Small Vessel Dysfunction Research Articles

Signals From Inflamed Perivascular Adipose Tissue Contribute to Small-Vessel Dysfunction in Women With Human Immunodeficiency Virus.

People with the human immunodeficiency virus (PWH) have microvascular disease. Because perivascular adipose tissue (PVAT) regulates microvascular function and adipose tissue is inflamed in PWH, we tested the hypothesis that PWH have inflamed PVAT that impairs the function of their small vessels. Subcutaneous small arteries were dissected with or without PVAT from a gluteal skin biopsy from 11 women with treated HIV (WWH) aged < 50 years and 10 matched women without HIV, and studied on isometric myographs. Nitric oxide (NO) and reactive oxygen species (ROS) were measured by fluorescence microscopy. Adipokines and markers of inflammation and ROS were assayed in PVAT. PVAT surrounding the small arteries in control women significantly (P < .05) enhanced acetylcholine-induced endothelium-dependent relaxation and NO, and reduced contractions to thromboxane and endothelin-1. However, these effects of PVAT were reduced significantly (P < .05) in WWH whose PVAT released less adiponectin but more markers of ROS and inflammation. Moderation of contractions by PVAT were correlated positively with adipose adiponectin. PVAT from WWH has oxidative stress, inflammation, and reduced release of adiponectin, which may contribute to enhanced contractions and therefore could promote small-artery dysfunction.

Asian flush gene variant increases mild cognitive impairment risk: a cross-sectional study of the Yoshinogari Brain MRI Checkup Cohort.

The East Asian-specific genetic diversity, the rs671 variant of aldehyde dehydrogenase 2, causes the "Asian flush" phenomenon following alcohol consumption, resulting in an alcohol avoidance phenotype. The variant is suggested as a risk factor for Alzheimer's disease; however, its association with mild cognitive impairment (MCI), an effective target for secondary prevention of dementia, remains unclear. This cross-sectional study examined 430 individuals aged 60-80 years (251 women) without overt cognitive impairment in Yoshinogari, Japan. The effect of the rs671 variant on MCI, defined by scores <26 or <25 on the Japanese version of the Montreal Cognitive Assessment, was evaluated using multivariate logistic regression. The models included APOEε4, sex, age, education, history of habitual drinking, Brinkman index, hypertension, diabetes, and subclinical magnetic resonance imaging findings and consistently estimated the risk of the rs671 variant. Subsequently, stratified analyses by history of habitual drinking were performed based on an interactive effect between rs671 and alcohol consumption, and the rs671 variant significantly influenced MCI in participants who did not drink habitually, with odds ratios ranging from 1.9 to 2.1 before and after adjusting for covariates, suggesting an association independent of hippocampal atrophy and small vessel dysfunction. Conversely, no such association with the rs671 variant was observed in participants with a history of habitual alcohol use. Instead, hippocampal atrophy and silent infarcts were associated with MCI. This is the first study to demonstrate an association between the rs671 variant and MCI morbidity. The findings highlight the need for race-specific preventive strategies and suggest potential unrecognized mechanisms in dementia development.

Identifying patients at risk for chronic thromboembolic pulmonary hypertension

Patients with chronic thromboembolic pulmonary hypertension represent a subgroup of patients suffering from pulmonary hypertension. The disease is characterized by chronic, non-resolving thromboembolic obstruction of pulmonary arteries following one or more episodes of pulmonary embolism and involving both large vessel and small vessel dysfunction in the lungs [ [1] Piazza G. Goldhaber S.Z. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011; 364: 351-360 Crossref PubMed Scopus (276) Google Scholar ]. Clinically, the most important manifestations are shortness of breath, fatigue and symptoms as a consequence of right sided heart failure, all resulting in a significantly affected quality of life and even enhanced mortality.

Features of Cerebral Small Vessel Disease Contributes to the Differential Diagnosis of Alzheimer's Disease.

Cerebral small vessel disease (CSVD), which comprises the typical features of white matter hyperintensity (WMH) and Vichor-Robin spaces (VRSs) in the brain, is one of the leading causes of aging-related cognitive decline and, ultimately, contributes to the occurrence of dementia, including Alzheimer's disease (AD). To investigate whether CSVD imaging markers modify the pathological processes of AD and whether these markers improve AD diagnosis. 208 participants were enrolled in the China Aging and Neurodegenerative Initiative (CANDI). Fluid AD biomarkers were detected using a single-molecule array, and cerebral small vessel dysfunction was determined using magnetic resonance imaging. WMH contributed to AD pathology only within the NC and MCI groups (CDR ≤0.5), whereas VRSs had no effect on AD pathology. The associations between AD biomarkers and cognitive mental status were consistent with the presence of CSVD pathology. That is, within individuals without CSVD pathology, the MMSE scores were correlated with AD fluid biomarkers, except for plasma Aβ42 and Aβ40. Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH (β= -0.465, p = 0.0016) or VRSs (β= -0.352, p = 0.0257) pathology. Plasma AD biomarkers combined with CSVD markers showed high accuracy in diagnosing dementia. Findings from this cross-sectional cohort study support the notion that CSVD is a risk factor for dementia and highlights that vascular pathology can promote AD biomarker levels, especially in the early course of the disease. Moreover, our results suggest that adding a vascular category to the ATN framework improves the diagnostic accuracy of AD.

Vascular and circulatory diseases of the retina associated with spent Covid-19- clinical cases

Introduction: Coronavirus disease 2019 has affected more than 130 million people since the outbreak. During the pandemic, the severe acute respiratory syndrome virus (SARS-CoV-2) was found to cause endothelial dysfunction of small blood vessels and can lead to late ocular complications such as acute occlusion of the central retinal artery and its branches, occlusion of the venous vessels of the retina, central serous retinopathy, papillophlebitis, anterior ischemic opticopathy, uveitis and neuroretinitis. The aim of the present study was to raise awareness of the risk of developing acute retinal vascular disease associated with COVID-19. Key words: COVID-19, endothelial dysfunction, vascular diseases,trombosis

Abstract P434: A Mouse Model To Control Vessel Diameter With Light

In diseases such as stroke, hypertension, vascular cognitive impairment, and Alzheimer’s disease, defects in the cerebrovascular system lead to reduced blood flow and vasoreactivity to stimuli. Recently, there has been increased appreciation for the role of small vessels in these vascular pathologies. For example, small vessel dysfunction can cause widespread microinfarcts and capillary stalling, which may underlie cognitive impairment in cases where large scale vascular abnormalities are not readily detected. However, vascular function is difficult to dissociate from concurrent neuronal deficits cause by damage to neuronal circuitry in brain pathology. Thus the ability to directly probe smooth muscle contraction of small, individual vessels in the intact brain would be a valuable tool for increasing our understanding of vascular contributions to cognitive impairment. We developed an experimental paradigm to optically probe the contractile function of arterioles in vivo with high spatiotemporal precision. This was done by expressing the excitatory opsin ReaChR in vascular smooth muscle cells and pericytes. Using a 594 nm light-emitting diode we were able to evoke widespread vasoconstriction across the cranial window. With a 1040 nm focused, pulsed laser for two-photon stimulation, we were able to evoke highly localized constrictions targeted to individual pial artery branches or penetrating arterioles. Our dual light-path imaging system allowed the optogenetic stimulation to be performed with simultaneous two-photon imaging to monitor vessel activity. Using a spatial light modulator, we were also able to constrict vessels both above and below the imaging plane. This is a powerful tool to assay vasoconstrictive function of single arterioles across 3-dimensional vascular networks in vivo. It also presents novel opportunities to study conductance of vascular signals and to modulate dynamics of functional hyperemia.

The effect of vitamin D3 and thyroid hormones on the capillaroscopy-confirmed microangiopathy in pediatric patients with a suspicion of systemic connective tissue disease-a single-center experience with Raynaud phenomenon.

Raynaud phenomenon (RP) may be the first manifestation of a systemic connective tissue disease (SCTD). Early detection of dysfunction of small vessels called microangiopathy is essential for the diagnostic process. The focus of this single-center, retrospective study was to investigate the potential dependencies between microvascular image and laboratory markers measured in children with RP. The study analyzed the nail-fold video-capillaroscopy (NVC) findings and laboratory results of 81 children between the ages 6 and 17 who were referred to pediatric rheumatologist with a suspicion of SCTD. Out of 52 patients presenting with RP at the time of evaluation, abnormalities in capillary microscopic imaging were found in 34. NVC findings were then compared to levels of specific biomarkers in serum. Vitamin D3 serum levels have been significantly decreased in patients with RP (23.4 ng/mL ± 8.76 vs. 30.0 ng/mL ± 12.66, P = 0.0148). There were positive significant correlations between levels of vitamin D3 and acute-phase reactants in serum, such as C-reactive protein (P = 0.0292). Furthermore, free thyroxine levels (fT4) in patients with both RP (P = 0.0126) and micro-angiopathy (P = 0.05496) persisted in the lower range of the normal limit (< 1.0 ng/dL). Regular oral supplementation of vitamin D3 should be always considered in children with RP if deficiency is found. Additionally, low fT4 level (< 1.0 ng/dL) should be considered as an indication to perform NVC in patients suspected of SCTD even when they do not present RP.

The effects of lockdown-induced air quality changes on the results of cardiac functional stress testing in coronary artery disease and heart failure patients.

In vulnerable subjects, the increase in air pollution worsens the signs of myocardial ischemia. Lockdown during COVID-19 pandemics substantially cleaned the air. The objective of this is to assess the effects of air cleaning due to lockdown on stress echocardiography (SE) results. We enrolled 19 patients with chronic coronary artery disease and/or heart failure referred to SE (semi-supine bicycle exercise, n = 8, or dipyridamole, n = 11). Before and soon after lockdown, we assessed regional wall motion abnormalities (abnormal value: worsening of ≥ 2 segments), B-lines (a sign of pulmonary congestion, 4-site simplified scan, abnormal value ≥ 2), and coronary flow velocity reserve in left anterior descending artery (CFVR, abnormal value < 2.0). Local air quality indicators (same day of SE) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were obtained from publicly available data sets of the regional authority of environmental protection. After lockdown, NO2 concentration decreased from 19 ± 10 to 10 ± 4 μg/m3 (p = 0.006). After lockdown, abnormal responses remained unchanged for ischemia (21% vs 16%, p = ns) and decreased for B-lines (42% vs 5%, p = 0.008) and CFVR (84 vs 42%, p = 0.007). Changes in coronary flow velocity reserve (CFVR) were correlated to same-day variations in NO2 (r = −0.578, p = 0.010) and preceding 30-day changes in PM2.5 (r = −0.518, p = 0.023). After lockdown, air cleaning was associated with a beneficial effect on coronary small vessel dysfunction and alveolar-capillary barrier distress mirrored by improvement of CFVR and B-lines during SE in vulnerable patients. ClinicalTrials.gov Identifier: NCT 030.49995

Zooming in on cerebral small vessel function in small vessel diseases with 7T MRI: Rationale and design of the "ZOOM@SVDs" study.

Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. Yet, specific treatment strategies are lacking in part because of a limited understanding of the underlying disease processes. There is therefore an urgent need to study SVDs at their core, the small vessels themselves. This paper presents the rationale and design of the ZOOM@SVDs study, which aims to establish measures of cerebral small vessel dysfunction on 7T MRI as novel disease markers of SVDs. ZOOM@SVDs is a prospective observational cohort study with two years follow-up. ZOOM@SVDs recruits participants with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL, N=20), sporadic SVDs (N=60), and healthy controls (N=40). Participants undergo 7T brain MRI to assess different aspects of small vessel function including small vessel reactivity, cerebral perforating artery flow, and pulsatility. Extensive work-up at baseline and follow-up further includes clinical and neuropsychological assessment as well as 3T brain MRI to assess conventional SVD imaging markers. Measures of small vessel dysfunction are compared between patients and controls, and related to the severity of clinical and conventional MRI manifestations of SVDs. ZOOM@SVDs will deliver novel markers of cerebral small vessel function in patients with monogenic and sporadic forms of SVDs, and establish their relation with disease burden and progression. These small vessel markers can support etiological studies in SVDs and may serve as surrogate outcome measures in future clinical trials to show target engagement of drugs directed at the small vessels.

Abnormalities of the lymphatic system and impaired fluid clearance in patients with heart failure with preserved ejection fraction

Abstract Background Coronary and skeletal muscle microvascular dysfunction have been proposed as main factors in the pathogenesis of Heart Failure with Preserved Ejection Fraction (HFpEF). However, assessment of systemic arterial function has only been indirect thus far; most importantly, no direct link between systemic microvasculature and congestion, one of the core characteristics of the syndrome, has yet been investigated. Purpose To provide direct functional and anatomical characterisation of the systemic microvasculature and to explore in vivo parameters of capillary fluid extravasation and lymphatic clearance in HFpEF. Methods In 16 patients with HFpEF and 16 age- and sex-matched healthy controls (72±6 and 68±5 years, respectively) we determined peripheral microvascular filtration coefficient (proportional to vascular permeability and area) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation) by venous occlusion plethysmography and collected a skin biopsy for vascular immunohistochemistry and gene expression analysis (TaqMan). Additionally, we measured brachial flow-mediated dilatation (FMD) and assessed by wire myography the vascular function of resistance arteries isolated from gluteal subcutaneous fat biopsies. Results Skin biopsies in patients with HFpEF showed rarefaction of small blood vessels (82±31 vs 112±21 vessels/mm2; p=0.003) and in ex-vivo analysis (n=6/group) we found defective relaxation of peripheral resistance arteries (p&amp;lt;0.001). Accordingly, post-ischaemic hyperaemic response (fold-change vs baseline, 4.6±1.6 vs 6.7±1.7; p=0.002) and FMD (3.9±2.1 vs 5.6±1.5%; p=0.014) were found to be reduced in patients with HFpEF compared to controls. In the skin of patients with HFpEF we also observed a reduced number (85±27 vs 130±60 vessels/mm2; p=0.012) but larger average diameter of lymphatic vessels (42±19 vs 26±9 μm2; p=0.007) compared to control subjects. These changes were paralleled by reduced expression of LYVE1 (p&amp;lt;0.05) and PROX1 (p&amp;lt;0.001), key determinants of lymphatic differentiation and function. Whilst patients with HFpEF had reduced peripheral capillary fluid extravasation compared to controls (microvascular filtration coefficient, leg 33.1±13.3 vs 48.4±15.2, p&amp;lt;0.01; trend for arm 49.9±20.5 vs 66.3±30.1, p=0.09), they had lower lymphatic clearance (isovolumetric pressure: leg 22±4 vs 16±4 mmHg, p&amp;lt;0.005; arm 25±5 vs 17±4 mmHg, p&amp;lt;0.001). Conclusions We provide direct evidence of systemic dysfunction and rarefaction of small blood vessels in patients with HFpEF. Despite a reduced microvascular filtration coefficient, which is in keeping with microvascular rarefaction, the clearance of extravasated fluid in HFpEF is limited by an anatomically and functionally defective lymphatic system. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation Centre of Research Excellence Award

Retinal capillary basement membrane thickening: Role in the pathogenesis of diabetic retinopathy.

Vascular basement membrane (BM) thickening has been hailed over half a century as the most prominent histological lesion in diabetic microangiopathy, and represents an early ultrastructural change in diabetic retinopathy (DR). Although vascular complications of DR have been clinically well established, specific cellular and molecular mechanisms underlying dysfunction of small vessels are not well understood. In DR, small vessels develop insidiously as BM thickening occurs. Studies examining high resolution imaging data have established BM thickening as one of the foremost structural abnormalities of retinal capillaries. This fundamental structural change develops, at least in part, from excess accumulation of BM components. Although BM thickening is closely associated with the development of DR, its contributory role in the pathogenesis of DR is coming to light recently. DR develops over several years before clinical manifestations appear, and it is during this clinically silent period that hyperglycemia induces excess synthesis of BM components, contributes to vascular BM thickening, and promotes structural and functional lesions including cell death and vascular leakage in the diabetic retina. Studies using animal models show promising results in preventing BM thickening with subsequent beneficial effects. Several gene regulatory approaches are being developed to prevent excess synthesis of vascular BM components in an effort to reduce BM thickening. This review highlights current understanding of capillary BM thickening development, role of BM thickening in retinal vascular lesions, and strategies for preventing vascular BM thickening as a potential therapeutic strategy in alleviating characteristic lesions associated with DR.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BackgroundCerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood–brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood–brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543.SummaryFactors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Analysis of dynamic texture and spatial spectral descriptors of dynamic contrast-enhanced brain magnetic resonance images for studying small vessel disease

Cerebral small vessel disease (SVD) comprises various pathological processes affecting small brain vessels and damaging white and grey matter. In this paper, we propose a framework comprising region of interest sampling, dynamic spectral and texture description, functional principal component analysis, and statistical analysis to study exogenous contrast agent distribution over time in various brain regions in patients with recent mild stroke and SVD features.We compared our results against current semi-quantitative surrogates of dysfunction such as signal enhancement area and slope. Biological sex, stroke lesion type and overall burden of white matter hyperintensities (WMH) were significant predictors of intensity, spectral, and texture features extracted from the ventricular region (p-value < 0.05), explaining between a fifth and a fourth of the data variance (0.20 ≤Adj.R2 ≤ 0.25). We observed that spectral feature reflected more the dysfunction compared to other descriptors since the overall WMH burden explained consistently the power spectra variability in blood vessels, cerebrospinal fluid, deep grey matter and white matter. Our preliminary results show the potential of the framework for the analysis of dynamic contrast-enhanced brain magnetic resonance imaging acquisitions in SVD since significant variation in our metrics was related to the burden of SVD features. Therefore, our proposal may increase sensitivity to detect subtle features of small vessel dysfunction. A public version of the code will be released on our research website.

Thunderclap headache and reversible cerebral vasoconstriction syndrome: Current theory and accumulated data

AbstractReversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent severe thunderclap headache and segmental vasoconstriction of cerebral arteries that resolves by 3 months. RCVS can either occur spontaneously or relate to an exogenous trigger, but the precise pathophysiology of RCVS remains unknown. Postulated mechanisms include small vessel and endothelial dysfunction, mitochondrial dysfunction with oxidative stress, hormonal and biochemical factors, and genetic predisposition. A prior history of migraine has been reported in 17%–40% of cases, suggesting that migraine and RCVS share mechanisms. Most RCVS patients have a favorable prognosis; however, for some patients, the condition may result in permanent disability or even death in a small minority of patients, secondary to complications such as ischemic stroke or intracranial hemorrhage. There is no proven treatment, so the cornerstone of RCVS management remains largely supportive, with prescription of bed rest, analgesics, and the removal of precipitating factors. The majority of clinical series studying RCVS treatment have investigated the efficacy of calcium channel antagonists. Although prescription of triptans for migraine is not suitable for patients with a history of RCVS, lasmiditan, a highly selective 5‐HT1F receptor agonist, may be suitable in such cases. Typical segmental vasoconstriction of major vessels is not seen in approximately 30% of patients eventually diagnosed with RCVS; if this diagnosis is suspected, repeat imaging should be performed. Early diagnosis of RCVS is important, as it allows progression to be prevented by the prompt removal of precipitating factors, unnecessary diagnostic procedures to be avoided, and appropriate management to be commenced.

Neuroimaging in cerebral small vessel disease: Update and new concepts.

ABSTRACT.In recent years, small vessel disease (SVD) has been recognized for its major impact on cognitive impairment in elderly people, where it is often difficult to separate its effects from those of neurodegenerative diseases individually. SVD is a systemic disease, probably related to diffuse endothelial dysfunction, which affects the perforating arterioles, capillaries and venules in the brain. Although often asymptomatic, it is responsible for almost half of all dementia cases and a significant proportion of stroke cases. Imaging features found on magnetic resonance include recent small subcortical infarctions, lacunes of presumed vascular origin, white matter hyperintensity of presumed vascular origin, prominent perivascular spaces and cerebral microbleeds. The recognition of these imaging findings as a spectrum of the same disease caused by endothelial dysfunction of small cerebral vessels can allow an overall analysis of the disease and thus the development of more effective preventive and therapeutic strategies.

Circulating cytological markers of endothelial dysfunction in acute lacunar stroke resulting from cerebral small vessels disease

Background: At the cellular level, chronic endothelial dysfunction of cerebral small vessels leads to permanent endothelial cells destruction.

Abstract P250: Comparison of Clinical Variables Independently Associated With Large Artery Stiffness and Microvascular Dysfunction in African-American Diabetic Patients

Rationale: Diabetes mellitus is a risk factor for large and small vessel disease and portends a disproportionate morbidity and mortality burden in African Americans. Diabetes is often accompanied by cardiovascular risk factors that predispose to arteriopathy, it’s been shown to impair large and small vessel function prior to onset of target organ damage. Factors contributing to subclinical vascular dysfunction have not been well studied in this population. The objective of this study was to compare clinical variables associated with large artery stiffness and microvascular dysfunction. Methods: A total of 141 patients with diabetes were recruited from medical clinics over a 6 month period. Medical information was obtained via interview and medical record review including laboratory results. Pooled Cohort Score was calculated for each subject. Microvascular function was assessed by vascular reactivity index (VRI), which assesses changes in digital temperature before and after release of arterial cuff occlusion (VENDYS 5000BC DTM system (Endothelix, Inc.). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV) using applanation tonometry (Sphygmocor, Atcor Inc.). Results: Mean age was 60+8 years, 64% were female. 80% had hypertension, 90% had dyslipidemia and 15% had chronic kidney disease. Mean HbA1C levels were 8.1+2.2%. On univariate analysis, Pooled-cohort-score was significantly correlated with PWV (r=.25, p=.003) but not with VRI (r=.02, p=.78). Neither PWV nor VRI was significantly correlated with HbA1c. On multivariate analysis, PWV was independently associated with age, gender, creatinine level and waist circumference but not with traditional risk factors (R2=.26, p&lt;.001 for model). VRI was not significantly correlated with any of the clinical or laboratory measures. Conclusions: Large artery stiffness is independently associated with age, female gender, renal function and waist circumference but not with poorer glycemic control. In contrast, microvascular dysfunction was not associated with any of the clinical or laboratory measures. The role of metabolic risk factors in the differential progression of subclinical large and small artery vessel dysfunction and outcomes merit further study.

P1759Association of endothelial dysfunction and remodeling of large and small vessels with biological markers level in coronary artery disease and microvascular angina patients

P1759Association of endothelial dysfunction and remodeling of large and small vessels with biological markers level in coronary artery disease and microvascular angina patients

Gestational diabetes mellitus and retinal microvasculature

BackgroundSmall-vessel dysfunction may be an important consequence of chronic hyperglycemia. We examined the association between gestational diabetes mellitus (GDM), a state of transient hyperglycemia during pregnancy, and retinal microvascular changes in pregnant women at 26–28 weeks of pregnancy.MethodsA total of 1136 pregnant women with singleton pregnancies were recruited during their first trimester at two major Singapore maternity hospitals in an on-going birth cohort study. Participants underwent an oral glucose tolerance test and retinal imaging at 26–28 weeks gestation (n = 542). We used the 1999 World Health Organization (WHO) criteria to define GDM: ≥7.0 mmol/L for fasting glucose and/or ≥7.8 mmol/L for 2-h post-glucose. Retinal microvasculature was measured using computer software (Singapore I Vessel Analyzer, SIVA version 3.0, Singapore Eye Research Institute, Singapore) from the retinal photographs.ResultsIn a multiple linear regression model adjusting for age, ethnicity and maternal education, mothers with GDM had narrower arteriolar caliber (−1.6 μm; 95% Confidence Interval [CI]: −3.1 μm, −0.2 μm), reduced arteriolar fractal dimension (−0.01 Df; 95% CI: −0.02 Df, −0.001 Df;), and larger arteriolar branching angle (1.8°; 95% CI: 0.3°, 3.3°) than mothers without GDM. After further adjusting for traditional risks of GDM, arteriolar branching angle remained significantly larger in mothers with GDM than those without GDM (2.0°; 95% CI: 0.5°, 3.6°).ConclusionsGDM was associated with a series of retinal arteriolar abnormalities, including narrower caliber, reduced fractal dimension and larger branching angle, suggesting that transient hyperglycemia during pregnancy may cause small-vessel dysfunction.

A severe pulmonary complication in a patient with COL4A1-related disorder: A case report

Patients with COL4A1 mutation-related disorders demonstrate a variety of disease phenotypes, which caused by small-vessel dysfunction in the brain, eyes, kidney, muscle, or heart. The involvement of organs mainly depends on the expression of the COL4A1 gene. Complication or dysfunction of the alveolar tissue has not been reported in the literature on COL4A1 mutation-related disorders. We herein report the case of a boy with schizencephaly, renovascular hypertension, and retinal arteriosclerosis of unknown origin, who suffered from severe and repetitive alveolar hemorrhage at 9 years of age. A novel COL4A1 mutation was finally identified as the genetic cause. The pulmonary complication in the present case represents an important pathophysiological mechanism COL4A1 mutation-related disorders; lung tissue with COL4A1 gene mutations may be vulnerable and environmental substances and microorganisms in the air could accumulate to cause chronic damage in the alveolar tissues, especially in patients with tracheostoma and renovascular hypertension.