinopathy (preproliferative or proliferative) ( P = 0.0130), advanced nephropathy (stage III or IV) ( P = 0.0151), or neuropathy ( P = 0.0013). Simple regression analysis showed that serum resistin was positively correlated with retinopathy stage ( P = 0.0212), nephropathy stage ( P = 0.0052), and neuropathy ( P = 0.0013). Multiple regression analysis adjusted for age, gender, and BMI, revealed that serum resistin was correlated with retinopathy stage ( P = 0.0144), nephropathy stage ( P = 0.0111), and neuropathy ( P = 0.0053). Serum resistin was positively correlated with the number of advanced microangiopathies, independent of age, gender, BMI, and either the duration of T2DM ( P = 0.0318) or serum creatinine ( P = 0.0092). Therefore, serum resistin was positively correlated with the severity of microangiopathies in T2DM.

Dotlike hemosiderin spots on T2*-weighted magnetic resonance imaging as a predictor of stroke recurrence: a prospective study

Microangiopathy associated with hypertension is a notable cause of cerebral small vessel disease (SVD), including deep intracerebral hemorrhage (ICH) and lacunar infarct. Dotlike low-intensity spots (dotlike hemosiderin spots: dotHSs) on T2*-weighted magnetic resonance (MR) images have been histologically diagnosed as old cerebral microbleeds associated with lipohyalinosis, amyloid angiopathy, or other microangiopathies and located in deep or subcortical regions. The aim of this study was to determine whether dotHSs indicate the severity of microangiopathy, and if so, whether large numbers of deep dotHSs are associated with SVD recurrence. The authors prospectively analyzed the number of dotHSs in 337 patients-191 men and 146 women with a mean age of 66 +/- 10.4 years (range 37-94 years)-with SVD (199 ICHs and 138 lacunar infarcts) who had been consecutively admitted to Hakodate Municipal Hospital. The follow-up period was 3.5 to 42 months (22.5 +/- 13.1 months). Patients were divided into two groups based on the recurrence. The hazard ratio (HR) for recurrence was estimated based on the Cox proportional hazard model by using the number of deep and subcortical dotHSs as well as other factors. Of 337 patients, 20 were readmitted with recurrence. Results of a multivariate analysis revealed an elevated rate of recurrence in patients with many subcortical dotHSs (> or = 5, HR 4.36, p = 0.0019) or a history of ICH (HR 3.82, p = 0.014). A trend toward a positive correlation (Pearson correlation coefficient 0.548, p < 0.0001) was found between the number of deep and subcortical dotHSs. Although a small sample size limited the power of analyses, the findings indicate that a large number of subcortical dotHSs may predict SVD recurrence.

Dot-like hemosiderin spots on gradient echo T2*-weighted magnetic resonance imaging are associated with past history of small vessel disease in patients with intracerebral hemorrhage.

Lipohyalinosis is considered an important cause of cerebral small vessel disease (SVD), including hypertensive intracerebral hematoma (ICH) and lacunar infarction. Dot-like low-intensity spots (dot-like hemosiderin spots [dotHSs]) on gradient-echo T2*-weighted (T2*-w) magnetic resonance imaging (MRI) have been histologically diagnosed as old microbleeds associated with microangiopathies (lipohyalinosis, amyloid angiopathy) and located in territories of perforating arteries (deep dotHSs) and subcortical regions (subcortical dotHSs). If dotHSs indicate the severity of lipohyalinosis, larger numbers of deep dotHSs may be associated with past history of SVD. The number of dotHSs was investigated in 213 patients with deep ICH (106 men, 107 women, 37 to 94 years old, mean age = 65.8 +/- 11.2 years). Patients were divided into 2 subgroups according to past history of SVD. Odds ratio (OR) for the history was estimated from logistic regression analyses of the number of deep or subcortical dotHSs, as well as other factors. Of 213 patients, 36 had a past history of SVD (symptomatic deep ICH in 18, symptomatic lacunar infarction in 17, and both in 1). An increased rate of history of SVD was found for patients with subcortical dotHSs. The OR per 1 subcortical dotHS was 1.09 (95% confidence internal (CI), 1.03-1.17; P =.005), and per deep dotHS, the OR was 1.07 (95% CI, 1.00-1.13; P =.039). The findings suggest that deep and subcortical dotHSs on T2*-w MRI may indicate the severity of microangiopathy and may predict recurrence of SVD in patients with deep ICH.

Dot‐like Hemosiderin Spots on Gradient Echo T2*‐Weighted Magnetic Resonance Imaging Are Associated With Past History of Small Vessel Disease in Patients With Intracerebral Hemorrhage

ABSTRACT Background and Purpose. Lipohyalinosis is considered an important cause of cerebral small vessel disease (SVD), including hypertensive intracerebral hematoma (ICH) and lacunar infarction. Dot‐like low‐intensity spots (dot‐like hemosiderin spots [dotHSs]) on gradient‐echo T2*‐weighted (T2*‐w) magnetic resonance imaging (MRI) have been histologically diagnosed as old microbleeds associated with microangiopathies (lipohyalinosis, amyloid angiopathy) and located in territories of perforating arteries (deep dotHSs) and subcortical regions (subcortical dotHSs). If dotHSs indicate the severity of lipohyalinosis, larger numbers of deep dotHSs may be associated with past history of SVD.Methods. The number of dotHSs was investigated in 213 patients with deep ICH (106 men, 107 women, 37 to 94 years old, mean age = 65.8 ± 11.2 years). Patients were divided into 2 subgroups according to past history of SVD. Odds ratio (OR) for the history was estimated from logistic regression analyses of the number of deep or subcortical dotHSs, as well as other factors.Results. Of 213 patients, 36 had a past history of SVD (symptomatic deep ICH in 18, symptomatic lacunar infarction in 17, and both in 1). An increased rate of history of SVD was found for patients with subcortical dotHSs. The OR per 1 subcortical dotHS was 1.09 (95% confidence internal (CI), 1.03–1.17;P= .005), and per deep dotHS, the OR was 1.07 (95% CI, 1.00–1.13;P= .039). Conclusions. The findings suggest that deep and subcortical dotHSs on T2*‐w MRI may indicate the severity of microangiopathy and may predict recurrence of SVD in patients with deep ICH.